Bella Capsules

Overview of Bella Capsules

Dosage Strengths of Bella Capsules

Bella 1 (Bupropion HCl / Phentermine HCl / Topiramate / Naltrexone HCl / Methylcobalamin) (Slow Release) 65/20/15/8/1mg
Bella 2 (Bupropion HCl / Phentermine HCl / Topiramate / Naltrexone HCl / Methylcobalamin) (Slow Release) 65/37.5/15/8/1mg
Bella 3 (Bupropion HCl / Caffeine / Oxytocin / Topiramate / Naltrexone HCl / Methylcobalamin) 65mg/20mg/100IU/15mg/8mg/1mg
Bella 4 (Bupropion HCl / Phentermine HCl / Topiramate / Naltrexone HCl / Methylcobalamin) (Slow Release) 65/15/15/8/1mg
Bella Decaf (Bupropion HCl / Oxytocin / Topiramate / Naltrexone HCl / Methylcobalamin) 65mg/100IU/15mg/8mg/1mg
Bella Plus Decaf (Bupropion HCl / Metformin / Oxytocin / Topiramate / Naltrexone HCl / Methylcobalamin) 65mg/250mg/100IU/15mg/8mg/1mg

General Information

Bupropion HCl

Bupropion is an oral antidepressant drug of the aminoketone class. It is not a tricyclic antidepressant and is unrelated to other known antidepressants. Bupropion has been well tolerated in patients experiencing orthostatic hypotension with tricyclic antidepressant drugs, however, it shows a greater potential for causing seizures than other antidepressants.1 Bupropion is also indicated for use as an aide to smoking cessation, and is used off-label for addiction to smokeless tobacco. The drug has been shown to help people with COPD quit smoking when combined with behavior modification. Bupropion is also used off-label for multiple neurological/psychological uses, including ADHD 2 and neuropathic pain 3. Bupropion hydrochloride was originally approved by the FDA in December 1985 but was removed from marketing for several years due to concern over drug-induced seizures. It was reintroduced in July 1989 as an antidepressant (i.e., Wellbutrin), and later in a sustained-release formulation (i.e., Wellbutrin SR). Another sustained-release oral dosage form, Zyban, was approved for the management of smoking cessation in May 1997. Zyban received an additional indication for use in combination with nicotine transdermal systems (NTS) for treating the symptoms of smoking cessation in 1999. A controlled-release formulation (Wellbutrin XL) was approved in August 2003 as a once-daily formulation for major depression in adults.456 In June 2006, Wellbutrin XL was FDA-approved for prevention of major depressive episodes in patients with a history of seasonal affective disorder (SAD). Wellbutrin XL is the first prescription product approved for patients with a history of SAD.7 In April 2008, a once-daily formulation of bupropion hydrobromide (Aplenzin) was approved by the FDA for depression, and in August 2012 Aplenzin was approved for the prevention of seasonal major depressive episodes in patients with SAD. Aplenzin differs from all previously marketed formulations which are the hydrochloride salt of bupropion.

Phentermine HCl

Phentermine is an oral sympathomimetic amine used as an adjunct for short-term (e.g., 8—12 weeks) treatment of exogenous obesity. The pharmacologic effects of phentermine are similar to amphetamines. Phentermine resin complex was approved by the FDA in 1959, but is no longer marketed in the US. Phentermine hydrochloride was FDA approved in 1973. In the mid-90s, there was renewed interest in phentermine in combination with another anorectic, fenfluramine, for the treatment of obesity and substance abuse, however, little scientific data support this practice. On July 8, 1997, the FDA issued a 'Dear Health Care Professional' letter warning physicians about the development of valvular heart disease and pulmonary hypertension in women receiving the combination of fenfluramine and phentermine; fenfluramine was subsequently withdrawn from the US market in fall of 1997. Use of phentermine with other anorectic agents for obesity has not been evaluated and is not recommended. In May 2011, the FDA approved a phentermine hydrochloride orally disintegrating tablet (Suprenza) for the treatment of exogenous obesity.8

Topiramate

Topiramate is an oral antiepileptic drug (AED) used for partial-onset, generalized primary tonic-clonic seizures, and as an adjunct therapy in Lennox-Gastaut syndrome. It is derived from the naturally occurring monosaccharide D-fructose and is structurally different from other AEDs. Unlike other AEDs, topiramate appears to block the spread of seizures rather than raise the seizure threshold. Topiramate possesses more than one mechanism of action, which may explain why it can be effective in patients with various seizures that are refractory to other agents. Topiramate continues to be studied as both add-on therapy and monotherapy in various refractory epilepsies in children and adults, including infantile spasms associated with West syndrome. It is also used for migraine prophylaxis in adult and pediatric patients. There is some evidence of a role for topiramate treatment 'off-label' for eating disorders such as binge-eating disorder, for tics due to Tourette's syndrome or other chronic tic disorders, or for substance abuse disorders such as alcohol dependence.91011121314151617

Naltrexone HCl

Naltrexone is an oral opiate receptor antagonist. It is derived from thebaine and is very similar in structure to oxymorphone. Like parenteral naloxone, naltrexone is a pure antagonist (i.e., agonist actions are not apparent), but naltrexone has better oral bioavailability and a much longer duration of action than naloxone. Clinically, naltrexone is used to help maintain an opiate-free state in patients who are known opiate abusers. Naltrexone is of greatest benefit in patients who take the drug as part of a comprehensive occupational rehabilitative program or other compliance-enhancing program. Unlike methadone or LAAM, naltrexone does not reinforce medication compliance and will not prevent withdrawal. Naltrexone has been used as part of rapid and ultrarapid detoxification techniques. These techniques are designed to precipitate withdrawal by administering opiate antagonists. These approaches are thought to minimize the risk of relapse and allow quick initiation of naltrexone maintenance and psychosocial supports. Ultrarapid detoxification is performed under general anesthesia or heavy sedation. While numerous studies have been performed examining the role of these detoxification techniques, a standardized procedure including appropriate medications and dose, safety, and effectiveness have not been determined in relation to standard detoxification techniques.18 Naltrexone supports abstinence, prevents relapse, and decreases alcohol consumption in patients treated for alcoholism. Naltrexone is not beneficial in all alcoholic patients and may only provide a small improvement in outcome when added to conventional therapy. The FDA approved naltrexone in 1984 for the adjuvant treatment of patients dependent on opiate agonists. FDA approval of naltrexone for the treatment of alcoholism was granted January 1995. The FDA approved Vivitrol, a once-monthly intramuscular naltrexone formulation used to help control cravings for alcohol in April 2006, and then in October 2010, the FDA approved Vivitrol for the prevention of relapse to opioid dependence after opioid detoxification.

Methylcobalamin

Methylcobalamin, or vitamin B12, is a B-vitamin. It is found in a variety of foods such as fish, shellfish, meats, and dairy products. Although methylcobalamin and vitamin B12 are terms used interchangeably, vitamin B12 is also available as hydroxocobalamin, a less commonly prescribed drug product (see Hydroxocobalamin monograph), and methylcobalamin. Methylcobalamin is used to treat pernicious anemia and vitamin B12 deficiency, as well as to determine vitamin B12 absorption in the Schilling test. Vitamin B12 is an essential vitamin found in the foods such as meat, eggs, and dairy products. Deficiency in healthy individuals is rare; the elderly, strict vegetarians (i.e., vegan), and patients with malabsorption problems are more likely to become deficient. If vitamin B12 deficiency is not treated with a vitamin B12 supplement, then anemia, intestinal problems, and irreversible nerve damage may occur.

The most chemically complex of all the vitamins, methylcobalamin is a water-soluble, organometallic compound with a trivalent cobalt ion bound inside a corrin ring which, although similar to the porphyrin ring found in heme, chlorophyll, and cytochrome, has two of the pyrrole rings directly bonded. The central metal ion is Co (cobalt). Methylcobalamin cannot be made by plants or by animals; the only type of organisms that have the enzymes required for the synthesis of methylcobalamin are bacteria and archaea. Higher plants do not concentrate methylcobalamin from the soil, making them a poor source of the substance as compared with animal tissues.

Caffeine

Caffeine is a naturally occurring xanthine derivative used as a CNS and respiratory stimulant, or as a mild diuretic. Other xanthine derivatives include the bronchodilator theophylline and theobromine, a compound found in cocoa and chocolate. Caffeine is found in many beverages and soft drinks. Caffeine is often combined with analgesics or with ergot alkaloids for the treatment of migraine and other types of headache. Caffeine is also sold without a prescription in products marketed to treat drowsiness, or in products for mild water-weight gain. Caffeine was first approved by the FDA for use in a drug product in 1938. Clinically, it is used both orally and parenterally as a respiratory stimulant in neonates with apnea of prematurity. Caffeine reduces the frequency of apneic episodes by 30—50% within 24 hours of administration.19 Caffeine is preferred over theophylline in neonates due to the ease of once per day administration, reliable oral absorption, and a wide therapeutic window. A commercial preparation of parenteral caffeine, Cafcit®, was FDA approved for the treatment of apnea of prematurity in October 1999, after years of availability only under orphan drug status (e.g., Neocaf). The FDA has continued the orphan drug status of the approved prescription formulation.

Oxytocin

Endogenous oxytocin is a hormone secreted by the supraoptic and paraventricular nuclei of the hypothalamus and stored in the posterior pituitary. It stimulates contraction of uterine smooth muscle during gestation and causes milk ejection after milk has been produced in the breast. Oxytocin has been associated with mating, parental, and social behaviors. Oxytocin is released during intercourse in both men and women, which has led to the belief that it is involved in sexual bonding. There is speculation that in addition to facilitating lactation and the birthing process, the hormone facilitates the emotional bond between mother and child.20 Oxytocin has also been studied in autism and have some sort of relation to the social and developmental impairments associated with the disease.21 Clinically, oxytocin is used most often to induce and strengthen labor and control postpartum bleeding. Intranasal preparations of oxytocin, used to stimulate postpartum milk ejection, are no longer manufactured in the U.S. Oxytocin was approved by the FDA in 1962.

Metformin

Metformin is an oral biguanide antidiabetic agent similar to phenformin, a drug that was withdrawn from US marketing in 1977 due to the development of lactic acidosis. The risk for this adverse reaction is considerably lower with metformin, however.22 The actions of metformin differ from, yet complement, those of the sulfonylureas and other antidiabetic therapies. Compared to glyburide in type 2 diabetes, metformin was found to achieve similar glycemic control. although it lead to a higher incidence of digestive complaints.23 Metformin has been found useful in the treatment of polycystic ovary syndrome (PCOS); it lowers serum androgens and restores normal menstrual cycles and ovulation, and may improve pregnancy rates.24 Additionally, limited data indicate that it may delay puberty onset in females with precocious puberty and delay menarche onset in females with early-normal onset of puberty.2526 The use of metformin versus intensive lifestyle modification in patients with impaired glucose tolerance has been investigated, and while both reduce the incidence of diabetes, lifestyle intervention has the greater effect.27 Although lifestyle intervention is highly effective, most patients fail lifestyle modifications when used alone within the first year of diagnosis. Therefore, a joint consensus algorithm for the treatment of type 2 diabetes mellitus, developed by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes, suggests that the combination of metformin with lifestyle interventions should be initiated at the time of diagnosis. Metformin was chosen as the initial drug therapy based on its efficacy, safety, and cost.282930 Additionally, in a follow-up study to the UKPDS, researchers found that after 10-years of resuming typical care, patients originally randomized to metformin therapy had a 33% relative reduction (RR 0.67, 95% CI 0.51—0.89; p=0.005) in the risk of myocardial infarction and a 27% relative reduction (RR 0.73, 95% CI 0.59—0.89; p=0.002) in the risk of death from any cause as compared to patients originally randomized to conventional therapy; it should be noted that these reductions in cardiovascular risks persisted even though HbA1c concentrations were similar in the 2 groups after 1 year of follow-up.31 Metformin was introduced in Europe in the 1950's but was not approved by the FDA until December 1994. It is approved for type 2 diabetes either as monotherapy or in combination with sulfonylureas, alpha-glucosidase inhibitors, or insulin. The regular-release tablets were approved for use in children >= 10 years in January 2001. An oral solution (Riomet) was approved in September 2003. Three extended-release formulations have been approved, Glucophage XR in October 2000, Fortamet in April 2004, and Glumetza in June 2005, each with a unique drug delivery system (see Pharmacokinetics section). The extended-release formulations provide similar glycemic control compared to regular-release metformin, but have the advantage of once-daily administration. Another advantage is a claim of decreased adverse events, specifically gastrointestinal-related adverse events (i.e., flatulence, diarrhea); however, larger trials comparing regular-release to extended-release metformin are needed to confirm these claims as current trial results are conflicting.323334

Mechanism of Action

Bupropion HCl

The action of bupropion is not fully understood. Bupropion selectively inhibits the neuronal reuptake of dopamine and is significantly more potent than either imipramine or amitriptyline in this regard.35 Actions on dopaminergic systems, however, require doses higher than those needed for a clinical antidepressant effect.35 The blockade of norepinephrine reuptake at the neuronal membrane is weaker for bupropion than for tricyclic antidepressants. CNS-stimulant effects are dose-related. Bupropion does not inhibit monoamine oxidase or the reuptake of serotonin. Bupropion does exhibit moderate anticholinergic effects, and produces a sensation of mild local anesthesia on the oral mucosa. Antidepressant activity is usually noted within 1—3 weeks of initiation of bupropion treatment; full effects may not be seen until 4 weeks of therapy.
 
The mechanism by which bupropion enhances the ability to abstain from tobacco smoking is unknown, but is probably related to inhibition of noradrenergic or dopaminergic neuronal uptake. The resultant increase in norepinephrine may attenuate nicotine withdrawal symptoms. Increased dopamine at neuronal sites may reduce nicotine cravings and the urge to smoke. Because the onset of activity is usually after 1 week of treatment, patients should start bupropion 1—2 weeks prior to their chosen smoking 'quit-day'. In smoking cessation, the ability to abstain from smoking continuously through the seventh week of bupropion therapy is associated with maintenance of long-term abstinence. Patients who have not stopped smoking by the seventh week of treatment are generally considered non-responsive to bupropion treatment.

Phentermine HCl

Limited data are available in reference texts regarding the mechanism of action of this drug. Phentermine is an analog of methamphetamine. Similar to the amphetamines, phentermine increases the release of norepinephrine and dopamine from nerve terminals and inhibits their reuptake. Thus, phentermine is classified as an indirect sympathomimetic.36 Other effects include a weak ability to dose-dependently raise serotonin levels, although the effect on serotonin occurs is less potent than that of methamphetamine itself.37 Clinical effects include CNS stimulation and elevation of blood pressure. Appetite suppression is believed to occur through direct stimulation of the satiety center in the hypothalamic and limbic region.

Tolerance to the anorexiant effects of phentermine usually develops within a few weeks of starting therapy. The mechanism of tolerance appears to be pharmacodynamic in nature; higher doses of phentermine are required to produce the same response. When tolerance develops to the anorexiant effects, it is generally recommended that phentermine be discontinued rather than the dose increased.

Topiramate

The exact mechanism of topiramate's anticonvulsant and migraine prophylaxis effects is unknown. It appears that topiramate may block the spread of seizures rather than raise the seizure threshold like other AEDs. The drug appears to have several mechanisms of action. First, topiramate reduces the duration of abnormal discharges and the number of action potentials within each discharge. This is probably secondary to its ability to block voltage-sensitive sodium channels. Second, topiramate enhances the activity of the inhibitory neurotransmitter gamma-aminobutyrate (GABA) at GABA-A receptors by increasing the frequency at which GABA activates GABA-A receptors. Third, topiramate inhibits excitatory transmission by antagonizing some types of glutamate receptors. Specifically, topiramate antagonizes the ability of kainate to activate the kainate/AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid; non-NMDA) subtype of excitatory amino acid (glutamate) receptor. There is no apparent effect on the activity of N-methyl-D-aspartate (NMDA) at the NMDA receptor subtype. Topiramate is also a weak carbonic anhydrase inhibitor (isozymes II and IV); however, while this action can cause a risk for metabolic acidosis, this mechanism does not appear to be involved in the anticonvulsant action of the drug.91011
 
In addition to its efficacy in epilepsy and migraine prophylaxis, topiramate has also demonstrated neuroprotective effects against hypoxic-ischemic brain damage in both in vitro and animal models. The cerebral damage of hypoxic-ischemic encephalopathy occurs in part due to an increased release of excitatory neurotransmitters, including glutamate. Glutamate activates AMPA receptors, depolarizes the cell, and promotes the removal of the voltage-sensitive magnesium block on NMDA receptors. This, in turn, promotes the entry of calcium into the cell, stimulating a series of reactions that lead to cell necrosis and apoptosis. The neuroprotective properties of topiramate appear to be primarily related to its inhibition of the kainate/AMPA subtype of glutamate receptors. In addition, blockade of sodium channels, high-voltage calcium currents, carbonic anhydrase isoenzymes, and mitochondrial permeability transition pore (MPTP) may also contribute to its neuroprotective effects.38

Naltrexone HCl

Like naloxone, naltrexone is a competitive antagonist at opiate receptors mu, kappa, and delta. Opiate receptors have been reclassified by an International Union of Pharmacology subcommittee as OP1 (delta), OP2 (kappa), and OP3 (mu). Naltrexone can either displace opiate agonists from binding at these receptors or prevent opiate binding. Naltrexone does not antagonize the effects of non-opiates such as cocaine, ethanol, amphetamines, barbiturates, or benzodiazepines. Blockade of opiate receptors by naltrexone is a competitive phenomenon and results in elimination of the euphoric effect of opiates. At usual opiate concentrations, naltrexone's greater affinity for the receptor prevents the binding of the opiate agonist to the receptor. However, when opiate concentrations are extremely high, the opiate can displace naltrexone, and respiratory depression and/or death is possible. Although naltrexone itself may possess some agonistic properties, these are minor compared to its potent antagonistic actions. Naltrexone is 17-times more potent than nalmorphine and twice as potent as naloxone. In patients who are physically dependent on opiates, naltrexone will precipitate an opiate withdrawal syndrome. Naltrexone use is not associated with tolerance or dependence, therefore, withdrawal from naltrexone does not occur. When co-administered with opiate agonists, naltrexone blocks the physical dependence to morphine, heroin, and other opiate agonists. Depending on the dose, the clinical effects of naltrexone can persist for up to 72 hours.


Endogenous opiods such as beta-endorphins and enkephalins may play an important role in alcoholism. An opioid reward system mediated by mu- and delta-receptors and an opposing aversions system mediated by kappa-receptors must be in balance to maintain a neutral state in regards to the development of addiction. Several therories regarding alcohol addiction and the function of endongeous opioids exist. All of these therories are based on an imbalance in favor of the endongenous reward pathways due to alcohol. Naltrexone inhibits the effects of endogenous opioids and decreases the positive or reward pathways associated with alcoholism. Naltrexone is not aversive therapy and will not produce a disulfiram-like reaction if opiates or ethanol are ingested while receiving naltrexone.

Methylcobalamin

Vitamin B12 is used in the body in two forms, methylcobalamin and 5-deoxyadenosyl cobalamin. The enzyme methionine synthase needs methylcobalamin as a cofactor. This enzyme is involved in the conversion of the amino acid homocysteine into methionine which is, in turn, required for DNA methylation. The other form, 5-deoxyadenosylcobalamin, is a cofactor needed by the enzyme that converts L-methylmalonyl-CoA to succinyl-CoA. This conversion is an important step in the extraction of energy from proteins and fats. Furthermore, succinyl CoA is necessary for the production of hemoglobin, the substance that carries oxygen in red blood cells.

Vitamin B12, or methylcobalamin, is essential to growth, cell reproduction, hematopoiesis, and nucleoprotein and myelin synthesis. Cells characterized by rapid division (epithelial cells, bone marrow, myeloid cells) appear to have the greatest requirement for methylcobalamin. Vitamin B12 can be converted to coenzyme B12 in tissues; in this form it is essential for conversion of methylmalonate to succinate and synthesis of methionine from homocysteine (a reaction which also requires folate). In the absence of coenzyme B12, tetrahydrofolate cannot be regenerated from its inactive storage form, 5-methyl tetrahydrofolate, resulting in functional folate deficiency. Vitamin B12 also may be involved in maintaining sulfhydryl (SH) groups in the reduced form required by many SH-activated enzyme systems. Through these reactions, vitamin B12 is associated with fat and carbohydrate metabolism and protein synthesis. Vitamin B12 deficiency results in megaloblastic anemia, GI lesions, and neurologic damage (which begins with an inability to produce myelin and is followed by gradual degeneration of the axon and nerve head). Vitamin B12 requires an intrinsic factor-mediated active transport for absorption, therefore, lack of or inhibition of intrinsic factor results in pernicious anemia.

Caffeine

Caffeine is a mild, direct stimulant at all levels of the CNS and also stimulates the heart and cardiovascular system. The related xanthine, theophylline, shares these properties and is widely used in the treatment of pulmonary disease. Both caffeine and theophylline are CNS stimulants, with theophylline exerting more dramatic effects than caffeine at higher concentrations. Caffeine also stimulates the medullary respiratory center and relaxes bronchial smooth muscle. Caffeine stimulates voluntary muscle and gastric acid secretion, increases renal blood flow, and is a mild diuretic.

While the clinical responses to caffeine are well known, the cellular mechanism of action is uncertain. Several theories have been proposed. At high concentrations, caffeine interferes with the uptake and storage of calcium by sarcoplasmic reticulum of striated muscle. While this action would explain the effects of caffeine on cardiac and skeletal muscle, it does not appear to occur at clinically achievable concentrations. Inhibition of phosphodiesterases (and subsequent accumulation of cyclic nucleotides) also does not appear to occur at clinically achievable concentrations.

Currently, it is believed that xanthines act as adenosine-receptor antagonists. Adenosine acts as an autocoid, and virtually every cell contains adenosine receptors within the plasma membrane. Adenosine exerts complex actions. It inhibits the release of neurotransmitters from presynaptic sites but works in concert with norepinephrine or angiotensin to augment their actions. Antagonism of adenosine receptors by caffeine would appear to promote neurotransmitter release, thus explaining the stimulatory effects of caffeine.Recently, a distinct syndrome has been associated with caffeine withdrawal. It is possible that the manifestations of caffeine withdrawal may be secondary to catecholamine or neurotransmitter depletion.

The following mechanisms of action are hypothesized for caffeine's action in apnea of prematurity: 1) stimulation of the respiratory center, 2) increased minute ventilation, 3) decreased threshold to hypercapnia, 4) increased response to hypercapnia, 5) increased skeletal muscle tone, 6) decreased diaphragmatic fatigue, 7) increased metabolic rate, and 8) increased oxygen consumption. All of these actions are thought to be related to adenosine receptor antagonism.

Oxytocin

Synthetic oxytocin elicits the same pharmacological response produced by endogenous oxytocin, with cervical dilation, parity, and gestational age as predictors of the dose response to oxytocin administration for labor stimulation.39 Oxytocin increases the sodium permeability of uterine myofibrils, indirectly stimulating contraction of the uterine smooth muscle. The uterus responds to oxytocin more readily in the presence of high estrogen concentrations and with the increased duration of pregnancy. There is a gradual increase in uterine response to oxytocin for 20 to 30 weeks gestation, followed by a plateau from 34 weeks of gestation until term, when sensitivity increases.39 Women who are in labor have a greater response to oxytocin compared to women who are not in labor; only very large doses will elicit contractions in early pregnancy. In the term uterus, contractions produced by exogenous oxytocin are similar to those that would occur during spontaneous labor. Oxytocin increases the amplitude and frequency of uterine contractions, which transiently impede uterine blood flow and decrease cervical activity, causing dilation and effacement of the cervix.

Oxytocin causes contraction of the myoepithelial cells surrounding the alveolar ducts of the of the breast. This forces milk from the alveolar channels into the larger sinuses, and thus facilitates milk ejection. While oxytocin possesses no galactopoietic properties, if it is absent the milk-ejection reflex in the breast fails.

Oxytocin causes dilation of vascular smooth muscle, thus increasing renal, coronary, and cerebral blood flow. Blood pressure usually remains unaffected, but with the administration of very large doses or high concentration solutions blood pressure may decrease transiently. This transient decrease in blood pressure leads to reflex tachycardia and an increase in cardiac output; any fall in blood pressure is usually followed by a small, but sustained, increase in blood pressure.

Oxytocin does possess antidiuretic effects, but they are minimal. If oxytocin is administered with an excessive volume of electrolyte-free IV solution and/or at too rapid a rate, the antidiuretic effects are more apparent and water intoxication can result.

Metformin

Metformin is an antihyperglycemic agent that improves glucose tolerance, lowering both basal and postprandial plasma glucose with mechanisms different from other classes of oral antidiabetic agents. Metformin decreases hepatic gluconeogenesis production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease. Metformin improve glucose utilization in skeletal muscle and adipose tissue by increasing cell membrane glucose transport. This effect may be due to improved binding of insulin to insulin receptors since metformin is not effective in diabetics without some residual functioning pancreatic islet cells.40 Unlike the sulfonylureas, metformin rarely causes hypoglycemia since it does not significantly change insulin concentrations. An important distinction is that sulfonylureas increase insulin secretion thus making them useful in non-obese patients with type 2 diabetes while metformin improves insulin resistance, a common pathophysiologic finding in obese patients with type 2 diabetes.40 Metformin causes a 10—20% decrease in fatty-acid oxidation and a slight increase in glucose oxidation. Unlike phenformin, metformin does not inhibit the mitochondrial oxidation of lactate unless plasma concentrations of metformin become excessive (i.e., in patients with renal failure) and/or hypoxia is present.22

Clinically, metformin lowers fasting and postprandial hyperglycemia. The decrease in fasting plasma glucose is approximately 25—30%. Unlike oral sulfonylureas, metformin rarely causes hypoglycemia. Thus, metformin demonstrates more of an antihyperglycemic action than a hypoglycemic action. Metformin does not cause weight gain and in fact, may cause a modest weight loss due to drug-induced anorexia. Metformin also decreases plasma VLDL triglycerides resulting in modest decreases in plasma triglycerides and total cholesterol. Patients receiving metformin show a significant improvement in hemoglobin A1c, and a tendency toward improvement in the lipid profile, especially when baseline values are abnormally elevated.

Insulin resistance is a primary cause of polycystic ovarian syndrome (PCOS). In PCOS patients, metformin reduces insulin resistance and lowers insulin levels, which lowers serum androgen concentrations, restores normal menstrual cycles and ovulation, and may help to resolve PCOS-associated infertility. Metformin, when administered to lean, overweight, and moderately obese women with PCOS, has been found to significantly reduce serum leuteinizing hormone (LH) and increase follicle stimulating hormone (FSH) and sex hormone binding globulin (SHBG). Serum testosterone concentrations were also found to decrease by approximately 50%.24

Pharmacokinetics

Bupropion HCl

Bupropion is administered orally as the hydrochloride salt (Wellbutrin, Wellbutrin SR, Wellbutrin XL, Zyban, Forfivo XL) or hydrobromide salt (Aplenzin). Bupropion is a racemic mixture; however, the pharmacologic actions and pharmacokinetics of the individual enantiomers have not been evaluated. The drug readily crosses the blood-brain barrier. Plasma protein binding is about 84%. Metabolism takes place in the liver, producing several metabolites; the 3 major active metabolites are hydroxybupropion, threohydrobupropion, and erythrohydrobupropion. CYP2B6 is involved in forming hydroxybupropion, the major metabolite, previously known as morpholinol. All active metabolites are present in higher concentrations in the plasma than the parent compound. In mice, hydroxybupropion appears to have one-half the potency of bupropion; the other metabolites are one-tenth to one-half as potent. Bupropion appears to induce its own metabolism, but this does not appear to be clinically significant. The terminal elimination half-life of immediate-release bupropion is approximately 14 hours with a range of 8 to 24 hours. The terminal elimination half-life of the sustained-release hydrochloride product and the extended-release hydrobromide product is roughly 21 hours. Half-lives for hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion are 20 hours, 33 hours, and 37 hours, respectively. Less than 1% is excreted unchanged in the urine. Over 60% is excreted as metabolites in the urine within 24 hours; over 80% is eliminated in 96 hours. Less than 10% of metabolites are excreted in the feces. Steady-state concentrations of bupropion and its metabolites are achieved in 5 to 8 days; however, antidepressant effects have an onset of roughly 1 to 3 weeks.
 
Affected cytochrome P450 isoenzymes: CYP2D6, CYP2B6, OCT2
Because of the extensive metabolism of bupropion by CYP2B6, clinically significant drug interactions are possible with drugs that are metabolized by or are inhibitors or inducers of this isoenzyme.41In vitro data indicate that bupropion and hydroxybupropion are inhibitors of CYP2D6. In vitro, bupropion and its 3 metabolites are inhibitors of the renal organic transporter OCT2 to a clinically significant extent; however, in vivo drug interaction studies have not found clinically significant drug-drug interactions with OCT-2 substrates.414243

Route-Specific Pharmacokinetics:

Oral Route: Based on animal data, the oral bioavailability is roughly 5—20%; oral bioavailability in humans has not been determined. Wellbutrin, Wellbutrin SR, and Wellbutrin XL: Bupropion XL has been found to be bioequivalent to the immediate-release tablet, sustained-release tablet, and extended-release hydrobromide tablet. In studies of healthy volunteers, administration with food increased Cmax and AUC by 11—35% and 16—19%, respectively. These changes are not considered clinically significant; therefore, bupropion can be taken with or without food.44 Peak plasma concentrations are achieved within 1.5 hours after administration of immediate-release bupropion, and within 3 hours after administration of sustained-release hydrochloride formulations. Peak plasma concentrations of the active metabolite hydroxybupropion occur about 3 hours after administration of immediate-release bupropion.41 Peak plasma concentrations of hydroxybupropion are about 10 times those of bupropion at steady state.41 Plasma bupropion concentrations are dose-proportional following single doses of 100 to 250 mg; however, it is not known if the proportionality between dose and plasma levels are maintained in chronic use.

Aplenzin: Peak plasma concentrations are achieved within approximately 5 hours after administration of the hydrobromide tablet. Peak plasma concentrations of the active metabolite hydroxybupropion occur about 6 hours after administration. Peak plasma concentrations of hydroxybupropion are about 10 times those of bupropion at steady state.43

Forfivo XL: Following a single dose of Forfivo XL, a 450 mg extended-release bupropion tablet formulation, the median time to peak plasma concentrations is about 5 hours under fasting conditions and 12 hours under fed conditions. The mean systemic exposure to bupropion is increased by 25% when taken with food. Peak plasma concentrations of hydroxybupropion occur about 10 hours after a dose of Forfivo XL under fasting conditions and 16 hours under fed conditions. The food effect is not considered clinically significant; therefore, Forfivo XL may be taken without regard to meals. In a single dose study under fasting conditions, one 450 mg dose of Forfivo XL was equivalent to a dose consisting of three 150 mg tablets of Wellbutrin XL.45

Special Populations:

Hepatic Impairment: Half-lives of bupropion and/or its major metabolites are prolonged in patients with alcoholic liver disease, cirrhosis, or left-ventricular dysfunction. In patients with hepatic disease, the mean AUC increased by roughly 1.5-fold for hydroxybupropion and roughly 2.5-fold for threo/erythrohydrobupropion. The median Tmax was observed 19 hours later for hydroxybupropion and 31 hours later for threo/erythrohydrobupropion. The mean half-lives for hydroxybupropion and threo/erythrohydrobupropion were increased 5- and 2-fold, respectively, in patients with severe hepatic cirrhosis compared to healthy volunteers. Dosage adjustment is required in patients with hepatic dysfunction.414346 Use of Forfivo XL, a 450 mg extended-release tablet formulation, is not recommended in patients with hepatic impairment, as the dose is fixed and no lower strength is available.45

Renal Impairment: An inter-study comparison of healthy subjects and those with end-stage renal failure showed that although the elimination of the parent compound was similar between groups, the Cmax and AUC of bupropion's active metabolites were increased in the renal failure group. In a separate study of patients with moderate to severe renal impairment, bupropion exposure after administration of the sustained-release product was about 2-fold higher in the renally impaired group than in normal subjects, while concentrations of the active metabolites of bupropion and placebo were similar.41 The clinical impact of these findings, if any, have not been described. Use of Forfivo XL, a 450 mg extended-release tablet formulation, is not recommended in patients with renal impairment as the dose is fixed and lower dosage strengths are not available.45

Pediatrics: Adolescents have been shown to metabolize bupropion SR to its active metabolites more rapidly than adults.47 Areas under the concentration curves for the hydroxybupropion, threohydrobupropion, and erythrohydrobupropion were 20, 12, and 2.7 times higher, respectively, than for bupropion. Relative to adults, the mean half-lives of bupropion (12.1 h) and threohydrobupropion (26.3 h) were significantly shorter, and AUC ratios of metabolites to bupropion were 19 to 80% higher. Until the clinical importance of bupropion's metabolites is clarified, bupropion SR should be given in divided doses to adolescents.47

Phentermine HCl

Phentermine is administered orally. The rate and extent of phentermine exposure under fasting conditions is equivalent regardless of oral formulation administered.8

Limited data exist on the pharmacokinetics of phentermine. Phentermine is primarily excreted by the kidneys. The elimination half-life ranges 19—24 hours and is influenced by urinary pH. Because the pKa of phentermine is 9.84, the elimination half-life decreases to about 7—8 hours under acidic urinary conditions.

Route-Specific Pharmacokinetics:

Oral Route: Following oral administration, most absorption of phentermine occurs from the small intestine. The duration of action following administration of the 8 mg capsules or tablets is about 4 hours and 12—14 hours after administration of the 30 mg capsules or the 37.5 mg tablets. Phentermine oral disintegrating tablet (ODT) reaches peak concentrations (Cmax) 3—4.4 hours post-administration. Water ingestion prior to swallowing the ODT did not affect the AUC. Despite a decrease in the Cmax (approximately 5%) and AUC (approximately 12%) when phentermine ODT was administered after a high fat/high calorie breakfast, phentermine ODT can be administered with or without food. The Cmax and AUC were decreased by approximately 7% and 8%, respectively, when the ODT was swallowed without prior disintegration.8

Special Populations:

Renal Impairment:Use with caution in patients with renal impairment. Cumulative urinary excretion of phentermine under uncontrolled urinary pH conditions is 62—85%, and exposure increases can be expected in patients with renal impairment.8

Topiramate

Topiramate is administered orally. Protein binding ranges from 15 to 41% to human plasma proteins over the concentration range of 0.5 to 250 mcg/mL. It is not metabolized to a great extent. Six metabolites have been identified and are formed via hydroxylation, hydrolysis, and glucuronidation. None of these metabolites constitutes more than 5% of an administered dose. About 70% of an administered dose is eliminated unchanged in the urine. Although not evaluated in humans, animal studies using probenecid along with topiramate showed a significant increase in renal clearance of topiramate. This suggests that topiramate may undergo renal tubular reabsorption. The mean plasma elimination half-life is 21 hours following single or multiple doses. Steady-state concentrations are reached in 4 to 8 days in adult patients with normal renal function.
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP2C19, CYP3A4
In vitro studies indicate that topiramate may induce CYP3A4 (weak inducer) and inhibit CYP2C19 (weak inhibitor). Some hepatic enzyme-inducing antiepileptic drugs (i.e., phenytoin, carbamazepine) have been shown to reduce topiramate serum concentrations by 40 to 48%.9

Route-Specific Pharmacokinetics:

Oral Route: Topiramate is absorbed rapidly with peak plasma concentrations occurring approximately 2 hours after oral administration of a 400 mg immediate-release dose. Peak plasma concentrations of topiramate are reached approximately 24 hours after a 200 mg dose of extended-release capsules. The relative bioavailability from the tablets is about 80% compared to topiramate solution. Bioavailability is not affected by coadministration with food. Oral sprinkle capsules of topiramate are bioequivalent to the tablets. At steady state, topiramate extended-release capsules administered once-daily were shown to be bioequivalent to the immediate-release tablet administered twice-daily.

Special Populations:

Hepatic Impairment: Topiramate pharmacokinetics may be affected by hepatic function impairment. In hepatically impaired patients, topiramate clearance may be decreased, but the mechanism is not well understood. Patients on hepatic enzyme-affecting co-therapies may have altered topiramate clearance (see Drug Interactions).

Renal Impairment: Topiramate pharmacokinetics may be affected by renal impairment. The clearance of topiramate is reduced by roughly 42% in moderate renal impairment (i.e., CrCl 30—69 ml/min) and by 54% in those with severe renal dysfunction (CrCl < 30 ml/min). The time to reach steady-state may be increased to 10—15 days in patients with moderate or severe renal impairment. Since topiramate is presumed to undergo significant tubular reabsorption, it is uncertain whether this experience can be generalized to all situations of renal impairment. It is conceivable that some forms of renal disease could differentially affect GFR and tubular reabsorption resulting in a clearance of topiramate not predicted by creatinine clearance. In general, however, use of one-half the usual dose is recommended in patients with moderate or severe renal impairment. Topiramate is cleared well by hemodialysis; the high clearance (compared to total oral clearance in healthy adults) during dialysis will remove a clinically significant amount of topiramate from the patient over the dialysis treatment period. Therefore, a supplemental dose may be required.

Pediatrics: In general, weight-adjusted clearance of topiramate is greater children vs. adults and in infants and younger children vs. older children and adolescents. With the same mg/kg dose, plasma concentrations may be lower in children vs. adults and also in younger children vs. older children and adolescents.910

Children and Adolescents >= 4 years: As with adults and young children, topiramate steady-state plasma concentrations appear to increase in proportion to the dose administered. In a pharmacokinetic study of pediatric patients with epilepsy (n = 18; age range: 4—17 years) receiving concomitant antiepileptics agents (AEDs), topiramate was initiated at an initial dose of 1 mg/kg/day and increased at weekly intervals to 3, 6, and 9 mg/kg/day, divided into twice daily dosing. At steady state, Cmax and AUC (1 mg/kg, 3 mg/kg, and 9 mg/kg doses, respectively) for age bands broken into children 4—7 years (Cmax = 2.32, 3.91, 10.55 mcg/mL; AUC = 23.5, 61.4, 157 mcg x hour/mL), 8—11 years (Cmax = 2.74, 4.29, 11.5 mcg/mL; AUC = 31.5, 81.4, 205.4 mcg x hour/mL), and 12—17 years (Cmax = 1.72, 5.26, 12.37 mcg/mL; AUC = 29.4, 96.3, 222.2 mcg x hour/mL) were linear. Clearance and half-life were independent of the dose. Half-life estimates were shorter in the younger age group (4—7 years; half-life = 8 hours) compared to the older patients (8—17 years; half life = 11—13 hours); estimates were also shorter in patients taking concomitant enzyme-inducing AEDs (7.5 hours vs. 15—16 hours).48 Studies indicate that the weight-adjusted clearance of topiramate is greater in children vs. adults and in younger children vs. older children and adolescents.9 In the aforementioned study, weight-adjusted drug plasma clearance was approximately 50% higher in children than adults for both those receiving adjunctive non-enzyme inducing AEDs (0.47 mL/kg/minute vs. 0.32 mL/kg/minute) and enzyme-inducing AEDs (1 mL/kg/minute vs. 0.66 mL/kg/minute). This information suggests that steady-state plasma topiramate concentrations for the same mg/kg dose would be approximately 33% lower in this age group compared to adults; therefore, larger weight-based dose requirements may be necessary to obtain therapeutic efficacy.48

Infants and Children < 4 years: Topiramate exposure appears to be linear over a dosage range of 3—25 mg/kg/day in infants and young children. In a pharmacokinetic study of 35 infants and children (age range: 2—22 months) with refractory partial-onset seizures, patients were randomized to receive adjuvant topiramate liquid or sprinkle formulation 3, 5, 15, or 25 mg/kg/day in divided doses every 12 hours. At steady state, Cmin was 1.9 +/- 1, 3.3 +/- 1.9,  9.7 +/- 4.8, and 13.6 +/- 5.2 mcg/mL and AUC was 29.1 +/- 12.4, 50 +/- 19.6, 143 +/- 53.8, and 211 +/- 58 mcg x hour/mL, respectively. Mean clearance values were similar across all groups independent of age, weight, and topiramate dose.49 Reported mean clearance values were similar to those reported in another study of 22 young children (mean age: 2.7 years; range: 0.8—3.9 years) receiving topiramate (mean dose: 7 mg/kg/day) plus adjuvant therapy with enzyme-inducing (1.41 vs. 1.42 mL/kg/minute), enzyme-inhibiting (0.71 vs. 0.82 mL/kg/minute), or neutral (0.66 vs. 0.77 mL/kg/minute) antiepileptic agents.4950 Studies indicate that the weight-adjusted clearance of topiramate is greater in infants and young children vs. older children, adolescents, and adults. In one study, the mean weight-normalized clearance rate of topiramate (1.41 mL/kg/minute) was 40% and 114% higher in children < 2 years receiving adjunctive enzyme-inducing antiepileptic agents than that reported in similarly treated older children (1 mL/kg/minute; age range: 4—17 years) and adults (0.66 mL/kg/minute), respectively.4849 In adult patients, topiramate is primarily eliminated via renal excretion (70—85%) with only a small fraction eliminated via hepatic metabolism 5148; it is not known whether renal excretion or metabolism is the major route of drug elimination in young children. However, elimination via both routes is potentially increased in this age group and may result in larger dose requirements on mg/kg basis to achieve therapeutic efficacy.49 

Neonates: Limited data available. Topiramate pharmacokinetics were investigated in a study of 13 full-term neonates with hypoxic ischemic encephalopathy who received either deep hypothermia (DH; 30—34 degrees C; n = 5) or mild hypothermia (MH; 33—35 degrees C; n = 8) with (n = 7) or without (n = 6) adjuvant phenobarbital. Patients received topiramate sprinkles (5 mg/kg/dose) mixed with water and administered via orogastric tube once daily for the first 3 days of life, starting at the initiation of hypothermia. It is important to note that this dose was arbitrarily chosen to rapidly achieve therapeutic plasma concentrations for a short period of time; investigators hypothesized hypothermia would result in higher drug plasma concentrations and a prolonged half-life. In the study, topiramate plasma concentrations were within the 5—20 mcg/mL reference range (extrapolated from adult data) in 11 of the 13 neonates who were cooled for 72 hours; 2 neonates in DH exceeded the upper limit. In patients who reached virtual steady state (n = 9; virtual steady state obtained if plasma concentration at 72 hours was within the reference range at 48 hours +/- 10%), peak plasma concentrations were achieved 3.8 +/- 2.2 hours after oral administration and ranged from 15.4—19.9 mcg/mL (mean Cmax: 18 mcg/mL). Mean plasma clearance was 0.26 mL/kg/minute and mean elimination half-life was 35.6 +/- 19.3 hours. The pharmacokinetic parameters between neonates treated with DH or MH did not significantly differ, although lower AUC (p = 0.096), lower average plasma concentration (p = 0.096), and prolonged half-life (p = 0.08) were observed in the DH group (DH AUC = 318.1 +/- 101.6 mcg x hour/mL, Cavg = 13.3 +/- 4.2 mcg/mL, half-life = 48.8 +/- 4.6 hours vs. MH AUC = 366.2 +/- 48.1 mcg x hour/mL, Cavg = 15.26 +/- 2 mcg/mL, half-life = 29 +/- 23.8 hours). Neonates treated with DH had higher topiramate concentrations between 48—72 hours than those treated with MH, most likely due to more irregular absorption and elimination. Neonates receiving concomitant phenobarbital (an enzyme inducer) therapy had a significantly lower minimum plasma concentration that those receiving topiramate monotherapy (8.7 +/- 2.9 vs. 11.7 +/- 0.9 mcg/mL; p = 0.032); lower Cmax (15.4 +/- 5.3 vs. 19.9 +/- 1.9 mcg/mL; p = 0.06), AUC (302.4 +/- 89.7 vs. 375.8 +/- 37.4 mcg x hour/mL; p = 0.068), average plasma concentration (12.6 +/- 3.7 vs. 15.7 +/- 1.6 mcg/mL; p = 0.068), shortened half-life (26.5 +/- 17.7 vs. 42.9 +/- 19.1 hours; p = 0.113), and higher plasma clearance (0.3 vs. 0.22 mL/kg/minute; p = 0.078) did not reach statistical significance, perhaps due to small sample size.52

Geriatric: No age-related difference in topiramate pharmacokinetics were seen in elderly patients versus younger adults. However, the possibility of age-associated renal functional abnormalities should be considered.

Naltrexone HCl

Naltrexone is administered orally or intramuscularly. Naltrexone is widely distributed throughout the body, and antagonistic activity appears to be related to plasma and tissue concentrations.CSF concentrations are not known. Protein binding is roughly 21—28%. Naltrexone is metabolized to 6-beta-naltrexol, which also has antagonistic activity but is less potent than its parent. Significantly less 6-beta-naltrexol is generated following IM administration of naltrexone compared to administration of oral naltrexone due to a reduction in first-pass hepatic metabolism. Two other minor metabolites have been identified: 2-hydroxy-3-methoxy-6-beta-naltrexol and 2-hydroxy-3-methyl-naltrexone. The cytochrome P450 system is not involved in the metabolism of naltrexone. There appears to be little accumulation of naltrexone and 6-beta-naltrexol after chronic administration. Naltrexone is a highly extracted drug (> 98% metabolized), and extra-hepatic sites of metabolism may exist. Following hepatic metabolism, both naltrexone and its metabolites conjugate with glucuronic acid. The maximum serum concentration and systemic exposure for both naltrexone and 6-beta-naltrexol are dose proportional. Total naltrexone exposure is 3—4 fold higher after a single, 380 mg IM injection as compared with daily oral doses of 50 mg for 28 days.
 
Both naltrexone and its metabolite are excreted primarily by the kidney (53—79% of the dose). Only about 2% of naltrexone is excreted in the urine unchanged within 24 hours. 6-beta-naltrexol appears to undergo renal tubular secretion. Although naltrexone and its metabolites may undergo enterohepatic recycling, fecal elimination is a minor elimination pathway. The mean elimination half-life of naltrexone after oral administration is 4 hours, and the elimination half-life of 6-beta-naltrexol is roughly 14 hours. The mean elimination half-life of both naltrexone and 6-beta-naltrexol after intramuscular administration is 5—10 days; elimination of naltrexone is dependent on erosion of the polymer.

Route-Specific Pharmacokinetics:

Oral Route: Oral absorption is rapid and almost complete (roughly 96%). Due to extensive first-pass metabolism in the liver, however, only 5—40% of the drug reaches the systemic circulation unchanged. Studies indicate that oral naltrexone 50 mg will block the pharmacologic effects of 25 mg IV heroin for as long as 24 hours. Additional data suggest that doubling the dose of naltrexone provides blockade for 48 hours and tripling the dose provides blockade for up to 72 hours.

Intramuscular Route: After IM naltrexone administration, an initial drug peak occurs around 2 hours after the injection. A second peak occurs 2—3 days later; measurable concentrations are available for more than 1 month. Steady-state is achieved at the end of the dosing interval after the first injection. First pass metabolism is reduced with IM administration.

Special Populations:

Hepatic Impairment: Pharmacokinetic parameters of naltrexone given intramuscularly are essentially unchanged in patients with mild or moderate (Child-Pugh class A or B) hepatic impairment. The disposition of naltrexone in patients with either severe hepatic impairment has not been evaluated. In patients with compensated and decompensated liver cirrhosis, the AUC of oral naltrexone increased 5- and 10-fold, respectively, as compared to patients with normal liver function. Dosage adjustments may be necessary in patients with hepatic dysfunction.

Renal Impairment: Pharmacokinetic parameters of naltrexone given intramuscularly are essentially unchanged in patients with a creatinine clearance of 50—80 ml/minute. The disposition of naltrexone in patients with moderate to severe renal impairment has not been evaluated. Dosage adjustments may be necessary in patients with renal dysfunction.

Methylcobalamin

Methylcobalamin is administered intranasally, orally, and parenterally, while hydroxocobalamin is administered only parenterally. Once absorbed, vitamin B12 is highly bound to transcobalamin II, a specific B-globulin carrier protein and is distributed and stored primarily in the liver as coenzyme B12. The bone marrow also stores a significant amount of the absorbed vitamin B12. This vitamin crosses the placenta and is distributed into breast milk. Enterohepatic recirculation conserves systemic stores. The half-life is about 6 days (400 days in the liver). Elimination is primarily through the bile; however, excess methylcobalamin is excreted unchanged in the urine.

Route-Specific Pharmacokinetics:

Intravenous Route: Peak plasma levels of cyanocobalamin are attained within 1 hour for parenteral doses.

Intramuscular Route: Bioavailability of the nasal gel and spray forms relative to an IM injection are about 9% and 6%, respectively. Because the intranasal forms have lower absorption than the IM dosage form, intranasal B12 forms are administered once weekly. After 1 month of treatment in pernicious anemia patients, the once weekly dosing of 500 mcg B12 intranasal gel resulted in a statistically significant increase in B12 levels when compared to a once monthly 100 mcg IM dose.

Caffeine

Caffeine is administered orally and intravenously. Therapeutic concentrations have been reported to be 5 to 25 mg/L in adults. Caffeine is rapidly distributed to all body tissues and readily crosses the blood-brain barrier. It also distributes into breast milk. Caffeine is roughly 36% bound to plasma proteins, the volume of distribution is 630 mL/kg, and the clearance is 90 mL/hour/kg.5354 Caffeine is partially metabolized in the liver via demethylation reactions dependent on the CYP-450 1A2 isoenzyme; major metabolites include paraxanthine (80%), theobromine (10%), and theophylline (4%).55 The plasma half-life is 3 to 7 hours in adults.53

Affected cytochrome P450 isoenzymes: CYP1A2

Caffeine is a substrate of the hepatic cytochrome isoenzyme CYP1A2.5653

Route-Specific Pharmacokinetics:

Oral Route: Caffeine and citrated caffeine are well absorbed from the GI tract. Following oral administration, peak plasma concentrations in adults are reached within 50—75 minutes. In neonates, the oral administration of caffeine results in peak concentrations in 0.5—2 hours; formula feedings do not affect the time to maximum concentrations after oral dosing.

Special Populations:

Hepatic Impairment: The pharmacokinetics of caffeine have not been studied in neonates with impaired hepatic function. Caffeine elimination is more dependent on renal clearance in premature neonates and neonates than in older infants or adults due to underdeveloped hepatic metabolism. However, if hepatic impairment is present, caffeine elimination may be reduced, and the manufacturer recommends monitoring serum concentrations and adjusting dosages accordingly to avoid toxicity.

Renal Impairment: The pharmacokinetics of caffeine have not been studied in neonates with impaired renal function; however, caffeine elimination is more dependent on renal clearance in premature neonates and neonates than in older infants or adults due to underdeveloped hepatic metabolism. If renal impairment is present, caffeine elimination may be reduced, and the manufacturer recommends monitoring serum concentrations and adjusting dosages accordingly to avoid toxicity.

Pediatrics:

Infants and Children: The mean volume of distribution of caffeine in infants (0.8 to 0.9 L/kg) is slightly higher than that in adults (0.6 L/kg). Young infants have a plasma half-life of caffeine of 3 to 4 days. By 9 months of age post-term, the plasma half-life (5 hours) approximates that of adults. During the first 3 months, unchanged caffeine is predominantly excreted in the urine, but the percentage gradually decreases to the adult value of less than 2% in infants 7 to 9 months of age. Additionally, the partially demethylated xanthines and urates found in adults are attained by 7 to 9 months of age.535758 Cytochrome P450 (CYP) metabolism of caffeine is inhibited in neonates and infants who are breast-fed; formula feeding does not appear to affect the pharmacokinetics of caffeine in neonates and infants.53

Neonates: Plasma half-life for neonates may vary widely, from 52 to 100 hours, decreasing with increasing gestational age and postnatal age. Caffeine metabolism in neonates is limited due to their immature hepatic enzyme systems, therefore the large majority of the drug is cleared by the kidneys. Unchanged caffeine and its metabolites are excreted in the urine. The fraction of caffeine excreted unchanged in the urine, from term neonates up to 1 month old, is roughly 86%. Studies have found that gestational age, postnatal age, and patient weight are all determinants in the maturation of caffeine metabolism. 535759

Premature Neonates:  In premature neonates, a half-life of 52 to 144 hours has been reported. In two studies including 199 extremely premature neonates, the average half-life was 101 hours (mean gestational age 27.5 weeks, average postnatal age 12 days) and 144 hours (mean gestational age 28.2 weeks, average postnatal age 4 days).5460 In a study with 17 premature neonates (mean gestational age 29.7 weeks, average postnatal age 20.7 days), the average half-life was 52.03 hours.61 In these studies, the volume of distribution (Vd) ranged from 780 to 970 mL/kg and the clearance was 4.9 to 6.96 mL/hour/kg. As expected, the Vd decreased and the clearance increased with rising postnatal age.615460 Caffeine metabolism in premature neonates is limited due to their immature hepatic enzyme systems.53 In this population, it is interesting to note that interconversion from theophylline to caffeine has been noted. After theophylline administration, caffeine concentrations are approximately 25% of theophylline concentrations and 3% to 8% of caffeine would be expected to convert to theophylline.53 Caffeine concentrations in the cerebrospinal fluid of premature neonates are approximately the same as plasma concentrations.53

Oxytocin

Oxytocin administered effectively by parenteral injection or nasal inhalation. Steady state, following parenteral administration, is usually achieved in plasma by 40 minutes.39 Oxytocin's plasma half-life is between 1 and 6 minutes. The drug distributes throughout the extracellular fluid, with minimal amounts reaching the fetus.

Oxytocinase, a glycoprotein aminopeptidase that is capable of degrading oxytocin, is produced during pregnancy and is present in the plasma. Enzyme activity increases gradually until term approaches, when there is a sharp rise in plasma levels and activity is high in the plasma, placenta and uterus. After delivery enzyme activity declines. Oxytocinase most likely originates from the placenta and regulates the amount of oxytocin in the uterus; there is little or no degradation of oxytocin in men, nonpregnant women, or cord blood. Oxytocin is rapidly removed from plasma by the liver and the kidneys, with only small amounts being excreted unchanged in the urine. Oxytocin is metabolized in the lactating mammary gland and is distributed into breast-milk.

Route-Specific Pharmacokinetics:

Oral Route: Chymotrypsin, present in the GI tract, destroys oxytocin, rendering oral administration ineffective.

Metformin

Metformin is administered orally as immediate-release tablets, a solution, or extended release tablets. The drug is distributed rapidly into peripheral body tissues and fluids and appears to distribute slowly into erythrocytes and to a deep tissue compartment (most likely GI tissues). The highest concentrations are found in the GI tract (10 times the concentrations in the plasma) and lower concentrations in the kidney, liver, and salivary gland tissue. Metformin does not bind to hepatic or plasma proteins.

Metformin is not metabolized by the liver and this fact may explain why the risk of lactic acidosis is much less for metformin than for phenformin (i.e., approximately 10% of patients have an inherited defect in the ability to metabolize phenformin).40 The drug is excreted by the kidneys, largely unchanged, through an active tubular process. Tubular secretion may be altered by many cationic drugs. Approximately 10% of an oral dose is excreted in the feces, presumably as unabsorbed metformin and about 90% of a dose is excreted by the kidneys within 24 hours. Although the average elimination half-life in the plasma is 6.2 hours in patients with normal renal function, metformin is distributed to and accumulates in red blood cells, which leads to a much longer elimination half-life in the blood (17.6 hours).6263

Route-Specific Pharmacokinetics:

Oral Route: The bioavailability of 500 mg tablets is 50—60% with peak plasma concentrations achieved at approximately 2.5 hours. Food decreases the extent and slightly delays the absorption. Studies indicate that dose proportionality is lacking with increasing doses due to a decrease in the oral absorption at higher doses.

Special Populations:

Hepatic Impairment: Specific pharmacokinetic studies have not been performed in patients with hepatic dysfunction receiving metformin, but hepatic impairment may increase the risk of lactic acidosis.

Renal Impairment: Metformin will accumulate in patients with CrCl < 60 ml/min, which may increase the risk of lactic acidosis. In patients with mild (CrCl = 61—90 ml/min), moderate (CrCl 31—60 ml/min), or severe (CrCl 10—30 ml/min) renal impairment, Cmax concentrations after an 850 mg single dose were 1.86 mcg/ml, 4.12 mcg/ml, and 3.93 mcg/ml respectively. Similarly, Tmax was 3.2 hours, 3.75 hours, and 4.01 hours, respectively. The elderly, due to age-related decreased renal function, may also accumulate metformin. Metformin is removed by hemodialysis.

Geriatric: The elderly, due to age-related decreased renal function, may accumulate metformin.

Gender Differences: Gender does not appear to affect metformin pharmacokinetics.

Ethnic Differences: Race does not appear to affect metformin pharmacokinetics.

Contraindications/Precautions

Bupropion HCl

IMPORTANT: Given that there are multiple dosage forms of bupropion available, it is important to be familiar with each product name, dosage form, and dosing schedule to avoid dosing errors. Bupropion products should not be used with other bupropion products, including the combination of bupropion-naltrexone. Duplication of bupropion can result in serious toxicity and convulsions.644442414643

Bupropion is contraindicated in patients with a history of hypersensitivity to bupropion or any inactive ingredients in the formulations. Delayed hypersensitivity reactions, consisting of arthralgia, myalgia, fever and rash have been reported in association with bupropion and may resemble serum sickness. Anaphylactoid/anaphylactic reactions and serious rash including Stevens-Johnson syndrome have also been reported.644442414643

Bupropion is contraindicated in patients with a pre-existing seizure disorder or conditions that increase the risk of seizures (e.g., severe head trauma, arteriovenous malformation, CNS tumor (e.g., brain tumor or intracranial mass), CNS infection, severe stroke, anorexia nervosa, bulimia nervosa, and in cases of abrupt benzodiazepine withdrawal as well as abrupt withdrawal from alcohol, barbiturates, or anti-epileptic drugs, because bupropion can cause seizures. Other predisposing factors that may increase the risk of seizures include alcoholism, substance abuse (e.g., cocaine or prescription abuse of stimulants such as amphetamines), metabolic disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, hypoxemia), diabetes mellitus treated with oral hypoglycemic agents or insulin, excessive use of benzodiazepines, sedative/hypnotics, or opiates, use of anorectic drugs for obesity treatment, or use of concomitant medications that lower the seizure threshold (e.g., other bupropion products, antipsychotics, tricyclic antidepressants, theophylline, tramadol, systemic corticosteroids). Bupropion should be discontinued and not re-initiated in patients who experience a seizure during treatment. The incidence of seizures with bupropion is dose-dependent. In studies using bupropion hydrochloride sustained-release up to 300 mg/day, the incidence of seizures was about 0.1%. The incidence of seizures in patients taking bupropion hydrochloride immediate-release 300 mg/day to 450 mg/day was about 0.4%. At higher immediate-release dosages between 450 mg/day and 600 mg/day, the estimated risk of seizures increases 10-fold compared to the seizure risk at 450 mg/day. The incidence of seizures has not been formally evaluated for the use of Aplenzin, Forfivo XL, or Wellbutrin XL. Do not exceed maximum recommended single or total daily dosages of any bupropion product. Patients who are taking bupropion for smoking cessation (e.g., Zyban) should not also take bupropion for depressive disorders (e.g., Wellbutrin, Aplenzin), and vice-versa. Healthcare professionals should be aware that bupropion is available under several brand names for various indications in order to avoid duplicative administration. During controlled trial evaluation of immediate-release bupropion, an increase in motor activity and agitation/excitement was demonstrated in normal volunteers, subjects with a history of multiple drug abuse, and depressed patients. Results from single-dose studies suggest that the recommended daily dose of bupropion when administered in divided doses is not likely to be significantly reinforcing to amphetamine or CNS stimulant abusers. However, because clinical trial results may not reliably predict the abuse potential of drugs, the benefits of treatment should be weighed against the potential for abuse prior to administering bupropion to patients with a history of substance abuse. It should be noted that bupropion extended-release formulations are intended for oral use only. The inhalation of crushed tablets or injection of dissolved bupropion has resulted in seizures and/or cases of death.4442414643

The safety and efficacy of bupropion is not established in pediatric patients less than 18 years of age. Children 6 years and older with a major depressive episode or attention deficit hyperactivity disorder (ADHD) have been studied in clinical trials of bupropion, but data regarding pediatric safety are limited. Careful screening and monitoring is recommended by the American Heart Association if bupropion is used in pediatric patients. In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. No suicides occurred in any of the pediatric trials. Nevertheless, the need for an antidepressant in children, adolescents, or young adults for any use must be weighed against the risk of suicidality; it is unknown if this risk extends to long-term use. All patients should be monitored for symptom worsening or suicidality, especially at treatment initiation or after dose changes. Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation. A change to the treatment regimen or discontinuation of bupropion may be necessary in patients with emerging suicidality or worsening depression.65464145

Patients with Tourette's syndrome or tics should be closely monitored for emerging or worsening tics during treatment with bupropion. Like other stimulant medications, bupropion may precipitate motor or phonetic tics in those with Tourette's syndrome or a tic disorder.6667

The use of antidepressants, such as bupropion, has been associated with the development of mania or hypomania in susceptible individuals. Patients should be adequately screened for bipolar disorder prior to initiating an antidepressant, including a detailed personal and family history of bipolar disorder, depression, and suicidal thoughts or actions. Patients with depression or comorbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of therapy and during dose adjustments. Caregivers should be advised to closely observe the patient on a daily basis and to communicate immediately with the prescriber the emergence of agitation, irritability, unusual changes in behavior, or emergence of suicidality. If a patient develops manic symptoms, bupropion should be held, and appropriate therapy initiated to treat the manic symptoms.41 Patients should be observed for a potential psychiatric event or worsening of pre-existing psychiatric illness (e.g., schizophrenia, depression, bipolar disorder) during treatment with bupropion, including smoking cessation products (e.g., Zyban), due to serious neuropsychiatric symptoms reported during postmarketing use of bupropion products for smoking cessation. If neuropsychiatric symptoms develop, evaluate the patient for symptom severity and the extent of benefit from treatment, and consider dose reduction or discontinuation, or continued treatment with closer monitoring. In many cases, resolution of symptoms has occurred after discontinuation, although the symptoms can persist; therefore, ongoing monitoring and supportive care should be provided until symptoms resolve. Postmarketing reports during use of bupropion smoking cessation products have included neuropsychiatric adverse events such as mood or behavioral changes (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempt, and completed suicide in patients with and without a psychiatric history. Some reported cases may have been complicated by symptoms of nicotine withdrawal, such as depressed mood, in patients who stopped smoking. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. Some reported neuropsychiatric events, including unusual and sometimes aggressive behavior directed to oneself or others, may have been worsened by concomitant use of alcohol. Advise patients and caregivers that the patient should stop taking bupropion and contact a healthcare provider immediately if agitation, depressed mood, suicidal ideation, suicidal behavior, or other behavioral changes that are not typical for the patient are observed. The boxed warning in the bupropion smoking cessation product labeling regarding serious neuropsychiatric effects was removed in December 2016 following results from the Evaluating Adverse Events in a& Global Smoking Cessation Study (EAGLES), which was a large, randomized, double-blind, active- and placebo-controlled smoking cessation clinical trial assessing varenicline, bupropion, and nicotine replacement therapy in patients with (n = 4,003) and without (n = 3,912) a history of a psychiatric disorder. The results showed that the benefits of taking smoking cessation products outweigh the risks, which are less frequent and severe than previously suspected.68

Bupropion is contraindicated with concurrent use of MAOI therapy intended to treat psychiatric disorders because of an increased risk of hypertensive reactions. At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and bupropion initiation. Conversely, allow at least 14 days after stopping bupropion before starting an MAOI intended to treat psychiatric disorders. Starting bupropion in a patient being treated with an MAOI such as linezolid or methylene blue is also contraindicated; however, there may be circumstances when it is necessary to initiate urgent treatment with linezolid or intravenous methylene blue in a patient taking bupropion. If acceptable alternatives are not available and benefits are judged to outweigh the risks of hypertensive reactions, bupropion should be promptly discontinued before initiating treatment with linezolid or methylene blue. Monitor the patient closely for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with bupropion may be resumed 24 hours after the last dose of linezolid or methylene blue. The risk of administering methylene blue by non-intravenous routes (e.g., oral tablets, local injection) or intravenous doses much less than 1 mg/kg with bupropion is unclear; however, clinicians should be aware that the potential for an interaction exists.4241

Use bupropion with caution during pregnancy; use during pregnancy only if the potential benefit justifies the potential risk to the fetus. When treating a pregnant woman, the physician should carefully consider the potential risks and benefits of treatment. If clinically feasible, tapering of the medication prior to labor and obstetric delivery may be considered. Pregnant smokers should be encouraged to attempt educational and behavioral interventions before pharmacologic approaches are used; nicotine has been used in pregnancy to help patients quit smoking. Smoking cessation programs in pregnancy reduce the proportion of women who continue to smoke, and reduce the risk for low birthweight and preterm birth. Data from epidemiological studies including pregnant women exposed to bupropion in the first trimester indicate no increased risk of congenital malformations. In addition, no increased risk of cardiovascular malformations during first trimester exposure to bupropion has been observed. The rate of cardiovascular malformations following 675 exposures to bupropion in the first trimester was 1.3% versus a background rate of about 1%. Data collected from the United Healthcare database and the National Birth Defects Prevention Study (6,853 infants with cardiovascular malformations and 5,763 with non-cardiovascular malformations) did not show an overall increased risk from cardiovascular malformations after bupropion exposure during the first trimester. Study findings on bupropion exposure during the first trimester and risk for left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions regarding a possible association. The United Healthcare database lacked sufficient power to evaluate this association; the NBDPS found increased risk for LVOTO, and the Slone Epidemiology case control study did not find increased risk for LVOTO. Study findings on bupropion exposure during the first trimester and risk for ventricular septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible association. The Slone Epidemiology Study found an increased risk for VSD following first trimester maternal bupropion exposure but did not find increased risk for any other cardiovascular malformations studied (including LVOTO). The NBDPS and United Healthcare database study did not find an association between first trimester maternal bupropion exposure and VSD. For the findings of LVOTO and VSD, the studies were limited by the small number of exposed cases, inconsistent findings among studies, and the potential for chance findings from multiple comparisons in case control studies. No clear evidence of teratogenic activity was found in reproductive developmental studies conducted in rats and rabbits. However, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at doses approximately equal to or more than the maximum recommended human dose (MRHD) and decreased fetal weights were seen at doses twice the MRHD and greater. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to bupropion; information about the registry can be obtained at womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants by calling 1-866-961-2388 or 1-844-405-6185.6444424169464370

Bupropion and its metabolites are excreted into human breast milk, and caution should be exercised when bupropion is administered to a breast-feeding woman.644442414643 Peak breast milk concentrations of bupropion and its metabolites are present within 2 to 4 hours after an oral dose. In one lactation study (n = 10), the average daily infant exposure to bupropion and its active metabolites (assuming 150 mL/kg daily consumption) was 2% of the maternal weight-adjusted dose.71 One case report describes a possible seizure in a breast-fed infant during maternal use of extended-release bupropion.72 In two other cases, no infant-related adverse events were noted during breast-feeding.73 Due to individual variability in response to antidepressants, it may be prudent to continue the existing regimen if ongoing treatment for depression is deemed necessary during breast-feeding. Alternatives may be considered in some cases. Because a pooled analysis found that maternal use of sertraline, along with nortriptyline and paroxetine, usually produced undetectable or low drug concentrations in infant serum, these agents may be the preferred antidepressants when initiating antidepressant therapy in a breast-feeding mother.74 For smoking cessation treatment, nicotine replacement products may be considered as an alternate therapy to bupropion if non-pharmacologic interventions are inadequate. The decision of whether to use nicotine replacement therapy in a woman who is breast-feeding should be evaluated in comparison to the risks associated with exposure of the infant to nicotine and other tobacco contaminants in the breast milk as well as those of passive exposure to tobacco smoke. Breast-feeding and eliminating an infant's exposure to tobacco smoke are considered important protective factors for serious pediatric health risks.75

Forfivo XL, a 450 mg extended-release tablet formulation of bupropion, is not recommended in patients with hepatic impairment because a lower dosage strength is not available for use in this patient population.45 For other bupropion formulations, the dosage or dosage frequency should be reduced in patients with moderate to severe hepatic impairment (Child-Pugh Score 7—15). For patients with mild hepatic dysfunction (Child-Pugh Score 5—6), reduced dosage or dosage frequency should be considered; however, no specific guidelines are available. Monitor patients with any degree of hepatic disease carefully. Bupropion undergoes extensive hepatic metabolism and excretion in the urine as metabolites; there is a risk for accumulation in hepatic impairment. In addition, caution is advisable when using bupropion in patients with severe hepatic impairment because this condition can increase the risk of seizures.4341444246

Forfivo XL, a 450 mg extended-release tablet formulation of bupropion, is not recommended in patients with renal impairment since a lower dosage strength is not available for use in this patient population.45 Other bupropion products should be used with extreme caution in patients with renal disease or renal failure because the parent compound or active metabolites could accumulate. Consider reduced dosages in these patient populations based on the degree of organ impairment, and closely monitor for adverse reactions that could indicate high drug or metabolite levels.

Of roughly 6,000 patients in bupropion sustained-release studies for both smoking cessation and depression, 275 were 65 and over and 47 were 75 and over. Several hundred geriatric patients 65 years and older have also been studied (in depression) with the immediate-release formulation. Both initial and maintenance bupropion doses should be reduced in geriatric patients if hepatic or renal impairment or debilitating disease is present; multiple-dose pharmacokinetic studies have indicated the elderly may be at risk for bupropion and metabolite accumulation. It may be useful to monitor renal function in the elderly. Bupropion may also cause weight loss which may be significant for elderly or otherwise debilitated patients.4341444246 The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antidepressants in residents of long-term care facilities. According to OBRA, follow the recommended duration of therapy per pertinent literature for the condition being treated, including clinical practice guidelines. All residents being treated for depression with any antidepressant should be monitored closely for worsening of depression and suicidal behavior or thinking, especially during initiation of therapy and during dose changes. Antidepressants may cause dizziness, nausea, diarrhea, anxiety, nervousness, insomnia, sedation, weight gain, anorexia, or increased appetite. Many of these effects can increase the risk of falls. Bupropion may increase seizure risk and activity in susceptible individuals. Before discontinuation, taper bupropion to avoid a withdrawal syndrome. Concurrent use of two or more antidepressants may increase the risk of side effects; in such cases, there should be documentation of expected benefits that outweigh the associated risks and monitoring for an increase in side effects. Monitoring should consist of a review for continued need at least quarterly, and documentation of the rationale for continuation. When the drug is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt to taper the medication as outlined in the OBRA guidelines, unless a taper is clinically contraindicated.76

Rarely, bupropion may cause a fast or irregular heart beat or increases in blood pressure in some patients. It should be used with caution in patients with a recent history of acute myocardial infarction or unstable cardiac disease, including heart failure. Pharmacokinetic studies suggest that left ventricular dysfunction results in lowered metabolism and excretion of bupropion and its metabolites. Because treatment with bupropion can result in elevated blood pressure and hypertension, patients should have their blood pressure checked prior to bupropion initiation and periodically throughout treatment. Bupropion may be used in combination with nicotine transdermal systems (NTS) as an aide to smoking cessation. In clinical trials, new onset treatment-induced hypertension or exacerbation of existing high blood pressure occurred more commonly in patients using the combination bupropion-NTS therapy. In some cases the exacerbation of hypertension required discontinuation of bupropion treatment. Patients should quit tobacco smoking prior to initiating the nicotine therapy in the bupropion-NTS combination regimen to reduce the risk of unwanted cardiac side effects. Close blood pressure monitoring is recommended.4241 Patients who are taking bupropion should not self-treat with OTC nicotine products; the bupropion-NTS combination should only be used under the prescription and advice of a health-care prescriber. When used as monotherapy, patients should schedule to stop tobacco smoking during the second week of taking bupropion. When bupropion is used for smoking cessation, it should be noted that cessation of tobacco smoking may result in elevated serum concentrations of some drugs that are hepatically metabolized, such as theophylline and warfarin due to lowered induction of hepatic oxidative microsomal enzymes (tobacco smoke induces hepatic enzymes). Downward dosage adjustments of such drugs and more frequent monitoring may be required during smoking cessation. Bupropion has been used in children and adolescents for the treatment of attention-deficit hyperactivity disorder (ADHD). Sudden unexplained death has occurred in adults and pediatric patients receiving stimulants at standard dosages for ADHD. Although bupropion is not a stimulant medication, the American Heart Association recommends conducting a detailed patient and family history and physical examination prior to initiating any ADHD pharmacologic treatment, and obtaining a baseline electrocardiogram (ECG) is a reasonable addition to the initial evaluation.65 Once the medication is started, a repeat ECG may be helpful if the original ECG was obtained before the child was 12 years old, if cardiac symptoms develop, or there is a change in family history. If a child or adolescent has any significant findings on physical examination, ECG, or family history, consult a pediatric cardiologist before initiating the medication.

Patients should be warned to use caution when driving or operating machinery or performing other tasks that require mental alertness until they know how bupropion will affect them. Some patients have reported lower alcohol tolerance during treatment with bupropion; advise patients that the consumption of alcohol should be minimized or avoided; avoid ethanol intoxication.

Caution is recommended when prescribing bupropion to patients with closed-angle glaucoma. The pupillary dilation that can occur with antidepressants may precipitate a closed-angle glaucoma attack in patients with anatomically narrow angles who do not have a patent iridectomy. An acute attack of closed-angle glaucoma is considered a medical emergency because the increased intraocular pressure is rapid and severe, and may quickly result in blindness if left untreated.43

It is generally recommended to avoid abrupt discontinuation of antidepressants. If discontinuing bupropion, the medication should be tapered as rapidly as possible, but with recognition that abrupt discontinuation can also cause adverse symptoms. Because Forfivo XL is only available in a 450 mg tablet, the manufacturer recommends using another bupropion formulation for tapering the dose prior to discontinuation.45

Laboratory test interference has been reported with bupropion use. False-positive urine immunoassay screening tests for amphetamines have been reported in patients taking bupropion. The false-positive result is due to lack of specificity of some screening tests. False-positive test results may result even following discontinuation of bupropion therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish bupropion from amphetamines.644442414643

Phentermine HCl

Phentermine is contraindicated for use in any patient with a prior history of sympathomimetic amine hypersensitivity.7778

According to the manufactures of phentermine capsules and tablets, its products are contraindicated in patients with cardiac disease, advanced arteriosclerosis, moderate to severe hypertension, agitated states, or glaucoma.79 Likewise, orally disintegrating tablets, are contraindicated in patients with a history of cardiac disease including coronary artery disease, stroke, cardiac arrhythmias, heart failure, and uncontrolled hypertension.78 Valvular heart disease has been reported in women receiving the combination of fenfluramine and phentermine; the safety and efficacy of combination therapy with phentermine and any other drug products for weight loss, including selective serotonin reuptake inhibitors (e.g., fluoxetine, sertraline, fluvoxamine, paroxetine), have not been established. Therefore, coadministration of these drug products for weight loss is not recommended. Further, primary pulmonary hypertension (PPH) has been reported to occur in patients receiving a combination of phentermine with fenfluramine or dexfenfluramine. The possibility of an association between the use of phentermine alone and PPH or valvular heart disease cannot be ruled out. The initial symptom of PPH is usually dyspnea. Other initial symptoms include: angina pectoris, syncope, or lower extremity edema. Patients should be advised to report immediately any deterioration in exercise tolerance. Treatment should be discontinued in patients who develop new, unexplained symptoms of dyspnea, angina pectoris, syncope, or lower extremity edema.

Because phentermine is a sympathomimetic agent, it is contraindicated in patients with hyperthyroidism. It should also be used with caution in patients with thyroid disease.

Phentermine is contraindicated for use during or within 14 days following the use of MAOI therapy or other drugs with MAO-inhibiting activity. Monoamine oxidase inhibitors (MAOIs), or drugs that possess MAO-inhibiting activity such as furazolidone or procarbazine, can prolong and intensify the cardiac stimulation and vasopressor effects of phentermine.77

Phentermine is contraindicated in patients with agitated states.aggravate these effects or cause an adverse drug reaction.77 Symptoms of chronic intoxication include insomnia, irritability, change in personality, and psychotic symptoms that may be clinically indistinguishable from other psychotic disorders, like schizophrenia. Phentermine could aggravate certain mental conditions, such as those patients who exhibit highly nervous or agitated behavior, including psychosis, mania, or severe anxiety.

The use of phentermine may cause dizziness, mask signs of fatigue or the need for rest, or impair the ability of a patient to participate in activities that require mental alertness. Advise patients to use caution when driving or operating machinery, or performing other tasks that require mental alertness until they are aware of how therapy will affect their mental and/or motor performance. In general, ethanol ingestion may aggravate these effects or cause an adverse drug reaction.77 Advise patients to avoid alcohol while taking phentermine.

Use phentermine cautiously in patients with diabetes mellitus. Insulin or other antidiabetic medication requirements may be altered in these patients when using phentermine during weight loss and due to altered dietary regimens. Patients should monitor their blood glucose regularly and follow the recommendations of their health care provider.78

Appetite suppressant therapy is not recommend for use in those patients with a history of anorexia nervosa or other eating disorders. Use of phentermine is contraindicated in patients with a known history of drug or substance abuse. Phentermine is chemically and pharmacologically related to the amphetamines which have been extensively abused. The possibility of abuse of phentermine should be kept in mind when evaluating the desirability of including a drug as part of a weight reduction program. The least amount reasonable should be prescribed or dispensed at one time in order to limit the potential for overuse or drug diversion.78

Phentermine products are now classified as FDA pregnancy risk category X, as are many anorexiants used for weight loss, and are contraindicated during pregnancy.7879 Safe use of phentermine during pregnancy has not been established; there is no known indication for use of phentermine during pregnancy. Phentermine should not be taken by pregnant women or by women who may become pregnant unless, in the opinion of the physician, the potential benefits outweigh the possible hazards.79

Abrupt discontinuation of phentermine after prolonged high doses may result in severe mental depression or extreme fatigue; sleep EEG changes have also been noted. Gradual withdrawal of therapy is recommended. If immediate discontinuation is medically necessary, careful monitoring and symptom management is warranted.77

Phentermine is contraindicated during breast-feeding.78 It is not known whether phentermine and its metabolites are excreted in breast milk; however, because of the potential for serious adverse effects in the nursing infants, breast-feeding while taking phentermine is not recommended.8079

Safety and effectiveness of phentermine in children have not been established. Phentermine is not recommended for children or adolescents 16 years of age and under. There is no established use of phentermine in infants or neonates.7778

The debilitated or geriatric patient may be more susceptible to the CNS and sympathomimetic side effects of phentermine; use with caution in elderly patients. Patients with renal impairment may also be more susceptible to side effects. Exposure increases can be expected in patients with renal impairment or renal failure. Use caution when administering phentermine to patients with renal impairment.77

The use of inhalational anesthetics during surgery may sensitize the myocardium to the effects of sympathomimetic drugs. Because of this, and its effects on blood pressure, in general, phentermine should be discontinued several days prior to surgery. Avoid abrupt discontinuation.

Topiramate

Topiramate is contraindicated for use in any patient hypersensitive to the drug or any of the product components. Serious and potentially fatal exfoliative dermatologic reactions have been reported in post-marketing experience with topiramate.910 Cross-sensitivity between antibiotic sulfonamides and nonantibiotic sulfonamides, such as topiramate, is controversial.81 Antibiotic sulfonamides contain an amine linked to a benzene ring (arylamine moiety), attached directly to the sulfonamide structure; this arylamine attached to the sulfonamide structure is believed to be the central pathogenesis of hypersensitivity reactions.8182 Although topiramate is a simple sulfonamide, the sulfonamide structure is not directly connected to a ring structure, and it lacks an arylamine moiety.8183 Some experts believe apparent cross-reactivity represents multiple concurrent and unlinked drug hypersensitivities in predisposed patients.8482 Although cross-reactivity with sulfonamide antibiotics appears unlikely, precaution or complete avoidance of nonantibiotic sulfonamides in individuals whose previous reaction was serious and/or life-threatening or in those with multiple drug hypersensitivities may be prudent.84818283

Monitor all patients beginning treatment with antiepileptic drugs (AEDs) or currently receiving topiramate closely for emerging or worsening depression or suicidal ideation. Advise patients and caregivers of the increased risk of suicidal thoughts and behaviors and to immediately report the emergence of new or worsening of depression, suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. AEDs should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with an increased risk of suicidal thoughts and behavior. If suicidal thoughts and behavior emerge during treatment, consider whether the emergence of these symptoms in any patient may be related to the illness being treated. There is an increased risk of suicidal ideation and behavior in patients receiving AEDs to treat epilepsy, psychiatric disorders, or other conditions (e.g., migraine, neuropathic pain). The primary analysis consisted of 199 placebo-controlled clinical studies with a total of 27,863 patients in drug treatment groups and 16,029 patients in placebo groups (5 years of age and older). There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving AEDs had approximately twice the risk of suicidal behavior or ideation as patients receiving placebo (0.43% vs. 0.24%, respectively; RR 1.8, 95% CI: 1.2 to 2.7). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions; however, the absolute risk differences were similar in trials for epilepsy and psychiatric indications. Age was not a determining factor. The increased risk of suicidal ideation and behavior was observed between 1 and 24 weeks after therapy initiation. However, a longer duration of therapy should not preclude the possibility of an association to the drug since most studies included in the analysis did not continue beyond 24 weeks.91011

In patients with or without a history of seizures or epilepsy, withdraw topiramate gradually to minimize the potential for seizures or increased seizure frequency. In situations where abrupt discontinuation of topiramate is medically required, appropriate monitoring is recommended.91011

Extended-release topiramate is contraindicated in patients with metabolic acidosis who are taking concomitant metformin. Topiramate can cause hyperchloremic, non-anion gap metabolic acidosis. Conditions or therapies that predispose patients to acidosis, such as kidney disease, severe pulmonary disease, status epilepticus, diarrhea, ketogenic diet, or certain drugs, may be additive to the bicarbonate lowering effects of topiramate. Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. If metabolic acidosis develops and persists, consider reducing the dose or discontinuing topiramate (using dose tapering). If the decision is made to continue patients on topiramate in the face of persistent acidosis, consider alkali treatment. Also, the concomitant use of topiramate with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet, may create a physiological environment that increases the risk of kidney stone formation, and should therefore be avoided.91011

Avoid alcohol with topiramate. Topiramate is a CNS depressant. Concomitant administration of topiramate with alcohol can result in significant CNS depression.11 Trokendi XR is contraindicated with recent ethanol ingestion or ethanol intoxication (i.e., within 6 hours before and 6 hours after use). In the presence of alcohol, the pattern of topiramate release from Trokendi XR is significantly altered. As a result, plasma concentrations of topiramate may be markedly higher soon after dosing and subtherapeutic later in the day.10

Closely monitor patients (especially neonates, infants, and children) treated with topiramate for evidence of decreased sweating and increased body temperature, especially in hot weather. Use caution when topiramate is given with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity. Oligohidrosis, infrequently resulting in hospitalization, has been reported in association with topiramate use. Some of the cases were reported after exposure to an ambient temperature increase. The majority of these reports have been in pediatric patients.851011

Hyperammonemia with and without encephalopathy has been observed in patients who were taking topiramate. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity (mitochondrial disease) may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, topiramate treatment or an interaction of concomitant topiramate-based product and valproic acid treatment may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status associated with any topiramate treatment, consider hyperammonemic encephalopathy and measure an ammonia concentration.98611

According to the Beers Criteria, anticonvulsants are considered potentially inappropriate medications (PIMs) in geriatric patients with a history of falls or fractures and should be avoided in these patient populations, except for treating seizure and mood disorders, since anticonvulsants can produce ataxia, impaired psychomotor function, syncope, and additional falls. If topiramate must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement strategies to reduce fall risk.87 The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities; the use of any anticonvulsant for any condition should be based on confirmation of the condition and its potential cause(s). Determine effectiveness and tolerability by evaluating symptoms, and use these as the basis for dosage adjustment for most patients. Therapeutic drug monitoring is not required or available for most anticonvulsants. Serum medication concentrations (when available) may assist in identifying toxicity. Monitor the treated patient for drug efficacy and side effects. Anticonvulsants can cause a variety of side effects; some adverse reactions can increase the risk of falls. When an anticonvulsant is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity as outlined in the OBRA guidelines.76]

Topiramate dosage adjustment is necessary for patients with renal impairment. Before dosing, obtain an estimated creatinine clearance in patients at high risk for renal disease (e.g., older patients, or those with diabetes mellitus, hypertension, or autoimmune disease). In patients with renal insufficiency, a reduction in the topiramate dose is needed. In patients with renal failure receiving dialysis, a supplemental topiramate dose may be required; topiramate is removed by hemodialysis at a rate greater than in patients with normal renal function. Also, conditions that predispose patients to acidosis, such as renal disease, may be additive to the bicarbonate lowering effects of topiramate. Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. If metabolic acidosis develops and persists, consider reducing the dose or discontinuing topiramate (using dose tapering). If the decision is made to continue patients on topiramate in the face of persistent acidosis, consider alkali treatment.91011

Serious rash (Stevens-Johnson syndrome [SJS] and toxic epidermal necrolysis [TEN]) has been reported in patients receiving topiramate. Discontinue topiramate at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, do not resume topiramate use and consider alternative therapy. Inform patients about the signs of serious skin reactions.9

Topiramate is associated with an increased risk of bleeding. In patients with serious bleeding events, conditions that increased the risk for bleeding were often present, or patients were often taking drugs that cause thrombocytopenia (other antiepileptic drugs) or affect platelet function or coagulation (e.g., aspirin, nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, or warfarin or other anticoagulant therapy).91011

Warn patients about the potential for somnolence, dizziness, confusion, difficulty concentrating, or visual effects, and advise patients against driving or operating machinery until they have gained sufficient experience on topiramate to gauge whether it adversely affects their mental performance, motor performance, and/or vision.91011

Topiramate can cause fetal harm when administered to a pregnant woman. Consider the benefits and risks of topiramate in women of childbearing potential, particularly when it is being considered for conditions not usually associated with permanent injury or death. Counsel women of childbearing potential regarding the potential risk to the fetus from topiramate exposure, and consider alternative therapeutic options in women who are planning a pregnancy. Data from pregnancy registries indicate infants exposed to topiramate during pregnancy have an increased risk for cleft lip and/or cleft palate and for being small for gestational age (SGA), defined as a birth weight below the tenth percentile. SGA has been seen at all doses and appears to be dose-dependent. SGA occurs more frequently in infants of women who received higher topiramate doses or continued topiramate use until later in pregnancy (i.e., third trimester). According to registry data, the prevalence of SGA was 18% to 25% in topiramate-exposed infants compared to 7% in infants exposed to a reference antiepileptic agent (AED) and 5% to 9% in those without antiepileptic drug (AED) exposure.10 The prevalence of oral clefts was 1.2% compared to 0.39% to 0.46% in infants exposed to another AED. The relative risk of oral clefts in topiramate-exposed pregnancies was 9.6 (95% CI 4 to 23) compared to untreated women.910 Oral clefts develop in the first trimester before many women know that they are pregnant.88 Pregnancy registry data also suggest a possible association between the use of topiramate during pregnancy and congenital malformations such as craniofacial defects, hypospadias, and anomalies of various body systems. Registry data and findings from other studies suggest that combination therapy with AEDs may increase the risk of teratogenic effects compared to monotherapy with an AED. Topiramate can cause metabolic acidosis which, when occurring during pregnancy, has been associated with decreased fetal growth, decreased fetal oxygenation, fetal death, and may impact the ability of the fetus to tolerate labor. Monitor women taking topiramate during pregnancy for metabolic acidosis and treat as in the nonpregnant state. Monitor newborns of mothers treated with topiramate for metabolic acidosis after birth. Limited data indicate topiramate may be associated with pre-term labor and premature delivery.910 There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to topiramate; information about the registry can be obtained at http://www.aedpregnancyregistry.org or by calling 1-888-233-2334.10

Topiramate is excreted in human breast milk. Diarrhea and somnolence have been observed in breast-fed infants whose mothers received topiramate. The effects of topiramate on milk production are unknown. Consider the developmental and health benefits from breast-feeding along with the mother's clinical need for topiramate and any potential adverse effects on the breast-fed infant from topiramate or the underlying maternal condition.10 Data from 5 breast-feeding infants has shown topiramate plasma concentrations of 10% to 20% of the maternal plasma concentration.9 Based on breast milk concentrations from 3 women taking 150 to 200 mg topiramate daily, it was estimated that a breast-fed infant (assuming a milk intake of 150 mL/kg/day) would receive approximately 0.1 to 0.7 mg/kg/day or 3% to 23% of the maternal weight-adjusted dose.89

Topiramate is associated with reproductive risk. Discuss contraception requirements with the patient. Women of childbearing age who are not planning a pregnancy should use effective contraception because of the fetal risks of oral clefts and being small for gestational age.10

Naltrexone HCl

Naltrexone is contraindicated in patients with hypersensitivity to naltrexone or any components of the commercially available product. Naltrexone is incorporated in 75:25 polylactide-co-glycolide (PLG) at a concentration of 337 mg of naltrexone per gram of microspheres. The diluent is composed of carboxymethylcellulose sodium salt, polysorbate 20, sodium chloride, and water for injection. Naltrexone should also not be used in patients with a known hypersensitivity to naloxone or nalmefene because these three drugs are all structurally similar.

The use of naltrexone in patients with hepatic disease should be carefully considered due to the hepatotoxic effects of naltrexone and the potential for decreased clearance of naltrexone. Naltrexone does not appear to be hepatotoxic at recommended doses. However, the margin between a safe dose and a hepatotoxic dose appears to be five-fold or less. There may be a higher risk of hepatocellular injury with single doses above 50 mg, and use of higher doses and extended dosing intervals should balance the possible risks against the probable benefits. There are reports of hepatitis and significant hepatic dysfunction in association with exposure to naltrexone oral tablets and parenteral naltrexone. In patients treated with naltrexone tablets or injection who presented with elevated transaminases, other potential causes were often identified, including pre-existing alcoholic liver disease, hepatitis B and/or C infection, and concomitant usage of other potentially hepatotoxic drugs. Opioid withdrawal does not typically manifest as clinically significant hepatic dysfunction, however, abruptly precipitated opioid withdrawal may lead to systemic sequelae including acute liver injury. Warn patients of the potential risk of hepatic injury and advise them to seek medical attention if they experience symptoms of acute hepatitis. Discontinue use of naltrexone if signs/symptoms of acute hepatitis occur.909192

Depression, suicide, attempted suicide and suicidal ideation have been reported in patients receiving naltrexone for the treatment of opioid dependence. No causal relationship has been demonstrated. In the literature, endogenous opioids have been theorized to contribute to a variety of conditions. Monitor alcohol and opioid dependent patients, including those taking naltrexone, for the development of depression or suicidal thinking. Inform families and caregivers of patients being treated with naltrexone to monitor patients for the emergence of symptoms of depression or suicidality, and to report such symptoms to the patient’s healthcare provider.92

Naltrexone is contraindicated in patients who are receiving opioid analgesics, partial opiate agonists (e.g., buprenorphine), those with current physiologic opioid dependence, and those in acute opioid withdrawal. Administration of naltrexone to these patients may precipitate an abrupt withdrawal severe enough to require hospitalization, and in some cases management in the intensive care unit. To prevent precipitation of withdrawal, patients should be opioid-free (including tramadol) for a minimum of 7—10 days prior to initiation of naltrexone. When transitioning from buprenorphine or methadone, patients may be vulnerable to precipitation of withdrawal symptoms for up to two weeks. In every case, be prepared to manage withdrawal symptomatically with non-opioid medications because there is no completely reliable method for determining whether a patient has had an adequate opioid-free period. Since the absence of an opiate drug in the urine is often not sufficient proof that a patient is opiate-free, a naloxone challenge should be done if there is any question of occult opioid dependence. A naloxone challenge test may be helpful; however, a few case reports have indicated that patients may experience precipitated withdrawal despite having a negative urine toxicology screen or tolerating a naloxone challenge test (usually in the setting of transitioning from buprenorphine treatment). Make patients aware of the risks associated with precipitated withdrawal and the need to give an accurate account of last opioid use. A positive reaction to the naloxone challenge predicts a similar response to naltrexone. Use of naltrexone is contraindicated in an individual who fails the naloxone challenge test or who has a positive urine test for opioids.The naloxone challenge can be repeated in 24 hours. Assess patients treated for alcohol dependence for underlying opioid dependence and for any recent use of opioids prior to initiation of treatment with naltrexone. Precipitated opioid withdrawal has been observed in alcohol-dependent patients in circumstances where the prescriber had been unaware of the additional use of opioids or co-dependence on opioids.909192

If a painful procedure such as surgery is planned, then naltrexone should be discontinued 72 hours prior to the procedure. Patients should be abstinent from opiate analgesia for at least 7 days before restarting naltrexone.

Naltrexone treated patients who require emergent opiate analgesia may require the administration of large opiate doses to provide adequate pain control, which may increase the risk of deep or prolonged respiratory depression. A rapidly acting opiate agonist is preferred for emergent analgesia to limit the duration of respiratory depression. Non-opiate receptor mediated actions (i.e., histamine-mediated) may occur with the use of opiates and should be expected (e.g., facial swelling, itching, generalized erythema or bronchoconstriction). Other alternatives for emergent analgesia in patients taking naltrexone include the use of regional analgesia, conscious sedation, non-opiate analgesics, or general anesthetics.

Attempts to overcome the antagonistic effects of naltrexone with large doses of an opioid agonist by patients maintained on naltrexone may result in potential for overdose or poisoning that may be fatal; cases of opioid overdose with fatal outcomes have been reported in patients after discontinuing treatment. Despite a prolonged pharmacologic effect, the blockade produced by naltrexone is surmountable. As the naltrexone blockade wanes and eventually dissipates, patients may respond to lower doses of opioids than previously used, potentially resulting in life-threatening opioid intoxication (respiratory compromise or arrest, circulatory collapse, etc.) if the patient uses previously tolerated doses of opioids. Patients are at particular risk at the end of the dosing interval, after missing a scheduled dose or after discontinuing naltrexone treatment. Patients should be informed of the serious consequences of attempting to overcome the opioid blockade and that they may be more sensitive to lower doses of opioid agonists once naltrexone therapy is stopped. Advise patients to inform family members and those closest to them of this increased sensitivity and risk of overdose.909192 Discuss the availability of naloxone with all patients and strongly consider prescribing it in patients treated for opioid use disorder (OUD) because of the potential for relapse. Inform patients and caregivers of their options for obtaining naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program).91

Naltrexone and its major active metabolite are excreted primarily by the kidney. Use caution in administering naltrexone to patients with renal impairment. Pharmacokinetic parameters of naltrexone given intramuscularly are essentially unchanged in patients with a creatinine clearance of 50—80 ml/minute. The disposition of naltrexone in patients with moderate to severe renal impairment has not been evaluated. Dosage adjustments may be necessary in patients with renal dysfunction.

The use of naltrexone for a substance abuse disorder during pregnancy should be considered only if supportive substance abuse prevention measures are ineffective. There are no adequate and well-controlled studies of naltrexone use in pregnant women to be informative of any drug-associated risks for birth defects or miscarriage, adverse maternal outcomes, or fetal outcomes. If treatment with naltrexone is selected, the potential benefit to the mother versus the potential risk to the fetus should be evaluated. There are known risks of opiate and alcohol addiction to the fetus. Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death. In addition, untreated opioid addiction often results in continued or relapsing illicit opioid use. Published studies have also demonstrated that alcohol is associated with fetal harm including growth restriction, facial abnormalities, central nervous system abnormalities, behavioral disorders, and impaired intellectual development. Daily oral administration of naltrexone to female rats and rabbits increased the incidence of early fetal loss at exposures 11 times or more and 2 times or more the human exposure, respectively. Daily oral administration of naltrexone to pregnant rats and rabbits during the period of organogenesis did not induce malformation at exposures up to 175 times and 14 times the human exposure, respectively. The effects of naltrexone during labor and delivery are unknown.9291

The developmental health benefits of breast-feeding should be considered along with the mother's clinical need for naltrexone and any potential adverse effects on the breastfed infant from naltrexone or the mother's underlying maternal condition. Naltrexone and its metabolite 6-beta-naltrexol are present in human breast milk. There are no data on the effects on the breastfed infant or the effects on milk production. Alcohol dependence and opiate addiction are known to have potential adverse drug risks to the nursing infant; alcohol and many opiates are excreted in breast milk.939291

The safe use of naltrexone in neonates, infants, children, and adolescents has not been established.91

Naltrexone may cause dizziness. Tell patients about the importance of not driving or operating machinery, or performing other potentially hazardous tasks, until they know how this medicine will affect them.9291

Naltrexone extended-release injectable suspension (e.g., Vivitrol) is for intramuscular administration only; intravenous administration and subcutaneous administration should be avoided. Serious injection site reactions have been reported. The risk of severe injection site reactions may be increased when the extended-release injectable suspension is deposited in subcutaneous or fatty tissue. Proper administration techniques and patient selection are imperative. Consider alternate treatment for patients whose body habitus (obesity) precludes a gluteal intramuscular injection with the provided needle. Also, variable depth of subcutaneous tissue exists between patients; the depth is dependent on the gender and weight of the patient. Women may be physiologically at higher risk for injection site reactions because of increased gluteal fat thickness vs. males, and in fact, postmarketing reports of injection site reactions have occurred primarily in females. Patients should be informed that any concerning injection site reactions should be brought to the attention of the healthcare provider. Patients exhibiting signs of abscess, cellulitis, tissue necrosis, or extensive swelling should be evaluated by a physician to determine if referral to a surgeon is warranted. As with any intramuscular injection, naltrexone extended-release injectable suspension should be administered with caution to patients with thrombocytopenia or any coagulation disorder (e.g., hemophilia or coagulopathy) due to the risk for hematoma or bleeding.91

Methylcobalamin

Who should not take this medication? Patients with early hereditary optic nerve atrophy, cyanocobalmin hypersensitivity, and those who are pregnant. Your health care provider needs to know if you have any of these conditions: kidney disease; Leber's disease; megaloblastic anemia; an unusual or allergic reaction to methylcobalamin, cobalt, other medicines, foods, dyes, or preservatives; pregnant or trying to get pregnant; breast-feeding.

Methylcobalamin is contraindicated in patients with methylcobalamin hypersensitivity or hypersensitivity to any of the medication components. Methylcobalamin is also contraindicated in patients with cobalt hypersensitivity because methylcobalamin contains cobalt. In the case of suspected cobalt hypersensitivity, an intradermal test dose should be administered because anaphylactic shock and death have followed parenteral administration of methylcobalamin.

Methylcobalamin should not be used in patients with early hereditary optic nerve atrophy (Leber's disease). Optic nerve atrophy can worsen in patients whose methylcobalamin levels are already elevated. Hydroxocobalamin is the preferred agent in this patient population (see separate monograph in Less Common Drugs).

Most formulations of methylcobalamin injection contain benzyl alcohol as a preservative. Benzyl alcohol may cause allergic reactions. Methylcobalamin injections should be used cautiously in those patients with benzyl alcohol hypersensitivity. Methylcobalamin, vitamin B12 preparations containing benzyl alcohol should be avoided in premature neonates because benzyl alcohol has been associated with 'gasping syndrome,' a potentially fatal condition characterized by metabolic acidosis and CNS, respiratory, circulatory, and renal dysfunction.

Vitamin B12 deficiency can suppress the symptoms of polycythemia vera. Treatment with methylcobalamin or hydroxocobalamin may unmask this condition.

Folic Acid, vitamin B9 is not a substitute for methylcobalamin, vitamin B12 deficiency, although it may improve vitamin B12 megaloblastic anemia. However, exclusive use of folic acid in treating vitamin B12 deficient megaloblastic anemia could result in progressive and irreversible neurologic damage. Before receiving folic acid or methylcobalamin, patients should be assessed for deficiency and appropriate therapy started concurrently. The intranasal formulations are not approved to treat acute B12 deficiency; all hematologic parameters should be normal before beginning the methylcobalamin intranasal formulations. Concurrent iron-deficiency anemia and folic acid deficiency may result in a blunted or impeded response to methylcobalamin therapy.

Certain conditions may blunt or impede therapeutic response to methylcobalamin therapy. These include serious infection, uremia or renal failure, drugs with bone marrow suppression properties (e.g., chloramphenicol), or concurrent undiagnosed folic acid or iron deficiency anemia. The mechanism appears to be interference with erythropoiesis. Patients with vitamin B12 deficiency and concurrent renal or hepatic disease may require increased doses or more frequent administration of methylcobalamin.

Clinical reports have not identified differences in responses between elderly and younger patients. Generally, dose selection for elderly patients should be done with caution. Elderly patients tend to have a greater frequency of decreased hepatic, renal, or cardiac function, and also have concomitant disease or receiving other drug therapy. Start with doses at the lower end of the dosing range.

Caffeine

Caffeine with sodium benzoate injection is not recommended for use in premature neonates because the benzoate may displace bilirubin and induce kernicterus. Elevated serum concentrations of benzoate, similar to benzyl alcohol, have also been associated with neurological disturbances, hypotension, gasping respiration, and metabolic acidosis (i.e., 'gasping syndrome') in neonates.94 Clinicians should use Cafcit, which does not contain sodium benzoate, or use an extemporaneously compounded caffeine citrate injection in newborns and premature neonates. The safety and efficacy of the prescription use of caffeine in neonates and infants for longer than 12 days, prophylaxis of sudden infant death syndrome (SIDS), or for use prior to extubation in mechanically ventilated infants has not been established.53

The OTC use of caffeine products is not recommended in children under the age of 12 years.

Caffeine is a central nervous system stimulant. Caffeine should be used cautiously in patients with anxiety disorders and/or panic disorder because it can aggravate these conditions. Patients suffering from insomnia should not consume caffeine, nor should caffeine be consumed prior to retiring because it can cause insomnia. In overdoses, caffeine has been associated with seizures and it should be prescribed cautiously to those patients with a seizure disorder.

Caffeine should be used cautiously in those patients, including neonates, with cardiac disease. Caffeine can stimulate the force of contraction and can increase heart rate. It may increase left ventricular output and stroke volume. Patients who have angina or a history of cardiac arrhythmias should not receive or should minimize their intake of caffeine. Caffeine should not be taken in the first few days—weeks after a myocardial infarction. Patients with hypertension should minimize their intake of caffeine.

Caffeine should be used cautiously in those with hepatic disease or hepatic impairment. Caffeine clearance may be delayed, leading to toxicity. Renal impairment or renal failure may also delay caffeine clearance. It should be noted that caffeine elimination is more dependent on renal clearance in premature neonates and term neonates than in older infants or adults, due to the underdeveloped hepatic metabolism and renal elimination of drugs in general. Thus monitoring of serum caffeine concentrations is recommended in neonates or premature neonates, especially those with renal or hepatic impairment.

Although the effects are mild, caffeine can either raise or decrease blood sugar; use with caution in patients with diabetes mellitus. In clinical studies reported in the literature, cases of hypoglycemia and hyperglycemia have been observed in neonates receiving caffeine citrate. Therefore, blood glucose may need to be periodically monitored in infants receiving caffeine citrate.53

Patients with thyroid disease, especially hyperthyroidism, should not receive or should minimize their intake of caffeine. The stimulatory effects of caffeine can be augmented in hyperthyroidism.

In neonates, there are reports in the literature suggesting a possible association between the use of methylxanthines like caffeine and the development of necrotizing enterocolitis. In a clinical trial (n = 85 neonates) evaluating the use of caffeine citrate in apnea of prematurity, necrotizing enterocolitis was reported in 6 patients, 5 of whom were administered caffeine. Three of the infants died. In a much larger clinical trial (n = 2,000 neonates) evaluating the use of caffeine citrate in apnea of prematurity, necrotizing enterocolitis was not more common in caffeine treated patients compared to placebo. Preterm neonates treated with caffeine should be monitored for the development of gastric side-effects (i.e., abdominal distension, vomiting, bloody stools, and lethargy).5395 Caffeine can stimulate gastric secretions and may aggravate gastroesophageal reflux disease (GERD). Clinical trial data are conflicting regarding the limitation of caffeine as an effective strategy to control GERD symptoms; however, recommended lifestyle modifications for patients with GERD often include moderation of caffeine intake.96

Caffeine citrate is used for neonatal apnea so concerns for teratogenicity are not relevant when administered to infants, however, when 50 mg/kg of sustained-release pellets were administered to pregnant mice during the period of organogenesis, a low incidence of cleft palate and exencephaly have been noted in the fetuses.53 Caffeine easily crosses the placenta; fetal blood and tissue concentrations approximate maternal concentrations. There are no large, well-controlled studies of caffeine administration in pregnant women; it is generally recommended that the intake of caffeine-containing beverages, like coffee, teas, and sodas, be limited in pregnancy (usually no more than 1 to 2 caffeine-containing beverages/day) or avoided if possible. Caffeine-containing medications should likewise, be limited to use only when absolutely necessary. Low to moderate caffeine intake does not appear to increase the risk of congenital malformation, spontaneous abortion, pre-term birth or low birth weight. The association between high daily intake (more than 500 mg/day) of caffeine and increased rates of low birth weight, spontaneous abortion, difficulty in getting pregnant or infertility is still controversial, as some studies have not controlled for concomitant cigarette smoking.97 There are no adequate and well-controlled studies of caffeine administration in pregnant women. Neonatal arrhythmias (e.g., tachycardia, premature atrial contractions) and tachypnea have been reported when caffeine was consumed during pregnancy in amounts > 500 mg/day; caffeine withdrawal after birth may account for these symptoms.98

Although the American Academy of Pediatrics has considered the use of mild to moderate use of caffeinated beverages to be compatible with lactation, mothers who are breast-feeding should limit their intake of caffeinated beverages if possible.93 Caffeine-containing drug-products should be used cautiously during lactation due to their high caffeine contents. Mothers who are breast-feeding infants who have been prescribed caffeine for apnea should generally avoid additional caffeine use.53 The CYPP450 hepatic metabolism of caffeine is inhibited in infants who are breastfed; formula feeding does not appear to affect the pharmacokinetics of caffeine in infants.99 Peak caffeine milk levels usually occur within 1 hour after the maternal ingestion of a caffeinated beverage; with milk: plasma ratios of 0.5 to 0.7 reported.100101 Although only small amounts are secreted in breast milk, caffeine can accumulate in the neonate if maternal ingestion is moderate to high. Higher caffeine intake (more than 500 mg/day) by a nursing mother may cause irritability or poor sleeping patterns in the infant who is breast-feeding.102 Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition.

Tobacco smoking (cigarettes) has been shown to increase the clearance of caffeine. Passive smoke exposure may also cause an increase in caffeine clearance. This may help to explain why tobacco smokers often have concomitantly high caffeine intakes. Tobacco smoke contains hydrocarbons that induce hepatic CYP450 microsomal enzymes. Because the effect on hepatic microsomal enzymes is not related to the nicotine component of tobacco, sudden smoking cessation may result in a reduced clearance of caffeine, despite the initiation of nicotine replacement. Caffeine dosage may need to be reduced at the cessation of smoking.

Caffeine can usually be ingested in normal amounts found in food or beverages (e.g., coffee) in the elderly; however, geriatric patients should be aware of the effects of caffeine on sleep and other physiologic functions, such as urination. Excessive caffeine intake, such as intake of non-prescription caffeine dietary supplements/medicines, should generally be avoided, as excessive use can cause tremor, insomnia, palpitations, and gastrointestinal complaints. Because caffeine is an ingredient in some non-prescription products, patients should be advised to read labels carefully or check with their prescriber or pharmacist if they are unsure if the medication contains caffeine.103

Caffeine intake should be limited along with MAOI therapy.

Oxytocin

Oxytocin is indicated during pregnancy to induce labor; it precipitates uterine contractions and abortion.39

Endogenous oxytocin is involved in the process of lactation and therefore, oxytocin has been used in mothers having difficulty with engorgement and breast-feeding. Because several small studies have failed to show a beneficial effect, oxytocin is not used for this indication. Oxytocin is excreted in the breast-milk, but is not expected to have adverse effects in the infant.104

Parenteral oxytocin should be used only by qualified professional personnel in a setting where intensive care and surgical facilities are immediately available. Furthermore, according to the manufacturer, oxytocin should only be used when induction of labor is necessary for medical reasons. It should not be used for elective induction of labor as available data are insufficient to evaluate the risk-benefit ratio in this indication. During oxytocin administration, uterine contractions, fetal and maternal heart rate, maternal blood pressure, and, if possible, intrauterine pressure should be continuously monitored to avoid complications. If uterine hyperactivity occurs, oxytocin administration should be immediately discontinued; oxytocin-induced stimulation of the uterine contractions usually decreases soon after discontinuance of the drug. The induction or continuance of labor with oxytocin should be avoided when the following conditions or situations are present: evidence of fetal distress, fetal prematurity, abnormal fetal position (including unengaged head), placenta previa, uterine prolapse, vasa previa, cephalopelvic disproportion, cervical cancer, grand multiparity, previous surgery of the uterus or cervix (including 2 or more cesarean deliveries), active genital herpes infection, or in any condition presenting as an obstetric emergency requiring surgical intervention. Use of oxytocin in any of these settings can aggravate the condition or cause unnecessary fetal or maternal distress.

Oxytocin may possess antidiuretic effects, and prolonged use can increase the possibility of an antidiuretic effect. Prolonged use of oxytocin and administration in large volumes of low-sodium infusion fluids are not recommended, particularly in patients with eclampsia or who have unresponsive uterine atony. Antidiuretic effects have the potential to lead to water intoxication and convulsive episodes due to hypertension.

Metformin

Your health care provider needs to know if you have any of these conditions: anemia; frequently drink alcohol-containing beverages; become easily dehydrated; heart attack; heart failure that is treated with medications; kidney disease; liver disease; polycystic ovary syndrome; serious infection or injury; vomiting; an unusual or allergic reaction to metformin, other medicines, foods, dyes, or preservatives; pregnant or trying to get pregnant; breast-feeding.

Do not use metformin in patients who have a known metformin hypersensitivity.

Metformin should not be used for Type 1 diabetes mellitus. Metformin is not an effective treatment of and use is contraindicated in diabetic ketoacidosis (DKA). DKA, with or without coma; DKA should be treated with insulin.

Metformin is contraindicated in patients with metabolic acidosis. It should not be used in patients with lactic acidosis. Lactic acidosis should be suspected in any diabetic patient withmetabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia). Lactic acidosis is a rare but serious complication that can occur due to metformin accumulation; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia or significant renal dysfunction. Lactic acidosis is characterized by elevated blood lactate levels, acidemia, electrolyte disturbances, an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels > 5 mcg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin is very low; in more than 20,000 patient-years exposure to metformin in clinical trials, there have been no reports of lactic acidosis and approximately 0.03 cases/1000 patient-years have been estimated with post-marketing surveillance. A nested case-control study of 50,048 patients with type 2 diabetes mellitus demonstrated that during concurrent use of oral diabetes drugs, there were 6 identified cases of lactic acidosis. The crude incidence rate was 3.3 cases per 100,000 person-years in patients treated with metformin; it should be noted that all of the subjects had relevant comorbidities known to be risk factors for lactic acidosis.105 The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradycardia with more marked acidemia. The patient and the prescriber must be aware of such symptoms and the patient should be instructed to notify the physician immediately if they occur. Metformin should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin levels may be useful.

Gastrointestinal side effects are common during metformin initiation. However, once a patient is stabilized on any dose of metformin, GI symptoms are unlikely to be drug related. Later occurrence of GI symptoms may be due to a change in clinical status and may increase the risk of lactic acidosis or other serious disease. Patients stable on metformin therapy who complain of an increase in GI symptoms should undergo laboratory investigation to determine the etiology of the GI symptoms. These include, but are not limited to, diarrhea and nausea/vomiting. Furthermore, withholding metformin therapy until the cause of the GI symptoms is known may be necessary. Finally, diarrhea and nausea/vomiting may alter gastric emptying and caloric intake, which could all affect blood glucose control, especially increasing the risk of low blood glucose. Patients should be advised to contact their prescriber if an increase in gastrointestinal symptoms occurs while taking metformin; patients should also be advised to monitor their blood glucose concentrations more frequently.

Before initiation of metformin and at least annually thereafter, renal function should be assessed. Metformin is substantially eliminated by the kidney and the risk of lactic acidosis increases with the degree of intrinsic renal disease or impairment. According to the manufacturer, metformin is contraindicated for use in patients with renal failure or renal impairment (defined as serum creatinine >= 1.4 mg/dl for females and >= 1.5 mg/dl for males by the manufacturer, although pharmacokinetic studies indicate significant metformin accumulation with CrCl < 60 ml/min) (see Pharmacokinetics). However, the American Diabetes Association and others suggest that metformin can be used in patients with lower creatinine clearances with close monitoring (see Dosage Adjustment Guidelines).106107 Certain medications used concomitantly with metformin may also increase the risk of lactic acidosis (see Drug Interactions).

According to the manufacturer, metformin should be used with caution in patients with congestive heart failure requiring pharmacologic treatment. However, a systematic review evaluating antidiabetic agents and outcomes in patients with heart failure and diabetes concluded that metformin is not associated with any measurable harm in patients with heart failure; in this analysis, metformin was associated with reduced mortality.108 It should be noted that in acute congestive heart failure characterized by acute hypoxia, lactic acidosis has occurred in patients taking metformin. To reduce the risk of lactic acidosis, metformin should be promptly withheld in the presence of any condition associated with hypoxemia. Acute hypoxia and acute cardiac disease (e.g., acute heart failure, cardiogenic shock, or acute myocardial infarction) and other conditions characterized by acute hypoxia have been associated with the development of lactic acidosis and may cause prerenal azotemia. If such events occur, discontinue metformin.

Use metformin with caution in geriatric patients; less than 3% of patients in clinical trials were >= 75 years of age. Metformin is substantially excreted by the kidney and the risk of adverse reactions (including lactic acidosis) is greater in patients with reduced renal function. Because aging is associated with renal function decline, care should be taken with dose selection and titration. Monitor renal function regularly. Unless renal function is normal, do not use metformin in those patients >= 80 years of age. Generally, elderly or debilitated patients should not be titrated up to maximum dosages (see Dosage).

Since the liver is important for clearing accumulated lactic acid, metformin should generally be avoided in patients with hepatic disease as the risk of lactic acidosis may be increased. Hepatic disease causes altered gluconeogenesis, which may affect glycemic control. Alcohol is known to potentiate the effect of metformin on lactate metabolism and patients should be warned against ethanol intoxication (acute or chronic) while on metformin. This drug is not recommended for those with alcoholism.

Parenteral radiographic contrast administration is contraindicated in patients taking metformin; it may cause acute renal failure and has been associated with lactic acidosis. Patients undergoing studies involving iodinated radiographic contrast media should have metformin temporarily withheld just prior to and for 48 hours after the completion of the procedure. Reinstitute therapy only after normal renal function is confirmed.

To reduce the risk of lactic acidosis, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Metformin therapy should be temporarily suspended for any surgery, except for minor procedures where intake of fluids and food is not restricted. Do not restart this drug until oral intake is resumed and renal function has been evaluated as normal. Temporary use of insulin in place of oral antidiabetic agents may be necessary during periods of physiologic stress (e.g., burns, systemic infection, trauma, surgery, or fever). Any change in clinical status, including diarrhea or vomiting, may also increase the risk of lactic acidosis and may require laboratory evaluation in patients on metformin and may require the drug be withheld.

Delayed stomach emptying may alter blood glucose control; monitor patients with diarrhea, gastroparesis, GI obstruction, ileus, or vomiting carefully. Conditions that predispose patients to developing hypoglycemia or hyperglycemia may alter antidiabetic agent efficacy. Conditions associated with hypoglycemia include debilitated physical condition, drug interactions, malnutrition, uncontrolled adrenal insufficiency, pituitary insufficiency or hypothyroidism. Hyperglycemia related conditions include drug interactions, female hormonal changes, high fever, severe psychological stress, and uncontrolled hypercortisolism or hyperthyroidism. More frequent blood glucose monitoring may be necessary in patients with these conditions while receiving metformin.

The safety and effectiveness of metformin have not been established in neonates, infants and children < 10 years; in general, there are limited experiences with metformin use in pediatric patients with Type 2 diabetes mellitus. The oral solution and regular-release tablet formulations of metformin have been approved for use in children >= 10 years and experience with children 10-16 years of age has demonstrated similar glycemic control to adults. However, the safety and efficacy of the extended-release tablet formulations have not been established in children under the age of 18 years.

Metformin may result in suboptimal vitamin B12 absorption, possibly due to interference with the B12-intrinsic factor complex. The interaction very rarely results in a pernicious anemia that appears reversible with discontinuation of metformin or with cyanocobalamin supplementation. Certain individuals may be predisposed to this type of anemia; a nested case-control study of 465 patients taking metformin (155 with vitamin B12 deficiency and 310 without) demonstrated that dose and duration of metformin use may be associated with an increased odds of vitamin B12 deficiency. Each 1 gram/day increment in dose significantly increased the odds of vitamin B12 deficiency (OR 2.88, 95% CI 2.15—3.87) as did taking metformin for >= 3 years (OR 2.39, 95% CI 1.46—3.91).109 Regular measurement of hematologic parameters is recommended in all patients on chronic metformin treatment.

Premenopausal anovulatory females with insulin resistance (i.e., those with polycystic ovary syndrome (PCOS)) may resume ovulation as a result of metformin therapy; patients may be at risk of conception if adequate contraception is not used in those not desiring to become pregnant. In some cases, metformin is used as an adjunct in PCOS patients to regulate menstrual cycles or to enhance fertility. Metformin is classified in FDA pregnancy risk category B; however, metformin is not recommended for routine use during pregnancy.62 Based on the results of a small study, it appears that metformin does pass through the placenta and the fetus is exposed to therapeutic concentrations of metformin. In 13 patients taking metformin throughout pregnancy, metformin concentrations were higher in the infant umbilical vein and umbilical artery than the maternal blood sample; the authors postulated that metformin is excreted into the amniotic fluid by the fetus and then swallowed allowing for reabsorption. Adverse effects on the pH of umbilical artery blood were not found.110 A study of 109 women with PCOS who were treated with metformin 1.5—2.55 g/day at the time of conception and continued treatment throughout pregnancy found no difference in the development of preeclampsia and a lower rate of gestational diabetes when compared to a control group of pregnant women without PCOS. Among the 126 infants born to the women with PCOS, two birth defects occurred: one sacrococcygeal teratoma and one tethered spinal cord. Follow up to 18 months of age found no differences in height or weight in infants exposed to metformin compared to controls and no abnormalities in motor or social development.111 Other epidemiologic data suggest no increase in the rates of expected birth defects in women taking metformin who become pregnant. Metformin has been studied during the second and third trimesters of pregnancy. The neonatal mortality rate appeared lower in patients receiving metformin than in mildly diabetic controls, but slightly higher incidences of polycythemia and necrotizing enterocolitis were noted in the metformin group. The most frequently encountered infant problems were jaundice, polycythemia, and hypoglycemia.112 The American College of Obstetrician and Gynecologists recommends insulin as the therapy of choice to maintain blood glucose as close to normal as possible during pregnancy in patients with type I or II diabetes mellitus, and, if diet therapy alone is not successful, for those patients with gestational diabetes.113114 More recent studies comparing metformin to insulin in the treatment of gestational diabetes found no significant differences in glycemic control or pregnancy outcomes.115 One study comparing metformin (n = 100) to insulin (n = 100) for the treatment of gestational diabetes found significantly lower weight gain during pregnancy and improved neonatal morbidity with respect to prematurity, neonatal jaundice, and admission to the neonatal unit in the metformin group.116

Animal data show that metformin is excreted into breast milk and reaches levels similar to those in plasma. Small studies indicate that metformin is excreted in human breast milk. Infant hypoglycemia or other side effects are a possibility; however, adverse effects on infant plasma glucose have not been reported in human studies.117118119 Furthermore, the use of metformin 2550 mg/day by mothers breast-feeding their infants for 6 months does not affect growth, motor, or social development; the effects beyond 6 months are not known.120 In all of these studies, the estimated weight-adjusted infant exposure to metformin ranged from 0.11—1.08% of the mother's dose. While the manufacturers of metformin recommend that a decision should be made to discontinue breast-feeding or discontinue the drug, the results of these studies indicate that maternal ingestion of metformin during breast-feeding is probably safe to the infant. However, a risk and benefit analysis should be made for each mother and her infant; if patients elect to continue metformin while breast-feeding, the mother should be aware of the potential risks to the infant. If metformin is discontinued and blood glucose is not controlled on diet and exercise alone, insulin therapy should be considered. Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breastmilk is not expecte;121 therefore, this agent may represent a reasonable alternative for some patients. In addition, the American Academy of Pediatrics (AAP) regards tolbutamide as usually compatible with breast-feeding; other sulfonylureas have not been evaluated by the AAP.122 If any oral hypoglycemics are used during breast feeding, the nursing infant should be monitored for signs of hypoglycemia, such as increased fussiness or somnolence.123

This list may not include all possible contraindications.

Pregnancy

Bupropion HCl

Use bupropion with caution during pregnancy; use during pregnancy only if the potential benefit justifies the potential risk to the fetus. When treating a pregnant woman, the physician should carefully consider the potential risks and benefits of treatment. If clinically feasible, tapering of the medication prior to labor and obstetric delivery may be considered. Pregnant smokers should be encouraged to attempt educational and behavioral interventions before pharmacologic approaches are used; nicotine has been used in pregnancy to help patients quit smoking. Smoking cessation programs in pregnancy reduce the proportion of women who continue to smoke, and reduce the risk for low birthweight and preterm birth. Data from epidemiological studies including pregnant women exposed to bupropion in the first trimester indicate no increased risk of congenital malformations. In addition, no increased risk of cardiovascular malformations during first trimester exposure to bupropion has been observed. The rate of cardiovascular malformations following 675 exposures to bupropion in the first trimester was 1.3% versus a background rate of about 1%. Data collected from the United Healthcare database and the National Birth Defects Prevention Study (6,853 infants with cardiovascular malformations and 5,763 with non-cardiovascular malformations) did not show an overall increased risk from cardiovascular malformations after bupropion exposure during the first trimester. Study findings on bupropion exposure during the first trimester and risk for left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions regarding a possible association. The United Healthcare database lacked sufficient power to evaluate this association; the NBDPS found increased risk for LVOTO, and the Slone Epidemiology case control study did not find increased risk for LVOTO. Study findings on bupropion exposure during the first trimester and risk for ventricular septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible association. The Slone Epidemiology Study found an increased risk for VSD following first trimester maternal bupropion exposure but did not find increased risk for any other cardiovascular malformations studied (including LVOTO). The NBDPS and United Healthcare database study did not find an association between first trimester maternal bupropion exposure and VSD. For the findings of LVOTO and VSD, the studies were limited by the small number of exposed cases, inconsistent findings among studies, and the potential for chance findings from multiple comparisons in case control studies. No clear evidence of teratogenic activity was found in reproductive developmental studies conducted in rats and rabbits. However, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at doses approximately equal to or more than the maximum recommended human dose (MRHD) and decreased fetal weights were seen at doses twice the MRHD and greater. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to bupropion; information about the registry can be obtained at womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants by calling 1-866-961-2388 or 1-844-405-6185.6444424169464370

Phentermine HCl

Phentermine products are now classified as FDA pregnancy risk category X, as are many anorexiants used for weight loss, and are contraindicated during pregnancy.7878 Safe use of phentermine during pregnancy has not been established; there is no known indication for use of phentermine during pregnancy. Phentermine should not be taken by pregnant women or by women who may become pregnant unless, in the opinion of the physician, the potential benefits outweigh the possible hazards.78

Topiramate

Topiramate can cause fetal harm when administered to a pregnant woman. Consider the benefits and risks of topiramate in women of childbearing potential, particularly when it is being considered for conditions not usually associated with permanent injury or death. Counsel women of childbearing potential regarding the potential risk to the fetus from topiramate exposure, and consider alternative therapeutic options in women who are planning a pregnancy. Data from pregnancy registries indicate infants exposed to topiramate during pregnancy have an increased risk for cleft lip and/or cleft palate and for being small for gestational age (SGA), defined as a birth weight below the tenth percentile. SGA has been seen at all doses and appears to be dose-dependent. SGA occurs more frequently in infants of women who received higher topiramate doses or continued topiramate use until later in pregnancy (i.e., third trimester). According to registry data, the prevalence of SGA was 18% to 25% in topiramate-exposed infants compared to 7% in infants exposed to a reference antiepileptic agent (AED) and 5% to 9% in those without antiepileptic drug (AED) exposure.10 The prevalence of oral clefts was 1.2% compared to 0.39% to 0.46% in infants exposed to another AED. The relative risk of oral clefts in topiramate-exposed pregnancies was 9.6 (95% CI 4 to 23) compared to untreated women.910 Oral clefts develop in the first trimester before many women know that they are pregnant.88 Pregnancy registry data also suggest a possible association between the use of topiramate during pregnancy and congenital malformations such as craniofacial defects, hypospadias, and anomalies of various body systems. Registry data and findings from other studies suggest that combination therapy with AEDs may increase the risk of teratogenic effects compared to monotherapy with an AED. Topiramate can cause metabolic acidosis which, when occurring during pregnancy, has been associated with decreased fetal growth, decreased fetal oxygenation, fetal death, and may impact the ability of the fetus to tolerate labor. Monitor women taking topiramate during pregnancy for metabolic acidosis and treat as in the nonpregnant state. Monitor newborns of mothers treated with topiramate for metabolic acidosis after birth. Limited data indicate topiramate may be associated with pre-term labor and premature delivery.910 There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to topiramate; information about the registry can be obtained at http://www.aedpregnancyregistry.org or by calling 1-888-233-2334.10

Naltrexone HCl

The use of naltrexone for a substance abuse disorder during pregnancy should be considered only if supportive substance abuse prevention measures are ineffective. There are no adequate and well-controlled studies of naltrexone use in pregnant women to be informative of any drug-associated risks for birth defects or miscarriage, adverse maternal outcomes, or fetal outcomes. If treatment with naltrexone is selected, the potential benefit to the mother versus the potential risk to the fetus should be evaluated. There are known risks of opiate and alcohol addiction to the fetus. Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as low birth weight, preterm birth, and fetal death. In addition, untreated opioid addiction often results in continued or relapsing illicit opioid use. Published studies have also demonstrated that alcohol is associated with fetal harm including growth restriction, facial abnormalities, central nervous system abnormalities, behavioral disorders, and impaired intellectual development. Daily oral administration of naltrexone to female rats and rabbits increased the incidence of early fetal loss at exposures 11 times or more and 2 times or more the human exposure, respectively. Daily oral administration of naltrexone to pregnant rats and rabbits during the period of organogenesis did not induce malformation at exposures up to 175 times and 14 times the human exposure, respectively. The effects of naltrexone during labor and delivery are unknown.9291

Methylcobalamin

Parenteral methylcobalamin is classified as pregnancy category C. Adequate studies in humans have not been conducted; however, no maternal or fetal complications have been associated with doses that are recommended during pregnancy, and appropriate treatment should not be withheld from pregnant women with vitamin B12 responsive anemias. Conversely, pernicious anemia resulting from vitamin B12 deficiency may cause infertility or poor pregnancy outcomes. Vitamin B12 deficiency has occurred in breast-fed infants of vegetarian mothers whose diets contain no animal products (e.g., eggs, dairy), even though the mothers had no symptoms of deficiency at the time. Maternal requirements for vitamin B12 increase during pregnancy. The usual daily recommended amounts of methylcobalamin, vitamin B12 either through dietary intake or supplementation should be taken during pregnancy (see Dosage).

Caffeine

Caffeine citrate is used for neonatal apnea so concerns for teratogenicity are not relevant when administered to infants, however, when 50 mg/kg of sustained-release pellets were administered to pregnant mice during the period of organogenesis, a low incidence of cleft palate and exencephaly have been noted in the fetuses.53 Caffeine easily crosses the placenta; fetal blood and tissue concentrations approximate maternal concentrations. There are no large, well-controlled studies of caffeine administration in pregnant women; it is generally recommended that the intake of caffeine-containing beverages, like coffee, teas, and sodas, be limited in pregnancy (usually no more than 1 to 2 caffeine-containing beverages/day) or avoided if possible. Caffeine-containing medications should likewise, be limited to use only when absolutely necessary. Low to moderate caffeine intake does not appear to increase the risk of congenital malformation, spontaneous abortion, pre-term birth or low birth weight. The association between high daily intake (more than 500 mg/day) of caffeine and increased rates of low birth weight, spontaneous abortion, difficulty in getting pregnant or infertility is still controversial, as some studies have not controlled for concomitant cigarette smoking.97 There are no adequate and well-controlled studies of caffeine administration in pregnant women. Neonatal arrhythmias (e.g., tachycardia, premature atrial contractions) and tachypnea have been reported when caffeine was consumed during pregnancy in amounts > 500 mg/day; caffeine withdrawal after birth may account for these symptoms.98Caffeine citrate is used for neonatal apnea so concerns for teratogenicity are not relevant when administered to infants, however, when 50 mg/kg of sustained-release pellets were administered to pregnant mice during the period of organogenesis, a low incidence of cleft palate and exencephaly have been noted in the fetuses.53 Caffeine easily crosses the placenta; fetal blood and tissue concentrations approximate maternal concentrations. There are no large, well-controlled studies of caffeine administration in pregnant women; it is generally recommended that the intake of caffeine-containing beverages, like coffee, teas, and sodas, be limited in pregnancy (usually no more than 1 to 2 caffeine-containing beverages/day) or avoided if possible. Caffeine-containing medications should likewise, be limited to use only when absolutely necessary. Low to moderate caffeine intake does not appear to increase the risk of congenital malformation, spontaneous abortion, pre-term birth or low birth weight. The association between high daily intake (more than 500 mg/day) of caffeine and increased rates of low birth weight, spontaneous abortion, difficulty in getting pregnant or infertility is still controversial, as some studies have not controlled for concomitant cigarette smoking.97 There are no adequate and well-controlled studies of caffeine administration in pregnant women. Neonatal arrhythmias (e.g., tachycardia, premature atrial contractions) and tachypnea have been reported when caffeine was consumed during pregnancy in amounts > 500 mg/day; caffeine withdrawal after birth may account for these symptoms.98

Oxytocin

Oxytocin is indicated during pregnancy to induce labor; it precipitates uterine contractions and abortion.39

Metformin

Premenopausal anovulatory females with insulin resistance (i.e., those with polycystic ovary syndrome (PCOS)) may resume ovulation as a result of metformin therapy; patients may be at risk of conception if adequate contraception is not used in those not desiring to become pregnant. In some cases, metformin is used as an adjunct in PCOS patients to regulate menstrual cycles or to enhance fertility. Metformin is classified in FDA pregnancy risk category B; however, metformin is not recommended for routine use during pregnancy.62 Based on the results of a small study, it appears that metformin does pass through the placenta and the fetus is exposed to therapeutic concentrations of metformin. In 13 patients taking metformin throughout pregnancy, metformin concentrations were higher in the infant umbilical vein and umbilical artery than the maternal blood sample; the authors postulated that metformin is excreted into the amniotic fluid by the fetus and then swallowed allowing for reabsorption. Adverse effects on the pH of umbilical artery blood were not found.110 A study of 109 women with PCOS who were treated with metformin 1.5—2.55 g/day at the time of conception and continued treatment throughout pregnancy found no difference in the development of preeclampsia and a lower rate of gestational diabetes when compared to a control group of pregnant women without PCOS. Among the 126 infants born to the women with PCOS, two birth defects occurred: one sacrococcygeal teratoma and one tethered spinal cord. Follow up to 18 months of age found no differences in height or weight in infants exposed to metformin compared to controls and no abnormalities in motor or social development.111 Other epidemiologic data suggest no increase in the rates of expected birth defects in women taking metformin who become pregnant. Metformin has been studied during the second and third trimesters of pregnancy. The neonatal mortality rate appeared lower in patients receiving metformin than in mildly diabetic controls, but slightly higher incidences of polycythemia and necrotizing enterocolitis were noted in the metformin group. The most frequently encountered infant problems were jaundice, polycythemia, and hypoglycemia.112 The American College of Obstetrician and Gynecologists recommends insulin as the therapy of choice to maintain blood glucose as close to normal as possible during pregnancy in patients with type I or II diabetes mellitus, and, if diet therapy alone is not successful, for those patients with gestational diabetes.113114 More recent studies comparing metformin to insulin in the treatment of gestational diabetes found no significant differences in glycemic control or pregnancy outcomes.115 One study comparing metformin (n = 100) to insulin (n = 100) for the treatment of gestational diabetes found significantly lower weight gain during pregnancy and improved neonatal morbidity with respect to prematurity, neonatal jaundice, and admission to the neonatal unit in the metformin group.116

Breast-feeding

Bupropion HCl

Bupropion and its metabolites are excreted into human breast milk, and caution should be exercised when bupropion is administered to a breast-feeding woman.644442414643 Peak breast milk concentrations of bupropion and its metabolites are present within 2 to 4 hours after an oral dose. In one lactation study (n = 10), the average daily infant exposure to bupropion and its active metabolites (assuming 150 mL/kg daily consumption) was 2% of the maternal weight-adjusted dose.71 One case report describes a possible seizure in a breast-fed infant during maternal use of extended-release bupropion.72 In two other cases, no infant-related adverse events were noted during breast-feeding.73 Due to individual variability in response to antidepressants, it may be prudent to continue the existing regimen if ongoing treatment for depression is deemed necessary during breast-feeding. Alternatives may be considered in some cases. Because a pooled analysis found that maternal use of sertraline, along with nortriptyline and paroxetine, usually produced undetectable or low drug concentrations in infant serum, these agents may be the preferred antidepressants when initiating antidepressant therapy in a breast-feeding mother.74 For smoking cessation treatment, nicotine replacement products may be considered as an alternate therapy to bupropion if non-pharmacologic interventions are inadequate. The decision of whether to use nicotine replacement therapy in a woman who is breast-feeding should be evaluated in comparison to the risks associated with exposure of the infant to nicotine and other tobacco contaminants in the breast milk as well as those of passive exposure to tobacco smoke. Breast-feeding and eliminating an infant's exposure to tobacco smoke are considered important protective factors for serious pediatric health risks.75

Phentermine HCl

Phentermine is contraindicated during breast-feeding.78 It is not known whether phentermine and its metabolites are excreted in breast milk; however, because of the potential for serious adverse effects in the nursing infants, breast-feeding while taking phentermine is not recommended.8079

Topiramate

Topiramate is excreted in human breast milk. Diarrhea and somnolence have been observed in breast-fed infants whose mothers received topiramate. The effects of topiramate on milk production are unknown. Consider the developmental and health benefits from breast-feeding along with the mother's clinical need for topiramate and any potential adverse effects on the breast-fed infant from topiramate or the underlying maternal condition.10 Data from 5 breast-feeding infants has shown topiramate plasma concentrations of 10% to 20% of the maternal plasma concentration.9 Based on breast milk concentrations from 3 women taking 150 to 200 mg topiramate daily, it was estimated that a breast-fed infant (assuming a milk intake of 150 mL/kg/day) would receive approximately 0.1 to 0.7 mg/kg/day or 3% to 23% of the maternal weight-adjusted dose.89

Naltrexone HCl

The developmental health benefits of breast-feeding should be considered along with the mother's clinical need for naltrexone and any potential adverse effects on the breastfed infant from naltrexone or the mother's underlying maternal condition. Naltrexone and its metabolite 6-beta-naltrexol are present in human breast milk. There are no data on the effects on the breastfed infant or the effects on milk production. Alcohol dependence and opiate addiction are known to have potential adverse drug risks to the nursing infant; alcohol and many opiates are excreted in breast milk.939291

Methylcobalamin

Methylcobalamin is distributed into breast milk in amounts similar to those in maternal plasma, and distribution in breast milk allows for adequate intakes of methylcobalamin by breast-feeding infants. Adequate maternal intake is important for both the mother and infant during nursing, and maternal requirements for vitamin B12 increase during lactation. According to the manufacturer, the usual daily recommended amounts of methylcobalamin, vitamin B12 for lactating women should be taken maternally during breast-feeding (see Dosage). The American Academy of Pediatrics considers vitamin B12 to be compatible with breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Caffeine

Although the American Academy of Pediatrics has considered the use of mild to moderate use of caffeinated beverages to be compatible with lactation, mothers who are breast-feeding should limit their intake of caffeinated beverages if possible.93 Caffeine-containing drug-products should be used cautiously during lactation due to their high caffeine contents. Mothers who are breast-feeding infants who have been prescribed caffeine for apnea should generally avoid additional caffeine use.53 The CYPP450 hepatic metabolism of caffeine is inhibited in infants who are breastfed; formula feeding does not appear to affect the pharmacokinetics of caffeine in infants.99 Peak caffeine milk levels usually occur within 1 hour after the maternal ingestion of a caffeinated beverage; with milk: plasma ratios of 0.5 to 0.7 reported.100101 Although only small amounts are secreted in breast milk, caffeine can accumulate in the neonate if maternal ingestion is moderate to high. Higher caffeine intake (more than 500 mg/day) by a nursing mother may cause irritability or poor sleeping patterns in the infant who is breast-feeding.102 Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition.

Oxytocin

Endogenous oxytocin is involved in the process of lactation and therefore, oxytocin has been used in mothers having difficulty with engorgement and breast-feeding. Because several small studies have failed to show a beneficial effect, oxytocin is not used for this indication. Oxytocin is excreted in the breast-milk, but is not expected to have adverse effects in the infant.104

Metformin

Animal data show that metformin is excreted into breast milk and reaches levels similar to those in plasma. Small studies indicate that metformin is excreted in human breast milk. Infant hypoglycemia or other side effects are a possibility; however, adverse effects on infant plasma glucose have not been reported in human studies.117118119 Furthermore, the use of metformin 2550 mg/day by mothers breast-feeding their infants for 6 months does not affect growth, motor, or social development; the effects beyond 6 months are not known.120 In all of these studies, the estimated weight-adjusted infant exposure to metformin ranged from 0.11—1.08% of the mother's dose. While the manufacturers of metformin recommend that a decision should be made to discontinue breast-feeding or discontinue the drug, the results of these studies indicate that maternal ingestion of metformin during breast-feeding is probably safe to the infant. However, a risk and benefit analysis should be made for each mother and her infant; if patients elect to continue metformin while breast-feeding, the mother should be aware of the potential risks to the infant. If metformin is discontinued and blood glucose is not controlled on diet and exercise alone, insulin therapy should be considered. Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breastmilk is not expected;121 therefore, this agent may represent a reasonable alternative for some patients. In addition, the American Academy of Pediatrics (AAP) regards tolbutamide as usually compatible with breast-feeding; other sulfonylureas have not been evaluated by the AAP.122 If any oral hypoglycemics are used during breast feeding, the nursing infant should be monitored for signs of hypoglycemia, such as increased fussiness or somnolence.123

Adverse Reactions/Side Effects

Bupropion HCl

Bupropion exhibits a greater potential for causing seizures than other antidepressants; the incidence of seizures with bupropion exceeds that of other commercially available antidepressants by up to 4-fold.141 The incidence of seizures occurring with bupropion is dose-dependent. Seizures occur in roughly 0.1% of patients receiving up to 300 mg/day (sustained-release) and 0.4% of patients receiving up to 450 mg/day (immediate-release) of bupropion. According to the manufacturer, the incidence of seizures in patients taking Wellbutrin XL as a single dose of 450 mg is 0.4%. Although seizure incidence has not been evaluated in clinical trials of the extended-release formulation of bupropion, its bioequivalence with the immediate-release and sustained-release formulations suggests that the risk may be similar to that encountered with use of these products. The incidence of seizures rises disproportionately at dosages > 450 mg/day (immediate-release).1 In patients receiving a 600-mg/day immediate-release regimen of bupropion, the risk of seizures was estimated to be 10-fold that of patients administered the 450-mg maximum daily recommended dose. The incidence of seizures during use of bupropion hydrobromide (Aplenzin) has not been formally evaluated by the manufacturer. To limit the risk of seizures, recommended single or maximum daily dosages of any dosage form of bupropion should not be exceeded. Some patients may be more at risk of experiencing seizures with bupropion therapy. The use or withdrawal of some medication regimens, including ethanol, may lower seizure threshold; these should be utilized cautiously with bupropion. When possible, concomitant use of these medications with bupropion should be avoided.4442414643

During clinical trials of immediate-release or extended-release bupropion formulations, the following centrally-mediated effects occurred more frequently with bupropion that placebo: insomnia (11—31% vs 6—21%), dizziness (6—11% vs 5—7%), tremor (2—21.1% vs < 1—7.6%), drowsiness (2—3% vs 1—2%), sedation or lethargy (19.8% vs 19.5%), cutaneous temperature disturbance (1.9% vs 1.6%), headache (25—34% vs 22.2—26%), migraine (1—25.7% vs 1—22.2%), impaired sleep quality (4% vs 1.6%), paresthesias (1—2% vs 1%), CNS stimulation or restlessness (1—2% vs 1%), and feeling jittery (3% vs 2%). In a comparative trial of sustained-release bupropion (Zyban) monotherapy, nicotine transdermal system (NTS) monotherapy, Zyban/NTS combination, or placebo, the following CNS effects and incidences were reported: insomnia (40%, 28%, 45%, 18%) and nervousness (1%, < 1%, 2%, 0%). The incidence of ataxia/incoordination ranged from < 0.1% to >= 1% of patients during pre-marketing or post-marketing use of bupropion. CNS effects reported in 0.1—1% of patients included vertigo, dysarthria, abnormal coordination, CNS stimulation, hypesthesia, and paresthesias. Rarely reported effects (< 0.1%) included EEG changes, abnormal neurological exam, impaired attention, and aphasia. Also observed were coma, neuralgia (neuropathic pain), neuropathy, and restlessness. Some symptoms may be dose-related and may respond to dosage reduction. To limit insomnia, do not give doses close to bedtime. In some cases these symptoms may require treatment with sedative/hypnotic therapy. In roughly 2% of patients treated, CNS symptoms will necessitate drug discontinuation.4442414643

All effective antidepressants can precipitate mania in predisposed individuals suffering from bipolar disorder. Mania and hypomania have been reported in 1% or more of bupropion recipients during clinical trials. Hypomania was reported rarely (less than 0.1%) during other pre-marketing evaluations. If mania occurs, bupropion should be held and appropriate therapy to treat the manic symptoms should be initiated.4442414643

Psychiatric effects reported more frequently with immediate-release or extended-release bupropion formulations than placebo during clinical trials included agitation (2% to 31.9%), anxiety (3.1% to 8%), memory impairment (less than 0.5 and up to 3% ), confusion (8.4%), delusions (1.2%), impaired concentration (3.1% to 9%), hostility (5.6%), irritability (2% to 3%), thinking abnormality (1%), and abnormal dreams (3% to 5%). These reactions may happen in patients treated for major depressive disorder (MDD) or in those who use bupropion for smoking cessation. In a comparative trial of sustained-release bupropion (Zyban) monotherapy, nicotine transdermal system (NTS) monotherapy, Zyban/NTS combination, or placebo, the following psychiatric effects and incidences were reported: dysphoria (less than 1%, 1%, 2%, 1%), anxiety (8%, 6%, 9%, 6%), impaired concentration (9%, 3%, 9%, 4%), and abnormal dreams (5%, 18%, 13%, 3%). During other pre-marketing or postmarketing use, hallucinations and agitation occurred in 1% or more of patients. Memory impairment, depersonalization, psychosis, confusion, dysphoria, emotional lability, hostility, paranoia, formal thought disorder (unspecified), and frigidity were reported in 0.1 to 1% of patients. Amnesia and derealization occurred rarely (less than 0.1%). Also observed were aggression, delirium, delusions. Aggression, paranoia, and abnormal dreams have been reported during postmarketing use.4442414643

Depressive symptoms have been reported in smoking cessation studies as well as psychiatric studies with bupropion. During clinical trials for major depressive disorder, akathisia (psychomotor restlessness) was reported in 1.5% of bupropion-treated patients. Suicide attempt and completed suicide have occurred in 0.1% to 1% of patients during clinical trial evaluation or postmarketing use of bupropion. Mania can occur in predisposed patients during treatment with an antidepressant. Monitor all antidepressant-treated patients for any indication for worsening of depression or the condition being treated and the emergence of suicidal behaviors or suicidal ideation, especially during the initial few months of drug therapy and after dosage changes. In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in the absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. No suicides occurred in any of the pediatric trials. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over 24 years of age; there was a reduction in risk with antidepressant use in patients aged 65 and older. A ten-year retrospective postmarketing safety review conducted by the FDA indicated that bupropion smoking cessation products were associated with 46 cases of suicidal ideation and 29 cases of suicidal behavior in patients with a prior psychiatric history (n = 18), without this history (n = 24), or an unknown psychiatric history (n = 33). In the cases of suicidal ideation for which demographics were available, 40% were male, 60% were female, and the median age was 46 years (range 26 to 70 years). In the cases reporting suicidal behavior, 59% were male, 41% were female, and the median age was 35 years (range 15 to 70 years). A significant change in thinking and/or behaviors was reported by 23% of the patients after treatment initiation. Seventy percent of the studied patients also had a diagnosis of depression. Of the cases considered serious (n = 59), outcomes were categorized as follows and were not mutually exclusive: death (17%), hospitalization (36%), life-threatening (27%), disability (8%), intervention required (3%), and other (31%). Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation.4644424143

Frequent neurological adverse events associated with bupropion include myoclonia. During clinical trials, the incidence of myoclonia in bupropion recipients was 1% or more. Patients with Gilles de la Tourette's syndrome or a family history of this syndrome may have motor or phonetic tics unmasked or exacerbated by the use of bupropion for ADHD symptoms. Exacerbation of tics may respond to dosage reduction; in some cases bupropion may need to be discontinued.4442414643

Bupropion may cause weight loss. A weight loss of more than 5 pounds occurred in 23.2% of patients taking immediate-release bupropion, approximately double that seen for patients on tricyclic antidepressants or placebo. Approximately 14% of patients on sustained-release formulations lose weight. Roughly 23% of patients receiving bupropion XL enrolled in seasonal affective disorder (SAD) trials had a weight loss of > 5 lbs. compared to 11% on placebo; alternatively 11% of bupropion XL patients had a weight gain > 5 lbs. compared to 21% on placebo. Weight gain may be associated with untreated depression. In general, weight gain is typically rare with bupropion treatment; across all formulations, weight gain occurred in 2—13.6% of bupropion recipients during clinical trials. It is not known if bupropion, like other ADHD therapies, causes growth inhibition in pediatric patients. The incidence of anorexia reported during trials was similar for patients taking bupropion and patients on placebo (roughly 1—18%) and may represent a symptom of the depressive illness rather than an adverse event. Although not as common, appetite stimulation (2—3.7%) was also reported following administration of bupropion during clinical trials.4442414643

Cardiac toxicity is relatively uncommon for bupropion when compared with tricyclic antidepressants. Hypertension occurred in 1—4.3% of patients taking bupropion during clinical trials, compared to 0—1.6% taking placebo. New onset or worsening of existing hypertension occurred in a higher percentage of patients (i.e., 6.1%) taking bupropion concurrently with nicotine transdermal systems (NTS) for smoking cessation; in some cases hypertension was severe. Other cardiovascular effects which occurred more frequently in those receiving immediate-release or extended-release bupropion formulations than placebo during clinical trials included: unspecified cardiac arrhythmias (5.3% vs 4.3%), dizziness (22.3% vs 16.2%), hypotension (2.5% vs 2.2%), palpitations (2—6% vs 0—2.2%), syncope (1.2% vs 0.5%), sinus tachycardia (10.8% vs 8.6%), chest pain (unspecified) (< 1% to 4% vs 1%), and flushing (1—4% vs < 0.5%). In a comparative trial of sustained-release bupropion (Zyban) monotherapy, nicotine transdermal system (NTS) monotherapy, Zyban/NTS combination, or placebo, the following cardiac effects and incidences were reported: hypertension (1%, < 1%, 2%, 0%), palpitations (2%, 0%, 1%, 0%), and chest pain (< 1%, 1%, 3%, 1%). Edema was reported in >= 1% of patients during pre-marketing evaluation of bupropion. Flushing was reported in <= 1% of patients. Cardiac effects reported in 0.1—1% of patients included unspecified chest pain, ECG abnormalities (premature beats and nonspecific ST-T changes), dyspnea, orthostatic hypotension, stroke, sinus tachycardia, and peripheral vasodilation. Pallor, phlebitis, syncope, and myocardial infarction occurred rarely (< 0.1%). Also observed were complete AV block, extrasystoles, and pulmonary embolism; however, the frequencies are unknown. Cardiac effects noted after overdose of bupropion as a single agent have included sinus tachycardia, ECG changes including QRS prolongation, and arrhythmias (unspecified). Hypotension has been reported after overdose of bupropion in conjunction with other medications.4442414643

Blurred vision affected 2—14.6% of bupropion-treated patients during clinical trials, compared to 2—10.3% taking placebo. Diplopia was reported in 2—3% of those receiving active drug versus 2% of those receiving placebo. During other pre-marketing or post-marketing use, blurred vision or diplopia was reported in > = 1% of patients. Other ocular effects that occurred in clinical trials or during post-marketing use included abnormal accommodation (0.1—1%), xerophthalmia (0.1—1%), ocular hypertension, and mydriasis.4442414643

During clinical trials of immediate-release or extended-release bupropion formulations, the following gastrointestinal effects and incidences compared to placebo included: dyspepsia (3.1% vs 2.2)), nausea (9—22.9% vs 8—18.9%), vomiting (2—22.9% vs 2—18.9%), diarrhea (4—7% vs 6—8.6%), constipation (5—26% vs 2—17.3%), xerostomia (10—27.6% vs 5—18.4%), hypersalivation (3.4% vs 3.8%), dysphagia (0—2% vs 0%), flatulence (6% vs 3%), abdominal pain (2—9% vs < 1—2%), and dysgeusia (2—4% vs < 0.5%). In a comparative trial of sustained-release bupropion (Zyban) monotherapy, nicotine transdermal system (NTS) monotherapy, Zyban/NTS combination, or placebo, the following GI effects and incidences were reported: nausea (9%, 7%, 11%, 4%), xerostomia (10%, 4%, 9%, 4%), constipation (8%, 4%, 9%, 3%), diarrhea (4%, 4%, 3%, 1%), oral ulceration (2%, 1%, 1%, 1%), abdominal pain (3%, 4%, 1%, 1%), dysgeusia (3%, 1%, 3%, 2%), and thirst (< 1%, < 1%, 2%, 0%). During other pre-marketing evaluations, stomatitis was reported in >= 1% of patients. Adverse digestive reactions occurring in roughly 0.1—1% of patients included teeth grinding (bruxism), elevated hepatic enzymes, jaundice, liver damage, excessive thirst (polydipsia), gastroesophageal reflux, gingivitis, glossitis, and hypersalivation. Rare events in < 0.1% of patients have included colitis, GI bleeding, GI perforation, and stomach ulcer. Digestive adverse reactions reported during post-marketing use of bupropion include esophagitis, gum bleeding, hepatitis, and pancreatitis. Due to the voluntary nature of post-market reports, neither incidence nor definitive association to bupropion can established.4442414643

Twice as many patients taking bupropion reported libido decrease (3.1%) compared to patients taking placebo (1.6%). Conversely, libido increase has been reported in >= 1% of patients receiving bupropion. Menstrual irregularity was reported as unspecified menstrual complaints by 4.7% of patients and as dysmenorrhea (2% vs < 1% for placebo) and/or vaginal bleeding in 0—2% of patients vs < 0.5% of placebo-treated patients. Impotence (erectile dysfunction) occurred in 3.4% and painful erections occurred in 0.1—1% of bupropion recipients during clinical trials. Cases of gynecomastia, prostate disorder, and testicular swelling have been reported in 0.1—1% of bupropion-treated patients. Other sexual or reproductive system reactions have also occurred and include ejaculation dysfunction (0.1—1%, reported as retarded ejaculation or painful ejaculation), painful erection, dyspareunia (< 0.1%), salpingitis, and vaginal irritation (0.1—1%). Causal effect may be uncertain as trials were not always conducted with adequate controls.4442414643

Depending on the dosage form of bupropion used, hot flashes have been reported in 1—3% of patients; menopause was reported in < 0.1% of bupropion recipients during clinical trials.4442414643

During clinical trials of immediate-release or extended-release bupropion formulations, hyperhidrosis occurred more frequently in the bupropion groups than the placebo groups (5—22.3% vs 2—14.6%). Rash (unspecified) (3—8%), pruritus (2—4%), urticaria (1—2%), alopecia (>= 1%), and xerosis (2%) were other dermatologic adverse reactions commonly reported by recipients of bupropion. Acne vulgaris (0.1—1%), maculopapular rash (< 0.1%), hirsutism (< 0.1%), photosensitivity (0.1—1%), and exfoliative dermatitis have also occurred infrequently or rarely with bupropion use. In a comparative trial of sustained-release bupropion (Zyban) monotherapy, nicotine transdermal system (NTS) monotherapy, Zyban/NTS combination, or placebo, the following dermatologic effects and incidences were reported: rash (4%, 3%, 3%, 2%), pruritus (3%, 1%, 5%, 1%), and urticaria (2%, 0%, 2%, 0%).4442414643

Some endocrine side effects have been reported during postmarketing use of bupropion. These rare endocrine-related side effects have included hyperglycemia, hypoglycemia, glycosuria, hyponatremia, and syndrome of inappropriate antidiuretic hormone (SIADH). Due to the voluntary nature of postmarketing reports, neither causality nor the incidence can be established.4442414643

Hematologic and lymphatic effects reported with bupropion include infrequent cases of ecchymosis (0.1—1%). Anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocytopenia, pancytopenia, and changes in the INR and/or PT have been noted; the incidence has not been reported. Causality has not been established.4442414643

Musculoskeletal events reported during clinical trials by patients receiving bupropion therapy included arthralgia (1—5% vs 1—3%), asthenia (2—4% vs 2%), myalgia (2—6% vs 1—3%), and muscle spasms (1.9% vs 3.2%). Other musculoskeletal adverse reactions reported during bupropion use include muscle twitching (1—2% vs < 0.5%), arthritis (0—3.1% vs 0—2.7%), neck pain (2% vs 0—1%), sciatica (< 0.1%), pain in extremity (3% vs 2%), and pain (unspecified) (2—3% vs 2%). In a comparative trial of sustained-release bupropion (Zyban) monotherapy, nicotine transdermal system (NTS) monotherapy, Zyban/NTS combination, or placebo, the following musculoskeletal effects and incidences were reported: myalgia (4%, 3%, 5%, 3), arthralgia (5%, 3%, 3%, 2%), and neck pain (2%, 1%, < 1%, 0%). Musculoskeletal effects reported in 0.1—1% of patients receiving bupropion during pre-marketing or post-marketing use included leg muscle cramps, back pain, inguinal hernia, and muscle twitching. Musculoskeletal chest pain was reported in <= 1% of patients and sciatica occurred rarely (< 0.1%). Arthralgia, myalgia, muscle weakness (myasthenia), and muscle rigidity with increased temperature and rhabdomyolysis have been reported during post-marketing use.4442414643

Rarely, anaphylactoid reactions characterized by symptoms such as rash, pruritus, urticaria (1% to 2%), angioedema, edema, chest pain, and dyspnea (1%) requiring medical treatment have been reported in clinical trials with bupropion. Most of these events occur in 0.1% to 0.3% or less of patients treated. In addition, there have been rare spontaneous postmarketing reports of erythema multiforme, Stevens-Johnson syndrome (SJS), and anaphylactic shock associated with bupropion. A case of a serum sickness reaction has also been reported in the literature. Serum-sickness-like reactions consist of delayed hypersensitivity reactions, arthralgia, myalgia, pyrexia, and rash.4442414643 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported during postmarketing use of bupropion according to the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS).124 Manifestations of DRESS typically include pyrexia, rash, facial swelling, and/or lymph node involvement in conjunction with other organ system abnormalities including hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis. Eosinophilia is often present. Early manifestations of DRESS such as pyrexia and lymph node involvement may be present without evidence of a rash. Bupropion should be promptly discontinued and appropriate medical treatment should be initiated in patients presenting with a rash or symptoms indicative of DRESS in whom an unrelated etiology cannot be identified.125126

Infections (8—9% vs 6% for placebo) have been reported by bupropion recipients during clinical trials. The types of infection included upper respiratory tract infections (5—9%) (e.g., sinusitis (1—5%), pharyngitis (3—13%), bronchitis (2%), pneumonia (< 0.1%)), urinary tract infections (1%), pelvic infections (< 0.1%), and influenza (>= 2%). Symptoms reported during use of bupropion that may be associated with these infections included rhinitis (12%), epistaxis (2%), increased cough (1—4%), nasal congestion (>= 2%), sinus congestion (>= 2%), pharyngolaryngeal pain (>= 2%), malaise (< 0.1%), fever (1—2%), fever/chills (1.2%), and bronchospasm (< 0.1%). In a comparative trial of sustained-release bupropion (Zyban) monotherapy, nicotine transdermal system (NTS) monotherapy, Zyban/NTS combination, or placebo, the following effects and incidences were reported: rhinitis (12%, 11%, 9%, 8%), increased cough (3%, 5%, < 1%, 1%), pharyngitis (3%, 2%, 3%, 0%), sinusitis (2%, 2%, 2%, 1%), dyspnea (1%, 0%, 2%, 1%), and epistaxis (2%, 1%, 1%, 0%).4442414643

Adverse reactions reported by recipients of bupropion during pre-marketing or post-marketing use, and not discussed elsewhere in the monograph, include peripheral edema (0.1—1%), fatigue (5% vs 8.6% for placebo), dental pain (0.1—1%), drug-induced body odor (< 0.1%), facial edema (0.1—1%), and hair discoloration (< 0.1%). Facial edema was also reported in a comparative trial of sustained-release bupropion (Zyban) monotherapy (< 1%), nicotine transdermal system (NTS) monotherapy (0%), Zyban/NTS combination (1%), or placebo (0%).4442414643

Urinary tract reactions reported more frequently with immediate-release or extended-release bupropion formulations than placebo during clinical trials included increased urinary frequency (2—5% vs 2—2.2%), urinary urgency (< 0.5—2% vs 0%), urinary retention (1.9% vs 2.2%), and urinary tract infection (0—1% vs < 0.5%). Nocturia and urinary frequency occurred in >= 1% of patients during pre-marketing evaluation. Polyuria, urinary urgency, and prostate disorder were reported in 0.1—1% of patients. Cystitis and dysuria occurred rarely (< 0.1%). Also observed post-marketing were cystitis, dysuria, urinary incontinence, and urinary retention; however, the frequencies were not reported.4442414643

During clinical trials of immediate-release or extended-release bupropion formulations, the following extrapyramidal symptoms occurred in the bupropion groups at similar incidences to placebo: bradykinesia (8%), and pseudoparkinsonism (1.5%). Extrapyramidal syndrome (unspecified) has been reported during use of bupropion. Extrapyramidal symptoms that have occurred in 1% or more of patients during pre-marketing evaluation include dystonic reaction and dyskinesia. Hyperkinesis and hypertonia have been reported in 0.1% to 1% of patients. Akinesia, hypokinesia, dystonia, dyskinesia, pseudoparkinsonism, and unmasking of tardive dyskinesia have also occurred during postmarketing use; however, the incidences are unknown.4442414643

During clinical trials of immediate-release or extended-release bupropion formulation, tinnitus was reported more frequently in patients receiving bupropion than placebo (3—6% vs < 1% to 2%). Unspecified sensory disturbance (4% vs 3.2%), auditory or hearing disturbance (5.3% vs 3.2%), and gustatory disturbance (3.1% vs 1.1%) were also reported more frequently in active treatment groups than placebo groups. Tinnitus occurred during a comparative trial of sustained-release bupropion (Zyban) monotherapy (1%), nicotine transdermal system (NTS) monotherapy (0%), Zyban/NTS combination (< 1%), and placebo (0%). During pre-marketing or post-marketing use of bupropion, deafness (hearing loss) has been reported.4442414643

While not reported for bupropion, a neonatal abstinence syndrome has been reported in infants exposed to certain antidepressants in utero. After birth, symptoms consistent with withdrawal (i.e., poor feeding, hypoglycemia, hypothermia, lethargy or irritability, vomiting, etc.) were noted. Such complications can arise immediately upon delivery. In some reports, serum concentrations of the agent were measurable in the infants affected, so the symptoms may have been due to a direct adverse effect of the antidepressant. The physician should carefully consider the potential risks and benefits of treatment. If clinically feasible, and taking the drug half-life into consideration, appropriate tapering of the agent prior to delivery may be considered as an alternative.4442414643

Euphoria was reported more frequently with immediate-release or extended-release bupropion formulations than placebo during clinical trial evaluation (1.2% vs. 0.5%). During controlled trials in patients with a history of multiple substance abuse, normal volunteers, and depressed patients, there was an increase in motor activity and agitation/excitement. In a single dose study of bupropion 400 mg in a population of individuals experienced with drugs of abuse, a mild amphetamine-like activity was produced as compared to placebo on the Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI), and a score intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These scales measure general feelings of euphoria and drug desirability. Although use of recommended daily dosages of bupropion when administered in divided doses is not likely to be significantly reinforcing to amphetamine or CNS stimulant abusers, higher doses (that could not be tested because of seizure risk) could theoretically be modestly attractive to those who abuse CNS stimulant drugs.42 In addition, the inhalation of crushed tablets or injection of dissolved bupropion has been reported. Seizures and/or cases of death have been reported when bupropion has been administered intranasally or by parenteral injection.46

In an ISMP safety report, bupropion was noted as 1 of the 19 overall drugs and one of the 9 antidepressants having the strongest signals for serotonin syndrome with 18 cases reported over 1 year to the FDA Adverse Event Reporting System (FAERS). Serotonin syndrome rarely happens with single drug therapy, and more commonly is reported with interactions between multiple serotonergic drugs or accidental or intentional drug overdoses.127 How bupropion might promote serotonergic excess is unclear, as bupropion is a relatively weak inhibitor of the neuronal reuptake of norepinephrine and dopamine, and does not inhibit the reuptake of serotonin. Bupropion does not inhibit monoamine oxidase. The manufacturers have not reported serotonin syndrome as a postmarketing event.

Phentermine HCl

Central nervous system adverse reactions that have been reported in patients receiving phentermine include dizziness, dysphoria, euphoria, headache, insomnia, overstimulation, restlessness, and tremor. Psychosis at recommended doses may occur rarely in some patients.36128129130

Primary pulmonary hypertension (PPH) and cardiac valvulopathy (regurgitant cardiac valvular disease) have been reported with phentermine. The initial symptom of PPH is usually dyspnea; other initial symptoms include: angina pectoris, syncope, or peripheral edema. Patients should be advised to report immediately any deterioration in exercise tolerance. Treatment should be discontinued in patients who develop new, unexplained symptoms of dyspnea, angina pectoris, syncope, or peripheral edema. Other cardiovascular adverse effects that have been reported include hypertension, ischemic events, palpitations, and sinus tachycardia.36128129130

Reported adverse gastrointestinal effects of phentermine include constipation, diarrhea, dysgeusia, nausea, and xerostomia.36128129130

Impotence (erectile dysfunction), libido increase, and libido decrease have been reported in patients receiving phentermine.36128129130

Urticaria has been reported in patients receiving phentermine.36128129130

Phentermine has not been systematically studied for its potential to produce dependence in obese patients treated with usual recommended dose ranges. Phentermine is related chemically and pharmacologically to the amphetamines, and these stimulant drugs have been extensively abused and the possibility of abuse of phentermine should be kept in mind when evaluating the desirability of including this drug product as part of a weight reduction program. Abuse of amphetamines and related drugs (e.g., phentermine) may be associated with intense psychological dependence and severe social dysfunction.12936128130 There are reports of patients who have increased the dosage of these drugs to many times than recommended. Physical dependence (physiological dependence) is a state that develops as a result of physiological adaptation in response to repeated drug use. Physical dependence manifests by drug-class-specific withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Limited data are available for phentermine. Abrupt cessation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on a sleep electroencephalogram. Thus, in situations where rapid withdrawal is required, appropriate medical monitoring is recommended.12936128130 Evidence-based data from the literature are relatively limited, and some experts suggest that long-term phentermine pharmacotherapy for obesity does not induce abuse or psychological dependence (addiction), drug craving, and that abrupt treatment cessation within the normal prescription dose range does not induce amphetamine-like withdrawal.131 More data are needed to confirm the dependence potential of phentermine-containing obesity products.

Tolerance to the anorexiant effects of phentermine usually develops within a few weeks of starting therapy. The mechanism of tolerance appears to be pharmacodynamic in nature; higher doses of phentermine are required to produce the same response. When tolerance develops to the anorexiant effects, it is generally recommended that phentermine be discontinued rather than the dose increased. The maximum recommended dose should not be exceeded.36128129130

Topiramate

Eleven percent of patients receiving topiramate 200 to 400 mg/day as adjunctive epilepsy therapy discontinued the drug due to adverse events. Of the 1,715 adult epileptic patients treated with topiramate at doses of 200 to 1,600 mg/day, 28% discontinued treatment because of adverse reactions which included sleepiness (3.2%), feeling dizzy (2.6%), balance issues (2.2%), paresthesia (2%), and language problems (2%). Side effects in pediatric patients at age and weight-adjusted dosages are similar to those of adults. Common adverse reactions reported in the monotherapy trials were similar to those reported in the adjunctive trials. Approximately 21% of the 159 adult patients in the 400 mg/day group who received topiramate as monotherapy in the controlled clinical trial discontinued therapy due to adverse events.9

During a monotherapy clinical trial of topiramate in the treatment of epilepsy in adults, the following centrally-mediated effects were reported in patients receiving 50 mg per day vs. 400 mg per day, respectively: paresthesias (21% vs. 40%), dizziness (13% vs. 14%), hypoesthesia (4% vs. 5%), ataxia (3% vs. 4%), drowsiness (10% vs. 15%), and insomnia (8% vs. 9%). During monotherapy evaluation of epilepsy in pediatric patients 6 to 15 years of age, paresthesias (3% vs. 12%), involuntary movements/muscle contractions (0% vs. 3%), and vertigo (0% vs. 3%) occurred in patients receiving topiramate 50 mg per day and 400 mg per day, respectively. In monotherapy clinical trials of topiramate 50 to 200 mg/day for the prophylaxis of migraines, the following CNS effects occurred more frequently with topiramate than placebo: paresthesias (35% to 51% vs. 6%), dizziness (8% to 12% vs. 10%), hypoesthesia (6% to 8% vs. 2%), language problems (6% to 7% vs. 2%), involuntary movements/muscle contractions (2% to 4% vs. 1%), ataxia (1% to 2% vs. < 1%), speech disorders/related speech problems such as dysarthria (<= 2% vs. < 1%), drowsiness (8% to 10% vs. 5%), and insomnia (6% to 7% vs. 5%). Dizziness (<= 6% vs. 4%), headache (2% to 8% vs. 2%), language problems (<= 15% vs. 2%), involuntary muscle contractions (<= 8% vs. 0%), insomnia (<= 9% vs. 2%), drowsiness (2% to 15% vs. 2%), and paresthesias (19% to 38% vs. 7%) were also reported during adolescent trials. Paresthesias, dizziness, drowsiness, and hypoesthesia were considered dose-related CNS effects. Aphasia (2%) and irritability (2%) were reported during adult adjunct therapy epilepsy trials. Other CNS effects reported during epilepsy clinical trials (monotherapy or adjunct therapy) in 0.1% to 1% of patients included peripheral neuropathy, apraxia, hyperesthesia, dysphonia, scotomata, ptosis, and EEG changes. Rare effects (< 0.1%) included upper motor neuron lesion, acute cerebellar syndrome, and tongue paralysis. During clinical trial evaluation of topiramate for the prophylaxis of migraines, headache, vertigo, tremor, sensory disturbance, and aggravated migraine were reported in > 1% of patients. Hyperkinesis (5%), hyporeflexia (2%), and grand mal seizures (1%) were reported in add-on epilepsy trials in pediatric patients.911

All patients beginning treatment with anticonvulsants or currently receiving such treatment should be closely monitored for emerging or worsening suicidal thoughts/behavior, depression, or other changes in mood/behavior. During a monotherapy clinical trial of topiramate in the treatment of epilepsy in adults, the following psychiatric effects were reported in patients receiving 50 mg per day vs. 400 mg per day, respectively: difficulty with memory NOS (memory impairment) (6% vs. 11%), depression (7% vs. 9%), impaired concentration/attention (7% vs. 8%), anxiety (4% vs. 6%), psychomotor impairment (3% vs. 5%), emotional lability (2% vs. 5%), cognitive impairment (1% vs. 4%), and libido decrease (0% vs. 3%). During monotherapy evaluation of epilepsy in pediatric patients 6 to 16 years of age, the following psychiatric effects were reported in patients in the 50 mg per day group vs. the 400 mg per day group: emotional lability (1% vs. 8%), impaired concentration/attention (7% vs. 10%), memory impairment (1% vs. 3%), cognitive impairment (1% vs. 6%), confusion (0% vs. 3%), depression (0% vs. 3%), and behavior problems (0% vs. 3%). In monotherapy adult clinical trials of topiramate 50 to 200 mg per day for migraine prophylaxis, the following effects occurred more frequently in the active treatment groups than the placebo group: memory impairment (7% to 11% vs. 2%), impaired concentration/attention (3% to 10% vs. 2%), anxiety (4% to 6% vs. 3%), emotional lability (3% to 6% vs. 2%), depression (3% to 6% vs. 4%), nervousness (4% vs. 2%), confusion (2% to 4% vs. 2%), psychomotor impairment (2% to 4% vs. 1%), libido decrease (1% to 2% vs. 1%), worsening depression (1% to 2% vs. 1%), agitation (1% to 2% vs. 1%), and cognitive impairment (< = 2% vs. 1%). Anxiety (<= 8% vs. 0%), impaired concentration/attention (<= 15% vs. 0%), memory impairment (<= 8% vs. 2%), emotional lability (2% to 8% vs. 4%), and psychomotor impairment (<= 8% vs. 0%) were also prevalent in adolescent migraine trials; in addition, nervousness was reported in >= 2% of adolescents. Hallucinations, psychosis, and suicide attempt were reported in > 1% of patients during clinical trials of topiramate as monotherapy or adjunct therapy for epilepsy. Euphoria, paranoia, delusions, delirium, and abnormal dreaming were reported 0.1% to 1% of patients. Rare effects (< 0.1%) included libido increase and mania (manic reaction). Anticonvulsants, including topiramate, are thought to carry an increased risk of suicidal ideation and behavior. An analysis by the FDA of previously gathered drug data showed that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) as patients receiving placebo (0.24%). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions. Age was not a determining factor. The increased risk of suicidal ideation and behavior occurred between 1 and 24 weeks after therapy initiation. However, a longer duration of therapy should not preclude the possibility of an association to the drug since most studies included in the analysis did not continue beyond 24 weeks. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior.9

Hyperammonemia with and without encephalopathy has been reported with topiramate use and may be dose-related. In adolescent migraine prophylaxis trials, the incidence of hyperammonemia was 9% for placebo, 14% for topiramate 50 mg/day, and 26% for 100 mg/day. The incidence of markedly increased hyperammonemia (i.e., ammonia values at least 50% higher than the upper limit of normal) was 3% for placebo, 0% for topiramate 50 mg/day, and 9% for 100 mg/day; markedly abnormal concentrations returned to normal in all but 1 patient during the trial, in whom concentrations decreased to high instead of markedly abnormal. Although hyperammonemia can occur with topiramate monotherapy, it appears to be more common with adjuvant valproate therapy. Concomitant administration of topiramate and valproate may exacerbate existing metabolic deficits or unmask deficiencies in susceptible persons, and has been associated with hyperammonemia in patients who have tolerated either drug alone. Monitor serum ammonia concentrations in patients who develop unexplained lethargy, vomiting, changes in mental status, or hypothermia (i.e., an unintentional drop in core body temperature to < 35 degrees C), as these may be symptoms of hyperammonemic encephalopathy. Hypothermia may also occur in the absence of hyperammonemia.9 Patients who develop unexplained symptoms of hyperammonemic encephalopathy or hypothermia while receiving antiepileptic therapy should discontinue the afflicting drug and receive prompt treatment for hyperammonemia, if present.9132 In most cases, signs and symptoms abate with discontinuation of either topiramate or valproate.9

During a monotherapy clinical trial of topiramate in the treatment of epilepsy in adults, the following gastrointestinal (GI) effects were reported in patients receiving 50 mg per day vs. 400 mg per day, respectively: constipation (1% vs. 4%), gastritis (0% vs. 3%), xerostomia (1% vs. 3%), dysgeusia (3% vs. 5%), gastroesophageal reflux (1% vs. 2%), anorexia (4% vs. 14%), and weight loss (6% vs. 17%). During monotherapy evaluation of epilepsy in pediatric patients 6 to 15 years of age, the following GI effects were reported in the 50 mg per day group vs. the 400 mg per day group: diarrhea (8% vs. 9%) and weight loss (7% vs. 17%). In monotherapy clinical trials of topiramate 50 to 200 mg per day for migraine prophylaxis, the following GI effects occurred more frequently with topiramate than placebo: nausea (9% to 14% vs. 8%), diarrhea (9% to 11% vs. 4%), abdominal pain (6% to 7% vs. 5%), dyspepsia (3% to 5% vs. 3%), xerostomia (2% to 5% vs. 2%), vomiting (1% to 3% vs. 2%), dysgeusia (8% to 15% vs. 1%), taste loss (1% to 2% vs. < 1%), anorexia (9% to 15% vs. 6%), weight loss (6% to 11%), and gastroenteritis (2% to 3% vs. 1%). Dysgeusia (2% to 8% vs. 2%), abdominal pain (7% to 15% vs. 9%), diarrhea (2% to 8% vs. 0%), nausea (<= 8% vs. 4%), weight loss (4% to 31% vs. 2%), anorexia (9% to 15% vs. 4%), and pharyngeal edema (<= 8% vs. 0%) were reported in adolescent migraine trials; vomiting and gastroenteritis also occurred in >= 2% of patients. Gingivitis was observed in 1% of adult patients receiving topiramate during add-on epilepsy trials; in pediatric patients, hypersalivation (6%), fecal incontinence (1%), flatulence (1%), glossitis (1%), dysphagia (1%), weight gain (1%), appetite stimulation (1%), and gingival hyperplasia (1%) were observed. Other GI effects reported in 0.1% to 1% of patients during clinical trials of topiramate as monotherapy or adjunct therapy for epilepsy included hemorrhoids, stomatitis, melena, gastritis, esophagitis, taste loss, and gingival bleeding. Tongue edema was reported rarely (< 0.1%). During clinical trial evaluation of topiramate for migraine prophylaxis, constipation and gastroesophageal reflux were reported in > 1% of patients.9

Topiramate is associated with an increased risk for bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported for topiramate (4.5% adults and 4.4% pediatrics) than for placebo (3% adults and 2.3% pediatrics); serious bleeding events occurred in 0.3% vs. 0.2% of adult patients and 0.4% vs. 0% of pediatric patients for those treated with topiramate and placebo, respectively. Adverse events reported ranged from mild epistaxis, ecchymosis, and increased menstrual bleeding to life-threatening hemorrhage. In those with serious events, risk factors for bleeding were often present, or patients were taking other drugs that cause thrombocytopenia or affect platelet function or coagulation. During clinical trial evaluation of topiramate for migraine prophylaxis, epistaxis was reported in > 1% of adult patients and 2% to 8% of adolescent patients. In pediatric monotherapy trials for epilepsy, epistaxis was reported in 0% of patients receiving topiramate 50 mg per day and 4% of patients receiving 400 mg per day.9 Intractable epistaxis was reported in a 61 year old woman with cardiovascular disease who was receiving topiramate 25 mg daily for lower extremity neuropathy. Epistaxis developed 7 days after treatment initiation and resolved within 1 week of discontinuation. A rechallenge with topiramate 3 months later again resulted in epistaxis requiring 2 units of packed blood cells. According to the Naranjo probability scale, topiramate was the probable cause of epistaxis. Topiramate may modulate voltage-gated L type calcium ion channels located on vascular smooth muscle and non-contractile tissues such as platelets.133 During a monotherapy clinical trial of topiramate in the treatment of epilepsy in adults, anemia was reported in 1% of patients receiving 50 mg per day and 2% of patients receiving 400 mg per day. In pediatric trials, anemia was reported in 1% of patients receiving 50 mg per day and 3% of patients receiving 400 mg per day. Leukopenia was reported in 1% to 2% of patients during add-on epilepsy trials in adults; in pediatric patients, thrombocytopenia (1%), purpura (8%), and hematoma (1%) were also observed. Deep vein thrombosis and thrombocytosis was reported infrequently (0.1% to 1%). Other hematologic effects reported rarely (< 0.1%) during clinical trials of topiramate as monotherapy or adjunct therapy for epilepsy included bone marrow depression, lymphadenopathy, eosinophilia, lymphopenia, granulocytopenia, and pancytopenia. Lymphocytosis and polycythemia were reported rarely (< 0.1%).9

Rapidly evaluate any patient with symptoms of visual disturbance. A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate who do not have a history of such conditions. Symptoms include acute onset of visual impairment and/or ocular pain. Ophthalmologic findings can include diplopia, myopia, blurred vision, anterior chamber shallowing, ocular hyperemia (redness) and increased intraocular pressure (ocular hypertension). Mydriasis may or may not be present. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary closed-angle glaucoma. Symptoms typically occur within 1 month of initiating topiramate therapy. In contrast to primary narrow-angle glaucoma, which is rare under 40 years of age, secondary closed-angle glaucoma associated with topiramate has been reported in children as well as adults. The primary treatment to reverse symptoms is discontinuation of topiramate as rapidly as possible, according to the judgment of the treating physician. Other measures in conjunction with discontinuation of topiramate may be helpful. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae including permanent vision loss. Visual field defects that are independent of elevated intraocular pressure have also been associated with topiramate therapy. These events are usually reversible following discontinuation of therapy. Consider discontinuing topiramate if visual problems occur. In monotherapy clinical trials of topiramate 50 to 200 mg per day for migraine prophylaxis, the following ophthalmic effects occurred more frequently with topiramate than placebo: visual impairment (1% to 3% vs. < 1%), blurred vision (2% to 4% vs. 2%), and conjunctivitis (1% to 2% vs. 1%). Nystagmus was reported in 10% to 11% of adult patients during add-on epilepsy trials; in pediatric patients, abnormal lacrimation (1%) was also reported. Conjunctivitis was reported in > 1% of adult patients during clinical trials of topiramate as monotherapy or adjunct therapy for epilepsy; incidence rates were <= 7% in adolescent migraine trials. Abnormal accomodation, photophobia, xerophthalmia, and strabismus were reported in 0.1% to 1% of patients. Rare effects (< 0.1%) included mydriasis and iritis. During clinical trial evaluation of topiramate for migraine prophylaxis, abnormal accomodation and ocular pain were reported in > 1% of adult patients; visual impairment and ocular pain were present in >= 2% of adolescent patients. Maculopathy has occurred during post-marketing use.9

During a monotherapy clinical trial of topiramate in the treatment of epilepsy in adults, the following respiratory effects, infections, or related symptoms were reported in patients receiving 50 mg per day vs. 400 mg per day, respectively: viral infection (6% vs. 8%), infection (unspecified) (2% vs. 3%), bronchitis (3% vs. 4%), rhinitis (2% vs. 4%), and dyspnea (1% vs. 2%). During monotherapy evaluation of epilepsy in pediatric patients 6 to 15 years of age, the following effects occurred in patients receiving topiramate 50 mg per day vs. 400 mg per day, respectively: fever (1% vs. 12%), viral infection (3% vs. 6%), infection (unspecified) (3% vs. 8%), upper respiratory tract infection (16% vs. 18%), rhinitis (5% vs. 6%), bronchitis (1% vs. 5%), and sinusitis (1% vs. 4%). In monotherapy clinical trials for migraine prophylaxis, the following effects occurred more frequently with topiramate 50 to 200 mg per day than placebo: fever (1% to 2% vs. 1%), influenza-like symptoms (< = 2% vs. < 1%), secondary malignancy (<= 2% vs. < 1%), viral infection (3% to 4% vs. 3%), upper respiratory tract infection (12% to 14% vs. 12%), sinusitis (6% to 10% vs. 6%), pharyngitis (2% to 6% vs. 4%), cough (2% to 4% vs. 2%), bronchitis (3% vs. 2%), dyspnea (1% to 3% vs. 2%), and rhinitis (1% to 2% vs. 1%). Adolescent migraine trials reported fever (<= 6% vs. 2%), viral infection (4% to 15% vs. 4%), otitis media (<= 8% vs. 0%), cough (<= 7% vs. 0%), laryngitis (<= 8% vs. 0%), rhinitis (6% to 8% vs. 2%), sinusitis (4% to 15% vs. 2%), and upper respiratory tract infection (23% to 26% vs. 11%); infection (unspecified), influenza-like symptoms, pharyngitis, bronchitis, and asthma occurred in >= 2% of adolescent migraine patients. Thrombocythemia and pulmonary embolism were reported in 0.1% to 1% of patients during clinical trials of topiramate as monotherapy or adjunct therapy for epilepsy. Polycythemia was reported rarely (< 0.1%). During clinical trial evaluation for migraine prophylaxis, infection, genital candidiasis, pneumonia, and asthma (bronchospasm) were reported in > 1% of patients. Pallor (1%) has been reported in pediatric patients.9

During a monotherapy clinical trial of topiramate in the treatment of epilepsy, the following genitourinary (GU) effects were reported in adult patients receiving 50 mg/day vs. 400 mg/day, respectively: cystitis (1% vs. 3%), renal calculus or kidney stones (0% vs. 3%), urinary tract infection (1% vs. 2%), and increased urinary frequency (0% vs. 2%). In pediatric trials, increased urinary frequency (0% vs. 3%) and urinary incontinence (1% vs. 3%) were reported in patients receiving 50 mg/day vs. 400 mg/day, respectively. Urinary incontinence (1% to 2%) and hematuria (2% or less) were reported in adult patients during add-on epilepsy trials; in pediatric patients, urinary incontinence (1% to 4%) and nocturia (1%) were reported. In monotherapy clinical trials of 50 to 200 mg/day for migraine prophylaxis, the following GU effects occurred more frequently with topiramate than placebo: urinary tract infection (2% to 4% vs. 2%) and renal calculus (0% to 2% vs. 0%); adolescent migraine prophylaxis trials reported renal calculus (less than 1%), urinary incontinence (2% or more), and urinary tract infection (2% or more). Other GU effects reported in 0.1% to 1% of patients during clinical trials of topiramate as monotherapy or adjunct therapy for epilepsy included urinary retention, renal pain, albuminuria, polyuria, and oliguria.9 Topiramate has weak carbonic anhydrase inhibitor activity; carbonic anhydrase inhibitors promote stone formation by reducing urinary citrate excretion and by increasing urinary pH. During clinical trials of topiramate as monotherapy epilepsy treatment, overall 1.3% of topiramate-treated adult patients developed nephrolithiasis; the incidence was slightly higher in adjunct therapy trials (1.5%). This incidence is about 2 to 4 times that expected in a similar, untreated population and was higher in men. In a long-term open-label epilepsy study in pediatric patients 1 to 24 months old, 7% developed kidney or bladder stones. The concomitant use of topiramate with other carbonic anhydrase inhibitors or in patients on a ketogenic diet may create a physiological environment that increases the risk of kidney stone formation and should therefore be avoided.9 Instruct patients who are receiving topiramate and who have a history of kidney stones to increase their fluid intake in order to reduce the formation of kidney stones. Evaluate evidence of hematuria, dysuria, or crystalluria by renal ultrasound.134 Nephrocalcinosis has been observed with topiramate use during postmarketing experience.9

Serious skin reactions (Stevens-Johnson syndrome [SJS] and toxic epidermal necrolysis [TEN]) have been reported in patients receiving topiramate. Discontinue topiramate at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, do not resume topiramate use and consider alternative therapy. In a monotherapy epilepsy clinical trial in adults (16 years and older), the following dermatologic effects were reported in patients receiving topiramate 50 mg/day vs. 400 mg/day, respectively: rash (1% vs. 4%), pruritus (1% vs. 4%), alopecia (3% vs. 4%), and acne vulgaris (2% vs. 3%). In pediatric patients (6 to 15 years), alopecia (1% vs. 4%) and rash (3% vs. 4%) were reported in the 50 mg/day and 400 mg/day groups, respectively. Unspecified skin disorder was reported in 3% of pediatric patients (2 to 15 years) receiving topiramate in a placebo-controlled (2%), adjunctive epilepsy trials. In placebo-controlled adjunctive epilepsy trials in adults receiving topiramate 200 to 1,000 mg/day, hot flashes (1% to 2%), drug-induced body odor (0% to 1%), skin disorder (1% to 2%), hyperhidrosis (1% or less), and erythematous rash (1% or less) were reported with equal or greater frequency than placebo. In an adjunctive epilepsy trial in pediatric patients (2 to 16 years), skin disorder (3%), alopecia (2%), dermatitis (2%), hypertrichosis (2%), erythematous rash (2%), eczema (1%), seborrhea (1%), and skin discoloration (1%) occurred more frequently in topiramate-treated patients compared to patients given placebo. Pruritus was reported in 4%, 2%, and 2% of patients (including adolescents) receiving topiramate 50 mg/day, 100 mg/day, and 200 mg/day, respectively, for migraines in placebo-controlled (2%) clinical trials. Erythematous rash was reported in 8% of adolescents receiving topiramate 200 mg/day in pooled, double-blind migraine prophylaxis studies; however, it was not reported in adolescents receiving topiramate 50 or 100 mg/day. Pemphigus and bullous skin reactions (bullous rash), including erythema multiforme, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), have been reported during postmarketing experience with topiramate.910

Oligohidrosis and hyperthermia have been reported in association with topiramate use; heat stroke may occur. Oligohidrosis and hyperthermia have occurred primarily in children who were exposed to elevated environmental temperatures or were performing vigorous activity. Infrequent hospitalizations have occurred. To help prevent these adverse reactions in patients treated with topiramate, proper hydration is suggested before and during strenuous activity or exposure to warm temperatures. Use caution when topiramate is prescribed with other drugs that predispose patients to heat-related disorders, such as drugs with anticholinergic activity, carbonic anhydrase inhibitors, and zonisamide. Since topiramate exhibits carbonic anhydrase inhibitor activity, use with other carbonic anhydrase inhibitors is not recommended.859

Topiramate is a weak carbonic anhydrase inhibitor and may lead to renal bicarbonate loss in a dose-dependent fashion. Hyperchloremic, non-anion gap, metabolic acidosis (hyperchloremic acidosis) is associated with topiramate. Metabolic acidosis due to topiramate is often asymptomatic.135 Measurement of baseline and periodic serum bicarbonate is recommended during topiramate therapy and prior to surgery. If metabolic acidosis develops and persists, consider a dosage reduction or discontinuation (using dose tapering). If the decision is made to continue topiramate despite persistent acidosis, alkali treatment should be considered.9 Bicarbonate loss is typically mild to moderate (roughly 4 mEq/L at an adult dose of 400 mg/day or a pediatric dose of 6 mg/kg/day) and tends to occur early in therapy, although cases can occur at any time. Rarely, bicarbonate loss may approach 10 mEq/L. Metabolic acidosis has been observed with doses as low as 50 mg/day. At doses of 400 mg/day in adjunctive epilepsy therapy trials, persistent reductions in serum bicarbonate < 20 mEq/L occurred at an incidence of roughly 32% vs. 1% placebo. Markedly abnormal serum bicarbonate (i.e., < 17 mEq/L and > 5 mEq/L reduction from baseline) occurred in 3% of topiramate-treated patients vs. 0% for placebo. In the monotherapy trials, the incidence of persistent decreases in serum bicarbonate in adults was 14% at doses of 50 mg/day and 25% for 400 mg/day. Markedly abnormal serum bicarbonate was observed in 1% of the 50 mg/day and 6% for the 400 mg/day adult group. During clinical trials for adjunctive treatment of Lennox-Gastaut syndrome or refractory partial onset seizures in pediatric patients 2 to 16 years of age, persistent decreases in serum bicarbonate occurred in 67% of topiramate-treated patients and 10% of placebo-treated patients; 11% of topiramate-treated patients had markedly abnormal serum concentrations. The incidence of markedly abnormal changes in adults receiving topiramate for migraine prophylaxis was < 1% for placebo, 11% for 200 mg/day, 9% for 100 mg/day, and 2% for 50 mg/day. This incidence was similar in adolescent migraine prophylaxis trials; 2% for placebo, 2% for 50 mg/day, and 6% for 100 mg/day (criterion not met by the low number of patients [n = 13] in the 200 mg/day group). Although not FDA-approved in this population, a controlled trial in infants and children younger than 2 years demonstrated that the degree of metabolic acidosis caused by topiramate was notably greater in this population than that observed in trials of older children and adults. The incidence of metabolic acidosis (serum bicarbonate < 20 mEq/L) was 0% for placebo, 30% for 5 mg/kg/day topiramate, 50% for 15 mg/kg/day, and 45% for 25 mg/kg/day. The incidence of markedly abnormal changes was 0% for placebo, 4% for 5 mg/kg/day, 5% for 15 mg/kg/day, and 5% for 25 mg/kg/day. Manifestations of metabolic acidosis, if symptomatic, may include: anorexia, cardiac arrhythmias, lethargy, hyperventilation, hypohidrosis, and stupor. Chronic metabolic acidosis may result in nephrolithiasis (renal stones), growth inhibition, osteomalacia, osteoporosis, and/or fractures. Some data in infants and toddlers with intractable partial seizures receiving topiramate showed reductions from baseline in z-scores for length, weight, and head circumference compared to age and sex-matched normative data; however, it should be noted that these patients with epilepsy are likely to have different growth rates than normal infants. Reductions in z-scores for length and weight were correlated to the degree of acidosis.9135136

During a monotherapy clinical trial of topiramate in the treatment of epilepsy in adults, vaginal bleeding (hemorrhage) was reported in 0% of patients receiving 50 mg per day and 3% of patients receiving 400 mg per day. In pediatric trials, intermenstrual bleeding was reported in 0% and 3% of pediatric patients receiving 50 mg per day and 400 mg per day, respectively. Amenorrhea (2%) and menorrhagia (1% to 2%) were reported during add-on epilepsy trials. In monotherapy clinical trials for migraine prophylaxis, the following reproductive effects occurred more frequently with topiramate 50 to 200 mg per day than placebo: menstrual irregularity (menstrual disorder 2% to 3% vs. 2%) and ejaculation dysfunction (premature ejaculation 0% to 3% vs. 0%). Impotence (erectile dysfunction) was reported in > 1% of patients during clinical trials of topiramate as monotherapy or adjunct therapy for epilepsy. Ejaculation disorder and breast discharge were reported in 0.1% to 1% of patients. During clinical trial evaluation for migraine prophylaxis, intermenstrual bleeding was reported in > 1% of patients. Leukorrhea (2%) has been reported in pediatric patients.9

During a monotherapy clinical trial of topiramate in the treatment of epilepsy in adults, chest pain (unspecified) was reported in 1% of patients receiving 50 mg/day and 2% of patients receiving 400 mg/day. Edema (1% to 2%) and hypertension (2%) have been reported during add-on epilepsy trials. Other cardiovascular effects reported during epilepsy clinical trials (monotherapy or adjunct therapy) in 0.1% to 1% of patients included peripheral vasodilation, hypotension, orthostatic hypotension, AV block, and angina. During clinical trial evaluation of topiramate for migraine prophylaxis, chest pain was reported in > 1% of patients. Bradycardia (1%) has been reported in pediatric patients. Though the clinical significance has not been clearly established, notable changes (increases and decreases) from baseline in blood pressure and pulse rate were observed more commonly in pediatric patients treated with topiramate compared to those treated with placebo during migraine prophylaxis trials; these changes were often dose-related. The most notable changes were systolic blood pressure (SBP) < 90 mmHg, diastolic blood pressure (DBP) < 50 mmHg, SBP or DBP variation >= 20 mmHg, and pulse rate variation >= 30 beats per minute.9

During a monotherapy clinical trial of topiramate in the treatment of epilepsy in adults, hypertonia was reported in 0% of patients receiving 50 mg/day and 3% of patients receiving 400 mg/day. Other extrapyramidal effects reported during clinical trials of topiramate as monotherapy or adjunct therapy of epilepsy in 0.1% to 1% of patients included dyskinesia and dystonic reaction.9

During clinical trials of topiramate as migraine prophylaxis, polydipsia was reported in 1% to 2% of patients receiving 50 mg/day vs. < 1% of patients receiving 400 mg/day. Hyperthyroidism was reported in 8% of adolescent patients receiving 200 mg/day during migraine prophylaxis trials. Other metabolic or nutritional effects reported in 0.1% to 1% of patients during clinical trials of topiramate as monotherapy or adjunct therapy for epilepsy included dehydration, hypocalcemia, hyperlipidemia, hyperglycemia, and diabetes mellitus. Rarely reported effects (< 0.1%) included hypernatremia, hyponatremia, hypocholesterolemia, and increased creatinine. Hypoglycemia (1%) has been reported in pediatric patients. The clinical significance of various laboratory abnormalities observed during topiramate clinical trials has not been clearly established. For example, markedly decreased serum phosphorus (hypophosphatemia) (6%), markedly increased serum alkaline phosphatase (3%), and decreased serum potassium (0.4%) have also been observed during adult epilepsy trials. Additionally, BUN, creatinine, alkaline phosphatase, uric acid, total protein, platelets, and eosinophils were abnormally elevated more frequently in patients receiving topiramate compared to those receiving placebo in pediatric migraine prophylaxis trials. Phosphorus, total white blood cell count, and neutrophils were abnormally decreased in some subjects. Changes in several laboratory values (i.e., increased creatinine, BUN, alkaline phosphatase, total protein, total eosinophil count, and decreased potassium) have been observed in children younger than 2 years treated with topiramate for partial onset seizures.9

Vascular effects reported in 0.1% to 1% of patients during clinical trials of topiramate as monotherapy or adjunct therapy for epilepsy included flushing, deep vein thrombosis, and phlebitis. Vasospasm was reported rarely (< 0.1%). Flushing was also reported in 0% and 5% of patients receiving topiramate 50 mg per day and 400 mg per day, respectively, during pediatric monotherapy trials for epilepsy.9

During a monotherapy clinical trial of topiramate in the treatment of epilepsy in adults, leg pain was reported in 2% of patients receiving 50 mg/day and 3% of patients receiving 400 mg/day. In monotherapy clinical trials of topiramate 50 to 200 mg/day for migraine prophylaxis, arthralgia occurred more frequently with topiramate (1% to 7%) than placebo (2%). Musculoskeletal effects reported in at least 1% of patients during clinical trials of topiramate as monotherapy or adjunct therapy for epilepsy included arthralgia (1% to 7%), leg muscle cramps (2%), and back pain (3% to 5%). Arthrosis (arthropathy) was reported infrequently (0.1% to 1%). During clinical trial evaluation of topiramate for migraine prophylaxis, myalgia was reported in > 1% of adult patients; myalgia, back pain, and pain (unspecified) were reported in >= 2% of adolescent patients.9

During a monotherapy clinical trial of topiramate in the treatment of epilepsy in adults, increased gamma-glutamyl transpeptidase (GGT) was reported in 1% of patients receiving 50 mg/day and 3% of patients receiving 400 mg/day. Hepatic effects reported in 0.1% to 1% of patients during clinical trials of topiramate as monotherapy or adjunct therapy for epilepsy included elevated hepatic enzymes (ALT, AST). During post-marketing use, hepatic failure (including fatalities), and hepatitis have occurred; however, causality to the drug has not been established.9

During topiramate epilepsy monotherapy trials, for daily doses of 50 mg vs. 400 mg, asthenia was reported in both adults (4% vs. 6%) and pediatric patients (0% vs. 3%). During migraine prophylaxis monotherapy trials, comparing topiramate 50 to 200 mg per day vs. placebo, the following were reported: fatigue (14% to 19% vs. 11%), injury (6% to 9% vs. 7%), asthenia (<= 2% vs. 1%), and allergy (<= 2% vs. < 1%); adolescent migraine trials also reported fatigue (7% to 15% vs. 7%). Syncope was reported in at least 1% of patients during epilepsy monotherapy or adjunct therapy trials. Enlarged abdomen, parosmia, and face edema were reported infrequently (0.1% to 1%), and alcohol intolerance was reported rarely (< 0.1%). During clinical trial evaluation for migraine prophylaxis, unspecified allergic reaction and pain were reported in > 1% of patients; leg pain was reported in 2% to 8% of adolescent patients. Pancreatitis has occurred during post-marketing use; however, causality to the drug has not been established.9

During migraine prophylaxis monotherapy trials, tinnitus (<= 2% vs. 1%) and otitis media (1% to 2% vs. < 1%) were reported with topiramate 50 to 200 mg per day compared to placebo. Hearing loss occurred in 1% to 2% of patients during add-on epilepsy trials.9

Naltrexone HCl

Naltrexone can cause hepatocellular injury when given in excessive doses. Naltrexone does not appear to be a hepatotoxin at the recommended doses. The hepatotoxic potential of naltrexone has been described in a placebo-controlled study using a 300 mg/day dose of naltrexone. In this study, 20% of patients experienced elevated hepatic enzymes (3—19 times baseline values). All patients were asymptomatic, and transaminase levels returned to baseline or decreased in a matter of weeks. Other studies of naltrexone doses > 50 mg/day in patients with opiate dependence or alcoholism also resulted in increased hepatic enzymes. Clinical trial data indicate that 7—13% of study patients receiving 380 mg of intramuscular naltrexone experienced elevated hepatic enzymes compared to 2—6% of those on placebo.91 Hepatitis, elevated hepatic enzymes, and hyperbilirubinemia have been reported in post-marketing reports with naltrexone. Warn patients of the risk of hepatic injury, and advise them to get immediate medical attention if they experience symptoms of acute hepatitis. A high index of suspicion for drug-related hepatic injury is critical if the occurrence of naltrexone-induced liver damage is to be detected at the earliest possible time. Evaluations to detect liver injury are recommended at a frequency appropriate to the clinical situation and to the naltrexone dose. Discontinue naltrexone if symptoms or signs of acute hepatitis develop.90

Central nervous system (CNS) effects occurring during clinical trials of oral naltrexone for alcohol or opiate dependence included headache (>= 7%), dizziness (4—9%), nervousness (>= 4%), insomnia (>= 3%), anxiety (>= 2%), fatigue (>= 4%), drowsiness (<= 2%), increased energy (< 10%), irritability (< 10%), paranoia (< 1%), restlessness (< 1%), confusion (< 1%), disorientation (< 1%), hallucinations (< 1%), nightmares (< 1%), yawning (< 1%), and hot flashes (< 1%).90 During clinical trials using 380 mg of extended-release injectable naltrexone suspension for alcohol opioid dependence, the following effects were reported more frequently with the active drug than placebo: dizziness or syncope (13% vs 4%), insomnia (6—14% vs 1—12%), headache (3—25% vs 2—18%), drowsiness (4% vs 1%), and anxiety (12% vs 8%).91 Cerebral arterial aneurysm, seizures, mental impairment, dysgeusia, euphoric mood (euphoria), migraine, ischemic stroke, irritability, disturbance in attention, abnormal dreams, agitation, delirium, hot flashes, and paresthesias were also reported during clinical trials of intramuscular naltrexone; however, the incidence of these effects is not known. CNS effects reported during post-marketing use of naltrexone include abnormal thinking, agitation, anxiety, headache, fatigue, confusion, euphoria, hallucinations, insomnia, nervousness, drowsiness, hot flashes, dizziness, and hyperkinesis. It is not always possible to distinguish these occurrences from signs and symptoms of naltrexone-induced opiate discontinuation syndrome.90

Depression, suicidal ideation, and attempted suicide have been reported in individuals receiving oral naltrexone, placebo, and in concurrent control groups undergoing treatment for alcoholism and opiate dependence.90 In controlled clinical trials of the extended-release injectable suspension of naltrexone, suicidal ideation, suicide attempts, or completed suicides occurred in 1% of patients and in no patients treated with placebo. In some cases, the suicidal thoughts or behavior occurred after study discontinuation but were in the context of an episode of depression that began while the patient was taking naltrexone. Two completed suicides occurred in patients who were taking naltrexone. Depression-related events associated with premature discontinuation of naltrexone also occurred in about 1% of patients and in no patients treated with placebo. In the 24-week, placebo-controlled, pivotal trial, adverse events involving depressed mood were reported by 10% of patients treated with naltrexone 380 mg IM as compared with 5% of patients treated with placebo. Monitor patients for the development of depression or suicidal thinking. Families and caregivers of patients being treated with naltrexone should be alerted to the need to monitor patients for the emergence of symptoms of depression or suicidality and to report such symptoms to the patient's health care provider. Physicians should be aware that treatment with naltrexone does not reduce the risk of suicide in patients.91

In clinical trials of the extended-release injectable suspension of naltrexone, patients who took naltrexone had increases in eosinophil counts (eosinophilia) relative to patients on placebo, but eosinophil counts returned to normal over a period of several months in the patients who continued to take naltrexone. One diagnosed case and 1 suspected case of eosinophilic pneumonia occurred. The pneumonia resolved with antibiotics and corticosteroids. Consider eosinophilic pneumonia if progressive shortness of breath and hypoxia develop and if patients do not respond to antibiotics.91

Patients treated with naltrexone 380 mg IM experienced a mean maximal decrease in platelet count of 17,800/mm3 as compared with 2600/mm3 in placebo patients. In randomized controlled trials, naltrexone administration was not associated with an increase in bleeding related adverse events. Idiopathic thrombocytopenic purpura was reported in one patient who may have been sensitized to naltrexone in a previous course of treatment with naltrexone. The condition cleared without sequelae after discontinuation of naltrexone and corticosteroid treatment. In addition, deep vein thrombosis and pulmonary embolism were reported as treatment-emergent adverse reactions during clinical trials of naltrexone suspension for injection; the incidences are unknown.91

Gastrointestinal (GI) effects occurring during clinical trials of oral naltrexone for alcohol or opiate dependence include nausea (>= 10%), vomiting (>= 3%), abdominal pain (> 10%), anorexia (< 10%), diarrhea (< 10%), constipation (< 10%), appetite stimulation (< 1%), weight loss (< 1%), weight gain (< 1%), xerostomia (< 1%), flatulence (< 1%), hemorrhoids (< 1%), and peptic ulcer (< 1%).90 During controlled trials of oral naltrexone 50 mg/day in alcohol dependence, approximately 5% of patients discontinued naltrexone due to nausea. During clinical trials using 380 mg of extended-release injectable naltrexone suspension for alcohol or opioid dependence, the following GI effects were reported more frequently with 380 mg of the active drug than placebo: nausea (33% vs 11%), vomiting (14% vs 6%), diarrhea (13% vs 10%), abdominal pain (11% vs 8%), xerostomia (5% vs 4%), dental pain (toothache 4% vs 2%), and anorexia (14% vs 3%).91 Weight loss, weight gain, abdominal discomfort, colitis, constipation, flatulence, appetite stimulation, gastroenteritis, gastroesophageal reflux disease (GERD), GI bleeding, hemorrhoids, acute pancreatitis, paralytic ileus, and perirectal abscess were also reported. In post-market experience of oral naltrexone, GI effects including anorexia, nausea, vomiting, abdominal pain, and diarrhea have been reported. It is not always possible to distinguish these occurrences from signs and symptoms of naltrexone-induced opiate discontinuation syndrome.90

Injection site reactions have been precipitated following self-administration of the naltrexone extended-release suspension (e.g., Vivitrol). Inform patients that the injection must be prepared by and administered by a healthcare professional. Of 440 patients who received 380 mg of the extended-release injectable suspension of naltrexone (Vivitrol) in clinical trials for alcohol dependence, 69% had an injection site reaction (pain, tenderness, induration, swelling, or itching) versus 50% of those receiving a placebo injection. Specific injection site reactions that occurred more frequently in the active treatment group than the placebo group included injection site tenderness (45% vs 39%), injection site induration (35% vs. 8%), injection site pain (5% to 17% vs. 1% to 7%), nodules/swelling (15% vs. 4%), itching at the injection site (10% vs. 0%), and injection site ecchymosis (7% vs. 5%). One patient developed an area of induration at the injection site that continued to enlarge after 4 weeks. Eventually, necrotic tissue that required surgical excision developed. The FDA has received 196 reports of injection site reactions including cellulitis, induration, hematoma, abscess, sterile abscess, and tissue necrosis. Sixteen patients required surgical intervention ranging from incision and drainage in the cases of abscesses to extensive surgical debridement in the cases that resulted in tissue necrosis. The extended-release injectable suspension of naltrexone should only be administered intramuscularly (IM); the risk of serious injection site reactions may be increased when Vivitrol is deposited in subcutaneous or fatty tissue. Instruct patients to monitor the injection site and to get medical care if they develop pain, swelling, tenderness, induration, bruising, itching, or redness at the injection site that does not improve or worsens within 2 weeks. Promptly refer patients with worsening injection site reactions to a surgeon.91

Urticaria, angioedema, and anaphylactoid reactions (anaphylaxis) have occurred in association with naltrexone administration in both clinical trials and during post-marketing use. Patients should be advised of the potential for serious hypersensitivity reactions while using naltrexone and instructed to seek immediate medical attention in the event of such a reaction.91

During clinical trials using 380 mg of intramuscular (IM) naltrexone, infections reported more frequently within the active drug group than the placebo group included nasopharyngitis (7% vs 2%) and influenza (5% vs 4%).91 Other respiratory or related effects that were reported during IM naltrexone clinical trials included upper respiratory tract infection, advanced HIV disease in HIV-infected patients, bronchitis, chronic obstructive pulmonary disease, dyspnea, laryngitis, pharyngolaryngeal pain, pneumonia, sinus congestion, and sinusitis. Respiratory effects or symptoms of infection occurring in less than 1% of patients during clinical trials of oral naltrexone for opiate dependence included nasal congestion, rhinorrhea, sneezing, sore throat, excess mucus, sinus trouble, hoarseness, cough, fever, and dyspnea.90 Additionally, eosinophilic pneumonia, which may present as dyspnea, coughing, and/or hypoxia, has been reported in association with injectable naltrexone use (see eosinophilic pneumonia).

In clinical trials of intramuscular naltrexone (380 mg) in patients with opioid dependence, 5% of study patients experienced hypertension compared to 3% of those on placebo.91 Other cardiovascular effects observed during clinical trials of intramuscular naltrexone included angina, atrial fibrillation, congestive heart failure, coronary artery atherosclerosis, myocardial infarction, and palpitations. Cardiovascular effects occurring in less than 1% of patients during clinical trials of oral naltrexone for opiate dependence included epistaxis, phlebitis, edema, increased blood pressure, unspecified ECG changes, palpitations, and sinus tachycardia. Cardiac effects reported during post-marketing use of naltrexone include chest pain (unspecified), palpitations, and changes in blood pressure. It is not always possible to distinguish these occurrences from signs and symptoms of naltrexone-induced opiate discontinuation syndrome.90

During clinical trials using 380 mg of intramuscular naltrexone suspension for opioid dependence, the following musculoskeletal effects or pain symptoms were reported more frequently with the active drug than placebo: arthralgia (12% vs 5%), back pain (6% vs 5%), and muscle cramps (8% vs 1%).91 Myalgia, joint stiffness, limb pain, and muscle spasms have also been reported. Musculoskeletal effects or pain symptoms occurring during clinical trials of oral naltrexone for opiate dependence included arthralgia and myalgia (> 10%), shoulder pain (< 1%), knee or leg pain (< 1%), tremor (< 1%), twitching (< 1%), inguinal pain (< 1%), and side pain.90 Tremor and myalgia have been reported during post-marketing use of naltrexone. It is not always possible to distinguish these occurrences from signs and symptoms of naltrexone-induced opiate discontinuation syndrome. Increased creatinine phosphokinase (CPK) concentrations have been associated with naltrexone use. In open-label trials, 16% of patients dosed for more than 6 months had increases in CPK. Increases in 1—2 times the upper limit of normal (ULN) were most common for both the oral naltrexone and IM naltrexone 380 mg groups. Although CPK elevations of 1—2 times ULN were most commonly encountered, elevations as high as 4 times ULN for the oral naltrexone group and 35 times ULN for the IM naltrexone group were noted. However, there were no differences between the placebo and either the oral or IM naltrexone groups with respect to the proportions of patients with a CPK value at least 3 times ULN. No factors other than naltrexone exposure were associated with the CPK elevations.90

Dermatologic or related effects occurring during clinical trials of oral naltrexone for opiate dependence included rash (unspecified) (< 10%), oily skin (< 1%), pruritus (< 1 %), acne vulgaris (< 1%), tinea pedis (< 1%), cold sores (< 1%), and alopecia (< 1%).90 During clinical trials using 380 mg of intramuscular naltrexone suspension, rash occurred more frequently with active drug than placebo (6% vs 4%).91 Other related effects reported with the intramuscular formulation included night sweats, pruritus, heat exhaustion, and hyperhidrosis. Rash and increased sweating have also been reported during post-marketing use of naltrexone. It is not always possible to distinguish these occurrences from signs and symptoms of naltrexone-induced opiate discontinuation syndrome.90

Genitourinary (GU) effects occurring during clinical trials of oral naltrexone included ejaculation dysfunction (delayed ejaculation < 10%), dysuria (< 1%), increased urinary frequency (< 1%), and libido increase or libido decrease (< 1%).90 Decreased libido and urinary tract infection have been reported with the use of the intramuscular formulation.91

Special senses effects (otic, ophthalmic) occurring in less than 1% of patients during clinical trials of oral naltrexone included blurred vision, ocular irritation (burning), light sensitivity (photophobia), eye swelling/ache (ocular inflammation), otalgia, and tinnitus. Unspecified visual impairment has been reported during post-marketing use of oral naltrexone.90 Conjunctivitis and blurred vision have also been reported with the use of the intramuscular formulation. Retinal artery occlusion has been reported rarely after injection with another drug product containing polylactide-co-glycolide (PLG) microspheres. This event has been reported in the presence of abnormal arteriovenous anastomosis. No cases of retinal artery occlusion have been reported during clinical trials or post-market use of the intramuscular formulation of naltrexone.91

Lymphadenopathy and increased white blood cell count have been reported with the use of naltrexone extended-release suspension for injection during clinical trials.91
Acute cholecystitis and cholelithiasis have been reported as treatment-emergent adverse effects in patients who received naltrexone extended-release suspension for injection for alcohol and/or opioid dependence; the incidence of these effects is unknown.91

General effects occurring during clinical trials of oral naltrexone for opiate dependence included increased thirst (polydipsia) (< 10%), chills (< 10%), swollen glands (< 1%), and cold feet (< 1%).90 During clinical trials using 380 mg of intramuscular naltrexone suspension for opioid dependence, asthenia was reported more frequently in the active treatment group than the placebo group (23% vs 12%). Other general events observed during clinical trial evaluation of intramuscular naltrexone included chest tightness, chills, face edema, pyrexia, rigors, and lethargy. Malaise and asthenia have been reported during post-market use of oral naltrexone.91

During clinical trial evaluation of intramuscular naltrexone suspension, metabolic or nutritional effects including dehydration and hypercholesterolemia were observed; however, the frequencies are unknown. In some individuals, the use of opiate antagonists has been associated with a change in baseline levels of some hypothalamic, pituitary, adrenal, or gonadal hormones. The clinical significance of these changes is not fully understood.91

Abrupt withdrawal precipitated by administration of an opioid antagonist to an opioid-dependent patient may result in a withdrawal syndrome severe enough to require hospitalization, and in some cases management in the intensive care unit. Opioid withdrawal has been precipitated following self-administration of the naltrexone extended-release suspension (e.g., Vivitrol). Inform patients that the injection must be prepared by and administered by a healthcare professional. To prevent precipitation of withdrawal, patients should be opioid-free for a minimum of 7 to 10 days prior to initiation of naltrexone. When transitioning from buprenorphine or methadone, patients may be vulnerable to precipitation of withdrawal symptoms for up to two weeks. Precipitated opioid withdrawal has also been observed in alcohol-dependent patients in circumstances where the prescriber had been unaware of the additional use of opioids or co-dependence on opioids. Make patients aware of the risks associated with precipitated withdrawal and the need to give an accurate account of last opioid use. Studies of naltrexone in alcoholic populations and in volunteers in clinical pharmacology studies have suggested that a small fraction of patients may experience an opioid discontinuation-like symptom complex including, but not limited to, tearfulness, abdominal cramps, bone, muscle, or joint pain, nasal symptoms, and feeling restless. These symptoms may represent the unmasking of occult opioid use or it may represent symptoms attributable to naltrexone. Patients treated for alcohol dependence with naltrexone should be assessed for underlying opioid dependence and for any recent use of opioids prior to initiation of treatment. Because there is no completely reliable method for determining whether a patient has had an adequate opioid-free period, prescribers should always be prepared to manage withdrawal symptomatically with non-opioid medications. A naloxone challenge test may be helpful; however, a few case reports have indicated that patients may experience precipitated withdrawal despite having a negative urine toxicology screen or tolerating a naloxone challenge test (usually in the setting of transitioning from buprenorphine treatment). Withdrawal symptoms and death have been reported during the use of naltrexone in ultra rapid detoxification programs; the causes of death are not known. If rapid transition from agonist to antagonist therapy is considered necessary and appropriate by the healthcare provider, patients should be closely monitored in an appropriate medical setting where precipitated withdrawal can be managed.9190

Caffeine

Caffeine has been noted to produce a variety of gastrointestinal (GI) effects. At therapeutic or nontoxic doses, caffeine can stimulate gastric secretions and may cause GI upset (dyspepsia), nausea, loose stools, and may aggravate gastroesophageal reflux disease (GERD).969495137 Occasionally diarrhea is reported. The mild dehydration that caffeine produces may aggravate constipation. A temporary reduction in weight gain has also been reported. In a study comparing caffeine to placebo, the mean difference in weight gain was the greatest after 2 weeks of therapy.138 Feeding intolerance (8.7%), gastritis (2.2%), and GI bleeding (2.2%) also occurred in the caffeine treatment groups.94 During a controlled clinical trial of caffeine citrate in premature infants (n = 85 neonates), necrotizing enterocolitis was reported in 6 patients, 5 of whom were administered caffeine. Three of the infants died. The incidence was 4.3% in caffeine-treatment groups vs. 2.6% of placebo-treated infants. In a much larger clinical trial (n = 2,000 neonates) evaluating the use of caffeine citrate in apnea of prematurity, necrotizing enterocolitis was not more common in caffeine treated patients compared to placebo.5395138 In a study evaluating the effect of caffeine on the splanchnic perfusion after a caffeine loading dose, the blood flow velocity was depressed for 2 to 3 hours after the infusion and slowly returned to baseline after approximately 6 hours.139 Clinicians should be alert for signs and symptoms of gastric distress, abdominal bloating, nausea, vomiting, bloody stools, and lethargy in treated infants.5394 Excessive caffeine intake or intoxication in children, adolescents, and adults may cause vomiting along with other signs of caffeine intoxication.137 In humans, a caffeine concentration of greater than 50 mg/L may produce toxic symptoms.

Caffeine is a CNS stimulant. Many adverse reactions to caffeine are an extension of caffeine's pharmacologic actions. At therapeutic or nontoxic doses, caffeine can commonly cause nervousness, mild tremor, and heightened attentiveness.137 Less frequent adverse reactions with usual consumption also include excitement, irritability, insomnia, headache, and muscle twitches.140141 Increased caffeine use among children and adolescents has been associated with insomnia, chronic headache, motor tics, irritability, learning difficulties, and other adverse health effects.137142143 After excessive doses, caffeine can cause considerable anxiety. Seizures and delirium are also possible.137 In humans, a caffeine level of > 50 mg/L may produce toxic symptoms. Other neurologic events have been reported in preterm neonates. In clinical trials of caffeine citrate in preterm neonates, cerebral hemorrhage (intracranial bleeding) was reported in 2.2% of treated patients versus 0% of neonates receiving placebo.53

Caffeine is a mild diuretic and patients may have increased urinary frequency. Polyuria can occur. Increased creatinine clearance and increased urinary calcium (hypercalciuria) and sodium excretion are reported in the literature.53

Adverse events to caffeine that have been described in the published literature include alterations in serum glucose such as hypoglycemia and hyperglycemia.53

In controlled clinical trials of caffeine citrate injection in premature neonates, the following adverse events occurred more commonly in caffeine-treatment groups than with placebo: accidental injury (2.2%), bleeding (2.2%), disseminated intravascular coagulation (2.2%), dyspnea (2.2%), pulmonary edema (2.2%), metabolic acidosis (2.2%), xerosis (2.2%), rash (unspecified) (8.7%), renal failure (unspecified) (2.2%), retinopathy of prematurity (2.2%), and skin breakdown (2.2%). In neonates, intolerance or overdose of caffeine may manifest as tachypnea. No deaths have been reported in relation to overdose of caffeine in neonates.53

Too much caffeine may occasionally cause rapid heartbeat.144 Cardiovascular effects of caffeine have been reported in the literature (i.e., palpitations, sinus tachycardia, increased left ventricular output, and increased stroke volume).53

High caffeine intake has been reported to negatively affect sperm quality, including spermatogenesis inhibition). The propensity for caffeine to negatively affect fertility is controversial. Although controversial, infertility, as manifested by increased difficulty in getting pregnant, has been reported in females. Couples who are pursuing pregnancy should probably limit excessive intake of caffeine.

A distinct caffeine withdrawal syndrome has been described. Patients who consume or receive caffeine daily for several weeks experience notable physical and psychiatric responses including lethargy, anxiety, dizziness, or rebound headache upon caffeine withdrawal.137

Metformin

Possible side effects include: Diarrhea; headache; heartburn; metallic taste in mouth; nausea; stomach gas, upset. This list may not describe all possible side effects. Call your doctor for medical advice about side effects.

Gastrointestinal adverse effects are the most common experienced by patients taking metformin.62 In clinical trials, diarrhea was experienced by 53.2% of patients receiving immediate-release metformin monotherapy, and was a reason for drug discontinuation in 6%. Extended-release formulations cause diarrhea in roughly 9.6% of patients. Nausea and vomiting are reported in 6.5—25.5% of all patients taking metformin; with the lower incidences seen in patients receiving extended-release products. Other common GI effects include flatulence (1—12.1%), indigestion or dyspepsia (1—7.1%), and abdominal pain or discomfort (1—6.4%). GI effects occurring in 1—5% of patients include include anorexia, dysgeusia (metallic taste or other taste disturbance), and a change in stool appearance. Frequent side effects tend to decline with continued use and can be minimized by initiating therapy with low doses of metformin. In pediatric patients with diabetes mellitus type 2 treated with metformin, the adverse event profiles and incidences are similar to those seen in adults.

The risk of hypoglycemia is much less common with metformin than with the sulfonylureas,40 however, it has been reported with metformin monotherapy in clinical trials at an incidence of 1—5%.62 Other studies have reported varying incidences of hypoglycemia. In one nested case-control analysis of over 50,000 subjects with type 2 diabetes mellitus, the rate of hypoglycemia due to metformin monotherapy yielded a crude incidence rate of 3.3 cases among 100,000 person-years compared with 4.8 cases among sulfonylurea users per 100,000 person years; the incidence of hypoglycemia was significantly higher in sulfonylurea-treated patients.105 In a separate systematic review, the rates for hypoglycemia with metformin monotherapy varied in the studies reviewed between 0—21%, with the risk of major hypoglycemic episodes reported to be rare.145 Hypoglycemia is more common when metformin is coadministered with other oral hypoglycemic agents (especially sulfonylureas), when ethanol has been ingested, or when there is deficient caloric intake or strenuous exercise not compensated by caloric supplementation.62145 Since metformin reverses insulin resistance, and subsequently causes a decrease in insulin concentrations, metformin-induced hypoglycemia is usually mild and does not necessitate the discontinuation of therapy. In overdose, hypoglycemia is noted in roughly 10% of patients, but causal association with metformin is not established.62

Asymptomatic vitamin B12 deficiency was reported with metformin monotherapy in 7% of patients during clinical trials.62 Serum folic acid concentrations did not decrease significantly. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin treatment or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at 2- to 3-year intervals may be useful. Rare cases of megaloblastic anemia have been reported with metformin (none in the US); incidence rates are expected to be < 1% for symptomatic deficiency.62

Mild weight loss may occur during therapy with metformin, perhaps as a result of its ability to cause anorexia. Such weight loss can be expected in almost any patient with type 2 diabetes receiving metformin monotherapy; however, weight loss may attenuate when metformin is combined with other treatments. A mean weight loss of 1—8.4 lbs was reported in clinical trials of adults receiving monotherapy with metformin immediate release products; a mean weight loss of 2—3 lbs was reported in pediatric studies.62 When extended-release tablets were used, the weight loss was not clinically significant in adults and mean reductions ranged from 0.7—2.2 lbs.62

Lactic acidosis is a rare, but serious, form of metabolic acidosis that can occur if metformin accumulates during treatment; when it occurs, it is fatal in approximately 50% of cases. The onset of lactic acidosis often is subtle, and accompanied only by early nonspecific symptoms such as malaise and myalgia (1—5% of patients), and quickly followed by respiratory distress (dyspnea 1—5%), increasing somnolence, and nonspecific abdominal distress. Lactic acidosis is a medical emergency that must be treated in a hospital setting; metformin should be discontinued immediately and general supportive measures promptly instituted. Prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery.62 Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels > 5 mcg/mL are generally found. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked metabolic acidosis. The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years); of nearly 20,000 patients in clinical trials, there were no reports of lactic acidosis.62 A nested case-control study of 50,048 patients with type 2 diabetes mellitus demonstrated that during concurrent use of oral diabetes drugs, there were 6 identified cases of lactic acidosis; all of the subjects had relevant co-morbidities known to be risk factors for lactic acidosis.105 The incidence of lactic acidosis appears to be no more common in metformin recipients without comorbid conditions than in recipients of other antidiabetic agents.145 Risk factors include significant renal insufficiency, the presence of multiple concomitant medical/surgical problems (e.g., liver disease, alcoholism, cardiorespiratory insufficiency or other conditions associated with tissue hypoperfusion or hypoxemia), and exposure to multiple concomitant medications known to increase risks. The risk of lactic acidosis increases with the degree of renal impairment and the patient's age. Lactic acidosis is less likely to occur with metformin than with other biguanide agents (e.g., phenformin), because metformin is not metabolized, does not bind to liver or plasma proteins, and is excreted by active tubular processes. Regular monitoring of renal function and by use of the minimum effective dose of metformin may reduce the risk of this adverse reaction. Patients should be informed to discontinue metformin should symptoms suggestive of lactic acidosis appear and promptly report the symptoms to their physician.

The following miscellaneous adverse reactions were reported in 1—5% of patients treated with metformin and occurred more commonly than in patients treated with placebo: lightheaded (dizziness), nail disorder, rash (unspecified), hyperhidrosis (sweating increased), chest pain (unspecified) or chest discomfort, chills, flu syndrome or upper respiratory infection, flushing, and palpitations.62

This list may not include all possible adverse reactions or side effects. Call your health care provider immediately if you are experiencing any signs of an allergic reaction: skin rash, itching or hives, swelling of the face, lips, or tongue, blue tint to skin, chest tightness, pain, difficulty breathing, wheezing, dizziness, red, a swollen painful area/areas on the leg.

Methylcobalamin

In most cases, methylcobalamin is nontoxic, even in large doses. Adverse reactions reported following methylcobalamin administration include headache, infection, nausea/vomiting, paresthesias, and rhinitis. Adverse reactions following intramuscular (IM) injection have included anxiety, mild transient diarrhea, ataxia, nervousness, pruritus, transitory exanthema, and a feeling of swelling of the entire body. Some patients have also experienced a hypersensitivity reaction following intramuscular injection that has resulted in anaphylactic shock and death. In cases of suspected cobalt hypersensitivity, an intradermal test dose should be administered.

During the initial treatment period with methylcobalamin, pulmonary edema and congestive heart failure have reportedly occurred early in treatment with parenteral methylcobalamin. This is believed to result from the increased blood volume induced by methylcobalamin. Peripheral vascular thrombosis has also occurred. In post-marketing experience, angioedema and angioedema-like reactions were reported with parenteral methylcobalamin.

Hypokalemia and thrombocytosis could occur upon conversion of severe megaloblastic anemia to normal erythropoiesis with methylcobalamin therapy. Therefore, monitoring of the platelet count and serum potassium concentrations are recommended during therapy. Polycythemia vera has also been reported with parenteral methylcobalamin.

Diarrhea and headache.

Call your health care provider immediately if you are experiencing any signs of an allergic reaction: skin rash, itching or hives, swelling of the face, lips, or tongue, blue tint to skin, chest tightness, pain, difficulty breathing, wheezing, dizziness, red, swollen painful area on the leg.

Oxytocin

Some patients can experience a hypersensitive uterine reaction to the effects of oxytocin. Excessive doses can have the same effect. This can produce increased, hypertonic uterine contractions, possibly prolonged, resulting in a number of adverse reactions such as cervical laceration, postpartum hemorrhage, pelvic hematoma, and uterine rupture.146

Oxytocin-induced afibrinogenemia has been reported; it results in increased postpartum bleeding and can potentially be life-threatening. Neonatal retinal hemorrhage has been reported. Also, intracranial bleeding including subarachnoid hemorrhage has been reported in patients receiving oxytocin.146 In one case, subarachnoid hemorrhage mimicked acute water intoxication and delayed the diagnosis of hemorrhage after an oxytocin assisted labor.147

Adverse maternal cardiovascular effects from oxytocin may include arrhythmia exacerbation, premature ventricular contractions (PVCs), and hypertension. In the fetus or neonate, fetal bradycardia, PVCs, and other arrhythmias have been noted.146

Oxytocin has an antidiuretic effect, and severe and fatal water intoxication has been noted and may occur if large doses (40—50 milliunits/minute) are infused for long periods. For example, water intoxication with seizures and coma has occurred in association with a slow oxytocin infusion over a 24-hour period. Management of water intoxication includes immediate oxytocin cessation and supportive therapy. In the fetus or neonate, fetal death, permanent CNS or brain damage, and neonatal seizures have been noted with oxytocin.146 The rare complications of blurred vision, ocular hemorrhage (of the conjunctiva), and pulmonary edema have been associated with oxytocin induced water intoxication.

Oxytocin administration has been associated with anaphylactoid reactions.146

Oxytocin-induced labor has been implicated in an increased incidence of neonatal hyperbilirubinemia, about 1.6 times more likely than after spontaneous labor. This can lead to neonatal jaundice.146

Nausea and vomiting have been noted with oxytoxin.146

Side effects that you should report to your doctor or health care professional as soon as possible:

  • allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue
  • breathing problems
  • excessive or continuing vaginal bleeding
  • fast, irregular heartbeat
  • feeling faint or lightheaded, falls
  • high blood pressure
  • seizures
  • unusual bleeding or bruising
  • unusual swelling, sudden weight gain

Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome):

  • headache
  • nausea and vomiting

This list may not include all possible adverse reactions or side effects. Call your health care provider immediately if you are experiencing any signs of an allergic reaction: skin rash, itching or hives, swelling of the face, lips, or tongue, blue tint to skin, chest tightness, pain, difficulty breathing, wheezing, dizziness, red, a swollen painful area/areas on the leg.

Storage

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond-use date. Do not flush unused medications or pour down a sink or drain.

  • 1. a. b. c. Skowron DM, Stimmel GL. Antidepressants and the risk of seizures. Pharmacotherapy 1992;12:18-22.
  • 2. Wilens TE, Haight BR, Horrigan JP, et al. Bupropion XL in adults with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled study. Biol Psychiatry 2005;57:793-801.
  • 3. Semenchuk MR, Sherman S, Davis B. Double-blind, randomized trial of bupropion SR for the treatment of neuropathic pain. Neurology 2001;57:1583-1588.
  • 4. Institute for Clinical Systems Improvement (ICSI). Major depression in adults for mental health care. Bloomington (MN): Institute for Clinical Systems Improvement (ICSI); 2004 May. Available on the World Wide Web at www.guideline.gov
  • 5. Care Management Institute, Kaiser Permanente. Adult primary care depression guidelines. Oakland (CA): Kaiser Permanente; 2004 Apr. Retrieved October 27, 2005. Available on the World Wide Web at www.guidelines.gov
  • 6. American Psychiatric Association. Practice guidelines for the treatment of patients with major depressive disorder. Am J Psychiatry 2000;157(4 Suppl):1-45.
  • 7. Modell JG, Rosenthal NE, Harriett AE, et al. Seasonal affective disorder and its prevention by anticipatory treatment with bupropion XL. Biol Psychiatry 2005;58:658-67.
  • 8. a. b. c. d. Suprenza (phentermine hydrochloride) package insert. Cranford, NJ: Akrimax Pharmaceuticals; 2011 Oct.
  • 9. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. q. r. s. t. u. v. w. x. y. z. . . . . . . . . . . . . . . . . . . . . . Topamax (topiramate) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2021 Jun.
  • 10. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. q. r. s. t. u. v. w. x. Trokendi XR (topiramate extended-release capsules) package insert. Rockville, MD: Supernus Pharmaceuticals; 2020 Nov.
  • 11. a. b. c. d. e. f. g. h. i. j. k. l. Qudexy XR (topiramate) package insert. Maple Grove, MN: Upsher-Smith Laboratories; 2021 Feb.
  • 12. Silberstein SD, Holland S, Freitag F, et al. Evidence based guideline update: pharmacologic treatment for episodic migraine prevention in adults. Report of the quality standards subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 2012;78:1337-1345.
  • 13. American Headache Society. The American Headache Society position statement on integrating new migraine treatments into clinical practice. Headache 2018;59:1-18.
  • 14. Oskoui M, Pringsheim T, Billinghurst L, et al. Practice guideline update summary: Pharmacologic treatment for pediatric migraine prevention: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 2019 [Epub ahead of print]
  • 15. McElroy SL. Pharmacologic treatments for binge-eating disorder. J Clin Psychiatry 2017;78:14-19.
  • 16. Work Group on Alcohol Use Disorder, American Psychiatric Association. Practice guideline for the pharmacological treatment of patients with alcohol use disorder. American Psychiatric Association 2018. Available on the web at https://psychiatryonline.org/doi/pdf/10.1176/appi.books.9781615371969.
  • 17. Pringsheim T, Okun MS, Muller-Vahl K, et al. Practice guideline recommendations summary: Treatment of tics in people with Tourette syndrome and chronic tic disorders. Neurology 2019;92:896-906.
  • 18. O’Connor PG, Kosten TR. Rapid and ultrarapid opioid detoxification techniques. JAMA 1998;279:229-234.
  • 19. Scanlon JEM, Chin KC, Morgan MEI, et al. Caffeine or theophylline for neonatal apnea? Arch Dis Child 1992;67:425-8.
  • 20. Cabanac M, Pfaff DW, Ogawa S, et al. Neural oxytocinergic systems as genomic targets for hormones and as modulators of hormone-dependent behaviors. Results Probl Cell Differ 1999;26:91-105.
  • 21. Modahl C, Green L, Fein D, et al. Plasma oxytocin levels in autistic children. Biol Psychiatry 1998;43:270-277.
  • 22. a. b. Lalau JD, Lacroix C, Compagnon P, et al. Role of metformin accumulation in metformin-associated lactic acidosis. Diabetes Care 1995;18:779-84.
  • 23. Hermann LS, Scherstein B, Bitzen PO, et al. Therapeutic comparison of metformin and sulfonylurea, alone, and in various combinations. A double-blind controlled study. Diabetes Care 1994;17:1100-9.
  • 24. a. b. Kosasa TS. Making a Case for Metformin. OB/GYN 2003;48:69-80.
  • 25. Ibanez L, Ong K, Valls C, et al. Metformin treatment to prevent early puberty in girls with precocious puberty. J Clin Endocrinol Metab 2006;91:2888-91.
  • 26. Ibanez L, Valls C, Ong K, et al. Metformin therapy during puberty delays menarche, prolongs puberal growth, and augments adult height: a randomized study in low-birth-weight girls with early-normal onset of puberty. J Clin Endocrinol Metab 2006;0:2068-73.
  • 27. Doggrell SA. Metformin & lifestyle intervention prevent Type 2 diabetes: lifestyle intervention has the greater effect. Expert Opin Pharmacother 2002;3:1011-3.
  • 28. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes
  • 29. American Diabetes Association. Standards of medical care in diabetes-2012. Diabetes Care 2012;35(suppl1):S11-S63.
  • 30. American Diabetes Association. Standards of medical care in diabetes-2014. Diabetes Care 2014;37(suppl1):S14-S80.
  • 31. Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577-89.
  • 32. Blonde L, Dailey GE, Jabbour SA, et al. Gastrointestinal tolerability of extended-release metformin tablets compared to immediate-release metformin tablets: results of a retrospective cohort study. Curr Med Res Opin 2004; 20(4):565-72.
  • 33. 31285
  • 34. Wagstaff AJ, Figgit DP. Extended-release metformin hydrochloride. Single composition osmotic tablet formulation. Treat Endocrinol 2004;3:327-32.
  • 35. a. b. Bryant SG, Guernsey BG, Ingrim NB. Review of bupropion. Clin Pharm 1983;2:525-37.
  • 36. a. b. c. d. e. f. g. h. i. Adipex-P (phentermine hydrochloride tablets and capsules) package insert. Sellersville, PA: Teva Pharmaceuticals; 2013 Jan.
  • 37. Zolkowska D, Rothman RB, Baumann MH. Amphetamine analogs increase plasma serotonin: implications for cardiac and pulmonary disease. J Pharmacol Exp Ther. 2006;318:604-610.
  • 38. Filippi L, Fiorini P, Daniotti M. Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI). BMC Pediatrics 2012;12:144-155.
  • 39. a. b. c. d. e. American College of Obstetrics and Gynecology (ACOG). ACOG Practice Bulletin Number 10: Clinical Management Guidelines for Obstetrician-Gynecologists. Induction of labor. Washington, DC: American College of Obstetricians and Gynecologists; November 1999.
  • 40. a. b. c. d. Bailey CJ, Turner RC. Metformin. N Engl J Med 1996;334:574-9.
  • 41. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. q. r. s. t. u. v. w. x. y. z. . . . . . . . . . . . . . . . . . . Wellbutrin (bupropion) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2020 Oct.
  • 42. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. q. r. s. t. u. v. w. x. y. z. . . . . . . . . . . . Wellbutrin XL (bupropion) package insert. Bridgewater, NJ: Bausch Health US, LLC; 2019 Nov.
  • 43. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. q. r. s. t. u. v. w. x. y. z. . . . . . . . . . . . Aplenzin (bupropion extended-release tablet) package insert. Bridgewater, NJ: Sanofi-aventis, LLC.; 2020 May.
  • 44. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. q. r. s. t. u. v. w. x. y. z. . . . . . . . . Wellbutrin SR (bupropion) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2020 Oct.
  • 45. a. b. c. d. e. f. g. Forfivo XL (bupropion hydrochloride extended-release tablets) package insert. Buffalo, NY: IntelGenx Corp; 2019 Dec.
  • 46. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. q. r. s. t. u. v. w. x. y. z. . . . . . . . . . . Zyban (bupropion sustained release tablets) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2021 Mar.
  • 47. a. b. Daviss WB, Perel JM, Rudolph GR, et al. Steady-state pharmacokinetics of bupropion SR in juvenile patients. J Am Acad Child Adolesc Psychiatry 2005;44:349-57.
  • 48. a. b. c. d. Rosenfeld WE, Doose DR, Walker SA. A study of topiramte pharmacokinetics and tolerability in children with epilepsy. Pediatr Neurol 1999;20:339-344.
  • 49. a. b. c. d. Manitpisitkul P, Shalayda K, Todd M. Pharmacokinetics and safety of adjunctive topiramate in infants (1-24 months) with refractory partial-onset seizures: a randomized, multicenter, open-label phase 1 study. Epilepsia 2013;54:156-164.
  • 50. Mikaeloff Y, Rey E, Soufflet C. Topiramate pharmacokinetics in children with epilepsy aged from 6 months to 4 years. Epilepsia 2004;45:1448-1452.
  • 51. Castano G, Mas R, Nodarse M, et al. One-year study of the efficacy and safety of policosanol (5 mg twice daily) in the treatment of type II hypercholesterolemia. Curr Ther Res 1995;56:296-304.
  • 52. Filippi L, la Marca G, Fiorini P. Topiramate concentrations in neonates treated with prolonged whole body hypothermia for hypoxic ischemic encephalopathy. Epilepsia 2009;50:2355-2361.
  • 53. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. q. r. s. t. u. v. w. x. Cafcit (caffeine citrate) package insert. Eatontown, NJ: West-Ward Pharmaceuticals; 2019 Dec.
  • 54. a. b. c. Charles BG, Townsend SR, Steer PA, et al. Caffeine citrate treatment for extremelypremature infants with apnea: population pharmacokinetics, absolute bioavailability, and implications for therapeutic drug monitoring. Ther Drug Monit 2008; 30:709–16
  • 55. Sawynok J, Yaksh T. Caffeine as an Analgesic Adjuvant: A Review of Pharmacology and Mechanisms of Action. Pharmacol Rev 1993; 45(1): 43 - 85.
  • 56. Hansten PD, Horn JR. Cytochrome P450 Enzymes and Drug Interactions, Table of Cytochrome P450 Substrates, Inhibitors, Inducers and P-glycoprotein, with Footnotes. In: The Top 100 Drug Interactions - A guide to Patient Management. 2008 Edition. Freeland, WA: H&H Publications; 2008:142-157.
  • 57. a. b. Spitzer AR. Evidence-Based Methylxanthine Use in the NICU. Clin Perinatol 2012. 39: 127-148.
  • 58. Aldridge A, Aranda JV, Neims AH. Caffeine metabolism in the newborn. Clin Pharmacol Ther; 1979 25(4):447-53.
  • 59. Al-Alaiyan S, Al-Rawithi S, Raines D et al. Caffeine Metabolism in Premature Infants. Journal of Clinical Pharmacology; 2001 41(6): 620-7.
  • 60. a. b. Lee T, Charles B, Steer P, et al. Population pharmacokinetics of intra-venous caffeine in neonates with apnea of prematurity. Clin Pharmacol Ther. 1997;61:628–640.
  • 61. a. b. Pearlman SA, Duran C, Wood MA, et al. Caffeine pharmacokinetics in preterm infants older than 2 weeks. Dev Pharmacol Ther 1989;12:65–9.
  • 62. a. b. c. d. e. f. g. h. i. j. k. l. m. n. Glucophage®/Glucophage® XR (metformin) package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2009 Jan.
  • 63. Robert F, Fendri S, Hary L,et al. Kinetics of plasma and erythrocyte metformin after acute administration in healthy subjects. Diabetes Metab 2003;Gerich JE. Oral hypoglycemic agents. N Engl J Med 1989;321:1231—45.:279–83.
  • 64. a. b. c. d. e. f. g. Wellbutrin XL (bupropion) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2019 Nov.
  • 65. a. b. Vetter VL, Elia J, Erickson C, et al. Cardiovascular monitoring of children and adolescents with heart disease receiving medications for attention deficit/hyperactivity disorder: a scientific statement from the American HeartAssociation Council on Cardiovascular Disease in the Young Congenital Heart Defects Committee and the Council on Cardiovascular Nursing. Circulation 2008; 117: 2407-23.
  • 66. Wigal SB. Efficacy and safety limitations of attention-deficit hyperactivity disorder pharmacotherapy in children and adults. CNS Drugs 2009;23:21-31.
  • 67. Spencer T, Biederman J, Steingard R, et al. Bupropion exacerbates tics in children with attention-deficit hyperactivity disorder and Tourette’s syndrome. J Am Acad Child Adolesc Psychiatry 1993;32:211-4.
  • 68. US Food and Drug Administration (FDA). FDA Safety Communication: FDA revises description of mental health side effects of the stop-smoking medicines Chantix (varenicline) and Zyban (bupropion) to reflect clinical trial findings. Retrieved Dec 22, 2016. Available on the World Wide Web at: http://www.fda.gov/Drugs/DrugSafety/ucm532221.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery
  • 69. a. b. Lumley J, Chamberlain C, Dowswell T, Oliver S, Oakley L, Watson L. Interventions for promoting smoking cessation during pregnancy. Cochrane Database Syst Rev. 2009:CD001055
  • 70. a. b. Massachusetts General Hospital Center for Women’s Mental Health. National Pregnancy Registry for Psychiatric Medications. Available on the World Wide Web at: https://womensmentalhealth.org/research/pregnancyregistry/.
  • 71. a. b. Haas JS, Kaplan CP, Barenboim D, et al. Bupropion in breast milk: an exposure assessment for potential treatment to prevent post-partum tobacco use. Tob Control 2004;13:52-6.
  • 72. a. b. Chaudron LH, Schoenecker CJ. Bupropion and breastfeeding: a case of a possible infant seizure. J Clin Psychiatry 2004;65:881-2.
  • 73. a. b. Baab SW, Peindl KS, Piontek CM, et al. Serum bupropion levels in 2 breastfeeding mother-infant pairs. J Clin Psychiatry 2002;63:910-11.
  • 74. a. b. Weissman AM, Levy BT, Hartz AJ, et al. Pooled analysis of antidepressant levels in lactating mothers, breast milk, and nursing infants. Am J Psychiatry 2004;161:1066-78.
  • 75. a. b. DiFranza JR, Aligne CA, Weitzman M. Prenatal and postnatal environmental tobacco smoke exposure and children’s health. Pediatrics. 2004;113:1007-1015.
  • 76. a. b. Health Care Financing Administration. Interpretive Guidelines for Long-term Care Facilities. Title 42 CFR 483.25(l) F329: Unnecessary Drugs. Revised 2015.
  • 77. a. b. c. d. e. f. g. Adipex-P (phentermine hydrochloride tablets and capsules) package insert. Sellersville, PA: Teva Pharmaceuticals; 2013 Jan.
  • 78. a. b. c. d. e. f. g. h. i. j. k. Suprenza (phentermine hydrochloride) package insert. Cranford, NJ: Akrimax Pharmaceuticals; 2011 Oct.
  • 79. a. b. c. d. e. Phentermine hydrochloride package insert. Newtown, PA: KVK-Tech Inc; 2010 April.
  • 80. a. b. Steiner E, Villen T, Hallberg M, et al. Amphetamine secretion in breast milk. Eur J Clin Pharmacol 1984;27:123-4.
  • 81. a. b. c. d. Kelly TE, Hackett PH. Acetazolamide and sulfonamide allergy: a not so simple story. High Alt Med Biol 2010;11:319-323.
  • 82. a. b. c. Brackett CC. Sulfonamide allergy and cross-reactivity. Curr Allergy Asthma Rep 2007;7:41-48.
  • 83. a. b. Platt D, Griggs RC. Use of acetazolamide in sulfonamide-allergic patients with neurologic channelopathies. Arch Neurol 2012;69:527-529.
  • 84. a. b. Strom BL, Schinnar R, Apter AJ, et al. Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. New Engl J Med 2003;349:1628-35.
  • 85. a. b. Ben-Zeev B, Watemberg N, Augarten A, et al. Oligohydrosis and hyperthermia: a pilot study of a novel topiramate adverse effect. J Child Neurol 2003;18:254-7.
  • 86. Yamamoto Y, Takahashi Y, Imai K. Risk factors for hyperammonemia in pediatric patients with epilepsy. Epilepsia 2013;54:983-989.
  • 87. The American Geriatrics Society 2019 Beers Criteria Update Expert Panel. American Geriatrics Society 2019 updated AGS Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc 2019;00:1-21.
  • 88. a. b. Food and Drug Administration MedWatch. Topamax (topiramate): label change - risk for development of cleft lip and/or cleft palate in newborns. Retrieved March 4, 2011. Available on the World Wide Web http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm245777.htm
  • 89. a. b. Ohman I, Vitols S, Luef G, et al. Topiramate kinetics during delivery, lactation, and in the neonate: preliminary observations. Epilepsia 2002;43:1157-60.
  • 90. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. q. r. s. Naltrexone (naltrexone hydrochloride) package insert. Hazelwood, MO: Mallinckrodt, Inc. 2009 Feb.
  • 91. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. q. r. s. t. u. v. w. x. y. z. . . . . Vivitrol (naltrexone extended release injectable suspension) package insert. Waltham, MA: Alkermes, Inc.; 2021 Mar.
  • 92. a. b. c. d. e. f. g. h. i. Revia (naltrexone hydrochloride) package insert. Pomona, NY: Duramed Pharmaceuticals, Inc. 2013 Oct.
  • 93. a. b. c. d. American Academy of Pediatrics (AAP) Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001;108(3):776-789.
  • 94. a. b. c. d. Bhatia J. Current options in the management of apnea of prematurity. Clin Pediatr 2000;39:327-36.
  • 95. a. b. c. Erenberg A, Leff RD, Haack DG, et al. Caffeine Citrate for the Treatment of Apnea of Prematurity: A Double-Blind, Placebo-Controlled Study. Pharmacotherapy 2000;20(6):644–652.
  • 96. a. b. Kaltenbach T, Crockett S, Gerson LB. Are lifestyle measures effective in patients with gastroesophageal reflux disease? An evidence-based approach. Arch Intern Med. 2006;166:965-971.
  • 97. a. b. c. Christian MS, Brent RL. Teratogen update: evaluation of the reproductive and developmental risks of caffeine. Teratology 2001;64:51-78.
  • 98. a. b. c. Hadeed A, Siegel S. Newborn cardiac arrhythmias associated with maternal caffeine use during pregnancy. Clin Pediatr 1993;32:45-7.
  • 99. a. b. Le Guennec JC, Billon B. Delay in caffeine elimination in breast-fed infants. Pediatrics 1987;79:264-8.
  • 100. a. b. Berlin CM, Denson HM, Daniel CH, et al. Disposition of dietary caffeine in milk, saliva, and plasma of lactating women. Pediatrics 1984;73:59-63.
  • 101. a. b. Tyrala EE, Dodson WE. Caffeine secretion into breast milk. Arch Dis Child 1979;54:787-800.
  • 102. a. b. Hill RM, Craig JP, Chaney MD, et al. Utilization of over-the-counter drugs during pregnancy. Clin Obstet Gynecol 1977;20:381-94.
  • 103. Awake (caffeine) tablet package insert. Deerfield, IL: Walgreen Co. 05/214.
  • 104. a. b. Mangesi L, Dowswell T. Treatments for breast engorgement during lactation. Cochrane Database Syst Rev. 2010;9:CD006946.
  • 105. a. b. c. Bodmer M, Meier C, Krahenbuhl S, et al. Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia. Diabetes Care 2008;31:2086-91.
  • 106. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position statement of the ADA and EASD. Diabetes Care 2012. Epub ahead of print, doi: 10.2337/dc12-0413
  • 107. Lipska KJ, Bailey CJ, Inzucchi SE. Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care 2011;34:1432-1437.
  • 108. Eurich DT, McAlister FA, Blackburn DF, et al. Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review. BMJ 2007;335(7618):497 Epub 2007 Aug 30
  • 109. Ting RZ, Szeto CC, Chan MH, et al. Risk factors of vitamin B12 deficiency in patients receiving metformin. Arch Intern Med 2006;166:1975-9.
  • 110. a. b. Vanky E, Zahlsen K, Spigset O, et al. Placental passage of metformin in women with polycystic ovary syndrome. Fertil Steril 2005;83:1575-8.
  • 111. a. b. Glueck CJ, Goldenberg N, Pranikoff J, et al. Height, weight, and motor-social development during the first 18 months of life in 126 infants born to 109 mothers with polycystic ovary syndrome who conceived on and continued metformin through pregnancy. Hum
  • 112. a. b. Coetzee EJ, Jackson WPU. Metformin in management of pregnant insulin-dependent diabetics. Diabetologia 1979;16:421-425.
  • 113. a. b. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin Number 60: Pregestational diabetes mellitus. Obstet Gynecol 2005;105:675-85.
  • 114. a. b. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin Number 30: Gestational diabetes. Obstet Gynecol 2001;98:525-38.
  • 115. a. b. Dhulkotia JS, Ola B, Fraser R, et al. Oral hypoglycemic agents vs insulin in management of gestational diabetes: a systematic review and metaanalysis. Am J Obstet Gynecol 2010;203:457.
  • 116. a. b. Balani J, Hyer SL, Rodin DA, et al. Pregnancy outcomes in women with gestational diabetes treated with metformin or insulin: a case-control study. Diabet Med 2009;26:798-802.
  • 117. a. b. Hale TW, Kristensen JH, Hackett LP, et al. Transfer of metformin into human milk. Diabetologia 2002;45:1509-14.
  • 118. a. b. Gardiner SJ, Kirkpatrick CMJ, Begg EJ, et al. Transfer of metformin into human milk. Clin Pharmacol Ther 2003;73:71-7.
  • 119. a. b. Briggs GG, Ambrose PJ, Nageotte MP, et al. Excretion of metformin into breast milk and the effect on nursing infants. Obstet Gynecol 2005;105:1437-41.
  • 120. a. b. Glueck CJ, Salehi M, Sieve L, et al. Growth, motor, and social development in breast- and formula- fed infants of metformin-treated women with polycystic ovary syndrome. J Pediatr 2006;148:628-32.
  • 121. a. b. Everett J. Use of oral antidiabetic agents during breastfeeding. J Hum Lact 1997;13:319-21.
  • 122. a. b. American Academy of Pediatrics (AAP) Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776-89.
  • 123. a. b. Spencer JP, Gonzalez LS, Barnhart DJ. Medications in the breast-feeding mother. Am Fam Physician; 64:119-26.
  • 124. Food and Drug Administration Adverse Event Reporting System. Potential signals of serious risks/new safety information identified from the FDA adverse event reporting system (FAERS): July - September 2017. Available on the worldwide web at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm592379.htm
  • 125. Descamps V, Ranger-Rogez S. DRESS syndrome. Joint Bone Spine 2014;81:15-21.
  • 126. Spriet S, Banks TA. Drug reaction with eosinophilia and systemic symptoms syndrome. Allergy Asthma Proc 2015;36:501-5.
  • 127. Institute for Safe Medication Practices (ISMP). Acute Care ISMP Medication Safety Alert 2018;23:1-2.
  • 128. a. b. c. d. e. f. g. h. Suprenza (phentermine hydrochloride) package insert. Cranford, NJ: Akrimax Pharmaceuticals; 2011 Oct.
  • 129. a. b. c. d. e. f. g. h. Phentermine hydrochloride package insert. Newtown, PA: KVK-Tech Inc; 2010 April.
  • 130. a. b. c. d. e. f. g. h. Lomaira (phentermine hydrochloride) package insert. Newton, PA: KVK-Tech, Inc.; 2016 Sept.
  • 131. Hendricks EJ, Srisurapanont M, Schmidt SL, et al. Addiction potential of phentermine prescribed during long-term treatment of obesity. Int J Obes (Lond). 2014;38:292-298.
  • 132. Depakote (divalproex sodium tablets) package insert. North Chicago, IL: AbbVie Inc.; 2020 May.
  • 133. Page RL, Bainbridge JL. Intractable Epistaxis Associated with Topiramate Administration. Ann Pharmacother. 2006; Accessed online on July 5, 2006. Published Online, 5 July 2006. Available on the World Wide Web at: www.theannals.com, DOI 10.1345/aph.1H078
  • 134. Kossoff EH, Pyzik PL, Furth SL. Kidney stones, carbonic anhydrase inhibitors, and the ketogenic diet. Epilepsia 2002;43:1168-1171.
  • 135. a. b. Groeper K, McCann ME. Topiramate and metabolic acidosis: a case series and review of the literature. Paediatr Anaesth 2005;15:167-70.
  • 136. Wilner A, Raymond K, Pollard R. Topiramate and metabolic acidosis. Epilepsia 1999;40:792-5.
  • 137. a. b. c. d. e. f. Nawrot P, Jordan S, Eastwood J, et al: Effects of caffeine on human health. Food Addit Contam 2003;20:1-30.
  • 138. a. b. Schmidt B, Roberts RS, Davis P, et al. Caffeine Therapy for Apnea of Prematurity. N Engl J Med 2006; 354:2112-2121.
  • 139. lane AJ, Coombs RC, et al. Effect of caffeine on neonatal splanchnic blood flow. Arch Dis Child Fetal Neonatal Ed 1999;80:F128–F129.
  • 140. Bhatt-Mehta V, Schumacher RE. Treatment of apnea of prematurity. Pediatr Drugs 2003;5:195-210.
  • 141. Caffeine tablets alertness aid supplement (product label). Woonsocket RI, CVS; 2012.
  • 142. Pollak C, Bright D. Caffeine consumption and weekly sleep patterns in US seventh-, eighth-, and ninth-graders. Pediatrics 2003;111:42-46.
  • 143. Davis R, Osorio I: Childhood caffeine tic syndrome. Pediatrics 1998;101:E4.
  • 144. Prolab Caffeine supplement product label. Chatsworth, CA Prolab Nutrition Inc; 2012.
  • 145. a. b. c. Bolen S, Feldman L, Vassy J, et al. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med 2007;147:386–99.
  • 146. a. b. c. d. e. f. g. Pitocin (oxytocin) package insert. Rochester, MI: JHP Pharmaceuticals, LLC; 2014 Sept.
  • 147. Curless RV, Beaumont DM, Sinar EJ, et al. Subarachnoid hemorrhage mimicking acute water intoxication during labour augmented by oxytocin infusion. Br J Clin Pract 1990;44(12):637-638.

Related Medications