Pharmacological Classifications: Sympathomimetic Amine
General Information: Diethylpropion is an oral, sympathomimetic amine that is used as an anorexiant agent. It is structurally and chemically related to the amphetamines. The pharmacologic effects of diethylpropion are also similar to amphetamines. Diethylpropion is utilized in the short-term (up to 12 weeks) management of obesity. Clinical trials report greater weight loss in adult obese subjects treated with dietary management and anorexiants versus patients treated with diet and placebo alone. Weight loss is generally greatest in the first weeks of therapy and decreases in succeeding weeks. Diethylpropion is recommended for short term treatment of obesity; however, longer periods of therapy, up to 25 weeks, may be safely and successfully utilized without the development of tolerance or drug dependence. Diethylpropion was approved by the FDA in 1959 and is available in both immediate-release and sustained-release tablets. It is only indicated for use as monotherapy.
Mechanism of Action: Diethylpropion is a sympathomimetic amine that possesses pharmacological properties similar to amphetamine. Although the exact mechanism of action has not been established, it is thought that appetite suppression is produced by a stimulant effect on the satiety center in the hypothalamic and limbic regions of the brain. Secondary actions include CNS stimulation and blood pressure elevation. Diethylpropion acts primarily on adrenergic pathways to increase the release of norepinephrine from nerve terminals and inhibit its reuptake; therefore, it is considered an indirect-acting sympathomimetic. There is evidence that diethylpropion may also provide some direct stimulation of the nerve terminal to produce the pharmacologic response.
Pharmacokinetics: Diethylpropion is administered orally. Diethylpropion is metabolized through a complex mechanism of N-dealkylation and reduction. N-dealkylation is thought to be responsible for metabolizing 45—55% of the dose whereas reduction accounts for 20—25% of the metabolic processes. Many of the diethylpropion metabolites are active. Diethylpropion and/or its metabolites are believed to cross the blood-brain-barrier and the placenta.
Diethylpropion and its metabolites are excreted primarily by the kidneys. Within 48 hours after dosing, over 75% of the dose is recovered in the urine, 3—6% as unchanged drug, and 64—67% as metabolites. The plasma half-life of the diethylpropion metabolites is approximately 4—8 hours.
Route-Specific Pharmacokinetics: Oral Route: The 75 mg sustained-release tablet has more gradual release characteristics than three 25 mg tablets given in a single dose, based on studies of plasma levels obtained with each dosage form. Diethylpropion is rapidly absorbed from the GI tract.
Indications: Diethylpropion is indicated in the treatment of obesity as a short-term adjunct in a regimen of caloric restriction in patients with an initial body mass index(BMI) of 30 or greater and who have not responded to a weight-reducing regimen of diet and exercise alone.
Contraindications and Precautions: Your health care provider needs to know if you have any of these conditions: heart or blood pressure conditions; glaucoma; are receiving or have received MAOIs within the last two weeks; hyperthyroidism; neurological or psychiatric conditions; are breast-feeding, pregnant, or trying to become pregnant; or a history of substance abuse as diethylpropion is chemically and pharmacologically related to the amphetamine family of sympathomimetic adrenergic agonists.
Patients with anorexia nervosa should not receive anorexiants, since this could worsen the patient's nutritional status. Further, diethylpropion should not be prescribed to patients who have been treated with anorexiant drugs in the preceding 12 months.
Due to its vasopressor effects, diethylpropion is contraindicated in patients with advanced arteriosclerosis, severe hypertension, or pulmonary hypertension. Diethylpropion is not recommended in patients with cardiac arrhythmias, heart murmur, or valvular heart disease. Valvular heart disease is associated with the use of some anorectic agents such as fenfluramine and dexfenfluramine. Cardiac valvulopathy has been very rarely reported with diethylpropion monotherapy, but the causal relationship remains uncertain. Possible contributing factors include use for extended periods of time, higher than recommended dose, and/or use in combination with other anorectic drugs. Baseline cardiac evaluation should be considered to detect preexisting valvular heart diseases or pulmonary hypertension prior to initiation of diethylpropion treatment. Echocardiogram during and after treatment could be useful for detecting any valvular disorders which may occur. In a case-control epidemiological study, the use of anorectic agents, including diethylpropion, was associated with an increased risk of developing pulmonary hypertension, a rare, but often fatal disorder. The use of anorectic agents for longer than 3 months was associated with a 23-fold increase in the risk of developing pulmonary hypertension.1 Increased risk of pulmonary hypertension with repeated courses of therapy cannot be excluded. The onset or aggravation of exertional dyspnea, or unexplained symptoms of angina pectoris, syncope, or lower extremity edema suggest the possibility of occurrence of pulmonary hypertension. Under these circumstances, diethylpropion should be immediately discontinued, and the patient should be evaluated for the possible presence of pulmonary hypertension. The potential risk of possible serious adverse effects such as valvular heart disease and pulmonary hypertension should be assessed carefully against the potential benefit of weight loss.
Because diethylpropion is a sympathomimetic agent, its use is contraindicated in patients with glaucoma.
Diethylpropion is contraindicated in patients receiving MAOI therapy, or within 14 days following the administration of a MAOI since hypertensive crisis may occur.
Diethylpropion is contraindicated in thyroid disease patients with hyperthyroidism, since sympathomimetic stimulation may induce cardiac arrhythmias or other side effects.
Diethylpropion is contraindicated in patients with a history of substance abuse. Diethylpropion is chemically and pharmacologically related to the amphetamines, which have been extensively abused. Physiological dependence can occur with diethylpropion. Abrupt discontinuation of prolonged high dose diethylpropion therapy can result in extreme fatigue and mental depression as well as changes in sleep EEG. If tolerance develops, the recommended dose should not be exceeded in an attempt to increase the effect; rather, the drug should be discontinued.
Diethylpropion is contraindicated in patients in an agitated state. Diethylpropion should be used cautiously in patients with psychosis or mania. Amphetamine-like agents have been shown to aggravate these conditions.
Safety and effectiveness of diethylpropion in children have not been established. Diethylpropion is not recommended for neonates, infants, children and adolescents under 16 years of age.
Reports suggest that diethylpropion may increase the risk of seizures in some epileptic patients. Patients with a seizure disorder receiving diethylpropion should be closely monitored.
Diethylpropion is classified as FDA pregnancy risk category B.2 Diethylpropion and/or its metabolites are thought to cross the placental barrier. Animal data reveal no harmful effects during pregnancy. Spontaneous reports of congenital malformation have been reported in humans, but no causal relationship to diethylpropion has been established. No adequate, well controlled studies exist in pregnant women, however, diethylpropion is not approved for use pregnant women.
Diethylpropion hydrochloride and its metabolites have been shown to be excreted into breast milk. However, it is unknown if diethylpropion or its metabolites will cause harm to the nursing infant.2 Because of the potential for adverse effects in the nursing infants, breast-feeding while taking diethylpropion should be avoided. 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 administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
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, diethylpropion should be discontinued several days prior to surgery.
Adequate numbers of geriatric patients were not included in diethylpropion clinical trials to determine if their response would be different from younger patients, although differences have not been seen. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range due to potential decreased hepatic, renal, or cardiac function, concomitant disease or other drug therapy. Diethylpropion is known to be substantially excreted by the kidney. Because elderly patients are more likely to have renal impairment or renal failure, care should be taken in dose selection and monitoring.
This list may not include all possible contraindications.
Pregnancy: Diethylpropion is classified as FDA pregnancy risk category B.2 Diethylpropion and/or its metabolites are thought to cross the placental barrier. Animal data reveal no harmful effects during pregnancy. Spontaneous reports of congenital malformation have been reported in humans, but no causal relationship to diethylpropion has been established. No adequate, well controlled studies exist in pregnant women, however, diethylpropion is not approved for use pregnant women.
Breast-feeding: Diethylpropion hydrochloride and its metabolites have been shown to be excreted into breast milk. However, it is unknown if diethylpropion or its metabolites will cause harm to the nursing infant.2 Because of the potential for adverse effects in the nursing infants, breast-feeding while taking diethylpropion should be avoided. 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 administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Interactions: Diethylpropion has vasopressor effects and may limit the benefit of antihypertensive agents particularly sympatholytic agents such as guanadrel, guanethidine, methyldopa or reserpine. Diethylpropion may displace guanethidine from the neuron and antagonize the neuronal blockade caused by guanethidine. Concomitant use of diethylpropion with methyldopa or reserpine may antagonize the antihypertensive effects of these agents. Although leading drug interaction texts differ in the potential for an interaction between diethylpropion and this group of antihypertensive agents, these effects are likely to be clinically significant and have been described in hypertensive patients on these medications.3
All sympathomimetics and psychostimulants, including other anorexiants, should be used cautiously or avoided in patients receiving diethylpropion. The efficacy of diethylpropion when used with other anorexiants such as amphetamine, benzphetamine, dexfenfluramine, fenfluramine, phendimetrazine, or phentermine has not been studied. The combined use of these agents may have the potential for serious cardiac adverse effects such as hypertensive crisis and cardiac arrhythmias. Similarly, diethylpropion should not be used in combination with OTC preparations and herbal products that may contain caffeine, ephedrine, ephedra alkaloids or Ma huang.456738
All sympathomimetics, including some beta-agonists, should be used cautiously or avoided in patients receiving diethylpropion. The combined use of these agents may have the potential for serious cardiac adverse effects such as hypertensive crisis and cardiac arrhythmias. Due to the pharmacology of salmeterol9 and similar beta-agonists, caution and close observation should also be used when fluticasone; salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects based on the pharmacology of salmeterol.9
Atomoxetine, an inhibitor of norepinephrine reuptake used for treatment of ADHD, has been shown to increase heart rate and blood pressure.10 Diethylpropion also inhibits norepinephrine reuptake. The combination of atomoxetine with diethylpropion should be used extremely cautiously, if at all, due to the potential for serious increases in blood pressure and/or heart rate. If these agents must be used concomitantly, consider monitoring blood pressure and heart rate at baseline and regularly throughout treatment.
Sibutramine is contraindicated in patients taking other centrally-acting appetite suppressant drugs, including diethylpropion.11
Diabetic patients may have decreased insulin requirements in association with the use of diethylpropion and the concomitant dietary regimen and weight loss. Diethylpropion enhances the hypoglycemic activity of insulin by increasing the uptake of glucose by skeletal muscle cells. Diethylpropion also exhibits intrinsic hypoglycemic activity and can lower postprandial blood glucose concentrations. Diethylpropion should be used cautiously in diabetic patients who are stabilized on insulin, sulfonylureas, or other antidiabetic agents or on diet alone.312
Interactions between sympathomimetics and MAOIs can be severe. Monoamine oxidase inhibitors (MAOIs) or other drugs that possess MAO-inhibiting activity such as furazolidone13, linezolid 14, or procarbazine 15, can prolong and intensify the cardiac stimulation and vasopressor effects of diethylpropion. In the presence of MAOIs, diethylpropion and other drugs that cause release of norepinephrine induce severe cardiovascular and cerebrovascular responses. Cases have been documented where seizures and pyrexia have occurred. Diethylpropion should not be administered during, or within 14 days following the use of most MAOIs, or drugs with MAO-inhibiting activity.3 Rasagiline is a selective MAO-B inhibitor at manufacturer recommended doses; therefore, serious reactions with sympathomimetics are not ordinarily expected.16 However, because a case of elevated blood pressure occurred during use of rasagiline and a sympathomimetic ophthalmic preparation, caution is advised when rasagiline is administered with sympathomimetics.
Concurrent use of diethylpropion and phenothiazines may antagonize the anorectic effects of diethylpropion. In addition, psychostimulants can aggravate psychotic states.3
Administration of tricyclic antidepressants with diethylpropion and other amphetamine derivatives has been reported to result in enhanced amphetamine effects from the release of norepinephrine. Acute increases in blood pressure have been noted. Conversely, tricyclic antidepressants may decrease the effects of anorexiants.17181920
Phentermine and diethylpropion have a similar mechanism of action. When phentermine was given with fluoxetine, adrenergic excess and dyskinesia were observed.21 Thus, diethylpropion may interact with fluoxetine similarly. It is unclear, however, if all SSRIs would be affected as fluoxetine has the longest half-life of the group.
Halogenated anesthetics sensitize the myocardium to the effects of the sympathomimetics. Because of this, and its effects on blood pressure, diethylpropion should be discontinued several days prior to surgery.2223242526
Diethylpropion has CNS depressant properties. Although not studied, the concomitant use of ethanol and Diethylpropion may result in an adverse reaction. The manufacturer recommends that alcohol should be avoided during diethylpropion therapy.3
Caution is advised when using thyroid hormones in combination with diethylpropion; co-administration of sympathomimetics and thyroid hormones can enhance the cardiovascular effects of both agents. Patients with coronary artery disease have an increased risk of developing coronary insufficiency from either agent. Use of these agents concomitantly may increase this risk even further.2728329
Use of medications that lower the seizure threshold should be carefully evaluated when considering intrathecal radiopaque contrast agents. Diethylpropion should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.3031
Bupropion is associated with a dose-related risk of seizures.32 Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk 32; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.This list may not include all possible drug interactions
Adverse Reactions/Side Effects: Most adverse reactions associated with diethylpropion therapy are centrally-mediated; however, central nervous system adverse reactions associated with diethylpropion therapy are less common than with amphetamine, and they are generally less severe than those symptoms attributed to amphetamine. Central nervous system adverse reactions noted to occur with diethylpropion therapy include anxiety, depression, dizziness, drowsiness, dyskinesia, dysphoria, euphoria, headache, insomnia, jitteriness, nervousness, overstimulation, restlessness, and tremor.2 In one controlled trial assessing the long-term safety and efficacy of diethylpropion in obese patients, the following CNS effects occurred more frequently with active treatment than placebo: insomnia (16.1—52.7% vs 9.1—21.9%), headache (9.7—33.3% vs 4.5—25%), dizziness (9.7—13.9% vs 4.5—9.4%), and tremor (6.4—8.3% vs <= 6.2%).33 Psychosis associated with diethylpropion therapy has been reported with therapeutic as well as high doses, but is more common in previous abusers of stimulant medications. Hallucinations have occurred rarely following high doses of the drug. Several cases of toxic psychosis have been reported following excessive use of the drug and some have been reported in which the recommended dose appears not to have been exceeded. Psychosis abated after the drug was discontinued. Seizures may occur in epileptic patients receiving diethylpropion. Psychological dependence may occur with diethylpropion, but is much less common than with other amphetamine-like agents such as dextroamphetamine and phentermine. The low abuse potential of diethylpropion is related to the lower incidence of euphoria as compared to other amphetamine-like drugs. Prolonged use of diethylpropion may result in physiological dependence leading to a withdrawal syndrome (e.g., extreme fatigue, depression) on cessation of therapy.2 It is advised to avoid abrupt discontinuation of therapy.
Cardiovascular or cerebrovascular adverse effects which have occurred during diethylpropion therapy include hypertension, precordial pain, palpitations, ECG changes, cardiac arrhythmias (including ventricular arrhythmias and sinus tachycardia), and stroke. A reflex sinus bradycardia is common, though usually not clinically significant. There is one case of torsade de pointes occurring in a patient on a restricted calorie diet and receiving diethylpropion in combination with a thiazide diuretic.34 Valvular heart disease associated with the use of some anorectic agents such as fenfluramine and dexfenfluramine has been reported. Cardiac valvulopathy has been very rarely reported with diethylpropion monotherapy, but the causal relationship remains uncertain.2 Possible contributing factors include use for extended periods of time, higher than recommended dose, and/or use in combination with other anorectic drugs.
Tolerance is common with the entire class of amphetamine-like drugs. Tolerance to the anorexiant effects of diethylpropion may develop within a few weeks of starting therapy. Higher doses may be required to produce the same response; however, the maximum recommended dose should not be exceeded in an attempt to increase the effect; instead, the drug should be discontinued.2 The long term pharmacologic benefit of diethylpropion may be maintained by utilizing pulse dosing. Once the weight loss appears to slow or stop, the drug is held for several weeks and is then restarted.
Anorectic agents have been associated with pulmonary hypertension. A case-control study assessed 95 patients with primary pulmonary hypertension and 355 controls from 35 centers in Europe. When the previous year was assessed, patients with primary pulmonary hypertension were 10 times as likely to have received anorectic agents (mainly derivatives of fenfluramine) and were 23 times as likely to have received anorectic agents for greater than 3 months when compared to controls.1 Although this does not prove causality, the manufacturer of diethylpropion recommends that treatment be discontinued if symptoms of pulmonary hypertension (e.g., dyspnea upon exertion, syncope, chest pain (unspecified), palpitations, or cardiac insufficiency) occur. The onset or aggravation of exertional dyspnea, angina pectoris, syncope, or lower extremity edema may suggest the occurrence of pulmonary hypertension, and patients with these symptoms should discontinue use of diethylpropion immediately. Patients should be advised to report immediately any deterioration in exercise tolerance.2
Adverse ophthalmic effects that have been reported during treatment with diethylpropion include blurred vision and mydriasis.2
The most common gastrointestinal (GI) adverse effects of diethylpropion are constipation and xerostomia. Other adverse GI effects include abdominal pain, diarrhea, dysgeusia, and nausea/vomiting.2 In one controlled trial assessing the long-term safety and efficacy of diethylpropion in obese patients, the following adverse GI effects occurred more frequently with active treatment than placebo: xerostomia (25.8—69.4% vs 22.7—40.6%) and constipation (22.6—38.9% vs 9.1—25%).33
Toxic effects of amphetamine-like agents (e.g., diethylpropion) appear to occur over a wide dosage range. Practitioners should be alert to the signs of excessive dosages or overdose which may include: angina, anxiety, agitation, blurred vision, delirium, diaphoresis, diarrhea, euphoria, hallucinations, hypotension or hypertension, insomnia, irritability, mydriasis, nausea, vomiting, palpitations, paranoia, psychosis, sinus tachycardia, tachypnea, or tremor. Minor manifestations of any of these symptoms during prescription use indicates a need for dosage reduction or discontinuation. Severe manifestations of diethylpropion overdose include cardiac arrhythmias including heart block, circulatory collapse, rhabdomyolysis, seizures, and death.2
Adverse endocrine effects that have occurred during treatment with diethylpropion include impotence (erectile dysfunction), changes in libido (libido increase or libido decrease, not specified), gynecomastia, and menstrual irregularity. Adverse genitourinary effects include dysuria and polyuria.2
Dermatologic effects that have been reported during treatment with diethylpropion include alopecia and hyperhidrosis. Hypersensitivity reactions include urticaria, rash (unspecified), ecchymosis, and erythema.2
Adverse hematologic effects that have been reported during treatment with diethylpropion include bone marrow depression, agranulocytosis, and leukopenia.2
General adverse effects not listed elsewhere that have been reported during treatment with diethylpropion include malaise and myalgia.2
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.
How is this medication best taken? You can take it with or without food. Follow the directions on the prescription label at regular intervals. Do not take this medicine close to bedtime as it may prevent you from sleeping. Do not take your medicine more often than directed. Do not suddenly stop taking your medicine unless directed by your health care provider. Talk to your pediatrician regarding the use of this medicine in children. Special care may be needed.
What do I do if I miss a dose? If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Take your next regularly scheduled dose. Do not take two doses at the same time.
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 expiration date. Do not flush unused medications or pour down a sink or drain.
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