Lipo Sculpt Cream

Overview of Lipo Sculpt Cream

Dosage Strengths of Lipo Sculpt Cream

Lipo Sculpt Cream (Aminophylline) 0.5% 60 mL Pump
Lipo Sculpt Lean Cream (Aminophylline / 7-Keto DHEA / Phenylephrine HCl) 0.5/2.5/0.25% 60 mL Pump
Lipo Sculpt Max Cream (Aminophylline / 7-Keto DHEA) 0.5/5% 60 mL Pump
Lipo Sculpt Meso Cream (Aminophylline / Phosphatidylcholine / Yohimbine HCl) 2/2/20% 100 mL Pump
Lipo Sculpt Meso Max Cream (Aminophylline / Phenylephrine / Phosphatidylcholine / Yohimbine HCl) 2/0.25/2/20% 100 mL Pump

General Information

Aminophylline

Theophylline is a xanthine derivative that is used both orally or intravenously in the treatment of apnea of prematurity and as an adjunct agent for patients with asthma. Theophylline occurs naturally in tea and is chemically similar to caffeine and theobromine.1 While theophylline was commonly used to treat asthma in the past, its use is much less common today because there are effective alternatives with better safety profiles. Oral theophylline is not recommended for asthma maintenance therapy in children less than 12 years. In adolescents and adults, low-dose sustained-release oral theophylline is considered an alternate, but not preferred, therapy to the use of inhaled corticosteroids (ICSs) or may be used as an alternate, adjunctive treatment to ICS in those with persistent asthma symptoms.23 Intravenous aminophylline and theophylline are not recommended for the management of acute asthma exacerbations because they appear to provide no additional benefit to optimal inhaled beta2-agonist therapy and may increase risk of adverse effects.2 There is contradictory evidence regarding the effectiveness of low-dose theophylline on exacerbation rates in chronic obstructive pulmonary disease (COPD); in general, the drug has a moderate bronchodilator effect that may result in an additive but mild improvement in FEV1 when added to beta-agonists. The risk for theophylline toxicity increases at dosages that produce therapeutic benefit. Theophylline and aminophylline are not recommended for the routine treatment of COPD and should not be used in acute COPD exacerbations due to the low efficacy at recommended doses and the potential for adverse reactions and toxicity.4 Theophylline is also approved for the treatment of apnea of prematurity in neonates; however, it is generally a second-line treatment option after caffeine due to its narrow therapeutic window for serum concentrations. Theophylline has been used off-label for the management of renal impairment and facilitation of extubation in neonates, the prevention of apnea during prostaglandin E1 infusion, and the treatment of methotrexate toxicity.56789 Aminophylline, a pro-drug of theophylline, is the form frequently used for IV therapy. Because 100 mg of aminophylline is equivalent to 80 mg of theophylline, errors in dosing are possible, and clinicians should carefully assess dosage adjustments and calculations when switching between aminophylline and theophylline.

7-Keto DHEA

7-keto-dehydroepiandrosterone (7-keto-DHEA), also called 7-oxo-DHEA, is a metabolite of the steroid hormone precursor DHEA.1 DHEA, in the form of its sulfate conjugate (DHEA-S), is the most abundant steroid present in human blood and has generated interest as a potential therapeutic agent in age-related and other health conditions based on studies in preclinical models.23 However, DHEA is converted to androgens and estrogens, including testosterone and estradiol, and can result in sex steroid-associated side effects, such as polycystic ovaries and signs of masculinization in females.234 Thus, 7-keto-DHEA has arisen as a promising alternative to DHEA because metabolites of DHEA, including 7-keto-DHEA, may mediate some the biological functions and physiological and clinical benefits of DHEA.5 Importantly, unlike DHEA, 7-keto-DHEA is not converted into testosterone or estradiol.26

Like DHEA, 7-keto-DHEA is produced endogenously in the adrenal glands, gonads, brain, liver, and skin.57 Physiological (serum) levels of 7-keto-DHEA vary widely among individuals; however, they appear to be similar among men and women.8 In a 2007 study of 215 individuals without endocrine disorders (91 males and 124 females; aged 5-71 years), no significant differences in 7-keto-DHEA levels were observed between males and females.8 The overall mean (±SD) and median of 7-keto-DHEA levels were 0.280 (±0.39) nmol/L and 0.239 nmol/L, respectively.8

At puberty, the level of 7-keto-DHEA rapidly increases and plateaus until approximately 35 years of age8; it then decreases with increasing age.9 Because the level of 7-keto-DHEA is directly related to the level of DHEA, decreasing 7-keto-DHEA levels are likely a reflection of decreasing DHEA levels, which are also known to decrease with age.10 Therefore, it is believed that DHEA and 7-keto-DHEA supplementation may help the body maintain a more youthful state and may be beneficial to individuals with low levels of DHEA or 7-keto-DHEA.6

7-keto-DHEA is typically administered orally as an acetyl ester of 7-oxo-DHEA (3β-acetyl-7-oxo-DHEA or 7-oxo-dehydroepiandrosterone-3 acetate11 ); this form (also often referred to as 7-keto-DHEA) is less susceptible to oxidation than 7-keto-DHEA during manufacturing and storage.31213 After administration, the 7-oxo-DHEA acetyl ester is rapidly converted to 7-oxo-DHEA-sulfate (7-keto-DHEA-S) in a concentration proportional to the administered dose.614

7-keto-DHEA has been shown to promote weight loss and increase resting metabolic rate in people who are overweight.151617 In two placebo-controlled double-blind trials, participants who received 7-keto-DHEA acetyl ester lost significantly more weight than those who received placebo (2000 study: mean, -2.88 kg vs -0.97 kg, respectively; P=.0115 and 2002 study: mean, -2.15 kg vs -0.72 kg, respectively; P=.03816).

Another placebo-controlled double-blind study with a 3-way cross-over design evaluated the effect of 7-keto-DHEA on resting metabolic rate in adults who were overweight.17 Participants received the 7-keto-DHEA acetyl ester (50 mg twice daily), HUM5007 (another 7-keto-DHEA acetyl ester containing supplement; 50 mg twice daily), or placebo in conjunction with a calorie-restricted diet for 7 days (each study period was followed by a 7-day washout period).17

7-keto-DHEA treatment increased resting metabolic rate compared with baseline levels (3.4% increase with HUM5007 and 1.4% increase with 7-keto-DHEA).17 Treatment with either 7-keto-DHEA product significantly increased the resting metabolic rate (+134 kcal/day [7.3% increase] with HUM5007 and +96 kcal/day [5.4% increase] with 7-keto-DHEA) compared with placebo (-75 kcal/day [3.9% decrease]; P=.001 for both).17  Therefore, in combination with a calorie-restricted diet, 7-keto-DHEA appears to not only reverse the decline in resting metabolic rate associated with dieting but to enhance it and may benefit individuals who are overweight or with impaired energy expenditure.

Phenylephrine

Phenylephrine is a synthetic sympathomimetic amine with selectivity for the alpha-1 adrenergic receptor. Phenylephrine lacks significant inotropic and chronotropic effects.18 Phenylephrine is used orally and intranasally to treat nasal congestion and is a common ingredient in nonprescription cough and cold products. Generally, nonprescription use of phenylephrine as a decongestant is not recommended in pediatric patients younger than 6 years due to adverse effects and fatalities resulting from unintentional overdose or concomitant use of other over-the-counter (OTC) products containing phenylephrine.1920 When administered topically to the eye, phenylephrine induces mydriasis and, thus, phenylephrine is often used as a diagnostic aid in ophthalmology.21 Parenterally, phenylephrine may reduce heart rate and cardiac output as a reflex response to its potent vasopressor effects, which is the rationale for its use to treat paroxysmal supraventricular tachycardia. Since it is a potent vasoconstrictor, phenylephrine injection can be used as a vasopressor. However, the predominance of alpha effects and lack of beta-1 inotropic effects limit the use of phenylephrine for the treatment of shock states. Phenylephrine substantially reduces splanchnic blood flow in septic shock patients. Alternative vasopressors that have additional inotropic effects such as dopamine or norepinephrine are preferred for the treatment of septic shock. Phenylephrine may have an advantage in treating shock states associated with tachycardia due to its lack of chronotropic effects.22 While use as a vasopressor is limited compared to other agents, phenylephrine has been used in select critical care situations, such as postoperatively after congenital heart surgery or for providing blood pressure support and preventing cerebral ischemia after traumatic brain injury (TBI).232425 Adverse reactions to phenylephrine are primarily attributable to excessive pharmacologic activity.26 

Yohimbine HCl

Yohimbine is an oral alpha-2 blocker that is chemically related to reserpine. It is an alkaloid found in the bark of Rubiaceae and related trees, but can also be found in Rauwolfia serpentina. Yohimbine has been proposed as a treatment for erectile dysfunction (ED), however only limited evidence exist. According to ED treatment guidelines, only one small study in the published literature used acceptable efficacy outcome measures; therefore, conclusions about the clinical efficacy of yohimbine have not been established and its use in the treatment of ED is not recommended. Further, associated adverse events such as elevations of blood pressure and heart rate, increased motor activity, irritability, and tremor may limit its use.2728 Yohimbine has been available since before 1938.

Mechanism of Action

Aminophylline

Despite decades of research, the mechanism of action for theophylline is still being debated. While its bronchoprotective effects are most well-known, theophylline appears to also possess antiinflammatory and immunomodulatory actions.29 Theophylline relaxes the smooth muscle of the bronchial airways and pulmonary blood vessels. In patients with asthma, theophylline reduces airway responsiveness to histamine, methacholine, adenosine, and allergen.29 The ability of theophylline to control chronic asthma, however, is disproportionately greater than is explainable by its relatively weak bronchodilatory action.29 Theophylline may even possess antiinflammatory actions as evidenced by its ability to attenuate late-phase reactions in asthma.30
Regarding its biochemical action, originally, it was believed that theophylline exerted its effects via the inhibition of type III or type IV phosphodiesterase (PDE) which is responsible for breaking down cyclic AMP in smooth muscle cells. While theophylline does possess this property, it is negligible at therapeutic serum concentrations and there is no evidence that intracellular concentrations of theophylline in airway smooth muscle cells are higher than serum concentrations. Drugs that exert greater inhibition of PDE than theophylline (e.g., dipyridamole, papaverine) have no bronchodilator effect.
Other explanations theophylline's action have been proposed including changes in smooth muscle calcium ion concentration, inhibition of histamine release and adenosine antagonism. Adenosine antagonism has been considered as an explanation for theophylline's bronchodilating effects. Supporting this theory are the facts that adenosine and theophylline are structurally similar, adenosine can provoke bronchoconstriction in asthmatic patients, and adenosine can antagonize theophylline-induced bronchodilation. In addition, theophylline can antagonize adenosine's actions in other tissues. However, controversy surrounds this explanation also.30 Contradicting the theory that theophylline bronchodilation is mediated by adenosine antagonism is the fact that enprofylline, another xanthine that is five times as potent a bronchodilator as theophylline, does not antagonize adenosine.30 Thus, clinicians do not believe adenosine antagonism explains the bronchoprotective actions of theophylline.29
Actions of theophylline other than bronchodilation, particularly those that are excitatory, may indeed be a function of adenosine antagonism, however. Since adenosine is a CNS depressant, antagonism of adenosine may explain theophylline's stimulant action on the medullary respiratory center, increasing the sensitivity to carbon dioxide. Further support of adenosine antagonism as an explanation for the extrapulmonary actions of theophylline was demonstrated by theophylline's ability to attenuate methotrexate-induced neurotoxicity, a syndrome believed due to elevated adenosine CNS concentrations.5 As a bronchodilator, theophylline's cellular mechanism of action is still uncertain.
Theophylline relaxes other types of smooth muscle but can stimulate cardiac and skeletal muscle contraction. Increased cardiac output can lead to diuresis, but tolerance may develop to this effect. Other extrapulmonary effects attributed to theophylline include CNS stimulation, improved diaphragmatic contractility, and prostaglandin inhibition. A central mechanism appears to be responsible for theophylline's ability to reduce central sleep apnea in patients with heart failure.31

7-Keto DHEA

7-keto-DHEA is believed promote weight maintenance or loss by increasing resting metabolic rate.17 On a molecular level, studies in preclinical animal models showed that 7-keto-DHEA increased the activity of enzymes involved in thermogenesis, including mitochondrial and cytosolic sn-glycerol-3-phosphate dehydrogenase and cytosolic malic enzyme.2318  It also increased the rate of mitochondrial substrate oxidation and the activity of enzymes involved in fatty acid oxidation, including liver catalase and fatty acyl-CoA oxidase.18 It is unknown how 7-keto-DHEA mediates these changes; however, it is believed the metabolites of 7-keto-DHEA, 7α-OH-DHEA and 7β-OH-DHEA, may be involved.318

Other effects of DHEA and 7-keto-DHEA, such as increased immune response, may also be mediated by 7α-OH-DHEA and 7β-OH-DHEA.23 Both 7α-OH-DHEA and 7β-OH-DHEA have been shown to inhibit the reduction of cortisone to cortisol in human skin; however, 7β-OH-DHEA was seven times more potent than 7α-OH-DHEA.19 Thus, it is possible that part of the physiological activity of 7-keto-DHEA and its metabolites is mediated by their ability to act as anti-glucocorticoids.19 However, given that cortisone and cortisol are present in substantially higher levels than 7α-OH-DHEA and 7β-OH-DHEA, these 7-keto-DHEA metabolites may not have a systemic effect, but they may act locally in tissues through autocrine or paracrine processes.19

Phenylephrine is a potent vasoconstrictor. It possesses both direct and indirect sympathomimetic effects. Phenylephrine is used parenterally to achieve cardiovascular effects. The dominant effect is agonism at alpha-adrenergic receptors (direct effect). In therapeutic doses, the drug has no substantial stimulant effect on the beta-adrenergic receptors of the heart (beta-1 adrenergic receptors), although activation of these receptors can occur when very large doses are given. Phenylephrine does not stimulate beta-adrenergic receptors of the bronchi or peripheral blood vessels (beta-2 adrenergic receptors). It is believed that alpha-adrenergic effects result from inhibition of cyclic adenosine-3',5'-monophosphate (cAMP) production through inhibition of the enzyme adenyl cyclase, whereas beta-adrenergic effects result from stimulation of adenyl cyclase activity. Phenylephrine also releases norepinephrine from its nerve terminal storage sites (indirect effect). Some investigators have reported that tachyphylaxis can develop. Phenylephrine lacks direct inotropic and chronotropic effects on the heart. The main effect of systemic doses is vasoconstriction, resulting in constriction of most vascular beds including renal, splanchnic, and pulmonary blood vessels. Pulmonary vascular resistance may increase and a slight reduction in cardiac output may occur. Reflex bradycardia may occur, which can be reversed by atropine.18 

Phenylephrine

Phenylephrine may be used to treat paroxysmal supraventricular tachycardia based on its effects to reduce heart rate as a reflex mechanism in response to its alpha1-agonist vasoconstrictive effects.18 

A dose-ranging study in septic shock patients, escalating doses ranging from 0.5 to 8 mcg/kg/minute IV at 30-minute intervals, has reported linear dose-related increases in mean arterial pressure (MAP) and systemic vascular resistance index (SVRI).32 Although phenylephrine has been reported to increase cardiac output in septic patients based on limited data, cardiac output may be reduced in some patients, presumably due to increased systemic vascular resistance and potential for reflex bradycardia.221832 Phenylephrine substantially reduces splanchnic blood flow in septic shock patients. 

Phenylephrine is used orally and intranasally to stimulate alpha-adrenergic receptors on the nasal mucosa (direct effect) causing vasoconstriction of local vessels. The vasoconstrictive action decreases mucosal edema, thereby leading to a decongestant effect.33 

Within the eye, phenylephrine also stimulates alpha-adrenergic receptors (direct effect). Stimulation of these receptors on the dilator muscle and arterioles of the conjunctiva leads to profound mydriasis and vasoconstriction, respectively.21 

Yohimbine HCl

The exact mechanism of action of yohimbine in the treatment of erectile dysfunction (ED) has yet to be determined; there are few data which support its role in ED. It is believed that yohimbine exerts its effects by blocking central alpha-2 receptors thereby producing an increase in sympathetic drive secondary to an increase in norepinephrine release and in firing rate of cells in the brain noradrenergic nuclei. This activity increases penile blood inflow, decreases penile blood outflow, or both, which causes erectile stimulation without increased sexual desire. Yohimbine-mediated norepinephrine release at the level of the corporeal tissues may also be involved as well as other neurotransmitters (e.g., dopamine and serotonin). Other actions of yohimbine include a stimulant effect on mood and an increase in blood pressure at higher doses. At high doses, yohimbine may nonselectively inhibit monoamine oxidase (MAO). Mild antidiuretic actions may also be present possibly due to release of antidiuretic hormone.

Pharmacokinetics

Aminophylline

Theophylline can be administered orally or intravenously. When rapid attainment of therapeutic serum concentrations is desired, IV "loading" doses can be given, although oral administration with regular-release tablets is equally effective. Unbound theophylline serum concentrations are usually in the range of 6—12 mcg/ml and concentrations should be obtained in patients with low protein binding (i.e., neonates, hepatic cirrhosis). Steady state serum concentrations are reached in 30—65 hours in adults. Aminophylline, a salt of theophylline, is the form frequently used for IV therapy. Since 100 mg of aminophylline is equivalent to 80 mg of theophylline, errors in dosing are possible, and clinicians should carefully assess dose adjustments and calculations when switching between aminophylline dose forms and theophylline dose forms.

Protein binding is approximately 40% for healthy adults and is lower in neonates and patients with hepatic impairment. Target peak serum concentration ranges for neonates for the treatment of apnea are therefore lower than those of adults, due to a greater proportion of free "active" theophylline. Unbound theophylline is distributed throughout extracellular body fluids and tissues, however, distribution into body fat is poor. Theophylline readily crosses the placenta and the blood-brain barrier and is excreted into breast milk.

Affected cytochrome P450 isoenzymes and drug transporters:  CYP1A2, CYP2E1, CYP3A4
Theophylline is primarily metabolized by CYP1A2 isoenzymes, with secondary pathways by CYP2E1 and CYP3A4. In vitro data suggest that while metabolism is mediated by CYP1A2 at low plasma concentrations, metabolism shifts to CYP2E1 at higher concentrations, and metabolism by CYP3A4 is minor, independent of theophylline plasma concentration.34 The manufacturer states that theophylline is a substrate of hepatic enzymes CYP1A2, 2E1, and 3A3 without mention of 3A4 35; however, cytochrome P450 genome experts no longer support the existence of CYP3A3 and instead attribute this isoform to a coding error of or a variant of CYP3A4.3637 Since the therapeutic range is narrow, it is prudent to monitor theophylline serum concentrations upon initiation, dosage adjustment, or discontinuation of medications that may alter the function of CYP1A2, CYP2E1, and/or CYP3A4 isoforms.

In the premature neonate, theophylline is metabolized to caffeine in significant amounts, and this compound can accumulate due to its long half-life. Elimination is usually a first-order process, but zero-order elimination has been reported in some cases. Theophyllines' half-life varies with patient age, hepatic function, smoking status, and drug interactions. Nonsmoking adults usually have a half-life of 6.5—10.5 hours. Metabolites are eliminated renally, with only about 10% excreted as unchanged theophylline.

Route-Specific Pharmacokinetics:

  • Oral Route:
    • Theophylline is generally well absorbed after oral administration. Regular (i.e., nonsustained-release) tablets produce peak serum concentrations within 60 minutes after administration. Liquids and suspensions are absorbed more rapidly. Sustained-release preparations vary in the rate of absorption. Food can delay the rate, but not the extent, of absorption of some sustained-release products. Large volumes of fluid can increase absorption.
    • Peak concentrations should usually occur 1—2 hours after oral dosing. Serum concentrations of 10—20 mcg/ml (55—110 micromoles/L) generally are regarded as therapeutic, however, the FDA has now lowered the target peak concentration range to 10—15 mcg/ml to minimize the risk of adverse reactions. Most clinicians use 8—15 mcg/ml as the target range.

Special Populations:

  • Hepatic Impairment:
    • Cirrhosis can prolong the half-life of theophylline to as long as 24 hours.
  • Pediatrics:
    • In children age 1—9 years, the half-life of theophylline can be as short as 4—5 hours. Neonates (<3 months old) have a much higher rate of excretion of unchanged theophylline (approximately 50%).
  • Smoking:
    • In smokers, the half-life of theophylline can be as short as 4—5 hours.
  • Cor pulmonale:
    • Cor pulmonale can prolong the half-life of theophylline to as long as 24 hours.
  • Pulmonary edema:
    • pulmonary edema can prolong the half-life of theophylline to as long as 24 hours.

7-Keto DHEA

When 3β-acetyl-7-oxo-DHEA was administered orally to healthy male volunteers it was rapidly converted to 7-oxo-DHEA-S, the concentrations of which were proportional to dose.6 The steroid sulfate did not accumulate over time; trough plasma concentrations, 12 hours after 3β-acetyl-7-oxo-DHEA administration (200 mg), on day 7 and day 28 were similar (15.8 mg/L and 16.3 mg/L, respectively), indicating that the ratio of the formation rate to clearance is constant during multiple dosing.6 The mean half-life of 3β-acetyl-7-oxo-DHEA was 2.17 hours, and the mean time to 7-oxo-DHEA-S peak plasma level was 2.2 hours, indicating rapid absorption of 3β-acetyl-7-oxo-DHEA and conversion to the sulfate ester.6 The apparent clearance for 7-oxo-DHEA-S averaged 172 L/h, and the apparent mean volume of distribution was 540 L.6

In human liver microsomal fractions, 7-oxo-DHEA was reduced mainly to 7β-OH-DHEA and to 7α-OH-DHEA (2:1 ratio), and after 120 minutes, the reaction showed some reversibility.5 Multiple enzymes appear to reduce 7-oxo-DHEA in the presence of NADP+/NADPH.5 The reversible conversion of 7-oxo-DHEA to 7α-OH-DHEA is mediated by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in the liver and by 11β-HSD2 in the kidney.5 Though, several enzymes appear to be capable of reducing 7-oxo-DHEA to both 7-hydroxy-isomers;5  in vitro studies showed that 11β-HSD1 reduces 7-oxo-DHEA to both 7α-OH-DHEA and 7β-OH-DHEA.7

Phenylephrine

Phenylephrine is administered orally, intranasally, ophthalmically, intravenously, intramuscularly, subcutaneously, and rectally.1821383940 The pharmacologic effects of phenylephrine are terminated at least partially by uptake of the drug into tissues. The volume of distribution at steady-state ranges from 184 to 543 L, suggesting high distribution into organs and peripheral tissues. Phenylephrine is primarily metabolized in the liver and intestine by monoamine oxidase (MAO) and sulfotransferase. The major metabolite, m-hydroxymandelic acid, accounts for 57% of the total administered dose.4126 Only 16% of the drug is excreted in the urine unchanged with IV administration, and 2.6% after oral administration. The average total serum clearance is approximately 2,100 mL/minute. The elimination half-life ranges between 2.1 to 3.4 hours after oral or IV administration.4226 

Affected cytochrome P450 isoenzymes and drug transporters: none 

Route-Specific Pharmacokinetics 

  • Oral Route 
  • Ophthalmic Route 

Maximum plasma concentrations occur 20 minutes after administration with maximal mydriasis in 20 to 90 minutes.2143 The duration of the mydriatic effect is roughly 3 hours after administration of the 2.5% solution; the duration may be as long as 7 hours after administration of the 10% solution. Systemic absorption is more likely to be significant with 10% solution use; nasolacrimal occlusion after dosing may limit systemic effects and is recommended.44 

The duration of action after intranasal administration ranges from 30 minutes to 4 hours.45 

  • Other Route(s) 

After subcutaneous administration, a pressor effect occurs within 10 to 15 minutes and persists for 50 minutes to 1 hour. 

  • Inhalation Route 

After IM administration, a pressor effect occurs within 10 to 15 minutes and persists for 30 minutes to 2 hours.1846 

  • Subcutaneous Route 

After IV administration, a pressor effect occurs almost immediately and persists for 15 to 20 minutes.41 With IV infusion, phenylephrine displays biexponential decline; the half-life of the alpha phase is approximately 5 minutes.42 

  • Intramuscular Route 

When administered orally, phenylephrine is completely absorbed. The drug has a bioavailability of 38% relative to IV administration. Peak plasma concentrations are achieved approximately 1 to 2 hours after administration.42 Onset of action can occur in 15 to 30 minutes.47 

  • Intravenous Route 

Yohimbine HCl

Yohimbine is administered orally. Yohimbine undergoes extensive hydroxylation in the liver to the inactive metabolite 10-hydroxy-yohimbine and the active metabolite 11-hydroxy-yohimbine. In vitro data indicate that 10-hydroxy-yohimbine is preferentially formed via CYP3A4 and 11-hydroxy-yohimbine is preferentially formed via CYP2D6. In one evaluation using intravenous administration, yohimbine metabolism to 11-hydroxy-yohimbine displayed more than a 1000-fold variability, with some subjects showing no metabolism. Among ethnic groups studied, those of European ancestry had the highest frequency of non-metabolism, and non-metabolizers had greater sympathetic nervous system activity. It was estimated that the contribution of CYP3A4 to the formation of 10-hydroxy-yohimbine was approximately 70% and the contribution of CYP2D6 to the formation of 11-hydroxy-yohimbine was approximately 80% after intravenous administration. The 10-hydroxy metabolite is highly water-soluble, rapidly eliminated, and is usually detected in urine but not plasma. The 11-hydroxy metabolite retains biologic activity on platelet aggregation and lipolysis; however, access to the alpha-2 receptor may be decreased compared to the parent compound due to lower albumin binding. The elimination half-life of yohimbine is less than 1 hour while the elimination half-life of 11-hydroxy-yohimbine is about 6.5 hours. About 1% of unchanged drug is excreted renally.48

Affected cytochrome P450 isoenzymes and drug transporters: CYP2D6, CYP3A4

In vitro data indicate that the inactive metabolite 10-hydroxy-yohimbine is preferentially formed via CYP3A4 and the active metabolite 11-hydroxy-yohimbine is preferentially formed via CYP2D6.4849

Route-Specific Pharmacokinetics:

  • Oral Route:
    • Following oral administration, bioavailability of yohimbine is highly variable, ranging from 7 to 87% (mean 33%). Absorption is generally complete within 45—60 minutes.

Contraindications/Precautions

Aminophylline

Theophylline can alter the results of some common laboratory tests. Serum concentrations levels of glucose, uric acid, free fatty acids (cholesterol, HDL), and urinary free cortisol excretion may all be reportedly increased. Also, transient decreases in triiodothyronine levels have been reported. The clinician should be aware of these alterations and should weigh the clinical importance of these changes to the benefits of theophylline therapy.

Patients with cardiac disease should be monitored more closely for adverse reactions to theophylline. Lower doses may be necessary for patients with congestive heart failure, including cor pulmonale, due to decreased theophylline clearance (>= 50% decrease). Also, theophylline can exacerbate existing cardiac arrhythmias and should be used with caution in patients at risk. Similarly, because theophylline can increase oxygen demand, it should be prescribed carefully in patients with coronary artery disease, especially those with a history of myocardial infarction.

Patients with hypothyroidism, acute pulmonary edema, sepsis with multiple organ failure, or shock may have decreased theophylline clearance. Any patients with any of the above conditions should be monitored carefully while receiving theophylline.

Increased theophylline clearance may occur in patients with hyperthyroidism or cystic fibrosis. Hypercalcemia has been reported in a patient with hyperthyroid disease at therapeutic theophylline concentrations. Any patients with cystic fibrosis or conditions affecting the thyroid should be monitored carefully while receiving theophylline.

Patients with uncorrected acidemia can have an increase in the volume of distribution of theophylline due to a decrease in plasma protein binding. Unbound serum theophylline concentrations should be monitored in these patients to avoid toxicity.

Since theophylline is metabolized hepatically, doses may need to be lower in patients with moderate to severe hepatic disease such as cirrhosis, acute hepatitis, cholestasis, or alcoholic liver disease. Patients who regularly consume ethanol but do not exhibit overt hepatic dysfunction may actually require larger doses than normal. The elderly may also have reduced hepatic metabolism, and their doses should generally be lower with cautious titration. Doses should be decreased in in infants under 1 year of age, especially premature neonates due to a less developed hepatic metabolism. Also, since neonates and young infants have a higher percentage of unchanged theophylline excreted via the kidneys (approximately 50% in newborns as compared to 10% in those older than 3 months), neonates and infants less than 3 months with renal impairment require lower doses.5051

Tobacco smoking has been shown to increase the clearance of theophylline by about 50% in young adult tobacco smokers and about 80% in elderly tobacco smokers. Also, passive smoke exposure may cause a an increase in theophylline clearance by up to 50%. Because the effect of tobacco on hepatic microsomal enzymes is not related to the nicotine component, sudden smoking cessation may result in a reduced clearance of theophylline, despite the initiation of nicotine replacement products. Following 1 week of abstinence from chronic tobacco smoking, theophylline clearance may decrease by roughly 40%, leading to an increase in serum theophylline concentrations. Theophylline serum concentrations should be monitored carefully when changes in smoking status occur.

Prolonged fever has been reported to reduce theophylline clearance. Lower doses should be considered in these conditions. Theophylline also should be used cautiously in patients with respiratory infection or severe hypoxemia.

Since theophylline can stimulate gastric secretions, it should be used with caution in patients with gastritis or active peptic ulcer disease. Theophylline may aggravate symptoms related to hiatal hernia or gastroesophageal reflux disease (GERD).

Theophylline relaxes smooth muscle and can increase urinary retention, so it should be used with caution in patients with prostatic hypertrophy. Use of theophylline initially can cause a diuretic effect.

Theophylline and aminophylline have not been proven to be teratogenic in humans; however, there are no adequate controlled trials of the drugs during pregnancy.515253 Decreased theophylline clearance has been reported during the third trimester of pregnancy. Theophylline is considered an alternative therapy for mild persistent asthma and adjunctive treatment for moderate to severe persistent asthma during pregnancy according to the Guidelines of the National Asthma Education and Prevention Program (NAEPP) Asthma and Pregnancy Working Group. Inhaled corticosteroids are the preferred asthma maintenance treatment during pregnancy due to the potential toxicities of theophylline and the propensity for drug interactions that can reduce theophylline clearance.54 If theophylline or aminophylline must be used, it is recommended that serum theophylline concentrations be regularly monitored and maintained between 5 to 12 mcg/mL. Use during pregnancy may lead to potentially dangerous serum theophylline and caffeine concentrations and/or symptoms of theophylline toxicity in newborns; an exposed infant should be closely monitored at birth. The selection of any pharmacologic treatment for asthma control during pregnancy should include the specific needs of the patient, based on an individual evaluation, and consideration of the potential benefits or risks to the fetus.545556 In studies in which pregnant mice, rats and rabbits were dosed during the period of organogenesis, theophylline produced teratogenic effects.515253

Use theophylline with caution during breast-feeding. Theophylline is excreted in breast milk in concentrations similar to the serum concentration of the mother. Breastfed infants whose mothers are taking theophylline may experience irritability or other mild signs of toxicity; however, serious adverse events are unlikely unless the mother has toxic serum concentrations. Close monitoring is recommended, particularly in a newborn. Theophylline or aminophylline are not preferred therapy for asthma in the lactating woman; these drugs are considered alternative therapy to inhaled corticosteroids for mild persistent asthma and an adjunctive medication for moderate to severe asthma during lactation according to the Guidelines of the National Asthma Education and Prevention Program (NAEPP) Asthma and Pregnancy Working Group. If used, it is recommended that serum theophylline concentrations be regularly monitored and maintained between 5 to 12 mcg/mL.54515253

Theophylline is contraindicated in patients who have demonstrated a hypersensitivity reaction to theophylline or any component in the commercial product. Some pre-mixed theophylline in dextrose intravenous infusions may be manufactured using corn or corn products and may be contraindicated in patients with corn hypersensitivity.

Theophylline should be used cautiously in patients with a history of seizure disorder due to the risk of exacerbating their condition.

Careful consideration must be given to the benefits and risks of theophylline or aminophylline use and the need for more intensive monitoring of serum theophylline concentrations in older adult and geriatric patients more than 60 years of age. The clearance of theophylline is decreased by an average of 30% in healthy geriatric adults vs younger adults; clearance may be further significantly decreased if concomitant disease states or other factors for reduced clearance are present. If the total daily dose is not appropriately reduced, severe and potentially fatal theophylline toxicity can occur.5135 The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to the OBRA guidelines, periodic monitoring of serum theophylline concentrations helps identify or verify toxicity, as well as monitoring the clinical status of the patient for signs and symptoms of toxicity, such as arrhythmias, seizures, GI upset, diarrhea, nausea/vomiting, abdominal pain, nervousness, headache, insomnia, distress, dizziness, muscle cramps, and tremor. There are potentially significant interactions with many other medications, particularly antibiotics, anticonvulsants, and cardiac medications.57

7-Keto DHEA

7-keto-DHEA may increase T3 levels.16 People interested in starting 7-keto-DHEA supplementation, particularly those who have a thyroid disorder or who are taking thyroid hormone, should consult a physician.

7-keto-DHEA may lower blood pressure.6 Individuals with low blood pressure should consult with a physician prior to use of this supplement.6

At the time of writing, there were no other reported contraindications/precautions for 7-keto-DHEA. Individuals with known allergy to any of the capsule components or DHEA should not use this product.

Phenylephrine

Phenylephrine injection therapy requires an experienced clinician. The manufacturer includes a black box warning for phenylephrine injection advising that prescribers should become familiar with the product label information before prescribing phenylephrine.18 

Systemic phenylephrine should not be combined with MAOI therapy or used within 2 weeks of such therapy; use caution with ophthalmic, nasal, and topical rectal products, which may be absorbed systemically. 

Some formulations of injectable phenylephrine are contraindicated in patients with severe hypertension or ventricular tachycardia.18 Because of its increasing blood pressure effects, phenylephrine can cause severe bradycardia and decrease cardiac output, precipitate angina in patients with severe arteriosclerosis or a history of angina, and exacerbate underlying heart failure or pulmonary hypertension. Excessive peripheral and visceral vasoconstriction and ischemia to vital organs may occur, especially in patients with significant peripheral vascular disease.18415826 The phenylephrine 10% ophthalmic solution is contraindicated in patients with hypertension; use the 2.5% solution in patients with hypertension or preexisting cardiac disease.21 In addition, use orally or nasally administered phenylephrine with caution in patients with known or suspected cardiac disease or high blood pressure.3859 

Phenylephrine should be avoided in patients with cerebrovascular disease such as cerebral arteriosclerosis, aneurysm, intracranial bleeding, history or stroke or organic brain syndrome because of the potential sympathomimetic (presumably alpha) effects in the CNS and the potential for cerebrovascular hemorrhage, especially with intravenous use. 

Avoid phenylephrine in patients with sulfite hypersensitivity unless the patient is being treated for an emergent condition such as anaphylaxis or cardiac arrest. Phenylephrine formulations contain sodium metabisulfite, a sulfite that can cause severe allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes in susceptible patients. The overall presence of sulfite hypersensitivity in the general population is unknown but presumed to be low. Sulfite hypersensitivity is seen most often in asthmatic patients compared to non-asthmatic patients.184158 

Systemic phenylephrine products should be used with caution in men with symptomatic, benign prostatic hypertrophy, due to the potential for urinary retention. 

The phenylephrine 10% ophthalmic solution is contraindicated in patients with thyrotoxicosis, including hyperthyroidism; the 2.5% solution should be used with caution in these patients.21 All dosage forms of phenylephrine should be used with caution in patients with hyperthyroidism as these patients can be more sensitive to catecholamines; thyrotoxic or cardiotoxic symptoms can occur.18 

Because phenylephrine is an adrenergic agent, it should be given with caution to patients with diabetes mellitus. 

Avoid extravasation of phenylephrine injection by checking infusion site for free flow. Extravasation of phenylephrine can cause necrosis and tissue sloughing.4126 

The 10% ophthalmic phenylephrine solution is contraindicated in neonates and infants younger than 1 year due to the potential for adverse cardiac effects. Infants and children are more susceptible than adults to systemic absorption from intranasal or ophthalmic use, especially with use of the 10% ophthalmic solution, increasing the risk of adverse events. Consider avoiding the use of the 10% solution in patients younger than 5 years. The adverse effects of systemically absorbed sympathomimetics, such as phenylephrine, can be severe, especially in infants and toddlers; CNS stimulation, hypertension and tachycardia may occur.60 Do not use oral nonprescription phenylephrine products in children and infants younger than 4 years; use any systemic decongestant sympathomimetic amine with caution in children 6 years and younger.61 Administration of cough and cold products to children and infants younger than 2 years is associated with a risk for serious injury or fatal overdose. Over a 2-year period, 1,519 children younger than 2 years were treated in emergency departments for adverse events related to cough and cold medications; some of these events were due to inadvertent inappropriate use and some fatalities occurred.19 Nonprescription cough and cold products containing phenylephrine are not recommended for use in children younger than 6 years. Over-the-counter cough and cold products are not recommended for use in infants and children younger than 2 years. Advise parents and caregivers to read labels carefully, to use caution when administering multiple products, and to use only measuring devices specifically designed for use with medications if using cough and cold products in children. Thoroughly assess each patient's use of similar products, both prescription and nonprescription, to avoid duplication of therapy and the potential for inadvertent overdose.6263 

There are no data on the use of phenylephrine injection during the first or second trimester of human pregnancy. Data from randomized controlled trials and meta-analyses with phenylephrine injection use in pregnant women during labor and obstetric delivery (i.e., Cesarean section) have not established a drug-associated risk of major birth defects and miscarriage. These studies have not identified an adverse effect on maternal outcomes of infant Apgar scores. At recommended doses, phenylephrine does not appear to affect fetal heart rate or fetal heart rate variability to a significant degree. Untreated hypotension associated with spinal anesthesia for Cesarean section is associated with an increase in maternal nausea and vomiting. A sustained decrease in uterine blood flow due to maternal hypotension may result in fetal bradycardia and acidosis. In animal studies, evidence of fetal malformation was noted when phenylephrine was administered during organogenesis via a 1-hour infusion at 1.2 times the human daily dose (HDD) of 10 mg/60 kg/day. Decreased pup weights were noted in the offspring of pregnant rats treated with 2.9 times the HDD.58 A study in rabbits indicated that continued moderate overexposure to oral phenylephrine (3 mg/day) during the second half of pregnancy may contribute to perinatal wastage, prematurity, premature labor, and possibly fetal anomalies; when phenylephrine (3 mg/day) was given to rabbits during the first half of pregnancy, a significant number gave birth to litters of low birth weight. Another study showed that phenylephrine was associated with anomalies of aortic arch and with ventricular septal defect in the chick embryo.64 It is not known whether phenylephrine ophthalmic solution can cause fetal harm or affect reproduction capacity. Use phenylephrine ophthalmic solution during pregnancy only if clearly needed.44 Under the direction of a health care professional, topical or nasal phenylephrine may be used during pregnancy.653959 

There are no data on the presence of phenylephrine or its metabolite in human or animal milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for phenylephrine and any potential adverse effects on the breast-fed infant from phenylephrine or from the underlying maternal condition.6458 Use caution when administering ophthalmic phenylephrine to a pregnant woman.44 Under the direction of a health care professional, topical or nasal phenylephrine may be used by a breast-feeding woman.653959 

The ophthalmic use of phenylephrine while wearing contact lenses is not recommended. 

Ophthalmic application of phenylephrine to eyes or adnexa that are diseased, traumatized or following ocular surgery, or to patients with suppressed lacrimation (e.g., during anesthesia) may result in sufficient absorption of phenylephrine to produce a systemic vasopressor effect.44 

In general, use caution in administering phenylephrine to geriatric patients. In general, elderly patients are more susceptible than younger adults to the drug's effects. The baroreceptor reflex response to phenylephrine may decrease with age. Elderly patients, especially those with pre-existing cardiac disease, may be more likely to experience adverse cardiovascular reactions including increased blood pressure, cardiac arrhythmias, or ischemia with systemic use.41 Phenylephrine, when administered by ophthalmic routes, should be also used with caution. The use of the 2.5% ophthalmic solution is preferred for elderly patients when using ophthalmic formulas; avoid use of the 10% ophthalmic solution.21 The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to the OBRA guidelines, use of cough, cold, and allergy medications should be limited to less than 14 days unless there is documented evidence of enduring symptoms that cannot otherwise be alleviated and for which a cause cannot be identified and corrected. OBRA guidelines also state that oral decongestants, such as phenylephrine, should be used cautiously in patients who have insomnia or hypertension. Oral decongestants may cause dizziness, nervousness, insomnia, palpitations, urinary retention, and elevated blood pressure. During use of phenylephrine to manage urinary incontinence, assessment of the underlying causes and identification of the type/category of urinary incontinence needs to be documented prior to or soon after initiating treatment. Medications for urinary incontinence have specific and limited indications based on the cause and categorization of incontinence. Patients should be assessed periodically for medication effects on urinary incontinence as well as lower urinary tract symptoms and treatment tolerability.57 

Some oral chewable formulations of phenylephrine contain aspartame and such products should be avoided or restricted in patients who have phenylketonuria or who must restrict intake of phenylalanine, an amino acid used in the synthesis of aspartame. 

Phenylephrine injection should be used cautiously during cyclopropane anesthesia or halothane anesthesia since these agents may sensitize the heart to the arrhythmic action of phenylephrine.18 

Monitor renal function closely in patients with septic shock; phenylephrine can increase the need for renal replacement therapy.415826 

Dose-response data indicate decreased responsiveness to injectable phenylephrine in patients with cirrhosis or hepatic disease (Child-Pugh Class B and C). Initiate treatment in the recommended range; more phenylephrine may be required in this population.415826 

Dose-response data indicate increased responsiveness to injectable phenylephrine in patients with end-stage renal disease (ESRD) or renal failure. Consider initiating treatment at the lower end of the recommended dosage range, and adjust the dose based on the target blood pressure goal.415826 

Use phenylephrine with caution in patients with autonomic neuropathy. Patients with autonomic dysfunction, such as those with spinal cord injury, may have an increased blood pressure response to adrenergic drugs.415826 

Yohimbine HCl

NOTE: Limited information about precautions and contraindications to yohimbine therapy exists.

Yohimbine is contraindicated in patients with a hypersensitivity to yohimbine. Yohimbine should not be used in patients with a history of rauwolfia alkaloid hypersensitivity. Rauwolfia alkaloids include deserpidine, rauwolfia serpentina, or reserpine. Patients sensitive to these agents may also be sensitive to yohimbine.

Yohimbine may worsen renal impairment, therefore administration of this drug in patients with renal disease or renal failure is contraindicated. Serious renal effects, including renal failure, have been reported to the FDA after the use of products containing yohimbe.

Yohimbine should not be used concurrently with MAOI therapy (see Drug Interactions).

Yohimbine should not be used in patients with angina pectoris, cardiac disease, or hypertension because these conditions may be aggravated or worsened by yohimbine. It is also recommended that this drug not be used in cardio-renal patients with history of peptic ulcer disease, children, and geriatric patients. Further, because yohimbine may enhance anxiety or other CNS symptoms, it should be used cautiously in patients with depression or other psychiatric illness.

According to the German E Commission monographs, the use of yohimbine in those with hepatic disease is contraindicated. In theory, patients with hepatic impairment may exhibit impaired metabolism of yohimbine. Although recommendations on the use of yohimbine in those with hepatic disease are not available from the manufacturer, it should be noted that patients with hepatic disease have generally been excluded from participation in clinical trials that assess safety and efficacy of the drug. Therefore, it is advisable to avoid the use of yohimbine in those with hepatic disease, including biliary cirrhosis or hepatic failure.

In general, yohimbine is not for use in females and must certainly not be used during pregnancy.66 A FDA pregnancy risk category has not been assigned to this drug. However, given yohimbine's similarity to other rauwolfia alkaloids, it is suggested that yohimbine most closely corresponds to an FDA pregnancy risk category D (see Reserpine monograph). There is no known indication at this time for the use of yohimbine in pregnancy which would justify the potential risks to the fetus.

Generally, this drug is not for use in females 66, and therefore should not be used during breast-feeding. Many of the rauwolfia alkaloids are excreted in human breast milk. A decision should be made to discontinue the medication or discontinue breast-feeding.

Pregnancy

Aminophylline

Theophylline and aminophylline have not been proven to be teratogenic in humans; however, there are no adequate controlled trials of the drugs during pregnancy.515253 Decreased theophylline clearance has been reported during the third trimester of pregnancy. Theophylline is considered an alternative therapy for mild persistent asthma and adjunctive treatment for moderate to severe persistent asthma during pregnancy according to the Guidelines of the National Asthma Education and Prevention Program (NAEPP) Asthma and Pregnancy Working Group. Inhaled corticosteroids are the preferred asthma maintenance treatment during pregnancy due to the potential toxicities of theophylline and the propensity for drug interactions that can reduce theophylline clearance.54 If theophylline or aminophylline must be used, it is recommended that serum theophylline concentrations be regularly monitored and maintained between 5 to 12 mcg/mL. Use during pregnancy may lead to potentially dangerous serum theophylline and caffeine concentrations and/or symptoms of theophylline toxicity in newborns; an exposed infant should be closely monitored at birth. The selection of any pharmacologic treatment for asthma control during pregnancy should include the specific needs of the patient, based on an individual evaluation, and consideration of the potential benefits or risks to the fetus.545556 In studies in which pregnant mice, rats and rabbits were dosed during the period of organogenesis, theophylline produced teratogenic effects.515253

7-Keto DHEA

The safety of 7-keto-DHEA has not been evaluated in pregnant women. Due to this lack of safety data, pregnant women should avoid the use of 7-keto-DHEA.

Phenylephrine

There are no data on the use of phenylephrine injection during the first or second trimester of human pregnancy. Data from randomized controlled trials and meta-analyses with phenylephrine injection use in pregnant women during labor and obstetric delivery (i.e., Cesarean section) have not established a drug-associated risk of major birth defects and miscarriage. These studies have not identified an adverse effect on maternal outcomes of infant Apgar scores. At recommended doses, phenylephrine does not appear to affect fetal heart rate or fetal heart rate variability to a significant degree. Untreated hypotension associated with spinal anesthesia for Cesarean section is associated with an increase in maternal nausea and vomiting. A sustained decrease in uterine blood flow due to maternal hypotension may result in fetal bradycardia and acidosis. In animal studies, evidence of fetal malformation was noted when phenylephrine was administered during organogenesis via a 1-hour infusion at 1.2 times the human daily dose (HDD) of 10 mg/60 kg/day. Decreased pup weights were noted in the offspring of pregnant rats treated with 2.9 times the HDD.58 A study in rabbits indicated that continued moderate overexposure to oral phenylephrine (3 mg/day) during the second half of pregnancy may contribute to perinatal wastage, prematurity, premature labor, and possibly fetal anomalies; when phenylephrine (3 mg/day) was given to rabbits during the first half of pregnancy, a significant number gave birth to litters of low birth weight. Another study showed that phenylephrine was associated with anomalies of aortic arch and with ventricular septal defect in the chick embryo.64 It is not known whether phenylephrine ophthalmic solution can cause fetal harm or affect reproduction capacity. Use phenylephrine ophthalmic solution during pregnancy only if clearly needed.44 Under the direction of a health care professional, topical or nasal phenylephrine may be used during pregnancy.653959 

Yohimbine HCl

In general, yohimbine is not for use in females and must certainly not be used during pregnancy.66 A FDA pregnancy risk category has not been assigned to this drug. However, given yohimbine's similarity to other rauwolfia alkaloids, it is suggested that yohimbine most closely corresponds to an FDA pregnancy risk category D (see Reserpine monograph). There is no known indication at this time for the use of yohimbine in pregnancy which would justify the potential risks to the fetus.

Breast-feeding

Aminophylline

Use theophylline with caution during breast-feeding. Theophylline is excreted in breast milk in concentrations similar to the serum concentration of the mother. Breastfed infants whose mothers are taking theophylline may experience irritability or other mild signs of toxicity; however, serious adverse events are unlikely unless the mother has toxic serum concentrations. Close monitoring is recommended, particularly in a newborn. Theophylline or aminophylline are not preferred therapy for asthma in the lactating woman; these drugs are considered alternative therapy to inhaled corticosteroids for mild persistent asthma and an adjunctive medication for moderate to severe asthma during lactation according to the Guidelines of the National Asthma Education and Prevention Program (NAEPP) Asthma and Pregnancy Working Group. If used, it is recommended that serum theophylline concentrations be regularly monitored and maintained between 5 to 12 mcg/mL.54515253

7-Keto DHEA

The safety of 7-keto-DHEA has not been evaluated in women who are breast feeding or children. Due to this lack of safety data, women who are breast feeding and children should avoid the use of 7-keto-DHEA.

Phenylephrine

There are no data on the presence of phenylephrine or its metabolite in human or animal milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for phenylephrine and any potential adverse effects on the breast-fed infant from phenylephrine or from the underlying maternal condition.6458 Use caution when administering ophthalmic phenylephrine to a pregnant woman.44 Under the direction of a health care professional, topical or nasal phenylephrine may be used by a breast-feeding woman.653959 

Yohimbine HCl

Generally, this drug is not for use in females 66, and therefore should not be used during breast-feeding. Many of the rauwolfia alkaloids are excreted in human breast milk. A decision should be made to discontinue the medication or discontinue breast-feeding.

Adverse Reactions/Side Effects

Aminophylline

Adverse GI reactions can be either a local irritant effect on the gastric mucosa or a centrally mediated effect. Transient caffeine-like adverse reactions, such as nausea and vomiting, can occur especially during initiation of theophylline. Initiate theophylline at a low dose and slowly titrate to decrease the occurrence of these reactions. These reactions may persist in a small percentage of patients (less than 3% pediatrics and less than 10% adults). A reduction in dosage may eliminate caffeine-like adverse reactions, but if they continue or become severe, theophylline may have to be discontinued. Diarrhea has also been reported as an adverse reaction in patients with therapeutic serum concentrations of theophylline. Nausea/vomiting and abdominal pain may be caused by gastroesophageal reflux, and this effect is more likely to occur if the patient is lying down. Children 2 years old and under, the elderly, and debilitated patients are more likely to suffer from this effect. Other GI effects include abdominal cramps, anorexia, and possible hematemesis. Local irritation can be minimized by taking the oral drug before or after meals, with a full glass of water or milk, or with antacids. Both adverse GI and CNS effects can be minimized if the dose is titrated over a period of 1 week. Repetitive vomiting may indicate theophylline toxicity and should be investigated. In studies evaluating signs and symptoms of theophylline overdose, vomiting was reported in 73% to 93% of patients after a large single ingestion (acute overdose) and 30% to 61% of patients after multiple excessive doses (chronic overdose).515067

Central nervous system (CNS) reactions associated with theophylline are generally mild when the peak serum concentrations are less than 20 mcg/mL and mainly consist of transient caffeine-like adverse effects such as headache, insomnia, anxiety, agitation, dizziness, and hyperactivity. Transient caffeine-like adverse reactions occur in about 50% of patients when theophylline therapy is initiated at doses higher than the recommended initial doses (e.g., greater than 300 mg/day in adults and greater than 12 mg/kg/day in children beyond 1 year of age). During the initiation of theophylline therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school-age children, but this response rarely persists. To minimize the occurrence of the caffeine-like adverse effects, initiate theophylline at a low dose, and slowly titrate. These reactions may persist in a small percentage of patients (less than 3% pediatrics and less than 10% adults), even at peak serum theophylline concentrations within the therapeutic range (i.e., 10 to 20 mcg/mL). A reduction in dosage may eliminate caffeine-like adverse reactions, but if they continue or become severe, theophylline may have to be discontinued.515067 Irritability, restlessness, and tremor have also been reported in patients with theophylline serum concentrations less than 20 mcg/mL. When peak serum theophylline concentrations exceed 20 mcg/mL, theophylline produces a wide range of adverse reactions including intractable seizures which can be lethal. Serum theophylline concentrations greater than 30 mcg/mL have also resulted in nervousness, tremors, and disorientation. There have been a few isolated reports of seizures at serum theophylline concentrations less than 20 mcg/mL in patients with an underlying neurological disease or elderly patients. The occurrence of seizures in elderly patients with serum theophylline concentrations less than 20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum theophylline concentration in the pharmacologically active unbound form. CNS reactions are more likely to occur in children than in adults and are also more likely following rapid IV administration or in patients with excessive theophylline serum concentrations. Serious reactions can occur without antecedent minor symptoms.515067

Theophylline is a weak diuretic and inotrope, and can cause a mild diuresis.51

Hypercalcemia has been reported in a patient with hyperthyroid disease at therapeutic theophylline concentrations.51

Hypersensitivity and dermatologic reactions reported with theophylline at concentrations less than 20 mcg/mL include anaphylactic reaction, anaphylactoid reactions, pruritus, rash, and urticaria. Severe allergic skin reactions, such as exfoliative dermatitis, can develop rarely after systemic administration of aminophylline in patients previously sensitized to ethylenediamine via topical administration of an ethylenediamine-containing product. Urticaria or contact dermatitis can develop in individuals who physically handle aminophylline from a hypersensitivity to the ethylenediamine salt.515067
Theophylline can affect the cardiovascular system. It decreases peripheral resistance, increases cardiac output, and causes a central vagal effect. Palpitations, sinus bradycardia, extrasystoles, hypotension, ventricular tachycardia, premature ventricular contractions (PVCs), and cardiac arrest have been reported. Although cardiovascular effects are generally mild and transient, serious reactions, such as ventricular arrhythmias, can develop without warning. Patients should be carefully monitored.515067

Theophylline toxicity appears to occur at lower serum concentrations after chronic overmedication than after acute overdose.6869 Also, acute overdose patients are more likely to exhibit hypotension, hypokalemia, and/or metabolic acidosis than are patients receiving chronic overmedication.68 Patients suffering from chronic overmedication can develop seizures and serious arrhythmias with serum concentrations of 28 to 70 mcg/mL.68 Cardiac arrhythmias include atrial fibrillation or atrial flutter, multifocal atrial tachycardia, sinus tachycardia, supraventricular tachycardia (SVT), premature ventricular contractions (PVCs), and other ventricular arrhythmias with hemodynamic instability. In studies evaluating signs and symptoms of theophylline overdose, sinus tachycardia was the most common cardiac symptom occurring in 86% to 100% of patients after large single ingestions (acute overdose) and 62% to 100% of patients after multiple excessive doses (chronic overdose). Multifocal atrial tachycardia and atrial flutter have been reported at serum concentrations 15 mcg/mL or more in patients with hypoxia secondary to COPD.515067

Theophylline is a pyridoxine antagonist and may lead to vitamin B6 deficiency. Supplementation with vitamin B6 may be beneficial in preventing depletion and reducing adverse reactions. Monitor patients during extended therapy.70

Rhabdomyolysis is a manifestation of theophylline toxicity and has been reported in studies where the theophylline concentrations were greater than 30 mcg/mL.67

Hyperglycemia is a manifestation of theophylline toxicity and has been reported in studies where the theophylline concentrations were greater than 30 mcg/mL.67

7-Keto DHEA

Adverse reactions and side effects of 7-keto-DHEA may include but are not limited to gastrointestinal upset/nausea617, headache6, decreased hemoglobin and hematocrit levels6, sensitivity to mosquito bite6, vertigo17, and increased serum triiodothyronine (T3) levels.16 Short-term studies in preclinical models revealed no adverse effects with 7-keto-DHEA.202122 Short-term studies in humans 7-keto-DHEA, administered as 3β-acetyl-7-oxo-DHEA, is safe and well tolerated.6 The long-term safety of 7-keto-DHEA, in any form, or its metabolites have not been conducted.

A safety study of 7-keto-DHEA administered as the acetyl ester (dose escalation: 50 mg/day for 7 days, 100 mg/day for 7 days, and 200 mg/day for 28 days) concluded that 3-acetyl-7-oxo-DHEA is safe and well tolerated.6 In this study of 22 healthy male participants,  82% of participants in the 7-keto-DHEA group (n=16) and 100% of those in the placebo group (n=6) reported mild adverse events. The most common adverse event was gastrointestinal upset, occurring in 18% of the 7-keto-DHEA recipients and 33% of the placebo recipients. Headaches (n=4) were reported in the 7-keto-DHEA group. Two adverse events were deemed as possibly related to 7-keto-DHEA therapy, decreased hemoglobin and hematocrit levels (n=1) and heightened sensitivity to mosquito bite (n=1). Participants who received the 7-keto-DHEA acetyl ester also had significantly decreased blood pressure during treatment compared with their baseline values.6

Nausea and vertigo17 and increased serum triiodothyronine (T3) levels16 have also been reported as adverse events and side effects, respectively, related to 7-keto-DHEA supplementation.

Phenylephrine

Adverse reactions to phenylephrine are primarily attributable to excessive pharmacologic activity.26 Few adverse reactions occur when given at recommended doses by oral, intranasal, or ophthalmic routes. 

Phenylephrine causes few adverse reactions when given at recommended doses. Adverse effects including hypertension, reflex bradycardia, excitability, restlessness, and rare arrhythmias are more likely after parenteral administration, but can also occur if phenylephrine is systemically absorbed after intranasal or ophthalmic use (more likely with 10% phenylephrine solution). Cardiovascular reactions, some fatal, including hypertension, syncope, myocardial infarction, sinus tachycardia, and arrhythmias have been reported in patients receiving the 10% ophthalmic solution. Use the 2.5% ophthalmic solution in patients with cardiovascular diseases. Phenylephrine is a powerful vasoconstrictor, and parenteral administration causes a rise in systolic and diastolic pressures (i.e., hypertension including hypertensive crisis), which may be accompanied by myocardial ischemia (i.e., angina), marked reflex sinus bradycardia, and AV block. An increased workload on the heart increases the risk of heart failure. Headache may be a sign of hypertension that can be relieved by administration of an alpha-adrenergic blocking agent (e.g., phentolamine). In general, geriatric patients are more susceptible than younger adults to a reduction in cardiac output after sinus bradycardia. Rarely, serious cardiac events including cardiac arrhythmias (e.g., ventricular tachycardia or bigeminy) or myocardial infarction may occur, but usually only with parenteral administration or occasionally when the 10% solution is given intranasally or by the ocular route in higher-risk patients (i.e., infants and children, geriatric patients, patients with preexisting cardiac disease). Infants and children, especially those of low body weight, are more susceptible than adults to systemic absorption from intranasal or ophthalmic use, necessitating careful dosage selection. Use phenylephrine with caution in geriatric patients, especially in those with potential for undiagnosed coronary artery disease or arteriosclerosis. Geriatric patients, especially those with preexisting cardiac disease may experience adverse cardiovascular reactions including increased blood pressure, cardiac arrhythmias, myocardial infarction, sinus tachycardia, syncope, and subarachnoid hemorrhage after intraocular administration of 10% phenylephrine ophthalmic solution; therefore, use of the 2.5% ophthalmic solution is preferred in these patients.1821415826 

Rare occurrences of intracranial bleeding (subarachnoid hemorrhage and rupture of aneurysms) have occurred following ocular administration of the 10% ophthalmic phenylephrine solution.21 

Extravasation of phenylephrine, especially with repeated injections or high infusion rates, can result in an injection site reaction with severe tissue damage and tissue necrosis. Additional skin disorders associated with phenylephrine injection include diaphoresis, pallor, piloerection, pruritus, and skin discoloration (i.e., skin blanching).4158 

A localized reaction inside the nose can occur from intranasal use of phenylephrine. This may cause nasal irritation with burning, stinging, and dryness. Rebound nasal congestion can result from overuse or higher than recommended doses which can lead to swelling of the nasal mucosa, sneezing, and rhinitis. Additionally, when used as a topical decongestant, tolerance to the effects can occur within a few days.40 

Ophthalmic solutions of phenylephrine can produce localized effects, including burning or stinging of the eyes, ocular pain, blurred vision/visual impairment or tearing, photophobia, and conjunctival sensitization. Geriatric patients may develop visual impairment (i.e., transient pigment floaters in the aqueous humor) 30 to 45 minutes after instillation due to a strong effect on the dilator muscle. Mydriasis can make the eyes more sensitive to light and possibly precipitate an attack of glaucoma in predisposed patients. Ocular pain may occasionally occur due to elevated intraocular pressure. Conjunctivitis, requiring drug withdrawal, has been reported including conjunctival hyperemia, follicular conjunctivitis, and rarely, blepharoconjunctivitis. Ocular allergy to phenylephrine may occur rarely.4421 Blurred vision has also been reported with the use of injectable phenylephrine.58 

Contact dermatitis has been associated with phenylephrine, with cross-sensitivity to ephedrine.41 

Nervous system adverse reactions associated with phenylephrine therapy, especially parenteral routes of administration, include anxiety, excitability, paresthesias, tremor, headache, and restlessness.41 

Nausea, vomiting, and abdominal pain have been reported with the injectable formulation of phenylephrine.4158 Mild nausea or stomach upset may occur with non-prescription oral use at usual doses for congestion, but such adverse effects are not frequent. Ischemic colitis (bowel ischemia) has been rarely associated with the use of sympathomimetics, even oral phenylephrine, and may present with symptoms of abdominal pain and bloody diarrhea. Colitis may result from reversible splanchnic arterial vasoconstriction.71 

Dyspnea, pulmonary edema, and rales have been reported with the use of injectable phenylephrine.4158 

Yohimbine HCl

Yohimbine readily crosses the blood-brain barrier and can therefore produce central nervous system adverse reactions. The most common CNS adverse reactions include anxiety, antidiuresis, dizziness, flushing, headache, hypertension, increased motor activity, irritability, nervousness or restlessness, sinus tachycardia, and tremor. Although yohimbine is not administered intravenously, diaphoresis, nausea and vomiting have been reported following IV administration of yohimbine.

Per the FDA (1993 out of print document), natural Yohimbe is a tree bark containing a variety of pharmacologically active chemicals; the major identified alkaloid in yohimbe is yohimbine. Yohimbe is marketed in a number of dietary supplements for body building and 'enhanced male performance.' Serious adverse effects, including renal failure (unspecified), seizures and death, have been reported to FDA with products containing yohimbe. Side effects that are well recognized may include central nervous system stimulation that causes anxiety attacks or agitation. At high doses, yohimbine is reported to inhibit monoamine oxidase (MAO). MAO inhibitors (MAOIs) can cause serious adverse effects (like severe hypertension) when taken concomitantly with tyramine-containing foods (e.g., liver, cheeses, red wine) or with over-the-counter (OTC) products containing phenylpropanolamine (PPA). Patients taking yohimbe should be warned to avoid these foods and PPA because of the increased likelihood of adverse effects.

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. Barnes PJ. Theophylline: new perspectives for an old drug. Am J Respir Crit Care Med. 2003;167:813-818.
  • 2. a. b. c. d. e. f. g. Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma (GINA) 2020. Available from: http://www.ginasthma.org. Accessed May 20th, 2020.
  • 3. a. b. c. d. e. f. g. Expert Panel Working Group of the National Heart, Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC), et al. 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol. 2020;146:1217-1270.
  • 4. a. b. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2021. Retrieved 3/8/2021. Available on the World Wide Web at https://goldcopd.org/wp-content/uploads/2020/11/GOLD-REPORT-2021-v1.1-25Nov20_WMV.pdf
  • 5. a. b. c. d. e. f. g. h. Bernini JC, Fort DW, Griener JC, et al. Aminophylline for methotrexate-induced neurotoxicity. Lancet 1995;345:544-7.
  • 6. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. q. Lynch BA, Gal P, Ransom JL, et al. Low-dose aminophylline for the treatment of neonatal non-oliguric renal failure - case series and review of the literature. J Pediatr Pharmacol Ther 2008;13:80-7.
  • 7. a. b. c. Hochwald C, Kennedy K, Chang J, Moya F. A randomized, controlled, double-blind trial comparing two loading doses of aminophylline. J Perinatol 2002; 22:275-278.
  • 8. a. b. c. d. e. Lim DS, Kulik TJ, Kim DW, et al. Aminophylline for the prevention of apnea during prostaglandin E1 infusion. Pediatrics 2003; 112: e22.
  • 9. a. b. Dalabih A, Harris ZL, Bondi SA, Arnold DH. Contemporary aminophylline use for status asthmaticus in pediatric ICUs. Chest 2012; 141: 1122-3.
  • 10. Orentreich N, Brind JL, Rizer RL, Vogelman JH. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab. 1984;59(3):551-555. doi:10.1210/jcem-59-3-551
  • 11. National Center for Biotechnology Information. 7-Oxodehydroepiandrosterone 3-acetate | C21H28O4 - PubChem. https://pubchem.ncbi.nlm.nih.gov/compound/7-Oxodehydroepiandrosterone-3-acetate. Accessed August 3, 2020.
  • 12. Worrel ME, Gurkovskaya O V, Leonard ST, Lewis PB, Winsauer PJ. Effects of 7-keto dehydroepiandrosterone on voluntary ethanol intake in male rats. Alcohol. 2011;45(4):349-354. doi:10.1016/j.alcohol.2010.08.020
  • 13. Lund-Pero M, Jeppson B, Arneklo-Nobin B, Sjögren HO, Holmgren K, Pero RW. Non-specific steroidal esterase activity and distribution in human and other mammalian tissues. Clin Chim Acta. 1994;224(1):9-20. doi:10.1016/0009-8981(94)90116-3
  • 14. Marwah A, Marwah P, Lardy H. Development and validation of a high-performance liquid chromatography assay for the quantitative determination of 7-oxo-dehydroepiandrosterone-3β-sulfate in human plasma. J Chromatogr B Biomed Sci Appl. 1999;721(2):197-205. doi:10.1016/S0378-4347(98)00474-5
  • 15. a. b. Kaiman DS, Colker CM, Swain MA, Torina GC, Shi Q. A randomized, double-blind, placebo-controlled study of 3-acetyl-7-oxo-dehydroepiandrosterone in healthy overweight adults. Curr Ther Res. 2000;61(7):435-442. doi:10.1016/S0011-393X(00)80026-0
  • 16. a. b. c. d. e. Zenk JL, Helmer TR, Kassen LJ, Kuskowski MA. The effect of 7-Keto NaturaleanTM on weight loss: A randomized, double-blind, placebo-controlled trial. Curr Ther Res. 2002;63(4):263-272. doi:10.1016/S0011-393X(02)80031-5
  • 17. a. b. c. d. e. f. g. h. i. Zenk JL, Frestedt JL, Kuskowski MA. HUM5007, a novel combination of thermogenic compounds, and 3-acetyl-7-oxo-dehydroepiandrosterone: each increases the resting metabolic rate of overweight adults. J Nutr Biochem. 2007;18(9):629-634. doi:10.1016/J.JNUTBIO.2006.11.008
  • 18. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. Phenylephrine hydrochloride injection package insert. Lake Forest, IL: Hospira, Inc.; 2005 Nov.
  • 19. a. b. c. d. e. Centers for Disease Control and Prevention (CDC). Infant deaths associated with cough and cold medications - two states, 2005. MMWR Weekly 2007;56:1-4.
  • 20. a. b. Tschudy MM, Arcara KM. The Harriet Lane handbook: a manual for pediatric house officers 19th ed. Philadelphia, PA: Mosby;2012.
  • 21. a. b. c. d. e. f. g. h. i. j. k. Phenylephrine hydrochloride ophthalmic solution, USP 2.5% and 10% package insert. Lake Forest, IL: Akorn, Inc.; 2019 Feb.
  • 22. a. b. c. Beale RJ, Hollenberg SM, Vincent JL, et al. Vasopressor and inotropic support in septic shock: an evidence-based review. Crit Care Med 2004;32:S455-65.
  • 23. Topjian AA, Berg RA, Nadkarni VM. State-of-the-Art Review Article. Pediatric Cardiopulmonary Resuscitation: Advances in Science, Techniques, and Outcomes. Pediatrics. 2008;122:1086-1098.
  • 24. Di Gennaro JL, Mack CD, Malakouti A, et al. Use and effect of vasopressors after pediatric traumatic brain injury. Dev Neurosci. 2010;32:420-430.
  • 25. Sookplung P, Siriussawakul A, Malakouti A, et al. Vasopressor use and effect on blood pressure after severe adult traumatic brain injury. Neurocrit Care. 2011;15:46-54.
  • 26. a. b. c. d. e. f. g. h. i. j. k. Biorphen (phenylephrine hydrochloride) injection package insert. Deer Park, IL; Eton Pharmaceuticals, Inc.: 2021 Mar.
  • 27. Montague DK, Jarow JP, Broderick GA, et al. Chapter 1: The management of erectile dysfunction: an AUA update. J Urol 2005;174:230-9.
  • 28. Lebret T, Herve JM, Gorny P, et al. Efficacy and safety of a novel combination of L-arginine glutamate and yohimbine hydrochloride: a new oral therapy for erectile dysfunction. Eur Urol 2002;41:608-13.
  • 29. a. b. c. d. Weinberger M, Hendeles L. Theophylline in asthma. N Engl J Med 1996;334:1380-8.
  • 30. a. b. c. Persson CGA. Overview of effects of theophylline. J Allergy Clin Immunol 1986;78:780-7.
  • 31. Javaheri S, Parker TJ, Wexler L, et al. Effect of theophylline on sleep-disordered breathing in heart failure. N Engl J Med 1996;335:562-7.
  • 32. a. b. Flancbaum L, Dick M, Dasta J, et al. A dose-response study of phenylephrine in critically ill, septic surgical patients. Eur J Clin Pharmacol 1997;51:461-5.
  • 33. Eccles R. Substitution of phenylephrine for pseudoephdrine as a nasal decongestant. An illogical way to control methamphetamine abuse. Br J Clin Pharmacol 2006;63:10-14.
  • 34. Zhang ZY, Kaminsky LS. Characterization of human cytochromes P450 involved in theophylline 8-hydroxylation. Biochem Pharmacol 1995;50:205-11.
  • 35. a. b. Uniphyl (theophylline, anhydrous) tablets package insert. Stamford, CT: Purdue Pharmaceutical Products LP; 2004 Mar.
  • 36. Thierry-Mieg D, Thierry-Mieg J. AceView: a comprehensive cDNA-supported gene and transcripts annotation. Genome Biol 2006;7(suppl 1):S12. Accessed December 8, 2008. Available on the World Wide Web at www.ncbi.nlm.nih.gov/IEB/Research/Acembly/av.cgi?db=human&l=CYP3A.
  • 37. Gellner K, Eiselt R, Hustert E, et al. Genomic organization of the human CYP3A locus: identification of a new, inducible CYP3A gene. Pharmacogenetics 2001;11:111-21.
  • 38. a. b. Sudafed PE (phenylephrine) tablets. New Brunswick, NJ: McNeil-PPC, Inc.; 2013 Apr.
  • 39. a. b. c. d. e. Formulation R (phenyephrine) rectal cream. South Plainfield, NJ: G&W Laboratories, Inc.; 2013 Apr.
  • 40. a. b. Little Noses decongestant nasal drops (phenylephrine HCl 0.125%). Prestige Brands, Inc.; 2013 Apr.
  • 41. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. Phenylephrine hydrochloride injection. Eatontown, NJ: West-Ward Pharmaceuticals; 12 Dec.
  • 42. a. b. c. Kanfer I, Dowse R, Vuma V. Pharmacokinetics of oral decongestants. Pharmacotherapy 1993;13(6 Pt 2):116S-128S.
  • 43. Kumar V, Schoenwald RD, Barcellos WA, et al. Aqueous vs. viscous phenylephrine. Arch Ophthalmol 1986;104:1189-1191.
  • 44. a. b. c. d. e. f. g. Phenylephrine hydrochloride ophthalmic solution, USP 2.5% sterile package insert. Lake Forest, IL: Akorn, Inc.; 2019 Feb.
  • 45. Neo-Synephrine Cold & Sinus Mild Strength Spray (phenyephrine HCl 0.25%). Bayer HealthCare; 2013 Apr.
  • 46. Ayorinde BT, Buczkowski P, Brown J, et al. Evaluation of pre-emptive intramuscular phenylephrine and ephedrine for reduction of spinal anesthesia induced hypotension during Caesarean section. Br J Anaesth 2001;86:372-376.
  • 47. Kollar C, Schneider H, Waksman J, et al. Meta-analysis of the efficacy of a single dose of phenylephrine 10 mg compared with placebo in adults with acute nasal congestion due to the common cold. Clin Ther 2007;29:1057-1070.
  • 48. a. b. Le Corre P, Parmer RJ, Kailasam MT, et al: Human sympathetic activation by alpha2-adrenergic blockade with yohimbine: Bimodal, epistatic influence of cytochrome P450-mediated drug metabolism. Clin Pharmacol Ther 2004;76(2):139-153.
  • 49. Bharucha AE, Skaar T, Andrews CN, et al. Relationship of cytochrome P450 pharmacogenetics to the effects of yohimbine on gastrointestinal transit and catecholamines in healthy subjects. Neurogastroenterol Motil 2008;20: 891–9.
  • 50. a. b. c. d. e. f. g. Aminophylline (aminophylline dihydrate) package insert. Lake Forest, IL: Hopsira, Inc.; 2009 Nov.
  • 51. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. Elixophyllin (theophylline, anhydrous) liquid package insert. Detroit, MI: Caraco Pharmaceutical Laboratories, Inc.; 2010 Feb.
  • 52. a. b. c. d. e. f. Theophylline extended-release (theophylline, anhydrous) tablet package insert. Pomona, NY: Pliva, Inc.; 2007 Feb.
  • 53. a. b. c. d. e. f. Theophylline injection package insert. Lake Forest, IL: Hospira, Inc.; 2008 July.
  • 54. a. b. c. d. e. f. NAEPP Working Group Report on Managing Asthma During Pregnancy. Recommendations for Pharmacologic Treatment-Update 2004. NIH Publication No. 05-3279. Bethesda, MD: U.S. Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute, 2004
  • 55. a. b. Hardy-Fairbanks AJ, Baker ER. Asthma in pregnancy: pathophysiology, diagnosis and management. Obstet Gynecol Clin North Am. 2010;37:159-172.
  • 56. a. b. Giles W, Murphy V. Asthma in pregnancy: a review. Obstet Med. 2013;6:58-63. Epub 2013 May 3. Review.
  • 57. a. b. Health Care Financing Administration. Interpretive Guidelines for Long-term Care Facilities. Title 42 CFR 483.25(l) F329: Unnecessary Drugs. Revised 2015.
  • 58. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. Vazculep (phenylephrine) injection package insert. Chesterfield, Mo: Avadel Legacy Pharmaceuticals, LLC; 2019 Oct.
  • 59. a. b. c. d. e. Neo-synephrine Cold & Sinus regular strength spray (phenylephrine HCl 0.5%). Bayer HealthCare; 2011 May.
  • 60. Gunn VL, Taha SH, Liebelt EL, et al. Toxicity of over-the counter cough and cold medications. Pediatrics 2001;108:1-5.
  • 61. Children’s Sudafed PE (phenylephrine). New Brunswick, NJ: McNeil-PPC, Inc.; 2013 Apr.
  • 62. Dart RC, Paul IM, Bond GR, et al. Pediatric fatalities associated with over the counter (nonprescription) cough and cold medications. Ann Emerg Med 2009;53:411-7.
  • 63. Rimsza ME, Newberry S. Unexpected infant deaths associated with use of cough and cold medications. Pediatrics 2008;122:e318-22.
  • 64. a. b. c. d. Promethazine hydrochloride and phenylephrine hydrochoride solution package insert. Branchburg, NJ: Amneal Pharmaceuticals, LLC; 2015 May.
  • 65. a. b. c. d. Formulation R (phenylephrine) suppository. South Plainfield, NJ: G&W Laboratories, Inc.; 2013 Apr.
  • 66. a. b. c. d. Yocon (yohimbine hydrochloride, USP) package insert. Englewood, NJ: Glenwood, LLC; 2003, Jan.
  • 67. a. b. c. d. e. f. g. h. Theo-24 (theophylline, anhydrous) package insert. Malvern, PA: Endo Pharmaceuticals, Inc.; 2019 Mar.
  • 68. a. b. c. Olson KR, Benowitz NL, Woo OF, et al. Theophylline overdose: Acute single ingestion versus chronic repeated overmedication. Am J Emerg Med 1985;3:386-94.
  • 69. Shannon M. Predictors of major toxicity after theophylline overdose. Ann Intern Med 1993;119:1161-7.
  • 70. Nutrient-Drug Interactions and Drug-Induced Nutrient Depletions. In: Stargrove MB, Treasure J, McKee DL. Herb, Nutrient, and Drug Interactions: Clinical Implications and Therapeutic Strategies. St. Louis: Mosby Elsevier; 2008:173-831.
  • 71. Ward PW, Shaneyfelt TM, Roan RM. Acute ischaemic colitis associated with oral phenylephrine decongestant use. BMJ Case Rep. 2014 Jun 3;2014.

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