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

General Information

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.2 3 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.2 3 4 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.2 6

Like DHEA, 7-keto-DHEA is produced endogenously in the adrenal glands, gonads, brain, liver, and skin.5 7 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.3 12 13 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.6 14

7-keto-DHEA has been shown to promote weight loss and increase resting metabolic rate in people who are overweight.15 16 17 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.19 20 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).23 24 25 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.27 28 Yohimbine has been available since before 1938.

Mechanism of Action

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.2 3 18 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.3 18

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.2 3 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).29 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.22 18 29 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.30

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.

Contraindications/Precautions

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.18 31 32 26 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.33 34

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.18 31 32

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.31 26

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.35 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.36 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.37 38

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.32 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.39 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.40 Under the direction of a health care professional, topical or nasal phenylephrine may be used during pregnancy.41 42 34

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.39 32 Use caution when administering ophthalmic phenylephrine to a pregnant woman.40 Under the direction of a health care professional, topical or nasal phenylephrine may be used by a breast-feeding woman.41 42 34

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.40

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.31 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.43

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.31 32 26

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.31 32 26

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.31 32 26

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.31 32 26

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.44 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, and therefore should not be used during breastfeeding.44 Many of the rauwolfia alkaloids are excreted in human breast milk. A decision should be made to discontinue the medication or discontinue breastfeeding.

Pregnancy

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.32 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.39 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.40 Under the direction of a health care professional, topical or nasal phenylephrine may be used during pregnancy.41 42 34

Yohimbine HCl

Breastfeeding

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.39 32 Use caution when administering ophthalmic phenylephrine to a pregnant woman.40 Under the direction of a health care professional, topical or nasal phenylephrine may be used by a breast-feeding woman.41 42 34

Yohimbine HCl

Generally, this drug is not for use in females 44, 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

7-Keto DHEA

Adverse reactions and side effects of 7-keto-DHEA may include but are not limited to gastrointestinal upset/nausea6 17, 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.20 21 22 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.18 21 31 32 26

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).31 32

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.45

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.40 21 Blurred vision has also been reported with the use of injectable phenylephrine.32

Contact dermatitis has been associated with phenylephrine, with cross-sensitivity to ephedrine.31

Nervous system adverse reactions associated with phenylephrine therapy, especially parenteral routes of administration, include anxiety, excitability, paresthesias, tremor, headache, and restlessness.31

Nausea, vomiting, and abdominal pain have been reported with the injectable formulation of phenylephrine.31 32 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.46

Dyspnea, pulmonary edema, and rales have been reported with the use of injectable phenylephrine.31 32

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.

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