Arousal Cream

Overview of Arousal Cream

Dosage Strengths of Arousal Cream

Arousal 1: Aminophylline 30 mg/mL, Ergoloid Mesylate 0.5 mg/mL, Pentoxifylline 50 mg/mL, Sildenafil Citrate 10 mg/mL, Testosterone 1 mg/mL, L-Arginine 60 mg/mL 30 mL Pump

Arousal 2: Aminophylline 30 mg/mL, Ergoloid Mesylate 0.5 mg/mL, Pentoxifylline 50 mg/mL, Sildenafil Citrate 10 mg/mL, Testosterone 1 mg/mL 30 mL Pump

Arousal 3: Aminophylline 30 mg/mL, Ergoloid Mesylate 0.5 mg/mL, Pentoxifylline 50 mg/mL, Testosterone 1 mg/mL, L-Arginine 60 mg/mL 30 mL Pump

Arousal 4: Aminophylline 30 mg/mL, Ergoloid Mesylate 0.5 mg/mL, Pentoxifylline 50 mg/mL, Sildenafil Citrate 10 mg/mL, L-Arginine 60 mg/mL 30 mL Pump

Arousal 5: Aminophylline 30 mg/mL, Ergoloid Mesylate 0.5 mg/mL, Pentoxifylline 50 mg/mL, Sildenafil Citrate 10 mg/mL 30 mL Pump

General Information

Arousal Cream, which may also go by the name of Scream Cream, is a topical cream that, when applied to the clitoris and/or external genitalia, can increase blood flow to the applied area and has been reported to improve sensitivity and rates of orgasm. Compounded from a mixture of prescription products, Arousal Cream is designed to act locally without substantial absorption into the blood stream. This transdermal (absorbed through the skin) cream is comprised of up to six different medications and products which include: aminophylline, ergoloid mesylate, L-arginine, pentoxifylline, sildenafil citrate, and testosterone. This synergistic medication draws upon the properties of each ingredient (one bronchodilator, four vasodilators, and the potent sex steroid hormone testosterone) that may provide female libido (sex drive) and sexual stimulation enhancement.

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.2 3 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.5 6 7 8 9 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.

Ergoloid Mesylate

Ergoloid mesylates contain a combination of synthetic derivatives of naturally occurring ergot alkaloids (dihydroergocornine, dihydroergocristine, and dihydroergocryptine). Ergoloid mesylates are approved for the symptomatic management of various dementias including vascular dementia, Alzheimer's disease, and primary progressive dementia. At therapeutic doses, ergoloid mesylates have few side effects and lack the vasoconstrictor properties of the natural ergot alkaloids. Despite a favorable safety profile, the role of ergoloid mesylates in the management of various dementias remains controversial. The majority of studies evaluating ergoloid mesylates for vascular dementia were conducted prior to the development of standardized diagnostic criteria and study results have been inconsistent. Practice guidelines do not support the use of ergoloid mesylates in the treatment of Alzheimer's disease.10 11 12 13 14 15 16

Pentoxifylline

Pentoxifylline is a synthetic dimethylxanthine derivative that is structurally related to theophylline and caffeine. Unlike these agents, pentoxifylline has hematological effects that are useful in the symptomatic treatment of complications of peripheral vascular diseases. Pentoxifylline also has been used to manage acute and chronic cerebrovascular insufficiency, sickle cell disease17, and painful diabetic neuropathy.18 Pentoxifylline was approved by the FDA in August 1984.

Sildenafil

Initially developed for the treatment of pulmonary hypertension, angina, and other cardiovascular conditions, sildenafil citrate was accidentally found to be beneficial in males who suffered from erectile dysfunction (ED). Prior to the discovery of its benefits in treating ED, this condition was considered to be an inevitable part of aging in men or due to underlying psychological causes. After its approval in 1998 by the U.S. Food and Drug Administration for the treatment of ED, the popularity of sildenafil citrate has skyrocketed over the past couple of decades as health care providers generally recommend this medication as the first-line therapy in the management of erectile dysfunction in men. Other contributing factors to its appeal and popularity is that sildenafil citrate can be taken orally on demand, is generally well tolerated, with minimal adverse effects.1

Sildenafil citrate is a vasoactive medication belonging to the drug class of phosphodiesterase – 5 enzyme (PDE-5) inhibitors; it is a competitive antagonist of this enzyme. PDE-5 can be found all over the human body especially in the corpus cavernosum within the penis, striated and smooth musculature, as well as in platelets. However, PDE-5 has the largest distribution in the penile corpus cavernosum which is why sildenafil citrate is able to work selectively in this part of the body.2

Sildenafil citrate is generally administered orally. However, it can also be administered intravenously or sublingually. Even though its most popular clinical indication for use is in the management of erectile dysfunction, it is also used in the management of pulmonary hypertension, persistent pulmonary hypertension of the newborn, Raynaud's phenomenon resistant to other vasodilators, as well as in the prevention of pulmonary edema at high altitudes. After oral ingestion, absorption of sildenafil citrate rapidly occurs mainly in the small intestine from where it is then transported in the bloodstream to its area of action. Sildenafil citrate is metabolized in the liver through the action of the hepatic isoenzymes cytochrome P450 3A4 and cytochrome P450 2C9. Following hepatic metabolism, the metabolites are excreted mainly in the stool and, to a lesser degree, in the urine.2 3 4

Sildenafil citrate is classified as a pregnancy category B drug by the Food and Drug Administration. Studies have not demonstrated definite risks to fetuses when sildenafil is administered to pregnant mothers. At present, there are no definite clinical indications that warrant the administration of sildenafil citrate in women. Studies done till date have not indicated that sildenafil citrate has comparable benefits in women as they do in men. There are other studies that are still ongoing, however, and their outcomes may provide further insight regarding the utility and benefits of sildenafil in women.5

Arginine

Arginine hydrochloride is a synthetic derivative of the essential amino acid L-arginine. Arginine hydrochloride may be used as an aid to the detection of growth hormone deficiency in conditions such as panhypopituitarism, pituitary dwarfism, chromophobe adenoma, postsurgical craniopharyngioma, hypophysectomy, pituitary trauma, and in problems with growth and stature. The drug has also been used in the evaluation of pituitary function in gigantism and acromegaly Further, arginine injection is used to treat high ammonia concentrations in patients with urea cycle disorders. Arginine tablets, which are dietary supplements, have been used to improve exercise capacity in patients with stable angina pectoris.19 Arginine injection was originally approved by the FDA in February 1973.

Testosterone

Testosterone is the primary androgen found in the body. Endogenous testosterone is synthesized by cells in the testis, ovary, and adrenal cortex. Therapeutically, testosterone is used in the management of hypogonadism, either congenital or acquired. Testosterone is also the most effective exogenous androgen for the palliative treatment of carcinoma of the breast in postmenopausal women. Testosterone was in use in 1938 and approved by the FDA in 1939. Anabolic steroids, derivatives of testosterone, have been used illicitly and are now controlled substances. Testosterone, like many anabolic steroids, was classified as a controlled substance in 1991. Developed in the United States by Uniumed Pharmaceuticals as AndroGel, testosterone cream was FDA approved in 2000 for the treatment of testosterone deficiency, which often results in a variety of hypogonadic conditions from mood and energy to sexual dysfunctions, as well as a treatment for several injury-related conditions like those experienced by severe burn and accident victims. A very popular form of testosterone, AndroGel is sold around the world under a couple of less popular brand/trade names most notably Testogel (manufactured in the UK by Laboratoires Besins and distributed by Bayer), Testim (manufactured in the U.S. by Auxilium Pharmaceuticals, Inc.), and various generic versions often sold under the name testosterone cream or gel.

The transdermal delivery system of testosterone gel targets the same, or at least very similar bodily regions as injections and other forms of testosterone. More specifically, maximum absorption of testosterone gel is achieved when (as with injectable testosterone) it's administered to densely muscled bodily regions. Since greater amounts of muscle at the point of application equates to a higher number of testosterone absorbing capillaries, testosterone can be more rapidly shuttled into the bloodstream.

Mechanism of Action

Arousal Cream’s four vasodilators contribute by relaxing the vascular smooth muscles, which consequently dilates peripheral blood vessels (arteries and especially veins). Dilatation (widening) of the blood vessels promotes peripheral pooling of blood and decreases venous return to the heart, thereby reducing left ventricular end-diastolic pressure and pulmonary capillary wedge pressure (preload). Such medications are primarily used to treat or prevent heart disease due to arterial plaque buildup, blood clots, platelet clumping, and to increase blood flow through the coronary artery. These medications are also used to ease migraines, improve blood pressure to organs and tissues, lessen recovery time after surgery, increase immune-boosting effects, and speed up tissue repair/wound healing. However, they contribute to the Arousal Cream complex by exerting effects on the female genitalia. The same vasoactive mechanisms used by these agents to improve blood flow to the heart, lungs, and many other bodily tissues and functions, is believed to also increase vaginal blood flow during stimulation, thereby effectively aiding in the treatment of sexual dysfunctions.

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.20 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.20 The ability of theophylline to control chronic asthma, however, is disproportionately greater than is explainable by its relatively weak bronchodilatory action.20 Theophylline may even possess antiinflammatory actions as evidenced by its ability to attenuate late-phase reactions in asthma.21

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.21 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.21 Thus, clinicians do not believe adenosine antagonism explains the bronchoprotective actions of theophylline.20

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.22

Ergoloid Mesylate

There is no specific evidence which clearly establishes the mechanism by which ergoloid mesylates preparations produce mental effects, nor is there conclusive evidence that the drug particularly affects cerebral arteriosclerosis or cerebrovascular insufficiency. Proposed mechanisms are largely based on animal in vitro data. Ergoloid mesylates are considered a cerebral metabolic enhancing agent; the proposed mechanism is improved oxygen uptake and improved neuronal cell metabolism, with potential normalization of depressed neurotransmitter levels. Ergoloid mesylates are associated with alpha-adrenergic blocking activity, and may act as agonists of serotonin and dopamine receptors. At therapeutic doses, ergoloid mesylates lack the vasoconstrictor properties of the natural ergot alkaloids.23 24

Pentoxifylline

The actions of pentoxifylline include increased erythrocyte flexibility and decreased blood viscosity. The mechanism of action for increasing erythrocyte flexibility is unknown, but the drug's actions appear to be related to inhibition of erythrocyte phosphodiesterase, which causes an increase in erythrocyte cAMP activity. This increase allows the erythrocyte membrane to maintain its integrity and become more resistant to deformity. Pentoxifylline's effect on blood viscosity is attributed to its reduction in plasma fibrinogen concentrations and an increase in fibrinolytic activity, as well as to its effects on erythrocytes. Improvement in blood viscosity results in increased blood flow to the microcirculation and enhanced tissue oxygenation. Unlike theophylline, pentoxifylline does not possess any bronchodilatory actions. Although pentoxifylline does not possess any direct anti-sickling properties, its actions on erythrocyte flexibility make it potentially beneficial in sickle cell disease.

Sildenafil

Sildenafil plays an indirect role in causing penile erection in men suffering from erectile dysfunction. In normal penile erection, sexual stimulation leads to the activation of the non-adrenergic as well as non-cholinergic nerves in the pelvic parasympathetic plexus. Following the activation of these nerves, the neurotransmitter nitric oxide is then released which then transverses the neuromuscular junction of the smooth muscle of the corpus cavernosum and the penile arteries. Nitric oxide then causes an increase in the production of the intracellular second messenger cyclic guanosine monophosphate (cGMP), which is a cyclic nucleotide derived from guanosine triphosphate (GTP). The release of cGMP leads to an increase in blood flow within the penile arteries as well as the relaxation of the smooth muscles of the corpus cavernosum, thereby resulting in penile erection. Penile detumescence is caused by the release of the phosphodiesterase-5 enzyme, which breaks down cGMP and, therefore leads to the contraction of the penile arteries and the corpus cavernosal smooth muscles.

Sildenafil has a chemical structure that is very similar to cGMP and binds competitively to phosphodiesterase-5 enzyme. By binding to the receptors on PDE-5, sildenafil prevents PDE-5 from binding to and degrading cGMP. This competitive antagonist action of sildenafil allows the actions of cGMP in the penile arteries and corpus cavernosum to be prolonged, resulting in the prolongation of penile erection.2 4 7

In addition to its location in the penile corpus cavernosum, the phosphodiesterase-5 is also located in large amounts within the pulmonary vasculature. In the lungs, PDE-5 breaks down cGMP, similar to its actions in the corpus cavernosum. Sildenafil also acts as a competitive antagonist to PDE-5 in the pulmonary vasculature preventing the breakdown of cGMP. This has the effect of causing a reduction in pulmonary vascular resistance as well as the mean pulmonary artery pressure. Due to this effect on the pulmonary vasculature, sildenafil has been proposed as an adjunct medication in the treatment of primary pulmonary hypertension, a disease of childhood with a typically poor prognosis. However, studies as to its efficacy in the management of this disorder are still ongoing.2

Arginine

Growth Hormone Deficiency Diagnosis: Arginine stimulates pituitary release of growth hormone in patients with normal pituitary function. Patients with impaired pituitary function who receive arginine will have lower or no increase in plasma concentrations of growth hormone after administration of arginine.25

Urea Cycle Disorders (UCDs): The urea cycle is normally responsible for maintaining low blood concentrations of ammonia and glutamine from protein breakdown. The normal urea cycle requires numerous enzyme-catalyzed steps to form nitrogenous waste such as urea. Hyperammonemia may occur when there is a deficiency in one or more urea cycle enzymes or a cofactor: N-acetylglutamate synthetase (NAGS), carbamyl phosphate synthetase (CPS), argininosuccinate synthetase (ASS), ornithine transcarbamylase (OTC), or argininosuccinate lyase (ASL). Arginine becomes an essential amino acid when any of these enzymes is deficient. If essential amino acids are not available, protein catabolism occurs, which increases ammonia concentrations. Exogenous arginine is administered in patients with UCDs to restore serum levels and prevent the breakdown of endogenous protein. Additionally, arginine administration lowers the blood ammonia level and increases the amount of nitrogen excreted in the urine by stimulating an alternative pathway for waste nitrogen excretion.26 27 28

Metabolic Alkalosis: Arginine is a precursor to hydrochloric acid and has a high chloride content and is, therefore, an alternative treatment for severe metabolic alkalosis.29

Cardiovascular disease: Arginine is a precursor of nitric oxide, which is a potent vasodilator with antiplatelet activity. Nitric oxide has been shown to induce vasodilation in patients with atherosclerosis.30 31

Testosterone

Endogenous testosterone is responsible for sexual maturation at all stages of development throughout life. Synthetically, it is prepared from cholesterol. The function of androgens in male development begins in the fetus, is crucial during puberty, and continues to play an important role in the adult male. Women also secrete small amounts of testosterone from the ovaries. The secretion of androgens from the adrenal cortex is insufficient to maintain male sexuality.

Increased androgen plasma concentrations suppress gonadotropin-releasing hormone (reducing endogenous testosterone), luteinizing hormone, and follicle-stimulating hormone by a negative-feedback mechanism. Testosterone also affects the formation of erythropoietin, the balance of calcium, and blood glucose. Androgens have a high lipid solubility, enabling them to rapidly enter cells of target tissues. Within the cells, testosterone undergoes enzymatic conversion to 5-alpha-dihydrotestosterone and forms a loosely bound complex with cystolic receptors. Androgen action arises from the initiation of transcription and cellular changes in the nucleus brought about by this steroid-receptor complex.

Normally, endogenous androgens stimulate RNA polymerase, resulting in an increased protein production.These proteins are responsible for normal male sexual development, including the growth and maturation of the prostate, seminal vesicle, penis, and scrotum. During puberty, androgens cause a sudden increase in growth and development of muscle, with redistribution of body fat. Changes also take place in the larynx and vocal cords, deepening the voice. Puberty is completed with beard development and growth of body hair. Fusion of the epiphyses and termination of growth is also governed by the androgens, as is the maintenance of spermatogenesis. When endogenous androgens are unavailable, use of exogenous androgens are necessary for normal male growth and development.

Pharmacokinetics

Transdermal application results is primarily localized action. As such, the expected pharmacokinetics for each of Arousal Cream’s six compounds mimics those of the individual compounds when administered topically. The differences resulting from simultaneous application have not been studied.

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.32 The manufacturer states that theophylline is a substrate of hepatic enzymes CYP1A2, 2E1, and 3A3 without mention of 3A4 33; 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 CYP3A4.34 35 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.

Elderly

Absorption of pentoxifylline from the gastrointestinal tract following oral administration is rapid and almost complete. There is significant first-pass effect after absorption. Peak plasma levels are attained within 2—4 hours. The rate but not the extent of absorption is affected by coadministration with food.

Special Populations

Renal Impairment

Ergoloid Mesylate

Ergoloid mesylates (dihydroergocornine, dihydroergocristine, and dihydroergocryptine) are administered orally. Ergoloid mesylates undergo significant (about 50%) first-pass hepatic metabolism. The mean half-life of ergoloid mesylates is about 3.5 hours (range 2.6 to 5.1 hours).24

Affected Cytochrome P450 enzymes and drug transporters: None known.

Route-Specific Pharmacokinetics

Oral Route

Ergoloid mesylates are rapidly absorbed from the gastrointestinal tract, but oral bioavailability is approximately 25%. Peak plasma concentrations occur within 1.5 to 3 hours. The finding of lower peak levels of ergoloid compared to the total drug-metabolite composite is consistent with a considerable first-pass liver metabolism, with less than 50% of the therapeutic moiety reaching the systemic circulation after oral administration. Oral tablet or solution dosage forms and sublingual dosage forms result in similar bioavailability. The clinical therapeutic effects of a particular dose may not be apparent for 3 to 4 weeks.24

Special Populations

Hepatic Impairment Ergoloid mesylates are extensively metabolized in the liver.24

Renal Impairment No data are available but renal impairment is not expected to have a significant effect on ergoloid mesylate pharmacokinetics.

Indications/Dosage

For the symptomatic management of Alzheimer's disease, vascular dementia, or primary progressive dementia

Oral dosage

Adults 1 mg PO 3 times per day. Clinical improvement may take 3 to 4 weeks after initiating therapy. Assess treatment benefits periodically. It is not known if there are patient traits that would usefully predict a positive response to ergoloid mesylates therapy. While doses up to 9 mg/day (3 mg PO 3 times per day) have been studied, statistically significant differences in effect at higher doses than the labeled dose have not been noted. The role of ergoloid mesylates in the management of dementia remains controversial. The majority of studies evaluating ergoloid mesylates for vascular dementia were conducted prior to the development of standardized diagnostic criteria and study results have been inconsistent. Practice guidelines do not support the use of ergoloid mesylates in the treatment of Alzheimer's disease.24 13 36 14 15 16

Maximum Dosage Limits

Adults 3 mg/day PO is usual dose; doses up to 9 mg/day have been studied.
Geriatric 3 mg/day PO is usual dose; doses up to 9 mg/day have been studied.
Adolescents Safety and efficacy have not been established.
Children Safety and efficacy have not been established.
Infants Not indicated.
Patients with Hepatic Impairment Dosing No guidelines for dosage adjustment are available; use with caution in patients with hepatic disease as ergoloid mesylates are extensively metabolized in the liver.24
Patients with Renal Impairment Dosing No dosage adjustment is needed.

Pentoxifylline

Pentoxifylline is administered orally.  The distribution of pentoxifylline has not been fully characterized, but it is known that the drug and its metabolites are distributed into breast milk (see Contraindications/Precautions).

Metabolism of pentoxifylline occurs in both the erythrocytes and the liver. All metabolites contribute to the hematological effects of pentoxifylline. The 5-hydroxyhexyl metabolite is equivalent to pentoxifylline in its pharmacologic effects. Once absorbed, pentoxifylline is metabolized rapidly by the erythrocytes to its 5-hydroxyhexyl metabolite and by the liver to its 3-carboxypropyl metabolite. The plasma half-lives of pentoxifylline and its metabolites are 0.4—0.8 hours and 1.6—1.8 hours, respectively. The elimination half-lives of pentoxifylline and its 5-hydroxyhexyl metabolite increase with increasing doses of the drug, but the elimination half-life of the 3-carboxypropyl metabolite does not. Excretion of pentoxifylline and its metabolites is primarily renal. The manufacturer states that the drug does not accumulate in plasma with multiple oral doses in patients with normal renal function.

Route-Specific Pharmacokinetics

Oral Route

Limited data indicate that the pentoxifylline AUC is increased and elimination rate decreased in patients aged 60—80 years when compared to younger adults (22—30 years). In elderly patients, dosage adjustments may be necessary based on tolerability and/or decreased renal function (see Dosage).

In patients with renal impairment (i.e., CrCl < 50 ml/min), the 5-hydroxyhexyl metabolite of pentoxifylline accumulates; eight hours after dose administration, the peak plasma concentration is reduced by 78% in patients with normal renal function, by 45% in patients with a CrCl of 10—20 ml/min, and by 11% in patients with a CrCl of < 10 ml/min. Dosage adjustments are recommended in patients with a CrCl of < 50 ml/min (see Dosage).37 38 In elderly patients, dosage adjustments may be necessary based on tolerability and/or decreased renal function (see Dosage).

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.

Sildenafil

As earlier stated, sildenafil citrate can be administered orally, sublingually, or intravenously. In the management of erectile dysfunction, however, the oral and sublingual routes are the means by which the medication is commonly administered. After oral ingestion, sildenafil citrate is rapidly absorbed within the small intestine, with a peak plasma concentration time of anywhere between 30 and 120 minutes and a median time of 60 minutes in fasting individuals. It has a bioavailability of approximately 40 percent after oral administration.2 4 8

Metabolism of sildenafil citrate occurs primarily in the liver through the action of the hepatic microsomal isoenzymes cytochrome P450 3A4 and 2C9. After the action of the isoenzymes on sildenafil, it is broken down into an N-desmethyl metabolite. Both sildenafil citrate as well as its N-desmethyl metabolite breakdown product are tightly bound to plasma proteins and they have an approximate half-life of four hours. it is estimated that about 96 percent of sildenafil and its metabolite are bound to plasma proteins after oral ingestion. Following its metabolism, the majority of sildenafil citrate is excreted in the stool; a lesser amount, about 13 percent of sildenafil metabolites, is excreted in the urine.4 8

There are a number of factors that can interfere with the metabolism of sildenafil, thereby increasing or decreasing its concentration in the body. Some of these factors include the following:

Hepatic impairment: Individuals who have significant hepatic disease such as liver cirrhosis may experience a significant increase in plasma sildenafil levels. This is because the production of the hepatic isoenzymes cytochrome P450 3A4 and 2C9 are markedly diminished in liver cirrhosis. As a result of this diminished production of the hepatic isoenzymes, the body is not able to adequately metabolize sildenafil citrate, resulting in increased plasma levels.

Renal impairment: Individuals with significant renal disease as evidenced with a creatinine clearance of less than 30mL/min will have a marked increase in plasma sildenafil levels after oral ingestion. Since sildenafil and its metabolites are excreted through the kidneys, renal diseases will impair the ability of the kidneys to perform this task adequately.

Age: For reasons that are yet to be fully determined, there is a 40 percent increase in the plasma levels of sildenafil and its N-desmethyl metabolite when administered to men greater than 65 years of age.

Cytochrome P450 3A4 inhibitors: The concomitant use of drugs known to inhibit the hepatic cytochrome P450 enzymes may result in increased plasma levels of sildenafil. Examples of drugs that are known P450 inhibitors are macrolide antibiotics such as erythromycin, antifungal agents such as ketoconazole, and protease inhibitors such as indinavir. By inhibiting the production of cytochrome P450, hepatic metabolism of sildenafil does not occur, leading to its increased levels in plasma.8

Arginine

Arginine is administered orally and via IV administration. Thirty grams of intravenous arginine increased urinary nitrate and cyclic GMP excretion rates by 97 +/- 28 and 66 +/- 20%, respectively. The onset and duration of vasodilator effect on endogenous nitric oxide production paralleled the plasma half-life of arginine.30

Route-Specific Pharmacokinetics:

Intravenous Route: Arginine elimination was biphasic, with concentration dependent renal clearance eliciting a rapid initial decrease in serum concentrations, followed by a slower decrease in serum concentrations due to nonrenal elimination.31 After 30 g IV infusion, about 5 g of arginine was excreted in the urine, with a major portion excreted within 90 minutes after drug administration. Renal clearance in 2 of 12 volunteers within the first 90 minutes after drug administration was 1.16—1.18 mL/kg/minute.31 In a study of 8 healthy males, after receiving 30 g IV of arginine, clearance was 544 +/- 24 mL/min, and after 6 g IV of arginine, clearance was 894 +/-164 mL/min. Elimination half life was dose dependent and was 41.6 min after 30 g IV and 59.6 min after 6 g IV.30

Testosterone

Testosterone is administered intramuscularly (IM); via subcutaneous injection; to the skin as a topical gel, solution, ointment or transdermal systems for transdermal absorption; by implantation of long-acting pellets, or; via buccal systems.

In serum, testosterone is bound to protein. It has a high affinity for sex hormone binding globulin (SHBG) and a low affinity for albumin. The albumin-bound portion freely dissociates. The affinity for SHBG changes throughout life. It is high during prepuberty, declines during adolescence and adult life, then rises again in old age. The active metabolite DHT has a greater affinity for SHBG than testosterone. Elimination half-life is 10—100 minutes and is dependent on the amount of free testosterone in the plasma.

Testosterone is metabolized primarily in the liver to various 17-keto steroids. It is a substrate for hepatic cytochrome P450 (CYP) 3A4 isoenzyme.39 Estradiol and dihydrotestosterone (DHT) are the major active metabolites, and DHT undergoes further metabolism. Testosterone activity appears to depend on formation of DHT, which binds to cytosol receptor proteins. Further metabolism of DHT takes place in reproductive tissues. About 90% of an intramuscular testosterone dose is excreted in the urine as conjugates of glucuronic and sulfuric acids. About 6% is excreted in the feces, largely unconjugated. There is considerable variation in the half-life of testosterone as reported in the literature, ranging from 10 to 100 minutes.40

Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, P-gp

Testosterone is a substrate for CYP3A4 and is also both transported by and an inhibitor of P-glycoprotein (P-gp) transport.39 41

Route-Specific Pharmacokinetics

Nasal Route: For intranasal use only; do not administer to other parts of the body. For first time use of the nasal gel, prime the pump by rotating the actuator over a sink and discarding any dispensed product. Wipe the tip of the dispenser clean with a dry tissue. Before administration, blow your nose and ensure the dispenser cap is removed from the dispenser pen. Slowly advance the tip of the actuator into the left nostril upwards until the finger on the pump reaches the base of the nose. Tilt the actuator so that the opening on the tip of the actuator is in contact with the lateral wall of the nostril to ensure that the gel is applied to the nasal wall. Slowly rotate the bottom of the dispenser pen to administer an actuation. Each actuation (click) of the metered dose pump dispenses 5 mg of testosterone. Remove the actuator from the nose while wiping the tip along the inside of the lateral nostril wall to fully transfer the gel. Repeat steps for administration of the next actuation, this time to the lateral wall of the right nostril. Wipe the tip of the actuator with a dry tissue, replace dispenser cap. Press on the nostrils at a point just below the bridge of the nose and lightly massage. Do not blow the nose or sniff for 1 hour after administration of the intranasal gel. If any gel gets on the hands, it is recommended to wash hands with warm water and soap.

Contraindications/Precautions

If you have contraindications with intercourse, you should consult your healthcare provider before using the medication and engaging in intercourse. You should not use this cream if you are allergic to any of the ingredients, have a history of genital herpes (*L-Arginine may facilitate replication of the herpes virus. An alternative formulation without L-Arginine is available.), chronic vaginal infections, or serious medical conditions such as heart disease or autoimmune disorder.

Additionally, despite acting almost exclusively locally, the contraindications for each of Arousal Cream’s compounds may apply. Provide your physician with information on Arousal Cream, as well as a list of your medical conditions before asking for a prescription.

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.42 43

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.43 44 45 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.46 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.46 47 48 In studies in which pregnant mice, rats and rabbits were dosed during the period of organogenesis, theophylline produced teratogenic effects.43 44 45

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.46 43 44 45

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.43 33 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.49

Ergoloid Mesylate

Careful diagnosis should be performed prior to prescribing ergoloid mesylates to rule out reversible or treatable underlying conditions which contribute to symptoms of dementia. Ergoloid mesylates are contraindicated in patients with sensitivity to ergoloid mesylates or in patients with known ergot alkaloid hypersensitivity. Ergoloid mesylates are also contraindicated in patients with acute or chronic psychosis, regardless of etiology; dopamine agonist activity may exacerbate pre-existing psychosis.
Ergoloid mesylates should be used with caution in patients with bradycardia or hypotension, since these conditions can be exacerbated during ergoloid mesylate therapy. Heart rate and blood pressure should be monitored during therapy; if significant bradycardia or hypotension occurs ergoloid mesylates should be discontinued.

Ergoloid mesylates are extensively metabolized by the liver. Therefore, ergoloid mesylates should be used with caution in patients with hepatic disease, since hepatic impairment could limit drug elimination mechanisms.

Although specific data are lacking for ergoloid mesylates, ergot derivatives should generally be avoided during breast-feeding.50 51 There are no specific studies evaluating the safety of ergoloid mesylates in breast-feeding; however, other ergot derivatives such as ergotamine are excreted in breast milk and may cause symptoms indicative of ergot toxicity including vomiting, diarrhea, seizures, weak pulse, and unstable blood pressure in nursing infants.52 53 Ergotamine is classified by the American Academy of Pediatrics (AAP) as a drug that has been associated with significant effects on some nursing infants and should be given to nursing mothers with caution.54 Therapeutic doses of ergoloid mesylates can decrease prolactin levels, and thus, interference with proper lactation is possible.55 56 Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Although specific data are lacking for ergoloid mesylates, natural ergot alkaloids are considered contraindicated (pregnancy risk category X) during pregnancy due to their oxytocic and uterine stimulant properties. Ergot alkaloids are also generally avoided during labor and obstetric delivery due to their oxytocic effect.52 Ergot alkaloids are not established human teratogens; however, limited data indicate that in utero exposure to ergotamine during pregnancy may be associated with fetal malformations, primarily consistent with ischemic injury.57 Because ergoloid mesylates preparations do not possess the vasoconstrictor properties of the natural ergot alkaloids, the fetal toxicity risk is unknown.24 Women of child-bearing potential should be counseled on the potential risks to the fetus should pregnancy occur during use of ergoloid mesylates.
In general, ergoloid mesylates dosing should be more cautious in geriatric patients, starting at the lower end of the dose range to account for differences in renal, hepatic, or cardiac systems as well as concomitant disease states and medications.24 The use of ergoloid mesylates in the therapy of dementia, including Alzheimer's disease and vascular dementia, is controversial; there is a lack of data to support efficacy.10 11 12 23 13 According to the Beers Criteria, ergoloid mesylates are considered a potentially inappropriate medication (PIM) for use in geriatric patients and should be avoided due to lack of established efficacy.58

There is no established use of ergoloid mesylates in children or infants < 18 years of age.

Pentoxifylline

Pentoxifylline is contraindicated in patients who have exhibited intolerance to pentoxifylline or methylxanthines (e.g., caffeine, theophylline, theobromine).

Pentoxifylline should be used cautiously in patients with risk factors complicated by bleeding. These patients include those with recent surgery or peptic ulcer disease. Periodic exams for bleeding including hematocrit and hemoglobin should be performed. Pentoxifylline is contraindicated in patients with intracranial bleeding or retinal bleeding.

Pentoxifylline and its active metabolites can accumulate in patients with renal impairment; such patients should be monitored carefully for adverse effects. Dosage adjustments are recommended in patients with renal impairment (CrCl < 50 ml/min) or renal failure (see Dosage). Dosage adjustments are recommended in patients who do not tolerate pentoxifylline (i.e., experience GI or CNS adverse effects) at usual prescribed dosages.

Clinical studies of pentoxifylline did not include sufficient numbers of subjects aged 65 years or older to determine whether they respond differently from younger subjects, and other reported clinical experience has not identified differences in responses between geriatric and younger patients. Because elderly patients are more likely to have decreased hepatic, renal, or cardiac function, they are at increased risk of adverse reactions due to decreased clearance of pentoxifylline and its metabolites. Elderly patients taking this drug should be monitored carefully, and it may be useful to monitor renal function.

Pentoxifylline is classified as FDA pregnancy risk category C. No controlled studies of pentoxifylline use have been conducted in women who are pregnant. Therefore, caution should be exercised when the drug is used during pregnancy.59

Pentoxifylline and its metabolites are excreted into human milk. According to the manufacturer, pentoxifylline has been shown to be tumorigenic in rats; therefore, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.59 A single dose of extended-release pentoxifylline was given to 5 women who had been breast-feeding for at least 6 weeks. Data from this study indicate an exclusively breastfed infant would receive about 2% of the maternal-adjusted dosage.60 Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

The safe and effective use of pentoxifylline in children has not been established.

Sildenafil

There are certain conditions under which sildenafil citrate should be administered with caution or outright avoided. Some of these conditions are:

Hypersensitivity: Sildenafil is absolutely contraindicated in individuals who have a demonstrated hypersensitivity to the drug or any of its components.9

Nitrate therapy: Individuals who are not nitrate therapy should not be administered sildenafil citrate. Nitrates are potent vasodilators typically used in the management of cardiac conditions such as angina pectoris. Since sildenafil also a vasodilatory effect through its actions on cGMP, it can potentiate the effects of nitrates when used concurrently which may result in severe hypotension, syncope, and myocardial infarction.9

Hepatic disease: Since sildenafil is metabolized by hepatic isozymes, hepatic diseases may lead to increased plasma levels of sildenafil and a prolongation of its effects. Care should be exercised when administering sildenafil to individuals with hepatic disease.9

Renal disease: Similar to hepatic diseases, renal diseases may prolong the effects of sildenafil citrate due to increased plasma levels as a result of diminished renal excretion. Caution should also be exercised when administering sildenafil to individuals with renal diseases.9

Visual abnormalities: There have been some instances of vision loss in individuals taking sildenafil citrate. The loss of vision is due to a reduction in blood flow to the optic nerve, a condition known as non-arteritic anterior ischemic optic neuropathy (NAION). Individuals with pre-existing visual disturbances may be administered sildenafil only when the benefits clearly outweigh the risks.9 12

Cardiovascular disorders: Caution should be exercised when administering sildenafil to individuals with known cardiac disorders such as arrhythmias, aortic stenosis, heart failure, and myocardial infarction, among others.

Arginine

Arginine injection is contraindicated in patients having know arginine hypersensitivity or a hypersensitivity to any components of the product.

Use arginine injection cautiously in patients with renal impairment, hepatic disease and/or an electrolyte imbalance. Arginine can be metabolized to nitrogen-containing products. Consider the nitrogen or acute amino acid burden on patients with impaired renal function when administering arginine injection. Additionally, arginine injection contains 47.5 mEq chloride/100 mL, which should be considered in patients with an existing electrolyte imbalance.25 In 2 adult patients with severe hepatic disease and moderate renal insufficiency, severe hyperkalemia developed during and after an arginine monohydrochloride infusion. Both patients had received spironolactone prior to the arginine infusion. Arginine shifts intracellular potassium to the extracellular compartment so caution should be used in patients with hepatic and renal failure due to decreased metabolism of arginine and decreased clearance of potassium.61

Use extreme caution when administering arginine injection to neonates, infants, children, and adolescents. Ensure the appropriate dose is being administered. Following high dose arginine hydrochloride administration in pediatric patients, hyperchloremic metabolic acidosis may occur. Chloride and bicarbonate levels should be monitored and bicarbonate should be administered if needed.26 In overdosages in pediatric patients, cerebral edema and death have been reported.25 28 In a review of adverse events reported to the FDA's Adverse Event Reporting System (AERS), 33 reports were identified and majority of cases involved pediatric patients less than 16 years old.62

Arginine injection is classified as FDA pregnancy category B. Basal and post-stimulation concentrations of growth hormone are elevated in pregnant women. There are no well-controlled studies for the use of arginine injection in pregnant women. Although animal studies have provided no evidence of harm to the fetus, animal reproductive studies are not always predictive of human response; therefore, the manufacturer recommends that arginine injection not be used during pregnancy.25

It is not known if intravenous arginine is secreted in human milk; however, systemically administered amino acids are secreted into breast milk in quantities not likely to be harmful to the infant.25 Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Testosterone

Your health care provider needs to know if you have any of these conditions: breast cancer; breathing problems while sleeping; diabetes; heart disease; if a female partner is pregnant or trying to get pregnant; kidney disease; liver disease; lung disease; prostate cancer, enlargement; any unusual or allergic reactions to testosterone or other products; pregnant or trying to get pregnant; breast-feeding. Your healthcare provider will need to have regular bloodwork drawn while on testosterone. This medication is banned from use in athletes by most athletic organizations.

Topical gels and solutions are typically flammable, therefore exposure to fire, flame, and tobacco smoking should be avoided while using any topical gel or solution formulation of testosterone.

Testosterone can stimulate the growth of cancerous tissue and is contraindicated in male patients with prostate cancer or breast cancer. Patients with prostatic hypertrophy should be treated with caution because androgen therapy may cause a worsening of the signs and symptoms of benign prostatic hypertrophy and may increase the risk for development of malignancy. Elderly patients and other patients with clinical or demographic characteristics that are recognized to be associated with an increased risk of prostate cancer should be evaluated for the presence of prostate cancer prior to initiation of testosterone replacement therapy. In patients receiving testosterone therapy, surveillance for prostate cancer should be consistent with current practices for eugonadal men. Testosterone replacement is not indicated in geriatric patients who have age-related hypogonadism only or andropause because there is insufficient safety and efficacy information to support such use.63 Additionally, the efficacy and long-term safety of testosterone topical solution in patients over 65 years of age has not been determined due to an insufficient number of geriatric patients involved in controlled trials.64 According to the Beers Criteria, testosterone is considered a potentially inappropriate medication (PIM) for use in geriatric patients and should be avoided due to the potential for cardiac problems and its contraindication in prostate cancer. The Beers expert panel considers use for moderate to severe hypogonadism to be acceptable.65

Because of reduced drug clearance and an increased risk of drug accumulation, patients with hepatic disease or hepatic dysfunction should be prescribed testosterone with caution. In addition, edema secondary to water and sodium retention may occur during treatment with androgens. Use testosterone with caution in patients with hepatic disease; renal disease, including nephritis and nephrosis; preexisting edema; or cardiac disease, including heart failure, coronary artery disease, and myocardial infarction (MI), as fluid retention may aggravate these conditions. Further, the possible association between testosterone use and the increased risk of severe cardiovascular events, irrespective of pre-existing cardiac disease, is currently under investigation. An observational study in the U.S. Veteran Affairs health system included adult male patients of an average age of 60 years. Patients (n = 8709) undergoing coronary angiography with a recorded low serum testosterone concentration of < 300 ng/dl were included in the retrospective analysis. Within the larger cohort, testosterone therapy was initiated in 1223 males after a median of 531 days following coronary angiography; 7486 males did not receive testosterone therapy. Three years after coronary angiography, 25.7% of patients receiving testosterone therapy compared to 19.9% of patients not receiving therapy suffered a severe and/or fatal cardiovascular event (MI, stroke, death).66 A second observational study, investigated the incidence of acute non-fatal MI following an initial testosterone prescription in both younger (<= 55 years) and older (>= 65 years) adult males (n = 55,593). The incidence rate of MI occurring within 90 days following the initial testosterone prescription was compared to the incidence rate of MI occurring in the one year leading-up to the first prescription. Among older males, a 2-fold increase in the risk of MI was observed within the 90 day window; among younger males with a pre-existing history of cardiac disease, a 2- to 3-fold increased risk of MI was observed. In contrast, no increased risk was observed in younger males without a history of cardiac disease.67 In light of these findings, the FDA announced in early 2014 an examination into the possible link between testosterone therapy and severe cardiovascular events. The FDA has NOT concluded that FDA-approved testosterone treatment increases the risk of stroke, MI, or death. However, health care professionals are urged to carefully consider whether the benefits of treatment are likely to exceed the potential risks. The FDA will communicate their final conclusions and recommendations when the evaluation is complete.68

The treatment of hypogonadal men with testosterone esters may potentiate sleep apnea, especially in patients that have risk factors for apnea such as obesity or chronic pulmonary disease. In addition, the safety and efficacy of testosterone topical solution and intranasal gel in obese males with BMI > 35 kg/m2 has not been established.64

Patients receiving high doses of testosterone are at risk for polycythemia. Periodically, patients receiving testosterone should have their hemoglobin and hematocrit concentrations measured to detect polycythemia.

Testosterone is contraindicated during pregnancy because of probable adverse effects on the fetus (FDA pregnancy risk category X). Women of childbearing potential who are receiving testosterone treatments should utilize adequate contraception. Because testosterone is not used during pregnancy, there should be no particular reason to administer the products to women during labor or obstetric delivery; safety and efficacy in these settings have not been established.64

Testosterone is specifically contraindicated in females; the drug is for males only; the dosage form supplies testosterone in excess of what should be prescribed to females under certain endocrine situations.69 In addition, Androgel, Androderm, Aveed, Fortesta, and Striant brand products are not indicated for use in females due to lack of controlled evaluations and/or the potential for virilizing effects.40 70 71 72 73 Female patients receiving other forms of testosterone therapy should be closely monitored for signs of virilization (deepening of the voice, hirsutism, acne, clitoromegaly, and menstrual irregularities). At high doses, virilization is common and is not prevented by concomitant use of estrogens. Some virilization may be judged to be acceptable during treatment for breast carcinoma; however, if mild virilism is evident, discontinuation of drug therapy is necessary to prevent long term virilization.63 Females should be aware that accidental exposure to some testosterone dosage forms (i.e., ointments, solutions, and gels) may occur if they come into direct contact with a treated patient. In clinical studies, within 2—12 hours of gel application by male subjects, 15-minute sessions of vigorous skin-to-skin contact with a female partner resulted in serum female testosterone levels > 2 times the female baseline values. When clothing covered the treated site on the male, the transfer of testosterone to the female was avoided. Accidental exposure to topical testosterone gel has also occurred in pediatric patients after contact between the child and the application site in treated individuals. The adverse events reported include genitalia enlargement, development of pubic hair, advanced bone age, increased libido, and aggressive behavior. Symptoms resolved in most patients when exposure to the product stopped. However, in a few patients, the genitalia enlargement and advanced bone age did not fully return to expected measurements. The FDA recommends taking precautions to minimize the potential for accidental exposure of topical testosterone products by washing hands with soap and warm water after each application, covering application site with clothing, and removing medication with soap and water when contact with another person is anticipated. In the case of direct skin-to-skin contact with the site of testosterone application, the non-treated person should wash the area with soap and water as soon as possible.64

Testosterone topical solution, transdermal patches, and gels are contraindicated in lactating women who are breast-feeding.64 40 It is recommended that other testosterone formulations be avoided during breast-feeding as well.74 63 Testosterone distribution into breast milk has not been determined; it is unclear if exposure would increase above levels normally found in human milk. Significant exposure to this androgen via breast-feeding may have adverse androgenic effects on the infant and the drug may also interfere with proper establishment of lactation in the mother.75 Historically, testosterone/androgens have been used adjunctively for lactation suppression.75 Alternative methods to breast-feeding are recommended in lactating women receiving testosterone therapy.

Androgen therapy, such as testosterone, can result in loss of diabetic control and should be used with caution in patients with diabetes mellitus. Close monitoring of blood glucose is recommended.

Testosterone has induced osteolysis and should be used with caution in patients with hypercalcemia, which can be exacerbated in patients with metastatic breast cancer.

Administration of testosterone undecanoate has been associated with cases of serious pulmonary oil microembolism (POME) reactions as well anaphylactoid reactions. Reported cases of POME reactions occurred during or immediately after a 1000 mg intramuscular injection of testosterone undecanoate. Symptoms included: cough, urge to cough, dyspnea, hyperhidrosis, throat tightening, chest pain, dizziness, and syncope. Most cases lasted a few minutes and resolved with supportive measures; however, some lasted up to several hours, and some required emergency care and/or hospitalization. When administering testosterone undecanoate, clinicians should take care to inject deeply into the gluteal muscle, avoiding intravascular injection. In addition to POME reactions, episodes of anaphylaxis, including life-threatening reactions, have also been reported following the intramuscular injection of testosterone undecanoate. Patients with suspected hypersensitivity reactions should not be retreated with testosterone undecanoate. After every administration, monitor patient for 30 minutes and provide appropriate medical treatment in the event of serious POME or anaphylactoid reactions. Due to the risk of serious POME and anaphylaxis reactions, testosterone undecanoate (Aveed) is only available through a restricted program called the Aveed REMS Program. Clinicians wanting to prescribe Aveed, must be certified with the REMS Program for purposes of ordering or dispensing the product. Healthcare settings must also be certified with the REMS Program and must have the resources to provide emergency medical treatment in cases of serious POME and anaphylaxis. Further information is available at www.AveedREMS.com or call 1—855—755—0494.73

Intranasal formulations of testosterone are not recommended for individuals with a history of nasal disorders such as nasal polyps; nasal septal perforation; nasal surgery; nasal trauma resulting in nasal fracture within the previous 6 months or nasal fracture that caused a deviated anterior nasal septum; sinus surgery or sinus disease. In addition, the safety and efficacy of intranasal testosterone has not been evaluated in individuals with mucosal inflammatory disorders such as Sjogren's syndrome. Patients with rhinorrhea (rhinitis) who are receiving intranasal formulations of testosterone may experience decreased medication absorption secondary to nasal discharge. These patients may experience a blunted or impeded response to the intranasal medication. In clinical evaluation, serum total testosterone concentrations were decreased by 21—24% in males with symptomatic allergic rhinitis, whether treated with nasal decongestants or left untreated. Treatment with intranasal testosterone should be delayed until symptoms resolve in patients with nasal congestion, allergic rhinitis, or upper respiratory infection. If severe rhinitis symptoms persist, an alternative testosterone replacement therapy is advised.

The safety and efficacy of testosterone topical products Androgel, Axiron, Fortesta, and Testim as well as Striant buccal tablets, and Aveed injectable testosterone undecenoate have not been established in neonates, infants, children, and adolescents < 18 years old.70 64 76 71 72 73 In addition, the safety and efficacy Depo-Testosterone injection has not be established in children < 12 years,74 and Androdem patches have not been evaluated in pediatric patients < 15 years.40 Generally, the use of testosterone in children should be undertaken only with extreme caution. Testosterone may accelerate bone maturation without stimulating compensatory linear growth, sometimes resulting in compromised adult stature. If testosterone is administered to prepubertal males, radiographic examinations of the hand and wrist should be performed every 6 months to assess the rate of bone maturation and the effect of the drug on epiphyseal centers. Once the epiphyses have closed, growth is terminated. Even after discontinuation of treatment, epiphyseal closure can be enhanced for several months. Accidental exposure to topical testosterone gel has also occurred in pediatric patients after skin to skin contact between the child and the application site in treated individuals. The adverse events reported include genitalia enlargement, development of pubic hair, advanced bone age, increased libido, and aggressive behavior. Symptoms resolved in most patients when exposure to the product stopped. However, in a few patients, the genitalia enlargement and advanced bone age did not fully return to expected measurements. The FDA recommends taking precautions to minimize the potential for accidental exposure by washing hands with soap and warm water after each application, covering application site with clothing, and removing medication with soap and water when contact with another person is anticipated. In the case of direct skin-to-skin contact with the site of testosterone application, the non-treated person should wash the area with soap and water as soon as possible.

Pregnancy

DO NOT USE AROUSAL CREAM while pregnant or trying to become pregnant: one of Arousal Cream’s ingredients, Testosterone, is an FDA pregnancy risk category X (adverse fetal effects are expected).77 An alternative formulation without testosterone is available.

Aminophylline

Ergoloid Mesylate

Pentoxifylline

Pentoxifylline is classified as FDA pregnancy risk category C. No controlled studies of pentoxifylline use have been conducted in women who are pregnant. Therefore, caution should be exercised when the drug is used during pregnancy.59

Sildenafil

Sildenafil citrate is classified as a Food and Drug Administration pregnancy category B drug. Studies have not demonstrated any evidence of birth defects, miscarriages, or adverse fetal or maternal outcomes when used in pregnancy. Insufficient data is available to make a clear determination about whether sildenafil citrate is expressed in breast milk and if there are any untoward effects.

Arginine

Arginine injection is classified as FDA pregnancy category B. Basal and post-stimulation concentrations of growth hormone are elevated in pregnant women. There are no well-controlled studies for the use of arginine injection in pregnant women. Although animal studies have provided no evidence of harm to the fetus, animal reproductive studies are not always predictive of human response; therefore, the manufacturer recommends that arginine injection not be used during pregnancy.25

Testosterone

Breast-feeding

As a testosterone-containing product, Arousal Cream is contraindicated in women who are breast-feeding.77 78

Aminophylline

Ergoloid Mesylate

Pentoxifylline

Pentoxifylline and its metabolites are excreted into human milk. According to the manufacturer, pentoxifylline has been shown to be tumorigenic in rats; therefore, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.59 A single dose of extended-release pentoxifylline was given to 5 women who had been breast-feeding for at least 6 weeks. Data from this study indicate an exclusively breastfed infant would receive about 2% of the maternal-adjusted dosage.60 Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Sildenafil

Arginine

It is not known if intravenous arginine is secreted in human milk; however, systemically administered amino acids are secreted into breast milk in quantities not likely to be harmful to the infant.25 Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Testosterone

Testosterone topical solution, transdermal patches, and gels are contraindicated in lactating women who are breast-feeding.64 40 It is recommended that other testosterone formulations be avoided during breast-feeding as well.74 68 Testosterone distribution into breast milk has not been determined; it is unclear if exposure would increase above levels normally found in human milk. Significant exposure to this androgen via breast-feeding may have adverse androgenic effects on the infant and the drug may also interfere with proper establishment of lactation in the mother.75 Historically, testosterone/androgens have been used adjunctively for lactation suppression.75 Alternative methods to breast-feeding are recommended in lactating women receiving testosterone therapy.

Interactions

Arousal Cream acts synergistically via six distinct pharmacologically active compounds and each has its own list of compounds it interacts with. Interactions resulting from the combination of these compounds have not been studied and may include more than the sum of all compounds. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

Arginine

Acetaminophen; Aspirin, ASA; Caffeine: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.79 80

Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.79 80

Aluminum Hydroxide: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.81 82

Aluminum Hydroxide; Magnesium Carbonate: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.81 82

Aluminum Hydroxide; Magnesium Hydroxide: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.81 82

Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.81 82

Aluminum Hydroxide; Magnesium Trisilicate: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.81 82

Antacids: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.81 82

Aspirin, ASA: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.79 80

Aspirin, ASA; Butalbital; Caffeine: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.79 80

Aspirin, ASA; Butalbital; Caffeine; Codeine: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.79 80

Aspirin, ASA; Caffeine; Dihydrocodeine: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.79 80

Aspirin, ASA; Carisoprodol: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.79 80

Aspirin, ASA; Carisoprodol; Codeine: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.79 80

Aspirin, ASA; Dipyridamole: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.79 80

Aspirin, ASA; Omeprazole: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.79 80

Aspirin, ASA; Oxycodone: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.79 80

Aspirin, ASA; Pravastatin: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.79 80

Bismuth Subsalicylate: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.79 80

Bismuth Subsalicylate; Metronidazole; Tetracycline: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.79 80

Calcium Carbonate; Magnesium Hydroxide: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.79 80

Choline Salicylate; Magnesium Salicylate: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.79 80

Colchicine: Colchicine is an alkaloid that is inhibited by acidifying agents. The colchicine dose may need adjustment.83

Magnesium Hydroxide: Aluminum hydroxide and magnesium hydroxide (as well as other antacids, i.e. aluminum hydroxide; magnesium carbonate, aluminum hydroxide; magaldrate; magnesium hydroxide, and aluminum hydroxide; magnesium trisilicate) may interact with urinary acidifiers by alkalinizing the urine. Frequent use of these high dose antacids should be avoided in patients receiving urinary acidifiers.79 80

Magnesium Salicylate: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.79 80

Methadone: As methadone is a weak base, the renal elimination of methadone is increased by urine acidification. Thus acidifying agents may lower the serum methadone concentration. The limited amounts of circulating methadone that undergo glomerular filtration are partially reabsorbed by the kidney tubules, and this reabsorption is pH-dependent. Several studies have demonstrated that methadone is cleared faster from the body with an acidic urinary pH as compared with a more basic pH.84 85 86 87

Salsalate: Acidification of the urine may increase serum concentrations of salicylates by increasing tubular reabsorption of salicylates, however, this interaction is not likely to be clinically significant since the urine is normally acidic.79 80

Testosterone

Possible interactions include: certain medicines for diabetes; certain medicines that treat or prevent blood clots like warfarin; oxyphenbutazone; propranolol; steroid medicines like prednisone or cortisone. This list may not describe all possible interactions.

NOTE: Testosterone is a substrate for hepatic cytochrome P450 (CYP) 3A4 isoenzyme.88 Testosterone is also both transported by and an inhibitor of P-glycoprotein transport.89

Testosterone can increase the anticoagulant action of warfarin.90 Serious bleeding has been reported in some patients with this drug-drug interaction. Although the mechanism is unclear, testosterone may reduce procoagulant factors. Reduction of warfarin dosage may be necessary if testosterone therapy is coadministered. More frequent monitoring of INR and prothrombin time in patients taking such oral anticoagulants is recommneded, especially at the initiation and termination of androgen therapy.40 It is unclear if testosterone can augment the anticoagulant response to heparin therapy or if testosterone alters the effect of other non-coumarin oral anticoagulants in a similar manner.

Based on case reports with methyltestosterone and danazol, androgens may increase plasma concentrations of cyclosporine, leading to a greater risk of nephrotoxicity.91 92 93 94

Coadministration of corticosteroids and testoterone may increase the risk of edema, especially in patients with underlying cardiac or hepatic disease. Corticosteroids with greater mineralocorticoid activity, such as fludrocortisone, may be more likely to cause edema. Administer these drugs in combination with caution.95

Goserelin96 and leuprolide97 inhibit steroidogenesis. Concomitant use of androgens with goserelin or leuprolide is relatively contraindicated and would defeat the purpose of goserelin or leuprolide therapy.

Androgens can increase the risk of hepatotoxicity and therefore should be used with caution when administered concomitantly with other hepatotoxic medications. Patients should be monitored closely for signs of liver damage, especially those with a history of liver disease.

Androgens may be necessary to assist in the growth response to human growth hormone, but excessive doses of androgens in prepubescent males can accelerate epiphyseal maturation.98

Androgens are known to stimulate erythropoiesis.99 Despite the fact that endogenous generation of erythropoietin is depressed in patients with chronic renal failure, other tissues besides the kidney can synthesize erythropoietin, albeit in small amounts. Concurrent administration of androgens can increase the patient's response to epoetin alfa, reducing the amount required to treat anemia. Because adverse reactions have been associated with an abrupt increase in blood viscosity, this drug combination should be avoided, if possible. Further evaluation of this combination needs to be made.

The antiandrogenic effects of the 5-alpha reductase inhibitors (i.e., dutasteride, finasteride) are antagonistic to the actions of androgens; it would be illogical for patients taking androgens to use these antiandrogenic drugs.100 101

Drug interactions with Saw palmetto, Serenoa repens have not been specifically studied or reported. Saw palmetto extracts appear to have antiandrogenic effects.102 103 The antiandrogenic effects of Saw palmetto, Serenoa repens would be expected to antagonize the actions of androgens; it would seem illogical for patients taking androgens to use this herbal supplement.

Limited data suggest that testosterone concentrations increase during fluconazole administration. It appears that fluconazole doses of 200 mg/day or greater are more likely to produce this effect than doses of 25—50 mg/day.104 The clinical significance of this interaction is unclear at this time. Although data are not available, a similar reaction may occur with voriconazole. Both fluconazole and voriconazole are inhibitors of CYP3A4, the hepatic microsomal isoenzyme responsible for metabolism of testosterone.105

Exogenously administered androgens (testosterone derivatives or anabolic steroids) have variable effects on blood glucose control in patients with diabetes mellitus. In general, low testosterone concentrations are associated with insulin resistance. Further, when hypogonadal men (with or without diabetes) are administered exogenous androgens, glycemic control typically improves as indicated by significant reductions in fasting plasma glucose concentrations and HbA1c. In one study in men with diabetes, testosterone undecenoate 120 mg PO/day for 3 months decreased HbA1c concentrations from a baseline of 10.4% to 8.6% (p < 0.05); fasting plasma glucose concentrations decreased from 8 mmol/l at baseline to 6 mmol/l (p < 0.05). Significant reductions in HbA1c and fasting plasma glucose concentrations did not occur in patients taking placebo.106 Similar results have been demonstrated with intramuscular testosterone 200 mg administered every 2 weeks for 3 months in hypogonadal men with diabetes.107 In healthy men, testosterone enanthate 300 mg IM/week for 6 weeks or nandrolone 300 mg/week IM for 6 weeks did not adversely affect glycemic control; however, nandrolone improved non-insulin mediated glucose disposal.108 It should be noted that some studies have shown that testosterone supplementation in hypogonadal men has no effect on glycemic control.109 110 Conversely, the administration of large doses of anabolic steroids in power lifters decreased glucose tolerance, possibly through inducing insulin resistance.111 While data are conflicting, it would be prudent to monitor all patients with type 2 diabetes on antidiabetic agents receiving androgens for changes in glycemic control, regardless of endogenous testosterone concentrations. Hypoglycemia or hyperglycemia can occur; dosage adjustments of the antidiabetic agent may be necessary.

In vitro, both genistein and daidzein inhibit 5 alpha-reductase isoenzyme II, resulting in decreased conversion of testosterone to the potent androgen 5-alpha-dihydrotestosterone (DHT) and a subsequent reduction in testosterone-dependent tissue proliferation.112 The action is similar to that of finasteride, but is thought to be less potent. Theoretically, because the soy isoflavones appear to inhibit type II 5-alpha-reductase, the soy isoflavones may counteract the activity of the androgens.

Conivaptan is a potent inhibitor of CYP3A4 and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A4. Testosterone is a substrate for CYP3A4 isoenzymes.105 The clinical significance of this theoretical interaction is not known.

Testosterone is an inhibitor of P-glycoprotein transport.105 Ranolazine is a substrate of P-glycoprotein, and inhibitors of P-glycoprotein may increase the absorption of ranolazine.113 In addition, ranolazine inhibits CYP3A and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A4 such as testosterone.105

Ambrisentan is a substrate for P-glycoprotein transport, an energy-dependent drug efflux pump.114 The inhibition of P-glycoprotein, by drugs such as testosterone,105 may lead to a decrease in the intestinal metabolism and an increase in the oral absorption of ambrisentan. If ambrisentan is coadministered with a P-glycoprotein inhibitor, patients should be monitored closely for adverse effects.

Coadministration of oxyphenbutazone and testosterone may lead to elevated concentrations of oxyphenbutazone. Monitor patients for adverse effects when coadministering these drugs together.95

Testosterone cypionate has been shown to increase the clearance of propranolol in one study. Monitor patients taking testosterone and propranolol together for decreased therapeutic efficacy of propranolol.95

Coadministration of dabigatran and testosterone may result in increased dabigatran serum concentrations, and, therefore, an increased risk of adverse effects. Coadministration of dabigatran and testosterone should be avoided in patients with severe renal impairment (CrCl 15—30 ml/min). Dabigatran is a substrate of P-gp; testosterone is a P-gp inhibitor.89 P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.115

Concomitant use of testosterone, a P-glycoprotein (P-gp) inhibitor,89 and afatinib, a P-gp substrate, may increase the exposure of afatinib. If the use of both agents is necessary, consider reducing the afatinib dose if the original dose is not tolerated.116

Concomitant use of intranasal testosterone and other intranasally administered drugs in not recommended; the drug interaction potential between these agents is unknown. Eighteen males with seasonal allergic rhinitis were treated with intranasal testosterone and randomized to receive oxymetazoline (30 minutes prior to intranasal testosterone) or no treatment. In general, serum total testosterone concentrations were decreased by 21—24% in males with symptomatic allergic rhinitis, due to the underlying condition. A mean decrease in AUC and Cmax (2.6% and 3.6%, respectively) for total testosterone was observed in males with symptomatic seasonal rhinitis when treated with oxymetazoline compared to untreated patients. Concomitant use of oxymetazoline does not impact the absorption of testosterone.

This list may not include all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

Adverse Reactions/Side Effects

Arousal Cream promotes blood flow to the applied area to improve sensitivity and rates of orgasm: it does not produce an orgasm. If not completely absorbed, it may cause irritation with your partner.

Arousal Cream is formulated to act locally so side effects are minimal, but may include skin irritation, headache, dizziness, and restlessness. However, possible side effects include but are not limited to those of each of Arousal Cream’s components. The side effects of these compounds in combination have not been studied.

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

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).43 42 117

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.43 42 117 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.43 42 117

Theophylline is a weak diuretic and inotrope, and can cause a mild diuresis.43

Hypercalcemia has been reported in a patient with hyperthyroid disease at therapeutic theophylline concentrations.43

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.43 42 117

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.43 42 117

Theophylline toxicity appears to occur at lower serum concentrations after chronic overmedication than after acute overdose.118 119 Also, acute overdose patients are more likely to exhibit hypotension, hypokalemia, and/or metabolic acidosis than are patients receiving chronic overmedication.118 Patients suffering from chronic overmedication can develop seizures and serious arrhythmias with serum concentrations of 28 to 70 mcg/mL.118 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.43 42 117

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.120

Rhabdomyolysis is a manifestation of theophylline toxicity and has been reported in studies where the theophylline concentrations were greater than 30 mcg/mL.117

Hyperglycemia is a manifestation of theophylline toxicity and has been reported in studies where the theophylline concentrations were greater than 30 mcg/mL.117

Ergoloid Mesylate

Gastrointestinal adverse effects which may frequently occur during therapy with ergoloid mesylates and include nausea, vomiting, stomach cramps, decreased appetite (anorexia), and transient dyspepsia.24 Sublingual irritation (soreness under the tongue) has been reported following administration of sublingual tablets.
At therapeutic doses, ergoloid mesylates (dihydrogenated ergot alkaloids) have few side effects and lack the vasoconstrictor properties of the natural ergot alkaloids.24 However, ergoloid mesylates have been associated with cardiovascular adverse effects including sinus bradycardia, hypotension, and orthostatic hypotension. Dizziness, headache, or syncope may accompany hypotensive effects. Blood pressure and heart rate should be monitored prior to initiating therapy and at periodic intervals during therapy. If significant bradycardia or hypotension occurs, ergoloid mesylates should be discontinued.
According to the manufacturer, therapeutic doses of ergoloid mesylates (dihydrogenated ergot alkaloids) have few side effects and lack certain properties of the natural ergot alkaloids.24 However, blurred vision, nasal congestion, rash (unspecified), and flushing may occur.

Pentoxifylline

Pentoxifylline therapy is associated with adverse effects involving the GI tract and the central nervous system. Adverse events are dose-related and if they do occur a dosage reduction should be considered. If adverse events continue at a reduced dosage, pentoxifylline therapy should be discontinued.

The following gastrointestinal-related adverse reactions were reported with pentoxifylline extended-release tablets during controlled clinical trials compared to placebo: nausea (2.2% vs. 0.8%), vomiting (1.2% vs. 0%), and belching/flatulence/bloating (0.6% vs. 0%). Anorexia, cholecystitis, constipation, and xerostomia/thirst have been reported spontaneously since marketing or occurred in other clinical trials with an incidence of less than 1%; the causal relationship was uncertain.121

Anxiety, confusion, depression, seizures, and aseptic meningitis have been reported spontaneously since pentoxifylline marketing or occurred in other clinical trials with an incidence of less than 1%; the causal relationship was uncertain.121

Angina/ chest pain (unspecified) was reported at an incidence of 0.3% in pentoxifylline-treated patients compared to 0% of placebo-treated patients in clinical trials. Dyspnea, edema, and hypotension were reported spontaneously since marketing or occurred in other clinical trials with an incidence of less than 1%; the causal relationship was uncertain. Arrhythmia exacerbation and sinus tachycardia have been reported rarely during post-marketing experience; a causal relationship has not been established.121

Epistaxis, influenza-like symptoms, laryngitis, and nasal congestion have been reported spontaneously since marketing of pentoxifylline or occurred in other clinical trials with an incidence of less than 1%; the causal relationship was uncertain.121

Angioedema has been reported spontaneously during post-marketing of pentoxifylline or in other clinical trials with an incidence of less than 1%; the causal relationship was uncertain. In addition, anaphylactoid reactions, including anaphylactic shock, have been reported rarely; a causal relationship has not been established. Pentoxifylline should be discontinued at the first sign of an anaphylactic reaction.121

Hepatitis, jaundice, cholestasis, and elevated hepatic enzymes have been reported rarely during post-marketing experience with pentoxifylline; a causal relationship has not been established.121

Leukopenia has been reported spontaneously since marketing of pentoxifylline or occurred in other clinical trials with an incidence of less than 1%; the causal relationship was uncertain. Decreased serum fibrinogen, pancytopenia, aplastic anemia, leukemia, purpura, and thrombocytopenia have been reported rarely during post-marketing experience with pentoxifylline; a causal relationship has not been established.121

Brittle fingernails, pruritus, rash (unspecified), and urticaria have been reported spontaneously since marketing pentoxifylline or in other clinical trials with an incidence of less than 1%; the causal relationship was uncertain.121

Blurred vision, conjunctivitis, earache, and scotomata have been reported spontaneously since marketing of pentoxifylline or in other clinical trials with an incidence of less than 1%; the causal relationship was uncertain.121

Bad taste, excessive salivation (hypersalivation), malaise, sore throat/swollen neck glands, and weight change (e.g., weight gain or weight loss) have been reported spontaneously since marketing of pentoxifylline or occurred in other clinical trials with an incidence of less than 1%; the causal relationship was uncertain.121

Sildenafil

Toxicity is one of the adverse effects that may be experienced in individuals on sildenafil therapy. The risk of developing toxic effects is especially higher in the presence of hepatic or renal disease, or in individuals on concurrent nitrate therapy. The toxic effects typically present as visual or cardiovascular disturbances. Other adverse reactions that may occur while on sildenafil therapy are tendon rupture, exfoliative dermatitis, hearing loss, seizures, and gastritis, among others.

Arginine

During clinical trials of arginine injection (R-Gene 10), one patient developed a maculopapular rash with reddening and swelling of the hands and face. The rash subsided after the infusion was terminated and 50 mg of diphenhydramine was administered. Hypersensitivity reactions, including anaphylactoid reactions, have been reported during post-market surveillance of arginine injection. If serious hypersensitivity or anaphylaxis occurs during arginine therapy, discontinue the infusion and initiate appropriate medical therapy.25

Nausea and vomiting were reported in approximately 3% of patients during clinical trials of arginine injection. Excessive rates of infusion may cause these adverse events; consider decreasing infusion rate if these symptoms develop. When dosing arginine for diagnostic purposes, inadequate dosing or prolongation of the infusion period may diminish the stimulus to the pituitary and nullify the test.25

Flushing and headache were reported in approximately 3% of patients during clinical trials of arginine injection. Excessive rates of infusion may cause flushing; consider decreasing infusion rate if these symptoms develop. When dosing arginine for diagnostic purposes, inadequate dosing or prolongation of the infusion period may diminish the stimulus to the
pituitary and nullify the test.25

During clinical trials of arginine injection, thrombocytopenia was reported in one patient (decrease in platelet count from 150,000 to 60,000).25

Metabolic acidosis and hyperventilation may occur with an overdosage of arginine injection. Ensure the appropriate dose is being administered. In overdosages in pediatric patients, cerebral edema and death have been reported.25 122 In a review of adverse events reported to the FDA's Adverse Event Reporting System (AERS), 33 reports were identified. most of which were pediatric patients. The acidosis and base deficit will usually self-compensate and return to normal following cessation of the infusion. If the acidosis persists, however, the deficit should be determined and an appropriate dose of an alkalinizing agent, such as bicarbonate, administered.25

Hematuria has been reported in post-marketing reports of arginine injection. Some cases occurred 1—2 days after administration of arginine.25

Extravasation causing a third-degree chemical burn (skin necrosis) requiring surgical intervention was in a 17 year old patient during post-market surveillance of arginine injection.62 An injection site reaction consisting of local venous irritation occurred in 3% of patients in clinical trials. Excessive rates of infusion may cause injection site reaction or skin irritation; consider decreasing infusion rate if local irritation develops. When dosing arginine for diagnostic purposes, inadequate dosing or prolongation of the infusion period may diminish the stimulus to the pituitary and nullify the test.25

Paresthesias were reported in approximately 3% of patients during clinical trials of arginine injection.25 Lethargy has also been reported with arginine administration.62

Arginine is a precursor of nitric oxide and accumulation of large amounts of excess arginine could lead to nitric oxide overproduction and result in vasodilation and hypotension. If hypotension is noted, reduction in arginine administration should be considered.27

Testosterone

Male patients can experience feminization during prolonged therapy with testosterone, which is believed to result from inhibition of gonadotropin secretion and conversion of androgens to estrogens. These effects are more pronounced in male patients with concurrent hepatic disease and include mastalgia and gynecomastia. In clinical evaluation of testosterone gel, gynecomastia (Testim: 1%; Androgel: 1—3%) and mastalgia (Androgel: 1—3%) were reported.70 76 Mastalgia and increased blood testosterone were reported in less than 1% of patients taking Axiron.64 Feminizing effects of testosterone are generally reversible. During exogenous administration of androgens, endogenous testosterone release is inhibited through feedback inhibition of pituitary luteinizing hormone (LH). At large doses of exogenous androgens, spermatogenesis inhibition may occur through feedback inhibition of pituitary follicle stimulating hormone (FSH).64 73 Similar to other testosterone therapies, decreased serum testosterone and oligospermia have been reported during post approval surveillance of testosterone topical gel.70 72

Testosterone therapy can produce libido decrease or libido increase.73 In clinical evaluation of testosterone gel (Androgel), libido decrease was reported in 1—3% of patients.70 Priapism and excessive sexual stimulation, more common in geriatric males, are generally the effect of excessive testosterone dosage. In 205 patients receiving testosterone gel (Testim 50 or 100 mg daily), spontaneous penile erection (1%) was reported.76 During post approval experience with testosterone topical gel (Fortesta), priapism as well as impotence (erectile dysfunction) were reported.72

Prostatic hypertrophy may develop during prolonged therapy with testosterone and these events are more likely to occur in elderly male patients. In 205 patients receiving testosterone gel (Testim 50 or 100 mg daily), benign prostatic hyperplasia, BPH was reported in 1% of patients.76 Clinical trials for testosterone patch (Androderm) include reports of unspecified prostate abnormalities in 5% of patients.40 Prostate neoplasm was reported in fewer than 1% of patients taking Axiron.64 In addition, increases in serum PSA concentrations have been reported in clinical trials for testosterone topical solution (Axiron: 1—4%), topical gel and (Fortesta: 1.3%).64 72 In a 180 Day, Phase 3 study of testosterone gel (Androgel), prostate disorder (3—5%) including enlarged prostate, BPH, and elevated PSA were reported; testis disorder (1.9—3%) including left varicocele and slight testicular sensitivity were also reported. In 162 hypogonadal men receiving testosterone gel (Androgel) during a 3-year open-label extension trial, increases in serum PSA concentrations (defined as >= 2x baseline concentrations or any single absolute value >= 6 ng/ml) were seen in approximately 18% of patients (n = 29). The majority of these increases were seen in the first year of therapy (23/29 or 79%). Four patients had a single value >= 6 ng/ml: 2 of these patients had prostate cancer detected upon biopsy. In the same study population, enlarged prostate and urinary symptoms including nocturia, urinary hesitancy, urinary incontinence, urinary retention, urinary urgency and weak urinary stream were also reported. Finally, 1 patient reported prostate disorder requiring a transurethral resection of the prostate (TURP) considered possibly related to treatment by investigators.70 Dysuria and hematuria have also been reported during postmarketing surveillance of testosterone therapy. Hematuria (< 3%), prostatitis (< 3%), and polyuria (< 3%) have been reported in patients receiving Androderm.40 In patients receiving testosterone therapy, surveillance for prostate cancer (as a secondary malignancy) should be consistent with current practices for eugonadal men. Signs of acute epididymitis (e.g., pyrexia, pain in the inguinal region) and/or urinary urgency should prompt withdrawal of the drug and reevaluation of dosage.

When androgens are given to females, virilization, manifested by acne, the growth of facial hair or an unwanted excess of body hair (hirsutism), enlarged clitoris, reduced breast size, and deepening of the voice, can occur. If testosterone treatment is discontinued when these symptoms first appear, they usually subside. Dermatologic reactions reported post-approval or in < 1% of patients using testosterone gel, regardless of brand, included hirsutism. Prolonged treatment can lead to irreversible masculinity, so the benefit of treatment should be measured against the risk.70 68 73 Disruption of the regular menstrual cycle secondary to testosterone-induced suppression of gonadotropin secretion can lead to amenorrhea or oligomenorrhea.70 68 Testosterone is associated with teratogenesis and may cause fetal harm. Exposure of a fetus (male or female) to androgens may result in varying degrees of virilization. Care should be taken to avoid exposure to testosterone during pregnancy, including via transfer of topical forms from male to female partners.

Topical testosterone products are associated with application site skin reactions. In clinical studies with testosterone patch (Androderm), transient mild to moderate erythema was observed at the site of application in the majority of patients at some time during treatment. The overall incidence of application site reactions of any kind was 28% (10 subjects with 13 adverse reactions). Application site adverse events reported include: pruritus (17—37%), burn-like blister reaction under system (12%), erythema (< 7%), exfoliation (< 3%), vesicular rash (6%), allergic contact dermatitis to the system (4%), burning (3%), and induration (3%); general rash (unspecified) (2%) was also reported. Blisters reported during trails sometimes involved bullous rash, skin necrosis, or the development of a skin ulcer. The majority of the lesions were found in cases where the patch was placed over bony prominences or on parts of the body that may have been subject to prolonged pressure during sleep or sitting. Other dermatological reactions at the application site, occurring in <1% of patients include: bullous rash, mechanical irritation, rash (unspecified), and contamination. Chronic skin irritation resulted in 5% of patients discontinuing treatment. Mild skin irritation may be ameliorated by treatment of affected skin with over-the-counter topical hydrocortisone cream applied after transdermal system removal. Additionally, applying a small amount of 0.1% triamcinolone acetonide cream to the skin under the central drug reservoir of the transdermal system has been shown to reduce the incidence and severity of skin irritation. The administration of 0.1% triamcinolone acetonide cream does not significantly alter transdermal absorption of testosterone from the system; ointment triamcinolone formulations should not be used for pretreatment as they may significantly reduce testosterone absorption.40 Dermatological reactions seen during testosterone topical solution (Axiron) clinical trials include: application site skin irritation (7—8%), erythema (5—7%), and folliculitis (< 1%).64 Other less common adverse reactions include: general erythema (< 1%) and application site edema and warmth (reported in at least 2 patients).64 Application site reactions have also been reported for testosterone gel (Fortesta: 16.1%; Androgel: 3—5.6%; Testim: 2—4%). Other dermatological reactions reported during clinical trials with testosterone gel (Androgel) include: xerosis (1.9%), acne (1—8%), and pruritis (1.9%). Contact dermatitis was reported in 2.1% of patients treated with testosterone gel (Androgel 1.62%).123 All testosterone therapy influences the growth and secretion of the sebaceous glands, which can cause seborrhea and acne indistinguishable from acne vulgaris.40 Acne vulgaris (> 1%) was reported in a clinical evaluation of testosterone solution (Axiron).64 Alopecia resembling male pattern baldness has also occurred in patients receiving long-term therapy or excessive testosterone doses. Dermatologic reactions reported post-approval or in < 1% of patients using testosterone gel, regardless of brand, include: acne, allergic dermatitis, diaphoresis, alopecia, erythema, hair discoloration, maculopapular rash, paresthesias, pruritus, rash (unspecified), skin irritation, swelling, and xerosis.70 76 72 During clinical evaluation and post marketing surveillance, hyperhidrosis (1.3%) was reported among patients receiving testosterone undecanoate.73

The testosterone buccal mucoadhesive system can cause dental pain, such as gum or mouth irritation (9.2%), a bitter taste in the mouth (dysgeusia, 4.1%), gum pain (3.1%), gum tenderness (3.1%), gum edema (2%), or taste perversion (dysgeusia, 2%). The majority of gum-related adverse events were transient; gum irritation generally resolved in 1—8 days and gum tenderness resolved in 1—14 days. The following adverse events occurred in 1 patient during clinical trials: buccal mucosal roughening, gingivitis, gum blister, nose edema, stinging of lips, and toothache. In clinical trials, 4.1% of patients discontinued treatment due to gum or mouth-related adverse events. Gum examinations were conducted in one study to assess for gingivitis, gum edema, oral lesions, oral ulceration, or leukoplakia with no new or worsening cases of any of these anomalies reported. In two long-term extension trials, the following adverse events occurred in 1 patient each: buccal inflammation, xerostomia, gum redness, stomatitis, taste bitter/ taste perversion (dysgeusia), and toothache.71 Dysgeusia (reported as taste disorder) was reported in 1% of patients receiving testosterone gel (Testim) and judged possibly, probably, or definitely related to the study drug.76 However, dysgeusia has not been noted as a side effect with other topical or injectable testosterone products and topically applied and systemic testosterone are not recognized as a common cause of taste disturbance.124

Early exposure to pharmaceutical doses of testosterone or other androgens in pre-pubertal males can induce virilism which can be a disadvantage because it is accompanied by premature epiphyseal closure. Once the epiphyses have closed, growth is terminated. Monitoring of skeletal maturation should be undertaken at about 6-month intervals. Once the epiphyses have closed, growth is terminated. Even after discontinuation of testosterone treatment, epiphyseal closure can be enhanced for several months.70

Androgen therapy has been associated with retention of sodium, chloride, water, potassium, and inorganic phosphates.68 73 Peripheral edema can occur as the result of increased fluid retention (in association with sodium chloride) and may be manifested by weight gain. These effects may be more prominent earlier in androgen therapy. If normal therapeutic testosterone doses are used in the treatment of hypogonadism, only a moderate amount of fluid retention occurs. In the treatment of patients with impaired renal function or congestive heart failure, the fluid retention is of greater significance.70 Animal models suggest the ability of testosterone to induce blood pressure increases and to alter naturesis thus affecting vasoconstriction and stimulation of the renin-angiotensin-aldosterone system. Therefore, androgens may affect blood pressure; however, the current role of testosterone in blood pressure regulation is not well understood. Hypertension has been reported during clinical evaluation as well as post-approval surveillance of testosterone therapy. In clinical studies, 2.1—3% of patients receiving testosterone gel (Androgel) reported hypertension.70 123 Hypertension (1%) as well as decreased diastolic pressure (1%) were reported in trials involving testosterone gel (Testim).76 Hypertension (>1%) was reported in patients using testosterone topical solution (Axiron).64 In addition to affecting blood pressure, androgens may affect the prevalence of cardiovascular disease. The possible association between testosterone use and the increased risk of severe cardiovascular events, irrespective of pre-existing cardiac disease, is currently under investigation. An observational study in the U.S. Veteran Affairs health system included adult male patients of an average age of 60 years. Patients (n = 8709) undergoing coronary angiography with a recorded low serum testosterone concentration of < 300 ng/dl were included in the retrospective analysis. Within the larger cohort, testosterone therapy was initiated in 1223 males after a median of 531 days following coronary angiography; 7486 males did not receive testosterone therapy. Three years after coronary angiography, 25.7% of patients receiving testosterone therapy compared to 19.9% of patients not receiving therapy suffered a severe and/or fatal cardiovascular event (myocardial infarction, stroke, death).66 A second observational study, investigated the incidence of acute non-fatal myocardial infarction (MI) following an initial testosterone prescription in both younger (<= 55 years) and older (>= 65 years) adult males (n = 55,593). The incidence rate of MI occurring within 90 days following the initial testosterone prescription was compared to the incidence rate of MI occurring in the one year leading-up to the first prescription. Among older males, a 2-fold increase in the risk of MI was observed within the 90 day window; among younger males with a pre-existing history of cardiac disease, a 2- to 3-fold increased risk of MI was observed. In contrast, no increased risk was observed in younger males without a history of cardiac disease.67 In light of these findings, the FDA announced in early 2014 an examination into the possible link between testosterone therapy and severe cardiovascular events. The FDA has NOT concluded that FDA-approved testosterone treatment increases the risk of stroke, MI, or death. However, health care professionals are urged to carefully consider whether the benefits of treatment are likely to exceed the potential risks. The FDA will communicate their final conclusions and recommendations when the evaluation is complete.68

Hepatic dysfunction can occur from use of certain androgens; therefore, periodic liver function test monitoring is advised.123 With use as prescribed, elevated hepatic enzymes are more likely to occur than overt jaundice or other liver dysfunction, which are rare with testosterone use in general. Adverse hepatic effects are more likely with administration 17-alpha-alkylandrogens (e.g., methyltestosterone) or with abuse of such androgenic hormones by athletes, where abuse results in liver changes consistent with fatty liver disease (steatosis) in an estimated 2.4% of individuals, even in the absence of other risk factors for fatty liver. Testosterone should be discontinued if cholestatic jaundice or hepatitis or other adverse liver dysfunction occurs. Peliosis hepatis and hepatic neoplasms occur rarely, but when they do, they are potentially life-threatening.70

Headache has been reported in several testosterone therapy trials; incidence rates of headache range from 1—6%, regardless of formulation. Some incidences of mood alterations including emotional lability (< 3%), confusion (1%), depression (1—3%), nervousness (1—3%), anxiety (> 1%), anger (> 1%), asthenia (<1%), hostility (<1%), and mood swings (1%) have also been reported across several testosterone studies.64 Abnormal dreams (Fortesta: 1.3%) and insomnia (Testim: 1%) have been reported in patients receiving testosterone gel.76 72 Hot flashes or flushing (Testim: 1%) and asthenia (Androgel: 1—3%) were also reported for patients receiving testosterone.76 70 Diarrhea (3—4%) and vomiting (3—4%) have been reported among patients receiving testosterone solution (Axiron).64 Diarrhea (< 3%), gastroesophageal reflux disease (< 3%), back pain (6%), chills (< 3%), fatigue (< 3%) have been reported in patients receiving Androderm transdermal patch.40 Miscellaneous adverse reactions reported post-approval or in < 1% of patients using exogenous testosterone, regardless of formulation include: abdominal pain (cramps), abnormal renal function, appetite stimulation, asthma, dizziness, hyperglycemia, increased lacrimation, malaise, nausea, pain in extremity (musculoskeletal pain), pelvic pain, and vitreous detachment. Other miscellaneous reactions reported during post approval surveillance of testosterone undecenoate include: sudden hearing loss, tinnitus, and myalgia.73

Testosterone therapy has induced osteolysis and can exacerbate hypercalcemia. Androgen-induced hypercalcemia occurs especially in immobile patients and those with metastatic carcinoma of the breast.70 Skeletal adverse reactions reported during post approval surveillance of testosterone undecanoate included osteopenia and osteoporosis.73

Testosterone may cause undesirable changes in serum lipid profiles, including hypercholesterolemia or hypertriglyceridemia. Periodic monitoring of lipid profiles may be desirable during treatment.73 Observational studies in post-menopausal women, bodybuilders, and weightlifters using anabolic steroids have revealed 'pro-atherogenic' changes in lipid profiles, including decreases in HDL concentrations and increases in LDL concentrations. Synthetic androgens may produce a greater lowering of the HDL-C:LDL-C ratio than does testosterone. Although the implications of androgen-induced hypercholesterolemia are unclear, caution should be exercised, particularly in patients predisposed to dyslipidemia or atherosclerosis. If lipid changes are significant, dose adjustment of testosterone or lipid lowering drugs or discontinuation of testosterone treatment may be needed; individualize therapy.70 73

Testosterone has a stimulatory effect on the formation of erythropoietin. Increased erythropoiesis, especially in women, can lead to erythrocytosis, secondary polycythemia, and its complications including: dizziness, migraine, tiredness (fatigue), unusual bleeding, flushing, or redness of the skin. Patients receiving high doses of testosterone are at risk for polycythemia. In clinical evaluation of testosterone solution (Axiron), increases in red blood cell count (< 1%), hematocrit (4—7%), and hemoglobin (> 1%) were reported.64 In studies of testosterone gel (Testim), patients receiving a 100 mg dose had clinically notable increases in both hematocrit (2.8%) and hemoglobin (2.3%).76 Likewise, 2.1% of patients treated with testosterone gel (Androgel 1.62%) reported increased hematocrit or hemoglobin. In intranasal testosterone gel analysis, 4 of 306 exposed patients developed a hematocrit level > 55% (baseline: 48—51%; did not exceed 58%). Therefore, periodic hemoglobin and hematocrit determinations should be considered in patients receiving long-term testosterone therapy. In general, testosterone therapy has been associated with suppression of clotting factors II, V, VII, and X and bleeding in patients on concomitant anticoagulant therapy.68 GI bleeding was reported in 2% of patients receiving testosterone patch (Androderm) therapy during clinical evaluation. Hemarthrosis (< 3%) has also been reported Androderm.40 During postmarketing surveillance of testosterone gel (Testim), prolonged aPPT and PT and prolonged bleeding time were reported.76 Anemia was reported in 2.5% of patients receiving testosterone gel (Androgel) during clinical evaluation.70 An increased risk of deep vein thrombosis (DVT) and acute pulmonary embolism (PE) is associated with testosterone use; events have been reported during post-marketing surveillance. Discontinue treatment with testosterone in patients reporting pain, swelling, warmth, and redness in the leg (DVT) or chest pain, trouble breathing, and cough (PE) and examine for possible VTE.72 Other miscellaneous reactions reported during post approval surveillance of testosterone undecenoate include: thrombocytopenia, hyperparathyroidism, and hypoglycemia.73

Intramuscular administration of anabolic steroids can cause inflammation, erythema, urticaria, post injection pain, induration and furunculosis. Inflammation and pain at the site of insertion of testosterone implant pellets is possible. Testosterone pellets may also slough out from the insertion site, which is usually secondary to superficial implantation or aseptic technique. Patients should be observed for any signs of an injection site reaction.68 73

Few cases of anaphylactoid reactions have been reported in association with oral and injectable testosterone therapy.40 68 Administration of testosterone undecanoate has been associated with cases of pulmonary embolism, specifically serious pulmonary oil microembolism (POME) reactions as well anaphylactoid reactions. Reported cases of POME reactions occurred during or immediately after a 1000 mg intramuscular injection of testosterone undecanoate. Symptoms included: cough, urge to cough, dyspnea, hyperhidrosis, throat tightening (acute bronchospasm), chest pain, dizziness, and syncope. Most cases lasted a few minutes and resolved with supportive measures; however, some lasted up to several hours and some required emergency care and/or hospitalization. In addition to POME reactions, episodes of anaphylaxis, including life-threatening reactions, have also been reported following the intramuscular injection of testosterone undecanoate. Overall, 9 POME events in 8 patients and 2 events of anaphylaxis among 3556 patients treated with testosterone undecanoate were reported in 18 clinical trials; cases of both POME and anaphylaxis were also reported post-approval. Cases have occurred following initial injection as well as during later injections in the normal course of treatment. After every administration, monitor patient for 30 minutes and provide appropriate medical treatment in the event of serious POME or anaphylactoid reactions.73 Due to the risk of serious POME and anaphylaxis reactions, testosterone undecanoate (Aveed) is only available through a restricted program called the Aveed REMS Program. Clinicians wanting to prescribe Aveed, must be certified with the REMS Program for purposes of ordering or dispensing the product. Healthcare settings must also be certified with the REMS Program and must have the resources to provide emergency medical treatment in cases of serious POME and anaphylaxis. Further information is available at www.AveedREMS.com or call 1—855—755—0494.73 Transient respiratory reactions including the urge to cough, coughing fits, and respiratory distress immediately after intramuscular injection of testosterone enanthate have been reported during post-marketing surveillance. Care should be taken to ensure slow and deep gluteal muscle injection of testosterone preparations.68 Nasopharyngitis or pharyngitis (> 1 %) was reported in patients receiving testosterone topical solution (Axiron).64

The treatment of hypogonadal men with testosterone may increase the risk of sleep apnea, especially in patients with risk factors for sleep apnea, such as obesity or chronic lung disease.70 73

In clinical evaluation of intranasal testosterone gel, the following nasal adverse reactions were reported among the most common adverse events: nasopharyngitis (3.8—8.7%), rhinorrhea (3.8—7.8%), parosmia (5.8%), epistaxis (3.8—6.5%), nasal irritation or discomfort (3.8—5.9%), nasal scabbing (3.8—5.8%), nasal dryness (4.2%), nasal congestion (3.9%), and procedural pain (4.3%). Although the majority of nasal complaints were mild or moderate in severity, long-term data on nasal safety is limited. Advise patients to report any distressing nasal symptoms; if present, determine the need for further evaluation or continued treatment. Other reported respiratory adverse reactions, include: bronchitis (3.8—4.3%), upper respiratory tract infection (3.8—4.3%), and sinusitis (3.8%).

How is This Medication Best Taken?

0.5 mL of Arousal Cream is most commonly applied onto the clitoris and/or external genital 15-30 minutes prior to sex. Arousal Cream should be massaged gently into the area until it is completely absorbed. Duration of effect is typically 30 minutes to 2 hours and reapplication may occur as needed.

Make sure to talk to your physician or pharmacist about how frequently you should be using Arousal Cream and how much you should apply.

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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Overview of Arousal Cream

Dosage Strengths of Arousal Cream

General Information

Aminophylline

Ergoloid Mesylate

Pentoxifylline

Sildenafil

Arginine

Testosterone

Mechanism of Action

Aminophylline

Ergoloid Mesylate

Pentoxifylline

Sildenafil

Arginine

Testosterone

Pharmacokinetics

Aminophylline

Ergoloid Mesylate

Pentoxifylline

Sildenafil

Arginine

Testosterone

Route-Specific Pharmacokinetics

Contraindications/Precautions

Aminophylline

Ergoloid Mesylate

Sildenafil

Arginine

Testosterone

Pregnancy

Aminophylline

Ergoloid Mesylate

Pentoxifylline

Sildenafil

Arginine

Testosterone

Breast-feeding

Aminophylline

Ergoloid Mesylate

Pentoxifylline

Sildenafil

Arginine

Testosterone

Interactions

Arginine

Testosterone

Adverse Reactions/Side Effects

Aminophylline

Ergoloid Mesylate

Pentoxifylline

Sildenafil

Arginine

Testosterone

How is This Medication Best Taken?

Storage

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