Sexual Health

QuadMixis administered as a penile self-injection, typically considered to be the most powerful class of anti-erectile dysfunction agents. While the components of QuadMix (Papaverine, Phentolamine, Prostaglandin E1, Atropine) are, on their own, indicated for a vast number of different conditions, the practice of bringing them together in concert to treat erectile dysfunction has become commonplace in sexual medicine and is now considered the go-to treatment if a patient is not responsive to conventional PDE5 inhibitors such as Viagra or Cialis.

QuadMix is used in the treatment of erectile dysfunction in males. QuadMix contains four drugs from complimentary classes designed to act synergistically, mixed into a sterile injection. They are:

Papaverine

A drug that causes blood vessels to expand (vasodilator); it produces an erection by allowing for increased blood flow to the penis. Papaverine interacts with adenylate cyclase resulting in increased cyclic adenosine monophosphate (cAMP) production, ultimately resulting in increased erectile capacity by relaxation of penile smooth muscle. This drug was one of the first effective therapies for erectile dysfunction administered by penile injection. Papaverine works by inhibiting phosphodiesterase nonspecifically, there are also multiple other mechanisms by which this drug acts to improve erectile capacity. The current body of medical literature has not established the predominant mechanism by which papaverine works. The multi-mechanistic manner by which this drug acts may be concentration dependent. Experimental data, performed in-vitro, displays papaverine acting to relax the penile arteries, the cavernosal sinusoids, and the penile veins. Experiments carried out in dogs display papaverine’s ability to decrease the resistance to arterial inflow while also increasing the resistance to venous outflow.  Papaverine’s ability to decrease resistance to venous outflow has been replicated in clinical studies. A veno-occlusive mechanism may be responsible for the aforementioned findings.

Biweekly intracavernous administration of papaverine for erectile dysfunction.

Participants: 50 patients age 40 to 70 years old
Administration: intracavernosal injection at base of the penis
Dosage: 60 mg papaverine in 5 ml saline every 2 weeks
Results: Erection of 80% or more of normal was achieved by all but one patient, improves sexual potency

Medical treatment of impotence with papaverine and phentolamine intracavernosal injection.

Participants: 20 patients age 32 to 72 years old
Administration: intracavernosal injection
Dosage: 30 mg papaverine and phentolamine 1 mg
Results: Response with erection in 20- 30 minutes, phentolamine and papaverine produced an erection sufficient for intercourse in 18 of the 20 subjects

Treatment of impotence by intrapenile injections of papaverine and phenoxybenzamine: a double blind, controlled trial.

Participants: 39 patients age 27 to 67 years old
Administration: intracavernosal injection
Dosage: 60 mg Papaverine in 10 ml saline
Results: 35% full restoration of erectile capacity; 65% partial restoration of erectile capacity

Evaluating erectile dysfunction: oral sildenafil versus intracavernosal injection of papaverine:

Participants: 39 patients age 21 to 65 years old
Administration: intracavernosal injection
Dosage: 30 mg papaverine
Results: Papaverine improved length and circumference papaverine is effective as injection therapy for erectile dysfunction

Phentolamine

When injected into the penis, it induces an erection by relaxing and dilating the blood vessels of the penis, as well as by elevating cardiac output.

Phentolamine is classified as an Alpha-Adrenoceptor Antagonists. Noradrenaline affects the smooth muscle tone of the penile tissues by keeping the corpora cavernosa in a contracted state. By blocking the functional noradrenaline receptors, the Alpha-Adrenoceptor, erectile response can be achieved. Phentolamine competes with endogenous norepinephrine for the Alpha1-Adrenoceptor and Alpha2-Adrenoceptor. Phentolamine has similar binding capacities to both receptors. The current literature suggests that this is the main mechanism by which phentolamine exerts its physiological effects. Phentolamine also blocks 5-HT receptors, inducing the release of histamine from mast cells. Some studies also show that NOS activation could possibly be involved in another mechanism, inducing increased vasodilation

The Alpha-Adrenoceptor Antagonist of phentolamine is considered to be complex. The non-selective receptor blocking action interacts with adrenergic nerves in a complex fashion. Phentolamine action on adrenergic nerves has not been fully established. It is thought that there might be counteracting regulation on pre-and post-junctional nerves. It is not known how the counteracting regulation might affect the efficacy of phentolamine for the treatment of erectile dysfunction.

In animal studies, penile arterial inflow resistance was decreased. This proves in vivo that the physiological response to phentolamine acts in a manner to achieve erectile response. However, phentolamine has not displayed a significant effect on the venous outflow from penile tissues in humans. The current body of literature has not established pharmacokinetics for phentolamine.

First pass metabolism effectively reduces the efficacy in the treatment of erectile dysfunction. Therefore, this drug has to be administered by injection. The half-life of phentolamine is 30 minutes, with an effect duration of 2.5 to 4 hours. After penile injection the concentration of phentolamine in serum reaches a maximum within 20 to 30 minutes. After this amount of time has passed the drug rapidly is metabolized.

Side effects of phentolamine are rare. However, it has been reported that orthostatic hypotension, tachycardia, arrhythmias and myocardial infarction, have occurred after penile injection. The mechanism to which this set of side effects occur has not been rationally deduced through scientific study. Phentolamine is usually added in combination with papaverine or vasoactive intestinal peptide to increase erectile response.

Medical treatment of impotence with papaverine and phentolamine intracavernosal injection.

Participants: 20 patients age 32 to 72 years old
Administration: intracavernosal injection
Dosage: 30 mg papaverine and phentolamine 1 mg
Results: Response with erection in 20- 30 minutes, phentolamine and papaverine produced an erection sufficient for intercourse in 18 of the 20 subjects

Prostaglandin E1

A potent hormone-like substance that induces erection by relaxing penile blood vessels and dilating cavernosal arteries Dilation of the cavernosal arteries is accompanied by increased arterial inflow velocity and increased venous outflow resistance allowing for more blood into and less blood out of the penis.

Prostaglandin E1 is administered intracavernosally. This drug is prescribed as a second-line treatment, after oral PDE5 inhibitors have been ineffective for treatment of erectile dysfunction. Several aspects of its effects and clinical use have been reviewed previously. Currently the body of medical literature demonstrates that 40 to 70% of erectile dysfunction patients respond to treatment with prostaglandin E1. The demonstration that prostaglandin E1 with S-nitrosoglutathione in combination is more effective than prostaglandin E1 alone may shed light on the lack of efficacy in some patients.

Medications to activate alternative relaxant pathways in addition to by prostaglandin E1 may be necessary in patients who fail to respond to prostaglandin E1. Relaxation of smooth muscle is a critical component of erectile capacity. Additional agents to work in combination with prostaglandin E1 might have significant therapeutic benefits. Prostaglandin E1 with S-nitrosoglutathione or other erectile dysfunction medications, might have advantages in the treatment of male erectile dysfunction. Empower Pharmacy strives to compound medications that take advantage of multi-compound synergy. When injected into penile tissue prostaglandin E1 is readily metabolized into other erectile promoting molecules. These molecules potentiate the efficacy of prostaglandin E1. Prostaglandin E1 has been demonstrated to alter the concentrations of noradrenaline, adding a secondary mechanism of action. However, it is still believed prostaglandin E1 primarily acts directly by increasing cAMP synthesis via EP receptor interaction, increasing muscular relaxation.

Prostaglandin E1 has ubiquitous actions in controlling processes in many tissues. Known effects of prostaglandin E1 include systemic vasodilation, prevention of platelet aggregation, and ask to stimulate intestinal activity. Thus, prostaglandin E1 has very rarely been administered in a fashion to elicit a systemic response. Pharmacokinetics data is currently lacking on prostaglandin E1, the current data suggest short action duration and high rate of metabolic breakdown. After the first pass through the lungs 70% is metabolized. Because prostaglandin E1 is readily metabolized throughout the body, penile injection effects mainly penile tissues. Furthermore, this further explains the rare circulatory side effects.

Atropine

Atropine sulfate has been used successfully in many studies in conjunction with vasoactive agents in the treatment of erectile dysfunction, when given as an intracavernosal injection.

Atropine sulfate works by inhibiting the nervous system receptors that control smooth muscle relaxation. Atropine sulfate is an anticholinergic agent that diminishes cholinergic inhibition of the adrenergic and cholinergic excitation of the nonadrenergic, noncholinergic neuroeffector systems that control neurogenic corporeal smooth muscle relaxation.

The mechanism of action also includes the release of endothelium derived relaxing factor, however this is more so involved at higher formal logical doses.

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.

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.

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.

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.

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.

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.

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.

There are several clinical conditions that may warrant the use of sildenafil citrate. These include:

• Erectile dysfunction: Especially in men, this is by far the most common reason that people take sildenafil citrate.
• Pulmonary hypertension: This condition may present in childhood, known as primary or idiopathic pulmonary hypertension, or in adulthood. In both idiopathic and adult-onset pulmonary hypertension, the blood vessels in the pulmonary vasculature are constricted and cause a significant increase in pulmonary arterial pressure; this, if not corrected, may result in cardiac failure.By inhibiting the activity of PDE-5, sildenafil allows cGMP to work within the lungs and dilate the pulmonary vessels. This results in a decrease in pulmonary arterial pressure, thereby leading to decreased strain on the heart and a concomitant improvement in cardiac performance.
• Raynaud’s phenomenon: Characterized by transient vasospasm and digital ischemia upon exposure to cold, sildenafil has been shown to be of demonstrable benefit in managing instances of Raynaud’s phenomenon that are not responsive to other vasodilator drugs

Tadalafil is a selective phosphodiesterase (PDE) type 5 inhibitor similar to sildenafil and vardenafil. It is administered orally for the treatment of male erectile dysfunction (ED), pulmonary arterial hypertension (PAH), benign prostatic hypertrophy (BPH), or the concurrent treatment of erectile dysfunction and BPH. Tadalafil does not inhibit prostaglandins as do some agents for treating impotence (e.g., alprostadil). Unlike sildenafil, visual disturbances have not been reported with tadalafil, which is more selective for PDE5 than for PDE6 present in the retina. The duration of action of tadalafil for the treatment of ED (up to 36 hours) appears to be longer than that of sildenafil and vardenafil. Because PDE inhibitors promote erection only in the presence of sexual stimulation, the longer duration of action of tadalafil allows for more spontaneity in sexual activity. According to ED treatment guidelines, oral phosphodiesterase type 5 inhibitors (PDE5 inhibitor) are considered first-line therapy. Tadalafil was in phase II trials for the treatment of female sexual dysfunction, however, further investigation was discontinued. FDA approval was granted November 2003 for treatment of male erectile dysfunction (ED), and in January 2008, approval was granted for once daily use without regard to timing of sexual activity. Tadalafil (Adcirca) was FDA approved for the treatment of pulmonary arterial hypertension (PAH) in May 2009. In clinical studies of patients with pulmonary arterial hypertension (PAH), tadalafil-treated patients experienced improved exercise capacity and less clinical worsening compared to placebo. In October 2011, tadalafil received FDA approval for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH) and for the concurrent treatment of erectile dysfunction and BPH.

Treatment of erectile dysfunction and/or benign prostatic hypertrophy.

Back pain; dizziness; flushing; headache; indigestion; muscle aches; nausea; stuffy or runny nose. This list may not describe all possible side effects. Call your healthcare provider immediate if you experience signs of an allergic reaction like skin rash, itching or hives, swelling of the face, lips, or tongue; breathing problems; changes in hearing; changes in vision; chest pain; erection lasting more than 4 hours; fast, irregular heartbeat; seizures.

Adverse reactions to tadalafil for the treatment of erectile dysfunction (ED) were evaluated based on worldwide clinical trials of tadalafil involving over 5700 men (mean age 59, range 22 to 88 years). Over 100 patients were treated for 1 year or longer and over 1300 were treated for 6 months or more. During placebo-controlled trials, the discontinuation rate for patients treated with tadalafil (10 or 20 mg) was 3.1% compared to 1.4% in placebo-treated patients. In the treatment of patients with elevated pulmonary arterial pressures (PAH), adverse reactions to tadalafil were evaluated based on worldwide clinical trials involving 398 patients; 311 patients were treated for at least 182 days and 251 patients were treated for at least 360 days. During placebo-controlled trials, the overall rate of discontinuation due to an adverse event was higher in placebo-treated patients than in patients treated with tadalafil 40 mg/day (15% vs. 9%, respectively). In addition, the rate of discontinuation due to an adverse event not related to worsening of PAH was 5% in placebo-treated patients compared to 4% in patients treated with tadalafil 40 mg/day. During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and erectile dysfunction, the rate of discontinuation due to an adverse effect was 3.6% of tadalafil-treated patients versus 1.6% of placebo-treated patients, and the mean age of study participants was 63 years.

During clinical trials, hypotension was reported in < 2% and hypertension was reported in 1—3% of all tadalafil recipients. The risk for serious hypotension is augmented by the use of nitrates; therefore, the use of tadalafil in patients receiving nitrate therapy is contraindicated. Other cardiac effects reported in less than 2% of patients during clinical trials include angina, chest pain (unspecified), myocardial infarction, orthostatic hypotension, palpitations, syncope, and sinus tachycardia. Sudden cardiac death, stroke, chest pain, palpitations, and sinus tachycardia have all been noted in post-marketing experience with tadalafil. Most of the affected patients had pre-existing cardiovascular risk factors. Many of these events occurred during or shortly after sexual activity. In some cases, the symptoms occurred hours to days after the use of tadalafil and sexual activity. The effects of tadalafil on cardiac function, hemodynamics, and exercise tolerance were investigated in a single clinical pharmacology study. In this blinded crossover trial, 23 subjects with stable coronary artery disease and evidence of exercise-induced cardiac ischemia were enrolled. The primary endpoint was time to cardiac ischemia. The mean difference in total exercise time was 3 seconds (tadalafil 10 mg minus placebo), which represented no clinically meaningful difference. Further statistical analysis demonstrated that tadalafil was non-inferior to placebo with respect to time to ischemia. Of note, in this study, in some subjects who received tadalafil followed by sublingual nitroglycerin in the post-exercise period, clinically significant reductions in blood pressure (hypotension) were observed, consistent with the augmentation by tadalafil of the blood-pressure-lowering effects of nitrates. In addition, tadalafil (20 mg) had no significant effect on supine or standing systolic and diastolic blood pressure in healthy male subjects compared to placebo; there was also no significant effect on heart rate.

The effect of a single 100-mg dose of tadalafil on QT prolongation was evaluated at the time of peak tadalafil concentration in a randomized, double-blinded, placebo, and active (intravenous ibutilide)-controlled crossover study in 90 healthy males aged 18 to 53 years. The mean change in QTc for tadalafil, relative to placebo, was 2.8 milliseconds using Individual QT correction and 3.5 milliseconds using Fridericia QT correction. A 100-mg dose of tadalafil (5 times the highest recommended dose) was chosen because this dose yields exposures covering those observed upon coadministration of tadalafil with potent CYP3A4 inhibitors or those observed in renal impairment. In this study, the mean increase in heart rate associated with a 100-mg dose of tadalafil compared to placebo was 3.1 beats per minute.

During clinical trials, adverse reactions occurring = 2% of patients with erectile dysfunction, = 9% of patients with pulmonary arterial hypertension, and more frequently in the tadalafil-treated groups than placebo included back pain (2—12%), myalgia (1—14%), and pain in limb (1—3%). Adverse musculoskeletal reactions reported in < 2% of tadalafil recipients included arthralgia and neck pain. During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and erectile dysfunction, the following musculoskeletal effects occurred in at least 1% of tadalafil-treated patients and more frequently than in placebo-treated patients: back pain (2.4% vs 1.4%), extremity musculoskeletal pain (1.4% vs 0%), and myalgia (1.2% vs 0.3%). Adverse musculoskeletal effects reported in less than 1% of patients included arthralgia and muscle spasms. Myalgia lead to treatment discontinuation in at least 2 patients during clinical trials for BPH or BPH/erectile dysfunction. In tadalafil clinical pharmacology trials, back pain or myalgia generally occurred 12 to 24 hours after dosing and typically resolved within 48 hours. The back pain/myalgia was described as diffuse bilateral lower lumbar, gluteal, thigh, or thoracolumbar muscular discomfort and was exacerbated by recumbency. Generally, pain was reported as mild or moderate in severity and resolved without medical treatment; severe back pain was reported infrequently. When medical treatment was needed, acetaminophen or NSAIDs were generally effective; however, in a small number of patients who required treatment, a mild narcotic (e.g., codeine) was used. Overall, approximately 0.5% of all tadalafil-treated patients discontinued treatment due to back pain/myalgia. Diagnostic testing, including measures for inflammation, muscle injury, or renal damage revealed no medically significant underlying pathology.

Headache occurred in 3—15% of patients during erectile dysfunction clinical trials and in 32—42% of patients during pulmonary arterial hypertension clinical trials; headache was reported more frequently in the tadalafil-treated groups than placebo. During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and erectile dysfunction, the following centrally-mediated effects occurred in at least 1% of tadalafil-treated patients and more frequently than in placebo-treated patients: headache (4.1% vs 2.3%) and dizziness (1% vs 0.5%). Headache lead to treatment discontinuation in at least 2 patients during clinical trials for BPH or BPH/erectile dysfunction. Adverse reactions reported in < 2% of tadalafil recipients during clinical trials and affecting the nervous system included hypoesthesia, insomnia, dizziness, paresthesias, vertigo, and somnolence or drowsiness. Migraine, transient global amnesia, seizures, and seizure recurrence have been reported during post-marketing use of tadalafil; due to the voluntary nature of the reports, the frequency of post-marketing adverse reactions is unknown and causality to the drug has not been established.

Dyspepsia occurred in 1—10% of patients during erectile dysfunction (ED) clinical trials and in 10—13% of patients in pulmonary arterial hypertension clinical trials; dyspepsia was reported more frequently in the tadalafil-treated groups than placebo. Other gastrointestinal/digestive adverse reactions reported by tadalafil recipients and more frequently than placebo included nausea (1—11%), viral gastroenteritis (3—5%), gastroesophageal reflux (1—3%), abdominal pain (1—2%), and diarrhea (1—2%). During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and erectile dysfunction, the following gastrointestinal effects occurred in at least 1% of tadalafil-treated patients and more frequently than in placebo-treated patients: dyspepsia (2.4% vs 0.2%) and diarrhea (1.4% vs 1%). Adverse GI reactions reported in less than 1% of patients included gastroesophageal reflux disease, upper abdominal pain, nausea, and vomiting. Upper abdominal pain lead to treatment discontinuation in at least 2 patients during clinical trials for BPH or BPH/erectile dysfunction. Dysphagia, elevated hepatic enzymes, esophagitis, gastritis, vomiting, increased GGTP, loose stools, upper abdominal pain, hemorrhoidal hemorrhage, rectal hemorrhage, and xerostomia were reported in < 2% of patients treated with tadalafil during clinical trials.

Nasal congestion occurred in 2—4% of patients during erectile dysfunction clinical trials and in 9% of patients during pulmonary arterial hypertension clinical trials; nasal congestion was reported more frequently in the tadalafil-treated groups than placebo. In addition, pharyngitis (reported as nasopharyngitis, 1—13%), upper and lower respiratory tract infection (3—13%), influenza (2—5%), cough (2—4%), bronchitis (2%), and urinary tract infection (2%) were reported in tadalafil-treated patients during clinical trials. During short-term clinical trials in patients with benign prostatic hyperplasia (BPH) or both BPH and erectile dysfunction, nasopharyngitis occurred more frequently in tadalafil-treated patients (2.1%) than placebo-treated patients (1.6%). Dyspnea, epistaxis, and pharyngitis were reported in less than 2% of patients in clinical trials.

Flushing occurred in 1—3% of patients during erectile dysfunction clinical trials and in 6—13% of patients during pulmonary arterial hypertension clinical trials; flushing was reported more frequently in the tadalafil-treated groups than those groups receiving placebo.

During clinical trials, blepharedema or swelling of the eyelids, conjunctivitis, increased lacrimation, and ocular pain were reported in < 2% of tadalafil recipients.

Single oral doses of phosphodiesterase inhibitors have demonstrated transient dose-related impairment of color discrimination (blue/green), using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. In a study to assess the effects of a single dose of tadalafil 40 mg on vision (n=59), no effects were observed on visual acuity, intraocular pressure, or pupillometry. Across all clinical studies with tadalafil, reports of changes in color vision were rare (< 0.1% of patients). Post-marketing reports have included cases of visual impairment such as retinal vein occlusion and visual field defects. Non-arteritic anterior ischemic optic neuropathy (NAION) has also been reported rarely in patients using phosphodiesterase type 5 (PDE5) inhibitors. It is thought that the vasoconstrictive effect of phosphodiesterase inhibitors may decrease blood flow to the optic nerve, especially in patients with a low cup to disk ratio. Symptoms, such as blurred vision (< 2%) and loss of visual field in one or both eyes, are usually reported within 24 hours of use. Most, but not all, of these patients who reported this adverse effect had underlying anatomic or vascular risk factors for development of NAION. These risk factors include, but are not limited to: low cup to disc ratio (‘crowded disc’), age over 50 years, diabetes, high blood pressure, coronary artery disease, hyperlipidemia, and smoking. Additionally, two patients had retinal detachment and one patient had hypoplastic optic neuropathy. It is not yet possible to determine if these adverse events are related directly to the use of PDE5 inhibitors, to the patient’s underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors.

Adverse reactions affecting hearing or otic special senses and occurring in < 2% of patients in controlled clinical trials of tadalafil include hearing loss and tinnitus. In addition, 29 reports of sudden changes in hearing including hearing loss or decrease in hearing, usually in 1 ear only, have been reported to the FDA during post-marketing surveillance in patients taking sildenafil, tadalafil, or vardenafil; the reports are associated with a strong temporal relationship to the dosing of these agents. Many times, the hearing changes are accompanied by vestibular effects including dizziness, tinnitus, and vertigo. Follow-up has been limited in many of the reports; however, in approximately one-third of the patients, the hearing loss was temporary. Concomitant medical conditions or patient factors may play a role, although risk factors for the onset of sudden hearing loss have not been identified. Patients should be instructed to promptly contact their physician if they experience changes in hearing.

There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for PDE5 inhibitors, such as tadalafil. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention. During clinical trial evaluation of tadalafil, genitourinary effects including increased erection, spontaneous penile erection, and renal impairment (unspecified) were reported in less than 2% of study patients receiving the drug.

During clinical trial evaluation of tadalafil, the following general adverse events were reported in less than 2% of patients receiving tadalafil: asthenia, facial edema, fatigue, and pain (unspecified).

During clinical trial evaluation of tadalafil, the following dermatologic effects were reported in less than 2% of study patients: pruritus, rash (unspecified), and hyperhidrosis. Stevens-Johnson syndrome, exfoliative dermatitis, and urticaria have all been noted in post-marketing experience with tadalafil. Due to the uncontrolled and voluntary nature of post-marketing reports, neither the frequency nor a definitive causal relationship to tadalafil can be established.

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

Amitriptyline HCL / Baclofen / Gabapentin Cream is a topical or intravaginal therapy used to treat symptoms related to vulvodynia and Provoked Vestibulodynia. These conditions cause vulvar discomfort, usually burning pain, and dyspareunia, in the absence of any specific cause. Vestibulodynia can have a profound effect on women’s sexuality and psychological well-being.

Amitriptyline

Amitriptyline is a tertiary amine tricyclic antidepressant (TCA) that is metabolized to an active metabolite, nortriptyline. Tertiary amines are generally more sedating and have greater anticholinergic effects than secondary amines. Amitriptyline is also related to the skeletal muscle relaxant cyclobenzaprine, although amitriptyline is not believed to possess muscle-relaxant properties. Amitriptyline is FDA-approved for the treatment of adults with major depressive disorder (MDD). Clinically, amitriptyline is also used to treat neuropathic pain and other conditions.

Baclofen

Baclofen is an oral skeletal muscle relaxant. It is a structural analog of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Clinically, baclofen is used to treat spasticity and improve mobility in patients with multiple sclerosis and other spinal cord lesions by decreasing the number and severity of spasms and relieving associated pain, clonus, and muscle rigidity.

Gabapentin

Gabapentin is an analog of gamma-aminobutyric acid (GABA) that has GABA agonist activity. Its unique pharmacokinetic properties make it especially useful in certain patients. Gabapentin possesses high lipid solubility, is not metabolized by the liver, has no protein binding, and is devoid of enzyme induction-related drug interactions. Originally developed as an anticonvulsant, gabapentin has been shown to be effective as adjunct therapy in the treatment of partial seizures with or without secondary generalized tonic-clonic seizures. Efficacy in the treatment of painful neuropathies has also been demonstrated. Investigational uses include monotherapy of refractory partial seizure disorders, treatment of spasticity in multiple sclerosis, and tremor. In addition, gabapentin appears to be effective in reducing hot flashes in menopausal women or women with breast cancer.

Topical gabapentin in the treatment of localized and generalized vulvodynia

Participants: 150 patients presenting with entry dyspareunia
Administration: Topical (local)
Dosage: 2% Cream
Conclusion: 80% of respondents demonstrated at least a 50% improvement in pain scores. Topical gabapentin seems to be well-tolerated and associated with significant pain relief in women with vulvodynia.

Use of amitriptyline cream in the management of entry dyspareunia due to provoked vestibulodynia

Participants: 35 women
Administration: Topical (local)
Dosage: 2% Cream
Conclusion: Topical amitriptyline cream should be considered for first-line treatment in the management of patients with provoked vestibulodynia causing entry dyspareunia. The response rate is reasonable (56%), and it eliminates the problems with systemic administration, namely, drowsiness and the difficulty patients have in accepting antidepressant medication for their condition.

Topical Amitriptyline-Baclofen Cream for the Treatment of Provoked Vestibulodynia

Participants: 38 women
Administration: Topical (local)
Dosage: 2% Baclofen & 2% Amitriptyline Cream
Conclusion: 71% response rate in women with refractory symptoms and the overall tolerability of treatment.

Amitriptyline Hydrochloride / Baclofen / Gabapentin Vaginal Cream may relieve symptoms associated with vulvodynia and Provoked Vestibulodynia.

This cream is formulated to act locally so side effects are generally minimal, but may include skin irritation, headache, dizziness, and somnolence. However, possible side effects include but are not limited to those of each of the 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.

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). An alternative formulation without testosterone is available.

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

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.

Apply 1/4 – 1/2 mL of cream onto 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 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.