Sildenafil / Tadalafil Capsule

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.

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.

Tadalafil

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.

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.

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.

Tadalafil

Tadalafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cGMP. Cyclic guanosine monophosphate causes smooth muscle relaxation in the corpus cavernosum thereby allowing inflow of blood; the exact mechanism by which cGMP stimulates relaxation of smooth muscles has not been determined. Phosphodiesterase type 5 is responsible for degradation of cGMP in the corpus cavernosum. Tadalafil enhances the effect of NO by inhibiting PDE5 thereby raising concentrations of cGMP in the corpus cavernosum. Tadalafil has no direct relaxant effect on isolated human corpus cavernosum and, at recommended doses, has no effect in the absence of sexual stimulation. In vitro studies show that tadalafil is selective for PDE5 and is 10,000-fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7, which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle, and other organs. Tadalafil is 10,000 fold more potent for PDE5 than for PDE3 found in the heart and blood vessels. Also, tadalafil has 700-fold greater selectivity for PDE5 versus PDE6, an enzyme found in the retina and involved in phototransduction. Compare this selectivity to the selectivity of sildenafil which has only a 10-fold selectivity for PDE5 versus PDE6. This lower selectivity of sildenafil for PDE5 vs PDE6 is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma concentrations of sildenafil. Further, tadalafil is 9000-fold more potent for PDE5 than for PDE8, PDE9, and PDE10. Tadalafil is 14-fold more potent for PDE5 than for PDE11A1 and 40-fold more potent for PDE5 than for PDE11A4. PDE11 is an enzyme found in human skeletal muscle, prostate, testes, and in other tissues. Inhibition of human recombinant PDE11A1, and to a lesser extent, PDE11A4 activities occur at tadalafil concentrations within the therapeutic range. The physiological role and clinical effects of PDE11 inhibition in humans have not been elucidated.

The mechanism by which tadalafil reduces the symptoms of benign prostatic hyperplasia (BPH) has not been established; however, the effect of PDE5 inhibition on cGMP concentrations in the corpus cavernosum and pulmonary arteries is also observed in the smooth muscle of the prostate, bladder, and their vascular supply.

Tadalafil can inhibit PDE5 present in lung tissue and esophageal smooth muscle. Inhibition of PDE5 in lung tissue results in relaxation of pulmonary vascular smooth muscle and subsequent pulmonary vasodilation, thereby making tadalafil an effective agent in treating pulmonary hypertension.

Inhibition of esophageal smooth muscle PDE5 can cause a marked reduction in esophageal motility as well as in lower esophageal sphincter (LES) tone. These effects may be beneficial in certain motor disorders involving the esophagus such as diffuse spasm, nutcracker esophagus, and hypertensive LES. However, the reduction in LES tone can worsen the symptoms of gastroesophageal reflux disease (GERD). Dyspepsia is one of the most common adverse reactions associated with PDE5 inhibitor therapy.

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.

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.

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.

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.

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.

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.

Tadalafil

Your health care provider needs to know if you have any of these conditions: bleeding disorders; eye or vision problems, including retinitis pigmentosa; Peyronie’s disease, or history of priapism (painful and prolonged erection); heart disease, angina, a history of heart attack, irregular heart beats; high or low blood pressure; history of blood diseases; history of stomach bleeding; kidney disease; liver disease; stroke; an unusual or allergic reaction to tadalafil. If you notice any changes in your vision while taking this drug, call your doctor or health care professional as soon as possible. Stop using this medicine and call your healthcare provider right away if you have a loss of sight in one or both eyes. Contact your healthcare provider right away if the erection lasts longer than 4 hours or if it becomes painful. If you experience symptoms of nausea, dizziness, chest pain or arm pain upon initiation of sexual activity after taking this medicine, you should refrain from further activity and call your healthcare provider immediately. Do not drink alcohol when taking this medicine as alcohol can increase your chances of getting a headache or getting dizzy, increasing your heart rate or lowering your blood pressure. Using this medicine does not protect you or your partner against HIV infection or other sexually transmitted infections.

Tadalafil is contraindicated in patients with a known hypersensitivity to the drug or any component of the tablet.

The safety and efficacy of combinations of tadalafil with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.

Because the efficacy of concurrent use of tadalafil and alpha-blockers in the treatment of benign prostatic hyperplasia (BPH) has not been adequately studied, and due to the potential vasodilatory effects of such combination treatment, tadalafil is not recommended for use with alpha-blockers when treating BPH (see Drug Interactions).

Tadalafil is contraindicated in patients who are currently on nitrate/nitrite therapy. Consistent with its known effects on the nitric oxide/cGMP pathway, tadalafil may potentiate the hypotensive effects of organic nitrates and nitrites. Patients receiving nitrates in any form are not to receive tadalafil. This includes any patient who receives intermittent nitrate therapies. It is unknown if it is safe for patients to receive nitrates once tadalafil has been administered.

Use tadalafil cautiously in patients with renal impairment. Dosing recommendations vary depending upon the severity of renal impairment, indication, and the dosing regimen being used (see Dosage in renal impairment). Tadalafil is not recommended in patients receiving the drug on a once daily basis for erectile dysfunction, benign prostatic hyperplasia, or pulmonary arterial hypertension when the creatinine clearance is less than 30 ml/min or the patient has renal failure or is receiving dialysis.

Use tadalafil with caution in patients with altered hepatic function secondary to hepatic disease and/or drug-induced inhibition. Dosage modifications are needed in patients with mild to moderate hepatic impairment (see Dosage). In patients with severe hepatic impairment, use of tadalafil is not recommended because of insufficient data. Additionally, tadalafil is metabolized by CYP3A4 in the liver. Dosage adjustments are necessary in patients taking potent CYP3A4 inhibitors such as ritonavir, ketoconazole, and itraconazole (see Dosage and Drug Interactions).

There is a degree of cardiac risk associated with sexual activity; therefore, prescribers should evaluate the cardiovascular status of their patients prior to initiating any treatment for erectile dysfunction. Tadalafil and other PDE5 inhibitors have mild systemic vasodilatory properties that may result in transient decreases in blood pressure. Health care professionals should consider whether the individual would be adversely affected by vasodilatory events. The following groups of patients with cardiac disease were excluded from clinical safety and efficacy trials for tadalafil, and, therefore, the manufacturer does not recommend the use of tadalafil in these groups until more data are available: myocardial infarction within the last 90 days; coronary artery disease resulting in unstable angina or angina occurring during sexual intercourse; NYHA Class II or greater heart failure in the last 6 months; uncontrolled cardiac arrhythmias; hypotension (< 90/50 mmHg); uncontrolled hypertension ( 170/100 mmHg); or a stroke within the last 6 months. Based on recommendations for sildenafil by the American College of Cardiology, it is recommended that tadalafil be used with caution in the following: patients with active coronary ischemia (angina) who are not taking nitrates (e.g., positive exercise test for ischemia); patients with congestive heart failure and borderline low blood pressure and borderline low volume status (hypovolemia); patients on a complicated, multidrug, antihypertensive program; and patients taking drugs that can prolong the half-life of tadalafil. Tadalafil is contraindicated in patients who are currently on nitrate/nitrite therapy. Also, patients with left ventricular outflow obstruction (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis) or severely impaired autonomic control of blood pressure can be sensitive to the action of vasodilators, including PDE5 inhibitors. Due to the pulmonary vasodilation caused by tadalafil, patients with pulmonary veno-occlusive disease (PVOD) may experience significant worsening in cardiovascular status. Due to a lack of clinical data on administration of tadalafil to patients with veno-occlusive disease, administration of tadalafil to such patients is not recommended. The possibility of associated PVOD should be considered should signs of pulmonary edema occur when tadalafil is administered.

Prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been associated with PDE5 inhibitor administration. 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. Use tadalafil, and other agents for the treatment of erectile dysfunction, with caution in patients with penile structural abnormality (such as angulation, cavernosal fibrosis, or Peyronie’s disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell disease, leukemia, multiple myeloma, polycythemia, or history of priapism).

Educate patients that tadalafil, when used for erectile dysfunction, offers no protection against sexually transmitted disease. Counsel patients about protective measures, including the prevention of transmission of human immunodeficiency virus (HIV) infection, as appropriate to the individual circumstances.

Use tadalafil cautiously in patients with pre-existing visual disturbance. Post-marketing reports of sudden vision loss have occurred with phosphodiesterase inhibitors. Vision loss is attributed to a condition known as non-arteritic anterior ischemic optic neuropathy (NAION), where blood flow is blocked to the optic nerve. Although visual disturbances have been reported rarely with tadalafil, there is no safety information on the administration of tadalafil to patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa. A minority of patients with the inherited condition retinitis pigmentosa have genetic disorders of retinal phosphodiesterases. Therefore, it is recommended that tadalafil not be administered to these patients until further data are available.

Geriatric patients ( = 65 years) made up approximately 25% of patients in the primary efficacy and safety studies of tadalafil for the treatment of erectile dysfunction and 28% of patients in the clinical study of tadalafil for pulmonary arterial hypertension. In clinical trials for benign prostatic hyperplasia, geriatric patients greater than 65 years of age accounted for 40% of study participants and those 75 years of age and older accounted for 10% of study participants. No overall differences in efficacy and safety were observed between older and younger patients for these indications. No dose adjustment is warranted based on age alone. However, greater sensitivity to medications in some older individuals should be considered.

Prior to initiating treatment with tadalafil for benign prostatic hyperplasia (BPH), consideration should be given to other urological conditions that may cause similar symptoms. Prostate cancer and benign prostatic hyperplasia (BPH) cause many of the same symptoms and frequently they coexist. Prior to starting tadalafil therapy for BPH, patients should be evaluated to rule out the presence of prostate cancer.

Tadalafil is classified as FDA pregnancy risk category B. There are no adequate and well-controlled studies of tadalafil in pregnant women. According to the manufacturer, Adcirca should be used during pregnancy only if clearly needed; Tadalafil is not indicated for use in women.

Use tadalafil cautiously in patients with gastroesophageal reflux disease (GERD) or hiatal hernia associated with reflux esophagitis. Like sildenafil, tadalafil can possibly decrease the tone of the lower esophageal sphincter and inhibit esophageal motility. Additionally, tadalafil is an inhibitor of phosphodiesterase type 5 (PDE5), which is found in platelets. Some data indicate that tadalafil does not potentiate the increase in bleeding time caused by aspirin. However, the manufacturer recommends caution when administering tadalafil to patients with significant active peptic ulcer disease (PUD) since the effects of the drug in this patient population have not been formally studied.

It is not known if tadalafil is excreted in breast milk. Adcirca should be used with caution in breast-feeding women; Tadalafil is not indicated for use in women. Consider the benefits of breastfeeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breastfeeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Tadalafil is an inhibitor of phosphodiesterase type 5 (PDE5), which is found in platelets. Some data indicate that tadalafil does not potentiate the increase in bleeding time caused by aspirin. However, the manufacturer recommends caution when administering tadalafil to patients with significant hematological disease (e.g., bleeding disorders) since the effects of the drug in this patient population have not been formally studied.

This list may not include all possible contraindications.

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.

Tadalafil

Tadalafil is classified as FDA pregnancy risk category B. There are no adequate and well-controlled studies of tadalafil in pregnant women. According to the manufacturer, Adcirca should be used during pregnancy only if clearly needed; Tadalafil is not indicated for use in women.

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.

Tadalafil

It is not known if tadalafil is excreted in breast milk. Adcirca should be used with caution in breast-feeding women; Tadalafil is not indicated for use in women. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated coAnchorndition. 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

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.

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.

Tadalafil

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.

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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