Tadalafil Tablets

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.1 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.

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.

Tadalafil is administered orally. The pharmacokinetics of tadalafil were evaluated in healthy young volunteers. Once absorbed, tadalafil is distributed into the tissues. Protein binding is 94% at therapeutic concentrations. Less than 0.0005% of the administered dose appeared in the semen of healthy subjects. The primary route of elimination for tadalfil is via the hepatic cytochrome P450 isoenzyme CYP3A4, which metabolizes the drug to a catechol metabolite. The catechol metabolite undergoes extensive methylation to form the methylcatechol metabolite and then glucuronidation to the form the methylcatechol glucuronide conjugate. The major circulating metabolite is the methylcatechol glucuronide, which is 13,000 times less potent for PDE5 than tadalafil. Methylcatechol concentrations are less than 10% of glucuronide concentrations. Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose). The mean elimination half-life is 17.5 hours in healthy subjects.

Route-Specific Pharmacokinetics:

Oral Route: The pharmacokinetics of tadalafil were evaluated in healthy young volunteers. After a single oral dose, the maximum observed plasma concentration (Cmax) occurs between 30 minutes and 6 hours (Tmax median time of 2 hours). The usual onset of action is within 30 to 45 minutes, and the usual duration is up to 36 hours. Food does not affect the pharmacokinetics of tadalafil; however, absolute bioavailability data are not available.

Special Populations:

Hepatic Impairment: In patients with mild to moderate hepatic impairment (Child-Pugh class A or B), the AUC following a 10 mg tadalafil dose was comparable to that of healthy subjects. There are no data available for doses higher than 10 mg of tadalafil in patients with hepatic impairment. Tadalafil has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

Renal Impairment: In clinical pharmacology studies involving persons with mild (CrCl 51—80 ml/min) or moderate renal impairment (CrCl 31—50 ml/min), tadalafil AUC was doubled after single doses of 5 to 10 mg compared to persons with normal renal function. In those with end-stage renal disease on hemodialysis, there was a two-fold increase in Cmax and 2.7- to 4.1-fold increase in AUC following single-dose administration of 10 or 20 mg tadalafil. Exposure to total methylcatechol (unconjugated plus glucuronide) was 2- to 4-fold higher in patients with renal impairment, compared to those with normal renal function. Hemodialysis (performed between 24 and 30 hours post-dose) had negligible effects on tadalafil or metabolite clearance.

Pediatrics: Tadalafil has not been studied in persons less than 18 years of age.

Geriatric: In a healthy volunteer study of elderly males ( = 65 years) and younger males (19—45 years), the AUC of tadalafil was 25% higher in the elderly males with no effect on Cmax. In patients with benign prostatic hyperplasia (BPH) receiving single and multiple doses of tadalafil 20 mg, there were no statistically significant differences in AUC and Cmax in elderly (70—85 years of age) patients compared to younger patients (<= 60 years of age). No dosage adjustment is warranted based on age alone. However, greater sensitivity to medications in some older individuals should be considered.

Diabetes mellitus: In male patients with diabetes mellitus after a 10 mg tadalafil dose, AUC was reduced approximately 19% and Cmax was 5% lower than that observed in healthy subjects. No dosage adjustment is necessary in diabetic patients as long as organ function is normal.

Treatment of erectile dysfunction and/or benign prostatic hypertrophy.

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 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.

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.

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.

It is not known if tadalafil is excreted in breast milk. Adcirca should be used with caution in breastfeeding 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 coAnchorndition. 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.

Possible interactions include certain drugs for high blood pressure; certain drugs for the treatment of HIV infection or AIDS; certain drugs used for fungal or yeast infections, like fluconazole, ketoconazole, and voriconazole; certain drugs used for seizures like carbamazepine, phenytoin, and phenobarbital; grapefruit juice; macrolide antibiotics; medicines for prostate problems; rifabutin, rifampin or rifapentine. This list may not describe 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.

The safety and efficacy of tadalafil administered concurrently with any other phosphodiesterase inhibitors (e.g., vardenafil and sildenafil) has not been studied. The manufacturer of tadalafil recommends to avoid the use of tadalafil with any other phosphodiesterase inhibitors.

Tadalafil has been shown to potentiate the hypotensive effects of nitrates. This interaction is consistent with tadalafil’s known effects on the nitric oxide/cGMP pathway. Deaths have been reported in men who were using a similar agent, sildenafil, while taking nitrate or nitrite therapy for angina. Tadalafil administration to patients who are concurrently using organic nitrates or nitrites in any form is contraindicated. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with other medications such as nitrates.

Concurrent use of phosphodiesterase (PDE5) inhibitors and alpha-blockers may lead to symptomatic hypotension in some patients. Tadalafil, other PDE5 inhibitors, and alpha-blockers are systemic vasodilators which can lower blood pressure. If vasodilators are used in combination, an additive effect on blood pressure is anticipated. 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 combination treatment, tadalafil is not recommended for use with alpha-blockers when treating BPH. Patients receiving alpha-blocker therapy for BPH prior to tadalafil initiation should discontinue the alpha-blocker at least one day prior to beginning tadalafil treatment. When tadalafil is co-administered with an alpha-blocker in a patient receiving tadalafil for erectile dysfunction (ED), the patient should be stable on alpha-blocker therapy before starting PDE5 inhibitor therapy. If hemodynamic instability is evident on alpha-blocker therapy alone, there is an increased risk of symptomatic hypotension with concomitant PDE5 inhibitor therapy. For patients with ED who are stable on alpha-blocker therapy, PDE5 inhibitors should be started at the lowest recommended dose. If a patient with ED is currently receiving an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increases in the alpha-blocker dose may be associated with further hypotension when taking a PDE5 inhibitor. Other variables, such as intravascular volume depletion and other antihypertensive drugs, may affect the safety of concomitant use of PDE5 inhibitors and alpha-blockers. Studies have been conducted to determine the effects of tadalafil on the potentiation of the blood-pressure-lowering effects of the alpha-blockers doxazosin and tamsulosin. When tadalafil 20 mg was administered to healthy subjects taking doxazosin (8 mg daily), an alpha-1-blocker, there was significant augmentation of the hypotensive effects of doxazosin. In contrast, coadministration of a single 20-mg dose of tadalafil to healthy subjects taking either 0.4 mg tamsulosin once-daily or 10 mg alfuzosin once daily, both of which are selective alpha-1A-blockers, resulted in no significant decreases in blood pressure. It should be noted that during once daily administration of tadalafil for ED or other indications, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with medications such as alpha-blockers.

Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors, such as tadalafil, to patients receiving certain protease inhibitors such as atazanavir, darunavir, ritonavir, amprenavir, fosamprenavir, indinavir, tipranavir, nelfinavir, or saquinavir.

Tadalafil is metabolized predominantly by CYP3A4. Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme. Similar precautions apply to combination products containing efavirenz such as efavirenz; emtricitabine; tenofovir.

Particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving delavirdine. Coadministration of delavirdine with these drugs is expected to substantially increase their plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. The manufacturer of tadalafil recommends that in patients receiving concomitant potent CYP3A4 inhibitors, the ‘as needed’ dose for erectile dysfunction should not exceed 10 mg within a 72 hour time period, and the ‘once-daily’ dose for erectile dysfunction or benign prostatic hyperplasia should not exceed 2.5 mg (see Dosage). It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4. When used for pulmonary arterial hypertension, tadalafil should not be co-administered with potent CYP3A inhibitors.

Tadalafil is metabolized predominantly by CYP3A4. Inhibitors of CYP3A4 may reduce tadalafil clearance. In theory, CYP3A4 inhibitors which may interact with tadalafil include amiodarone, cimetidine, clarithomycin or products containing clarithomycin, conivaptan, diltiazem, erythromycin or products containing erythromycin, fluconazole, fluoxetine or combination products with fluoxetine, fluvoxamine, ketoconazole, imatinib, STI-571, itraconazole, mibefradil, nefazodone, quinidine or combination products with quinidine, troleandomycin, voriconazole, zafirlukast, and zileuton. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. The manufacturer of tadalafil recommends that in patients receiving concomitant potent CYP3A4 inhibitors, the ‘as needed’ dose for erectile dysfunction should not exceed 10 mg within a 72 hour time period, and the ‘once-daily’ dose for erectile dysfunction or benign prostatic hyperplasia should not exceed 2.5 mg (see Dosage).

Etravirine is an inducer of CYP3A4; coadministration may result in decreased tadalafil concentrations. Dosage adjustments may be needed based on clinical efficacy.

Tadalafil is metabolized via the CYP3A4 isozyme. Grapefruit juice (food) has been reported to decrease the metabolism of drugs metabolized via this enzyme. Grapefruit juice contains a furano-coumarin compound, 6,7—dihydroxybergamottin that inhibits CYP3A4 in enterocytes in the GI tract. Tadalafil levels may increase; it is possible that tadalafil-induced side effects could also be increased in some individuals.

Although specific interaction studies have not been performed, CYP3A4 inducers such as barbiturates, bosentan, carbamazepine, dexamethasone, phenytoin or fosphenytoin, nevirapine, rifabutin, troglitazone, rifampin, or isoniazid would likely decrease tadalafil AUC since tadalafil is primarily metabolized by CYP3A4. Patients should be monitored for loss of efficacy of tadalafil during concurrent use

Mifepristone, RU-486 inhibits CYP3A4 in vitro. Coadministration of mifepristone may lead to an increase in serum levels of drugs metabolized via CYP3A4, such as tadalafil. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration.

The combination of tadalafil and substantial consumption of ethanol can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache. Ethanol and PDE5 inhibitors, including tadalafil, are mild systemic vasodilators. As reported by the manufacturer, the interaction of tadalafil with ethanol was evaluated in 3 clinical pharmacology studies. In 2 of the studies, ethanol was administered at a dose of 0.7 g/kg, which is equivalent to approximately 6 ounces of 80-proof vodka in an 80-kg male, and tadalafil was administered at a dose of 10 mg in 1 study and 20 mg in another. In both of these studies, all patients consumed the entire ethanol dose within 10 minutes of starting. In one of these studies, blood ethanol concentrations of 0.08% were confirmed. In these two studies, more patients had clinically significant decreases in blood pressure on the combination of tadalafil and ethanol as compared to ethanol alone. Some subjects reported postural dizziness, and orthostatic hypotension was observed in some subjects. When tadalafil 20 mg was administered with a lower dose of ethanol (0.6 g/kg, which is equivalent to approximately 4 ounces of 80-proof vodka, administered in less than 10 minutes), orthostatic hypotension was not observed, dizziness occurred with similar frequency to ethanol alone, and hypotensive effects of ethanol were not potentiated. Tadalafil did not affect ethanol plasma concentrations and ethanol did not affect tadalafil plasma concentrations. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for an interaction when a substantial amount of ethanol is consumed.

Nilotinib is a competitive inhibitor of CYP3A4, and tadalafil is a CYP3A4 substrate. Concurrent administration of the CYP3A4 substrate midazolam with nilotinib increased midazolam exposure by 30%. Caution should be exercised when coadministering nilotinib with CYP3A4 substrates, especially substrates with a narrow therapeutic index.

Sapropterin acts as a cofactor in the synthesis of nitric oxide and may cause vasorelaxation. Caution should be exercised when administering sapropterin in combination with drugs that affect nitric oxide-mediated vasorelaxation such as tadalafil. When given together these agents may produce an additive reduction in blood pressure. The combination of sapropterin and a phosphodiesterase inhibitor did not significantly reduce blood pressure when administered concomitantly in animal studies. The additive effect of these agents has not studied been in humans.

Nifedipine can have additive hypotensive effects when administered with phosphodiesterase inhibitors (PDE 5 inhibitors). The patient should be monitored carefully and the dosage should be adjusted based on clinical response. Vardenafil (20 mg) did not affect the AUC or Cmax of slow-release nifedipine (30 or 60 mg daily), which is metabolized by CYP3A4. Nifedipine did not alter plasma levels of vardenafil. In patients whose hypertension was controlled with nifedipine, vardenafil produced mean additional supine systolic/diastolic blood pressure reductions of 6/5 mm Hg compared to placebo.

Potent inhibitors of CYP3A4, such as telithromycin, may reduce tadalafil clearance; tadalafil is metabolized predominantly by CYP3A4. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. The manufacturer of tadalafil recommends that in patients receiving concomitant potent CYP3A4 inhibitors, the ‘as needed’ dose for erectile dysfunction should not exceed 10 mg within a 72 hour time period, and the ‘once-daily’ dose for erectile dysfunction or benign prostatic hyperplasia should not exceed 2.5 mg (see Dosage). It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4. When used for pulmonary arterial hypertension, tadalafil should not be co-administered with potent CYP3A inhibitors.

Tadalafil, when used for pulmonary arterial hypertension (PAH), is contraindicated with telaprevir. Coadministration of telaprevir with phosphodiesterase type 5 (PDE5) inhibitors is expected to substantially increase their plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Telaprevir can be used cautiously with tadalafil for erectile dysfunction; use tadalafil at a reduced dose of 10 mg no more frequently than every 72 hours with increased monitoring for adverse reactions.

Studies have shown that tadalafil does not inhibit or induce cytochrome P450 (CYP) enzymes 1A2, 3A4, 2C9, 2C19, 2D6, and 2E1. Therefore, tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized by CYP enzymes. When tadalafil was administered with theophylline, a CYP1A2 substrate, a small augmentation (3 beats per minute) of the increase in heart rate associated with theophylline was observed. However, tadalafil had no clinically significant effect on the pharmacokinetics of theophylline. Tadalafil had no clinically significant on the AUCs of the CYP3A4 substrates midazolam or lovastatin. Additionally, no clinically significant effect was observed on S-warfarin and R-warfarin AUC when coadministered with tadalafil; prothrombin time changes induced by warfarin were not affected by tadalafil.

Tadalafil and other PDE5 inhibitors are mild systemic vasodilators. Studies were conducted to assess the interaction of tadalafil 10 mg and sustained-release metoprolol (25 to 200 mg daily), bendroflumethiazide (2.5 mg daily), or enalapril (10 to 20 mg daily). Following dosing of tadalafil with metoprolol, the mean reduction in supine systolic/diastolic blood pressure was 5/3 mmHg, compared to placebo. After dosing of tadalafil with bendroflumethiazide, the mean reduction in supine systolic/diastolic blood pressure was 6/4 mmHg, compared to placebo. Following dosing of tadalafil with enalapril, the mean reduction in supine systolic/diastolic blood pressure was 4/1 mmHg, compared to placebo.

Tadalafil and other PDE5 inhibitors are mild systemic vasodilators. A study was conducted to assess the interaction of tadalafil 20 mg and angiotensin II receptor blockers. Study subjects were taking any marketed angiotensin II receptor blocker, either alone, as a component of a combination product, or as part of a multiple antihypertensive regimen. Following dosing, ambulatory measurements of blood pressure revealed differences between tadalafil and placebo of 8/4 mmHg in systolic/diastolic blood pressure.

The increase in pH associated with nizatidine administration had no significant effect on tadalafil pharmacokinetics. Additionally, simultaneous administration of an antacid (magnesium hydroxide; aluminum hydroxide) and tadalafil reduced the apparent rate of absorption of tadalafil without altering the AUC of tadalafil.

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.

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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