Tadalafil

Tadalafil is a Phosphodiesterase-5 Enzyme Inhibitor belonging to Vasodilator.

Tadalafil is a phosphodiesterase 5 inhibitor used to treat erectile dysfunction, benign prostatic hyperplasia, and pulmonary arterial hypertension.

After single oral-dose administration, the maximum observed plasma concentration (Cmax) of tadalafil is achieved between 30 minutes and 6 hours (median time of 2 hours). The mean apparent volume of distribution following oral administration is approximately 63 L, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins. Tadalafil is predominantly metabolized by CYP3A4 to a catechol metabolite. The mean oral clearance for tadalafil is 2.5 L/hr and the mean terminal half-life is 17.5 hours in healthy subjects. 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).

Tadalafil shows common side effects like Headache, indigestion or heartburn, Nausea, diarrhea, Flushing, pain in the stomach, back, muscles, arms, or legs, cough.

Tadalafil is available in the form of Oral suspension and Oral Tablet.

Tadalafil is available in India, US, Singapore, Malaysia, France, Spain, Canada, Russia, Japan, China, Italy, and Australia.

Tadalafil belongs to the Vasodilator acts as a Phosphodiesterase-5 Enzyme Inhibitor.

Mechanism of action for Benign Prostatic Hyperplasia (BPH): Exact mechanism unknown; effects likely due to PDE-5 mediated reduction in smooth muscle and endothelial cell proliferation, decreased nerve activity, and increased smooth muscle relaxation and tissue perfusion of the prostate and bladder

Mechanism of action for Erectile dysfunction: Does not directly cause penile erections but affects the response to sexual stimulation. The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation and inflow of blood to the corpus cavernosum. Tadalafil enhances the effect of NO by inhibiting phosphodiesterase type 5 (PDE-5), which is responsible for degradation of cGMP in the corpus cavernosum; when sexual stimulation causes local release of NO, inhibition of PDE-5 by tadalafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. At recommended doses, it has no effect in the absence of sexual stimulation.

Mechanism of action for Pulmonary arterial hypertension (PAH): Inhibits phosphodiesterase type 5 (PDE-5) in smooth muscle of pulmonary vasculature where PDE-5 is responsible for the degradation of cyclic guanosine monophosphate (cGMP). Increased cGMP concentration results in pulmonary vasculature relaxation; vasodilation in the pulmonary bed and the systemic circulation (to a lesser degree) may occur.

The Onset of action of Tadalafil is about ~60 minutes.

The Duration of action of Tadalafil is up to 36 hours.

The Tmax of Tadalafil is approximately 75-90 minute.

Tadalafil is available in the form of Oral Suspension and Oral Tablet.

Tadalafil tablet is taken orally, usually once daily.

Tadalafil is a medicine used for the treatment of erectile dysfunction (a condition that occurs when a man has difficulty in getting and/or keeping an erection firm enough for sexual intercourse). It is also used to treat urinary symptoms caused due to an enlargement of the prostate gland (a walnut-sized gland located just below the bladder that secretes fluid to nourish and transport the sperm) in older men.

Tadalafil is a Phosphodiesterase-5 Enzyme Inhibitor belonging to Vasodilator.

Tadalafil works by relaxing the blood vessels in the penis, increasing the flow of blood to the penis. This medicine also relaxes the muscles present in the prostate gland and bladder thereby, improving the symptoms associated with an enlarged prostate gland.

Tadalafil is approved for use in the following clinical indications

• Erectile Dysfunction

Tadalafil is indicated for the treatment of erectile dysfunction (ED).

• Benign Prostatic Hyperplasia

Tadalafil is indicated for the treatment of the signs and symptoms of Benign prostatic hyperplasia (BPH).

• Pulmonary arterial hypertension

Although not approved, there have been certain off-label indications. These include

• High-altitude pulmonary edema

• Erectile Dysfunction

As-needed dosing:

Oral: Initial: 10 mg as a single dose ≥30 minutes prior to anticipated sexual activity; do not take more than once daily. Erectile function may be improved for up to 36 hours following a single dose. Adjust dose based on effectiveness and tolerability; may decrease to 5 mg or increase to 20 mg per dose.

Once-daily dosing:

Oral: Initial: 2.5 mg once daily without regard to timing of sexual activity; may increase to 5 mg once daily based on effectiveness and tolerability.

• Benign Prostatic Hyperplasia

Oral: 5 mg once daily.

• Pulmonary arterial hypertension

Oral: Initial: 40 mg once daily; may also start with 20 mg once daily and increase to 40 mg after ~4 weeks.

• High-altitude pulmonary edema

Prevention:

Oral: 10 mg every 12 hours starting the day of ascent; continue for 3 to 5 days after reaching maximal altitude; can extend for up to 7 days in individuals who ascend faster than recommended.

Treatment:

Oral: 10 mg every 12 hours; continue until descent is complete, symptoms resolve, and oxygenation is normal for the altitude.

Tadalafil is available in various strengths as 20mg/5mL, 2.5mg, 5mg, 10mg and 20mg.

Tadalafil is available in the form of Oral Suspension and Oral Tablet.

• Dosage Adjustment in Kidney Patient

CrCl >80 mL/minute

Benign prostatic hyperplasia: 5 mg every 24 hours

Erectile dysfunction (as needed dosing): Initial: 10 mg as a single dose ≥30 minutes prior to anticipated sexual activity; do not take more than once every 24 hours. Dose may be adjusted between 5 and 20 mg administered no more frequently than once every 24 hours based on effectiveness and tolerability.

Erectile dysfunction (once-daily dosing): Initial: 2.5 mg every 24 hours (not necessary to time with sexual activity); may increase to 5 mg every 24 hours based on effectiveness and tolerability.

High altitude pulmonary edema: 10 mg every 12 hours

Pulmonary arterial hypertension: 20 to 40 mg every 24 hours; if 20 mg every 24 hours is initiated, increase to 40 mg every 24 hours after ~4 weeks.

CrCl >50 to 80 mL/minute

Benign prostatic hyperplasia: 5 mg every 24 hours; may decrease to 2.5 mg every 24 hours based on effectiveness and tolerability.

Erectile dysfunction (as needed dosing): Initial: 10 mg as a single dose ≥30 minutes prior to anticipated sexual activity; may repeat no more frequently than once every 24 to 48 hours (a 48-hour interval may be preferred initially since AUC is doubled in these patients). Dose may be adjusted between 5 and 20 mg administered no more frequently than once every 24 hours based on efficacy and tolerability.

Erectile dysfunction (once-daily dosing): 2.5 mg every 24 hours (not necessary to time with sexual activity); may increase to 5 mg every 24 hours based on effectiveness and tolerability.

High altitude pulmonary edema: 10 mg every 12 hours; may reduce to 10 mg every 24 hours if intolerable adverse effects occur.

Pulmonary arterial hypertension: Initial: 20 mg every 24 hours; may increase to 40 mg every 24 hours based on efficacy and tolerability.

CrCl 30 to 50 mL/minute

Benign prostatic hyperplasia: Initial: 2.5 mg every 24 hours; may increase to 5 mg every 24 hours based on effectiveness and tolerability.

Erectile dysfunction (as needed dosing): Initial: 5 mg as a single dose ≥30 minutes prior to anticipated sexual activity; do not take more than once every 24 hours. Dose may be decreased to 2.5 mg administered no more frequently than once every 24 hours or increased to 10 mg administered no more frequently than once every 48 hours based on effectiveness and tolerability.

Erectile dysfunction (once-daily dosing): 2.5 mg every 24 hours (not necessary to time with sexual activity); may increase to 5 mg every 24 hours based on effectiveness and tolerability.

High altitude pulmonary edema: 10 mg every 24 hours

Pulmonary arterial hypertension: Initial: 20 mg every 24 hours; may increase to 40 mg every 24 hours based on efficacy and tolerability.

CrCl <30 mL/minute

Benign prostatic hyperplasia: Avoid use due to increased tadalafil exposure; limited clinical experience.

Erectile dysfunction (as needed dosing): 5 mg as a single dose ≥30 minutes prior to anticipated sexual activity; may repeat no more frequently than once every 72 hours.

Erectile dysfunction (once-daily dosing): Avoid use due to increased tadalafil exposure; limited clinical experience.

High altitude pulmonary edema: Avoid use due to increased tadalafil exposure; limited clinical experience.

Pulmonary arterial hypertension: Avoid use due to increased tadalafil exposure; limited clinical experience.

• Dosage Adjustment in Hepatic impairment Patient

Benign prostatic hyperplasia

Mild to moderate hepatic impairment (Child-Pugh class A or B): Use with caution; the use of tadalafil for once-daily use has not been extensively evaluated in patients with hepatic impairment.

Severe hepatic impairment (Child-Pugh class C): Use is not recommended.

Erectile dysfunction

As-needed use:

Mild to moderate impairment (Child-Pugh class A or B): Use with caution; dose should not exceed 10 mg once daily. The use of tadalafil once per day has not been evaluated extensively in patients with hepatic impairment.

Severe impairment (Child-Pugh class C): Use is not recommended.

Once-daily use:

Mild to moderate impairment (Child-Pugh class A or B): Use with caution; the use of tadalafil for once-daily use has not been extensively evaluated in patients with hepatic impairment.

Severe impairment (Child-Pugh class C): Use is not recommended.

Pulmonary arterial hypertension

Mild to moderate hepatic impairment (Child-Pugh class A or B): Use with caution; consider initial dose of 20 mg once daily.

Severe hepatic impairment (Child-Pugh class C): Avoid use; has not been studied in patients with severe hepatic cirrhosis.

Avoid consumption of Grapefruit. Grapefruit juice may increase serum levels/toxicity of tadalafil.

Tadalafil is contraindicated in patients with

• Nitrates

Administration of Tadalafil to patients who are using any form of organic nitrate, either regularly and/or intermittently, is contraindicated. In clinical pharmacology studies, Tadalafil was shown to potentiate the hypotensive effect of nitrates.

• Hypersensitivity Reactions

Tadalafil is contraindicated in patients with a known serious hypersensitivity to tadalafil. Hypersensitivity reactions have been reported, including Stevens-Johnson syndrome and exfoliative dermatitis.

• Concomitant Guanylate Cyclase (GC) Stimulators

Do not use Tadalafil in patients who are using a GC stimulator, such as Riociguat. PDE5 inhibitors, including Tadalafil, may potentiate the hypotensive effects of GC stimulators.

• Anginal chest pain: Patients experiencing anginal chest pain after tadalafil administration should seek immediate medical attention.
• Color discrimination: May cause dose-related impairment of color discrimination.
• Anatomical penis deformation: Use with caution in patients with anatomical deformation of the penis (angulation, cavernosal fibrosis, or Peyronie disease).
• Bleeding disorders: Use with caution in patients with bleeding disorders; safety and efficacy have not been established. In vitro studies have suggested a decreased effect on platelet aggregation.
• Cardiovascular disease: Use is not recommended in patients with hypotension (<90/50 mm Hg), uncontrolled hypertension (>170/100 mm Hg), NYHA class II-IV heart failure within the last 6 months, uncontrolled arrhythmias, stroke within the last 6 months, MI within the last 3 months, unstable angina or angina during sexual intercourse; safety and efficacy have not been evaluated in these patients. Safety and efficacy in PAH have not been evaluated in patients with clinically significant aortic and/or mitral valve disease, life-threatening arrhythmias, hypotension (<90/50 mm Hg), uncontrolled hypertension, significant left ventricular dysfunction, pericardial constriction, restrictive or congestive cardiomyopathy, symptomatic coronary artery disease. There is a degree of cardiac risk associated with sexual activity; therefore, physicians may wish to consider the cardiovascular status of their patients prior to initiating any treatment for erectile dysfunction.
• Hereditary degenerative retinal disorders (eg, retinitis pigmentosa): Use caution in patients with retinitis pigmentosa; a minority have genetic disorders of retinal phosphodiesterases. Safety has not been evaluated in patients with known hereditary degenerative retinal disorders; use is not recommended.
• Peptic ulcer disease: Use with caution in patients with active peptic ulcer disease because of effect on platelets (bleeding); safety and efficacy have not been established.
• Pulmonary veno-occlusive disease (PVOD): Pulmonary vasodilators may exacerbate the cardiovascular status in patients with PVOD. Use is not recommended; no clinical data exists in patients with PVOD. In patients with unrecognized PVOD, signs of pulmonary edema should prompt investigation into this diagnosis.

Avoid consumption of alcohol during treatment with Tadalafil as it may lower your blood pressure.

Tadalafil is not indicated for use in women. It is not known whether tadalafil is excreted into human milk. While tadalafil or some metabolite of tadalafil was excreted into rat milk, drug levels in animal breast milk may not accurately predict levels of drug in human breast milk. Tadalafil and/or its metabolites were secreted into the milk in lactating rats at concentrations approximately 2.4-fold greater than found in the plasma.

Tadalafil likely crosses the placenta. Untreated pulmonary arterial hypertension is associated with adverse maternal outcomes, including heart failure, preterm delivery, stroke, and maternal/fetal death. Females with pulmonary arterial hypertension are encouraged to avoid pregnancy.

Avoid consumption of Grapefruit. Grapefruit juice may increase serum levels/toxicity of tadalafil.

Common Adverse effects

• Flushing, Dyspepsia, nausea, headache, Back pain, limb pain, myalgia, Lower respiratory tract infection, nasopharyngitis, upper respiratory tract infection, Acute myocardial infarction, angina pectoris, chest pain, hypertension, hypotension, orthostatic hypotension, palpitations, peripheral edema, syncope, tachycardia, Diaphoresis, pruritus, skin rash, Increased gamma-glutamyl transferase, Abdominal pain, diarrhea, dysphagia, esophagitis, gastritis, gastroenteritis, gastroesophageal reflux disease, hemorrhoidal bleeding, loose stools, rectal hemorrhage, upper abdominal pain, vomiting, xerostomia, Prolonged erection, spontaneous erections, urinary tract infection, Abnormal hepatic function test, Facial edema, Asthenia, dizziness, drowsiness, fatigue, hypoesthesia, insomnia, pain, paresthesia, vertigo, Arthralgia, neck pain, Blurred vision, conjunctival hyperemia, conjunctivitis, eye pain, eyelid edema, increased lacrimation, vision color changes, Hearing loss, tinnitus, Renal insufficiency, Cough, dyspnea, epistaxis, nasal congestion, paranasal sinus congestion, pharyngitis

Rare Adverse effects

• Cardiovascular toxicity, Basal cell carcinoma of skin, exfoliative dermatitis, malignant melanoma, Stevens-Johnson syndrome, Priapism, Amnesia, cerebrovascular accident, migraine, seizure, Anterior ischemic optic neuropathy, chorioretinitis, increased intraocular pressure, retinal artery occlusion, retinal vein occlusion, vision loss.

• Nitrates

Administration of Tadalafil to patients who are using any form of organic nitrate, is contraindicated. In clinical pharmacology studies, Tadalafil was shown to potentiate the hypotensive effect of nitrates. In a patient who has taken Tadalafil, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should elapse after the last dose of Tadalafil before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring.

• Alpha-Blockers

Caution is advised when PDE5 inhibitors are coadministered with alpha-blockers. PDE5 inhibitors, including Tadalafil, and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. Clinical pharmacology studies have been conducted with coadministration of tadalafil with doxazosin, tamsulosin or alfuzosin.

• Antihypertensives

PDE5 inhibitors, including tadalafil, are mild systemic vasodilators. Clinical pharmacology studies were conducted to assess the effect of tadalafil on the potentiation of the blood-pressure-lowering effects of selected antihypertensive medications (amlodipine, angiotensin II receptor blockers, bendrofluazide, enalapril, and metoprolol). Small reductions in blood pressure occurred following coadministration of tadalafil with these agents compared with placebo.

• Alcohol

Both alcohol and tadalafil, a PDE5 inhibitor, act as mild vasodilators. When mild vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased. Substantial consumption of alcohol (e.g., 5 units or greater) in combination with Tadalafil can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache. Tadalafil did not affect alcohol plasma concentrations and alcohol did not affect tadalafil plasma concentrations.

• Antacids

Simultaneous administration of an antacid (magnesium hydroxide/aluminum hydroxide) and tadalafil reduced the apparent rate of absorption of tadalafil without altering exposure (AUC) to tadalafil.

• H2 Antagonists (e.g., Nizatidine)

An increase in gastric pH resulting from administration of nizatidine had no significant effect on pharmacokinetics.

• Cytochrome P450 Inhibitors

Tadalafil is a substrate of and predominantly metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase tadalafil exposure.

• CYP3A4 (e.g., Ketoconazole)

Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A4, increased tadalafil 20 mg single-dose exposure (AUC) by 312% and Cmax by 22%, relative to the values for tadalafil 20 mg alone. Ketoconazole (200 mg daily) increased tadalafil 10-mg single-dose exposure (AUC) by 107% and Cmax by 15%, relative to the values for tadalafil 10 mg alone. Although specific interactions have not been studied, other CYP3A4 inhibitors, such as erythromycin, itraconazole, and grapefruit juice, would likely increase tadalafil exposure.

• HIV Protease Inhibitor

Ritonavir (500 mg or 600 mg twice daily at steady state), an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil 20-mg single-dose exposure (AUC) by 32% with a 30% reduction in Cmax, relative to the values for tadalafil 20 mg alone. Ritonavir (200 mg twice daily), increased tadalafil 20-mg single-dose exposure (AUC) by 124% with no change in Cmax, relative to the values for tadalafil 20 mg alone. Although specific interactions have not been studied, other HIV protease inhibitors would likely increase tadalafil exposure.

• Cytochrome P450 Inducers

Studies have shown that drugs that induce CYP3A4 can decrease tadalafil exposure.

• CYP3A4 (e.g., Rifampin)

Rifampin (600 mg daily), a CYP3A4 inducer, reduced tadalafil 10-mg single-dose exposure (AUC) by 88% and Cmax by 46%, relative to the values for tadalafil 10 mg alone. Although specific interactions have not been studied, other CYP3A4 inducers, such as carbamazepine, phenytoin, and phenobarbital, would likely decrease tadalafil exposure. No dose adjustment is warranted. The reduced exposure of tadalafil with the coadministration of Rifampin or other CYP3A4 inducers can be anticipated to decrease the efficacy of Tadalafil for once daily use; the magnitude of decreased efficacy is unknown.

• Aspirin

Tadalafil did not potentiate the increase in bleeding time caused by aspirin.

• Cytochrome P450 Substrates

Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized by cytochrome P450 (CYP) isoforms. Studies have shown that tadalafil does not inhibit or induce P450 isoforms CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP2E1.

• CYP1A2 (e.g. Theophylline)

Tadalafil had no significant effect on the pharmacokinetics of theophylline. When tadalafil was administered to subjects taking theophylline, a small augmentation (3 beats per minute) of the increase in heart rate associated with theophylline was observed.

• CYP2C9 (e.g. Warfarin)

Tadalafil had no significant effect on exposure (AUC) to S-warfarin or R-warfarin, nor did tadalafil affect changes in prothrombin time induced by warfarin.

• CYP3A4 (e.g. Midazolam or Lovastatin)

Tadalafil had no significant effect on exposure (AUC) to midazolam or Lovastatin.

• P-glycoprotein (e.g. Digoxin)

Coadministration of tadalafil (40 mg once per day) for 10 days did not have a significant effect on the steady-state pharmacokinetics of digoxin (0.25 mg/day) in healthy subjects.

The common side effects of Tadalafil include the following

Common

● Headache, indigestion or heartburn, Nausea, diarrhea, Flushing, pain in the stomach, back, muscles, arms, or legs, cough.

Rare

● Sudden decrease or loss of vision, blurred vision, changes in color vision, sudden decrease or loss of hearing, ringing in ears, erection that lasts longer than 4 hours, dizziness, chest pain, hives, rash, difficulty breathing or swallowing, swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs, blistering or peeling of skin.

• Pregnancy

Pregnancy Category B

Tadalafil is not indicated for use in women. There are no adequate and well controlled studies of Tadalafil use in pregnant women. Animal reproduction studies in rats and mice revealed no evidence of fetal harm. Animal reproduction studies showed no evidence of teratogenicity, embryotoxicity, or fetotoxicity when tadalafil was given to pregnant rats or mice at exposures up to 11 times the maximum recommended human dose (MRHD) of 20 mg/day during organogenesis. In one of two perinatal/postnatal developmental studies in rats, postnatal pup survival decreased following maternal exposure to tadalafil doses greater than 10 times the MRHD based on AUC. Signs of maternal toxicity occurred at doses greater than 16 times the MRHD based on AUC. Surviving offspring had normal development and reproductive performance. In a rat prenatal and postnatal development study at doses of 60, 200, and 1000 mg/kg, a reduction in postnatal survival of pups was observed. The no observed effect level (NOEL) for maternal toxicity was 200 mg/kg/day and for developmental toxicity was 30 mg/kg/day. This gives approximately 16- and 10-fold exposure multiples, respectively, of the human AUC for the MRHD of 20 mg. Tadalafil and/or its metabolites cross the placenta, resulting in fetal exposure in rats.

• Nursing Mothers

Tadalafil is not indicated for use in women. It is not known whether tadalafil is excreted into human milk. While tadalafil or some metabolite of tadalafil was excreted into rat milk, drug levels in animal breast milk may not accurately predict levels of drug in human breast milk. Tadalafil and/or its metabolites were secreted into the milk in lactating rats at concentrations approximately 2.4-fold greater than found in the plasma.

• Pediatric Use

As per FDA, Tadalafil is not indicated for use in pediatric patients. Safety and efficacy in patients below the age of 18 years has not been established.

• Geriatric Use

Of the total number of subjects in ED clinical studies of tadalafil, approximately 25 percent were 65 and over, while approximately 3 percent were 75 and over. Of the total number of subjects in BPH clinical studies of tadalafil (including the ED/BPH study), approximately 40 percent were over 65, while approximately 10 percent were 75 and over. In these clinical trials, no overall differences in efficacy or safety were observed between older (>65 and ≥75 years of age) and younger subjects (≤65 years of age). Therefore, no dose adjustment is warranted based on age alone. However, a greater sensitivity to medications in some older individuals should be considered.

Single doses up to 500 mg have been given to healthy subjects, and multiple daily doses up to 100 mg have been given to patients. Adverse events were similar to those seen at lower doses. In cases of overdose, standard supportive measures should be adopted as required. Hemodialysis contributes negligibly to tadalafil elimination.

Pharmacodynamic

Tadalafil exerts a therapeutic effect in ED by increasing sexual stimulation-dependant smooth muscle relaxation in the penis, allowing the corpus cavernosum to fill with blood to produce an erection. Smooth muscle relaxation in the pulmonary vasculature helps to produce vasodilation in PAH which reduces blood pressure in the pulmonary arteries. In BPH, tadalafil may contribute to decreased smooth muscle cell proliferation which may reduce the size of the prostate and relieve the anatomical obstruction which produces urinary symptoms of BPH. The decreased affinity of tadalafil for PDE6 compared to other PDE5 inhibitors may explain the reduced incidence of visual side effects.

Pharmacokinetics

• Absorption

After single oral-dose administration, the maximum observed plasma concentration (Cmax) of tadalafil is achieved between 30 minutes and 6 hours (median time of 2 hours). Absolute bioavailability of tadalafil following oral dosing has not been determined.

• Distribution

The mean apparent volume of distribution following oral administration is approximately 63 L, indicating that tadalafil is distributed into tissues. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins. Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.

• Metabolism and Excretion

Tadalafil is predominantly metabolized by CYP3A4 to a catechol metabolite. The catechol metabolite undergoes extensive methylation and glucuronidation to form the methylcatechol and methylcatechol glucuronide conjugate, respectively. The major circulating metabolite is the methylcatechol glucuronide. Methylcatechol concentrations are less than 10% of glucuronide concentrations. In vitro data suggests that metabolites are not expected to be pharmacologically active at observed metabolite concentrations. The mean oral clearance for tadalafil is 2.5 L/hr and the mean terminal half-life is 17.5 hours in healthy subjects. 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).

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