8 USE IN SPECIFIC POPULATIONS

No such events were reported following placebo.

Two such events were reported following administration of tadalafil.

• Some men may not respond adequately to 10 mg tadalafil.
• Doctor may increase to 20 mg for on-demand use if tolerated.
• Conversely, side effects may prompt a decrease to 5 mg.
• Do not change your dose without consulting your physician.
• It may take several attempts to find the optimal dosing regimen.
• Patience and communication with your doctor are key.

Vertigo was reported in one subject that began 7 hours after dosing and lasted about 5 days.

2.2 Tadalafil Tablets for Once Daily Use for Erectile Dysfunction

Tadalafil is 14-fold more potent for PDE5 than for PDE11A1 and 40-fold more potent for PDE5 than for PDE11A4, two of the four known forms of PDE11. PDE11 is an enzyme found in human prostate, testes, skeletal muscle and in other tissues (e.g., adrenal cortex). In vitro, tadalafil inhibits human recombinant PDE11A1 and, to a lesser degree, PDE11A4 activities at concentrations within the therapeutic range. The physiological role and clinical consequence of PDE11 inhibition in humans have not been defined.12.2 PharmacodynamicsEffects on Blood PressureTadalafil 20 mg administered to healthy male subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (difference in the mean maximal decrease of 1.6/0.8 mm Hg, respectively) and in standing systolic and diastolic blood pressure (difference in the mean maximal decrease of 0.2/4.6 mm Hg, respectively). In addition, there was no significant effect on heart rate.Effects on Blood Pressure When Administered with NitratesIn clinical pharmacology studies, tadalafil (5 to 20 mg) was shown to potentiate the hypotensive effect of nitrates.

Tadalafil may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

Therefore, the use of tadalafil tablets in patients taking any form of nitrates is contraindicated [see Contraindications ( 4.1)] .A study was conducted to assess the degree of interaction between nitroglycerin and tadalafil, should nitroglycerin be required in an emergency situation after tadalafil was taken. This was a 10mg tadalafil double-blind, placebo-controlled, crossover study in 150 male subjects at least 40 years of age (including subjects with diabetes mellitus and/or controlled hypertension) and receiving daily doses of tadalafil 20 mg or matching placebo for 7 days. Subjects were administered a single dose of 0.4 mg sublingual nitroglycerin (NTG) at pre-specified timepoints, following their last dose of tadalafil (2, 4, 8, 24, 48, 72, and 96 hours after tadalafil). The objective of the study was to determine when, after tadalafil dosing, no apparent blood pressure interaction was observed. In this study, a significant interaction between tadalafil and NTG was observed at each timepoint up to and including 24 hours. This subject previously experienced a mild episode of vertigo on doxazosin and placebo.

Dizziness was reported in another subject that began 25 minutes after dosing and lasted 1 day.

No syncope was reported.In the second doxazosin study, a single oral dose of tadalafil 20 mg was administered to healthy subjects taking oral doxazosin, either 4 or 8 mg daily.

Brand names

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of ActionPenile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE5) enhances erectile function by increasing the amount of cGMP. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 by tadalafil has no effect in the absence of sexual stimulation.The effect of PDE5 inhibition on cGMP concentration in the corpus cavernosum and pulmonary arteries is also observed in the smooth muscle of the prostate, the bladder and their vascular supply.

Dosing Modifications

The mechanism for reducing BPH symptoms has not been established.Studies in vitrohave demonstrated that tadalafil is a selective inhibitor of PDE5. PDE5 is found in the smooth muscle of the corpus cavernosum, prostate, and bladder as well as in vascular and visceral smooth muscle, skeletal muscle, urethra, platelets, kidney, lung, cerebellum, heart, liver, testis, seminal vesicle, and pancreas.In vitrostudies have shown that the effect of tadalafil is more potent on PDE5 than on other phosphodiesterases. These studies have shown that tadalafil is >10,000-fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7 enzymes, 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, an enzyme found in the heart and blood vessels. Additionally, tadalafil is 700-fold more potent for PDE5 than for PDE6, which is found in the retina and is responsible for phototransduction. The study (N=72 subjects) was conducted in three parts, each a 3-period crossover.In part A (N=24), subjects were titrated to doxazosin 4 mg administered daily at 8 a.m.

Tadalafil was administered at either 8 a.m., 4 p.m., or 8 p.m. There was no placebo control.In part B (N=24), subjects were titrated to doxazosin 4 mg administered daily at 8 p.m.

• Discontinue tadalafil and seek help if erection lasts >4 hours.
• Priapism can cause permanent damage to penile tissue.
• Treatment for priapism may involve draining blood from the penis.
• This is a urological emergency requiring immediate hospital care.
• Risk factors for priapism: sickle cell anemia, multiple myeloma.
• Having a prior episode of priapism increases your risk.

Tadalafil was administered at either 8 a.m., 4 p.m., or 8 p.m. There was no placebo control.In part C (N=24), subjects were titrated to doxazosin 8 mg administered daily at 8 a.m.

5.3 Prolonged Erection

In clinical pharmacology studies using single-dose tadalafil (5 to 10 mg), tadalafil exposure (AUC) doubled in subjects with creatinine clearance 30 to 80 mL/min. 10 OVERDOSAGE 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. 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.

Product Details

Tadalafil has the empirical formula C 22H 19N 3O 4representing a molecular weight of 389.41. It is a crystalline solid that is practically insoluble in water and very slightly soluble in ethanol.Tadalafil tablets, USP are available as almond-shaped tablets for oral administration. Each tablet contains 2.5, 5, 10, or 20 mg of tadalafil, USP and the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, iron oxide yellow, iron oxide red, ferrosoferric oxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide, polyvinyl alcohol-partially hydrolyzed, macrogol/PEG 3350 and lecithin (soya). It is a crystalline solid that is practically insoluble in water and very slightly soluble in ethanol. Tadalafil tablets, USP are available as almond-shaped tablets for oral administration. In this part, tadalafil or placebo were administered at either 8 a.m.

6.1 Clinical Trials Experience

At 48 hours, by most hemodynamic measures, the interaction between tadalafil and NTG was not observed, although a few more tadalafil subjects compared to placebo experienced greater blood-pressure lowering at this timepoint. After 48 hours, the interaction was not detectable ( seeFigure 1).Figure 1: Mean Maximal Change in Blood Pressure (Tadalafil Minus Placebo, Point Estimate with 90% CI) in Response to Sublingual Nitroglycerin at 2 (Supine Only), 4, 8, 24, 48, 72, and 96 Hours after the Last Dose of Tadalafil 20 mg or PlaceboTherefore, tadalafil tablets administration with nitrates is contraindicated. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring [see Contraindications ( 4.1)] .Effect on Blood Pressure When Administered with Alpha-BlockersSix randomized, double-blinded, crossover clinical pharmacology studies were conducted to investigate the potential interaction of tadalafil with alpha-blocker agents in healthy male subjects [see Dosage and Administration ( 2.7) and Warnings and Precautions ( 5.6)] . In four studies, a single oral dose of tadalafil was administered to healthy male subjects taking daily (at least 7 days duration) an oral alpha-blocker. In two studies, a daily oral alpha-blocker (at least 7 days duration) was administered to healthy male subjects taking repeated daily doses of tadalafil.Doxazosin— Three clinical pharmacology studies were conducted with tadalafil and doxazosin, an alpha[1]-adrenergic blocker.In the first doxazosin study, a single oral dose of tadalafil 20 mg or placebo was administered in a 2-period, crossover design to healthy subjects taking oral doxazosin 8 mg daily (N=18 subjects).

Tadalafil 10 mg: How long does it last?

Doxazosin was administered at the same time as tadalafil or placebo after a minimum of seven days of doxazosin dosing ( seeTable 5 and Figure 2).Table 5: Doxazosin (8 mg/day) Study 1: Mean Maximal Decrease (95% CI) in Systolic Blood PressureFigure 2: Doxazosin Study 1: Mean Change from Baseline in Systolic Blood PressureBlood pressure was measured manually at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours after tadalafil or placebo administration. Outliers were defined as subjects with a standing systolic blood pressure of <85 mm Hg or a decrease from baseline in standing systolic blood pressure of >30 mm Hg at one or more time points. There were nine and three outliers following administration of tadalafil 20 mg and placebo, respectively. Five and two subjects were outliers due to a decrease from baseline in standing systolic BP of >30 mm Hg, while five and one subject were outliers due to standing systolic BP <85 mm Hg following tadalafil and placebo, respectively. Severe adverse events potentially related to blood-pressure effects were assessed. or 8 p.m.The placebo-subtracted mean maximal decreases in systolic blood pressure over a 12-hour period after dosing in the placebo-controlled portion of the study (part C) are shown in Table 6 and Figure 3.Table 6: Doxazosin (8 mg/day) Study 2 (Part C): Mean Maximal Decrease in Systolic Blood PressureFigure 3: Doxazosin Study 2 (Part C): Mean Change from Time-Matched Baseline in Systolic Blood PressureBlood pressure was measured by ABPM every 15 to 30 minutes for up to 36 hours after tadalafil or placebo.