CIAFAL

Tadalafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).

Tadalafil has the empirical formula

C 22 H 19 N 3 O 4 representing a molecular weight of 389.41.

The structural formula is

The chemical designation is pyrazino[1´,2´:1,6]pyrido[3,4-b]indole-1,4-dione, 6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6R,12aR)-.

It is a crystalline solid that is practically insoluble in water and very slightly soluble in ethanol.

Tadalafil tablet, USP is available as yellow colored, oval-shaped, film coated tablets for oral administration.

Each tablet contains 2.5, 5, 10, or 20 mg of tadalafil and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, copovidone, sodium lauryl sulfate, magnesium stearate, hypromellose, titanium dioxide, iron oxide yellow and triacetin.

Treatment of erectile dysfunction in adult men.

Sexual stimulation is required to make tadalafil effective.

AGREEMENT is not indicated in women.

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Penile 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.

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.

Tadalafil inhibits

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.

The mechanism for reducing

BPH symptoms has not been established.

Studies in vitro have 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 vitro studies 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.

Tadalafil is >9,000-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, 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 Pharmacodynamics Effects on Blood Pressure Tadalafil 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 Nitrates In clinical pharmacology studies, tadalafil (5 to 20 mg) was shown to potentiate the hypotensive effect of nitrates.

Therefore, the use of tadalafil tablets in patients taking any form of nitrates is contraindicated.

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 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 time points, 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 time point up to and including 24 hours.

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 time point.

After 48 hours, the interaction was not detectable.

Figure 1: Mean Maximal Change in Blood Pressure (Tadalafil Minus Placebo, Point Estimate with 90% Cl) 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 Placebo Therefore, tadalafil tablets administration with nitrates is contraindicated.

In a patient who has taken tadalafil tablets, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should elapse after the last dose of tadalafil tablets before nitrate administration is considered.

In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring.

Tadalafil-tablets-figure-1 Effect on Blood Pressure When Administered With Alpha-Blockers Six randomized, double-blinded, crossover clinical pharmacology studies were conducted to investigate the potential interaction of tadalafil with alpha-blocker agents in healthy male subjects.

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-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).

Doxazosin was administered at the same time as tadalafil or placebo after a minimum of seven days of doxazosin dosing.

Table 5: Doxazosin (8 mg/day) Study 1: Mean Maximal Decrease (95% CI) in Systolic Blood Pressure Placebo-subtracted mean maximal decrease in systolic blood pressure (mm Hg) Tadalafil 20 mg Supine 3.6 (-1.5, 8.8) Standing 9.8 Figure 2: Doxazosin Study 1: Mean Change from Baseline in Systolic Blood Pressure Blood 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.

No such events were reported following placebo.

Two such events were reported following administration of tadalafil.

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

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.

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.

B (N=24), subjects were titrated to doxazosin 4 mg administered daily at 8 p.m.

C (N=24), subjects were titrated to doxazosin 8 mg administered daily at 8 a.m.

In this part, tadalafil or placebo were administered at either 8 a.m. 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 and Figure 3.

Table 6: Doxazosin (8 mg/day) Study 2 (Part C): Mean Maximal Decrease in Systolic Blood Pressure Placebo-subtracted mean maximal decrease in systolic blood pressure (mm Hg) Tadalafil 20 mg at 8 a.m.

Tadalafil 20 mg at 8 p.m.

Monitoring (ABPM) 7 8 Figure 3: Doxazosin Study 2 (Part C): Mean Change from Time-Matched Baseline in Systolic Blood Pressure Blood pressure was measured by ABPM every to 30 minutes for up to 36 hours after tadalafil or placebo.

Subjects were categorized as outliers if one or more systolic blood pressure readings of <85 mm Hg were recorded or one or more decreases in systolic blood pressure of >30 mm Hg from a time-matched baseline occurred during the analysis interval.

Of the 24 subjects in part C, 16 subjects were categorized as outliers following administration of tadalafil and 6 subjects were categorized as outliers following placebo during the 24-hour period after 8 a.m. dosing of tadalafil or placebo.

Of these, 5 and were outliers due to systolic BP <85 mm Hg, while and 4 were outliers due to a decrease from baseline in systolic BP of >30 mm Hg following tadalafil and placebo, respectively.

During the 24-hour period after 8 p.m. dosing, 17 subjects were categorized as outliers following administration of tadalafil and 7 subjects following placebo.

Of these, 10 and 2 subjects were outliers due to systolic BP <85 mm Hg, while and 5 subjects were outliers due to a decrease from baseline in systolic BP of >30 mm Hg, following tadalafil and placebo, respectively.

Some additional subjects in both the tadalafil and placebo groups were categorized as outliers in the period beyond 24 hours.

In the study (N=72 subjects), 2 such events were reported following administration of tadalafil (symptomatic hypotension in one subject that began 10 hours after dosing and lasted approximately 1 hour, and dizziness in another subject that began 11 hours after dosing and lasted 2 minutes).

In the period prior to tadalafil dosing, one severe event (dizziness) was reported in a subject during the doxazosin run-in phase.

In the third doxazosin study, healthy subjects (N=45 treated; 37 completed) received 28 days of once per day dosing of tadalafil 5 mg or placebo in a two-period crossover design.

After 7 days, doxazosin was initiated at 1 mg and titrated up to 4 mg daily over the last 21 days of each period (7 days on 1 mg; 7 days of 2 mg; 7 days of 4 mg doxazosin).

The results are shown in

Table 7.

Table 7: Doxazosin Study 3: Mean Maximal Decrease (95% CI) in Systolic Blood Pressure Placebo-subtracted mean maximal decrease in systolic blood pressure Tadalafil 5 mg Day of 4 mg Doxazosin Supine 2.4 (-0.4, 5.2) Standing -0.5 (-4.0, 3.1) Day of 4 mg Doxazosin Supine 2.8 (-0.1, 5.7) Standing 1.1 (-2.9, 5.0) Blood pressure was measured manually pre-dose at two time points (-30 and -15 minutes) and then at and 24 hours post dose on the first day of each doxazosin dose, (1 mg, 2 m.

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The most commonly reported adverse reactions in patients taking tadalafil for the treatment of erectile dysfunction or benign prostate hypertrophy were headache, dyspepsia, back pain and myalgia, the incidence of which increases with increased tadalafil dose.

The reported adverse reactions were transient and, generally, mild or moderate in intensity.

The majority of the headaches reported with tadalafil in daily dosing occur within 10-30 days of the start of treatment.

Summary of the adverse reactions

The table below presents the adverse reactions observed from spontaneous reports and in controlled placebo trials (carrying on a total of 8 022 patients treated with tadalafil and 4 422 patients receiving tadalafil in a day-to-day dosing procedure.

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.

Administration of tadalafil tablets to patients using any form of organic nitrate is contraindicated.

Tadalafil was shown to potentiate the hypotensive effect of nitrates.

History of known serious hypersensitivity reaction to tadalafil or ADCIRCA ® .

Administration with guanylate cyclase (GC) stimulators, such as riociguat. 4.1 Nitrates Administration of tadalafil tablets 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. 4.2 Hypersensitivity Reactions Tadalafil tablets are contraindicated in patients with a known serious hypersensitivity to tadalafil (tadalafil tablets or ADCIRCA ® ).

Hypersensitivity reactions have been reported, including Stevens-Johnson syndrome and exfoliative dermatitis. 4.3 Concomitant Guanylate Cyclase (GC) Stimulators Do not use tadalafil tablets in patients who are using a GC stimulator, such as riociguat.

PDE5 inhibitors, including tadalafil may potentiate the hypotensive effects of GC stimulators.

Do not split tadalafil tablets; entire dose should be taken.

Tadalafil tablets for use as needed

ED: Starting dose: 10 mg as needed prior to sexual activity.

Increase to 20 mg or decrease to 5 mg based upon efficacy/tolerability.

Improves erectile function compared to placebo up to 36 hours post dose.

Not to be taken more than once per day.

Tadalafil tablets for once daily use

ED: 2.5 mg taken once daily, without regard to timing of sexual activity.

May increase to 5 mg based upon efficacy and tolerability.

BPH: 5 mg, taken at approximately the same time every day ED and BPH: 5 mg, taken at approximately the same time every day Tadalafil tablets may be taken without regard to food. 2.1 Tadalafil Tablets for Use as Needed for Erectile Dysfunction The recommended starting dose of tadalafil tablets for use as needed in most patients is 10 mg, taken prior to anticipated sexual activity.

The dose may be increased to 20 mg or decreased to 5 mg, based on individual efficacy and tolerability.

The maximum recommended dosing frequency is once per day in most patients.

Tadalafil tablets for use as needed were shown to improve erectile function compared to placebo up to 36 hours following dosing.

Therefore, when advising patients on optimal use of tadalafil tablets, this should be taken into consideration. 2.2 Tadalafil Tablets for Once Daily Use for Erectile Dysfunction The recommended starting dose of tadalafil tablets for once daily use is 2.5 mg, taken at approximately the same time every day, without regard to timing of sexual activity.

The tadalafil tablets dose for once daily use may be increased to 5 mg, based on individual efficacy and tolerability. 2.3 Tadalafil Tablets for Once Daily Use for Benign Prostatic Hyperplasia The recommended dose of tadalafil tablets for once daily use is 5 mg, taken at approximately the same time every day. When therapy for BPH is initiated with tadalafil and finasteride, the recommended dose of tadalafil tablets for once daily use is 5 mg, taken at approximately the same time every day for up to 26 weeks. 2.4 Tadalafil Tablets for Once Daily Use for Erectile Dysfunction and Benign Prostatic Hyperplasia The recommended dose of tadalafil tablets for once daily use is 5 mg, taken at approximately the same time every day, without regard to timing of sexual activity. 2.5 Use with Food Tadalafil tablets may be taken without regard to food. 2.6 Use in Specific Populations Renal Impairment Tadalafil Tablets for Use as Needed Creatinine clearance to 50 mL/min: A starting dose of 5 mg not more than once per day is recommended, and the maximum dose is 10 mg not more than once in every 48 hours.

Creatinine clearance less than 30 mL/min or on hemodialysis: The maximum dose is 5 mg not more than once in every 72 hours.

Tadalafil Tablets for Once Daily Use Erectile Dysfunction Creatinine clearance less than 30 mL/min or on hemodialysis: Tadalafil tablets for once daily use is not recommended.

Dysfunction/Benign Prostatic Hyperplasia Creatinine clearance to 50 mL/min: A starting dose of 2.5 mg is recommended.

An increase to 5 mg may be considered based on individual response.

Creatinine clearance less than 30 mL/min or on hemodialysis: Tadalafil tablets for once daily use is not recommended.

Hepatic Impairment Tadalafil tablets for Use as Needed Mild or moderate (Child Pugh Class A or B): The dose should not exceed 10 mg once per day. The use of tadalafil tablets once per day has not been extensively evaluated in patients with hepatic impairment and therefore, caution is advised.

Severe (Child Pugh Class C): The use of tadalafil tablets is not recommended.

Tadalafil tablets for Once Daily Use

Mild or moderate (Child Pugh Class A or B): Tadalafil tablets for once daily use has not been extensively evaluated in patients with hepatic impairment.

Therefore, caution is advised if tadalafil tablets for once daily use is prescribed to these patients.

Severe (Child Pugh Class C): The use of tadalafil tablet is not recommended. 2.7 Concomitant Medications Nitrates Concomitant use of nitrates in any form is contraindicated.

ED —When tadalafil tablets are co-administered with an alpha-blocker in patients being treated for ED, patients should be stable on alpha-blocker therapy prior to initiating treatment, and tadalafil tablets should be initiated at the lowest recommended dose.

BPH — Tadalafil tablets are not recommended for use in combination with alpha-blockers for the treatment of BPH.

CYP3A4 Inhibitors Tadalafil tablets for Use as Needed — For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the maximum recommended dose of tadalafil tablets is 10 mg, not to exceed once every 72 hours.

Tadalafil tablets for Once Daily

Use — For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the maximum recommended dose is 2.5 mg.

50090-7315 NDC: 50090-7315-0 90 TABLET, FILM COATED in a BOTTLE.

Tadalafil tablets are not indicated for use in females.

There are no data with the use of tadalafil tablets in pregnant women to inform any drug-associated risks for adverse developmental outcomes.

In animal reproduction studies, no adverse developmental effects were observed with oral administration of tadalafil to pregnant rats or mice during organogenesis at exposures up to 11 times the maximum recommended human dose (MRHD) of 20 mg/day.

Animal reproduction studies showed no evidence of teratogenicity, embryotoxicity, or fetotoxicity when tadalafil was given orally to pregnant rats or mice at exposures up to 11 times the maximum recommended human dose (MRHD) of 20 mg/day during organogenesis.

In a prenatal/postnatal developmental study 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 another 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 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.

Tadalafil tablets are not indicated for use in pediatric patients.

Safety and efficacy in patients below the age of 18 years have not been established.

A randomized, double-blind, placebo-controlled trial in pediatric patients (7 to 14 years of age) with Duchenne muscular dystrophy, who received tadalafil 0.3 mg/kg, tadalafil 0.6 mg/kg, or placebo daily for 48 weeks failed to demonstrate any benefit of treatment with tadalafil on a range of assessments of muscle strength and performance.

No adverse effects were observed in a study in which tadalafil was administered orally at doses of 60, 200, and 1000 mg/kg/day to juvenile rats on postnatal days to 90.

The highest plasma tadalafil exposures (AUC) achieved were approximately 10-fold that observed at the MRHD.

Of the total number of subjects in ED clinical studies of tadalafil, approximately 19 percent were and over, while approximately 2 percent were 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 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).

However, in placebo-controlled studies with tadalafil tablets for use as needed for ED, diarrhea was reported more frequently in patients 65 years of age and older who were treated with tadalafil tablets (2.5% of patients) .

No dose adjustment is warranted based on age alone.

However, a greater sensitivity to medications in some older individuals should be considered. .