SILDENAFIL_- sildenafil_tablet, film coated

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 in the corpus cavernosum and allowing inflow of blood. Sildenafil enhances the effect of NO by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil at recommended doses has no effect in the absence of sexual stimulation. Binding Characteristics in vitro [see Clinical Pharmacology ( 12. 2 In addition to human corpus cavernosum smooth muscle, PDE5 is also found in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle, brain, heart, liver, kidney, lung, pancreas, prostate, bladder, testis, and seminal vesicle. The inhibition of PDE5 in some of these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of NO observed in vitro in vivo in vivo Effects of Sildenafil on Erectile Response: Effects of Sildenafil on Blood Pressure: [see Contraindications ( 4. 1 Figure 1: Mean Change from Baseline in Sitting Systolic Blood Pressure, Healthy Volunteers. Effects of Sildenafil on Blood Pressure When Nitroglycerin is Subsequently Administered: [see Contraindications ( 4. 1 Effects of Sildenafil on Blood Pressure When Co-administered with Alpha-Blockers: Study 1: Sildenafil with Doxazosin Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) Sildenafil tablets 25 mg Supine 7. 7) Standing 6. 8) The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 25 mg sildenafil tablets or matching placebo are shown in Figure 2. Blood pressure was measured immediately pre-dose and at 15, 30, 45 minutes, and 1, 1. 5, 3, 4, 6 and 8 hours after sildenafil or matching placebo. Outliers were defined as subjects with a standing systolic blood pressure of 30 mmHg at one or more timepoints. There were no subjects treated with sildenafil tablets 25 mg who had a standing SBP 30mmHg following sildenafil tablets 25 mg, one subject with a decrease from baseline in standing systolic BP > 30 mmHg following placebo and two subjects with a decrease from baseline in standing systolic BP > 30 mmHg following both sildenafil and placebo. No severe adverse events potentially related to blood pressure effects were reported in this group. Study 2: Sildenafil with Doxazosin In the second study, a single oral dose of sildenafil tablets 50 mg or matching placebo was administered in a 2-period crossover design to 20 generally healthy males with BPH. Following at least 14 consecutive days of doxazosin, sildenafil tablets 50 mg or matching placebo was administered simultaneously with doxazosin 4 mg (17 subjects) or with doxazosin 8 mg (3 subjects). The mean subject age in this study was 63. Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) Sildenafil Tablets 50 mg (95% CI) Supine 9. 68) Standing 11. 90) The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 50 mg sildenafil or matching placebo are shown in Figure 3. Blood pressure was measured after administration of sildenafil tablets at the same times as those specified for the first doxazosin study. There were two subjects who had a standing SBP of 30mmHg following sildenafil tablets 50 mg and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both sildenafil tablets 50 mg and placebo. There were no severe adverse events potentially related to blood pressure and no episodes of syncope reported in this study. Study 3: Sildenafil with Doxazosin In the third study, a single oral dose of sildenafil tablets 100 mg or matching placebo was administered in a 3-period crossover design to 20 generally healthy males with BPH. In dose period 1, subjects were administered open label doxazosin and a single dose of sildenafil tablets 50 mg simultaneously, after at least 14 consecutive days of doxazosin. If a subject did not successfully complete this first dosing period, he was discontinued from the study. Subjects who had successfully completed the previous doxazosin interaction study (using sildenafil tablets 50 mg), including no significant hemodynamic adverse events, were allowed to skip dose period 1. Treatment with doxazosin continued for at least 7 days after dose period 1. Thereafter, sildenafil tablets 100 mg or matching placebo was administered simultaneously with doxazosin 4 mg (14 subjects) or doxazosin 8 mg (6 subjects) in standard crossover fashion. The mean subject age in this study was 66. Twenty-five subjects were screened. Two were discontinued after study period 1: one failed to meet pre-dose screening qualifications and the other experienced symptomatic hypotension as a moderately severe adverse event 30 minutes after dosing with open-label sildenafil tablets 50 mg. Of the twenty subjects who were ultimately assigned to treatment, a total of 13 subjects successfully completed dose period 1, and seven had successfully completed the previous doxazosin study (using sildenafil tablets 50 mg). For the 20 subjects who received sildenafil tablets 100 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows: Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) Sildenafil tablets 100 mg Supine 7. 1) Standing 4. 3) The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 100 mg sildenafil tablets or matching placebo are shown in Figure 4. Blood pressure was measured after administration of sildenafil at the same times as those specified for the previous doxazosin studies. There were three subjects who had a standing SBP of 30 mmHg following sildenafil tablets 100 mg, one subject with a decrease from baseline in standing systolic BP > 30 mmHg following placebo and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both sildenafil and placebo. While there were no severe adverse events potentially related to blood pressure reported in this study, one subject reported moderate vasodilatation after both sildenafil tablets 50 mg and 100 mg. There were no episodes of syncope reported in this study. Effect of Sildenafil on Blood Pressure When Co-administered with Anti-hypertensives: Effect of Sildenafil on Blood Pressure When Co-administered with Alcohol: [see Drug Interactions ( 7. 5 Effects of Sildenafil on Cardiac Parameters: Table 3. Hemodynamic Data in Patients with Stable Ischemic Heart Disease after Intravenous Administration of 40 mg of Sildenafil Means +/- SD At rest After 4 minutes of exercise N Baseline n Sildenafil n Baseline n Sildenafil PAOP (mmHg) 8 8. 3 Mean PAP (mmHg) 8 16. 7 +/- 4 8 12. 2 Mean RAP (mmHg) 7 5. 7 - - - - Systolic SAP (mmHg) 8 150. 0 Diastolic SAP (mmHg) 8 73. 9 +/- 10 8 84. 4 Cardiac output (L/min) 8 5. 5 Heart rate (bpm) 8 67 +/- 11. 9 +/- 12 8 101. 4 In a double-blind study, 144 patients with erectile dysfunction and chronic stable angina limited by exercise, not receiving chronic oral nitrates, were randomized to a single dose of placebo or sildenafil tablets 100 mg 1 hour prior to exercise testing. The primary endpoint was time to limiting angina in the evaluable cohort. The mean times (adjusted for baseline) to onset of limiting angina were 423. 7 seconds for sildenafil (N=70) and placebo, respectively. These results demonstrated that the effect of sildenafil on the primary endpoint was statistically non-inferior to placebo. Effects of Sildenafil on Vision: Effects of Sildenafil on Sperm: fig-1 fig-2 fig-3 fig-4 Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 25- 63%). The pharmacokinetics of sildenafil are dose-proportional over the recommended dose range. It is eliminated predominantly by hepatic metabolism (mainly CYP3A4) and is converted to an active metabolite with properties similar to the parent, sildenafil. Both sildenafil and the metabolite have terminal half lives of about 4 hours. Mean sildenafil plasma concentrations measured after the administration of a single oral dose of 100 mg to healthy male volunteers is depicted below: Absorption and Distribution: max max ss Metabolism and Excretion: in vitro Pharmacokinetics in Special Populations Geriatrics: [see Dosage and Administration ( 2. 5 Renal Impairment: max [see Dosage and Administration ( 2. 6 max Hepatic Impairment: max [see Dosage and Administration ( 2. 7 [see Dosage and Administration ( 2. 5 Drug Interaction Studies Effects of Other Drugs on sildenafil Sildenafil metabolism is principally mediated by CYP3A4 (major route) and CYP2C9 (minor route). [see Dosage and Administration ( 2. 4 In vivo studies: Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with sildenafil (50 mg) to healthy volunteers. max max [see Dosage and Administration ( 2. 4 max [see Dosage and Administration ( 2. 4 max Effects of Sildenafil on Other Drugs In vitro studies: In vivo studies: In a study of healthy male volunteers, sildenafil (100 mg) did not affect the steady state pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, both of which are CYP3A4 substrates. Sildenafil tablets (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg). Sildenafil at steady state, at a dose not approved for the treatment of erectile dysfunction (80 mg t. ) resulted in a 50% increase in AUC and a 42% increase in C max fig-5.

Sildenafil tablets are indicated for the treatment of erectile dysfunction. Sildenafil tablets are phosphodiesterase-5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction (ED) ( 1.

For most patients, the recommended dose is 50 mg taken, as needed, approximately 1 hour before sexual activity. However, sildenafil tablets may be taken anywhere from 30 minutes to 4 hours before sexual activity ( 2. 1 Based on effectiveness and toleration, may increase to a maximum of 100 mg or decrease to 25 mg ( 2. 1 Maximum recommended dosing frequency is once per day ( 2. 1 For most patients, the recommended dose is 50 mg taken, as needed, approximately 1 hour before sexual activity. However, sildenafil tablets may be taken anywhere from 30 minutes to 4 hours before sexual activity. Sildenafil tablets may be taken with or without food. Sildenafil tablets were shown to potentiate the hypotensive effects of nitrates and its administration in patients who use nitric oxide donors such as organic nitrates or organic nitrites in any form is therefore contraindicated [see Contraindications ( 4. 2 [see Warnings and Precautions ( 5. 2 Ritonavir [see Warnings and Precautions ( 5. 3 CYP3A4 Inhibitors [see Drug Interactions ( 7. 3 Consider a starting dose of 25 mg in patients > 65 years, patients with hepatic impairment (e. , cirrhosis), and patients with severe renal impairment (creatinine clearance <30 mL/minute) because administration of sildenafil tablets [see Use in Specific Populations ( 8.

The following are discussed in more detail in other sections of the labeling: Cardiovascular [see Warnings and Precautions ( 5. 1 Prolonged Erection and Priapism [see Warnings and Precautions ( 5. 2 Effects on the Eye [see Warnings and Precautions ( 5. 3 Hearing Loss [see Warnings and Precautions ( 5. 4 Hypotension when Co-administered with Alpha-blockers or Anti-hypertensives [see Warnings and Precautions ( 5. 5 Adverse Reactions with the Concomitant Use of Ritonavir [see Warnings and Precautions ( 5. 6 Combination with other PDE5 Inhibitors or Other Erectile Dysfunction Therapies [see Warnings and Precautions ( 5. 7 Effects on Bleeding [see Warnings and Precautions ( 5. 8 Counseling Patients About Sexually Transmitted Diseases [see Warnings and Precautions ( 5. 9 The most common adverse reactions reported in clinical trials (> 2%) are headache, flushing, dyspepsia, abnormal vision, nasal congestion, back pain, myalgia, nausea, dizziness, and rash. Most common adverse reactions (> 2%) include headache, flushing, dyspepsia, abnormal vision, nasal congestion, back pain, myalgia, nausea, dizziness and rash ( 6. 1 To report SUSPECTED ADVERSE REACTIONS, contact Macleods PharmaUSA, Inc. , at 1-888-943-3210 or 1-855-926-3384 or FDA at 1-800-FDA-1088 or www. gov/medwatch. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Table 1: Adverse Reactions Reported by >=2% of Patients Treated with Sildenafil and More Frequent than Placebo in Fixed-Dose Phase II/III Studies Adverse Reaction 25 mg 50 mg 100 mg Placebo Headache 16% 21% 28% 7% Flushing 10% 19% 18% 2% Dyspepsia 3% 9% 17% 2% Abnormal visiondagger 1% 2% 11% 1% Nasal congestion 4% 4% 9% 2% Back pain 3% 4% 4% 2% Myalgia 2% 2% 4% 1% Nausea 2% 3% 3% 1% Dizziness 3% 4% 3% 2% Rash 1% 2% 3% 1% daggerAbnormal Vision: Mild to moderate in severity and transient, predominantly color tinge to vision, but also increased sensitivity to light, or blurred vision. Adverse Reactions Reported by >=2% of Patients Treated with Sildenafil and More Frequent than Placebo in Flexible-Dose Phase II/III Studies Adverse Reaction Sildenafil Tablets PLACEBO N=734 N=725 Headache 16% 4% Flushing 10% 1% Dyspepsia 7% 2% Nasal Congestion 4% 2% Abnormal Visiondagger 3% 0% Back pain 2% 2% Dizziness 2% 1% Rash 2% 1% daggerAbnormal Vision: Mild and transient, predominantly color tinge to vision, but also increased sensitivity to light or blurred vision. In these studies, only one patient discontinued due to abnormal vision. Body as a Whole: Cardiovascular: Digestive: Hemic and Lymphatic: Metabolic and Nutritional: Musculoskeletal: Nervous: Respiratory: Skin and Appendages: Special Senses: Urogenital: The following adverse reactions have been identified during post approval use of sildenafil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion either due to their seriousness, reporting frequency, lack of clear alternative causation, or a combination of these factors. [see Warnings and Precautions ( 5. 1 17 Hemic and Lymphatic: Nervous: Respiratory: Special senses: Hearing: [see Warnings and Precautions ( 5. 4 17 Ocular: [see Warnings and Precautions ( 5. 3 17 Urogenital: [see Warnings and Precautions ( 5.

Administration of sildenafil to patients using nitric oxide donors, such as organic nitrates or organic nitrites in any form. Sildenafil was shown to potentiate the hypotensive effect of nitrates ( 4. 2 Known hypersensitivity to sildenafil or any component of tablet ( 4. 2 Administration with guanylate cyclase (GC) stimulators, such as riociguat ( 4. 3 Consistent with its known effects on the nitric oxide/cGMP pathway [see Clinical Pharmacology ( 12. 2 After patients have taken sildenafil, it is unknown when nitrates, if necessary, can be safely administered. Although plasma levels of sildenafil at 24 hours post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely co-administered at this time point [see Dosage and Administration ( 2. 2 Sildenafil is contraindicated in patients with a known hypersensitivity to sildenafil, as contained in sildenafil and REVATIO, or any component of the tablet. Hypersensitivity reactions have been reported, including rash and urticaria [see Adverse Reactions ( 6. 1 Do not use sildenafil in patients who are using a GC stimulator, such as riociguat. PDE5 inhibitors, including sildenafil, may potentiate the hypotensive effects of GC stimulators.

Geriatric use: Consider a starting dose of 25 mg ( 2. 5 Severe renal impairment: Consider a starting dose of 25 mg ( 2. 6 Hepatic impairment: Consider a starting dose of 25 mg ( 2. 7 Risk Summary Sildenafil is not indicated for use in females. 2 (see Data). Data No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits which received up to 200 mg/kg/day during organogenesis. These doses represent, respectively, about 16 and 32 times the MRHD on a mg/m 2 2 Risk Summary Sildenafil is not indicated for use in females. Limited data indicate that sildenafil and its active metabolite are present in human milk. There is no information on the effects on the breastfed child, or the effects on milk production. Sildenafil is not indicated for use in pediatric patients. Safety and effectiveness have not been established in pediatric patients. Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil resulting in approximately 84% and 107% higher plasma AUC values of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy young volunteers (18-45 years) [see Clinical Pharmacology ( 12. 3 [see Clinical Pharmacology ( 12. 3 [see Dosage and Administration ( 2. 5 No dose adjustment is required for mild (CLcr=50-80 mL/min) and moderate (CLcr=30-49 mL/min) renal impairment. In volunteers with severe renal impairment (Clcr<30 mL/min), sildenafil clearance was reduced, resulting in higher plasma exposure of sildenafil (~2 fold), approximately doubling of C max [see Dosage and Administration ( 2. 3 In volunteers with hepatic impairment (Child-Pugh Class A and B), sildenafil clearance was reduced, resulting in higher plasma exposure of sildenafil (47% for C max [see Dosage and Administration ( 2.

Sildenafil can potentiate the hypotensive effects of nitrates, alpha blockers, and anti-hypertensives ( 4. 2 With concomitant use of alpha blockers, initiate sildenafil tablets at 25 mg dose ( 2. 3 CYP3A4 inhibitors (e. , ritonavir, ketoconazole, itraconazole, erythromycin): Increase sildenafil tablets exposure ( 2. 3 Ritonavir: Do not exceed a maximum single dose of 25 mg in a 48 hour period ( 2. 6 Erythromycin or strong CYP3A4 inhibitors (e. , ketoconazole, itraconazole, saquinavir): Consider a starting dose of 25 mg ( 2. 4 Administration of sildenafil with nitric oxide donors such as organic nitrates or organic nitrites in any form is contraindicated. Consistent with its known effects on the nitric oxide/cGMP pathway, sildenafil was shown to potentiate the hypotensive effects of nitrates [see Dosage and Administration ( 2. 2 Use caution when co-administering alpha-blockers with sildenafil because of potential additive blood pressurelowering effects. When sildenafil is co-administered with an alpha-blocker, patients should be stable on alphablocker therapy prior to initiating sildenafil treatment and sildenafil should be initiated at the lowest dose [see Dosage and Administration ( 2. 2 When sildenafil tablets 100 mg was co-administered with amlodipine (5 mg or 10 mg) to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic [see Warnings and Precautions ( 5. 2 Co-administration of ritonavir, a strong CYP3A4 inhibitor, greatly increased the systemic exposure of sildenafil (11-fold increase in AUC). It is therefore recommended not to exceed a maximum single dose of 25 mg of sildenafil in a 48 hour period [see Dosage and Administration ( 2. 3 max max [see Dosage and Administration ( 2. 3 In a drug-drug interaction study sildenafil 50 mg given with alcohol 0. 5 g/kg in which mean maximum blood alcohol levels of 0. 08% was achieved, sildenafil did not potentiate the hypotensive effect of alcohol in healthy volunteers [see Clinical Pharmacology ( 12.

OVERDOSAGE
In studies with healthy volunteers of single doses up to 800 mg, adverse reactions were similar to those seen at lower doses but incidence rates and severities were increased. In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine.
NONCLINICAL TOXICOLOGY
Carcinogenesis Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure (AUCs) for unbound sildenafil and its major metabolite of 20- and 38- times, for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 100 mg. Sildenafil was not carcinogenic when administered to mice for 18-21 months at dosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately 0.4 times the MRHD on a mg/m2 basis in a 50 kg subject. Mutagenesis Sildenafil was negative in in vitro in vitro in vivo Impairment of Fertility There was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days to females and 102 days to males, a dose producing an AUC value of more than 25 times the human male AUC.
CLINICAL STUDIES
In clinical studies, sildenafil was assessed for its effect on the ability of men with erectile dysfunction (ED) to engage in sexual activity and in many cases specifically on the ability to achieve and maintain an erection sufficient for satisfactory sexual activity. Sildenafil was evaluated primarily at doses of 25 mg, 50 mg and 100 mg in 21 randomized, double-blind, placebo-controlled trials of up to 6 months in duration, using a variety of study designs (fixed dose, titration, parallel, crossover). Sildenafil was administered to more than 3,000 patients aged 19 to 87 years, with ED of various etiologies (organic, psychogenic, mixed) with a mean duration of 5 years. Sildenafil demonstrated statistically significant improvement compared to placebo in all 21 studies. The studies that established benefit demonstrated improvements in success rates for sexual intercourse compared with placebo. Efficacy Endpoints in Controlled Clinical Studies Efficacy Results from Controlled Clinical Studies Figure 6. Effect of Sildenafil tablets and Placebo on Maintenance of Erection by Baseline Score. Percentage of Patients Reporting an Improvement in Erections. Across all trials, sildenafil improved the erections of 43% of radical prostatectomy patients compared to 15% on placebo. Efficacy Results in Subpopulations in Controlled Clinical Studies sildenafil-fig-6-part-1. jpg sildenafil-fig-6-part-2.

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