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. Binding Characteristics in vitro [see Clinical Pharmacology (12. in vivo in vivo Effects of Sildenafil Tablets on Erectile Response: Effects of Sildenafil Tablets on Blood Pressure: [see Contraindications (4. Figure 1: Mean Change from Baseline in Sitting Effects of Sildenafil Tablets on Blood Pressure When Nitroglycerin is Subsequently Administered [see Contraindications (4. Effects of Sildenafil Tablets on Blood Pressure When Co-administered with Alpha-Blockers Study 1: Sildenafil tablets with Doxazosin Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) Sildenafil tablets 25 mg Supine 7. 7) Standing 6 (-0. 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. Figure 2: Mean Standing Systolic Blood Pressure Change from Baseline Study 2: Sildenafil tablets with Doxazosin 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 tablets or matching placebo are shown in Figure 3. Figure 3: Mean Standing Systolic Blood Pressure Change from Baseline Study 3: Sildenafil tablets with Doxazosin 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. Figure 4: Mean Standing Systolic Blood Pressure Change from Baseline Effect of Sildenafil Tablets on Blood Pressure When Co-administered with Anti-hypertensives Effect of Sildenafil Tablets on Blood Pressure When Co-administered with Alcohol [see Drug Interactions (7. Effects of Sildenafil Tablets on Cardiac Parameters: Table 3. Hemodynamic Data in Patients with Stable Ischemic Heart Disease after Intravenous Administration of 40 mg of Sildenafil Mean +/- SD At rest After 4 minutes of exercise N Baseline n Sildenafil (D1) n Baseline n Sildenafil PAOP (mmHg) 8 8. 3 8 36 +/- 13. 3 Mean PAP (mmHg) 8 16. 7 +/- 4 8 12. 2 Mean RAP (mmHg) 7 5. 7 - - - - Systolic SAP (mmHg) 8 150. 8 +/- 30 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. 6 8 99 +/- 20. 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 tablets on the primary endpoint was statistically non-inferior to placebo. Effects of Sildenafil Tablets on Vision: Effects of Sildenafil Tablets on Sperm: sildenafilfigure1 sildenafilfigure2 sildenafilfigure3 sildenafilfigure4 Sildenafil tablets are rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 25 to 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. Figure 5: Mean Sildenafil Plasma Concentrations Absorption and Distribution Metabolism and Excretion: Pharmacokinetics in Special Populations Geriatrics: see Dosage and Administration (2. 5)] Renal Impairment: [see Dosage and Administration (2. Hepatic Impairment: [see Dosage and Administration (2. [see Dosage and Administration (2. Drug Interaction Studies Effects of Other Drugs on Sildenafil Tablets [see Dosage and Administration (2. In vivo studies: [see Dosage and Administration (2. Effects of Sildenafil Tablets on Other Drugs In vitro studies: In vivo studies: sildenafilfigure5.

Sildenafil tablets are indicated for the treatment of erectile dysfunction. Sildenafil tablet is a 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) 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. The maximum recommended dosing frequency is once per day. 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. [see Warnings and Precautions (5. Ritonavir [see Warnings and Precautions (5. CYP3A4 Inhibitors (7. 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 in these patients resulted in higher plasma levels of sildenafil [see Use in Specific Populations ( 8. 7) Clinical Pharmacology ( 12.

The following are discussed in more detail in other sections of the labeling: [see Warnings and Precautions (5. 1)] [see Warnings and Precautions (5. 2)] [see Warnings and Precautions (5. 3)] see Warnings and Precautions (5. 4)] [see Warnings and Precautions (5. 5)] [see Warnings and Precautions (5. 6)] [see Warnings and Precautions (5. 7)] [see Warnings and Precautions (5. 8)] [see Warnings and Precautions (5. 9)] 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 Hetero Labs Limited at 866-495-1995 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 with Sildenafil Tablets and More Frequently than Placebo in Fixed-Dose Phase II/III Studies dagger dagger Table 2. Adverse Reactions Reported by >=2% of Patients Treated with Sildenafil Tablets and More Frequent than Placebo in Flexible-Dose Phase II/III Studies dagger dagger 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 tablets. 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. Cardiovascular and cerebrovascular [see Warnings and Precautions (5. Hemic and Lymphatic: Nervous: Respiratory: Special senses: Hearing: [see Warnings and Precautions (5. Ocular: [see Warnings and Precautions (5. Urogenital: [see Warnings and Precautions (5.

Administration of sildenafil tablets to patients using nitric oxide donors, such as organic nitrates or organic nitrites in any form. Sildenafil tablets were shown to potentiate the hypotensive effect of nitrates ( 4. 3) Consistent with its known effects on the nitric oxide/cGMP pathway [see Clinical Pharmacology ( 12. 2)] , [see Dosage and Administration (2. Sildenafil tablets are contraindicated in patients with a known hypersensitivity to sildenafil, as contained in sildenafil tablets and REVATIO, or any component of the tablet. Hypersensitivity reactions have been reported, including rash and urticaria [see Adverse Reactions (6. Do not use sildenafil tablets in patients who are using a GC stimulator, such as riociguat. PDE5 inhibitors, including sildenafil tablets, may potentiate the hypotensive effects of GC stimulators.

Geriatric use: Consider a starting dose of 25 mg (2. 7) Risk Summary Data Risk Summary Sildenafil tablets are 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 to 45 years) [see Clinical Pharmacology (12. [see Clinical Pharmacology (12. [see Dosage and Administration (2. No dose adjustment is required for mild (CLcr=50 to 80 mL/min) and moderate (CLcr=30 to 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 Cmax and AUC. A starting dose of 25 mg should be considered in patients with severe renal impairment [see Dosage and Administration (2. In volunteers with hepatic impairment (Child-Pugh Class A and B), sildenafil clearance was reduced, resulting in higher plasma exposure of sildenafil (47% for Cmax and 85% for AUC). The pharmacokinetics of sildenafil in patients with severely impaired hepatic function (Child-Pugh Class C) have not been studied. A starting dose of 25 mg should be considered in patients with any degree of hepatic impairment [see Dosage and Administration (2.

Sildenafil tablets can potentiate the hypotensive effects of nitrates, alpha blockers, and anti-hypertensives ( 4. 4) Administration of sildenafil tablets 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 tablets were shown to potentiate the hypotensive effects of nitrates [see Dosage and Administration (2. Use caution when co-administering alpha-blockers with sildenafil tablets because of potential additive blood pressure-lowering effects. When sildenafil tablets are co-administered with an alpha-blocker, patients should be stable on alpha-blocker therapy prior to initiating sildenafil tablets treatment and sildenafil tablets should be initiated at the lowest dose [see Dosage and Administration (2. When sildenafil tablets 100 mg were 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. 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 tablets in a 48 hour period [see Dosage and Administration ( 2. [see Dosage and Administration (2. 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.
NONCLINICAL TOXICOLOGY
Carcinogenesis Mutagenesis in vitro in vitro in vivo Impairment of Fertility
CLINICAL STUDIES
In clinical studies, sildenafil tablets 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 tablets were 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 tablets were 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 tablets 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 Effect of Placebo on Maintenance of Erection by Figure 6. Effect of Sildenafil Tablets and Placebo on Overall treatment p<0. 0001 Figure 7. Percentage of Patients Reporting Efficacy Results in Subpopulations in Controlled Clinical Studies sildenafilfigure6a sildenafilfigure6b Sildenafilfigure7.
Patient Information
Patient Information Tell all your healthcare providers that you take sildenafil tablets. What are sildenafil tablets? Who should not take sildenafil tablets? What should I tell my healthcare provider before taking sildenafil tablets? Tell your healthcare provider about all the medicines you take*, (see ''What is the most important information I should know about sildenafil tablets?'') How should I take sildenafil tablets? What are the possible side effects of sildenafil tablets? an erection that will not go away (priapism) sudden vision loss in one or both eyes sudden hearing decrease or hearing loss The most common side effects of sildenafil tablets are: How should I store sildenafil tablets? Keep sildenafil tablets and all medicines out of the reach of children. What are the ingredients in sildenafil tablets? Active ingredient: Inactive ingredients: Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

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