SILDENAFIL CITRATE- sildenafil citrate_tablet

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. 2) in vitro in vivo in vivo. Effects of sildenafil on Erectile Response: registered registered Effects of sildenafil on Blood Pressure: see Contraindications (4. 1) 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 sildenafil citrate 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 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 25 mg who had a standing SBP 30mmHg following sildenafil 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. Placebo-subtracted mean maximum decrease sildenafil citrate 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 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 50 mg and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both sildenafil 50 mg and placebo. There were no severe adverse events potentially related to blood pressure and no episodes of syncope reported in this study. Placebo-subtracted mean maximum decrease sildenafil citrate 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 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 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 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 (B2) n Sildenafil (D1) 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 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: sildenafil-citrate-figure-1 sildenafil-citrate-figure-2 sildenafil-citrate-figure-3 sildenafil-citrate-figure-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. Absorption and Distribution: max max Metabolism and Excretion: in vitro Pharmacokinetics in Special Populations Geriatrics: see Dosage and Administration (2. 5) Use in Specific Populations (8. 5) Renal Impairment: max see Dosage and Administration (2. 6) max Hepatic Impairment: max see Dosage and Administration (2. 5) and Use in Specific Populations (8. 7) see Dosage and Administration (2. 5) Drug Interaction Studies Effects of Other Drugs on sildenafil see Dosage and Administration (2. 4) In vivo max max see Dosage and Administration (2. 4) Drug Interactions (7. 4) max see Dosage and Administration (2. 4) max Effects of sildenafil on Other Drugs In vitro In vivo max sildenafil-citrate-figure-5.

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

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. The maximum recommended dosing frequency is once per day. Sildenafil tablets may be taken with or without food. Sildenafil tablets was 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. 1) Drug Interactions (7. 1) Clinical Pharmacology (12. 2) see Warnings and Precautions (5. 5) Drug Interactions (7. 2) Clinical Pharmacology (12. 2) Ritonavir see Warnings and Precautions (5. 6) Drug Interactions (7. 4) Clinical Pharmacology (12. 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 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: 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 Nivagen Pharmaceuticals, Inc. at 1-877-977-0687 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% dagger Abnormal Vision: Mild to moderate in severity and transient, predominantly color tinge to vision, but also increased sensitivity to light, or blurred vision. When sildenafil was taken as recommended (on an as-needed basis) in flexible-dose, placebo-controlled clinical trials of two to twenty-six weeks duration, patients took sildenafil at least once weekly, and the following adverse reactions were reported: Table 2. 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 CITRATE PLACEBO N=734 N=725 Headache 16% 4% Flushing 10% 1% Dyspepsia 7% 2% Nasal Congestion 4% 2% Abnormal Vision dagger 3% 0% Back pain 2% 2% Dizziness 2% 1% Rash 2% 1% 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. Cardiovascular and cerebrovascular see Warnings and Precautions (5. 1) Patient Counseling Information (17) ]. Hemic and Lymphatic: Nervous: Respiratory: Special senses: Hearing: see Warnings and Precautions (5. 4) Patient Counseling Information (17) Ocular: see Warnings and Precautions (5. 3) Patient Counseling Information (17) Urogenital: see Warnings and Precautions (5. 2) and Patient Counseling Information (17).

Administration of sildenafil tablets to patients using nitric oxide donors, such as organic nitrates or organic nitrites in any form. Sildenafil tablets 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 see Dosage and Administration (2. 3) Drug Interactions (7. 1) Clinical Pharmacology (12. 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. 1) Do not use sildenafil tablets 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 2 see Data Data Animal Data 2 2 Risk Summary Sildenafil is not indicated for use in females. 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. 5) and Clinical Pharmacology (12. 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. 5) Clinical Pharmacology (12.

Sildenafil can potentiate the hypotensive effects of nitrates, alpha blockers, and anti-hypertensives ( 4. 2 With concomitant use of alpha blockers, initiate sildenafil at 25 mg dose ( 2. 3 CYP3A4 inhibitors (e. , ritonavir, ketoconazole, itraconazole, erythromycin): Increase sildenafil 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. 3) , Contraindications (4. 1) , Clinical Pharmacology (12. 2) Use caution when co-administering alpha-blockers with sildenafil because of potential additive blood pressure-lowering effects. When sildenafil is co-administered with an alpha-blocker, patients should be stable on alpha-blocker therapy prior to initiating sildenafil treatment and sildenafil should be initiated at the lowest dose [ see Dosage and Administration (2. 3) Warnings and Precautions (5. 5) Clinical Pharmacology (12. 2) When sildenafil 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. 4) Warnings and Precautions (5. 6) Clinical Pharmacology (12. 3) max max see Dosage and Administration (2. 4) Clinical Pharmacology (12. 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.
NONCLINICAL TOXICOLOGY
Carcinogenesis 2 Mutagenesis in vitro in vitro in vivo Impairment of Fertility
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 and Placebo on Maintenance of Erection by Baseline Score. Overall treatment p<0. 0001 Figure 7. Percentage of Patients Reporting an Improvement in Erections. Efficacy Results in Subpopulations in Controlled Clinical Studies sildenafil-citrate-figure-6 sildenafil-citrate-figure-7.

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