Sildenafil

12.1 Mechanism of Action 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 Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, >80-fold for PDE1, >700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). Sildenafil is approximately 4,000-fold more selective for PDE5 compared to PDE3. PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina which is involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision [ 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 antiagg

1 INDICATIONS AND USAGE 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)

2 DOSAGE AND ADMINISTRATION 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 ) 2.1 Dosage Information 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. Based on effectiveness and toleration, the dose may be increased to a maximum recommended dose of 100 mg or decreased to 25 mg. 2.2 Use with Food Sildenafil tablets may be taken with or without food. 2.3 Dosage Adjustments in Specific Situations 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) , and Clinical Pharmacology (12.2) ]. 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 25 mg [ see Warnings and Precautions (5.5) , Drug Interactions (7.2) , and Clinical Pharmacology (12.2) ]. 2.4 Dosage Adjustments Due to Drug Interactions Ritonavir The recommended dose for ritonavir-treated patients is 25 mg prior to sexual activity and the recommended maximum dose is 25 mg within a 48 hour period because concomitant administration increased the blood levels of sildenafil by 11-fold [ see Warnings and Precautions (5.6) , Drug Interactions (7.4) , and Clinical Pharmacology (12.3) ]. CYP3A4 Inhibitors Consider a starting dose of 25 mg in patients treated with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, or saquinavir) or erythromycin. Clinical data have shown that co-administration with saquinavir or erythromycin increased plasma levels of sildenafil by about 3 fold [ see Drug Interactions (7.4) and Clinical Pharmacology (12.3) ]. 2.5 Dosage Adjustments in Special Populations Consider a starting dose of 25 mg in patients > 65 years, patients with hepatic impairment (e.g., 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 (8.5 , 8.6, 8.7) and Clinical Pharmacology (12.3) ].

6 ADVERSE REACTIONS 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.fda.gov/medwatch . 6.1 Clinical Trials Experience 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. Sildenafil was administered to over 3700 patients (aged 19-87 years) during pre-marketing clinical trials worldwide. Over 550 patients were treated for longer than one year. In placebo-controlled clinical studies, the discontinuation rate due to adverse reactions for sildenafil (2.5%) was not significantly different from placebo (2.3%). In fixed-dose studies, the incidence of some adverse reactions increased with dose. The type of adverse reactions in flexible-dose studies, which reflect the recommended dosage regimen, was similar to that for fixed- dose studies. At doses above the recommended dose range, adverse reactions were similar to those detailed in Table 1 below but generally were reported more frequently. 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 (n=312) 50 mg (n=511) 100 mg (n=506) Placebo (n=607) Headache 16% 21% 28% 7% Flushing 10% 19% 18% 2% Dyspepsia 3% 9% 17% 2% Abnormal vision† 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% † 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 † 3% 0% Back pain 2% 2% Dizziness 2% 1% Rash 2% 1% † Abnormal 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. The following events occurred in <2% of patients in controlled clinical trials; a causal relationship to sildenafil is uncertain. Reported events include those with a plausible relation to drug use; omitted are minor events and reports too imprecise to be meaningful: Body as a Whole: face edema, photosensitivity reaction, shock, asthenia, pain, chills, accidental fall, abdominal pain, allergic reaction, chest pain, accidental injury. Cardiovascular: angina pectoris, AV block, migraine, syncope, tachycardia, palpitation, hypotension, postural hypotension, myocardial ischemia, cerebral thrombosis, cardiac arrest, heart failure, abnormal electrocardiogram, cardiomyopathy. Digestive: vomiting, glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, dry mouth, liver function tests abnormal, rectal hemorrhage, gingivitis. Hemic and Lymphatic: anemia and leukopenia. Metabolic and Nutritional: thirst, edema, gout, unstable diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemic reaction, hypernatremia. Musculoskeletal: arthritis, arthrosis, myalgia, tendon rupture, tenosynovitis, bone pain, myasthenia, synovitis. Nervous: ataxia, hypertonia, neuralgia, neuropathy, paresthesia, tremor, vertig

7 DRUG INTERACTIONS Sildenafil can potentiate the hypotensive effects of nitrates, alpha blockers, and anti-hypertensives ( 4.1 , 5.5 , 7.1 , 7.2 , 7.3 , 12.2 ) With concomitant use of alpha blockers, initiate sildenafil at 25 mg dose ( 2.3 ) CYP3A4 inhibitors (e.g., ritonavir, ketoconazole, itraconazole, erythromycin): Increase sildenafil exposure ( 2.4 , 7.4 , 12.3 ) Ritonavir: Do not exceed a maximum single dose of 25 mg in a 48 hour period ( 2.4 , 5.6 ) Erythromycin or strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, saquinavir): Consider a starting dose of 25 mg ( 2.4 , 7.4 ) 7.1 Nitrates 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) ]. 7.2 Alpha-blockers 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) ]. 7.3 Amlodipine 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 (5.5) , Clinical Pharmacology (12.2) ]. 7.4 Ritonavir and other CYP3A4 inhibitors 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) ]. Co-administration of erythromycin, a moderate CYP3A4 inhibitor, resulted in a 160% and 182% increases in sildenafil C max and AUC, respectively. Co-administration of saquinavir, a strong CYP3A4 inhibitor, resulted in 140% and 210% increases in sildenafil C max and AUC, respectively. Stronger CYP3A4 inhibitors such as ketoconazole or itraconazole could be expected to have greater effects than seen with saquinavir. A starting dose of 25 mg of sildenafil should be considered in patients taking erythromycin or strong CYP3A4 inhibitors (such as saquinavir, ketoconazole, itraconazole) [ see Dosage and Administration (2.4) , Clinical Pharmacology (12.3) ]. 7.5 Alcohol 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 (12.2) ].