SILDENAFIL CITRATE

Sildenafil Tablets, USP phosphodiesterase-5 (PDE-5) inhibitor, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type-5 (PDE-5). Sildenafil is also marketed as VIAGRA ® for erectile dysfunction. Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H -pyrazolo [4,3- d ] pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate and has the following structural formula: Sildenafil citrate is a white or almost white, slightly hygroscopic crystalline powder. Slightly soluble in water & methanol, practically insoluble in hexane and a molecular weight of 666.7. Sildenafil tablets: Sildenafil tablets is white round, biconvex film coated tablets, debossed with R on one side and 20 on the other, containing sildenafil citrate equivalent to 20 mg of sildenafil. In addition to the active ingredient, sildenafil citrate , each tablet contains the following inactive ingredients: Crospovidone, Hypromellose, Hydrophobic colloidal silica, Lactose monohydrate, Magnesium stearate, Microcrystalline cellulose, Titanium dioxide, and Triacetin. Structure Formula

Sildenafil tablets are phosphodiesterase-5 (PDE-5) inhibitor indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) in adults to improve exercise ability and delay clinical worsening. Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately patients with NYHA Functional Class II-III symptoms. Etiologies were idiopathic (71%) or associated with connective tissue disease (25%). ( 1 ) Limitation of Use : Adding sildenafil to bosentan therapy does not result in any beneficial effect on exercise capacity. ( 1 , 14 ) Sildenafil tablets are indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in adults to improve exercise ability and delay clinical worsening. The delay in clinical worsening was demonstrated when Sildenafil tablets were added to background epoprostenol therapy [see Clinical Studies (14) ]. Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately patients with New York Heart Association (NYHA) Functional Class II-III symptoms and idiopathic etiology (71%) or associated with connective tissue disease (CTD) (25%). Limitation of Use : Adding sildenafil to bosentan therapy does not result in any beneficial effect on exercise capacity [see Clinical Studies (14) ].

Tablets: 20 mg three times a day, 4 to 6 hours apart ( 2.1 ) 2.1 Sildenafil Tablets The recommended dose of sildenafil tablets is 20 mg three times a day. Administer sildenafil tablet doses 4–6 hours apart. In the clinical trial no greater efficacy was achieved with the use of higher doses. Treatment with doses higher than 20 mg three times a day is not recommended.

Use with organic nitrates or riociguat ( 4 ) History of hypersensitivity reaction to sildenafil or any component of the tablet ( 4 ) Sildenafil tablets are contraindicated in patients with: Concomitant use of organic nitrates in any form, either regularly or intermittently, because of the greater risk of hypotension [see Warnings and Precautions (5.2) ]. Concomitant use of riociguat, a guanylate cyclase stimulator. PDE-5 inhibitors, including sildenafil, may potentiate the hypotensive effects of riociguat. Known hypersensitivity to sildenafil or any component of the tablet. Hypersensitivity, including anaphylactic reaction, anaphylactic shock and anaphylactoid reaction, has been reported in association with the use of sildenafil.

Most common adverse reactions greater than or equal to 3% and more frequent than placebo were epistaxis, headache, dyspepsia, flushing, insomnia, erythema, dyspnea, and rhinitis. ( 6.1 , 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact TruPharma LLC at 1-800-541-5504. or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following serious adverse events are discussed elsewhere in the labeling: Mortality with pediatric use [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4) ] Hypotension [see Warnings and Precautions (5.2) ] Vision loss [see Warnings and Precautions (5.5) ] Hearing loss [see Warnings and Precautions (5.6) ] Priapism [see Warnings and Precautions (5.8) ] Vaso-occlusive crisis [see Warnings and Precautions (5.9) ] 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 practice. Safety data of sildenafil tablets in adults were obtained from the 12-week, placebo-controlled clinical study (Study 1) and an open-label extension study in 277 sildenafil tablets-treated patients with PAH, WHO Group I. [see Clinical Studies (14) ]. The overall frequency of discontinuation in sildenafil tablets-treated patients on 20 mg three times a day was 3% and was the same for the placebo group. In Study 1, the adverse reactions that were reported by at least 3% of sildenafil tablets-treated patients (20 mg three times a day) and were more frequent in sildenafil tablets-treated patients than in placebo-treated patients are shown in Table 1. Adverse reactions were generally transient and mild to moderate in nature. Table 1. Most Common Adverse Reactions in Patients with PAH in Study 1 (More Frequent in Sildenafil tablets-Treated Patients than Placebo-Treated Patients and Incidence ≥ 3% in Sildenafil tablets-Treated Patients) Placebo, % (n = 70) Sildenafil 20 mg three times a day, % (n = 69) Placebo-Subtracted, % Epistaxis 1 9 8 Headache 39 46 7 Dyspepsia 7 13 6 Flushing 4 10 6 Insomnia 1 7 6 Erythema 1 6 5 Dyspnea exacerbated 3 7 4 Rhinitis 0 4 4 Diarrhea 6 9 3 Myalgia 4 7 3 Pyrexia 3 6 3 Gastritis 0 3 3 Sinusitis 0 3 3 Paresthesia 0 3 3 At doses higher than the recommended 20 mg three times a day, there was a greater incidence of some adverse reactions including flushing, diarrhea, myalgia and visual disturbances. Visual disturbances were identified as mild and transient, and were predominately color-tinge to vision, but also increased sensitivity to light or blurred vision. The incidence of retinal hemorrhage with sildenafil tablets 20 mg three times a day was 1.4% versus 0% placebo and for all sildenafil tablets doses studied was 1.9% versus 0% placebo. The incidence of eye hemorrhage at both 20 mg three times a day and at all doses studied was 1.4% for sildenafil tablets versus 1.4% for placebo. The patients experiencing these reactions had risk factors for hemorrhage including concurrent anticoagulant therapy. In a placebo-controlled fixed dose titration study (Study 2) of sildenafil tablets (starting with recommended dose of 20 mg and increased to 40 mg and then 80 mg all three times a day) as an adjunct to intravenous epoprostenol in patients with PAH, the adverse reactions that were more frequent in the sildenafil tablets + epoprostenol group than in the epoprostenol group (greater than 6% difference) are shown in Table 2 [see Clinical Studies (14) ]. Table 2. Adverse Reactions (%) in patients with PAH in Study 2(incidence in Sildenafil tablets + Epoprostenol group at least 6% greater than Epoprostenol group) ^includes peripheral edema Sildenafil tablets + Epoprostenol (n = 134) Epoprostenol (n = 131) (Sildenafil tablets + Epoprostenol) minus Epoprostenol Headache 57 34 23 Edema^ 25 13 14 Dyspepsia 16 2 14 Pain in extremity 17 6 11 Diarrhea 25 18 7 Nausea 25 18 7 Nasal congestion 9 2 7 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of sildenafil (marketed for both PAH and erectile dysfunction). 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. Cardiovascular Events In postmarketing experience with sildenafil at doses indicated for erectile dysfunction, serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, pulmonary hemorrhage, and subarachnoid and intracerebral hemorrhages have been reported in temporal association with the use of the drug. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of sildenafil without sexual activity. Others were reported to have occurred hours to days after use concurrent with sexual activity. It is not possible to determine whether these events are related directly to sildenafil, to sexual activity, to the patient's underlying cardiovascular disease, or to a combination of these or other factors. Nervous system Seizure, seizure recurrence Ophthalmologic NAION [see Warnings and Precautions (5.5) and Patient Counseling Information (17) ].

Concomitant alpha-blockers or amlodipine: Note additive blood pressure lowering effects. ( 7 ) Use with ritonavir and other potent CYP3A inhibitors: Not recommended. ( 7 , 12.3 ) Concomitant PDE-5 inhibitors: Avoid use with Viagra or other PDE-5 inhibitors. ( 5.7 ). Nitrates Concomitant use of sildenafil tablets with nitrates in any form is contraindicated [see Contraindications (4) ]. Ritonavir and other Potent CYP3A Inhibitors Concomitant use of sildenafil tablets with ritonavir and other potent CYP3A inhibitors is not recommended [see Clinical Pharmacology (12.3) ]. Other drugs that reduce blood pressure Alpha blockers. In drug-drug interaction studies, sildenafil (25 mg, 50 mg, or 100 mg) and the alpha-blocker doxazosin (4 mg or 8 mg) were administered simultaneously to patients with benign prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In these study populations, mean additional reductions of supine systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg, respectively, were observed. Mean additional reductions of standing blood pressure of 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively, were also observed. There were infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and light-headedness, but not syncope. Amlodipine. When sildenafil 100 mg oral was co-administered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic. Monitor blood pressure when co-administering blood pressure lowering drugs with sildenafil tablets [see Warnings and Precautions (5.2) ].