1 INDICATIONS & USAGE 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 ) ].

Sildenafil is a 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 )

6 ADVERSE REACTIONS 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) ] 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 Macleods Pharma USA, Inc., at 1-888-943-3210 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 practice.

Safety data of sildenafil in adults were obtained from the 12-week, placebo-controlled clinical study (Study 1) and an open-label extension study in 277 sildenafil-treated patients with PAH, WHO Group I [see Clinical Studies (14)] .

The overall frequency of discontinuation in sildenafil-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-treated patients (20 mg three times a day) and were more frequent in sildenafil-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-Treated Patients than Placebo-Treated Patients and Incidence ≥3% in Sildenafil-Treated Patients) Placebo, % (n = 70) Sildenafil tablets 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 20 mg three times a day was 1.4% versus 0% placebo and for all sildenafil 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 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 (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 + 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 + Epoprostenol group at least 6% greater than Epoprostenol group) Sildenafil + Epoprostenol (n = 134) Epoprostenol (n = 131) (Sildenafil + Epoprostenol)minus Epoprostenol % Headache 57 34 23 Edema includes peripheral 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 ) ].