Sildenafil (Page 2 of 7)

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.

In a 12-week, placebo-controlled clinical study and an open-label extension study (SUPER-1) in 277 sildenafil -treated adults with PAH (WHO Group I) [see Clinical Studies ( 14)] the adverse reactions that were reported by at least 10% of sildenafil -treated patients in any dosing group, 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. The overall frequency of discontinuation in sildenafil-treated patients was 3% (20 mg and 40 mg three times a day) and 8% (80 mg three times a day). The overall frequency of discontinuation for placebo was 3%.

Table 1. Most Common Adverse Reactions in Patients Treated with Sildenafil 20 mg, 40 mg, 80 mg and Placebo three times per day in SUPER-1 (More Frequent in Sildenafil -Treated Patients than Placebo-Treated Patients)

	Sildenafil 20 mg (n = 69)	Sildenafil 40 mg (n = 67)	Sildenafil 80 mg (n = 71)	Placebo (n = 70)
Headache	46%	42%	49%	39%
Flushing	10%	9%	16%	4%
Pain in Limb	7%	15%	9%	6%
Myalgia	7%	6%	14%	4%
Back Pain	13%	13%	9%	11%
Dyspepsia	13%	8%	13%	7%
Diarrhea	9%	12%	10%	6%

In a placebo-controlled fixed dose titration study (PACES-1) 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, no new safety issues were identified except for edema, which occurred in 25% of subjects in the combined sildenafil+ epoprostenol group compared with 13% of subjects in the epoprostenol group [see Clinical Studies ( 14)].

In a study to assess the effects of multiple doses of sildenafil on mortality in adults with PAH (StudyA1481324), the lower dose 5 mg TID group showed a higher observed number of deaths (all related to underlying disease/disease under study), serious adverse events, and severe adverse events than the 20 mg and 80 mg TID groups [see Clinical Studies ( 14)]. Overall, the safety data for sildenafil 80 mg TID dose in Study A1481324 was consistent with the established safety profile of sildenafil in previous adult PAH studies.

Pediatric Patients

Sildenafil was studied in a total of 234 PAH pediatric patients 1 to 17 years of age in a 16-week, double-blind placebo-controlled study (STARTS-1); 220 patients continued in a long- term extension study (STARTS-2). Erection increased was observed in 9% of patients treated with sildenafil in STARTS-1. No other new adverse reactions were identified in pediatric patients [see Use in Specific Populations ( 8.4)].

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 ( 5.4), Patient Counseling Information ( 17)].

7 DRUG INTERACTIONS

Nitrates

Concomitant use of sildenafil with nitrates in any form is contraindicated [see Contraindications ( 4)].

Strong CYP3A Inhibitors

Concomitant use of sildenafil with strong CYP3A inhibitors is not recommended [see Clinical Pharmacology ( 12.3)].

Moderate-to-Strong CYP3A Inducers

Concomitant use of sildenafil with moderate-to-strong CYP3A inducers (such as bosentan) decreases the sildenafil exposure. Dose up-titration of sildenafil may be needed when initiating treatment with moderate-to-strong CYP3A inducers. Reduce the dose of sildenafil to 20 mg three times a day when discontinuing treatment with moderate-to-strong CYP3A inducers [see Clinical Pharmacology ( 12.3) and Clinical Studies ( 14)].