CLINICAL DATA: Oral: In the pivotal placebo-controlled study of Revatio in pulmonary arterial hypertension, a total of 207 patients were randomized to and treated with 20 mg, 40 mg, or 80 mg TID doses of Revatio and 70 patients were randomized to placebo. The duration of treatment was 12 weeks. The overall frequency of discontinuation in sildenafil treated patients at doses of 20 mg, 40 mg and 80 mg TID was 2.9%, 3.0% and 8.5% respectively, compared to 2.9% with placebo. Of the 277 subjects treated in the pivotal study, 259 entered a long-term extension study. Doses up to 80 mg three times a day (4 times the recommended dose of 20 mg three times a day) were administered and after 3 years 87% of 183 patients on study treatment were receiving Revatio 80 mg TID.
In a placebo-controlled study of Revatio as an adjunct to intravenous epoprostenol in pulmonary arterial hypertension, a total of 134 patients were treated with Revatio (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day, as tolerated) and epoprostenol, and 131 patients were treated with placebo and epoprostenol. The duration of treatment was 16 weeks. The overall frequency of discontinuations in sildenafil/epoprostenol treated patients due to adverse events was 5.2% compared to 10.7% in the placebo/epoprostenol treated patients. Newly reported adverse reactions, which occurred more frequently in the sildenafil/epoprostenol group, were ocular hyperaemia, vision blurred, nasal congestion, night sweats, back pain and dry mouth. The known adverse reactions headache, flushing, pain in extremity and oedema were noted in a higher frequency in sildenafil/epoprostenol treated patients compared to placebo/epoprostenol treated patients. Of the subjects who completed the initial study, 242 entered a long-term extension study. Doses up to 80 mg TID were administered and after 3 years 68% of 133 patients on study treatment were receiving Revatio 80 mg three times a day.
The most commonly reported adverse reactions that occurred (≥10%) in the Revatio combined data set compared to placebo were headache, flushing, dyspepsia, diarrhoea, and pain in extremity.
Adverse reactions that were reported in ≥3% of Revatio-treated patients and were more frequent (>1% difference) on Revatio in the pivotal study or in the Revatio combined data set of the two placebo controlled studies in PAH, at doses of 20, 40 or 80 mg three times a day are shown in Table 5. (See Table 5.)
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Solution for Injection: Study A1481262 was a single center, open label study to assess the safety, tolerability and pharmacokinetics of a single intravenous dose of sildenafil (10 mg) administered as a bolus injection to patients with PAH who were stable on oral Revatio 20 mg three times a day.
A total of 10 PAH subjects enrolled and completed the study. The mean postural changes in systolic and diastolic blood pressure over time were small (<10 mmHg) and returned towards baseline beyond 2 hours. No symptoms of hypotension were associated with these changes. The mean changes in heart rate were clinically insignificant. Two subjects experienced a total of 3 adverse reactions (flushing, flatulence and hot flush). There was one serious adverse event in a subject with severe ischemic cardiomyopathy who experienced ventricular fibrillation and death 6 days post study drug; the event was judged to be unrelated to study drug.
Clinical Trials Experience (Pediatric Patients): Revatio has been studied in a total of 234 PAH pediatric subjects 1 through 17 years of age in a 16-week, double-blind placebo-controlled study. Of these subjects, 220 patients continued in a long-term extension study. Long term survival status has been assessed for a minimum of 3 years.
The adverse reactions profile seen in this pediatric study was consistent with that in adults. A total of 174 patients were treated with Revatio in the initial 16-week study and 60 patients received placebo.
The most frequently reported adverse drug reactions in the sildenafil treatment groups, reported with greater frequency than placebo (>2%), are shown in Table 6. (See Table 6.)
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The overall frequency of discontinuation in Revatio-treated patients was 2.3% and was similar to the placebo group.
Of the 234 pediatric subjects treated in the short-term, placebo-controlled study, 220 subjects entered the long-term extension study. Subjects on active sildenafil therapy continued on the same treatment regimen, while those in the placebo group in the short-term study were randomly reassigned to sildenafil treatment; subjects ≤20 kg of body weight entered the medium or high dose groups, while subjects weighing >20 kg entered the low, medium or high dose groups. Of the total 229 subjects who received sildenafil, there were 55, 74, and 100 subjects in the low, medium and high dose groups, respectively. Median duration of sildenafil treatment was 1696 days.
The most common adverse reactions reported across the duration of the short-term and long-term studies were generally similar to those observed in the short-term study. Adverse reactions reported in >10% of 229 subjects treated with sildenafil (combined dose group) were upper respiratory infection (31%), headache (26%), vomiting (22%), bronchitis (20%), pharyngitis (18%), pyrexia (17%), diarrhoea (15%), and influenza, epistaxis (12% each). Most of these adverse reactions were considered mild to moderate in severity.
Serious adverse events were reported in 94 (41%) of the 229 subjects receiving sildenafil. Of the 94 subjects reporting a serious adverse event, 14/55 (25.5%) subjects were in the low dose group, 35/74 (47.3%) in the medium dose group, and 45/100 (45%) in the high dose group. The most common serious adverse events that occurred with a frequency ≥ 1% in sildenafil patients (combined doses) were pneumonia (7.4%), cardiac failure, pulmonary hypertension (each 5.2%), upper respiratory tract infection (3.1%), right ventricular failure, gastroenteritis (each 2.6%), syncope, bronchitis, bronchopneumonia, pulmonary arterial hypertension (each 2.2%), chest pain, dental caries (each 1.7%), and cardiogenic shock, gastroenteritis viral, urinary tract infection (each 1.3%).
The following serious adverse events were considered to be treatment related, enterocolitis, convulsion, hypersensitivity, stridor, hypoxia, neurosensory deafness and ventricular arrhythmia.
During the conduct of the study, there were a total of 42 deaths reported. 37 deaths occurred prior to a decision to down titrate subjects to a lower dosage, based on an observed mortality imbalance with increasing sildenafil doses. Among these 37 deaths, the number (%) of deaths was 5/55 (9.1%), 10/74 (13.5%), and 22/100 (22%) in the sildenafil low, medium, and high dose groups, respectively. An additional 5 deaths (3 in the medium dose group, and 2 in the high dose group) were reported subsequently. The causes of deaths were typical of patients with PAH. Higher than recommended doses should not be used in pediatric patients with PAH (see Dosage & Administration, Precautions and Pharmacology: Pharmacodynamics under Actions).
Post-marketing experience: In the post-marketing experience these additional adverse reactions were reported with Revatio: Reproductive system and breast disorders: priapism, erection increased (frequency not known).