Revatio

Treatment should only be initiated and monitored by a physician experienced in the treatment of pulmonary arterial hypertension. In case of clinical deterioration in spite of Revatio treatment, alternative therapies should be considered.

Posology Adults The recommended dose is 20 mg three times a day (TID). Physicians should advise patients who forget to take Revatio to take a dose as soon as possible and then continue with the normal dose. Patients should not take a double dose to compensate for the missed dose.

Paediatric population (1 year to 17 years) For paediatric patients aged 1 year to 17 years old, the recommended dose in patients ≤ 20 kg is 10 mg three times a day and for patients > 20 kg is 20 mg three times a day. 1). The 20 mg tablet should not be used in cases where 10 mg TID should be administered in younger patients.

Other pharmaceutical forms are available for administration to patients ≤ 20 kg and other younger patients who are not able to swallow tablets. 3 Patients using other medicinal products In general, any dose adjustment should be administered only after a careful benefit-risk assessment.

A downward dose adjustment to 20 mg twice daily should be considered when sildenafil is co-administered to patients already receiving CYP3A4 inhibitors like erythromycin or saquinavir. A downward dose adjustment to 20 mg once daily is recommended in case of co-administration with more potent CYP3A4 inhibitors clarithromycin, telithromycin and nefazodone.

For the use of sildenafil with the most potent CYP3A4 inhibitors, see section

Summary of the safety profile 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. 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. 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 TID. 10 In the two placebo-controlled studies adverse events were generally mild to moderate in severity.

The most commonly reported adverse reactions that occurred (greater or equal to 10 %) on Revatio compared to placebo were headache, flushing, dyspepsia, diarrhoea and pain in extremity. In a study to assess the effects of different dose levels of sildenafil the safety data for sildenafil 20 mg TID (recommended dose) and for sildenafil 80 mg TID (4 times the recommended dose), were consistent with the established safety profile of sildenafil in previous adult PAH studies.

The efficacy of Revatio has not been established in patients with severe pulmonary arterial hypertension (functional class IV). 2). The benefit-risk balance of sildenafil has not been established in patients assessed to be at WHO functional class I pulmonary arterial hypertension.

1). The use of sildenafil in other forms of PAH is not recommended. In the long term paediatric extension study, an increase in deaths was observed in patients administered doses higher than the recommended dose. 1). Retinitis pigmentosa The safety of sildenafil has not been studied in patients with known hereditary degenerative retinal disorders such as retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases) and therefore its use is not recommended.

4). Cardiovascular risk factors In post-marketing experience with sildenafil for male erectile dysfunction, serious cardiovascular events, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, hypertension and hypotension have been reported in temporal association with the use of sildenafil.

Most, but not all, of these patients had pre- existing cardiovascular risk factors. Many events were reported to occur during or shortly after sexual intercourse and a few were reported to occur shortly after the use of sildenafil without sexual activity.

It is not possible to determine whether these events are related directly to these factors or to other factors. Priapism Sildenafil should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie’s disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anaemia, multiple myeloma or leukaemia).

Prolonged erections and priapism have been reported with sildenafil in post-marketing experience. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. 8). 5 Vaso-occlusive crises in patients with sickle cell anaemia Sildenafil should not be used in patients with pulmonary hypertension secondary to sickle cell anaemia.

3. 5). Special populations Elderly (≥ 65 years) Dose adjustments are not required in elderly patients. Clinical efficacy as measured by 6-minute walk distance could be less in elderly patients. Renal impairment Initial dose adjustments are not required in patients with renal impairment, including severe renal impairment (creatinine clearance < 30 ml/min).

A downward dose adjustment to 20 mg twice daily should be considered after a careful benefit-risk assessment only if therapy is not well-tolerated. Hepatic impairment Initial dose adjustments are not required in patients with hepatic impairment (Child-Pugh class A and B).

A downward dose adjustment to 20 mg twice daily should be considered after a careful benefit-risk assessment only if therapy is not well-tolerated. 3). 1). The safety and efficacy of Revatio in other conditions in children below 1 year of age has not been established.

No data are available. Discontinuation of treatment Limited data suggest that the abrupt discontinuation of Revatio is not associated with rebound worsening of pulmonary arterial hypertension. However to avoid the possible occurrence of sudden clinical deterioration during withdrawal, a gradual dose reduction should be considered.

Intensified monitoring is recommended during the discontinuation period. Method of administration Revatio is for oral use only. Tablets should be taken approximately 6 to 8 hours apart with or without food. 1. 1). 5). 5). 4). The safety of sildenafil has not been studied in the following sub-groups of patients and its use is therefore contraindicated: Severe hepatic impairment, Recent history of stroke or myocardial infarction, Severe hypotension (blood pressure < 90/50 mmHg) at initiation.