Drug Class Description
Drugs used in erectile dysfunction

Generic Name
Sildenafil (as Citrate)

Drug Description
Each film-coated tablet contains 20 mg of sildenafil (as citrate). Revatio tablets also contain lactose.

Presentation
Film-coated tablet.White, round, biconvex film-coated tablets marked “PFIZER” on one side and “RVT 20”on the other.

Indications
Treatment of patients with pulmonary arterial hypertension classified as WHO functional class III, to improve exercise capacity. Efficacy has been shown in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease.

Adult Dosage
Revatio is intended for oral use.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.Use in adults ( 18 years):The recommended dose is 20 mg three times a day. Tablets should be taken approximately 6 to 8 hours apart with or without food.Use in the elderly ( 65 years):Dosage adjustments are not required in elderly patients. Clinical efficacy as measured by 6-minute walk distance could be less in elderly patients.Use in patients with impaired renal function: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.Use in patients with impaired hepatic function: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.Revatio is contraindicated in patients with severe hepatic impairment (Child-Pugh class C).Use in children and adolescents (< 18 years):The safety and efficacy in children and adolescents have not been studied in large controlled clinical trials. Therefore, the use of sildenafil is not recommended in these patients.Discontinuation of treatment:Limited data suggests 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.Use in patients using other medicines:Co-administration of sildenafil and intravenous epoprostenol has been eva luated.The efficacy and safety of sildenafil co-administered with other treatments for pulmonary arterial hypertension (eg. bosentan, iloprost) has not been studied in controlled clinical trials. Therefore caution is recommended in case of co-administration.The safety and efficacy of Revatio when co-administered with other PDE5 inhibitors has not been studied in pulmonary arterial hypertension patients.

Child Dosage
The safety and efficacy in children and adolescents have not been studied in large controlled clinical trials. Therefore, the use of sildenafil is not recommended in these patients.

Elderly Dosage
Dosage adjustments are not required in elderly patients. Clinical efficacy as measured by 6-minute walk distance could be less in elderly patients.

Contra Indications
Hypersensitivity to the active substance or to any of the excipients.Consistent with its known effects on the nitric oxide/cyclic guanosine monophosphate (cGMP) pathway, sildenafil was shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxide donors (such as amyl nitrite) or nitrates in any form is therefore contraindicated.Combination with potent CYP3A4 inhibitors (eg. ketoconazole, itraconazole, ritonavir).Revatio is contraindicated in patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure.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.

Special Precautions
The efficacy of Revatio has not been established in patients with severe pulmonary arterial hypertension (functional class IV). If the clinical situation deteriorates, therapies that are recommended at the severe stage of the disease (e.g. epoprostenol) should be considered.The benefit-risk balance of sildenafil has not been established in patients with class I functional classification of pulmonary arterial hypertension. No studies have been performed in related forms of pulmonary arterial hypertension other than related to connective tissue disease and surgical repair.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.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 medium potency CYP3A4 inhibitors like erythromycin or saquinavir. A downward dose adjustment to 20 mg once daily is recommended in case of co-administration with CYP3A4 inhibitors of intermediate potency like clarithromycin, telithromycin and nefazodone. Co-administration of potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir) with sildenafil for pulmonary arterial hypertension is contraindicated (see section 4.3). Dose adjustments of sildenafil may be required when co-administered with CYP3A4 inducers.When prescribing sildenafil, physicians should carefully consider whether patients with certain underlying conditions could be adversely affected by sildenafil's mild to moderate vasodilatory effects, for example patients with hypotension, patients with fluid depletion, severe left ventricular outflow obstruction or autonomic dysfunction.Sildenafil potentiates the hypotensive effect of nitrates therefore concomitant use of Revatio with nitrates is contraindicated.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.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).Visual defects and cases of non-arteritic anterior ischaemic optic neuropathy have been reported in connection with the intake of sildenafil and other PDE5 inhibitors. The patient should be advised that in case of sudden visual defect, he should stop taking Revatio and consult a physician immediately.Caution is advised when sildenafil is administered to patients taking an alpha-blocker as the co-administration may lead to symptomatic hypotension in susceptible individuals. In order to minimize the potential for developing postural hypotension, patients should be hemodynamically stable on alpha-blocker therapy prior to initiating sildenafil treatment. Physicians should advise patients what to do in the event of postural hypotensive symptoms.Studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside in vitro. There is no safety information on the administration of sildenafil to patients with bleeding disorders or active peptic ulceration. Therefore sildenafil should be administered to these patients only after careful benefit-risk assessment.In pulmonary arterial hypertension patients, there may be a potential for increased risk of bleeding when sildenafil is initiated in patients already using a Vitamin K antagonist, particularly in patients with pulmonary arterial hypertension secondary to connective tissue disease.No data are available with sildenafil in patients with pulmonary hypertension associated with pulmonary veno-occlusive disease. However, cases of life threatening pulmonary oedema have been reported with vasodilators (mainly prostacyclin) when used in those patients. Consequently, should signs of pulmonary oedema occur when sildenafil is administered in patients with pulmonary hypertension, the possibility of associated veno-occlusive disease should be considered.Lactose monohydrate is present in the tablet film coat. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Interactions
Effects of other medicinal products on sildenafilIn vitro studies:Sildenafil metabolism is principally mediated by the cytochrome P450 (CYP) isoforms 3A4 (major route) and 2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance.In vivo studies:Population pharmacokinetic analysis of pulmonary arterial hypertension clinical trial data indicated a reduction in sildenafil clearance and/or an increase of oral bioavailability when co-administered with CYP3A4 substrates and the combination of CYP3A4 substrates and beta-blockers. These were the only factors with a statistically significant impact on sildenafil pharmacokinetics in patients with pulmonary arterial hypertension. The exposure to sildenafil in patients on CYP3A4 substrates and CYP3A4 substrates plus beta-blockers was 43 % and 66 % higher, respectively, compared to patients not receiving these classes of medicines. Sildenafil exposure was 5-fold higher at a dose of 80 mg three times a day compared to the exposure at a dose of 20 mg three times a day. This concentration range covers the increase in sildenafil exposure observed in specifically designed drug interaction studies with CYP3A4 inhibitors (except more potent CYP3A4 inhibitors e.g. ketoconazole, itraconazole, ritonavir).CYP3A4 inducers seemed to have a substantial impact on the pharmacokinetics of sildenafil in pulmonary arterial hypertension patients, which was confirmed in the in-vivo interaction study with CYP3A4 inducer bosentan.Co-administration of bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of CYP2C19) 125mg twice daily with sildenafil 80 mg three times a day (at steady state) concomitantly administered during 6 days in healthy volunteers resulted in a 63% decrease of sildenafil AUC. Caution is recommended in case of co-administration.Efficacy of sildenafil should be closely monitored in patients using concomitant potent CYP3A4 inducers, such as carbamazepine, phenytoin, phenobarbital, St John's Wort and rifamipicine.Co-administration of the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg twice daily) with sildenafil (100 mg single dose) resulted in a 300 % (4-fold) increase in sildenafil Cmax and a 1,000 % (11-fold) increase in sildenafil plasma AUC. At 24 hours, the plasma levels of sildenafil were still approximately 200 ng/ml, compared to approximately 5 ng/ml when sildenafil was administered alone. This is consistent with ritonavir's marked effects on a broad range of P450 substrates. Based on these pharmacokinetic results co-administration of sildenafil with ritonavir is contraindicated in pulmonary arterial hypertension patients.Co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady state (1200 mg three times a day) with sildenafil (100 mg single dose) resulted in a 140 % increase in sildenafil Cmax and a 210 % increase in sildenafil AUC. Sildenafil had no effect on saquinavir pharmacokinetics.When a single 100 mg dose of sildenafil was administered with erythromycin, a specific CYP3A4 inhibitor, at steady state (500 mg twice daily for 5 days), there was a 182 % increase in sildenafil systemic exposure (AUC). In normal healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC, Cmax, Tmax, elimination rate constant, or subsequent half-life of sildenafil or its principal circulating metabolite. Cimetidine (800 mg), a cytochrome P450 inhibitor and non-specific CYP3A4 inhibitor, caused a 56 % increase in plasma sildenafil concentrations when co-administered with sildenafil (50 mg) to healthy volunteers.Potent CYP3A4 inhibitors such as ketoconazole and itraconazole would be expected to have effects similar to ritonavir. CYP3A4 inhibitors of intermediate potency (e.g. clarithromycin, telithromycin and nefazodone) are expected to have an effect in between that of ritonavir and CYP3A4 inhibitors of medium potency (e.g. saquinavir/erythromycin), a seven-fold increase in exposure is assumed. Therefore dose adjustments are recommended when using CYP3A4 inhibitors of intermediate potency.The population pharmacokinetic analysis in pulmonary arterial hypertension patients suggested that co-administration of beta-blockers in combination with CYP3A4 substrates might result in an additional increase in sildenafil exposure compared with administration of CYP3A4 substrates alone.Grapefruit juice is a weak inhibitor of CYP3A4 gut wall metabolism and may give rise to modest increases in plasma levels of sildenafil.Single doses of antacid (magnesium hydroxide/aluminium hydroxide) did not affect the bioavailability of sildenafil.Co-administration of oral contraceptives (ethinyloestradiol 30 μg and levonorgestrel 150 μg) did not affect the pharmacokinetics of sildenafil.Nicorandil is a hybrid of potassium channel activator and nitrate. Due to the nitrate component it has the potential to have serious interaction with sildenafil.Effects of sildenafil on other medicinal productsIn vitro studies:Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 μM).There are no data on the interaction of sildenafil and non-specific phosphodiesterase inhibitors such as theophylline or dipyridamole.In vivo studies:No significant interactions were shown when sildenafil (50 mg) was co-administered with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolised by CYP2C9.Sildenafil had no significant effect on atorvastatin exposure (AUC increased 11%), suggesting that sildenafil does not have a clinically relevant effect on CYP3A4.No interactions were observed between sildenafil (100 mg single dose) and acenocoumarol.Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by acetyl salicylic acid (150 mg).Sildenafil (50 mg) did not potentiate the hypotensive effects of alcohol in healthy volunteers with mean maximum blood alcohol levels of 80 mg/dl.In a study of healthy volunteers sildenafil at steady state (80 mg three times a day) resulted in a 50% increase in bosentan AUC (125 mg twice daily). Caution is recommended in case of co-administration.In a specific interaction study, where sildenafil (100 mg) was co-administered with amlodipine in hypertensive patients, there was an additional reduction on supine systolic blood pressure of 8 mmHg. The corresponding additional reduction in supine diastolic blood pressure was 7 mmHg. These additional blood pressure reductions were of a similar magnitude to those seen when sildenafil was administered alone to healthy volunteers.In three specific drug-drug interaction studies, the alpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, or 100 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, and mean additional reductions of standing blood pressure of 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively were observed. When sildenafil and doxazosin were administered simultaneously to patients stabilized on doxazosin therapy, there were infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and lightheadedness, but not syncope. Concomitant administration of sildenafil to patients taking alpha-blocker therapy may lead to symptomatic hypotension in susceptible individuals.Sildenafil (100 mg single dose) did not affect the steady state pharmacokinetics of the HIV protease inhibitor saquinavir, which is a CYP3A4 substrate/inhibitor.Consistent with its known effects on the nitric oxide/cGMP pathway (see section 5.1), sildenafil was shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxide donors or nitrates in any form is therefore contraindicated.Sildenafil had no clinically significant impact on the plasma levels of oral contraceptives (ethinyloestradiol 30 μg and levonorgestrel 150 μg).

Adverse Reactions
In the pivotal placebo-controlled study of Revatio in pulmonary arterial hypertension, a total of 207 patients were treated with Revatio at daily doses ranging from 20 mg to 80 mg three times a day and 70 patients were treated with placebo. The duration of treatment was 12 weeks. 259 subjects who completed the pivotal study 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 studied (N=149 patients treated for at least 1 year, 101 on 80 mg three times a day). The overall frequency of discontinuation in sildenafil treated patients at the recommended daily dose of 20 mg three times a day (2.9 %) was low and the same as placebo (2.9 %).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) 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 drug reactions, which occurred more frequently in the sildenafil/ epoprostenol group, were bloodshot eyes/red eyes, blurred vision, nasal congestion, night sweats, back pain and dry mouth. The known adverse events headache, flushing, pain in extremity and oedema were noted in a higher frequency in sildenafil/epoprostenol treated patients compared to placebo/epoprostenol treated patients.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 limb pain.Adverse reactions which occurred in >1 % of Revatio-treated patients and were more frequent (>1 % difference) on Revatio in the study or in the Revatio combined data set of both placebo-controlled studies in pulmonary arterial hypertension at doses of 20, 40 or 80 mg three times a day, listed in the table below by class and frequency grouping (very common (1/10), common (1/100, <1/10), uncommon (1/1000, <1/100) and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.Reports from post-marketing experience are in italics.MedDRA System Organ ClassAdverse Drug ReactionInfections and infestationsCommonCellulitus, influenza, sinusitis not otherwise specified (NOS)Blood and the lymphatic system disordersCommonAnaemia NOSMetabolism and nutrition disordersCommonFluid retentionPsychiatric disordersCommonInsomnia, anxietyNervous system disordersVery CommonHeadacheCommonMigraine NOS, tremor, paresthesia, burning sensation NOS, hypoaesthesiaEye disordersCommonRetinal haemorrhage, visual disturbance NOS, blurred vision, photophobia, chromatopsia, cyanopsia, eye irritation, blood shot eyes/red eyesUncommonVisual acuity reduced, diplopia, abnormal sensation in eyeEar and labyrinth disordersCommonVertigoNot knownSudden deafness*Vascular disordersVery CommonFlushingRespiratory, thoracic and mediastinal disordersCommonBronchitis NOS, epistaxis, rhinitis NOS, cough, nasal congestionGastrointestinal disordersVery CommonDiarrhoea, dyspepsiaCommonGastritis NOS, gastroenteritis NOS, gastrooesophageal reflux disease, haemorrhoids, abdominal distension, dry mouthSkin and subcutaneous tissue disordersCommonAlopecia, erythema, night sweatsNot knownSkin rashMusculoskeletal, connective tissue and bone disordersVery CommonLimb painCommonMyalgia, back painReproductive system and breast disordersUncommonGynaecomastiaNot knownPriapism, prolonged erectionGeneral disorders and administration site conditionsCommonPyrexia• Sudden decrease or loss of hearing has been reported in a small number of post-marketing and clinical trial cases with the use of all PDE5 inhibitors, including sildenafil.In post marketing surveillance, adverse events/reactions that have been reported with an unknown frequency in the treatment of male erectile dysfunction (MED) include: Eye disorders: Non-arteritic anterior ischaemic optic neuropathy (NAION), retinal vascular occlusion and visual field defect.

Manufacturer
Pfizer

Drug Availability
(POM)

Updated
12 August 2009