Brief Summary of Prescribing Information . Consult Full Prescribing Information at REVATIOHCP . com
INDICATION AND USAGE
REVATIO is 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 REVATIO was added to background epoprostenol therapy .
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 .
DOSAGE AND ADMINISTRATION
REVATIO Tablets and Oral Suspension The recommended dose of REVATIO is 5 mg or 20 mg three times a day . Administer REVATIO doses 4 – 6 hours apart . In the clinical trial no greater efficacy was achieved with the use of higher doses . Treatment with doses higher than 20 mg three times a day is not recommended .
Reconstitution of the Powder for Oral Suspension 1 . Tap the bottle to release the powder . 2 . Remove the cap . 3 . Accurately measure out 60 mL of water and pour the water into the bottle . 4 . Replace the cap and shake the bottle vigorously for a minimum of 30 seconds . 5 . Remove the cap . 6 . Accurately measure out another 30 mL of water and add this to the bottle . You should always add a total of 90 mL of water irrespective of the dose prescribed . 7 . Replace the cap and shake the bottle vigorously for a minimum of 30 seconds . 8 . Remove the cap . 9 . Press the bottle adaptor into the neck of the bottle . The adaptor is provided so that you can fill the oral syringe with medicine from the bottle . Replace the cap on the bottle . 10 . Write the expiration date of the constituted oral suspension on the bottle label ( the expiration date of the constituted oral suspension is 60 days from the date of constitution ).
Incompatibilities Do not mix with any other medication or additional flavoring agent .
CONTRAINDICATIONS
REVATIO is contraindicated in patients with concomitant use of organic nitrates in any form , either regularly or intermittently , because of the greater risk of hypotension [ see Warnings and Precautions ], Concomitant use of riociguat , a guanylate cyclase stimulator . PDE5 inhibitors , including sildenafil , may potentiate the hypotensive effects of riociguat . REVATIO is also contraindicated in patients with known hypersensitivity to sildenafil or any component of the tablet , injection , or oral suspension . Hypersensitivity , including anaphylactic reaction , anaphylactic shock and anaphylactoid reaction , has been reported in association with the use of sildenafil .
WARNINGS AND PRECAUTIONS
Mortality with Pediatric Use In a long-term trial in pediatric patients with PAH , an increase in mortality with increasing REVATIO dose was observed . Deaths were first observed after about 1 year and causes of death were typical of patients with PAH . Use of REVATIO , particularly chronic use , is not recommended in children [ see Use in Specific Populations ].
Hypotension REVATIO has vasodilatory properties , resulting in mild and transient decreases in blood pressure . Before prescribing REVATIO , carefully consider whether patients with certain underlying conditions could be adversely affected by such vasodilatory effects ( e . g ., patients on antihypertensive therapy or with resting hypotension [ BP less than 90 / 50 ], fluid depletion , severe left ventricular outflow obstruction , or automatic dysfunction ). Monitor blood pressure when coadministering blood pressure lowering drugs with REVATIO .
Worsening Pulmonary Vascular Occlusive Disease Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease ( PVOD ). Since there are no clinical data on administration of REVATIO to patients with veno-occlusive disease , administration of REVATIO to such patients is not recommended . Should signs of pulmonary edema occur when REVATIO is administered , consider the possibility of associated PVOD .
Epistaxis The incidence of epistaxis was 13 % in patients taking REVATIO with PAH secondary to CTD . This effect was not seen in idiopathic PAH ( REVATIO 3 %, placebo 2 %) patients . The incidence of epistaxis was also higher in REVATIO-treated patients with a concomitant oral vitamin K antagonist ( 9 % versus 2 % in those not treated with concomitant vitamin K antagonist ). The safety of REVATIO is unknown in patients with bleeding disorders or active peptic ulceration .
Visual Loss When used to treat erectile dysfunction , non-arteritic anterior ischemic optic neuropathy ( NAION ), a cause of decreased vision including permanent loss of vision , has been reported postmarketing in temporal association with the use of phosphodiesterase type 5 ( PDE-5 ) inhibitors , including sildenafil . Most , but not all , of these patients had underlying anatomic or vascular risk factors for developing NAION , including but not necessarily limited to : low cup to disc ratio (“ crowded disc ”), age over 50 , diabetes , hypertension , coronary artery disease , hyperlipidemia and smoking . Based on published literature , the annual incidence of NAION is 2.5 – 11.8 cases per 100,000 males aged ≥ 50 per year in the general population . An observational study evaluated whether recent , episodic use of PDE5 inhibitors ( as a class ), typical of erectile dysfunction treatment , was associated with acute onset of NAION . The results suggest an approximately 2-fold increase in the risk of NAION within 5 half-lives of PDE5 inhibitor use . It is not possible to determine whether these events are related directly to the use of PDE-5 inhibitors , to the patient ’ s underlying vascular risk factors or anatomical defects , to a combination of these factors , or to other factors . Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking PDE-5 inhibitors , including REVATIO . Physicians should also discuss the increased risk of NAION with patients who have already experienced NAION in one eye , including whether such individuals could be adversely affected by use of vasodilators , such as PDE-5 inhibitors .
There are no controlled clinical data on the safety or efficacy of REVATIO in patients with retinitis pigmentosa , a minority whom have genetic disorders of retinal phosphodiesterases . Prescribe REVATIO with caution in these patients .
Hearing Loss Cases of sudden decrease or loss of hearing , which may be accompanied by tinnitus and dizziness , have been reported in temporal association with the use of PDE-5 inhibitors , including REVATIO . In some of the cases , medical conditions and other factors were reported that may have played a role . In many cases , medical follow-up information was limited . It is not possible to determine whether these reported events are related directly to the use of REVATIO , to the patient ’ s underlying risk factors for hearing loss , a combination of these factors , or to other factors . Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking PDE-5 inhibitors , including REVATIO .
Combination with Other PDE-5 Inhibitors Sildenafil is also marketed as VIAGRA ® . The safety and efficacy of combinations of REVATIO with VIAGRA or other PDE-5 inhibitors have not been studied . Inform patients taking REVATIO not to take VIAGRA or other PDE-5 inhibitors .
Priapism Use REVATIO with caution in patients with anatomical deformation of the penis ( e . g ., angulation , cavernosal fibrosis , or Peyronie ’ s disease ) or in patients who have conditions , which may predispose them to priapism ( e . g ., sickle cell anemia , multiple myeloma , or leukemia ). In the event of an erection that persists longer than 4 hours , the patient should seek immediate medical assistance . If priapism ( painful erection greater than 6 hours in duration ) is not treated immediately , penile tissue damage and permanent loss of potency could result .
Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle Cell Anemia In a small , prematurely terminated study of patients with pulmonary hypertension ( PH ) secondary to sickle cell disease , vaso-occlusive crises requiring hospitalization were more commonly reported by patients who received REVATIO than by those randomized to placebo . The effectiveness and safety of REVATIO in the treatment of PAH secondary to sickle cell anemia has not been established .
ADVERSE REACTIONS
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 REVATIO in adults were obtained from the 12-week , placebo-controlled clinical study ( Study 1 ) and an open-label extension study in 277 REVATIO-treated patients with PAH , WHO Group I .
The overall frequency of discontinuation in REVATIO-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 REVATIO-treated patients ( 20 mg three times a day ) and were more frequent in REVATIO-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 REVATIO-Treated Patients than Placebo-Treated Patients and Incidence ≥3 % in REVATIO- Treated Patients )
Placebo , % ( n = 70 )
REVATIO 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 REVATIO 20 mg three times a day was 1.4 % versus 0 % placebo and for all REVATIO 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 REVATIO versus 1.4 % for placebo . The patients experiencing these reactions had risk factors for hemorrhage including concurrent anticoagulant therapy .
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 .
DRUG INTERACTIONS
Nitrates Concomitant use of REVATIO with nitrates in any form is contraindicated [ see Contraindications ].
Ritonavir and other Potent CYP3A Inhibitors Concomitant use of REVATIO with ritonavir and other potent CYP3A inhibitors is not recommended .