Sildenafil (Revatio^®)

Treatments for Pulmonary Hypertension

Issued by PHA’s Scientific Leadership Council. Information is based on the United States Food and Drug Administration drug labeling.
Last Updated February 2012

Read about Sildenafil for Pediatric Use

What is sildenafil?

Sildenafil is a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of pulmonary arterial hypertension (PAH) in World Health Organization (WHO) Group 1 patients in order to improve exercise ability and delay clinical worsening.  Studies establishing effectiveness included predominantly patients with WHO Functional Class II-III symptoms and etiologies of idiopathic PAH (71%) or PAH associated with connective tissue diseases (25%).

Sildenafil is marketed as Revatio^® for PAH and was approved by the United States Food and Drug Administration (FDA) in 2005.  Sildenafil is also marketed as Viagra® which is FDA approved for the treatment of erectile dysfunction but not for the treatment of PAH.

How does sildenafil work?

Phosphodiesterase 5 (PDE-5) is a substance produced in the lungs and other parts of the body that breaks down (metabolizes) another substance called cyclic guanosine monophosphate (GMP). Cyclic GMP causes the blood vessels (arteries) to relax, that is, to widen. Sildenafil inhibits PDE-5, so that more cyclic GMP is available for the blood vessels inside the lungs to relax, leading to widening of the blood vessels. Relaxing and widening of the blood vessels in the lungs makes it easier for the heart to pump blood through the lungs. This reduces blood pressure in the lungs which should lead to improvement in physical activity level and well being.

A multi-center short-term (12 week) randomized study of adult PAH patients demonstrated that sildenafil improved exercise capacity, sense of well being and mean pulmonary artery pressure. Long-term follow-up data involving the patients enrolled in that study demonstrated sustained improvement in exercise ability over one year for those patients who remained on sildenafil either alone or with the addition of other PAH specific medications.  Nonetheless, long-term follow-up data involving the patients enrolled in that study must be interpreted cautiously.

A second short-term randomized study compared PAH patients stabilized on intravenous epoprostenol who either received sildenafil or placebo (sugar pill).  The patients on both sildenafil and intravenous epoprostenol demonstrated increased exercise capacity, improved mean pulmonary artery pressure and delay in clinical worsening.

How is sildenafil given?

The recommended dose for sildenafil as Revatio^® in the pill form for treatment of PAH is 20 mg (one pill) taken orally three times a day, approximately 4 to 6 hours apart, with or without food. The FDA-approved dose is 20 mg three times a day; although patients have received up to 80 mg three times a day in clinical trials.

Sildenafil as Revatio^® in the injection form would generally only be used in the hospital setting and is administered as 10 mg (12.5 mL) three times daily.

How is sildenafil supplied?

Revatio^® is available as a round, white 20 mg pill only, to distinguish it from Viagra^®, which is a blue diamond-shaped pill.

Revatio^® injection is supplied as a single use vial containing 10 mg (12.5 mL) of sildenafil.

How can a patient obtain sildenafil?

Sildenafil must be prescribed by a physician and insurance approval must be obtained prior to starting therapy. It is carried by most retail and specialty pharmacies including Accredo Health Inc., Aetna Specialty Pharmacy, CVS Caremark, Cigna Tel-Drug, CuraScript, Kaiser Permanente Specialty Pharmacy, Precision Rx, Walgreens Specialty Pharmacy (Medmark), and WellCare.

Will insurance pay for sildenafil?

It is expected that most insurance plans will pay for sildenafil prescriptions; however, plans with a set co-payment may result in additional cost to the patient.

Medicaid and most state-run insurance plans will pay for sildenafil. Medicare will also cover sildenafil in most cases under the part D component of that program.

Pfizer RSVP Program (888-327-7787) offers a variety of options to cover the cost of the co-payment for any patient with qualifying financial circumstances. Caring Voice Coalition (888-267-1440), an organization that provides grants to assist with drug cost for patients with chronic illnesses, may also provide coverage if the patient qualifies for such assistance.

What are the frequent side effects of sildenafil?

Sildenafil is generally well tolerated.

The most common side effects of sildenafil are nose bleeds, headache, upset stomach and heartburn, flushing, difficulty sleeping, skin reddening, worsening shortness of breath, and nasal inflammation and congestion.

Other side effects include fluid retention, nausea and diarrhea, pain in the extremity (arm or leg), temporary muscle aches, fever, and numbness.

Additional potential side effects that deserve specific mention are noted below.

A reduction in systemic blood pressure may occur as sildenafil opens up blood vessels (arteries) throughout the body. Careful consideration should be used for patients with resting systemic hypotension (low blood pressure, for example less than 90/50 mmHg), fluid depletion, severe left ventricular outflow obstruction or autonomic dysfunction. Taking certain drugs such as nitrates, nitric oxide donors or alpha blockers along with sildenafil can cause a significant drop in blood pressure, which could result in loss of consciousness or even death. You should make certain that you are not taking these medications before starting sildenafil. Use of sildenafil with organic nitrates is CONTRAINDICATED.

Prolonged erection (greater than 4 hours) in a male patient is a rare but very serious side effect; if this should happen to you, you should contact your doctor immediately.

Sudden loss of vision in one or both eyes has occurred in patients on PDE5 inhibitors. Such an event may represent serious dysfunction of the optic nerve and requires immediate medical attention.

Sudden loss of hearing may occur and may be accompanied by dizziness and/or ear ringing. Patients should seek prompt medical attention should this occur.

In patients with PAH associated with connective tissue disease (for example, scleroderma), nose bleeding may occur.

If you experience any of the symptoms mentioned in the previous section, you should promptly notify your physician.

How are side effects of sildenafil monitored?

No regular bloodwork for side effects is required.

Your doctor may ask you to monitor your blood pressure on a regular basis particularly during your first few days on treatment or with a dose increase.

Attention to the symptoms mentioned in the previous section with prompt notification of your physician should you experience any such symptoms.

What are considerations for use of sildenafil in special populations?

Sildenafil does not exhibit harm to the fetus in animal studies; however, it has not been studied in pregnant or nursing women. As there are no adequate and well controlled human studies, sildenafil should be used in pregnancy only if clearly needed and caution should be exercised in nursing women.

The safety and effectiveness of sildenafil in pediatric PAH patients has not been established.

Mild to moderate hepatic (liver) impairment does not require a dose adjustment. Severe liver disease has not been studied.

No dose adjustment is required in renal (kidney) disease.

Sildenafil may be associated with vaso-occlusive crisis in patients with PH and sickle cell disease. The effectiveness of sildenafil in PH secondary to sickle cell anemia has not been established.

Sildenafil is not recommended in patients with pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis.

Could a patient be allergic to sildenafil?

This is possible, although unlikely. Any medication can cause side effects or sensitivities and you should check with your doctor if you experience a problem such as a rash or throat tightening.

What are important drug interactions with sildenafil? (Please see package insert for full details)

Sildenafil should not be used in combination with nitrates or nitric oxide donors as an unsafe drop in systemic blood pressure may occur.

Caution should be used with alpha blockers and amlodipine, a calcium channel blocker, because of additive systemic blood pressure-lowering effects.

Concomitant use of bosentan and sildenafil may result in increased bosentan blood levels and decreased sildenafil blood levels. It is not known if these changes are clinically significant.

Use of sildenafil with epoprostenol may reduce the blood level of sildenafil.

Ritonavir and other CYP3A inhibitors (e.g., cimetidine, erythromycin, saquinavir) may significantly increase sildenafil blood levels.

Use of sildenafil with beta blockers (another type of heart of blood pressue medicine) may increase the levels of sildenafil).

Can sildenafil be taken with other medications?

As stated earlier, you should not be taking nitrates or nitric oxide donors in any form while taking sildenafil. Caution should also be used when taking sildenafil in combination with drugs known as alpha-blockers. These drugs can lower blood pressure to dangerous levels when used together with sildenafil. Studies are currently underway investigating the use of sildenafil in combination with the other PAH therapies. Although a drug interaction has been demonstrated with sildenafil and bosentan, dose adjustments are presently not recommended for either drug.

Miscellaneous considerations:
 

Is there any risk of blindness when using sildenafil?

There have been rare reports of blindness with use of all the currently available phosphodiesterase-5 inhibitors, including sildenafil. This type of blindness, which may be permanent, is called non-arteritic anterior ischemic optic neuropathy (NAION). It is not yet clear whether this is related to the use of sildenafil, or to the underlying cardiovascular diseases that place the persons at risk for this particular type of blindness, even in the absence of sildenafil use.

There is no research to determine whether use of sildenafil is beneficial or safe in patients with retinitis pigmentosa.

As noted above, patients taking sildenafil should seek immediate medical attention in the event of sudden vision loss.

Can men and women take sildenafil?

Yes, studies have evaluated sildenafil in both men and women with PAH and no differences in side effects have been reported between genders. Peer-reviewed studies have not shown any effect on sexual function in women who have taken sildenafil.

Use of sildenafil in pregnant and nursing women:

Sildenafil has not been studied in pregnant or nursing women, and therefore is not recommended for use in pregnant or nursing women. Appropriate contraceptives should be used for prevention of pregnancy while taking sildenafil.

Use of sildenafil in children:

The safety and effectiveness of sildenafil in pediatric PAH patients has not been established. Studies are currently ongoing.

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