Potential Side Effects and Management

Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, greater

Supplemental material

Overall, the safety data for sildenafil 80 mg TID dose in Study A1481324 was consistent with the established safety profile of sildenafil in previous adult PAH studies. Sildenafil was studied in a total of 234 PAH pediatric patients 1 to 17 years of age in a 16-week, double-blind placebo-controlled study (STARTS-1); 220 patients continued in a long-term extension study (STARTS-2). Erection increased was observed in 9% of patients treated with sildenafil in STARTS-1. No other new adverse reactions were identified in pediatric patients [see Use in Specific Populations (8.4)]. Adverse events with sildenafil injection were similar to those seen with oral tablets.

8.5 Geriatric Use

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. 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.

Interactions that increase your risk for side effects

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. NAION [see Warnings and Precautions (5.4), Patient Counseling Information (17)]. Concomitant use of sildenafil with nitrates in any form is contraindicated [see Contraindications (4)]. Concomitant use of sildenafil with strong CYP3A inhibitors is not recommended [see Clinical Pharmacology (12.3)]. than 80-fold for PDE1, greater than 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11).

• Common side effects include headache, flushing, and dizziness.
• Allergic reactions are rare but require immediate medical attention.
• Effects usually last for 4 to 6 hours.

The approximately 4,000-fold selectivity for PDE-5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility.

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Sildenafil is only about 10 times as potent for PDE5 compared to PDE6, an enzyme found in the retina and involved in the phototransduction pathway of the retina.

Condition	Recommended Range	Notes
Temperature	2°C to 25°C	Keep away from freezing or excessive heat
Light exposure	Store in opaque container	Protect from light
Humidity	Dry environment	Avoid moisture to prevent degradation
Shelf life	24 months	Check expiry date before use

This lower selectivity is thought to be the basis for abnormalities related to

What special precautions should I follow?

Concomitant use of sildenafil with moderate-to-strong CYP3A inducers (such as bosentan) decreases the sildenafil exposure. Dose up-titration of sildenafil may be needed when initiating treatment with moderate-to-strong CYP3A inducers. Reduce the dose of sildenafil to 20 mg three times a day when discontinuing treatment with moderate-to-strong CYP3A inducers [see Clinical Pharmacology (12.3) and Clinical Studies (14)]. Limited published data from randomized controlled trials, case-controlled trials, and case series do not report a clear association with sildenafil and major birth defects, miscarriage, or adverse maternal or fetal outcomes when sildenafil is used during pregnancy. There are risks to the mother and fetus from untreated pulmonary arterial hypertension (see Clinical Considerations).

5.2 Worsening Pulmonary Vascular Occlusive Disease

Animal reproduction studies conducted with sildenafil showed no evidence of embryo-fetal toxicity or teratogenicity at doses up to 32- and 65-times the recommended human dose (RHD) of 20 mg three times a day in rats and rabbits, respectively (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

8.1 Pregnancy

Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m2 basis, 32- and 65-times, respectively, the recommended human dose (RHD) of 20 mg three times a day. In a rat pre- and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m2 basis). Limited published data from a case report describe the presence of sildenafil and its active metabolite in human milk. There is insufficient information about the effects of sildenafil on the breastfed infant and no information on the effects of sildenafil on milk production. color vision observed with higher doses or plasma levels [see Clinical Pharmacology (12.2)].

• It is not recommended for use in children or women.
• Overdose symptoms include dizziness, vision changes, and prolonged erections.
• Seek urgent medical help in case of overdose.

In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE5 is

What’s the typical Revatio dosage for adults?

In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine. Sildenafil is also marketed as VIAGRA® for erectile dysfunction. Sildenafil for oral suspension is supplied as white to off-white granular powder containing 1.57 g of sildenafil citrate USP (equivalent to 1.12 g sildenafil) in an amber PET bottle intended for reconstitution. Following reconstitution with 90 mL water, the volume of the oral suspension is 112 mL and the oral suspension contains 10 mg/mL sildenafil. also found in other tissues including vascular and visceral smooth muscle and in platelets.

• Sildenafil oral solution is prescribed by a healthcare provider.
• It should be taken on an empty stomach for faster effects.
• The liquid form provides flexibility in dosing.

The inhibition of PDE5 in these tissues by sildenafil may be the basis for the enhanced

Drug Class	Potential Effect	Clinical Note
Nitrates	Severe hypotension	Absolute contraindication
Alpha-blockers	Increased risk of hypotension	Use with caution
CYP3A4 inhibitors (e.g., ketoconazole)	Increased sildenafil levels	Dose adjustment needed
Other vasodilators	Enhanced vasodilatory effects	Monitor blood pressure

platelet anti-aggregatory activity of nitric oxide observed in vitro, and the mild peripheral arterial-venous dilatation in vivo.

Aspect	Oral Solution	Tablets
Onset of action	Faster due to quicker absorption	Slightly slower
Ease of dose adjustment	Easy to modify dose in small increments	Fixed doses
Swallowing difficulties	Easier for children and elderly	Requires swallowing whole
Taste masking	Usually palatable with flavors	No taste masking needed
Storage and stability	Sensitive to temperature and light	Generally more stable

Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared

• Patients should avoid heavy meals before taking sildenafil solution.
• Use caution if combining with other blood pressure medications.
• Regular medical check-ups are advised during treatment.

to those on placebo in a study with no background vasodilators [see SUPER-1 in Clinical Studies (14)].

Plain Language Summary

Limited clinical data during lactation preclude a clear determination of the risk of sildenafil to an infant during lactation. The safety and efficacy of sildenafil have been established in pediatric patients 1 to 17 years old, for the treatment of PAH (WHO Group I) to improve exercise ability and, in patients too young to perform standard exercising testing, pulmonary hemodynamics thought to underlie improvements in exercise. Use of sildenafil for this indication is supported by evidence from adequate and well-controlled studies in adults with additional PK and safety data in pediatric patients aged 1 year and older [see Adverse Reactions (6.1), Clinical Studies (14)]. The safety and effectiveness of sildenafil have not been established in pediatric patients younger than 1 year of age. During the conduct of the pediatric sildenafil citrate 100 mg studies (STARTS-1 and STARTS-2) [see Clinical Studies (14)], an imbalance in the number of deaths was noted: 5/55 (9.1%), 10/74 (13.5%), and 22/100 (22%) in the sildenafil low, medium, and high dose groups, respectively.

Drug Interactions

The causes of death were related to the progression of PAH. This safety observation in pediatrics was not confirmed in a study conducted in adults designed to evaluate this risk (Study A1481324). Given the beneficial effects on clinical worsening and death observed in adults with increasing doses (Study A1481324) and the expected similarity of disease in pediatrics and adults, a causal association for the observed dose-related effect on mortality in pediatric patients is unlikely, and therefore, the available data support dosing in pediatric patients > 45 kg up to a maximum of 40 mg three times a day. Clinical studies of sildenafil did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

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In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)]. No dose adjustment for mild to moderate impairment is required. Severe impairment has not been studied [see Clinical Pharmacology (12.3)]. No dose adjustment is required (including severe impairment CLcr < 30 mL/min) [see Clinical Pharmacology (12.3)]. In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but rates and severities were increased. Data on other hemodynamic measures for the sildenafil 20 mg three times a day and placebo dosing regimens is displayed in Table 2. The relationship between these effects and improvements in 6-minute walk distance is unknown.

What Are Warnings and Precautions for Sildenafil?

In addition to the bottle, a press-in bottle adapter and an oral dosing syringe (with 1 mL and 2 mL dose markings) are provided. Sildenafil is an inhibitor of cGMP specific PDE-5 in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with PAH, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation. Studies in vitro have shown that sildenafil is selective for PDE5.