Revatio (sildenafil citrate)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Sildenafil, a selective phosphodiesterase (PDE) type 5 inhibitor, is a vasodilating agent.
Sildenafil is a selective inhibitor of phosphodiesterases (PDEs), with the greatest selectivity for PDE type 5. At least 10 isoenzyme families of PDE have been identified, several of which (e.g., PDE types 5 and 6) selectively hydrolyze cyclic guanosine monophosphate (cGMP) relative to cyclic adenosine monophosphate (cAMP). Sildenafil selectively inhibits cGMP-specific PDE type 5, the principal isoenzyme involved in the metabolism of cGMP to GMP in the vascular smooth muscle, smooth muscle of the pulmonary vasculature, and corpora cavernosa of the penis.
By inhibiting PDE type 5, sildenafil causes accumulation of cGMP in various tissues. Sildenafil also exhibits some activity against other PDE isoenzymes.
Sildenafil-induced vasodilation and decreases in blood pressure probably result from inhibition of PDE type 5 present in vascular smooth muscle. Sildenafil doses of 25-100 mg reduce the maximum supine systolic/diastolic blood pressure by an average of about 8.4/5.5 mm Hg within 1-2 hours after administration of the drug in healthy adults, returning to baseline values within 4-8 hours after a dose. In patients with pulmonary hypertension, sildenafil induces vasodilation of the pulmonary vascular bed, and to a lesser degree, vasodilation in the systemic circulation.
In such patients, pulmonary and systemic vascular resistance and resting arterial pressure are decreased, allowing for an increase in the cardiac output. In pediatric patients on medium- and high-dose sildenafil, dose-related improvements in pulmonary vascular resistance index and mean pulmonary arterial pressure compared to those on placebo were achieved; cardiac index improvements occurred in all 3 sildenafil dose groups over placebo.
Sildenafil is rapidly absorbed following oral administration; the mean absolute bioavailability is 41% (25-63%). Although single-dose studies indicate that more than 90% of an oral sildenafil dose is absorbed from the GI tract, the drug undergoes extensive metabolism in the GI mucosa during absorption and on first pass through the liver, with only about 40% of a dose reaching systemic circulation unchanged.
Pharmacokinetics of the drug (as determined by peak plasma concentrations or AUC) are dose proportional over the single-dose range of 1.25-200 mg. Plasma concentrations of the active N-desmethyl metabolite are approximately 40% of those seen for sildenafil, and the metabolite reportedly accounts for about 20% of sildenafil's pharmacologic activity. Peak plasma concentrations of sildenafil and its active N-desmethyl metabolite are achieved within 30-120 (median: 60) minutes following oral administration in fasting adults.
Administration with a high-fat meal delays GI absorption of sildenafil, with a reduction in peak plasma concentrations of about 30% and a delay in time to peak plasma concentrations of about 60 minutes; the extent of absorption is not affected. Bioequivalence has been established between the 20-mg tablet and the 10-mg/mL oral suspension when administered as a single oral dose of 20 mg. Sildenafil appears to be widely distributed in the body.
Limited data indicate that sildenafil and its active metabolite are present in human milk. Sildenafil and its major circulating N-desmethyl metabolite are each approximately 96% bound to plasma proteins. Plasma sildenafil concentrations appear to decline in a biphasic manner following oral administration, with a terminal elimination half-life of about 4 hours.
Sildenafil is metabolized principally via hepatic cytochrome P-450 (CYP) microsomal isoenzymes 3A4 (major route) and 2C9 (minor route).
Body weight has been shown to be a good predictor of drug exposure in children. Sildenafil plasma concentration half-life values are estimated to range from 2.9 to 4.4 hours for a 10 to 70 kg range of body weight; peak plasma concentration occurs in approximately 1 hour.
Plasma concentrations of the active N-desmethyl metabolite are approximately 40% of those seen for sildenafil, and the metabolite reportedly accounts for about 20% of sildenafil pharmacologic activity.
Sildenafil, after oral or IV administration, is eliminated mainly in the feces as metabolites; approximately 80% of an oral dose is excreted as metabolites in feces and 13% is excreted in urine.
USES: Sildenafil is used to treat high blood pressure in the lungs (pulmonary hypertension). It works by relaxing and widening the blood vessels in your lungs which allows the blood to flow more easily. Decreasing high blood pressure in the lungs allows your heart and lungs to work better and improves your ability to exercise.
Generic name: sildenafil citrate
Pronunciation: (sil-DEN-a-fil)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Revatio
Indications
The following indications are listed for Revatio:
- Pulmonary Arterial Hypertension
Also known as: Hypertensive Pulmonary Arterial Disease, Pulmonary Hypertensive Arterial Disease.
Dosing
No dosing information is available for this tab.
Sildenafil is administered orally (as tablets or oral suspension) for the treatment of pulmonary arterial hypertension (PAH); the drug is also available in a parenteral formulation that is administered by IV injection for the continued treatment of patients with PAH who are currently prescribed oral sildenafil and who are temporarily unable to take oral medications.
No dosing information is available for this tab.
No dosing information is available for this tab.
Drug interactions
Sildenafil is metabolized principally via hepatic cytochrome P-450 (CYP) microsomal isoenzymes 3A4 (major route) and 2C9 (minor route). Inhibitors and inducers of these isoenzymes may reduce or increase sildenafil clearance, respectively.
Predictions based on a pharmacokinetic model suggest that drug-drug interactions with CYP3A inhibitors will be less following IV administration than those observed after oral administration.
In vitro studies indicate that sildenafil is a weak inhibitor of the CYP isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4. Sildenafil is not expected to affect the pharmacokinetics of compounds which are substrates of these CYP enzymes at clinically relevant concentrations.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
*Concomitant use of organic nitrates (e.g., sodium nitroprusside) in any form (e.g., orally, sublingually, transmucosally, parenterally), either regularly or intermittently.
*Concomitant use of guanylate cyclase stimulators (e.g., riociguat).
*Hypersensitivity to sildenafil.
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
The most common adverse effects reported in adults receiving sildenafil for PAH include headache, dyspepsia, flushing, pain in limb, myalgia, back pain, and diarrhea.
The most common adverse effect reported in children receiving sildenafil for PAH include priapism.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
No enhanced messaging available.
The manufacturer states that safety and efficacy of sildenafil have been established in pediatric patients 1 to 17 years of age children for the treatment of PAH (WHO functional class I) to improve exercise ability and, in patients too young to perform standard exercising testing, pulmonary hemodynamics thought to underly improvements in exercise.
Use of sildenafil for this indication is also supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients >=1 year of age.
The manufacturer states that safety and efficacy of sildenafil have not been established in pediatric patients < 1 year of age.
In the dose-ranging study (STARTS-1) in children and adolescents, patients 1-17 years of age with PAH (idiopathic, familial, or PAH associated with connective tissue or congenital heart disease) received placebo or sildenafil at a low, medium, or high dosage for 16 weeks. During the 16 week portion of the trial, there was no statistically significant improvement in exercise capacity in sildenafil-treated patients; no patients died during this time.
After completion of the placebo-controlled portion of the study, patients were enrolled in an ongoing extension phase (STARTS-2) during which all patients received sildenafil therapy; placebo patients were randomized to low-, medium-, or high-dose sildenafil. Although clinical improvements (e.g., exercise capacity, hemodynamic parameters, WHO functional class) were observed compared with placebo, 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.
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). The manufacturer states that 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 3 times a day.
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. Pregnant women with untreated pulmonary arterial hypertension (PAH) are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. Experts recommend avoiding pregnancy in patients with PAH.
No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in rats and rabbits receiving up to 200 mg/kg daily of sildenafil during organogenesis. These doses represent, respectively, about 32- and 68 times the maximum recommended human dose (MRHD) of 20 mg 3 times a day. No adverse effects were observed in a prenatal and postnatal development study in rats receiving 30 mg/kg daily, equivalent to 5 times the MRHD on a mg/m2 basis.
Limited data indicate that sildenafil and its active metabolite are present 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; this precludes a clear determination of the risk to an infant during lactation.
The manufacturer recommends cautious dosage selection in geriatric patients, reflecting the greater frequency of decreased hepatic, renal, and/or cardiac function, and of concomitant disease or drug therapy.
Clinical studies of sildenafil for PAH did not include sufficient numbers of patients >=65 years of age to determine whether they respond differently than younger adults. Other reported clinical experience has not identified differences in response between geriatric and younger patients with PAH. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly should be considered in dosage selection for the treatment of PAH.
Plasma concentrations of sildenafil are increased in geriatric patients and in patients with hepatic or severe renal impairment. AUCs for total sildenafil and its N-demethylated metabolite in geriatric individuals are approximately 84 and 107% higher, respectively, than those observed in healthy younger adults (i.e., 18-45 years of age). Free plasma sildenafil concentrations are increased by about 45% in healthy geriatric individuals (i.e., older than 65 years of age) compared with younger adults as a result of age-related differences in plasma protein binding; plasma concentrations of the N-demethylated metabolite also are increased 57%.
ICD codes
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Last reviewed · Source: First Databank (FDB) drug data
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