Drug class: Phosphodiesterase type 5 inhibitors

Introduction

Vasodilating agent; a selective phosphodiesterase (PDE) type 5 inhibitor.

Uses for Sildenafil (Pulmonary Hypertension)

Pulmonary Arterial Hypertension (PAH)

Management of adults with PAH (WHO group 1 pulmonary hypertension) to improve exercise capacity and delay clinical worsening.

Parenteral preparation used for continued treatment in patients with PAH who are temporarily unable to take oral medication.

Efficacy established principally in adult patients with WHO functional class II–III PAH (idiopathic or associated with connective tissue diseases).

Expert consensus guidelines recommend that all adult patients with symptomatic PAH be treated with PAH-targeted medications. PDE type 5 inhibitors such as sildenafil are recommended among several options for treatment of WHO/NYHA class II or III PAH. Selection of drug therapy should be based on disease severity (WHO/NYHA class) in addition to comorbid conditions, concomitant medications, adverse effects, route of administration, costs, and patient preferences.

Management of pediatric patients 1-17 years of age with PAH (WHO group 1 pulmonary hypertension) to improve exercise capacity (or pulmonary hemodynamics in patients too young to perform standardized exercise testing).

In pediatric patients, sildenafil monotherapy is a recommended option in patients with lower-risk PAH and negative acute vasoreactivity testing.

Sildenafil (Pulmonary Hypertension) Dosage and Administration

Administration

Oral Administration

Administer orally (as tablets or oral suspension).

Powder for Oral Suspension (Revatio and generics): Reconstitute with a total volume of 90 mL of water. To reconstitute, tap bottle to release the powder. Add 60 mL of water to the bottle; recap and shake vigorously for at least 30 seconds. Add another 30 mL to bottle, recap and shake for at least 30 seconds. Use provided bottle adapter to fill 2-mL oral syringe (with 0.5- and 2-mL dose markings) with the reconstituted suspension.

Commercially available ready-to-use sildenafil 10 mg/mL oral suspension (Liqrev): Use a calibrated measuring device to measure and deliver the prescribed dose accurately.

IV Administration

May administer by direct IV injection in patients who temporarily cannot take oral medication.

Dosage

Available as sildenafil citrate; dosage expressed in terms of sildenafil.

Pediatric Patients

PAH

Oral

Dosage is based on body weight (see Table 1). Based on experience in adults, dosage may be titrated to a maximum of 40 mg 3 times a day for pediatric patients weighing >45 kg, if required, based on symptoms and tolerability.

Adults

PAH

Oral

20 mg 3 times daily. Some manufacturers state that dosage may be titrated to a maximum of 80 mg 3 times a day, if required, based on symptoms and tolerability.

IV

10 mg 3 times daily by direct IV injection.

Special Populations

Hepatic Impairment

Mild to moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustments necessary.

Severe hepatic impairment (Child-Pugh class C): Not studied.

Renal Impairment

No dosage adjustment needed, even with severe impairment (Clcr <30 mL/minute).

Geriatric Use

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Body Weight

Do not adjust dosage of IV sildenafil injection for body weight.

Cautions for Sildenafil (Pulmonary Hypertension)

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.

Warnings/Precautions

Hypotension

Mild and transient decreases in BP reported.

Caution is advised in patients with certain underlying conditions (e.g., patients on antihypertensive therapy or with resting hypotension [BP <90/50 mm Hg], fluid depletion, severe left ventricular outflow obstruction, or autonomic dysfunction).

Monitor BP in patients taking BP lowering drugs.

Worsening Pulmonary Vascular Occlusive Disease

Pulmonary vasodilators may worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD).

Manufacturer states use of the drug in such patients not recommended.

Consider possibility of underlying PVOD in any patient exhibiting manifestations of pulmonary edema during sildenafil therapy.

Bleeding

Use with caution in patients with bleeding disorders or active peptic ulcers.

Incidence of epistaxis in sildenafil-treated patients is higher in those with PAH secondary to connective tissue disease than in those with idiopathic PAH.

Vision Loss

Nonarteritic anterior ischemic optic neuropathy (NAION) reported rarely in patients receiving PDE type 5 inhibitors.

Most patients had underlying anatomic or vascular risk factors for the development of NAION, including low cup-to-disc ratio (“crowded” optic disc).

Clinicians should discuss increased risk of NAION in the second eye in patients who already have had NAION in one eye.

Use not recommended in patients with retinitis pigmentosa.

Discontinue drug and contact a clinician immediately if sudden vision loss or decreased vision occurs in one or both eyes.

Hearing Loss

Sudden decrease or loss of hearing reported with all PDE type 5 inhibitors.

Although not clear whether such effects are directly related to PDE type 5 inhibitors or to other factors (e.g., patient’s underlying medical condition, concomitant use of other ototoxic drugs), a strong temporal relationship has been observed.

Patient should seek prompt medical attention in the event of sudden decrease or loss of hearing.

Combination with other PDE type 5 inhibitors

Safety and efficacy not established for use in combination with other PDE type 5 inhibitor treatments for erectile dysfunction (ED).

Priapism

Use with caution in patients with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, Peyronie’s disease).

May result in penile tissue damage and permanent loss of potency if priapism is not treated immediately. Use with caution in patients with conditions predisposing to priapism (e.g., sickle cell anemia, multiple myeloma, leukemia).

Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle Cell Anemia.

Vaso-occlusive crisis requiring hospitalization reported in patients with pulmonary hypertension secondary to sickle cell disease who received sildenafil. Efficacy and safety of sildenafil in patients with sickle cell anemia not established.

Specific Populations

Pregnancy

Limited human data from randomized controlled trials, case-controlled trials, and case series.

Sildenafil administration in animal studies did not result in teratogenicity embryotoxicity, or fetotoxicity.

Pregnant women with untreated PAH are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. Experts recommend avoiding pregnancy.

Lactation

Distributed into milk (including active metabolite). Insufficient information precludes determination of risk to an infant.

Females and Males of Reproductive Potential

No evidence of impaired fertility.

Pediatric Use

Safety and efficacy established in pediatric patients 1 to 17 years of age for treatment of PAH.

Safety and efficacy not established in pediatric patients < 1 year of age.

Geriatric Use

Insufficient data from clinical trials to determine whether geriatric patients with PAH respond differently than younger adults, but other clinical experience has not identified overall differences in response relative to younger patients. Select dosage carefully due to greater frequency of decreased renal, hepatic, and/or cardiac function and of concomitant disease or drug therapy observed in geriatric patients.

Hepatic Impairment

Mild or moderate hepatic cirrhosis (Child-Pugh class A or B): Decreased clearance. No dosage adjustment.

Severe hepatic impairment (Child-Pugh class C): Not studied.

Renal Impairment

Mild (Cl_cr 50–80 mL/minute) or moderate (Cl_cr 30–49 mL/minute) renal impairment: Pharmacokinetics unchanged. No dosage adjustment is necessary.

Severe renal impairment (Cl_cr ≤30 mL/minute): Decreased clearance. No dosage adjustment is necessary.

Common Adverse Effects

Adults: Headache, dyspepsia, flushing, pain in limb, myalgia, back pain, and diarrhea.

Children: Priapism.

Drug Interactions

Metabolized principally by CYP3A4 and to some extent by CYP2C9; weakly inhibits CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 in vitro.

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4 and CYP2C9: Potential pharmacokinetic interaction (increased plasma sildenafil concentrations).

Inducers of CYP3A4: Potential pharmacokinetic interaction (decreased plasma sildenafil concentrations).

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4: At clinically relevant concentrations, pharmacokinetic interaction unlikely.

Specific Drugs and Foods

Sildenafil (Pulmonary Hypertension) Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration; however, only about 40% of a dose reaches systemic circulation unchanged.

Peak plasma concentration usually attained within 30–120 minutes.

Pediatric patients: Body weight predicts drug exposure. Peak plasma concentration occurs in approximately 1 hour.

Food

Administration with a high-fat meal delays GI absorption; peak plasma concentrations reduced by about 30% and time to peak plasma concentration delayed by about 60 minutes.

Distribution

Extent

Appears to be widely distributed in the body.

Sildenafil and its active metabolite are present in human milk.

Plasma Protein Binding

Approximately 96%.

Elimination

Metabolism

Undergoes extensive metabolism in GI mucosa during absorption and on first pass through liver.

Metabolized in the liver principally by CYP3A4 and to a lesser extent by CYP2C9.

Elimination Route

Excreted as metabolites in the feces (approximately 80%) and urine (approximately 13%).

Half-life

Biphasic; terminal elimination half-life about 4 hours.

Pediatric patients: Estimated plasma concentration half-life ranges from 2.9 to 4.4 hours for 10 to 70 kg range of body weight.

Special Populations

Clearance in patients ≥65 years of age is reduced compared with that in younger adults.

In patients with severe renal impairment (Cl_cr <30 mL/minute), clearance was reduced resulting in a two-fold increase in AUC and increased peak plasma concentrations compared with values in healthy adults. Pharmacokinetics not altered in mild to moderate renal impairment.

Reduced clearance in patients with hepatic cirrhosis (Child-Pugh class A or B). Not studied in severe hepatic impairment (Child-Pugh class C).

In pediatric patients, body weight predicts drug exposure. Estimated plasma concentration half-life ranges from 2.9 to 4.4 hours for 10 to 70 kg range of body weight; peak plasma concentration occurred in approximately 1 hour.

Stability

Storage

Oral

Oral Suspension

Powder for suspension (Revatio and generics): <30°C in original package to protect from moisture. After reconstitution, store at <30°C or in refrigerator (2–8°C); do not freeze. Discard any remaining oral suspension 60 days after reconstitution.

Oral suspension (Liqrev): store at 20°C to 25°C (excursions permitted between 15°C to 30°C.

Tablets

20-25°C (excursions permitted to 15–30°C).

Parenteral

Injection

20-25°C (excursions permitted to 15–30°C).

Actions

• Selective inhibitor of PDEs, with a great selectivity for 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.

• Mild peripheral arterial-venous dilatation. In patients with PAH, 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 an increase in cardiac output. Vasodilation and decreases in BP probably result from inhibition of PDE type 5 present in vascular smooth muscle.

• In pediatric patients, cardiac index is improved; pulmonary vascular resistance index and mean pulmonary arterial pressure improvements are dose-related.

Advice to Patients

• Importance of instructing patients and caregivers to read the manufacturer’s patient information before starting sildenafil therapy and each time their prescription is refilled.

• Instruct patients and caregivers to avoid contraindicated medications such as regular and/or intermittent use of organic nitrates, organic nitrites (e.g., “poppers”), and riociguat.

• Inform patients and caregivers that sildenafil is marketed for erectile dysfunction (Viagra) and pulmonary arterial hypertension (Revatio). Advise patients taking Revatio not to take Viagra or other PDE type 5 inhibitors.

• Advise patients and caregivers to seek immediate medical attention for a sudden loss of vision in one or both eyes while taking sildenafil. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including possible permanent loss of vision.

• Advise patients and caregivers to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking sildenafil. These events may be accompanied by tinnitus and dizziness.

• Advise patients and caregivers to seek prompt medical attention for an erection that lasts more than 4 hours. If it is not treated right away, priapism can permanently damage the penis.

• Risk of symptomatic low BP (e.g., dizziness, lightheadedness, fainting). Monitor BP when administering sildenafil with BP lowering drugs (e.g., -adrenergic blocking agents).

• Advise patients and caregivers to take sildenafil tablets or oral suspension 3 times a day at the same times every day.

• Advise patients and caregivers to not take more than one dose of sildenafil at a time, and to not change the dose or stop taking the drug on their own.

• Advise patients and caregivers that sildenafil oral suspension will be mixed by the pharmacist. Do not mix sildenafil oral suspension with any other medicine or flavoring. Shake well for at least 10 seconds before each dose.

• Instruct patients and caregivers to store reconstituted sildenafil oral suspension at room temperature (<30°C) or in the refrigerator (2-8°C); do not freeze and discard the drug after 60 days.

• Advise patient to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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