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Sildenafil Citrate

Pronunciation

Pronunciation: sil-DEN-a-fil
Class: Phosphodiesterase type 5 inhibitor

Trade Names

Revatio
- Tablets 20 mg
- Injection, solution 10 mg per 12.5 mL

Viagra
- Tablets 25 mg
- Tablets 50 mg
- Tablets 100 mg

Pharmacology

Viagra

Enhances the effect of nitric oxide by inhibiting phosphodiesterase type 5 (PDE5) in the corpus cavernosum of the penis. This results in vasodilation and increased inflow of blood into the corpus cavernosum, with ensuing penile erection upon sexual stimulation.

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Revatio

Inhibits cGMP-specific PDE5 in the smooth muscle of the pulmonary vasculature, where PDE5 is responsible for degradation of cGMP. This increases cGMP within pulmonary vascular smooth muscle cells, resulting in relaxation. This leads to vasodilation of the pulmonary vascular bed in patients with pulmonary hypertension.

Pharmacokinetics

Absorption

Bioavailability is 41%. T max is 30 to 120 min (mean, 60 min). The drug is rapidly absorbed. When taken with a high-fat meal, the absorption rate is reduced with a mean delay in T max of 60 min and a mean reduction of C max of 29%.

Distribution

Vd is 105 L; 96% bound to plasma proteins.

Metabolism

Undergoes hepatic metabolism (mainly CYP3A4). The major circulating metabolite results from N-desmethylation.

Elimination

Half-life is 4 h. The drug is cleared primarily by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes, and is excreted primarily in feces (approximately 80%) and, to a lesser extent, in urine (approximately 13%).

Duration

Duration of action is up to 4 h.

Special Populations

Renal Function Impairment
Viagra

Severe renal impairment is associated with increased plasma levels.

Hepatic Function Impairment
Viagra

Hepatic impairment is associated with increased plasma levels.

Elderly
Viagra

Age older than 65 yr is associated with increased plasma levels.

Indications and Usage

Treatment of erectile dysfunction ( Viagra ); treatment of pulmonary arterial hypertension to improve exercise ability and delay clinical worsening ( Revatio ).

Contraindications

Use with nitrates; hypersensitivity to any component of the product.

Dosage and Administration

Erectile Dysfunction ( Viagra only)
Adults

PO 50 mg once, 0.5 to 4 h prior to sexual activity. Titration to a 25 or a 100 mg dose may be used based on tolerability or efficacy. The max recommended dosage is 100 mg per day and max recommended frequency is once daily.

Dosage Adjustments ( Viagra only)
Adults

PO Consider a starting dose of 25 mg in patients older than 65 yr of age, or in patients with hepatic impairment, severe renal impairment, or concurrent use of potent CYP3A4 inhibitors (eg, erythromycin, itraconazole, ketoconazole, saquinavir).

Alpha-blockers

Patients should be on stable alpha-blocker therapy prior to initiating treatment and should be initiated on sildenafil at the lowest dose.

Protease inhibitors

Do not exceed a max single dose of sildenafil 25 mg in a 48-h period.

Pulmonary Arterial Hypertension ( Revatio only)
Adults

PO 20 mg 3 times daily. IV 10 mg (12.5 mL) administered as a bolus injection 3 times daily.

General Advice

  • Administer without regard to meals. Administer with food if GI upset occurs.
  • Revatio
  • Administer doses approximately 4 to 6 h apart.

Storage/Stability

Store at controlled room temperature (59° to 86°F).

Drug Interactions

Alpha-blockers (eg, doxazosin)

Simultaneous administration may lead to symptomatic hypotension. When sildenafil is coadministered with an alpha-blocker, patients should be on stable alpha-blocker therapy prior to initiating treatment; initiate sildenafil at the lowest dose. In patients already taking an optimized dose of sildenafil, initiate alpha-blocker therapy at the lowest dose.

Amlodipine

Coadministration produced an additional mean reduction in BP of 8/7 mm Hg. Monitor BP and adjust the amlodipine dose as needed.

Antihypertensive agents

BP-lowering effects of antihypertensive agents may be increased. Monitor BP and adjust the dose of the antihypertensive agent as needed.

Bosentan

Coadministration may result in a decrease in sildenafil AUC and C max . In addition, sildenafil administration may increase bosentan AUC and C max . Use with caution. Monitor the clinical response of the patient and observe for bosentan adverse reactions.

CYP3A4 inhibitors (eg, azole antifungal agents [eg, itraconazole, ketoconazole], cimetidine, fluvoxamine, macrolide antibiotics [eg, erythromycin], protease inhibitors [eg, ritonavir, saquinavir], tacrolimus)

Sildenafil plasma levels may be elevated, increasing the risk of adverse reactions. Use with caution. Consider starting with a lower dose of sildenafil. In patients receiving azole antifungal agents or saquinavir, consider a starting dose of sildenafil 25 mg. In patients taking ritonavir, the dose of sildenafil should not exceed 25 mg in a 48-h period.

Delavirdine

Use with caution. Coadministration may substantially increase sildenafil plasma levels. Consider a max dose of sildenafil 25 mg in a 48-h period in patients taking delavirdine.

Food

When sildenafil is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in T max of 60 min and a mean reduction in C max of 29%. If taken after a high-fat meal (eg, cheeseburger and french fries), sildenafil may take slightly longer for the onset of effect.

Grapefruit juice

Sildenafil plasma concentrations may be prolonged; however, data are conflicting. Observe the patient for sildenafil adverse reactions and adjust treatment as needed.

HMG-CoA reductase inhibitors (eg, simvastatin)

At least 1 case of rhabdomyolysis has been reported during coadministration of sildenafil and simvastatin. Advise patients to report any unexplained muscle pain, tenderness, or weakness to their health care provider.

Inducers of CYP3A4 (eg, rifampin)

May decrease sildenafil levels. Closely monitor the clinical response to sildenafil.

Nitrates

Sildenafil has been shown to potentiate the hypotensive effects of nitrates. Coadministration is contraindicated.

Opioid analgesics (eg, dihydrocodeine)

Effects of sildenafil may be prolonged, resulting in prolonged erections following orgasm.

Vitamin K antagonists

Coadministration may lead to increased bleeding (primarily epistaxis). Closely monitor the patient for bleeding. If indicated, consider administering vitamin K.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Abnormal ECG, angina pectoris, AV block, cardiac arrest, cardiomyopathy, cerebral thrombosis, heart failure, hypotension, myocardial ischemia, palpitation, postural hypotension, syncope, tachycardia (less than 2%); cerebrovascular hemorrhage, hypertension, MI, pulmonary hemorrhage, subarachnoid and intracerebral hemorrhages, sudden cardiac death, transient ischemic attack, ventricular arrhythmia (postmarketing).

CNS

Headache (46%); insomnia (7%); paresthesia (3%); dizziness (2%); abnormal dreams, ataxia, decreased reflexes, depression, hypertonia, hypesthesia, insomnia, migraine, neuralgia, neuropathy, somnolence, tremor, vertigo (less than 2%); anxiety, seizure, seizure recurrence, transient global amnesia (postmarketing).

Dermatologic

Flushing (10%); erythema (6%); rash (2%); contact dermatitis, exfoliative dermatitis, herpes simplex, pruritus, skin ulcer, sweating, urticaria (less than 2%).

EENT

Epistaxis (9%); nasal congestion, rhinitis (4%); abnormal vision (mild and transient, predominantly color tinge to vision, increased sensitivity to light, or blurred vision) (3%); cataract, conjunctivitis, dry eyes, ear pain, eye hemorrhage, eye pain, mydriasis, photophobia, sudden decrease or loss of hearing, tinnitus (less than 2%); bloodshot appearance, diplopia, increased IOP, ocular burning, ocular redness, ocular swelling/pressure, paramacular edema, retinal vascular disease or bleeding, temporary vision loss/decreased vision, vitreous detachment/traction (postmarketing).

GI

Dyspepsia (13%); diarrhea (9%); gastritis (3%); colitis, dry mouth, dysphagia, esophagitis, gastroenteritis, gingivitis, glossitis, rectal hemorrhage, stomatitis, vomiting (less than 2%).

Genitourinary

UTI (3%); abnormal ejaculation, anorgasmia, breast enlargement, cystitis, genital edema, nocturia, urinary frequency, urinary incontinence (less than 2%); hematuria, priapism, prolonged erection (postmarketing).

Hematologic

Anemia, leukopenia (less than 2%).

Hepatic

Abnormal LFTs (less than 2%).

Metabolic

Edema, gout, hyperglycemia, hypernatremia, hyperuricemia, hypoglycemic reaction, peripheral edema, thirst, unstable diabetes.

Musculoskeletal

Myalgia (7%); arthritis, arthrosis, bone pain, myasthenia, synovitis, tendon rupture, tenosynovitis.

Respiratory

Dyspnea exacerbated (7%); sinusitis (3%); asthma, bronchitis, dyspnea, increased cough, increased sputum, laryngitis, pharyngitis (less than 2%).

Miscellaneous

Pyrexia (6%); abdominal pain, accidental falls, accidental injury, allergic reaction, asthenia, chest pain, chills, face edema, pain, photosensitivity, shock (less than 2%).

Precautions

Pregnancy

Category B .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Revatio

Dose selection should be cautious, usually starting at the lower end of the dosing range, reflecting the greater frequency of decreased hepatic and renal function and comorbidity.

Viagra

Consider initial dose of 25 mg in patients older than 65 yr of age.

Renal Function

Revatio

No dose adjustments are required for renal impairment (CrCl less than 30 mL/min).

Viagra

Consider initial dose of 25 mg in patients with severe renal impairment (CrCl less than 30 mL/min).

Hepatic Function

Revatio

No dose adjustments are required for Child-Pugh class A or B hepatic impairment.

Viagra

Consider initial dose of 25 mg in patients with hepatic impairment.

Anatomical deformation of the penis

Use with caution in patients with anatomical deformation of the penis (eg, angulation, cavernosal fibrosis, Peyronie disease) or patients prone to priapism (eg, leukemia, multiple myeloma, sickle cell anemia).

Bleeding disorders/active peptic ulceration

Safety of sildenafil is unknown in patients with bleeding disorders or active peptic ulceration.

Cardiac risk

Exertion from renewed sexual activity may pose a risk of cardiac events such as cerebrovascular hemorrhage, hypertension, MI, sudden cardiac death, transient ischemic attack, and ventricular arrhythmia.

Concurrent medical conditions

Safety and efficacy have not been established for the use of sildenafil in the following situations: patients who have experienced MI, stroke, or life-threatening arrhythmia in last 6 mo; patients with cardiac failure or coronary artery disease causing unstable angina; patients with resting hypotension (BP less than 90/50) or hypertension (BP greater than 170/110); patients with retinitis pigmentosa; patients currently on bosentan therapy. Use with caution if sildenafil is prescribed in any of these situations.

Epistaxis

Occurred at a higher incidence in patients with PAH secondary to connective tissue disease.

Priapism

Prolonged erection lasting more than 4 h and priapism have been infrequently reported.

Pulmonary veno-occlusive disease

Pulmonary vasodilators may significantly worsen CV status of patients with pulmonary veno-occlusive disease. Administration of Revatio to such patients is not recommended. Consider the possibility of pulmonary veno-occlusive disease if signs of pulmonary edema occur when Revatio is administered.

Vasodilation

Prior to starting sildenafil, carefully consider whether patients with certain underlying conditions (eg, autonomic dysfunction, fluid depletion, resting hypotension [BP less than 90/50], severe left ventricular outflow obstruction) could be adversely affected by vasodilatory effects.

Overdosage

Symptoms

None well documented.

Patient Information

  • Advise patient to review the patient information leaflet carefully before starting therapy and to read and check for new information each time the medication is refilled.
  • Review dosing schedule with patient.
  • Advise patient to take prescribed dose without regard to meals but to take with food if stomach upset occurs.
  • Caution patient not to stop taking or change the dose unless advised by health care provider.
  • Advise patient not to take sildenafil with other PDE5 inhibitors.
  • Advise patients of the potential for sildenafil to augment the BP-lowering effect of alpha-blockers and antihypertensive medications.
  • Instruct patient to stop using and contact health care provider immediately if any of the following occur: chest pain, dizziness, erection persisting longer than 4 h, fainting, painful erection, sudden decrease or loss of hearing, or sudden loss of vision in 1 or both eyes.
  • Revatio
  • Advise patient to take prescribed dose 3 times daily, separating doses by at least 4 to 6 h.
  • Viagra
  • Advise patient that medication may be most effective if taken approximately 60 min before anticipated sexual activity, but that medication can be taken anywhere from 30 min to 4 h before sexual activity.
  • Caution patient not to take more than 1 dose in a 24-h period.
  • Advise patient that sexual stimulation will be required for medication to work and an erection to occur.
  • Advise patient to contact health care provider if not satisfied with sexual performance after taking medication or if bothersome adverse reactions occur.
  • Caution patient to avoid using poppers (eg, amyl nitrate, butyl nitrate) while taking this medication.
  • Caution patient that medication is not a form of birth control, nor does it provide protection against STDs. Advise patient to use protective measures as indicated.

Copyright © 2009 Wolters Kluwer Health.

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