Medications> Erectile dysfunction>

INDICATIONS

• Treatment of erectile dysfunction (ED) 
• Treatment of pulmonary arterial hypertension (WHO Group I) to improve exercise ability and delay clinical worsening.

MECHANISM

• Phosphodiesterase (PDE) type 5 inhibitor, an enzyme found in trabecular smooth muscle, that promotes erection through smooth muscle relaxation.
• PDE - 5 catalyzes the degradation of cGMP, resulting in an elevated cytosolic calcium concentration and smooth-muscle contraction.

USUAL ADULT DOSING

• 50 mg PO once daily 1 hour (range: 30 minutes to 4 hours) before sexual activity; dosing range: 25-100 mg once daily. Max dose 100 mg/dose, 1 dose/day.
• Start 25 mg PO once if >65 years old, with renal or hepatic impairment, or with the co-administration of CYP3A4 inhibitors (see drug interaction section for list)
• May be administered without regard to meals but may take longer to be effective after a high-fat meal

FORMS

*Prices represent cost per unit specified and are representative of "Average Wholesale Price" (AWP). AWP Prices were obtained and gathered by Lakshmi Vasist Pharm D using the Red Book, manufacturer's information, and the McKesson database.

^Dosage is indicated in mg unless otherwise noted.

DOSING IN SPECIAL POPULATIONS

• CrCl > 30 ml/min: no dosage adjustment needed.
• CrCl < 30 ml/min: reduce starting dose to 25 mg

• Cirrhosis (Child-Pugh Class A and B): reduce starting dose to 25 mg. Do not exceed a maximum single dose of 25 mg sildenafil in a 48 hour period

• Classified  as FDA pregnancy risk category B. Animal studies have shown no evidence of teratogenicity of sildenafil during organogenesis, but no information on the use of sildenafil in humans during pregnancy. Not indicated for use in pregnant women.

• No information on the use of sildenafil in humans during breastfeeding. Not indicated for use in lactating women.

ADVERSE DRUG REACTIONS

• Headache, flushing, dyspepsia, and visual disturbances (including sudden decrease in vision, photosensitivity, or seeing a "bluish tinge")
• Caution should be used with cardiac disease  
• CONTRAINDICATED IN PATIENTS TAKING NITRATES

• Nasal congestion, urinary tract infection, diarrhea, dizziness and rash.

• Priapism, palpitations, hypotension, serious cardiovascular events (myocardial infarction, cardiac arrest, angina pectoris), allergic reaction.
• Unclear association: respiratory tract infection, back pain, flu syndrome, arthralgia, asthenia, chills, angioedema, pain, and shock
• Sudden hearing loss

DRUG INTERACTIONS

• Potent inhibitors of hepatic CYP3A4 or 2C9 isoenzymes, decreasing sildenafil clearance and metabolism, increasing sildenafil concentration; use with caution or dose reduction if sildenafil required (maximum dose 25 mg q48h) with the co-administration of the following drugs: conivaptan, erythromycin, fluconazole, imatinib, itraconazole, ketoconazole, voriconazole, posaconazole, mibefradil, nefazodone, other macrolide antibiotics (clarithromycin, troleandomycin), quinidine, ranolazine, sparfloxacin (withdrawn from the US market), voriconazole, zafirlukast, zileuton, delavirdine, HIV protease inhibitors (ritonavir, saquinavir, indinavir, darunavir, fosamprenavir, atazanavir, nelfinavir, lopinavir, tipranavir).
• Moderate inhibitors of hepatic CYP3A4 or 2C9 isoenzymes, decreasing sildenafil clearance and metabolism, increasing sildenafil concentration: use with caution or decrease dose to 25 mg q48 hrs with increased monitoring for adverse reactions with co-administration of the following drugs: cimetidine, diltiazem, grapefruit juice, mifepristone, tacrilomus, monoamine oxidse inhibitors (MAOIs), nilotinib, ciprofloxacin, aprepitant, fosaprepitant; fluoxetine, fluvoxamine, verapamil,
• Inducers of hepatic CYP3A4 or 2C9 isoenzymes, increasing sildenafil clearance and metabolism, decreasing sildenafil concentration: etravirine, efavirenz, bosentan, barbiturates, carbamazapine, dexamethasone, phenytoin, phosphenytoin, nevirapine, rifabutin, rifampin, troglitazone (withdrawn from the US market), nebivolol.
• Alpha-blockers: may increase risk of hypotension. Use with close BP monitoring. Patients should be stable on their alpha-blocker prior to initiating sildenafil.
• Nitrates: CONTRAINDICATED. Co-administration with sildenafil is contraindicated due to significant hypotension.
• Amlodipine: additional blood pressure reduction of 8 mmHg systolic and 7 mmHg diastolic were noted with sildenafil co-administration.
• Cisapride (no longer on the U.S market) is substrate for CYP3A4, avoid concurrent sildenafil and cisapride use as sildenafil (weak inhibitor of CYP3A4) could increase concentration of cispride, leading to cardiac arrhythmias.
• Prolonged erections may be seen with sildenafil and dihydrocodeine, use caution.
• No significant interactions noted with aspirin, ethanol, thiazide diuretics, ACE inhibitors, warfarin, antacids, or tolbutamide. If taking alpha blockers, should be on stable dose; start with low dose sildenafil.
• Sapropterin acts as cofactor in synthesis of nitric oxide, may cause vasorelaxation, use with caution as may decrease blood pressure.

PHARMACOKINETIC

COMMENTS

• Sildenafil potentiates hypotensive effects of nitrates, concurrent use of nitrates or nitrites contraindicated.
• Use with caution in patients with left ventricular outflow obstruction (e.g. aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure.
• Expected response to sildanefil is less compared to patients without diabetes, but 50 - 80% of patients with diabetes report benefit (Ng, Price, Blonde, Stuckey)
• Newer PDE-5 inhibitors such as vardenafil (Levitra) (Ishii, Goldstein) and tadalafil (Cialis) (Sáenz de Tejada) are also effective in the treatment of ED for patients with diabetes but have not been studied as extensively 
• Vardenafil has a peak effect at 1 hour and may last up to 4 - 6 hours;
• Tadalafil has a peak effect at 2 hours and may last up to 36 - 48 hours

REFERENCES

RELATED MODULES

• Autonomic Neuropathy