Sildenafil Citrate

(BANM, USAN, rINNM)
Sildenafil Citrate Chemical formula
Synonyms: Citrato de sildenafilo; Sildénafil, citrate de; Sildenafil Sitrat; Sildenafili citras; UK-92480-10. 5-[2-Ethoxy-5-(4-methylpiperazin-1ylsulfonyl)phenyl]-1,6-dihydro-1-methyl-3-propylpyrazolo[4,3d]pyrimidin-7-one citrate; 1-{[3-(6,7-Dihydro-1-methyl-7-oxo-3propyl-1H-pyrazolo[4,3d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl}-4-methylpiperazone citrate.
Cyrillic synonym: Сильденафила Цитрат.

💊 Chemical information

Chemical formula: C22H30N6O4S,C6H8O7 = 666.7.
CAS — 139755-83-2 (sildenafil); 171599-83-0 (sildenafil citrate).
ATC — G04BE03.
ATC Vet — QG04BE03.

Stability.

Sildenafil citrate tablets were ground to a powder and combined with a 1:1 mixture of methylcellulose 1% and simple syrup (USNF), or with a 1:1 mixture of Ora-Plus and Ora-Sweet (both Paddock, USA), to a nominal concentration of 2.5 mg/mL sildenafil citrate in each suspension. 1 Both suspensions were found to be chemically and physically stable for 91 days in plastic bottles, at both 4° and 25°. 1. Nahata MC, et al. Extemporaneous sildenafil citrate oral suspensions for the treatment of pulmonary hypertension in children. Am J Health-Syst Pharm 2006; 63: 254–7.

💊 Adverse Effects

Adverse effects most commonly reported with sildenafil are headache, flushing, and dyspepsia. Also common are visual disturbances such as blurred vision, photophobia, chromatopsia, cyanopsia, eye irritation, pain and redness of the eyes. Retinal haemorrhage has occurred, and non-arteritic anterior ischaemic optic neuropathy (NAION) causing permanent loss of vision has been reported rarely. Other common adverse effects include dizziness, insomnia, anxiety, vertigo, epistaxis, nasal congestion, pyrexia, and gastrointestinal disturbances such as diarrhoea and vomiting. Priapism can occur. Other adverse effects include skin rashes, erythema, alopecia, limb and/or back pain, myalgia, facial oedema, fluid retention, paraesthesia, and urinary-tract infection. Dyspnoea, cough, rhinitis, sinusitis, bronchitis, and cellulitis can occur. Sudden decrease or loss of hearing has been reported. Other reported effects include anaemia, leucopenia, gynaecomastia, urinary frequency or incontinence, haematuria, and seizures. Cerebrovascular haemorrhage and transient ischaemic attacks have occurred. There have also been reports of palpitations, syncope, hypertension, hypotension, and serious cardiovascular events including myocardial infarction, arrhythmias, tachycardia, unstable angina, and sudden cardiac death.
1. Vitezic D. A risk-benefit assessment of sildenafil in the treatment of erectile dysfunction. Drug Safety 2001; 24: 255–65
2. Padma-nathan H, et al. A 4-year update on the safety of sildenafil citrate (Viagra). Urology 2002; 60 (suppl 2): 67–90.

Convulsions.

A report1 of 2 patients who had a first tonic-clonic seizure shortly after taking sildenafil.
1. Gilad R, et al. Tonic-clonic seizures in patients taking sildenafil. BMJ 2002; 325: 869.

Effects on the cardiovascular system.

The effects of phosphodiesterase type-5 inhibitors (sildenafil, tadalafil, and vardenafil) on the cardiovascular system,1,2 and the potential risks of sexual activity in men with cardiovascular disease,3 have been reviewed. There has been considerable uncertainty about the potential cardiovascular risk associated with sildenafil treatment. Minor effects associated with vasodilatation, such as headache and flushing are relatively common, but in patients without pre-existing cardiovascular risk factors the risk of serious cardiovascular events associated with the drug appears to be low. However, there have been reports of myocardial infarction in patients who had no apparent risk factors,4,5 and a consensus document issued by the American College of Cardiology and the American Heart Association (ACC/AHA) has pointed out that patients with erectile dysfunction are mostly over 45 years of age and are more likely to have risk factors predisposing them to cardiovascular disease.6 As of November 1998, 130 deaths in US patients taking sildenafil had been reported to the FDA; 3 of these were due to stroke and 77 to some other cardiovascular event.7 The nature of the relationship between drug and event was considered unclear, but some of these patients were also receiving nitrates, a combination now contra-indicated because of the greatly increased risk of potentially life-threatening hypotension.6 The Australian Adverse Drug Reactions Advisory Committee8 stated in June 2002 that it had received 773 reports of adverse reactions associated with the use of sildenafil. There were 20 reports of myocardial infarction, including 4 fatalities; 9 of these 20 patients had preexisting cardiovascular disease or diabetes or were considered to be at high risk of cardiovascular disease, and 1 patient was taking nitrates. Other cardiovascular effects reported included 26 reports of chest pain and 10 other fatalities (6 sudden unexplained deaths, 2 strokes, and 2 subarachnoid haemorrhages). However, it was pointed out that the timing of these adverse effects in relation to sildenafil ingestion was often not reported and that, since sildenafil is taken in the context of sexual activity and, in some cases, underlying coronary disease, the contribution of sildenafil to cardiac events was difficult to assess. It is still uncertain whether patients with pre-existing cardiovascular disease are at increased risk when taking sildenafil without concomitant nitrates. The ACC/AHA consensus statement noted that the evidence was scanty and suggested that sildenafil could be used, but with caution, in patients with stable coronary artery disease provided that nitrates were not taken.6 A later review9and studies using exercise testing10,11 also concluded that sildenafil appeared to be well tolerated in most patients with chronic stable coronary artery disease. In men with mild to moderate chronic heart failure, small studies have found that sildenafil was well tolerated and effective for erectile dysfunction,12-14 and improved measures of exercise capacity.12 Analyses15,16 of combined trial data have examined the effects of sildenafil in men stabilised on antihypertensive treatment (including diuretics, beta blockers, alpha blockers, ACE inhibitors, and calciumchannel blockers) compared with men who did not have hypertension. Similar results were found for both groups in terms of sildenafil’s efficacy for erectile dysfunction.16 Also, changes in blood pressure and heart rate after a dose of sildenafil,15 and the incidence of treatment-related adverse effects that were potentially related to blood pressure decrease,16 were not significantly different between the groups. Evidence to assess the risk in other cardiovascular disorders is less extensive, although a case report of a patient with hypertrophic cardiomyopathy who had cardiovascular adverse effects after a dose of sildenafil suggested that the drug may precipitate an unstable haemodynamic state in this condition.17
1. Brindis RG, Kloner RA. Sildenafil in patients with cardiovascular disease. Am J Cardiol 2003; 92 (suppl): 26M–36M
2. Kloner RA. Cardiovascular effects of the 3 phosphodiesterase5 inhibitors approved for the treatment of erectile dysfunction. Circulation 2004; 110: 3149–55
3. Kostis JB, et al. Sexual dysfunction and cardiac risk (the Second Princeton Consensus Conference). Am J Cardiol 2005; 96: 313–21
4. Feenstra J, et al. Acute myocardial infarction associated with sildenafil. Lancet 1998; 352: 957–8
5. Kekilli M, et al. Acute myocardial infarction after sildenafil citrate ingestion. Ann Pharmacother 2005; 39: 1362–4
6. Cheitlin MD, et al. Use of sildenafil (Viagra) in patients with cardiovascular disease. ACC/AHA Expert Consensus Document. J Am Coll Cardiol 1999; 33: 273–82. Correction. ibid.; 34: 1850. Also available at: http://circ.ahajournals.org/cgi/ reprint/99/1/168.pdf (accessed 29/11/05
7. FDA. Postmarketing safety of sildenafil citrate (Viagra): summary of reports of death in Viagra users received from marketing (late March) through mid-November 1998. Available at: http://www.fda.gov/cder/consumerinfo/viagra/safety3.htm (accessed 29/11/05
8. Adverse Drug Reactions Advisory Committee (ADRAC). Sildenafil—three years experience. Aust Adverse Drug React Bull 2002; 21: 6. Also available at: http:// www.tga.gov.au/adr/aadrb/aadr0206.pdf (accessed 02/09/08
9. Tran D, Howes LG. Cardiovascular safety of sildenafil. Drug Safety 2003; 26: 453–60
10. Arruda-Olson AM, et al. Cardiovascular effects of sildenafil during exercise in men with known or probable coronary artery disease: a randomized crossover trial. JAMA 2002; 287: 719–25
11. Fox KM, et al. Sildenafil citrate does not reduce exercise tolerance in men with erectile dysfunction and chronic stable angina. Eur Heart J 2003; 24: 2206–12
12. Bocchi EA, et al. Sildenafil effects on exercise, neurohormonal activation, and erectile dysfunction in congestive heart failure: a double-blind, placebo-controlled, randomized study followed by a prospective treatment for erectile dysfunction. Circulation 2002; 106: 1097–1103
13. Webster LJ, et al. Use of sildenafil for safe improvement of erectile function and quality of life in men with New York Heart Association classes II and III congestive heart failure: a prospective, placebo-controlled, double-blind crossover trial. Arch Intern Med 2004; 164: 514–20
14. Katz SD, et al. Efficacy and safety of sildenafil citrate in men with erectile dysfunction and chronic heart failure. Am J Cardiol 2005; 95: 36–42
15. Zusman RM, et al. Effect of sildenafil citrate on blood pressure and heart rate in men with erectile dysfunction taking concomitant antihypertensive medication. J Hypertens 2000; 18: 1865–9
16. Kloner RA, et al. Effect of sildenafil in patients with erectile dysfunction taking antihypertensive therapy. Am J Hypertens 2001; 14: 70–3
17. Stauffer J-C, et al. Subaortic obstruction after sildenafil in a patient with hypertrophic cardiomyopathy. N Engl J Med 1999; 341: 700–701.

Effects on the ears.

As of October 2007, the US FDA had received a total of 29 postmarketing reports of sudden hearing loss with phosphodiesterase type-5 inhibitors. The problem was sometimes accompanied by tinnitus, vertigo, or dizziness. In most of the cases, the hearing loss involved one ear, and it was either a partial or complete loss of hearing. In about one-third of cases, the loss was temporary. While a causal relationship could not be established, patients should be advised that hearing loss may be related to these drugs, and to seek medical attention if affected.1
1. FDA. FDA announces revisions to labels for Cialis, Levitra and Viagra: potential risk of sudden hearing loss with ED drugs to be displayed more prominently (issued 18th October 2007). Available at: http://www.fda.gov/bbs/topics/NEWS/2007/ NEW01730.html (accessed 18/01/08)

Effects on the eyes.

The Australian Adverse Drug Reactions Advisory Committee1 stated in June 2002 that it had received 65 reports of abnormal vision from a total of 773 adverse reactions associated with use of sildenafil reported over 3 years. A bluish tinge or haze to vision and some increased light sensitivity has been reported by patients taking sildenafil, with the percentage of reports increasing with increasing dose.2 The visual symptoms usually peak 1 to 2 hours after ingestion and resolve about 3 to 4 hours later. The effects of a single dose of sildenafil 100 mg were studied in 5 healthy subjects.3 Electroretinogram measurements showed significant changes that correlated well with plasmasildenafil concentrations, peaking at 1 hour after administration and showing complete recovery at the 6-hour measurements. Inhibition of phosphodiesterase type-6 in rod photoreceptors is the most likely mechanism of sildenafil-associated retinal dysfunction. However, there is as yet no clear evidence of retinal toxic effects or whether repeated dosing with sildenafil causes prolonged or further retinal dysfunction.2,3 Likewise, it remains to be determined whether recovery of function as plasma-sildenafil concentrations subside also occurs in older patients or those with retinal degenerative disorders such as retinitis pigmentosa. Other visual disturbances reported in patients taking sildenafil have included temporary loss of vision and increased intra-ocular pressure.4 A 69-year-old man who had permanent loss of vision in one eye a few hours after taking sildenafil 100 mg was found to have an occlusion in a retinal artery.5 In another similar case of retinal artery occlusion6 the patient also had uncontrolled hypertension; the authors suggested that embolisation by a preexisting arteriosclerotic plaque of the carotid artery resulted from elevated blood pressure and cardiac workload during sexual activity, rather than as a direct adverse effect of sildenafil. Several cases of persistent blurred vision and visual loss caused by nonarteritic anterior ischaemic optic neuropathy (NAION; vascular insufficiency and ischaemia at the optic nerve head) associated with sildenafil use have been reported.7-10 Generally, visual defects developed in one eye only within 24 hours of sildenafil ingestion, although many of these men had taken doses of sildenafil on past occasions without adverse effect. A small number of cases have also been reported for tadalafil10-13 and vardenafil.10 However, many of these men had underlying anatomic or vascular risk factors for NAION, including low cup to disc ratio (crowded disc), age over 50, diabetes, hypertension, ischaemic heart disease, hyperlipidaemia, and smoking. As of May 2005 the FDA had concluded that it was not possible to determine whether NAION was directly related to the use of phosphodiesterase type-5 inhibitors, the patients’ underlying vascular risk factors or anatomical defects, a combination of these factors, or other factors.10
1. Adverse Drug Reactions Advisory Committee (ADRAC). Sildenafil—three years experience. Aust Adverse Drug React Bull 2002; 21: 6. Also available at: http://www.tga.gov.au/ adr/aadrb/aadr0206.pdf (accessed 02/09/08
2. Marmor MF. Sildenafil (Viagra) and ophthalmology. Arch Ophthalmol 1999; 117: 518–19
3. Vobig MA, et al. Retinal side-effects of sildenafil. Lancet 1999; 353: 375
4. Committee on Safety of Medicines/Medicines Control Agency. Sildenafil (Viagra). Current Problems 1999; 25: 16. Also available at: http://www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE& dDocName=CON2023713&RevisionSelectionMethod= LatestReleased (accessed 02/09/08
5. Tripathi A, O’Donnell N. Branch retinal artery occlusion; another complication of sildenafil. Br J Ophthalmol 2000; 84: 934–5
6. Bertolucci A, et al. Hemi-retinal artery occlusion associated with sexual activity and sildenafil citrate (Viagra). Acta Ophthalmol Scand 2003; 81: 198–200
7. Boshier A, et al. A case of nonarteritic ischemic optic neuropathy (NAION) in a male patient taking sildenafil. Int J Clin Pharmacol Ther 2002; 40: 422–3
8. Pomeranz HD, et al. Sildenafil-associated nonarteritic anterior ischemic optic neuropathy. Ophthalmology 2002; 109: 584–7
9. Pomeranz HD, Bhavsar AR. Nonarteritic ischemic optic neuropathy developing soon after use of sildenafil (Viagra): a report of seven new cases. J Neuroophthalmol 2005; 25: 9–13
10. FDA. Alert 07/2005: Sildenafil (marketed as Viagra). Available at: http://www.fda.gov/cder/drug/InfoSheets/HCP/sildenafilHCP.pdf (accessed 28/07/05
11. Peter NM, et al. Tadalafil-associated anterior ischaemic optic neuropathy. Eye 2005; 19: 715–17
12. Escaravage GK, et al. Tadalafil associated with anterior ischemic optic neuropathy. Arch Ophthalmol 2005; 123: 399–400
13. Bollinger K, Lee MS. Recurrent visual field defect and ischemic optic neuropathy associated with tadalafil rechallenge. Arch Ophthalmol 2005; 123: 400–401.

Effects on mental function.

There have been a few cases reported1-3 of transient global amnesia after the use of sildenafil or tadalafil. Between January 1998 and February 2001, the FDA had received 35 reports of amnesia in which sildenafil was listed as the primary causal suspect.4
1. Gandolfo C, et al. Sildenafil and transient global amnesia. Neurol Sci 2003; 24: 145–6
2. Savitz SA, Caplan LR. Transient global amnesia after sildenafil (Viagra) use. Neurology 2002; 59: 778
3. Schiefer J, Sparing R. Transient global amnesia after intake of tadalafil, a PDE-5 inhibitor: a possible association? Int J Impot Res 2005; 17: 383–4
4. Milman HA, Arnold SB. Neurologic, psychological, and aggressive disturbances with sildenafil. Ann Pharmacother 2002; 36: 1129–34.

💊 Precautions

Caution is required in patients with hepatic or severe renal impairment, and dosage reduction of sildenafil may be necessary. Care is also needed in patients with anatomical deformation of the penis or haematological disorders that may predispose them to priapism. In the event of prolonged erection (for more than 4 hours), patients should seek medical assistance, as penile tissue damage and permanent loss of potency can occur. Patients are also advised to stop taking sildenafil and seek medical advice in cases of sudden visual or hearing loss. Sildenafil should not be given to those with loss of vision in one eye caused by non-arteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this was in connection with previous phosphodiesterase type-5 inhibitors or not. Patients who experience dizziness or visual disturbances should not drive or operate hazardous machinery. The safety of sildenafil is uncertain in patients with severe hepatic impairment, bleeding disorders, active peptic ulceration, hypotension, hypertension, a recent history of stroke, myocardial infarction, or life-threatening arrhythmia, unstable angina, heart failure, or retinal disorders such as retinitis pigmentosa (a minority of whom have genetic disorders of retinal phosphodiesterases). Licensed product information advises that it should not be used in these groups.

Cardiovascular disease.

For mention of a consensus statement on the use of sildenafil in patients with cardiovascular disease, see above.

💊 Interactions

Sildenafil or other phosphodiesterase type-5 inhibitors may potentiate the hypotensive effects of organic nitrates, and are therefore contra-indicated in patients receiving such drugs. Sildenafil may also enhance the hypotensive effect of nicorandil and use of the two drugs together should be avoided. Symptomatic hypotension may also occur when phosphodiesterase type5 inhibitors are given with alpha blockers. Generally, the patient should be stabilised on alpha blocker therapy before the phosphodiesterase type-5 inhibitor is started at a low dose and adjusted according to response. Drugs that inhibit the cytochrome P450 isoenzyme CYP3A4, such as cimetidine, delavirdine, erythromycin, itraconazole, and ketoconazole, may reduce the clearance of phosphodiesterase type-5 inhibitors, necessitating a reduction in dosage. Plasma concentrations of phosphodiesterase type-5 inhibitors are significantly increased by HIV-protease inhibitors, and particularly so by ritonavir-boosted regimens. Such combinations should not be given unless absolutely essential. Grapefruit juice should be avoided with sildenafil or other phosphodiesterase type-5 inhibitors as it may increase their plasma concentrations. Inducers of CYP3A4, such as rifampicin, are likely to decrease plasma concentrations of phosphodiesterase type-5 inhibitors. Bosentan also reduces exposure to sildenafil. Specific dosage recommendations have been made for the use of phosphodiesterase type-5 inhibitors with many of these drugs; see Uses and Administration under Sildenafil (below), Tadalafil, and Vardenafil.

Antivirals.

Rises in sildenafil concentrations after use of saquinavir or ritonavir were consistent1 with inhibition of metabolism mediated by the cytochrome P450 isoenzyme CYP3A4. The larger increases seen with ritonavir may be due to its additional inhibition of the isoenzyme CYP2C9. Fatal myocardial infarction has been reported2 in a 47-year-old patient who took sildenafil 25 mg with ritonavir and saquinavir. In a study3 of 6 HIV-positive men being treated with triple antiretroviral therapy that included indinavir, plasma concentrations of sildenafil were found to be significantly increased compared with historical controls.
1. Muirhead GJ, et al. Pharmacokinetic interactions between sildenafil and saquinavir/ritonavir. Br J Pharmacol 2000; 50: 99–107
2. Hall MCS, Ahmad S. Interaction between sildenafil and HIV-1 combination therapy. Lancet 1999; 353: 2071–2
3. Merry C, et al. Interaction of sildenafil and indinavir when coadministered to HIV-positive patients. AIDS 1999; 13: F101–F107.

Cardiovascular drugs.

For the effects of sildenafil in men stabilised on antihypertensives in general, see Effects on the Cardiovascular System, above. For mention of a possible interaction between sildenafil and verapamil, see Immunosuppressants, below. The plasma concentration of sildenafil was reduced by bosentan in a study1 of 10 patients with pulmonary hypertension, probably by induction of the cytochrome P450 isoenzyme CYP3A4, which would increase the metabolism of sildenafil. The use of bosentan with sildenafil in pulmonary hypertension has been reported (see below) and this potential interaction should be taken into account.
1. Paul GA, et al. Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension. Br J Clin Pharmacol 2005; 60: 107–12.

Dihydrocodeine.

The use of dihydrocodeine with sildenafil was associated with priapism in 2 men who had previously been treated successfully with sildenafil.1 The first patient had two prolonged erections, lasting 4 and 5 hours, and the effect did not recur when the dihydrocodeine was stopped. The second patient had priapism on 3 occasions in the first week of dihydrocodeine treatment, but not in the subsequent 2 weeks despite continuing both drugs.
1. Goldmeier D, Lamba H. Prolonged erections produced by dihydrocodeine and sildenafil. BMJ 2002; 324: 1555.

Food.

Grapefruit juice has been shown to increase bioavailability but delay absorption of sildenafil in healthy subjects.1
1. Jetter A, et al. Effects of grapefruit juice on the pharmacokinetics of sildenafil. Clin Pharmacol Ther 2002; 71: 21–9.

Immunosuppressants.

Studies in men with erectile dysfunction who were receiving tacrolimus after kidney transplantation found that sildenafil had no effect on tacrolimus pharmacokinetics.1,2 However, the pharmacokinetic profile of sildenafil differed from that reported in healthy subjects; the maximal plasma concentration was higher, the area under the concentration-time curve was increased, and the elimination half-life was prolonged.1 Reductions in blood pressure were also found when sildenafil was given, although this may have been due to an interaction with verapamil. The authors suggested that an initial dose of 25 mg sildenafil should be used, and that on the days of sildenafil use the doses of antihypertensive drugs may need to be adjusted according to blood pressure response.1,2
1. Christ B, et al. Interactions of sildenafil and tacrolimus in men with erectile dysfunction after kidney transplantation. Urology 2001; 58: 589–93
2. Christ B, et al. Investigation on interaction between tacrolimus and sildenafil in kidney-transplanted patients with erectile dysfunction. Int J Clin Pharmacol Ther 2004; 42: 149–56.

Nitrates.

Giving sildenafil 50 mg to patients receiving isosorbide mononitrate, or sublingual glyceryl trinitrate given 1 hour after sildenafil, resulted in substantially greater decreases in blood pressure than when the nitrate was given alone in 2 crossover studies in patients with angina.1 Treatment-related adverse effects were reported in 8 of 16 patients who received sildenafil with isosorbide mononitrate and 3 of 15 who took sildenafil with glyceryl trinitrate. The authors confirmed that sildenafil should not be taken with nitrates.
1. Webb DJ, et al. Sildenafil citrate potentiates the hypotensive effects of nitric oxide donor drugs in male patients with stable angina. J Am Coll Cardiol 2000; 36: 25–31.

💊 Pharmacokinetics

Sildenafil is rapidly absorbed after an oral dose, with a bioavailability of about 40%. Peak plasma concentrations are attained within 30 to 120 minutes; the rate of absorption is reduced when sildenafil is given with food. Sildenafil is widely distributed into tissues and is about 96% bound to plasma proteins. It is metabolised in the liver mainly by cytochrome P450 isoenzymes CYP3A4 (the major route) and CYP2C9. The major metabolite, N-desmethylsildenafil (UK-103320) also has some activity. The terminal half-lives of sildenafil and the N-desmethyl metabolite are about 4 hours. Sildenafil is excreted as metabolites, mainly in the faeces, and to a lesser extent the urine. Clearance may be reduced in the elderly and in patients with hepatic or severe renal impairment.
1. Nichols DJ, et al. Pharmacokinetics of sildenafil citrate after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality. Br J Clin Pharmacol 2002; 53 (suppl 1): 5S–12S
2. Muirhead GJ, et al. The effects of age and renal and hepatic impairment on the pharmacokinetics of sildenafil. Br J Clin Pharmacol 2002; 53 (suppl 1): 21S–30S
3. Gupta M, et al. The clinical pharmacokinetics of phosphodiesterase-5 inhibitors for erectile dysfunction. J Clin Pharmacol 2005; 45: 987–1003.

💊 Uses and Administration

Sildenafil is a phosphodiesterase type-5 inhibitor used in the management of erectile dysfunction and pulmonary arterial hypertension. It is given orally as the citrate although doses are expressed in terms of the base; 14 mg of sildenafil citrate is equivalent to about 10 mg of sildenafil. In erectile dysfunction the usual dose is equivalent to sildenafil 50 mg about one hour before sexual intercourse. The dose may be increased or decreased depending on response. The maximum recommended dose is 100 mg, and sildenafil should not be taken more than once in 24 hours.
An initial dose of 25 mg has been suggested in the USA for patients over 65 years of age, though such initial reductions are not considered necessary in the UK.
An initial dose of no more than 25 mg daily is advised in patients taking sildenafil with inhibitors of cytochrome P450 isoenzyme CYP3A4; the dose should not exceed 25 mg every 48 hours if given with ritonavir-boosted HIV-protease inhibitors, although such a combination is best avoided entirely (see Interactions, above).
In patients stabilised on alpha blocker therapy, an initial dose of sildenafil 25 mg should be considered. To improve exercise ability in pulmonary arterial hypertension, sildenafil is given orally in a dose of 20 mg three times daily. The dose may need adjustment to account for drug interactions (see above) although licensed product information suggests that in these patients no adjustment is required when sildenafil is given with erythromycin or saquinavir. It also suggests that no adjustment is generally needed for pulmonary hypertension patients with renal or hepatic impairment, although patients with severe hepatic impairment (Child-Pugh category C) have not been studied. Although not licensed in the UK for children, the BNFC allows for a dose in neonates and children up to 18 years of age, of 250 to 500 micrograms/kg given orally every 4 to 8 hours, adjusted according to response up to a maximum of 2 mg/kg every 4 hours. Treatment should be withdrawn gradually in neonates. For doses in hepatic and renal impairment, see below.

Administration in hepatic impairment.

Sildenafil clearance is reduced in patients with hepatic impairment. Safety has not been established in patients with severe hepatic impairment (Child-Pugh class C) and its use is contra-indicated in these patients for this reason. Licensed product information for patients with erectile dysfunction recommends an initial dose of 25 mg in patients with hepatic impairment. Licensed product information for patients with pulmonary arterial hypertension states that initial dose adjustments are not needed for patients with mild or moderate hepatic impairment (Child-Pugh class A or B); in the UK, it is recommended that a reduction to 20 mg twice daily should be considered if therapy is not well tolerated.

Administration in renal impairment.

Sildenafil clearance is reduced in patients with severe renal impairment. Licensed product information for patients with erectile dysfunction recommends that in these patients, an initial dose of 25 mg should be considered. In the UK it is stated that the dose may be increased to 50 or 100 mg, if needed and tolerated. Licensed product information for patients with pulmonary arterial hypertension states that no dose adjustments are required for patients with renal impairment, including those with severe renal impairment (creatinine clearance less than 30 mL/minute). However, in the UK, consideration of a reduction to 20 mg twice daily is suggested if therapy is not well tolerated.

Erectile dysfunction.

Sildenafil, an inhibitor of phosphodiesterase type-5, is used as an oral therapy for erectile dysfunction. It is effective in erectile dysfunction of psychogenic causes and organic causes such as diabetes mellitus, spinal-cord injury, and prostatectomy.
1. Langtry HD, Markham A. Sildenafil: a review of its use in erectile dysfunction. Drugs 1999; 57: 967–89
2. Montorsi F, et al. Efficacy and safety of fixed-dose oral sildenafil in the treatment of erectile dysfunction of various etiologies. Urology 1999; 53: 1011–18
3. Rendell MS, et al. Sildenafil for treatment of erectile dysfunction in men with diabetes: a randomized controlled trial. JAMA 1999; 281: 421–6
4. Kedia S, et al. Treatment of erectile dysfunction with sildenafil citrate (Viagra) after radiation therapy for prostate cancer. Urology 1999; 54: 308–12
5. Zippe CD, et al. Role of Viagra after radical prostatectomy. Urology 2000; 55: 241–5
6. Fink HA, et al. Sildenafil for male erectile dysfunction: a systematic review and meta-analysis. Arch Intern Med 2002; 162: 1349–60
7. Fedele D, et al. Experience with sildenafil in diabetes. Diabetes Nutr Metab 2002; 15: 49–52
8. Derry F, et al. Efficacy and safety of sildenafil citrate (Viagra ) in men with erectile dysfunction and spinal cord injury: a review. Urology 2002; 60 (suppl): 49–57
9. Raina R, et al. Long-term effect of sildenafil citrate on erectile dysfunction after radical prostatectomy: 3-year follow-up. Urology 2003; 62: 110–15
10. Carson CC. Sildenafil: a 4-year update in the treatment of 20 million erectile dysfunction patients. Curr Urol Rep 2003; 4: 488–96
11. Setter SM, et al. Phosphodiesterase 5 inhibitors for erectile dysfunction. Ann Pharmacother 2005; 39: 1286–95
12. Shields KM, Hrometz SL. Use of sildenafil for female sexual dysfunction. Ann Pharmacother 2006; 40: 931–4.

High-altitude disorders.

Hypoxic pulmonary hypertension associated with high altitude may respond to sildenafil. Small studies have shown some promising results.1-3
1. Ghofrani HA, et al. Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest base camp: a randomized, double-blind, placebo-controlled crossover trial. Ann Intern Med 2004; 141: 169–77
2. Richalet JP, et al. Sildenafil inhibits altitude-induced hypoxemia and pulmonary hypertension. Am J Respir Crit Care Med 2005; 171: 275–81
3. Ricart A, et al. Effects of sildenafil on the human response to acute hypoxia and exercise. High Alt Med Biol 2005; 6: 43–9.

Oesophageal motility disorders.

Preliminary studies1-3have investigated the use of sildenafil in patients with oesophageal motility disorders such as achalasia or nutcracker oesophagus. Although some benefit has been reported, further studies are needed.
1. Bortolotti M, et al. Effects of sildenafil on esophageal motility of patients with idiopathic achalasia. Gastroenterology 2000; 118: 253–7
2. Eherer AJ, et al. Effect of sildenafil on oesophageal motor function in healthy subjects and patients with oesophageal motor disorders. Gut 2002; 50: 758–64
3. Lee JI, et al. The effect of sildenafil on oesophageal motor function in healthy subjects and patients with nutcracker oesophagus. Neurogastroenterol Motil 2003; 15: 617–23.

Premature ejaculation.

Early reports have suggested that sildenafil may be effective in the management of premature ejaculation and the rationale for such use has been reviewed.1
1. Abdel-Hamid IA. Phosphodiesterase 5 inhibitors in rapid ejaculation: potential use and possible mechanisms of action. Drugs 2004; 64: 13–26.

Priapism.

Sildenafil has been reported to be effective in the treatment of priapism in 3 patients with sickle-cell disease.1 In 2 of these patients, sildenafil was also successful in preventing further episodes of priapism when it was taken at the onset of symptoms.
1. Bialecki ES. Sildenafil relieves priapism in patients with sickle cell disease. Am J Med 2002; 113: 252.

Pulmonary hypertension.

Oral sildenafil has produced beneficial responses in patients with pulmonary arterial hypertension and may have a role, particularly in patients who fail to respond to other therapies. It has been given either alone1-7 or with other treatments such as inhaled nitric oxide,6 inhaled iloprost,1 intravenous epoprostenol,8,9 or oral beraprost.10 Sildenafil has also been added to bosentan therapy, with some benefit, in a small number of patients.11 For a report on the pharmacokinetic interaction of these 2 drugs see Cardiovascular Drugs, above. The results of short-term and long-term studies of sildenafil have been reviewed.12,13 In a study14 using single doses of phosphodiesterase type-5 inhibitors, it was found that sildenafil and tadalafil had greater selectivity for the pulmonary circulation than vardenafil, and that arterial oxygenation was improved by sildenafil only. In a pivotal study,7 sildenafil improved exercise capacity and haemodynamics in patients. Sildenafil was given at 20, 40, or 80 mg orally three times daily. While there was no evidence of a dose-response relationship in the primary end-point of exercise capacity, there was a linear trend in the response in haemodynamic measures. In an extension study, all patients were treated with 80 mg orally three times daily if tolerated. Some have questioned whether the licensed dose of 20 mg three times daily is sufficient,15 especially if patients are given bosentan at the same time, leading the authors of the original study to suggest that this may be used as an initial dose, with an increase to 40 or 80 mg three times daily in order to achieve or maintain favourable effects.16 Sildenafil has also been studied for paediatric pulmonary hypertension. Some consider that it may have a role in persistent pulmonary hypertension in neonates,17,18 as well as in those with pulmonary arterial hypertension associated with congenital heart disease, or secondary to lung disease, or in postoperative pulmonary hypertension and in neonates who are difficult to wean from inhaled nitric oxide.18 However, further controlled studies are needed.17,18 Nevertheless, although unlicensed in the UK, the BNFC suggests that sildenafil may be given orally to neonates and children for pulmonary hypertension after cardiac surgery, weaning from nitric oxide, idiopathic pulmonary arterial hypertension, and persistent pulmonary hypertension of the newborn (see above for details of doses). Sildenafil has also been reported to be of benefit in high-altitude pulmonary hypertension.19
1. Ghofrani HA, et al. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med 2002; 136: 515–22
2. Ghofrani HA, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet 2002; 360: 895–900
3. Watanabe H, et al. Sildenafil for primary and secondary pulmonary hypertension. Clin Pharmacol Ther 2002; 71: 398–402
4. Carroll WD, Dhillon R. Sildenafil as a treatment for pulmonary hypertension. Arch Dis Child 2003; 88: 827–8
5. Sastry BKS, et al. Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study. J Am Coll Cardiol 2004; 43: 1149–53
6. Michelakis E, et al. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation 2002; 105: 2398–2403
7. Galiè N, et al. Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005; 353: 2148–57
8. Bhatia S, et al. Immediate and long-term hemodynamic and clinical effects of sildenafil in patients with pulmonary arterial hypertension receiving vasodilator therapy. Mayo Clin Proc 2003; 78: 1207–13
9. Stiebellehner L, et al. Long-term treatment with oral sildenafil in addition to continuous IV epoprostenol in patients with pulmonary arterial hypertension. Chest 2003; 123: 1293–5
10. Ikeda D, et al. Addition of oral sildenafil to beraprost is a safe and effective therapeutic option for patients with pulmonary hypertension. J Cardiovasc Pharmacol 2005; 45: 286–9
11. Hoeper MM, et al. Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension. Eur Respir J 2004; 24: 1007–10
12. Lee AJ, et al. Sildenafil for pulmonary hypertension. Ann Pharmacother 2005; 39: 869–84
13. Croom KF, Curran, MP. Sildenafil: a review of its use in pulmonary arterial hypertension. Drugs 2008; 68: 383–97
14. Ghofrani HA, et al. Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension: a randomized prospective study. J Am Coll Cardiol 2004; 44: 1488–96
15. Hoeper MM, Welte T. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2006; 354: 1091
16. Galiè N, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2006; 354: 1092–3
17. Shah PS, Ohlsson A. Sildenafil for pulmonary hypertension in neonates. Available in The Cochrane Database of Systematic Reviews; Issu
3. Chichester: John Wiley; 2007 (accessed 18/01/08)
18. Leibovitch L, et al. Therapeutic applications of sildenafil citrate in the management of paediatric pulmonary hypertension. Drugs 2007; 67: 57–73
19. Aldashev AA, et al. Phosphodiesterase type 5 and high altitude pulmonary hypertension. Thorax 2005; 60: 683–7.

Raynaud’s syndrome.

Sildenafil has been reported to be of benefit in Raynaud’s phenomenon resistant to vasodilator therapy.1
1. Fries R, et al. Sildenafil in the treatment of Raynaud’s phenomenon resistant to vasodilatory therapy. Circulation 2005; 112: 2980–5.

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Published November 20, 2018.