Viagra (Sildenafil)
sildenafil citrate tablets — for erectile dysfunction
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Erectile dysfunction (ED) | Adult males | PRN monotherapy | FDA Approved |
Sildenafil was the first phosphodiesterase type 5 (PDE5) inhibitor approved for erectile dysfunction, receiving FDA approval in March 1998 under the brand name Viagra. It remains one of the most widely prescribed ED treatments globally. Sildenafil is administered on an as-needed basis before anticipated sexual activity and requires sexual stimulation to be effective. The drug has been evaluated in over 3,700 patients in pre-marketing clinical trials across a broad range of ED aetiologies including organic (58%), psychogenic (17%), and mixed (24%). In pivotal trials, 63%, 74%, and 82% of patients on 25 mg, 50 mg, and 100 mg respectively reported improved erections compared with 24% on placebo. Sildenafil is also marketed separately as Revatio for pulmonary arterial hypertension at different doses; this monograph covers the ED indication only.
Raynaud phenomenon: PDE5 inhibition promotes digital vasodilation; evidence from small RCTs supports benefit in frequency and severity of attacks. Evidence quality: Moderate.
Female sexual arousal disorder: Investigated in clinical trials with mixed results; not FDA-approved for women. Evidence quality: Low.
Altitude sickness prevention: Used at lower doses for high-altitude pulmonary oedema prophylaxis in some mountaineering medicine protocols. Evidence quality: Moderate.
Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| ED — standard adult (<65 years) | 50 mg PRN | 25–100 mg PRN | 100 mg/day | Take ~1 hour before sexual activity (range 30 min to 4 hours) Maximum once daily; with or without food; high-fat meal delays Tmax by 60 min |
| ED — elderly (≥65 years) | 25 mg PRN | 25–100 mg PRN | 100 mg/day | AUC 84% higher in elderly; start low and titrate No upper age limit, but higher plasma levels increase AE risk |
| ED — severe renal impairment (CrCl <30) | 25 mg PRN | 25–100 mg PRN | 100 mg/day | ~2-fold increase in AUC and Cmax No adjustment for mild-moderate renal impairment |
| ED — hepatic impairment (Child-Pugh A/B) | 25 mg PRN | 25–100 mg PRN | 100 mg/day | Cmax +47%, AUC +85% in hepatic cirrhosis Child-Pugh C not studied |
| ED — concurrent alpha-blocker therapy | 25 mg PRN | 25–100 mg PRN | 100 mg/day | Patient must be stable on alpha-blocker before starting sildenafil Additive hypotension risk; monitor BP |
| ED — concurrent ritonavir | 25 mg PRN | 25 mg PRN | 25 mg per 48 hours | Ritonavir increases sildenafil AUC 11-fold Do not exceed 25 mg in any 48-hour period |
| ED — concurrent strong CYP3A4 inhibitors (ketoconazole, itraconazole, saquinavir) or erythromycin | 25 mg PRN | 25–50 mg PRN | Titrate cautiously | Erythromycin: AUC +182%; saquinavir: AUC +210% Consider 25 mg starting dose with any potent CYP3A4 inhibitor |
Sildenafil onset of action typically occurs within 30–60 minutes, with the response lasting up to 4 hours (though diminished compared to 2 hours). A high-fat meal delays Tmax by approximately 60 minutes and reduces Cmax by 29%, though the overall AUC reduction is only 11%. For optimal timing, advise patients to take the dose on an empty stomach or after a light meal approximately 1 hour before planned sexual activity. The drug requires sexual stimulation to produce an erection and has no effect in its absence.
Pharmacology
Mechanism of Action
Erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO activates guanylate cyclase, increasing levels of cyclic guanosine monophosphate (cGMP), which produces smooth muscle relaxation and allows blood inflow into the corpora cavernosa. Sildenafil enhances the effect of NO by selectively inhibiting PDE5, the enzyme responsible for cGMP degradation in the corpus cavernosum. By preventing cGMP breakdown, sildenafil sustains higher cGMP levels during sexual stimulation, facilitating and maintaining erection. Sildenafil has no direct relaxant effect on isolated corpus cavernosum tissue and has no effect in the absence of sexual stimulation. Sildenafil is approximately 4,000-fold more selective for PDE5 than PDE3 (involved in cardiac contractility), but only about 10-fold selective over PDE6 (found in the retina), which explains the visual disturbances seen at higher doses.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Rapidly absorbed; Tmax 30–120 min (median 60 min) fasted; absolute bioavailability ~40%; high-fat meal delays Tmax by 60 min and reduces Cmax by 29% | Take on empty stomach or after light meal for fastest onset; response begins within 30 min and lasts up to 4 h |
| Distribution | Vss 105 L; ~96% protein-bound (independent of concentration); <0.001% of dose appears in semen | Moderate distribution to tissues; high protein binding makes dialysis ineffective in overdose |
| Metabolism | Predominantly hepatic via CYP3A4 (major) and CYP2C9 (minor); active N-desmethyl metabolite (~50% potency of parent for PDE5, ~40% of parent AUC); both parent and metabolite have t½ ~4 h | Strong CYP3A4 inhibitors dramatically increase exposure (ritonavir: 11-fold AUC); active metabolite contributes to clinical effect; weak inhibitor of CYP1A2, 2C9, 2C19, 2D6, 2E1, 3A4 |
| Elimination | t½ ~4 h (parent and active metabolite); 80% feces, 13% urine (as metabolites); renal clearance not a major pathway | Short half-life supports PRN dosing; hepatic impairment substantially increases exposure; renal impairment effect is moderate |
Side Effects
| Adverse Effect | 25 mg | 50 mg | 100 mg | Placebo | Clinical Note |
|---|---|---|---|---|---|
| Headache | 16% | 21% | 28% | 7% | Most common AE; dose-related; usually mild-moderate and transient; due to PDE5-mediated vasodilation |
| Flushing | 10% | 19% | 18% | 2% | Reflects vasodilatory mechanism; typically facial/neck warmth; transient |
| Dyspepsia | 3% | 9% | 17% | 2% | Strongly dose-related; GI smooth muscle PDE5 inhibition |
| Abnormal vision | 1% | 2% | 11% | 1% | Blue/green colour tinge, increased light sensitivity, or blurred vision; due to PDE6 cross-inhibition in retina; mild, transient |
| Adverse Effect | 25 mg | 50 mg | 100 mg | Placebo | Clinical Note |
|---|---|---|---|---|---|
| Nasal congestion | 4% | 4% | 9% | 2% | Vasodilation of nasal mucosa; dose-related at 100 mg |
| Back pain | 3% | 4% | 4% | 2% | Mild; not clearly dose-related above 25 mg |
| Myalgia | 2% | 2% | 4% | 1% | Dose-related at 100 mg; mild and self-limiting |
| Nausea | 2% | 3% | 3% | 1% | GI-related; taking with food may reduce |
| Dizziness | 3% | 4% | 3% | 2% | Vasodilation-related; warn patients about postural changes |
| Rash | 1% | 2% | 3% | 1% | Mild; discontinuation rarely required |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Priapism (erection >4 hours) | Rare (postmarketing) | During or after sexual activity | Seek emergency care if erection >4 h; untreated priapism (>6 h) risks permanent penile tissue damage and loss of potency |
| Non-arteritic anterior ischemic optic neuropathy (NAION) | Rare (postmarketing); ~2-fold risk with PDE5 inhibitor class | Variable; temporal association with dose | Discontinue all PDE5 inhibitors immediately; ophthalmology referral; increased risk with “crowded disc,” age >50, diabetes, HTN |
| Sudden sensorineural hearing loss | Rare (postmarketing) | Variable; may be accompanied by tinnitus and dizziness | Discontinue sildenafil; seek prompt medical evaluation; causality not definitively established |
| Cardiovascular events (MI, sudden cardiac death, arrhythmia, stroke) | Rare (postmarketing) | During or shortly after sexual activity; some hours to days after dose | Emergency care; most patients had pre-existing CV risk factors; assess cardiac risk before prescribing; not necessarily drug-related |
| Severe hypotension (with nitrates or alpha-blockers) | Predictable if combined with nitrates | Within hours of co-administration | Nitrate co-administration is absolutely contraindicated; supportive care; IV fluids for hypotension |
Headache, flushing, dyspepsia, and visual disturbances are all strongly dose-related. If a patient experiences bothersome side effects at 100 mg, reducing to 50 mg often maintains efficacy while substantially lowering the adverse effect burden. Pre-treatment with a simple analgesic (paracetamol/acetaminophen) may reduce headache. Dyspepsia may be managed by taking the dose with a light meal, though this will slightly delay onset. Visual disturbances (blue colour tinge) are due to PDE6 cross-reactivity in the retina and are always transient and reversible.
Drug Interactions
Sildenafil is primarily metabolised by CYP3A4, making it highly susceptible to interactions with CYP3A4 inhibitors and inducers. The most critical interaction is the absolute contraindication with nitrates, which produces severe and potentially fatal hypotension through synergistic vasodilation of the NO/cGMP pathway. Sildenafil itself is a weak inhibitor of CYP isoenzymes at therapeutic concentrations and does not significantly alter levels of co-administered drugs metabolised by these pathways.
Monitoring
- Cardiovascular StatusBefore prescribing
RoutineAssess whether the patient’s cardiovascular status permits the physical exertion of sexual activity; do not prescribe to patients with recent MI, stroke, or life-threatening arrhythmia (<6 months), resting hypotension (<90/50), uncontrolled hypertension (>170/110), unstable angina, or cardiac failure - Nitrate UseAt each prescription; every refill
RoutineScreen for nitrate use at every encounter including prescription nitrates, over-the-counter nitrate supplements, and recreational nitrite “poppers”; co-administration is absolutely contraindicated - Blood PressureBaseline; if symptomatic
Trigger-basedMean maximum BP decrease of ~8.4/5.5 mmHg (supine) at 100 mg; monitor in patients on alpha-blockers or multiple antihypertensives; avoid in patients with resting hypotension - Visual FunctionIf symptoms occur
Trigger-basedAdvise patients to discontinue and seek immediate evaluation for sudden vision loss (potential NAION); use with caution in patients with retinitis pigmentosa; “crowded disc” is a risk factor for NAION - HearingIf symptoms occur
Trigger-basedCounsel patients to stop sildenafil and seek prompt evaluation for any sudden decrease or loss of hearing, with or without tinnitus and dizziness - Efficacy ResponseAfter initial use; as needed
RoutineConfirm adequate instruction on timing (1 h before, with sexual stimulation); titrate dose between 25–100 mg based on efficacy and tolerability; address unrealistic expectations
Contraindications & Cautions
Absolute Contraindications
- Concurrent nitrate use: Administration with organic nitrates or nitric oxide donors in any form (regular or intermittent) is contraindicated; includes nitroglycerin, isosorbide mononitrate/dinitrate, sodium nitroprusside, and recreational amyl nitrite/nitrate
- Known hypersensitivity: Hypersensitivity to sildenafil (as in Viagra or Revatio) or any excipient
Relative Contraindications (Specialist Input Recommended)
- Recent MI, stroke, or life-threatening arrhythmia (<6 months): No controlled safety data; sexual activity itself poses cardiovascular risk in these patients
- Resting hypotension (BP <90/50 mmHg): Sildenafil causes additional blood pressure reduction; risk of syncope
- Resting hypertension (BP >170/110 mmHg): No safety data; treat hypertension first
- Cardiac failure or unstable angina: Risk-benefit must be carefully evaluated
- Prior NAION in either eye: Increased risk of recurrence; use only when anticipated benefits outweigh risks
Use with Caution
- Anatomical penile deformation: Peyronie’s disease, angulation, or cavernosal fibrosis; increased risk of priapism
- Conditions predisposing to priapism: Sickle cell anaemia, multiple myeloma, leukaemia
- Concurrent alpha-blocker therapy: Additive hypotension; must be stable on alpha-blocker first; initiate sildenafil at 25 mg
- Retinitis pigmentosa: No safety/efficacy data; genetic disorders of retinal phosphodiesterases may be affected
- Bleeding disorders or active peptic ulceration: Safety unknown; sildenafil potentiates antiaggregatory effect of NO in vitro
Sildenafil potentiates the hypotensive effects of nitrates through synergistic vasodilation via the NO/cGMP pathway. This interaction is the single most dangerous drug interaction associated with PDE5 inhibitors and has resulted in fatalities. Nitrate co-administration in any form (sublingual, oral, transdermal, IV, or recreational “poppers”) is absolutely contraindicated. After a patient takes sildenafil, it is unknown when nitrates can be safely administered, as plasma levels remain elevated for 24+ hours in elderly, hepatic-impaired, or CYP3A4-inhibited patients.
Patient Counselling
Purpose of Therapy
Sildenafil helps achieve and maintain an erection by improving blood flow to the penis during sexual stimulation. It does not cure erectile dysfunction, increase sexual desire, or act as an aphrodisiac. The medication only works when you are sexually aroused and has no effect without stimulation.
How to Take
Take one tablet approximately 1 hour before planned sexual activity. The medication can work as early as 30 minutes and its effect lasts up to 4 hours, though the response diminishes after 2 hours. Do not take more than one dose per day. The tablet can be taken with or without food, but a high-fat meal will delay the onset by about 1 hour.
Sources
- Viagra (sildenafil citrate) tablets — Full Prescribing Information. Pfizer Inc. Revised March 2014. FDA LabelPrimary regulatory source for ED indication, dosing, adverse reaction Tables 1–2, PK parameters, drug interactions (ritonavir, saquinavir, erythromycin, amlodipine), and contraindications.
- Viagra (sildenafil citrate) tablets — Earlier FDA Label with PK detail. FDA Label 2007Contains detailed pharmacokinetic data including absorption, Vss (105 L), protein binding (96%), metabolism (CYP3A4/CYP2C9), and half-life (~4 h).
- Goldstein I, Lue TF, Padma-Nathan H, et al. Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med. 1998;338(20):1397–1404. PubMed: 9580646Landmark pivotal trial establishing sildenafil efficacy across organic, psychogenic, and mixed ED aetiologies in 532 men over 24 weeks.
- Fink HA, MacDonald R, Rutks IR, et al. Sildenafil for male erectile dysfunction: a systematic review and meta-analysis. Arch Intern Med. 2002;162(12):1349–1360. PubMed: 12076233Systematic review of 27 RCTs confirming sildenafil efficacy and safety across multiple ED populations including diabetes and post-prostatectomy.
- Giuliano F, Jackson G, Montorsi F, et al. Safety of sildenafil citrate: review of 67 double-blind placebo-controlled trials and the postmarketing safety database. BMC Urol. 2010;10:17. PubMed: 20932307Comprehensive safety review of sildenafil across 67 trials and postmarketing data, confirming the cardiovascular safety profile in patients without nitrate co-administration.
- Burnett AL, Nehra A, Breau RH, et al. Erectile dysfunction: AUA guideline. J Urol. 2018;200(3):633–641. PubMed: 29746858AUA guideline positioning PDE5 inhibitors as first-line pharmacotherapy for ED; includes guidance on cardiovascular risk assessment and nitrate screening.
- Salonia A, Bettocchi C, Boeri L, et al. European Association of Urology guidelines on sexual and reproductive health — 2021 update. Eur Urol. 2021;80(3):333–357. PubMed: 34183196EAU guideline covering ED evaluation and management, including PDE5 inhibitor selection, contraindications, and cardiovascular risk stratification.
- Boolell M, Allen MJ, Ballard SA, et al. Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res. 1996;8(2):47–52. PubMed: 8858389Early mechanistic paper describing PDE5 selectivity profile of sildenafil and the NO/cGMP signalling pathway in erectile physiology.
- Corbin JD, Francis SH. Pharmacology of phosphodiesterase-5 inhibitors. Int J Clin Pract. 2002;56(6):453–459. PubMed: 12166544Review of PDE5 pharmacology explaining the selectivity ratios for PDE5 vs PDE6 (retinal) and PDE3 (cardiac), underpinning the side effect profile.
- Nichols DJ, Muirhead GJ, Harness JA. Pharmacokinetics of sildenafil 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. PubMed: 11879254Definitive PK study establishing absolute bioavailability (41%), food effect (Cmax −29%, Tmax delayed 1 h), and approximate dose proportionality across 25–200 mg.
- Muirhead GJ, Rance DJ, Walker DK, et al. Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man. Xenobiotica. 1999;29(3):297–310. PubMed: 10219969Cross-species PK study confirming human half-life of 3.7 h, Vd of 1–2 L/kg, and identifying CYP3A4 as the primary metabolic pathway.