Viagra: Dosages and Ingredients | Full Prescribing Info

Sildenafil, in its citrate form (Viagra), is available in various dosages including 25 mg, 50 mg, and 100 mg formulations. Each film-coated tablet for the 25 mg dosage contains sildenafil citrate that is equivalent to 25 mg of sildenafil. The 50 mg variant contains 50 mg of sildenafil, while the 100 mg tablet comprises a full 100 mg of sildenafil. As an oral treatment specifically for erectile dysfunction, sildenafil functions as the citrate salt of sildenafil—an effective and selective inhibitor of the enzyme phosphodiesterase type 5 (PDE5), which breaks down cyclic guanosine monophosphate (cGMP) in the body.
Chemically, sildenafil citrate is defined as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine citrate. This compound appears as a white to off-white crystalline powder and possesses a solubility in water of approximately 3.5 mg/mL, with a total molecular weight of about 666.7, facilitating its absorption in the body when taken orally.

Pharmacologic Category: Phosphodiesterase-5 Inhibitor.
Pharmacology: Pharmacodynamics: The mechanism behind the erection of the penis primarily revolves around the release of nitric oxide (NO) within the corpus cavernosum during moments of sexual arousal.
Subsequently, NO activates guanylate cyclase, resulting in elevated concentrations of cGMP, which induce relaxation of the smooth muscle in the corpus cavernosum and promote increased blood flow. It is noteworthy that sildenafil does not directly relax the corpus cavernosum muscles; rather, it amplifies the effects of NO by inhibiting PDE5, the enzyme responsible for cGMP breakdown in the corpus cavernosum. When sexual activity triggers NO release, sildenafil's inhibition of PDE5 leads to heightened levels of cGMP, culminating in smooth muscle relaxation and enhanced blood inflow to the corpus cavernosum.
At clinically recommended doses, sildenafil does not exert any effects without the presence of sexual stimulation. In vitro studies have demonstrated that sildenafil selectively inhibits PDE5, showing a potency that is significantly greater for PDE5 compared to other phosphodiesterases—ten times more potent for PDE6, more than eighty times for PDE1, and over seven hundred times more for PDE2, PDE3, and PDE4, with an approximate four-thousand-fold selectivity for PDE5 versus PDE3, an important distinction since PDE3 is implicated in cardiac contractility regulation.
Clinical Studies: Cardiac assessments indicate that single oral doses of sildenafil up to 100 mg did not induce clinically significant alterations in the ECGs of healthy male volunteers. The average maximum reductions in supine systolic blood pressure after 100 mg dosing was recorded at 8.3 mmHg, with corresponding declines in supine diastolic blood pressure averaging 5.3 mmHg. Notably, patients taking concurrent nitrates experienced larger, yet transient, blood pressure declines (see Contraindications and Interactions).
In a trial evaluating the hemodynamic impact of a 100 mg dose in 14 patients suffering from severe coronary artery disease (CAD), mean resting systolic and diastolic blood pressures decreased by 7% and 6% from baseline, respectively, with a 9% reduction in mean pulmonary systolic blood pressure. Importantly, sildenafil did not affect cardiac output nor impaired blood flow through stenosed coronary arteries, and it may have enhanced coronary flow reserve by approximately 13% in both affected and unaffected arteries.
A placebo-controlled investigation involving 144 erectile dysfunction patients with stable angina, all adhering to their standard antianginal medication routine (excluding nitrates), revealed that sildenafil-treated individuals exhibited a statistically significant increase in treadmill exercise duration (19.9 seconds; 95% confidence interval: 0.9-38.9 seconds) when compared to the placebo group. Notably, mean adjusted exercise times until limiting angina onset were 423.6 seconds for sildenafil and 403.7 seconds for placebo.
In another randomized, double-blind, placebo-controlled flexible-dose study involving 568 men suffering from erectile dysfunction and arterial hypertension, where patients were on multiple antihypertensive medications, sildenafil resulted in successful erections for 71% of men, compared to only 18% in the placebo group. Furthermore, the success rate of sexual intercourse attempts was 62% with sildenafil versus 26% with placebo. The adverse events recorded were consistent with findings across various patient populations, including those on multiple antihypertensive agents.
Visual effects: At times, transient mild differences in color perception (specifically concerning blue/green discrimination) were noted in some individuals administered a single 100 mg dose, particularly 60 minutes post-dose, with effects dissipating after 120 minutes. The hypothesized mechanism behind these changes is linked to PDE6 inhibition, which plays a role in retinal phototransduction. Importantly, sildenafil does not influence visual acuity, contrast sensitivity, electroretinograms, intraocular pressure, or pupillometry.
In a controlled cross-over study involving patients with early age-related macular degeneration (n=9), a single 100 mg dose of sildenafil appeared well-tolerated, exhibiting no significant changes in visual assessments (including acuity, Amsler grid, color discrimination, simulated traffic lights, and photostress).
Efficacy evaluation: The effectiveness and safety of sildenafil have been appraised across 21 randomized, double-blind, placebo-controlled trials lasting up to 6 months, administered to over 3000 patients aged between 19 and 87, experiencing erectile dysfunction stemming from various etiologies (organic, psychogenic, and mixed). Efficacy was gauged utilizing several methods, including global assessment questions, diaries of erections, the International Index of Erectile Function (IIEF), and partner questionnaires. Results consistently supported sildenafil's ability to facilitate and maintain erections adequate for sexual activity across all trials, with sustained results noted in long-term extension studies spanning one year. For fixed-dose investigations, the percentage of patients reporting improved erections was 62% with 25 mg, 74% with 50 mg, and 82% with 100 mg, in contrast to just 25% in placebo groups. Beyond improvement in erectile dysfunction, IIEF analyses indicated enhancements in orgasm satisfaction, overall sexual satisfaction, and satisfaction with intercourse.
In conclusion, across all studies, 59% of diabetic patients, 43% of individuals who had undergone radical prostatectomy, and 83% of patients with spinal cord injuries reported improvements with sildenafil, contrasting with placebo rates of 16%, 15%, and 12% accordingly.

Sildenafil pharmacokinetics demonstrate proportionality across the approved dosage spectrum. The drug is primarily metabolized in the liver, chiefly via the cytochrome P450 isoenzyme 3A4, leading to the formation of an active metabolite that exhibits similar characteristics to the parent compound, sildenafil. The absorption profile indicates that sildenafil is rapidly absorbed after oral administration, achieving a mean absolute bioavailability of 41% (with a variation ranging from 25% to 63%). The human PDE5 enzyme is inhibited by sildenafil in vitro at a concentration of 3.5 nM; in human subjects, the average peak plasma concentration following a single 100 mg oral dose is about 18 ng/mL, translating to approximately 38 nM.
Plasma concentrations reach their maximum between 30 to 120 minutes (with a median of 60 minutes) post-dosing under fasting conditions. When sildenafil film-coated tablets are ingested alongside a high-fat meal, there can be a reduction in the absorption rate, characterized by a mean delay of 60 minutes in T_max and a mean C_max reduction of 29%, although the overall absorption extent remains largely unchanged (AUC decreasing by only 11%).
The volume of distribution (V_ss) at steady state is 105 L, indicating pronounced tissue distribution. Both sildenafil and its key circulating N-desmethyl metabolite exhibit approximately 96% binding to plasma proteins, a binding level that is independent of the overall drug concentration. An intriguing observation is that following administration, less than 0.0002% (averaging 188 ng) of the sildenafil dose may appear in the semen of healthy males, measured 90 minutes post-dose.
Further detailing the metabolism, sildenafil is primarily cleared by CYP3A4 (the main pathway) and CYP2C9 (a secondary route) in the liver. The major circulating metabolite arises from N-desmethylation of sildenafil, retaining a similar PDE selectivity profile, with its in vitro potency for PDE5 approximately 50% that of sildenafil. In healthy volunteers, the plasma concentrations of this metabolite are around 40% of those observed for sildenafil. The N-desmethyl metabolite is also further metabolized, and it has a terminal half-life of roughly 4 hours.
Elimination dynamics show that the total body clearance of sildenafil is approximately 41 L/h, with a terminal phase half-life ranging from 3 to 5 hours. Post-oral or intravenous administration, the majority of sildenafil is excreted as metabolites (around 80% of the oral dose) mainly in feces, with about 13% excreted through urine.
Regarding pharmacokinetics across various patient demographics, healthy elderly individuals (65 years or older) exhibit reduced sildenafil clearance, resulting in plasma concentrations that are about 90% higher than those found in younger healthy volunteers (ages 18-45). The increase in free sildenafil plasma concentration correlates to roughly 40% due to age-related differences in plasma protein binding.
In patients with mild renal impairment (creatinine clearance of 50-80 mL/min) and moderate renal impairment (creatinine clearance of 30-49 mL/min), single oral doses of sildenafil (50 mg) maintain pharmacokinetics unaffected. However, in individuals with severe renal impairment (creatinine clearance <30 mL/min), sildenafil clearance is diminished, leading to approximately double AUC (100%) and C_max (88%) relative to healthy age-matched participants without renal impairment (see Dosage & Administration).
Moreover, the AUC and C_max of the N-desmethyl metabolite are significantly increased by 200% and 79%, respectively, in subjects facing severe renal impairment compared to those with normal renal function.
In the context of hepatic insufficiency, individuals with liver cirrhosis (Child-Pugh classes A and B) display reduced sildenafil clearance, with resultant increases in AUC (85%) and C_max (47%) compared to age-matched peers without liver impairment (see Dosage & Administration). The pharmacokinetic properties of sildenafil have not been examined in patients with severely compromised hepatic function (Child-Pugh class C).

Preclinical Safety Data: Investigations into the potential carcinogenicity of sildenafil have revealed no evidence of drug-related carcinogenic effects in rats subjected to a 24-month study involving doses up to 42 times the Maximum Recommended Human Dose (MRHD) on a mg/kg basis and about five times on a mg/m² basis. Similar results were seen in mice undergoing an 18-21 month study with doses reaching up to 21 times the MRHD on a mg/kg basis (approximately two times the MRHD on a mg/m² basis). Bacterial and in vivo mutagenicity tests conducted showed negative findings. There have been no documented impacts on sperm motility or morphology following administration of a single 100 mg oral dose of sildenafil in healthy volunteers.

Sildenafil is indicated primarily for the management of erectile dysfunction, which is defined as the inability to achieve or sustain a penile erection that is sufficient for satisfying sexual performance. It is essential to acknowledge that for sildenafil to exert its therapeutic effect, sexual stimulation is a prerequisite.

Sildenafil tablets are designated for oral use.
Use in Adults: Film-coated tablets: For the majority of patients, a standard recommended dosage is 50 mg, administered as needed approximately one hour prior to sexual activity. Dosages may be adjusted based on both effectiveness and tolerability, with a maximum allowed dosage of 100 mg or a minimum of 25 mg. Note that the maximum dosing frequency permissible is once per day.
Use in Patients with Impaired Renal Function: Adjustments for dosage are unnecessary in those with mild to moderate renal impairment (creatinine clearance = 30 - 80 mL/min). Given that sildenafil clearance diminishes in individuals suffering from severe renal impairment (creatinine clearance <30 mL/min), consideration of a 25 mg dosage is advised.
Use in Patients with Impaired Hepatic Function: For patients experiencing hepatic impairment (such as cirrhosis), a recommended starting dose of 25 mg is suggested.
Use in Patients Using Other Medications: Due to the potential interactions observed in patients concurrently treated with ritonavir (see Interactions), it is advised that no more than a single dose of 25 mg sildenafil be administered in a 48-hour timeframe. Patients receiving concomitant therapy involving CYP3A4 inhibitors (for instance, erythromycin, saquinavir, ketoconazole, and itraconazole) should consider a starting dose of 25 mg (see Interactions).
To reduce the risk of developing postural hypotension, patients should be stabilized on alpha-blocker therapy prior to initiating sildenafil treatment. In this scenario, starting sildenafil at lower doses is advisable (see Precautions and Interactions). Use in Children: Sildenafil is not intended for pediatric use (<18 years old).
Use in Elderly Men: Adjustments to dosage are generally not necessary in older patients.

In trials involving healthy volunteers, administration of single doses up to 800 mg produced adverse events comparable to those observed at lower dose levels, albeit with increased incidence rates and severities. Should an overdose occur, standard supportive measures should be implemented as necessary. It is important to note that renal dialysis is not expected to expedite clearance due to sildenafil's high plasma protein binding and lack of urinary elimination.

Sildenafil is contraindicated in individuals with a known hypersensitivity to any tablet components, including microcrystalline cellulose, calcium hydrogen phosphate, croscarmellose sodium, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, lactose, triacetin, and FD & C Blue #2 aluminum lake. It has been observed that sildenafil enhances the hypotensive effects associated with both acute and chronic nitrates, making its concurrent use with nitric oxide donors, organic nitrates, or organic nitrites in any formulation—either on a regular or intermittent basis—strongly contraindicated (see Interactions). Additionally, the co-administration of PDE5 inhibitors, including sildenafil, and guanylate cyclase stimulators, such as riociguat, is also contraindicated due to the potential for symptomatic hypotension.

A comprehensive medical history and thorough physical examination should be conducted to accurately diagnose erectile dysfunction, ascertain its potential underlying causes, and determine appropriate treatment options.
Given the cardiovascular risks associated with sexual activity, physicians may wish to evaluate the cardiovascular status of patients before initiating any treatment for erectile dysfunction. Medications aimed at treating erectile dysfunction should not be prescribed to men for whom sexual activity is contraindicated.
There have been reports of serious cardiovascular events—such as myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhages, and transient ischemic attacks—following the use of sildenafil, typically associated with sexual activity. Many of these patients had pre-existing cardiovascular risk factors. Such events may occur during or shortly after sexual activity, or shortly after sildenafil use without sexual interaction, as well as hours to days thereafter. Direct links between these occurrences and sildenafil, sexual activity, underlying cardiovascular disease, or other factors remain indeterminate.
In clinical trials, sildenafil has exhibited vasodilatory properties that may transiently lower blood pressure (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions). For most patients, this is of limited concern, but physicians must consider potential adverse effects on patients with certain pre-existing conditions, particularly in relation to sexual activity. Individuals particularly susceptible to the effects of vasodilators include those with left ventricular outflow obstructions (for example, aortic stenosis or hypertrophic obstructive cardiomyopathy) and those with rare syndromes, such as multiple system atrophy, resulting in severely impaired blood pressure autonomic control.
Instances of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition leading to vision loss, have been infrequently reported following the use of all PDE5 inhibitors, including sildenafil. Most affected patients had risk factors like low cup-to-disc ratios ("crowded disc"), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia, and smoking. An observational study indicated recent PDE5 inhibitor use may correlate with a two-fold increase in NAION risk within five half-lives of the drug's usage. According to published data, the general annual incidence of NAION is estimated at 2.5-11.8 cases per 100,000 males aged 50 and above in the population. Patients experiencing sudden visual loss should cease sildenafil and seek immediate medical attention.
Those who have previously suffered from NAION are at heightened risk for recurrence, thus healthcare providers should communicate this risk with such patients, weighing anticipated benefits against potential risks when considering PDE5 inhibitor therapy. Close monitoring is advised when sildenafil is administered to patients taking alpha-blockers, given the possibility of symptomatic hypotension in a select few individuals (see Interactions). To minimize postural hypotension risk, patients should be hemodynamically stable on alpha-blocker therapy before commencing sildenafil treatment. Initiating sildenafil at reduced doses should also be considered (see Dosage & Administration), and healthcare professionals should guide patients on how to respond to postural hypotensive symptoms.
A small minority of patients diagnosed with retinitis pigmentosa exhibit inherited disorders of retinal phosphodiesterases. Given the lack of safety data on sildenafil for such patients, caution is warranted when prescribing the drug. In vitro studies suggest sildenafil may enhance the antiaggregatory impact of sodium nitroprusside (a nitric oxide donor); therefore, exercise caution in patients with bleeding disorders or active peptic ulcers when considering sildenafil therapy.
Finally, treatment for erectile dysfunction using these agents should be approached carefully in patients with anatomical anomalies of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie's disease) or in individuals predisposed to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia). Instances of prolonged erections and priapism have been documented post-marketing for sildenafil. If an erection persists beyond four hours, immediate medical assistance should be sought, as neglected priapism can result in irreversible penile tissue damage and permanent impotence.
The safety and effectiveness of sildenafil used in combination with other PDE5 inhibitors or other pulmonary arterial hypertension (PAH) treatment regimens containing sildenafil (e.g., REVATIO), or other erectile dysfunction therapies remain uninvestigated and hence, is not recommended.
Reports of sudden hearing loss or decrease in hearing have occurred in a limited number of post-marketing and clinical trial cases involving all PDE5 inhibitors including sildenafil. Most presented with pre-existing risk factors for sudden hearing loss. While no causal relationship has been established between PDE5 inhibitors and sudden hearing changes, it is prudent to instruct patients to cease sildenafil and consult a physician immediately in such instances.
Effects on Ability to Drive and use Machines: Given that dizziness and altered visual perception have been reported during clinical trials with sildenafil, patients should be aware of their individual reactions to the medication before engaging in driving or operating machinery. The impact of sildenafil on driving and machinery operation abilities remains unexamined.

Sildenafil is contraindicated for use in women. No teratogenic effects, fertility impairments, or adverse outcomes on peri-/post-natal development have been noted in reproduction studies conducted with rats and rabbits following oral sildenafil administration. Adequately controlled studies in pregnant or lactating women are still lacking.

The reported adverse events are typically transient and range from mild to moderate intensity. In fixed-dose studies, a higher incidence of certain adverse events was noted as dosage increased. The nature of adverse events observed in flexible-dose studies, which most accurately depict the recommended dosage regimen, mirrored those from fixed-dose studies.
The most frequently reported adverse reactions include headaches and flushing. (Refer to accompanying table.)

Click on icon to see table/diagram/image

At the previously mentioned recommended dosage range, adverse events communicated were similar to those detailed prior, albeit generally reported with higher frequency. In an extensive analysis of double-blind, placebo-controlled clinical trials encompassing over 700 person-years of observation on placebo and exceeding 1300 person-years on sildenafil, no disparities were evident regarding the incidence rate of myocardial infarctions (MI) or cardiovascular mortality among patients receiving sildenafil compared to those on placebo. The rates of MI were calculated at 1.1 per 100 person-years for both sildenafil and placebo utilizers, while the cardiovascular mortality rates were 0.3 per 100 person-years among both groups.

Effects of Other Medicinal Products on Sildenafil: In vitro studies: Sildenafil's metabolism is chiefly mediated through cytochrome P450 (CYP) isoforms 3A4 (predominantly) and 2C9 (to a lesser extent). Consequently, inhibitors of these isoenzymes may reduce sildenafil clearance, whereas inducers may enhance it.
In vivo studies: Population-based pharmacokinetic analyses of clinical trial data indicated a reduction in sildenafil clearance upon co-administration with CYP3A4 inhibitors (e.g., ketoconazole, erythromycin, cimetidine). When cimetidine (800 mg) was concurrently administered with sildenafil (50 mg) in healthy volunteers, a 56% increase in plasma sildenafil levels was observed. The administration of a single 100 mg sildenafil dose alongside erythromycin (at steady-state, 500 mg twice daily over 5 days) caused a substantial 182% increase in sildenafil's systemic exposure (AUC). In a similar vein, concurrent dosing of the HIV protease inhibitor saquinavir (also a CYP3A4 inhibitor) at steady-state (1200 mg three times daily) with sildenafil (100 mg single dose) resulted in a 140% increase in C_max and a remarkable 210% increase in AUC. Notably, sildenafil does not alter saquinavir's pharmacokinetics (see Dosage & Administration). It is anticipated that the effects of more potent CYP3A4 inhibitors such as ketoconazole and itraconazole would result in even more pronounced changes.
Co-administration with ritonavir—a potent CYP450 inhibitor—at steady-state (500 mg twice daily) yielded a staggering 300% (4-fold) increase in C_max and a staggering 1000% (11-fold) increase in sildenafil plasma AUC. Even after 24 hours, plasma sildenafil levels remained elevated at approximately 200 ng/mL, compared to roughly 5 ng/mL when sildenafil was administered in isolation. This aligns with ritonavir's significant effects across a broad spectrum of P450 substrates. When sildenafil is appropriately dosed for subjects receiving intense CYP3A4 inhibitors, the maximum free plasma sildenafil concentration does not surpass 200 nM for any individual, remaining consistently well tolerated. Instances of antacid (magnesium hydroxide/aluminum hydroxide) administration produced no alterations in sildenafil's bioavailability.
In a study involving healthy male participants, the endothelin antagonist bosentan (moderate CYP3A4 inducer) administered at steady-state (125 mg twice per day) alongside sildenafil at steady-state (80 mg three times a day) resulted in a notable 62.6% and 55.4% drop in sildenafil AUC and C_max, respectively. Conversely, sildenafil elevated bosentan's AUC and C_max by 49.8% and 42%, correspondingly. Co-administration of potent CYP3A4 inducers (like rifampin) is anticipated to produce more substantial decreases in sildenafil plasma concentrations.
Pharmacokinetic data from clinical trial participants indicated no alterations in sildenafil pharmacokinetics consequent to CYP2C9 inhibitors (like tolbutamide, warfarin), CYP2D6 inhibitors (including selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide diuretics, ACE inhibitors, and calcium channel blockers. No significant effects were documented when sildenafil (50 mg) was administered alongside tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9. Administration of sildenafil (100 mg) did not impact the pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, which are also CYP3A4 substrates (as previously discussed). An Additional study involving sildenafil at steady state (80 mg three times a day) resulted in a 49.8% increase in bosentan AUC and a 42% uptick in bosentan C_max (125 mg twice daily) (refer to earlier discussions under Effects of Other Medicinal Products on Sildenafil).
Sildenafil (50 mg) did not amplify the increase in bleeding duration instigated by aspirin (150 mg) nor did it augment the hypotensive effect of alcohol in healthy volunteers, where mean maximum blood alcohol levels reached 0.08% (80 mg/dL). No significant interaction was detected while sildenafil (100 mg) was co-administered with amlodipine in hypertensive individuals, with mean additional reductions in supine blood pressure recorded at 8 mmHg systolic and 7 mmHg diastolic. A review of the safety database indicated no discernible differences in adverse events between patients receiving sildenafil with versus without antihypertensive medications.

Incompatibilities: Not applicable.

Store at temperatures not exceeding 30°C.

G04BE03 - sildenafil; Belongs to the class of medications utilized in the treatment of erectile dysfunction.