5. WARNINGS AND PRECAUTIONS

Drug Interactions
Brand names
5.8 Effects on Bleeding
Renal Dose Adjustments
2.3 Dosage Adjustments in Specific Situations
5.6 Adverse Reactions with the Concomitant Use of Ritonavir
5.5 Hypotension when Co-administered with Alpha-blockers or Anti-hypertensives

Drug Interactions

Sildenafil is approximately 4,000-fold more selective for PDE5 compared to PDE3. PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina which is involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision [ see Clinical Pharmacology (12.2)].In addition to human corpus cavernosum smooth muscle, PDE5 is also found in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle, brain, heart, liver, kidney, lung, pancreas, prostate, bladder, testis, and seminal vesicle. The inhibition of PDE5 in some of these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of NO observed in vitro, an inhibition of platelet thrombus formation in vivoand peripheral arterial-venous dilatation in vivo.12.2 PharmacodynamicsEffects of Sildenafil citrate on Erectile Response:In eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction, sexual stimulation resulted in improved erections, as assessed by an objective measurement of hardness and duration of erections (RigiScan ®), after sildenafil citrate administration compared with placebo.

Related treatment guides

Most studies assessed the efficacy of sildenafil citrate approximately 60 minutes post dose. The erectile response, as assessed by RigiScan ®, generally increased with increasing sildenafil dose and plasma concentration. The time course of effect was examined in one study, showing an effect for up to 4 hours but the response was diminished compared to 2 hours.Effects of Sildenafil citrate on Blood Pressure:Single oral doses of sildenafil (100 mg) administered to healthy volunteers produced decreases in sitting blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8.3/5.3 mmHg). The decrease in sitting blood pressure was most notable approximately 1 to 2 hours after dosing, and was not different than placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg of Sildenafil citrate, therefore the effects are not related to dose or plasma levels within this dosage range. There are no data with the use of Sildenafil Citrate in pregnant women to inform any drug-associated risks for adverse developmental outcomes. Animal reproduction studies conducted with sildenafil did not show adverse developmental outcomes when administered during organogenesis in rats and rabbits at oral doses up to 16 and 32 times, respectively, the maximum recommended human dose (MRHD) of 100 mg/day on a mg/m 2basis (see Data). No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits which received oral doses up to 200 mg/kg/day during organogenesis. In the rat pre- and postnatal development study, the no observed adverse effect dose was 30 mg/kg/day given for 36 days, about 2 times the MRHD on a mg/m 2basis in a 50 kg subject. Sildenafil citrate is not indicated for use in pediatric patients.

Country	Approval Status	Maximum Allowed Dose	Remarks
United States	Approved for ED and pulmonary hypertension	120 mg	Prescription-only, controlled use
European Union	Approved for ED, off-label for other uses	120 mg	Stringent prescribing regulations
Canada	Approved, similar to US	120 mg	Must be prescribed by healthcare provider
Australia	Approved with restrictions	120 mg	Medical supervision required
India	Available, OTC in some regions	120 mg	Use under medical guidance recommended

Safety and effectiveness have not been established in pediatric patients. Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil resulting in approximately 84% and 107% higher plasma AUC values of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy young volunteers (18 to 45 years) [ see Clinical Pharmacology (12.3)].

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Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively [ see Clinical Pharmacology (12.3)].

Property	Description	Typical Dose	Onset of Action	Duration of Effect	Mechanism of Action
Bioavailability	Approximately 40%	120 mg	30-60 minutes	Up to 6 hours	Inhibits PDE5 enzyme in smooth muscle
Half-life	Approximately 4 hours	N/A	N/A	N/A	Enhances nitric oxide signaling
Metabolism	Liver via CYP3A4 and CYP2C9	N/A	N/A	N/A	Prevents cGMP breakdown
Excretion	Mainly via feces (80%), urine (13%)	N/A	N/A	N/A	Eliminates unchanged drug
Peak Plasma Levels	Achieved within 30-120 minutes	120 mg	30 minutes	N/A	Related to dose and absorption rate

Brand names

11 DESCRIPTION Sildenafil tablets USP, an oral therapy for erectile dysfunction, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).Sildenafil citrate, USP is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H-pyrazolo [4,3- d] pyrimidin-5-yl)-4- ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate and has the following structural formula:Sildenafil citrate, USP is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7.Sildenafil Citrate USP is formulated as blue, round, biconvex, film-coated tablets containing sildenafil citrate equivalent to 25 mg, 50 mg or 100 mg of sildenafil for oral administration. In addition to the active ingredient, sildenafil citrate, each tablet contains the following inactive ingredients: croscarmellose sodium, dibasic calcium phosphate anhydrous, hypromellose, lake of indigo carmine, microcrystalline cellulose, sodium stearyl fumarate, titanium dioxide and triacetin. Sildenafil tablets USP, an oral therapy for erectile dysfunction, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Sildenafil citrate, USP is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H-pyrazolo [4,3- d] pyrimidin-5-yl)-4- ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate and has the following structural formula: Sildenafil citrate, USP is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7. Sildenafil Citrate USP is formulated as blue, round, biconvex, film-coated tablets containing sildenafil citrate equivalent to 25 mg, 50 mg or 100 mg of sildenafil for oral administration.

Interactions that increase your risk for side effects

12 CLINICAL chew sildenafil PHARMACOLOGY 12.1 Mechanism of ActionThe physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood.Sildenafil enhances the effect of NO by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil at recommended doses has no effect in the absence of sexual stimulation.Binding CharacteristicsStudies in vitrohave shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, >80-fold for PDE1, >700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). No dose adjustment is required for mild (CLcr=50 to 80 mL/min) and moderate (CLcr=30 to 49 mL/min) renal impairment.

5.8 Effects on Bleeding

Of the total number of subjects in clinical studies of sildenafil citrate, 18% were 65 years and older, while 2% were 75 years and older. No overall differences in safety or efficacy were observed between older (≥ 65 years of age) and younger (< 65 years of age) subjects. However, since higher plasma levels may increase the incidence of adverse reactions, a starting dose of 25 mg should be considered in older subjects due to the higher systemic exposure [ see Dosage and Administration (2.5)]. No dose adjustment is required for mild (CLcr=50 to 80 mL/min) and moderate (CLcr=30 to 49 mL/min) renal impairment. A starting dose of 25 mg should be considered in patients with severe renal impairment [ see Dosage and Administration (2.5)and Clinical Pharmacology (12.3)].

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In volunteers with hepatic impairment (Child-Pugh Class A and B), sildenafil clearance was reduced, resulting in higher plasma exposure of sildenafil (47% for C maxand 85% for AUC). 10 OVERDOSAGE In studies with healthy volunteers of single doses up to 800 mg, adverse reactions were similar to those seen at lower doses but incidence rates and severities were increased.In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine. In studies with healthy volunteers of single doses up to 800 mg, adverse reactions were similar to those seen at lower doses but incidence rates and severities were increased. In cases of overdose, standard supportive measures should be adopted as required. A starting dose of 25 mg should be considered in patients with severe renal impairment [ see Dosage and Administration (2.5)and Clinical Pharmacology (12.3)]. In volunteers with hepatic impairment (Child-Pugh Class A and B), sildenafil clearance was reduced, resulting in higher plasma exposure of sildenafil (47% for C maxand 85% for AUC). 10 OVERDOSAGE In studies with healthy volunteers of single doses up to 800 mg, adverse reactions were similar to those seen at lower doses but incidence rates and severities were increased.In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine. In studies with healthy volunteers of single doses up to 800 mg, adverse reactions were similar to those seen at lower doses but incidence rates and severities were increased. In cases of overdose, standard supportive measures should be adopted as required. 11 DESCRIPTION Sildenafil tablets USP, an oral therapy for erectile dysfunction, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).Sildenafil citrate, USP is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H-pyrazolo [4,3- d] pyrimidin-5-yl)-4- ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate and has the following structural formula:Sildenafil citrate, USP is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7.Sildenafil Citrate USP is formulated as blue, round, biconvex, film-coated tablets containing sildenafil citrate equivalent to 25 mg, 50 mg or 100 mg of sildenafil for oral administration.

Condition	Risk Factors	Precautionary Notes
Nitrate use (e.g., nitroglycerin)	Risk of severe hypotension	Do not use sildenafil if on nitrates
Cardiovascular disease	Increased risk of adverse events	Consult cardiologist before use
Severe hepatic impairment	Slower drug metabolism	Adjust dosage accordingly
Retinitis pigmentosa	Possible worsening of condition	Use with caution, consult ophthalmologist
Recent stroke or MI	Elevated risk for complications	Avoid use unless cleared by a doctor

In addition to the active ingredient, sildenafil citrate, each tablet contains the following inactive ingredients: croscarmellose sodium, dibasic calcium phosphate anhydrous, hypromellose, lake of indigo carmine, microcrystalline cellulose, sodium stearyl fumarate, titanium dioxide and triacetin. Sildenafil tablets USP, an oral therapy for erectile dysfunction, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).

The drug should be taken on an empty stomach for faster effect.
Use of 120 mg may lead to priapism, a painful, prolonged erection.
Sildenafil is also used to treat pulmonary arterial hypertension at lower doses.
Do not exceed prescribed doses to avoid serious adverse reactions.
Efficacy of sildenafil depends on individual health and possible drug interactions.
Sildenafil can impair vision temporarily, including blue-tinted vision.

Sildenafil citrate, USP is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H-pyrazolo [4,3- d] pyrimidin-5-yl)-4- ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate and has the following structural formula: Sildenafil citrate, USP is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7. Sildenafil Citrate USP is formulated as blue, round, biconvex, film-coated tablets containing sildenafil citrate equivalent to 25 mg, 50 mg or 100 mg of sildenafil for oral administration.

Renal Dose Adjustments

2.3 Dosage Adjustments in Specific Situations

A starting dose of 25 mg should be considered in patients with any degree of hepatic impairment [ see Dosage and Administration (2.5)and Clinical Pharmacology (12.3)]. Sildenafil Citrate is not indicated for use in females. There are no data with the use of Sildenafil Citrate in pregnant women to inform any drug-associated risks for adverse developmental outcomes. Animal reproduction studies conducted with sildenafil did not show adverse developmental outcomes when administered during organogenesis in rats and rabbits at oral doses up to 16 and 32 times, respectively, the maximum recommended human dose (MRHD) of 100 mg/day on a mg/m 2basis (see Data). No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits which received oral doses up to 200 mg/kg/day during organogenesis.

Sildenafil Tablets or Oral Suspension for PAH

In the rat pre- and postnatal development study, the no observed adverse effect dose was 30 mg/kg/day given for 36 days, about 2 times the MRHD on a mg/m 2basis in a 50 kg subject. Sildenafil citrate is not indicated for use in pediatric patients. Safety and effectiveness have not been established in pediatric patients. Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil resulting in approximately 84% and 107% higher plasma AUC values of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy young volunteers (18 to 45 years) [ see Clinical Pharmacology (12.3)]. Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively [ see Clinical Pharmacology (12.3)]. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, >80-fold for PDE1, >700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). Sildenafil is approximately 4,000-fold more selective for PDE5 compared to PDE3. PDE3 is involved in control of cardiac contractility.

Patients with liver or kidney issues need dose adjustments and careful monitoring.
The recommended maximum dose for sildenafil is generally 100 mg per day.
Excessive use increases the likelihood of adverse cardiovascular events.
Use of sildenafil does not provide protection against sexually transmitted infections.
Some users report a persistent blue-tinged vision after high doses.
It’s essential to obtain sildenafil from reputable sources to avoid counterfeit products.

Sildenafil is only about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina which is involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision [ see Clinical Pharmacology (12.2)].In addition to human corpus cavernosum smooth muscle, PDE5 is also found in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle, brain, heart, liver, kidney, lung, pancreas, prostate, bladder, testis, and seminal vesicle.

5.6 Adverse Reactions with the Concomitant Use of Ritonavir

Larger effects were recorded among patients receiving concomitant nitrates [ see Contraindications (4.1)].Figure 1: Mean Change from Baseline in Sitting Systolic Blood Pressure, Healthy Volunteers.Effects of Sildenafil citrate on Blood Pressure When Nitroglycerin is Subsequently Administered:Based on the pharmacokinetic profile of a single 100 mg oral dose given to healthy normal volunteers, the plasma levels of sildenafil at 24 hours post dose are approximately 2 ng/mL (compared to peak plasma levels of approximately 440 ng/mL). In the following patients: age >65 years, hepatic impairment (e.g., cirrhosis), severe renal impairment (e.g., creatinine clearance <30 mL/min), and concomitant use of erythromycin or strong CYP3A4 inhibitors, plasma levels of sildenafil at 24 hours post dose have been found to be 3 to 8 times higher than those seen in healthy volunteers. Although plasma levels of sildenafil at 24 hours post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely co-administered at this time point [ see Contraindications (4.1)].Effects of Sildenafil citrate on Blood Pressure When Co-administered with Alpha-Blockers:Three double-blind, placebo-controlled, randomized, two-way crossover studies were conducted to assess the interaction of Sildenafil citrate with doxazosin, an alpha-adrenergic blocking agent.Study 1: Sildenafil citrate with DoxazosinIn the first study, a single oral dose of Sildenafil citrate 100 mg or matching placebo was administered in a 2-period crossover design to 4 generally healthy males with benign prostatic hyperplasia (BPH). The inhibition of PDE5 in some of these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of NO observed in vitro, an inhibition of platelet thrombus formation in vivoand peripheral arterial-venous dilatation in vivo.12.2 PharmacodynamicsEffects of Sildenafil citrate on Erectile Response:In eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction, sexual stimulation resulted in improved erections, as assessed by an objective measurement of hardness and duration of erections (RigiScan ®), after sildenafil citrate administration compared with placebo. Most studies assessed the efficacy of sildenafil citrate approximately 60 minutes post dose. The erectile response, as assessed by RigiScan ®, generally increased with increasing sildenafil dose and plasma concentration. The time course of effect was examined in one study, showing an effect for up to 4 hours but the response was diminished compared to 2 hours.Effects of Sildenafil citrate on Blood Pressure:Single oral doses of sildenafil (100 mg) administered to healthy volunteers produced decreases in sitting blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8.3/5.3 mmHg).

Sildenafil citrate 120 mg is often used illicitly, which increases health risks.
Long-term safety data for high doses are limited; risks are not fully understood.
Use should be personalized based on medical history and current health status.
Do not crush or chew sildenafil tablets; take them whole with water.
Combining sildenafil with other vasodilators can lead to dangerous blood pressure drops.
Always seek professional guidance before initiating or adjusting sildenafil dosage.

The decrease in sitting blood pressure was most notable approximately 1 to 2 hours after dosing, and was not different than placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg of Sildenafil citrate, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates [ see Contraindications (4.1)].Figure 1: Mean Change from Baseline in Sitting Systolic Blood Pressure, Healthy Volunteers.Effects of Sildenafil citrate on Blood Pressure When Nitroglycerin is Subsequently Administered:Based on the pharmacokinetic profile of a single 100 mg oral dose given to healthy normal volunteers, the plasma levels of sildenafil at 24 hours post dose are approximately 2 ng/mL (compared to peak plasma levels of approximately 440 ng/mL). In the following patients: age >65 years, hepatic impairment (e.g., cirrhosis), severe renal impairment (e.g., creatinine clearance <30 mL/min), and concomitant use of erythromycin or strong CYP3A4 inhibitors, plasma levels of sildenafil at 24 hours post dose have been found to be 3 to 8 times higher than those seen in healthy volunteers.

5.5 Hypotension when Co-administered with Alpha-blockers or Anti-hypertensives

Although plasma levels of sildenafil at 24 hours post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely co-administered at this time point [ see Contraindications (4.1)].Effects of Sildenafil citrate on Blood Pressure When Co-administered with Alpha-Blockers:Three double-blind, placebo-controlled, randomized, two-way crossover studies were conducted to assess the interaction of Sildenafil citrate with doxazosin, an alpha-adrenergic blocking agent.Study 1: Sildenafil citrate with DoxazosinIn the first study, a single oral dose of Sildenafil citrate 100 mg or matching placebo was administered in a 2-period crossover design to 4 generally healthy males with benign prostatic hyperplasia (BPH).

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