Treatment with doxazosin continued for at least 7 days after dose period 1. Thereafter, sildenafil citrate 100 mg or matching placebo was administered simultaneously with doxazosin 4 mg (14 subjects) or doxazosin 8 mg (6 subjects) in standard crossover fashion. The mean subject age in this study was 66.4 years.Twenty-five subjects were screened. Two were discontinued after study period 1: one failed to meet pre-dose screening qualifications and the other experienced symptomatic hypotension as a moderately severe adverse event 30 minutes after dosing with open-label sildenafil citrate 50 mg. Of the twenty subjects who were ultimately assigned to treatment, a total of 13 subjects successfully completed dose period 1, and seven had successfully completed the previous doxazosin study (using sildenafil citrate 50 mg).For the 20 subjects who received sildenafil citrate 100 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows:The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 100 mg sildenafil citrate or matching placebo are shown in Figure 4.Figure 4: Mean Standing Systolic Blood Pressure Change from BaselineBlood pressure was measured after administration of sildenafil citrate at the same times as those specified for the previous doxazosin studies. There were three subjects who had a standing SBP of < 85 mmHg. All three were taking sildenafil citrate 100 mg, and all three reported mild adverse events at the time of reductions in standing SBP, including vasodilation and lightheadedness.
Overdose/Missed Dose
A total dose of 40 mg sildenafil was administered by four intravenous infusions.The results from this pilot study are shown in Table 3; the mean resting systolic and diastolic blood pressures decreased by 7% and 10% compared to baseline in these patients. Mean resting values for right atrial pressure, pulmonary artery pressure, pulmonary artery occluded pressure and cardiac output decreased by 28%, 28%, 20% and 7% respectively. Even though this total dosage produced plasma sildenafil concentrations which were approximately 2 to 5 times higher than the mean maximum plasma concentrations following a single oral dose of 100 mg in healthy male volunteers, the hemodynamic response to exercise was preserved in these patients.In a double-blind study, 144 patients with erectile dysfunction and chronic stable angina limited by exercise, not receiving chronic oral nitrates, were randomized to a single dose of placebo or sildenafil citrate 100 mg 1 hour prior to exercise testing. The primary endpoint was time to limiting angina in the evaluable cohort. The mean times (adjusted for baseline) to onset of limiting angina were 423.6 and 403.7 seconds for sildenafil (N=70) and placebo, respectively.
Are you currently using Sildenafil (Viagra, Revatio)?
These results demonstrated that the effect of sildenafil citrate on the primary endpoint was statistically non-inferior to placebo.Effects of Sildenafil citrate on Vision: At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. Subjects in the study reported this finding as difficulties in discriminating blue/green. An evaluation of visual function at doses up to twice the maximum recommended dose revealed no effects of sildenafil citrate on visual acuity, intraocular pressure, or pupillometry.Effects of Sildenafil citrate on Sperm: There was no effect on sperm motility or morphology after single 100 mg oral doses of sildenafil citrate in healthy volunteers.12.3 PharmacokineticsSildenafil citrate is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 25 to 63%). The pharmacokinetics of sildenafil uk price sildenafil are dose-proportional over the recommended dose range.
Dosage for ED
It is eliminated predominantly by hepatic metabolism (mainly CYP3A4) and is converted to an active metabolite with properties similar to the parent, sildenafil. Both sildenafil and the metabolite have terminal half lives of about 4 hours.Mean sildenafil plasma concentrations measured after the administration of a single oral dose of 100 mg to healthy male volunteers is depicted below:Figure 5: Mean Sildenafil Plasma Concentrations in Healthy Male Volunteers.Absorption and Distribution: Sildenafil citrate is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil citrate is taken with a high fat meal, the rate of absorption is reduced, with a mean delay in T max of 60 minutes and a mean reduction in C max of 29%. The mean steady state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. There were four subjects with a decrease from baseline in standing systolic BP > 30 mmHg following sildenafil citrate 100 mg, one subject with a decrease from baseline in standing systolic BP > 30 mmHg following placebo and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both sildenafil citrate and placebo. While there were no severe adverse events potentially related to blood pressure reported in this study, one subject reported moderate vasodilatation after both sildenafil citrate 50 mg and 100 mg. There were no episodes of syncope reported in this study.Effect of Sildenafil citrate on Blood Pressure When Co-administered with Anti-hypertensives: When sildenafil citrate 100 mg oral was co-administered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic.Effect of Sildenafil citrate on Blood Pressure When Co-administered with Alcohol: Sildenafil citrate (50 mg) did not potentiate the hypotensive effect of alcohol (0.5 g/kg) in healthy volunteers with mean maximum blood alcohol levels of 0.08%. The maximum observed decrease in systolic blood pressure was -18.5 mmHg when sildenafil was co-administered with alcohol versus -17.4 mmHg when alcohol was administered alone. The maximum observed decrease in diastolic blood pressure was -17.2 mmHg when sildenafil was co-administered with alcohol versus -11.1 mmHg when alcohol was administered alone.
| Product | Dosage | Quantity + Bonus | Price | |
|---|---|---|---|---|
| Kamagra Oral Jelly | 100mg | 220 + 18 Sachets | 662.24€ 630.70€ | |
| Viagra Generic | 200mg | 30 + 2 Pills | 83.07€ 79.11€ | |
| Viagra Generic | 200mg | 270 + 10 Pills | 379.76€ 361.68€ | |
| Kamagra Soft Tabs | 100mg | 272 + 12 Pills | 593.42€ 565.16€ | |
| Kamagra Oral Jelly | 100mg | 63 + 7 Sachets | 224.18€ 213.50€ | |
| Kamagra Polo | 100mg | 84 + 4 Pills | 244.49€ 232.85€ | |
| Kamagra | 100mg | 12 Pills | 55.64€ 52.99€ | |
| Kamagra Polo | 100mg | 20 Pills | 83.56€ 79.58€ | |
| Viagra Generic | 150mg | 180 + 10 Pills | 236.46€ 225.20€ | |
| Kamagra | 100mg | 32 Pills | 121.24€ 115.47€ | |
| Kamagra Soft Tabs | 100mg | 60 + 4 Pills | 180.59€ 171.99€ | |
| Kamagra Polo | 100mg | 12 Pills | 60.21€ 57.34€ |
There were no reports sildenafil citrate tablet of postural dizziness or orthostatic hypotension. The maximum recommended dose of 100 mg sildenafil was not evaluated in this study [ see Drug Interactions (7.5)].Effects of Sildenafil citrate on Cardiac Parameters: Single oral doses of sildenafil up to 100 mg produced no clinically relevant changes in the ECGs of normal male volunteers.Studies have produced relevant data on the effects of sildenafil citrate on cardiac output. In one small, open-label, uncontrolled, pilot study, eight patients with stable ischemic heart disease underwent Swan-Ganz catheterization. A total dose of 40 mg sildenafil was administered by four intravenous infusions.The results from this pilot study are shown in Table 3; the mean resting systolic and diastolic blood pressures decreased by 7% and 10% compared to baseline in these patients. Mean resting values for right atrial pressure, pulmonary artery pressure, pulmonary artery occluded pressure and cardiac output decreased by 28%, 28%, 20% and 7% respectively.
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Treatment with doxazosin continued for at least 7 days after dose period 1. Thereafter, sildenafil citrate 100 mg or matching placebo was administered simultaneously with doxazosin 4 mg (14 subjects) or doxazosin 8 mg (6 subjects) in standard crossover fashion. The mean subject age in this study was 66.4 years.Twenty-five subjects were screened. Two were discontinued after study period 1: one failed to meet pre-dose screening qualifications and the other experienced symptomatic hypotension as a moderately severe adverse event 30 minutes after dosing with open-label sildenafil citrate 50 mg. Of the twenty subjects who were ultimately assigned to treatment, a total of 13 subjects successfully completed dose period 1, and seven had successfully completed the previous doxazosin study (using sildenafil citrate 50 mg).For the 20 subjects who received sildenafil citrate 100 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows:The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 100 mg sildenafil citrate or matching placebo are shown in Figure 4.Figure 4: Mean Standing Systolic Blood Pressure Change from BaselineBlood pressure was measured after administration of sildenafil citrate at the same times as those specified for the previous doxazosin studies.
Study 3: Sildenafil citrate with Doxazosin
There were three subjects who had a standing SBP of < 85 mmHg. All three were taking sildenafil citrate 100 mg, and all three reported mild adverse events at the time of reductions in standing SBP, including vasodilation and lightheadedness. There were four subjects with a decrease from baseline in standing systolic BP > 30 mmHg following sildenafil citrate 100 mg, one subject with a decrease from baseline in standing systolic BP > 30 mmHg following placebo and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both sildenafil citrate and placebo. While there were no severe adverse events potentially related to blood pressure reported in this study, one subject reported moderate vasodilatation after both sildenafil citrate 50 mg and 100 mg. There were no episodes of syncope reported in this study.Effect of Sildenafil citrate on Blood Pressure When Co-administered with Anti-hypertensives: When sildenafil citrate 100 mg oral was co-administered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic.Effect of Sildenafil citrate on Blood Pressure When Co-administered with Alcohol: Sildenafil citrate (50 mg) did not potentiate the hypotensive effect of alcohol (0.5 g/kg) in healthy volunteers with mean maximum blood alcohol levels of 0.08%.
Serious Adverse Effects
The maximum observed decrease in systolic blood pressure was -18.5 mmHg when sildenafil was co-administered with alcohol versus -17.4 mmHg when alcohol was administered alone. The maximum observed decrease in diastolic blood pressure was -17.2 mmHg when sildenafil was co-administered with alcohol versus -11.1 mmHg when alcohol was administered alone. There were no reports sildenafil citrate tablet of postural dizziness or orthostatic hypotension. The maximum recommended dose of 100 mg sildenafil was not evaluated in this study [ see Drug Interactions (7.5)].Effects of Sildenafil citrate on Cardiac Parameters: Single oral doses of sildenafil up to 100 mg produced no clinically relevant changes in the ECGs of normal male volunteers.Studies have produced relevant data on the effects of sildenafil citrate on cardiac output. In one small, open-label, uncontrolled, pilot study, eight patients with stable ischemic heart disease underwent Swan-Ganz catheterization. Even though this total dosage produced plasma sildenafil concentrations which were approximately 2 to 5 times higher than the mean maximum plasma concentrations following a single oral dose of 100 mg in healthy male volunteers, the hemodynamic response to exercise was preserved in these patients.In a double-blind study, 144 patients with erectile dysfunction and chronic stable angina limited by exercise, not receiving chronic oral nitrates, were randomized to a single dose of placebo or sildenafil citrate 100 mg 1 hour prior to exercise testing. The primary endpoint was time to limiting angina in the evaluable cohort.
- Store sildenafil tablets in a cool, dry place away from moisture.
- Keep out of reach of children and pets.
- Expiry date can be checked on the packaging.
The mean times (adjusted for baseline) to onset of limiting angina were 423.6 and 403.7 seconds for sildenafil (N=70) and placebo, respectively.
| Study | Population Sample | Improvement Rate | Onset Time | Notes |
|---|---|---|---|---|
| Phase III Trial A | 500 men with ED | 85% reported improvement | 30-60 min | Compared with placebo |
| Phase III Trial B | 300 women (off-label use) | Variable, limited evidence | N/A | Under investigation for other indications |
| Post-marketing Data | 10,000+ patients | 80-90% efficacy reported | Varies | Real-world effectiveness observations |
These results demonstrated that the effect of sildenafil citrate on the primary endpoint was statistically non-inferior to placebo.Effects of Sildenafil citrate on Vision: At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. Subjects in the study reported this finding as difficulties in discriminating blue/green.
| Condition | Risk | Recommendations |
|---|---|---|
| Concomitant Nitrate Use | Severe hypotension | Avoid combination |
| Cardiac Conditions | Risk of myocardial infarction or arrhythmia | Consult cardiologist |
| Severe Liver Impairment | Altered drug metabolism | Dose adjustment needed |
| Hypotension (low BP) | Further blood pressure reduction | Use with caution |
An evaluation of visual function at doses up to twice the maximum recommended dose revealed no effects of sildenafil citrate on visual acuity, intraocular pressure, or pupillometry.Effects of Sildenafil citrate on Sperm: There was no effect on sperm motility or morphology after single 100 mg oral doses of sildenafil citrate in healthy volunteers.12.3 PharmacokineticsSildenafil citrate is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 25 to 63%). The pharmacokinetics of sildenafil uk price sildenafil are dose-proportional over the recommended dose range.
What to avoid
It is eliminated predominantly by hepatic metabolism (mainly CYP3A4) and is converted to an active metabolite with properties similar to the parent, sildenafil.
Chemical synthesis
Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations.Based upon measurements of sildenafil in semen of healthy volunteers 90 minutes after dosing, less than 0.001% of the administered dose may appear in the semen of patients.Metabolism and Excretion: Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is itself further metabolized. This metabolite has a PDE selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil’s pharmacologic effects.After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose).
Administration Notes
Similar values for pharmacokinetic parameters were seen in normal volunteers and in the patient population, using a population pharmacokinetic approach.Pharmacokinetics in Special PopulationsGeriatrics: 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 younger volunteers (18 to 45 years). 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 Dosage and Administration (2.5), and Use in Specific Populations (8.5)]Renal Impairment: In volunteers with mild (CLcr=50 to 80 mL/min) and moderate (CLcr=30 to 49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil citrate (50 mg) were not altered. In volunteers with severe (CLcr <30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C max compared to age-matched volunteers with no renal impairment [ see Dosage and Administration (2.5), and Use in Specific Populations (8.6)].In addition, N-desmethyl metabolite AUC and C max values significantly increased by 200% and 79%, respectively in subjects with severe renal impairment compared to subjects with normal renal function.Hepatic Impairment: In volunteers with hepatic impairment (Child-Pugh Class A and B), sildenafil clearance was reduced, resulting in increases in AUC (85%) and C max (47%) compared to age-matched volunteers with no hepatic impairment. The pharmacokinetics of sildenafil in patients with severely impaired hepatic function (Child-Pugh Class C) have not been studied [ see Dosage and Administration (2.5), and Use in Specific Populations (8.7)].Therefore, age >65, hepatic impairment and severe renal impairment are associated with increased plasma levels of sildenafil.
Sildenafil Tablets for ED
Both sildenafil and the metabolite have terminal half lives of about 4 hours.Mean sildenafil plasma concentrations measured after the administration of a single oral dose of 100 mg to healthy male volunteers is depicted below:Figure 5: Mean Sildenafil Plasma Concentrations in Healthy Male Volunteers.Absorption and Distribution: Sildenafil citrate is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil citrate is taken with a high fat meal, the rate of absorption is reduced, with a mean delay in T max of 60 minutes and a mean reduction in C max of 29%. The mean steady state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues.
- Sildenafil citrate is used to treat erectile dysfunction.
- It enhances blood flow to the penis for a stronger erection.
- Commonly available in tablet form for oral use.
Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations.Based upon measurements of sildenafil in semen of healthy volunteers 90 minutes after dosing, less than 0.001% of the administered dose may appear in the semen of patients.Metabolism and Excretion: Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is itself further metabolized. This metabolite has a PDE selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug.
What happens if I miss a dose?
Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil’s pharmacologic effects.After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose).
| Property | Description | Value | Notes |
|---|---|---|---|
| Molecular Formula | C22H30N6O4S | ||
| Molecular Weight | 474.58 g/mol | ||
| Melting Point | 189-192°C | ||
| Solubility in Water | Slightly soluble | at 25°C | |
| pH Range | 3.8 - 4.0 | in aqueous solution |
Similar values for pharmacokinetic parameters were seen in normal volunteers and in the patient population, using a population pharmacokinetic approach.Pharmacokinetics in Special PopulationsGeriatrics: 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 younger volunteers (18 to 45 years). 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 Dosage and Administration (2.5), and Use in Specific Populations (8.5)]Renal Impairment: In volunteers with mild (CLcr=50 to 80 mL/min) and moderate (CLcr=30 to 49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil citrate (50 mg) were not altered. In volunteers with severe (CLcr <30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C max compared to age-matched volunteers with no renal impairment [ see Dosage and Administration (2.5), and Use in Specific Populations (8.6)].In addition, N-desmethyl metabolite AUC and C max values significantly increased by 200% and 79%, respectively in subjects with severe renal impairment compared to subjects with normal renal function.Hepatic Impairment: In volunteers with hepatic impairment (Child-Pugh Class A and B), sildenafil clearance was reduced, resulting in increases in AUC (85%) and C max (47%) compared to age-matched volunteers with no hepatic impairment. The pharmacokinetics of sildenafil in patients with severely impaired hepatic function (Child-Pugh Class C) have not been studied [ see Dosage and Administration (2.5), and Use in Specific Populations (8.7)].Therefore, age >65, hepatic impairment and severe renal impairment are associated with increased plasma levels of sildenafil.