Label: SILDENAFIL CITRATE tablet
The AUC of the active metabolite, N-desmethyl sildenafil, was increased 62% by loop and potassium-sparing diuretics and 102% by nonspecific beta-blockers. These effects on the metabolite are not expected to be of clinical consequence.Effects of sildenafil on Other DrugsIn vitrostudies:Sildenafil is a weak inhibitor of the CYP isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 µM). Given sildenafil peak plasma concentrations of approximately 1 µM after recommended doses, it is unlikely that sildenafil will alter the clearance of substrates of these isoenzymes.In vivostudies:No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9.In a study of healthy male volunteers, sildenafil (100 mg) did not affect the steady state pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, both of which are CYP3A4 substrates.Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg).Sildenafil at steady state, at a dose not approved for the treatment of erectile dysfunction (80 mg t.i.d.) resulted in a 50% increase in AUC and a 42% increase in C maxof bosentan (125 mg b.i.d.).
Dosages of Sildenafil
The AUC of the active metabolite, N-desmethyl sildenafil, was increased 62% by loop and potassium-sparing diuretics and 102% by nonspecific beta-blockers. These effects on the metabolite are not expected to be of clinical consequence.Effects of sildenafil on Other DrugsIn vitrostudies:Sildenafil is a weak inhibitor of the CYP isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 µM). Given sildenafil peak plasma concentrations of approximately 1 µM after recommended doses, it is unlikely that sildenafil will alter the clearance of substrates of these isoenzymes.In vivostudies:No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9.In a study of healthy male volunteers, sildenafil (100 mg) did not affect the steady state pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, both of which are CYP3A4 substrates.Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg).Sildenafil at steady state, at a dose not approved for the treatment of erectile dysfunction (80 mg t.i.d.) resulted in a 50% increase in AUC and a 42% increase in C maxof bosentan (125 mg b.i.d.). The 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.
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Effects of sildenafil 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 administration compared with placebo. 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. The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 25 mg sildenafil or matching placebo are shown in Figure 2. Blood pressure was measured immediately pre-dose and at 15, 30, 45 minutes, and 1, 1.5, 2, 2.5, 3, 4, 6 and 8 hours after sildenafil or matching placebo. No severe adverse events potentially related to blood pressure effects were reported in this group. The 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. Effects of sildenafil 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 administration compared with placebo. 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.
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The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 25 mg sildenafil or matching placebo are shown in Figure 2. Blood pressure was measured immediately pre-dose and at 15, 30, 45 minutes, and 1, 1.5, 2, 2.5, 3, 4, 6 and 8 hours after sildenafil or matching placebo.
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Absorption and Distribution: Sildenafil is rapidly absorbed. Protein binding is independent of total drug concentrations. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesisSildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure (AUCs) for unbound sildenafil and its major metabolite of 20- and 38- times, for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 100 mg. Sildenafil was not carcinogenic when administered to mice for 18-21 months at dosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately 0.4 times the MRHD on a mg/m 2basis in a 50 kg subject.MutagenesisSildenafil was negative in in vitrobacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitrohuman lymphocytes and in vivomouse micronucleus assays to detect clastogenicity.Impairment of FertilityThere was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days to females and 102 days to males, a dose producing an AUC value of more than 25 times the human male AUC. 14 CLINICAL STUDIES In clinical studies, sildenafil was assessed for its effect on the ability of men with erectile dysfunction (ED) to engage in sexual activity and in many cases specifically on the ability to achieve and maintain an erection sufficient for satisfactory sexual activity.
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Sildenafil was evaluated primarily at doses of 25 mg, 50 mg and 100 mg in 21 randomized, double-blind, placebo-controlled trials of up to 6 months in duration, using a variety of study designs (fixed dose, titration, parallel, crossover). Sildenafil was administered to more than 3,000 patients aged 19 to 87 years, with ED of various etiologies (organic, psychogenic, mixed) with a mean duration of 5 years. Sildenafil demonstrated statistically significant improvement compared to placebo in all 21 studies. The studies that established benefit demonstrated improvements in success rates for sexual intercourse compared with placebo.Efficacy Endpoints in Controlled Clinical StudiesThe effectiveness of sildenafil was evaluated in most studies using several assessment instruments. The primary measure in the principal studies was a sexual function questionnaire (the International Index of Erectile Function-IIEF) administered during a 4-week treatment-free run-in period, at baseline, at follow-up visits, and at the end of double-blind, placebo-controlled, at-home treatment. No severe adverse events potentially related to blood pressure effects were reported in this group. The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 50 mg sildenafil or matching placebo are shown in Figure 3. Blood pressure was measured after administration of sildenafil at the same times as those specified for the first doxazosin study. There were no severe adverse events potentially related to blood pressure and no episodes of syncope reported in this study.
- Sildenafil was originally developed for hypertension and angina.
- It was repurposed for erectile dysfunction after unintended effects were observed.
- The medication is marketed under various brand names like Viagra.
- Generic sildenafil citrate became available after patent expiration.
The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 100 mg sildenafil or matching placebo are shown in Figure 4. Blood pressure was measured after administration of sildenafil at the same times as those specified for the previous doxazosin studies. There were no episodes of syncope reported in this study. In a double-blind study, 144 patients with erectile dysfunction and chronic stable angina limited by exercise, not receiving chronic oral nitrates, were randomized sildenafil citrate 100mg tablets to a single dose of placebo or sildenafil 100 mg 1 hour prior to exercise testing.
- Patients should inform their doctor of any allergic reactions.
- Use caution if you have eye or vision problems before use.
- Sildenafil is not a cure but alleviates symptoms temporarily.
- Combining it with other medications may increase risks.
These results demonstrated that the effect of sildenafil on the primary endpoint was statistically non-inferior to placebo. Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 25-63%).
2.5 Dosage Adjustments in Special Populations
Two of the questions from the IIEF served as primary study endpoints; categorical responses were elicited to questions about (1) the ability to achieve erections sufficient for sexual intercourse and (2) the maintenance of erections after penetration. The patient addressed both questions at the final visit for the last 4 weeks of the study. The possible categorical responses to these questions were (0) no attempted intercourse, (1) never or almost never, (2) a few times, (3) sometimes, (4) most times, and (5) almost always or always. Also collected as part of the IIEF was information about other aspects of sexual function, including information on erectile function, orgasm, desire, satisfaction with intercourse, and overall sexual satisfaction. Sexual function data were also recorded by patients in a daily diary.
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In addition, patients were asked a global efficacy question and an optional partner questionnaire was administered.Efficacy Results from Controlled Clinical StudiesThe effect on one of the major end points, maintenance of erections after penetration, is shown in Figure 6, for the pooled results of 5 fixed-dose, dose-response studies of greater than one month duration, showing response according to baseline function. Results with all doses have been pooled, but scores showed greater improvement at the 50 and 100 mg doses than at 25 mg. The pattern of responses was similar for the other principal question, the ability to sildenafil tablets 125 achieve an erection sufficient for intercourse. The titration studies, in which most patients received 100 mg, showed similar results. Figure 6 shows that regardless of the baseline levels of function, subsequent function in patients treated with sildenafil was better than that seen in patients treated with placebo. Both sildenafil and the metabolite have terminal half lives of about 4 hours.
- The onset and duration of effect vary depending on individual factors.
- Typical duration of an erection after taking sildenafil is 4-6 hours.
- If an erection persists longer than 4 hours, seek medical help immediately.
- Do not use sildenafil if you have been advised against sexual activity.
Absorption and Distribution: Sildenafil is rapidly absorbed. Protein binding is independent of total drug concentrations. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesisSildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure (AUCs) for unbound sildenafil and its major metabolite of 20- and 38- times, for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 100 mg. Sildenafil was not carcinogenic when administered to mice for 18-21 months at dosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately 0.4 times the MRHD on a mg/m 2basis in a 50 kg subject.MutagenesisSildenafil was negative in in vitrobacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitrohuman lymphocytes and in vivomouse micronucleus assays to detect clastogenicity.Impairment of FertilityThere was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days to females and 102 days to males, a dose producing an AUC value of more than 25 times the human male AUC. 14 CLINICAL STUDIES In clinical studies, sildenafil was assessed for its effect on the ability of men with erectile dysfunction (ED) to engage in sexual activity and in many cases specifically on the ability to achieve and maintain an erection sufficient for satisfactory sexual activity. Sildenafil was evaluated primarily at doses of 25 mg, 50 mg and 100 mg in 21 randomized, double-blind, placebo-controlled trials of up to 6 months in duration, using a variety of study designs (fixed dose, titration, parallel, crossover). Sildenafil was administered to more than 3,000 patients aged 19 to 87 years, with ED of various etiologies (organic, psychogenic, mixed) with a mean duration of 5 years. Sildenafil demonstrated statistically significant improvement compared to placebo in all 21 studies. The studies that established benefit demonstrated improvements in success rates for sexual intercourse compared with placebo.Efficacy Endpoints in Controlled Clinical StudiesThe effectiveness of sildenafil was evaluated in most studies using several assessment instruments. The primary measure in the principal studies was a sexual function questionnaire (the International Index of Erectile Function-IIEF) administered during a 4-week treatment-free run-in period, at baseline, at follow-up visits, and at the end of double-blind, placebo-controlled, at-home treatment.
12.2 Pharmacodynamics
The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 50 mg sildenafil or matching placebo are shown in Figure 3. Blood pressure was measured after administration of sildenafil at the same times as those specified for the first doxazosin study. There were no severe adverse events potentially related to blood pressure and no episodes of syncope reported in this study. The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 100 mg sildenafil or matching placebo are shown in Figure 4. Blood pressure was measured after administration of sildenafil at the same times as those specified for the previous doxazosin studies.
Dosage questions
There were no episodes of syncope reported in this study. In a double-blind study, 144 patients with erectile dysfunction and chronic stable angina limited by exercise, not receiving chronic oral nitrates, were randomized sildenafil citrate 100mg tablets to a single dose of placebo or sildenafil 100 mg 1 hour prior to exercise testing. These results demonstrated that the effect of sildenafil on the primary endpoint was statistically non-inferior to placebo. Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 25-63%). Both sildenafil and the metabolite have terminal half lives of about 4 hours. Two of the questions from the IIEF served as primary study endpoints; categorical responses were elicited to questions about (1) the ability to achieve erections sufficient for sexual intercourse and (2) the maintenance of erections after penetration. The patient addressed both questions at the final visit for the last 4 weeks of the study.
| Drug/Class | Interaction Effect | Clinical Significance | Recommendation |
|---|---|---|---|
| Nitrates | Severe hypotension | Contraindicated | Avoid concomitant use |
| Alpha-blockers | Additive blood pressure lowering | Hypotension risk | Monitor blood pressure closely |
| CYP3A4 inhibitors | Increased sildenafil levels | Increased side effects | Dose adjustment may be necessary |
| Alcohol | Enhanced hypotensive effects | Increased dizziness risk | Use with caution |
The possible categorical responses to these questions were (0) no attempted intercourse, (1) never or almost never, (2) a few times, (3) sometimes, (4) most times, and (5) almost always or always.
Usual Geriatric Dose for Erectile Dysfunction
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Also collected as part of the IIEF was information about other aspects of sexual function, including information on erectile function, orgasm, desire, satisfaction with intercourse, and overall sexual satisfaction. Sexual function data were also recorded by patients in a daily diary. In addition, patients were asked a global efficacy question and an optional partner questionnaire was administered.Efficacy Results from Controlled Clinical StudiesThe effect on one of the major end points, maintenance of erections after penetration, is shown in Figure 6, for the pooled results of 5 fixed-dose, dose-response studies of greater than one month duration, showing response according to baseline function. Results with all doses have been pooled, but scores showed greater improvement at the 50 and 100 mg doses than at 25 mg. The pattern of responses was similar for the other principal question, the ability to sildenafil tablets 125 achieve an erection sufficient for intercourse.
5.8 Effects on Bleeding
At the same time, on-treatment function was better in treated patients who were less impaired at baseline.Figure 6. Effect of sildenafil and Placebo on Maintenance of Erection by Baseline Score.The frequency of patients reporting improvement of erections in response to a global question in four of the randomized, double-blind, parallel, placebo-controlled fixed dose studies (1797 patients) of 12 to 24 weeks duration is shown in Figure 7. These patients had erectile dysfunction at baseline that was characterized by median categorical scores of 2 (a few times) on principal IIEF questions. Erectile dysfunction was attributed to organic (58%; generally not characterized, but including diabetes and excluding spinal cord injury), psychogenic (17%), or mixed (24%) etiologies. Sixty-three percent, 74%, and 82% of the patients on 25 mg, 50 mg and 100 mg of sildenafil, respectively, reported an improvement in their erections, compared to 24% on placebo.
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In the titration studies (n=644) (with most patients eventually receiving 100 mg), results were similar.Overall treatment p<0.0001Figure 7. Percentage of Patients Reporting an Improvement in Erections.The patients in studies had varying degrees of ED. One-third to one-half of the subjects in these studies reported successful intercourse at least once during a 4-week, treatment-free run-in period.In many of the studies, of both fixed dose and titration designs, daily diaries were kept by patients. In these studies, involving about 1600 patients, analyses of patient diaries showed no effect of sildenafil on rates of attempted intercourse (about 2 per week), but there was clear treatment-related improvement in sexual function: per patient weekly success rates averaged 1.3 on 50-100 mg of sildenafil vs 0.4 on placebo; similarly, group mean success rates (total successes divided by total attempts) were about 66% on sildenafil vs about 20% on placebo.During 3 to 6 months of double-blind treatment or longer-term (1 year), open-label studies, few patients withdrew from active treatment for any reason, including lack of effectiveness. The titration studies, in which most patients received 100 mg, showed similar results. Figure 6 shows that regardless of the baseline levels of function, subsequent function in patients treated with sildenafil was better than that seen in patients treated with placebo. At the same time, on-treatment function was better in treated patients who were less impaired at baseline.Figure 6. Effect of sildenafil and Placebo on Maintenance of Erection by Baseline Score.The frequency of patients reporting improvement of erections in response to a global question in four of the randomized, double-blind, parallel, placebo-controlled fixed dose studies (1797 patients) of 12 to 24 weeks duration is shown in Figure 7. These patients had erectile dysfunction at baseline that was characterized by median categorical scores of 2 (a few times) on principal IIEF questions.
- Sildenafil is a phosphodiesterase type 5 (PDE5) inhibitor.
- Its primary function is to improve blood flow to the penis.
- The medication does not protect against sexually transmitted infections.
- Use condoms for protection regardless of medication use.
Erectile dysfunction was attributed to organic (58%; generally not characterized, but including diabetes and excluding spinal cord injury), psychogenic (17%), or mixed (24%) etiologies. Sixty-three percent, 74%, and 82% of the patients on 25 mg, 50 mg and 100 mg of sildenafil, respectively, reported an improvement in their erections, compared to 24% on placebo. In the titration studies (n=644) (with most patients eventually receiving 100 mg), results were similar.Overall treatment p<0.0001Figure 7. Percentage of Patients Reporting an Improvement in Erections.The patients in studies had varying degrees of ED. One-third to one-half of the subjects in these studies reported successful intercourse at least once during a 4-week, treatment-free run-in period.In many of the studies, of both fixed dose and titration designs, daily diaries were kept by patients. In these studies, involving about 1600 patients, analyses of patient diaries showed no effect of sildenafil on rates of attempted intercourse (about 2 per week), but there was clear treatment-related improvement in sexual function: per patient weekly success rates averaged 1.3 on 50-100 mg of sildenafil vs 0.4 on placebo; similarly, group mean success rates (total successes divided by total attempts) were about 66% on sildenafil vs about 20% on placebo.During 3 to 6 months of double-blind treatment or longer-term (1 year), open-label studies, few patients withdrew from active treatment for any reason, including lack of effectiveness.