14 CLINICAL STUDIES
This metabolite has a PDE selectivity profile similar to sildenafil and an in vitropotency for PDE5 approximately 50% of the parent drug.
- Sildenafil 200 mg may cause visual disturbances like blurred vision.
- Consult your doctor if side effects persist or worsen.
- Avoid grapefruit or grapefruit juice while taking sildenafil.
- This medication should only be used under medical supervision.
- Sildenafil is also used to treat pulmonary arterial hypertension.
- Do not share sildenafil 200 mg with others.
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).
| Side Effect | Frequency | Severity | Management Suggestions |
|---|---|---|---|
| Headache | Common | Mild | Analgesics, hydration |
| Visual disturbances | Less common | Mild-moderate | Discontinue use if persistent |
| Dizziness | Common | Mild | Sit or lie down, avoid driving |
| Priapism | Rare | Severe | Seek immediate medical attention |
| Hearing loss | Very rare | Severe | Discontinue medication, seek help |
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 (18-45 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=50-80 mL/min) and moderate (CLcr=30-49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) were not altered.
- Sildenafil 200 mg is a high dose used to treat severe erectile dysfunction.
- This medication increases blood flow to the penis for improved erection.
- It is important to follow a doctor's prescription for 200 mg dosage.
- Common side effects include headaches, flushing, and nasal congestion.
- Sildenafil should not be mixed with nitrates due to risk of low blood pressure.
- The drug is typically taken about an hour before sexual activity.
In volunteers with severe (CLcr <30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and C maxcompared 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 maxvalues 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. A starting oral dose of 25 mg should be considered in those patients [ see Dosage and Administration (2.5)].Drug Interaction StudiesEffects of Other Drugs on sildenafilSildenafil metabolism is principally mediated by CYP3A4 (major route) and CYP2C9 (minor route).
- The proper administration of sildenafil involves taking it on an empty stomach or with light food.
- Seek immediate medical help if experiencing chest pain or prolonged erection.
- Sildenafil's interaction with other drugs can alter its effectiveness.
- Regular check-ups are recommended for long-term users.
- Sildenafil does not cause spontaneous erections without sexual stimulation.
- Never combine sildenafil 200 mg with recreational drugs like poppers.
Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. The concomitant use of erythromycin or strong CYP3A4 inhibitors (e.g., saquinavir, ketoconazole, itraconazole) as well as the nonspecific CYP inhibitor, cimetidine, is associated with increased plasma levels of sildenafil [ see Dosage and Administration (2.4)].In vivostudies:Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with sildenafil (50 mg) to healthy volunteers.When a single 100 mg dose of sildenafil was administered with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg bid for 5 days), there was a 160% increase in sildenafil C maxand a 182% increase in sildenafil AUC. In addition, in a study performed in healthy male volunteers, co-administration of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor, at steady state (1200 mg tid) with sildenafil (100 mg single dose) resulted in a 140% increase in sildenafil C maxand a 210% increase in sildenafil AUC. A stronger CYP3A4 inhibitor such as ketoconazole or itraconazole could be expected to have greater effect than that seen with saquinavir. Population pharmacokinetic data from patients in clinical trials also indicated a reduction in sildenafil clearance when it was co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, or cimetidine) [ see Dosage and Administration (2.4) and Drug Interactions (7.4)].In another study in healthy male volunteers, co-administration with the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg bid) with sildenafil (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil C maxand a 1000% (11-fold) increase in sildenafil plasma AUC. At 24 hours the plasma levels of sildenafil were still approximately 200 ng/mL, compared to approximately 5 ng/mL when sildenafil was dosed alone.
16. How is Sildenafil Tablets supplied
This is consistent with ritonavir's marked effects on a broad range of P450 substrates.
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Sildenafil had no effect on ritonavir pharmacokinetics [ see Dosage and Administration (2.4)and Drug Interactions (7.4)].Although the interaction between other protease inhibitors and sildenafil has not been studied, their concomitant use is expected to increase sildenafil levels.In a study of healthy male volunteers, co-administration of sildenafil at steady state (80 mg t.i.d.) with endothelin receptor antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of CYP2C19) at steady state (125 mg b.i.d.) resulted in a 63% decrease of sildenafil AUC and a 55% decrease in sildenafil C max. Concomitant administration of strong CYP3A4 inducers, such as rifampin, is expected to cause greater decreases in plasma levels of sildenafil.Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of sildenafil.In healthy male volunteers, there was no evidence of a clinically significant effect of azithromycin (500 mg daily for 3 days) on the systemic exposure of sildenafil or its major circulating metabolite.Pharmacokinetic data from patients in clinical trials showed no effect on sildenafil pharmacokinetics of CYP2C9 inhibitors sildenafil 50 mg tab (such as tolbutamide, warfarin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and related diuretics, ACE inhibitors, and calcium channel blockers. 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.
| Use Case | Patient Group | Effect Duration | Common Side Effects |
|---|---|---|---|
| Erectile Dysfunction | Men aged 40-70 | 4-6 hours | Headache, flushing, nasal congestion |
| Pulmonary Hypertension | Adults with PAH | 4-6 hours | Dizziness, visual disturbances |
| Off-label Sexual Enhancement | Men over 40 | Varies | Muscle aches, digestive upset |
| Sildenafil for High Altitude Sickness | Travelers | 4-6 hours | Low blood pressure, dizziness |
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.
7.1 Nitrates
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. 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.
5.7 Combination with other PDE5 Inhibitors or Other Erectile Dysfunction Therapies
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. 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. 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.
| Patient Group | Recommended Dosage | Administration Tips | Contraindications |
|---|---|---|---|
| Adult Men with ED | 200 mg once daily | Take 30-60 min before activity | Nitrate medication use, severe liver impairment |
| Pulmonary Hypertension | 20 mg three times daily | Take with water, on an empty stomach | Concurrent use of compatible medications |
| Elderly Patients | Start with lower doses | Adjust based on response | Liver or kidney impairment |
| Patients with Kidney Disease | Dose adjustment may be needed | Follow physician instructions | Severe renal impairment |
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 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.
Overdose/Missed Dose
This metabolite has a PDE selectivity profile similar to sildenafil and an in vitropotency 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). 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 (18-45 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=50-80 mL/min) and moderate (CLcr=30-49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (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 maxcompared 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 maxvalues 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.
What are the common side effects of PDE5 inhibitors?
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. A starting oral dose of 25 mg should be considered in those patients [ see Dosage and Administration (2.5)].Drug Interaction StudiesEffects of Other Drugs on sildenafilSildenafil metabolism is principally mediated by CYP3A4 (major route) and CYP2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. The concomitant use of erythromycin or strong CYP3A4 inhibitors (e.g., saquinavir, ketoconazole, itraconazole) as well as the nonspecific CYP inhibitor, cimetidine, is associated with increased plasma levels of sildenafil [ see Dosage and Administration (2.4)].In vivostudies:Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with sildenafil (50 mg) to healthy volunteers.When a single 100 mg dose of sildenafil was administered with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg bid for 5 days), there was a 160% increase in sildenafil C maxand a 182% increase in sildenafil AUC. In addition, in a study performed in healthy male volunteers, co-administration of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor, at steady state (1200 mg tid) with sildenafil (100 mg single dose) resulted in a 140% increase in sildenafil C maxand a 210% increase in sildenafil AUC. 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.
- Sildenafil 200 mg's safety profile depends on individual health conditions.
- It is important to inform your doctor of all medications being taken.
- Use sildenafil only when needed for sexual activity.
- Avoid engaging in activities that require alertness until effects are known.
- The drug is often part of a broader erectile dysfunction treatment strategy.
- Safe storage is essential to prevent accidental ingestion by children or others.
There were no episodes of syncope reported in this study.
14. Clinical Studies
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 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.
Is 20 or 25mg Sildenafil Enough for ED?
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 100 mg 1 hour prior to exercise testing.
11. Sildenafil Tablets Description
A stronger CYP3A4 inhibitor such as ketoconazole or itraconazole could be expected to have greater effect than that seen with saquinavir. Population pharmacokinetic data from patients in clinical trials also indicated a reduction in sildenafil clearance when it was co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, or cimetidine) [ see Dosage and Administration (2.4) and Drug Interactions (7.4)].In another study in healthy male volunteers, co-administration with the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg bid) with sildenafil (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil C maxand a 1000% (11-fold) increase in sildenafil plasma AUC. At 24 hours the plasma levels of sildenafil were still approximately 200 ng/mL, compared to approximately 5 ng/mL when sildenafil was dosed alone. This is consistent with ritonavir's marked effects on a broad range of P450 substrates. Sildenafil had no effect on ritonavir pharmacokinetics [ see Dosage and Administration (2.4)and Drug Interactions (7.4)].Although the interaction between other protease inhibitors and sildenafil has not been studied, their concomitant use is expected to increase sildenafil levels.In a study of healthy male volunteers, co-administration of sildenafil at steady state (80 mg t.i.d.) with endothelin receptor antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of CYP2C19) at steady state (125 mg b.i.d.) resulted in a 63% decrease of sildenafil AUC and a 55% decrease in sildenafil C max.
2.1 Dosage Information
Concomitant administration of strong CYP3A4 inducers, such as rifampin, is expected to cause greater decreases in plasma levels of sildenafil.Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of sildenafil.In healthy male volunteers, there was no evidence of a clinically significant effect of azithromycin (500 mg daily for 3 days) on the systemic exposure of sildenafil or its major circulating metabolite.Pharmacokinetic data from patients in clinical trials showed no effect on sildenafil pharmacokinetics of CYP2C9 inhibitors sildenafil 50 mg tab (such as tolbutamide, warfarin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and related diuretics, ACE inhibitors, and calcium channel blockers. 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. These results demonstrated that the effect of sildenafil on the primary endpoint was statistically non-inferior to placebo.
- Legal Status of Sildenafil Without a Prescription
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- 3. DOSAGE FORMS AND STRENGTHS
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