DRUG INTERACTIONS
Effects of Other Drugs on REVATIO
In vitro studies: Sildenafil metabolism is principally mediated by the CYP3A4 (major route) and CYP2C9 (minor route) cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance.
In vivo studies: Population pharmacokinetic analysis of clinical trial data indicated a reduction in sildenafil clearance and/or an increase of oral bioavailability when co-administered with CYP3A4 substrates and the combination of CYP3A4 substrates and beta-blockers. These were the only factors with a statistically significant impact on sildenafil pharmacokinetics.
Population data from patients in clinical trials indicated a reduction in sildenafil clearance when it was co-administered with CYP3A4 inhibitors. Sildenafil exposure without concomitant medication is shown to be 5-fold higher at a dose of 80 mg t.i.d. compared to its exposure at a dose of 20 mg t.i.d. This concentration range covers the same increased sildenafil exposure observed in specifically-designed drug interaction studies with CYP3A4 inhibitors (except for potent inhibitors such as ketoconazole, itraconazole, and ritonavir). 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 co-administered with erythromycin, a CYP3A4 inhibitor, at steady state (500 mg twice daily [b.i.d.] for 5 days), there was a 182% increase in sildenafil systemic exposure (AUC). In a study performed in healthy volunteers, co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady state (1200 mg t.i.d.) with sildenafil (100 mg single dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC. Stronger CYP3A4 inhibitors will have still greater effects on plasma levels of sildenafil (see DOSAGE AND ADMINISTRATION).
In another study in healthy volunteers, co-administration with the HIV protease inhibitor ritonavir, a potent CYP3A4 inhibitor, at steady state (500 mg b.i.d.) with sildenafil (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil Cmax and 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 (see WARNINGS and DOSAGE AND ADMINISTRATION). Although the interaction between other protease inhibitors and REVATIO 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 the endothelin receptor antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of cytochrome P450 2C19) at steady state (125 mg b.i.d.) resulted in a 63% decrease of sildenafil AUC and a 55% decrease in sildenafil Cmax. The combination of both drugs did not lead to clinically significant changes in blood pressure (supine or standing). Concomitant administration of potent CYP3A4 inducers is expected to cause greater decreases in plasma levels of sildenafil.
In drug-drug interaction studies, sildenafil (25 mg, 50 mg, or 100 mg) and the alpha-blocker doxazosin (4 mg or 8 mg) were administered simultaneously to patients with benign prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In these study populations, mean additional reductions of supine systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg, respectively, were observed. Mean additional reductions of standing blood pressure of 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively, were also observed. There were infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and light-headedness, but not syncope (see PRECAUTIONS: General).
Concomitant administration of oral contraceptives (ethinyl estradiol 30 µg and levonorgestrel 150 µg) did not affect the pharmacokinetics of sildenafil.
Concomitant administration of a single 100 mg dose of sildenafil with 10 mg of atorvastatin did not alter the pharmacokinetics of either sildenafil or atorvastatin.
Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of sildenafil.
Effects of REVATIO on Other Drugs
In vitro studies: Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 µM).
In vivo studies: When sildenafil 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.
No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9.
Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg).
Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%.
In healthy subjects, co-administration of 125 mg b.i.d. bosentan and 80 mg t.i.d. sildenafil resulted in a 63% decrease in AUC of sildenafil and a 50% increase in AUC of bosentan.
In a study of healthy 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 had no impact on the plasma levels of oral contraceptives (ethinyl estradiol 30 µg and levonorgestrel 150 µg).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Sildenafil was not carcinogenic when administered to rats for up to 24 months at 60 mg/kg/day, a dose resulting in total systemic exposure (AUC) to unbound sildenafil and its major metabolite 33 and 37 times, for male and female rats respectively, the human exposure at the Recommended Human Dose (RHD) of 20 mg t.i.d. Sildenafil was not carcinogenic when administered to male and female mice for up to 21 and 18 months, respectively, at doses up to a maximally tolerated level of 10 mg/kg/day, a dose equivalent to the RHD on a mg/m2 basis.
Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity.
There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day, a dose producing a total systemic exposure (AUC) to unbound sildenafil and its major metabolite of 19 and 38 times for males and females, respectively, the human exposure at the RHD of 20 mg t.i.d.
Pregnancy
Pregnancy Category B
No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in pregnant rats or rabbits, dosed with 200 mg sildenafil/kg/day during organogenesis, a level that is, on a mg/m2 basis, 32- and 68-times, respectively, the RHD of 20 mg t.i.d. In a rat pre- and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m2 basis). There are no adequate and well-controlled studies of sildenafil in pregnant women.
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