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REVATIO®
(sildenafil citrate) Tablets
DESCRIPTION
REVATIO®, an oral therapy for pulmonary arterial hypertension, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type-5 (PDE5). Sildenafil is also marketed as VIAGRA® for male erectile dysfunction.
Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate and has the following structural formula:
Sildenafil citrate 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. REVATIO (sildenafil citrate) is formulated as white, film-coated round tablets equivalent to 20 mg of sildenafil for oral administration. In addition to the active ingredient, sildenafil citrate, each tablet contains the following inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, lactose monohydrate, and triacetin.
CLINICAL PHARMACOLOGY
Mechanism of Action
Sildenafil is an inhibitor of cGMP specific phosphodiesterase type-5 (PDE5) in the smooth muscle of the pulmonary vasculature, where PDE5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with pulmonary hypertension, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation.
Studies in vitro have 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). The approximately 4,000-fold selectivity for PDE5 versus PDE3 is important because 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 and involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels (see Pharmacodynamics).
In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE5 in these tissues by sildenafil may be the basis for the enhanced platelet anti-aggregatory activity of nitric oxide observed in vitro, and the mild peripheral arterial-venous dilatation in vivo.
Pharmacokinetics and Metabolism
Pharmacokinetics in Special Populations
Population pharmacokinetics
Age, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in pulmonary arterial hypertension patients. The data set available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated with hepatic and renal function. None of these factors had a statistically significant impact on sildenafil pharmacokinetics in patients with pulmonary hypertension.
In patients with pulmonary hypertension, the average steady-state concentrations were 20–50% higher when compared to those of healthy volunteers. There was also a doubling of Cmin levels compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with pulmonary hypertension compared to healthy volunteers.
Pharmacodynamics
Clinical Studies
A randomized, double-blind, placebo-controlled study was conducted in 277 patients with pulmonary arterial hypertension (PAH, defined as a mean pulmonary artery pressure of ≥25 mmHg at rest with a pulmonary capillary wedge pressure <15 mmHg). Patients were predominantly functional classes II–III. Allowed background therapy included a combination of anticoagulation, digoxin, calcium channel blockers, diuretics or oxygen. The use of prostacyclin analogues, endothelin receptor antagonists, and arginine supplementation were not permitted. Subjects who had failed to respond to bosentan were also excluded. Patients with left ventricular ejection fraction <45% or left ventricular shortening fraction <0.2 also were not studied.
Patients were randomized to receive placebo (n=70) or REVATIO 20 mg (n=69), 40 mg (n=67) or 80 mg (n=71) t.i.d. for a period of 12 weeks. They had either primary pulmonary hypertension (63%), PAH associated with connective tissue disease (30%), or PAH following surgical repair of left-to-right congenital heart lesions (7%). The study population consisted of 25% men and 75% women with a mean age of 49 years (range: 18–81 years) and baseline 6-minute walk test distance between 100 and 450 meters.
The primary efficacy endpoint was the change from baseline at week 12 in 6-minute walk distance at least 4 hours after the last dose. Placebo-corrected mean increases in walk distance of 45–50 meters were observed with all doses of sildenafil. These increases were highly significantly different from placebo, but the dose groups were not different from each other (Figure 1). The improvement in walk distance was apparent after 4 weeks of treatment and was maintained at week 8 and week 12.
Figure 1: Change from Baseline in 6-Minute Walk Distance (meters): Mean (95% Confidence Interval)
Pre-defined subpopulations in the pivotal study were also evaluated for efficacy, including patient differences in baseline walk distance, disease etiology, functional class, gender, age, and secondary hemodynamic parameters (Figure 2).
Figure 2: Placebo Corrected Change From Baseline in 6-Minute Walk Distance (meters) by study subpopulation: Mean (95% Confidence Interval)
Key: PAH = pulmonary arterial hypertension; CTD = connective tissue disease; PH, pulmonary hypertension; PAP = pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; TID = three times daily.
Patients on all REVATIO doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo. Doses of 20 mg, 40 mg, and 80 mg t.i.d. produced a placebo-corrected decrease in mPAP of -2.7 mmHg, -3.0 mmHg, and -5.1 mmHg, respectively. There was no evidence of a difference in effect between sildenafil 20 mg t.i.d. and the higher doses tested. Data from other hemodynamic parameters can be found in Table 1. The relationship between these effects and improvements in 6-minute walk distance is unknown.
| PARAMETER [mean (95% CI)] | Placebo (N=65) | Sildenafil 20 mg t.i.d. (N=65) |
|---|---|---|
| PVR (dyn∙s/cm5) | 49 (-54, 153) | -122 (-217, -27) |
| SVR (dyn∙s/cm5) | -78 (-197, 41) | -167 (-307, -26) |
| RAP (mmHg) | 0.3 (-0.9, 1.5) | -0.8 (-1.9, 0.3) |
| CO (L/min) | -0.1 (-0.4, 0.2) | 0.4 (0.1, 0.7) |
| HR (beats/min) | -1.3 (-4.1, 1.4) | -3.7 (-5.9, -1.4) |
259 of the 277 treated patients entered a long-term, uncontrolled extension study. At the end of 1 year, 94% of these patients were still alive. Additionally, walk distance and functional class status appeared to be stable in patients taking sildenafil. Without a control group, these data must be interpreted cautiously.
INDICATIONS AND USAGE
REVATIO is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) to improve exercise ability.
The efficacy of REVATIO has not been evaluated in patients currently on bosentan therapy.
CONTRAINDICATIONS
Consistent with its known effects on the nitric oxide/cGMP pathway (see CLINICAL PHARMACOLOGY), sildenafil was shown to potentiate the hypotensive effects of nitrates, and its administration to patients who are using organic nitrates, either regularly and/or intermittently, in any form is therefore contraindicated.
REVATIO is contraindicated in patients with a known hypersensitivity to any component of the tablet.
WARNINGS
The concomitant administration of the protease inhibitor ritonavir (a highly potent CYP3A4 inhibitor) substantially increases serum concentrations of sildenafil, therefore co-administration with REVATIO is not recommended (see Drug Interactions and DOSAGE AND ADMINISTRATION).
REVATIO has vasodilator properties, resulting in mild and transient decreases in blood pressure (see PRECAUTIONS). Prior to prescribing REVATIO, physicians should carefully consider whether their patients with certain underlying conditions could be adversely affected by such vasodilatory effects, for example patients with resting hypotension (BP <90/50), or with fluid depletion, severe left ventricular outflow obstruction, or autonomic dysfunction.
Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of REVATIO to patients with veno-occlusive disease, administration of REVATIO to such patients is not recommended. Should signs of pulmonary edema occur when sildenafil is administered, the possibility of associated PVOD should be considered.
There is no controlled clinical data on the safety or efficacy of REVATIO in the following groups; if prescribed, this should be done with caution:
- Patients who have suffered a myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months;
- Patients with coronary artery disease causing unstable angina;
- Patients with hypertension (BP >170/110);
- Patients with retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases).
- Patients currently on bosentan therapy.
PRECAUTIONS
General
Before prescribing REVATIO, it is important to note the following:
- Caution is advised when phosphodiesterase type 5 (PDE5) inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including sildenafil, and alpha-adrenergic blocking agents are both vasodilators with blood pressure lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly, leading to symptomatic hypotension. In the sildenafil interaction studies with alpha-blockers (see Drug Interactions), cases of symptomatic hypotension consisting of dizziness and lightheadedness were reported. No cases of syncope or fainting were reported during these interaction studies. Consideration should be given to the fact that safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and concomitant use of anti-hypertensive drugs.
- REVATIO should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie's disease) or in patients who have conditions, which may predispose them to priapism (such as sickle cell anemia, multiple myeloma or leukemia). In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism (painful erections greater than 6 hours in duration) is not treated immediately, penile tissue damage and permanent loss of potency could result.
- In humans, sildenafil has no effect on bleeding time when taken alone or with aspirin. In vitro studies with human platelets indicate that sildenafil potentiates the anti-aggregatory effect of sodium nitroprusside (a nitric oxide donor). The combination of heparin and sildenafil had an additive effect on bleeding time in the anesthetized rabbit, but this interaction has not been studied in humans.
- The incidence of epistaxis was higher in patients with PAH secondary to CTD (sildenafil 13%, placebo 0%) than in PPH patients (sildenafil 3%, placebo 2%). The incidence of epistaxis was also higher in sildenafil-treated patients with concomitant oral vitamin K antagonist (9% versus 2% in those not treated with concomitant vitamin K antagonist).
- The safety of REVATIO is unknown in patients with bleeding disorders and patients with active peptic ulceration.
Information for Patients
Physicians should discuss with patients the contraindication of REVATIO with regular and/or intermittent use of organic nitrates.
Sildenafil is also marketed as VIAGRA® for male erectile dysfunction.
Physicians should advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking all PDE5 inhibitors, including REVATIO. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, that has been reported rarely post-marketing in temporal association with the use of all PDE5 inhibitors when used in the treatment of male-erectile dysfunction. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors. Physicians should also discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators, such as PDE5 inhibitors (see ADVERSE REACTIONS).
Drug Interactions
In PAH patients, the concomitant use of vitamin K antagonists and sildenafil resulted in a greater incidence of reports of bleeding (primarily epistaxis) versus placebo.
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
Nursing Mothers
It is not known if sildenafil citrate and/or metabolites are excreted in human breast milk. Since many drugs are excreted in human milk, caution should be used when REVATIO is administered to nursing women.
Pediatric Use
Safety and Effectiveness of sildenafil in pediatric pulmonary hypertension patients has not been established.
Geriatric Use
Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, but studies did not include sufficient numbers of subjects to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger pulmonary arterial hypertension patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
ADVERSE REACTIONS
Safety data were obtained from the pivotal study and an open-label extension study in 277 treated patients with pulmonary arterial hypertension. Doses up to 80 mg t.i.d. were studied.
The overall frequency of discontinuation in REVATIO-treated patients at the recommended dose of 20 mg t.i.d. was low (3%) and the same as placebo (3%).
In the pivotal placebo-controlled trial in pulmonary arterial hypertension, the adverse drug reactions that were reported by at least 3% of REVATIO patients treated at the recommended dosage (20 mg t.i.d.) and were more frequent in REVATIO patients than placebo patients, are shown in Table 2. Adverse events were generally transient and mild to moderate in nature.
| ADVERSE EVENT % | Placebo (n=70) | Sildenafil 20 mg t.i.d. (n=69) | Placebo Subtracted |
|---|---|---|---|
| Epistaxis | 1 | 9 | 8 |
| Headache | 39 | 46 | 7 |
| Dyspepsia | 7 | 13 | 6 |
| Flushing | 4 | 10 | 6 |
| Insomnia | 1 | 7 | 6 |
| Erythema | 1 | 6 | 5 |
| Dyspnea exacerbated | 3 | 7 | 4 |
| Rhinitis nos | 0 | 4 | 4 |
| Diarrhea nos | 6 | 9 | 3 |
| Myalgia | 4 | 7 | 3 |
| Pyrexia | 3 | 6 | 3 |
| Gastritis nos | 0 | 3 | 3 |
| Sinusitis | 0 | 3 | 3 |
| Paresthesia | 0 | 3 | 3 |
At doses higher than the recommended 20 mg t.i.d. there was a greater incidence of some adverse events including flushing, diarrhea, myalgia and visual disturbances. Visual disturbances were identified as mild and transient, and were predominately color-tinge to vision, but also increased sensitivity to light or blurred vision.
In the pivotal study, the incidence of retinal hemorrhage at the recommended sildenafil 20 mg t.i.d. dose was 1.4% versus 0% placebo and for all sildenafil doses studied was 1.9% versus 0% placebo. The incidence of eye hemorrhage at both the recommended dose and at all doses studied was 1.4% for sildenafil versus 1.4% for placebo. The patients experiencing these events had risk factors for hemorrhage including concurrent anticoagulant therapy.
In post-marketing experience with sildenafil citrate at doses indicated for male erectile dysfunction, serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, pulmonary hemorrhage, and subarachnoid and intracerebral hemorrhages have been reported in temporal association with the use of the drug. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of sildenafil without sexual activity. Others were reported to have occurred hours to days after use concurrent with sexual activity. It is not possible to determine whether these events are related directly to sildenafil citrate, to sexual activity, to the patient's underlying cardiovascular disease, or to a combination of these or other factors.
When used to treat male-erectile dysfunction, non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely post-marketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors, including sildenafil citrate. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing NAION, including but not necessarily limited to: low cup to disc ratio ("crowded disc"), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient's underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors (see PRECAUTIONS/Information for Patients).
OVERDOSAGE
In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but rates 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.
DOSAGE AND ADMINISTRATION
The recommended dose of REVATIO is 20 mg three times a day (t.i.d.). REVATIO tablets should be taken approximately 4–6 hours apart, with or without food. In the clinical trial no greater efficacy was achieved with the use of higher doses. Treatment with doses higher than 20 mg t.i.d. is not recommended. Dosages lower than 20 mg t.i.d. were not tested. Whether dosages lower than 20 mg t.i.d. are effective is not known.
In general, dose selection for elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see CLINICAL PHARMACOLOGY)
No dose adjustments are required for renal impaired patients (including severe renal impairment, creatinine clearance <30 mL/min), or for hepatic impaired patients (Child Pugh class A and B).
No dose adjustments are required for the co-administration of REVATIO with erythromycin or saquinavir.
Co-administration of REVATIO with CYP3A4 inducers (including bosentan; and more potent inducers such as barbiturates, carbamazepine, phenytoin, efavirenz, nevirapine, rifampin, rifabutin) may alter plasma levels of either or both medications. Dosage adjustments may be necessary (see PRECAUTIONS: Drug Interactions).
Co-administration of potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir) with REVATIO substantially increases serum concentrations of sildenafil and is therefore not recommended (see WARNINGS and PRECAUTIONS: Drug Interactions).
Sildenafil was shown to potentiate the hypotensive effects of nitrates and its administration in patients who use nitric oxide donors, or nitrates in any form, is therefore contraindicated.
HOW SUPPLIED
REVATIO (sildenafil citrate) is supplied as white, film-coated, round tablets containing sildenafil citrate equivalent to the nominally indicated amount of sildenafil as follows:
| REVATIO Tablets | |||
|---|---|---|---|
| Package Configuration | Tablet Strength (mg) | NDC | Engraving on Tablet |
| Bottle of 90 | 20 mg | 0069-4190-68 | RVT20 |
Recommended Storage
Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature].
Rx Only
LAB-0313-7.0
July 2006