REVATIO
(sildenafil) Tablets
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 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)-4ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate and has the following structural formula:
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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 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.
Last updated on RxList: 5/21/2009
REVATIO® is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) to improve exercise ability and delay clinical worsening. The delay in clinical worsening was demonstrated when REVATIO was added to background epoprostenol therapy [see Clinical Studies].
The efficacy of REVATIO has not been adequately evaluated in patients taking bosentan concurrently.
The recommended dose of REVATIO is 20 mg three times a day (TID). 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 TID is not recommended. Dosages lower than 20 mg TID were not tested. Whether dosages lower than 20 mg TID are effective is not known.
REVATIO is supplied as white, film-coated, round tablets engraved with “RVT20” containing sildenafil citrate equivalent to 20 mg of sildenafil.
REVATIO 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].
Distributed by : Pfizer Labs, Division of Pfizer Inc, NY, NY 10017. MAY –2009
Last updated on RxList: 5/21/2009
The following serious adverse reactions are discussed elsewhere in the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Safety data were obtained from the 12 week, placebo-controlled clinical study and an open-label extension study in 277 treated patients with pulmonary arterial hypertension. Doses up to 80 mg TID were studied.
The overall frequency of discontinuation in REVATIO-treated patients at the recommended dose of 20 mg TID was 3% and was the same for the placebo group.
In the 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 TID) and were more frequent in REVATIO patients than placebo patients, are shown in Table 1. Adverse events were generally transient and mild to moderate in nature.
Table 1. REVATIO All Causality Adverse Events in ≥
3% of Patients and More Frequent ( > 1%) than Placebo
| ADVERSE EVENT % | Placebo (n = 70) |
REVATIO 20 mg TID (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 |
| nos: Not otherwise specified | |||
At doses higher than the recommended 20 mg TID, 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.
The incidence of retinal hemorrhage at the recommended sildenafil 20 mg TID 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 a placebo-controlled fixed dose titration study of REVATIO (starting with recommended dose of 20 mg TID and increased to 40 mg TID and then 80 mg TID) as an adjunct to intravenous epoprostenol in pulmonary arterial hypertension, the adverse events that were reported were more frequent than in the placebo arm ( > 6% difference) are shown in Table 2.
Table 2. REVATIO-Epoprostenol Adverse Events More
Frequent ( > 6%) than Placebo
| ADVERSE EVENT % | Placebo + Epoprostenol (n = 131) | REVATIO + Epoprostenol (n = 134) | Placebo- Subtracted % |
| Headache | 34 | 57 | 23 |
| Edema^ | 13 | 25 | 14 |
| Dyspepsia | 2 | 16 | 14 |
| Pain in extremity | 6 | 17 | 11 |
| Diarrhea | 18 | 25 | 7 |
| Nausea | 18 | 25 | 7 |
| Nasal congestion | 2 | 9 | 7 |
| ^includes peripheral edema | |||
The following adverse reactions have been identified during postapproval use of sildenafil (marketed for both PAH and erectile dysfunction). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
In postmarketing experience with sildenafil at doses indicated for 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, to sexual activity, to the patient's underlying cardiovascular disease, or to a combination of these or other factors.
When used to treat erectile dysfunction, non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported postmarketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors, including sildenafil. 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 WARNINGS AND PRECAUTIONS].
Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including REVATIO. In some of the cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of REVATIO, to the patient's underlying risk factors for hearing loss, a combination of these factors, or to other factors [see WARNINGS AND PRECAUTIONS].
The following list includes other adverse events that have been identified during postmarketing use of REVATIO. The list does not include adverse events that are reported from clinical trials and that are listed elsewhere in this section. These events have been chosen for inclusion either due to their seriousness, reporting frequency, lack of clear alternative causation, or a combination of these factors. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Nervous system: Seizure, seizure recurrence
Concomitant use of REVATIO with nitrates in any form is contraindicated [see CONTRAINDICATIONS].
Concomitant use of REVATIO with ritonavir and other potent CYP3A inhibitors is not recommended [see WARNINGS AND PRECAUTIONS].
Use caution when co-administering alpha-blockers with REVATIO because of additive blood pressure-lowering effects [see WARNINGS AND PRECAUTIONS].
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.
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.
Last updated on RxList: 5/21/2009
REVATIO has vasodilatory properties, resulting in mild and transient decreases in blood pressure. Before prescribing REVATIO, carefully consider whether patients with certain underlying conditions could be adversely affected by such vasodilatory effects (e.g., patients with resting hypotension [BP < 90/50], 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 REVATIO is administered, consider the possibility of associated PVOD.
As there are no controlled clinical data on the safety or efficacy of REVATIO in the following groups, prescribe with caution for:
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, cases of symptomatic hypotension consisting of dizziness and lightheadedness were reported [see DRUG INTERACTIONS]. No cases of syncope or fainting were reported during these interaction studies. The 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.
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 13% in patients taking sildenafil with PAH secondary to connective tissue disease (CTD). This effect was not seen in primary pulmonary hypertension (PPH) (sildenafil 3%, placebo 2%) patients. The incidence of epistaxis was also higher in sildenafil-treated patients with a 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 or active peptic ulceration.
The concomitant administration of the protease inhibitor ritonavir (a highly potent CYP3A inhibitor) substantially increases serum concentrations of sildenafil; therefore, co-administration of ritonavir or other potent CYP3A inhibitors with REVATIO is not recommended [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].
Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking 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 postmarketing in temporal association with the use of all PDE5 inhibitors, including sildenafil, when used in the treatment of 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 the increased risk of NAION with patients 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].
There are no controlled clinical data on the safety or efficacy of REVATIO in patients with retinitis pigmentosa, a minority whom have genetic disorders of retinal phosphodiesterases. Prescribe REVATIO with caution in these patients.
Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking PDE5 inhibitors, including REVATIO. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including REVATIO. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [see ADVERSE REACTIONS].
Sildenafil is also marketed as VIAGRA®. The safety and efficacy of combinations of REVATIO with VIAGRA or other PDE5 inhibitors have not been studied. Inform patients taking REVATIO not to take VIAGRA or other PDE5 inhibitors.
Use REVATIO with caution in patients with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie's disease) or in patients who have conditions, which may predispose them to priapism (e.g., 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 erection greater than 6 hours in duration) is not treated immediately, penile tissue damage and permanent loss of potency could result.
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 RHD of 20 mg TID. 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 TID.
No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m² basis, 32- and 68-times, respectively, the recommended human dose (RHD) of 20 mg TID. 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, however, no adequate and well-controlled studies of sildenafil in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
The safety and efficacy of Revatio during labor and delivery has not been studied.
It is not known if sildenafil or its metabolites are excreted in human breast milk. Because many drugs are excreted in human milk, caution should be exercised when REVATIO is administered to a nursing woman.
Safety and effectiveness of sildenafil in pediatric pulmonary hypertension patients have not been established.
Clinical studies of REVATIO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger 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 [see CLINICAL PHARMACOLOGY].
No dose adjustment for mild to moderate impairment is required. Severe impairment has not been studied [see CLINICAL PHARMACOLOGY].
No dose adjustment is required (including severe impairment CLcr < 30 mL/min) [see CLINICAL PHARMACOLOGY].
Last updated on RxList: 5/21/2009
In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but rates and severities 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.
Do not use REVATIO in patients taking organic nitrates in any form. Consistent with its known effects on the nitric oxide/cGMP pathway, sildenafil was shown to potentiate the hypotensive effects of nitrates.
REVATIO is contraindicated in patients with a known hypersensitivity to sildenafil or any component of the tablet.
Rare cases of hypersensitivity have been reported in association with the use of sildenafil including anaphylactic reaction/shock events and anaphylactoid reaction. The majority of reported events were non-serious hypersensitivity reactions.
Last updated on RxList: 5/21/2009
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.
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.
Single oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). The decrease in blood pressure was most notable approximately 1-2 hours after dosing, and was not different from placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg doses of sildenafil, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates [see CONTRAINDICATIONS].
Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg TID to patients with pulmonary arterial hypertension, no clinically relevant effects on ECG were reported.
After chronic dosing of 80 mg TID sildenafil to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9.0 mmHg and 8.4 mmHg, respectively.
After chronic dosing of 80 mg TID sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 mmHg and 9.1 mmHg, respectively.
After chronic dosing of 80 mg TID sildenafil to patients with pulmonary arterial hypertension, lesser reductions than above in systolic and diastolic blood pressures were observed (a decrease in both of 2 mmHg).
At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) 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. An evaluation of visual function at doses up to 200 mg revealed no effects of REVATIO on visual acuity, intraocular pressure, or pupillometry.
REVATIO is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25-63%). Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When REVATIO is taken with a high-fat meal, the rate of absorption is reduced, with a mean delay in Tmax of 60 minutes and a mean reduction in Cmax of 29%. The mean steady state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations.
Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (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 phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. In healthy volunteers, 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. In patients with pulmonary arterial hypertension, however, the ratio of the metabolite to sildenafil is higher. Both sildenafil and the active metabolite have terminal half-lives of about 4 hours.
After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose).
Age, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in patients with PAH. The dataset 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 significant impact on sildenafil pharmacokinetics in patients with PAH.
In patients with PAH, 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.
Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma concentrations 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.
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) was not altered. In volunteers with severe (CLcr < 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and Cmax compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and Cmax values were significantly increased 200 % and 79 %, respectively, in subjects with severe renal impairment compared to subjects with normal renal function.
In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and Cmax (47%) compared to age-matched volunteers with no hepatic impairment. Patients with severe hepatic impairment (Child-Pugh class C) have not been studied.
Sildenafil metabolism is principally mediated by the CYP3A (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.
Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A (IC50 > 150 μM).
In study in healthy volunteers, co-administration with ritonavir, a potent CYP3A inhibitor, at steady state (500 mg BID) 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. Although the interaction between other protease inhibitors (except saquinavir) and REVATIO has not been studied, their concomitant use is expected to increase sildenafil levels.
Population data from patients in clinical trials indicated a reduction in sildenafil clearance when it was co-administered with CYP3A inhibitors. Sildenafil exposure without concomitant medication is shown to be 5-fold higher at a dose of 80 mg TID compared to its exposure at a dose of 20 mg TID. This concentration range covers the same increased sildenafil exposure observed in specifically-designed drug interaction studies with CYP3A 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 CYP3A inhibitor, at steady state (500 mg BID 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 CYP3A inhibitor, at steady state (1200 mg TID) with sildenafil (100 mg single dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC.
In a study of healthy male volunteers, co-administration of sildenafil at steady state (80 mg TID) with bosentan (a moderate inducer of CYP3A, CYP2C9 and possibly of cytochrome P450 2C19) at steady state (125 mg BID) resulted in a 63% decrease of sildenafil AUC and a 55% decrease in sildenafil Cmax. Co-administration resulted in a 50% increase in AUC of bosentan. The combination of both drugs did not lead to clinically significant changes in blood pressure (supine or standing). Concomitant administration of potent CYP3A inducers is expected to cause greater decreases in plasma levels of sildenafil.
The mean reduction of sildenafil (80 mg tid) bioavailability due to co-administration of epoprostenol was 28%, resulting in about 22% lower mean average steady state concentrations. Therefore, the slight decrease of sildenafil exposure in the presence of epoprostenol is not considered clinically relevant. The effect of sildenafil on epoprostenol pharmacokinetics is not known.
Population pharmacokinetic analysis of clinical trial data indicated a reduction in sildenafil clearance or an increase of oral bioavailability when co-administered with CYP3A substrates and the combination of CYP3A substrates and beta-blockers.
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 CYP3A substrates.
No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9.
Concomitant administration of oral contraceptives (ethinyl estradiol 30 mcg and levonorgestrel 150 mcg) did not affect the pharmacokinetics of sildenafil. Sildenafil had no impact on the plasma levels of oral contraceptives (ethinyl estradiol 30 mcg and levonorgestrel 150 mcg).
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.
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%.
A randomized, double-blind, placebo-controlled study was conducted in 277 patients with 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 anticoagulants, digoxin, calcium channel blockers, diuretics, and 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) TID for a period of 12 weeks. They had either PPH (63%), PAH associated with CTD (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 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 REVATIO. These increases were significantly different from placebo, but the dose groups were not different from each other (Figure 1), indicating no additional clinical benefit from doses higher than 20 mg TID. 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 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. Data from other hemodynamic parameters can be found in Table 3. The relationship between these effects and improvements in 6-minute walk distance is unknown.
Table 3. Changes from Baseline to Week 12 in Hemodynamic
Parameters at REVATIO 20 mg TID Dose
| PARAMETER [mean (95% CI)] | Placebo (n = 65)* | REVATIO 20 mg TID (n = 65)* |
| mPAP (mmHg) | 0.6 (-0.8, 2.0) | -2.1 (-4.3, 0.0) |
| 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) |
| *The number of patients per treatment group varied slightly for each parameter due to missing assessments. | ||
Of the 277 treated patients, 259 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.
A randomized, double-blind, placebo controlled study was conducted in 267 patients with PAH who were stabilized on intravenous epoprostenol. Patients had to have a mean pulmonary artery pressure (mPAP) ≥ 25 mmHg and a pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg at rest via right heart catheterization within 21 days before randomization, and a baseline 6-minute walk test distance ≥ 100 m and ≤ 450 m. Patients were randomized to placebo or REVATIO (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day) when used in combination with intravenous epoprostenol
Patients had primary pulmonary hypertension (80%) or PAH secondary to CTD (20%). Patients had WHO functional class I (1%), II (26%), III (67%), or IV (6%) at baseline. The mean age was 48 years, 80% were female, and 79% were Caucasian.
Analysis of the primary endpoint showed that there was a statistically significant greater increase in 6-minute walk distance for the REVATIO group compared with the placebo group at Week 16. The mean change from baseline at Week 16 (last observation carried forward) was 30 m for the sildenafil group compared with 4.m for the placebo group giving an adjusted treatment difference of 26 m (95% CI: 10.8, 41.2) (p = 0.0009).
Patients on sildenafil achieved a statistically significant reduction in mPAP compared to those on placebo. A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favor of REVATIO (95% CI: -5.7, -2.1) (p = 0.00003).
Time to clinical worsening of PAH was defined as the time from randomization to the first occurrence of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical deterioration requiring a change in epoprostenol therapy). Patients with clinical worsening events are summarized in Table 4. Kaplan-Meier estimates and a stratified log-rank test demonstrated that placebo patients were 3 times more likely to experience an event and that patients receiving REVATIO experienced a significant delay in time to clinical worsening versus placebo (p = 0.0074).
Table 4. Clinical Worsening Events
| Placebo (N = 131) | REVATIO (N = 134) | |||
| Number of subjects with clinical worsening event n (%) | 23 (17.6) | 8 (6.0) | ||
| Incidence of Clinical Worsening Events | First Event | All Events | First Event | All Events |
| Death | 3 | 4 | 0 | 0 |
| Lung Transplantation | 1 | 1 | 0 | 0 |
| Hospitalization due to PAH | 9 | 11 | 8 | 8 |
| Clinical deterioration resulting in: Change of Epoprostenol Dose Initiation of Bosentan Therapy | 9 1 | 16 1 | 0 0 | 2 0 |
| Proportion Worsened 95% Confidence Intervals | 0.187 (0.12 - 0.26) | 0.062 (0.02 - 0.10) | ||
Figure 3. Kaplan-Meier Plot of Time to Clinical Worsening
(Days), ITT Population
 |
Improvements in functional class were also demonstrated in subjects on sildenafil compared to placebo. More than twice as many sildenafil treated patients (36%) as the placebo group (14%) showed an improvement of at least one functional class.
Last updated on RxList: 5/21/2009
REVATIO®
(re-VAH-tee-oh)
(sildenafil) tablets
Read the Patient Information that comes with REVATIO before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or treatment. If you have any questions about REVATIO, ask your doctor or pharmacist.
What is the most important information I should know about REVATIO (sildenafil)?
Never take REVATIO with any nitrate medicines. Your blood pressure could drop quickly. It could fall to an unsafe level. Nitrate medicines include:
Medicines that treat chest pain (angina)
Nitroglycerin in any form
Isosorbide mononitrate or dinitrate
Street drugs called “poppers” (amyl nitrate or nitrite)
Ask your doctor or pharmacist if you are not sure if you are taking a nitrate medicine.
What is REVATIO (sildenafil)?
REVATIO is a prescription medicine used to treat pulmonary arterial hypertension (PAH). With PAH, the blood pressure in your lungs is too high. Your heart has to work hard to pump blood into your lungs. REVATIO improves the ability to exercise and can help lessen symptoms and slow down worsening changes in your physical condition.
REVATIO has not been studied
REVATIO contains the same medicine as VIAGRA® (sildenafil), which is used to treat erectile dysfunction (impotence). Do not take REVATIO with VIAGRA or other PDE5 inhibitors.
Who should not take REVATIO (sildenafil)?
Do not take REVATIO if you
What should I tell my doctor before taking REVATIO (sildenafil)?
Tell your doctor about all of your medical conditions, including if you
Tell your doctor about all of the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal products. REVATIO and certain other medicines can cause side effects if you take them together. The doses of some of your medicines may need to be adjusted while you take REVATIO.
Especially tell your doctor if you
Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine.
How should I take REVATIO (sildenafil)?
What are the possible side effects of REVATIO (sildenafil)?
The following side effects were reported in patients taking REVATIO. Some of these were serious.
The following side effects were reported rarely in patients taking sildenafil:
The most common side effects are nosebleed, headache, upset stomach, getting red or hot in the face (flushing), and trouble sleeping.
Tell your doctor if you have any side effect that bothers you or doesn't go away.
These are not all the possible side effects of REVATIO. For more information, ask your doctor or pharmacist.
How should I store REVATIO (sildenafil )?
General information about REVATIO (sildenafil)
Medicines are sometimes prescribed for conditions that are not in the patient leaflet. Do not use REVATIO for a condition for which it was not prescribed. Do not give REVATIO to other people, even if they have the same symptoms you have. It could harm them.
This patient leaflet summarizes the most important information about REVATIO. If you would like more information about REVATIO:
What are the ingredients in REVATIO (sildenafil)?
Active ingredients: sildenafil citrate
Inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, lactose monohydrate, and triacetin
Last updated on RxList: 5/21/2009
IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.
SILDENAFIL - ORAL
(sill-DEN-uh-fil)
COMMON BRAND NAME(S): Viagra
USES: Sildenafil is used to treat male sexual function problems (impotence or erectile dysfunction) by blocking a certain enzyme (phosphodiesterase-PDE5) in the body. In combination with sexual stimulation, sildenafil works by helping the blood flow into the penis to achieve and maintain an erection.
This drug is not indicated for use in women.
Use of this drug does not protect against sexually transmitted diseases (e.g., HIV, hepatitis B, gonorrhea, syphilis). Practice "safe sex" such as using latex condoms. Consult your doctor or pharmacist for more details.
HOW TO USE: Read the Patient Information Leaflet provided by your pharmacist before you start taking sildenafil and each time you get a refill. If you have any questions, consult your doctor or pharmacist.
This drug is taken by mouth as needed, at least 30 minutes, but no more than 4 hours, before sexual activity (1 hour before is the most effective). Do not take more often than once daily, and take as directed.
A high fat meal may delay the time of onset of this drug.
Avoid eating grapefruit or drinking grapefruit juice while you are being treated with this medication unless your doctor instructs you otherwise.
The dosage is based on your medical condition, response to therapy, and other medications you may be taking (see also Drug Interactions section). Consult your doctor or pharmacist for more details.
Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.
Rarely, a sudden loss of eyesight in one or both eyes (NAION) may occur. This may or may not be due to sildenafil. If this serious problem occurs, seek immediate medical attention. You have a slightly greater chance of developing this serious eye problem if you have heart disease, diabetes, high cholesterol, certain eye problems ("crowded disk"), high blood pressure, are over 50 years of age, or if you smoke.
Sexual activity may put extra strain on your heart, especially if you have heart problems. If you have heart problems and experience any of these serious side effects while having sex, stop and seek immediate medical attention: severe dizziness, fainting, chest pain, nausea.
For males, in the very unlikely event you have a painful or prolonged erection lasting 4 or more hours, stop using this drug and seek immediate medical attention, or permanent problems could occur.
Rarely, sildenafil may cause sudden hearing problems, or ringing in the ears. Seek immediate medical attention if these effects occur.
A serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction include: rash, itching, unusual swelling, severe dizziness, trouble breathing.
This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.
Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.
PRECAUTIONS: Before taking sildenafil, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.
Before using this medication, tell your doctor or pharmacist your medical history, especially of: penis conditions (e.g., angulation, fibrosis/scarring, Peyronie's disease), history of painful/prolonged erection (priapism), sickle cell anemia, blood system cancers (e.g., leukemia or myeloma), eye problems (e.g., retina diseases like retinitis pigmentosa), kidney disease, liver disease, bleeding disorders, active stomach ulcers, heart problems (e.g., recent heart attack or serious arrhythmia within past 6 months, heart failure, coronary artery disease with unstable angina, aortic stenosis, idiopathic hypertrophic subaortic stenosis), recent stroke within past 6 months, very high or low blood pressure.
This drug may make you dizzy or cause vision changes; use caution engaging in activities requiring alertness such as driving or using machinery. Limit alcoholic beverages.
To minimize dizziness and lightheadedness, get up slowly when rising from a seated or lying position.
Do not take this medication with any other product that contains sildenafil or other similar medications for erection problems (e.g., tadalafil, vardenafil).
Caution is advised when using this drug in the elderly because they may be more sensitive to the side effects of the drug.
This drug is not indicated for use in women or children.
See also How To Use section for drug-food interactions.
This drug should not be used with the following medications because very serious (possibly fatal) interactions may occur: nitrates (e.g., nitroglycerin, isosorbide), nitroprusside (or any "nitric oxide donor" drugs), recreational drugs called "poppers" containing amyl or butyl nitrite.
If you are currently using any of these medications, tell your doctor or pharmacist before starting sildenafil.
Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: alpha-blocker medication (e.g., doxazosin, prazosin, terazosin), other medications for impotence, bosentan, high blood pressure medicines, drugs affecting liver enzymes that remove sildenafil from your body (such as azole antifungals including ketoconazole/itraconazole, macrolide antibiotics including erythromycin, cimetidine, delavirdine, rifamycins including rifabutin/rifampin, St. John's wort, certain anti-seizure medicines including carbamazepine).
If you are taking an HIV protease inhibitor (e.g., ritonavir, saquinavir), do not take more than a 25 milligrams dose of sildenafil in a 48 hour period.
If you are taking more than a 25 milligrams dose of sildenafil and are also taking an alpha-blocker medication (e.g., doxazosin, prazosin, terazosin) for various conditions (e.g., enlarged prostate), separate the time between taking these medications by more than 4 hours.
This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.
OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. Symptoms of overdose may include severe dizziness, fainting, or prolonged erection.
NOTES: Do not share this medication with others, since they may have a problem that is not effectively treated by this drug, or they may have a condition that is complicated by this drug.
MISSED DOSE: Not applicable.
STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59 and 86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.
Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.
Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.
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