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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.
Studies establishing effectiveness included predominately patients with NYHA Functional Class II-III symptoms and etiologies of primary pulmonary hypertension (71%) or pulmonary hypertension associated with connective tissue disease (25%).
Limitation of Use
The efficacy of Revatio has not been adequately evaluated in patients taking bosentan concurrently.
Revatio Tablets
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 Injection
Revatio injection is for the continued treatment of patients with pulmonary arterial hypertension (PAH) who are currently prescribed oral Revatio and who are temporarily unable to take oral medication.
The recommended dose is 10 mg (corresponding to 12.5 mL) administered as an intravenous bolus injection three times a day. The dose of Revatio injection does not need to be adjusted for body weight.
A 10 mg dose of Revatio injection is predicted to provide pharmacological effect of sildenafil and its N-desmethyl metabolite equivalent to that of a 20 mg oral dose.
Revatio Tablets
Revatio tablets are supplied as white, film-coated, round tablets engraved with "RVT20" containing sildenafil citrate equivalent to 20 mg of sildenafil.
Revatio Injection
Revatio injection is supplied as a single use vial containing 10 mg (12.5 mL) of sildenafil.
Do not use Revatio in patients taking organic nitrates in any form, either regularly or intermittently. 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 or injection.
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.
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:
Use 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, cases of symptomatic hypotension consisting of dizziness and lightheadedness were reported [see Drug Interactions (7)]. 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 (7) and Clinical Pharmacology (12.3)].
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 (6.2)].
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 (6.2)].
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.
In a small, prematurely terminated study of patients with pulmonary hypertension (PH) secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported by patients who received Revatio than by those randomized to placebo. The effectiveness of Revatio in PH secondary to sickle cell anemia has not been established.
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.
| ADVERSE EVENT % | Placebo (n = 70) | Revatio 20 mg TID (n = 69) | Placebo- Subtracted |
|---|---|---|---|
| nos: Not otherwise specified | |||
| 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 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.
| 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 |
Revatio Injection
Revatio injection was studied in a 66-patient, placebo-controlled study at doses targeting plasma concentrations between 10 and 500 ng/mL (up to 8 times the exposure of the recommended dose). Adverse events in PAH patients were similar to those seen with oral tablets.
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.
Cardiovascular Events
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.
Decreases in and Loss of Vision
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 (5.4)].
Loss of Hearing
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 (5.5)].
Other Events
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
Nitrates
Concomitant use of Revatio with nitrates in any form is contraindicated [see Contraindications (4)].
Ritonavir and other Potent CYP3A Inhibitors
Concomitant use of Revatio with ritonavir and other potent CYP3A inhibitors is not recommended [see Warnings and Precautions (5.3)].
Alpha-blockers
Use caution when co-administering alpha-blockers with Revatio because of additive blood pressure-lowering effects [see Warnings and Precautions (5.1)].
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.
Amlodipine
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.
Pregnancy Category B
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, Revatio 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 (12.3)].
No dose adjustment for mild to moderate impairment is required. Severe impairment has not been studied [see Clinical Pharmacology (12.3)].
No dose adjustment is required (including severe impairment CLcr < 30 mL/min) [see Clinical Pharmacology (12.3)].
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.
Revatio, a 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)-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 Tablets: 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.
Revatio Injection: Revatio is supplied as a clear, colorless, sterile, ready to use solution containing 10 mg (12.5 mL) of sildenafil. Each mL of solution contains 1.124 mg sildenafil citrate, 50.5 mg dextrose and water for injection.
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 Clinical Pharmacology (12.2)].
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.
Effects of Revatio on Blood Pressure
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 (4)].
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).
Effects of Revatio on Vision
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.
Absorption and Distribution
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.
Metabolism and Excretion
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).
Revatio Injection: The pharmacokinetic profile of Revatio has been characterized following intravenous administration. A 10 mg dose of Revatio Injection is predicted to provide a pharmacological effect of sildenafil and its N-desmethyl metabolite equivalent to that of a 20 mg oral dose.
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 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.
Geriatric Patients
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.
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) 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.
Hepatic Impairment
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.
Drug Interaction Studies
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).
Ritonavir and other CYP3A Inhibitors
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.
Revatio Injection: Predictions based on a pharmacokinetic model suggest that drug-drug interactions with CYP3A inhibitors will be less than those observed after oral sildenafil administration.
Bosentan
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.
Epoprostenol
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.
CYP Substrates and Beta-blockers
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.
Oral Contraceptives
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).
Atorvastatin
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.
Antacids
Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of sildenafil.
Aspirin
Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg).
Alcohol
Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%.
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.
Study 1
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 (mean 343).
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.
| 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) |
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.
Study 2
A randomized, double-blind, placebo controlled study was conduct
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Diclofenac Patch is a nonsteroidal anti-inflammatory drug (NSAID). It may cause an increased risk of serious and sometimes fatal heart and blood vessel problems (eg, a heart attack, a stroke, blood clots). The risk may be greater if you already have heart problems or if you take Diclofenac Patch for a long time. Do not use Diclofenac Patch right before or after bypass heart surgery.
Diclofenac Patch may cause an increased risk of serious and sometimes fatal stomach ulcers and bleeding. Elderly patients may be at greater risk. This may occur without warning signs.
Treating pain caused by minor strains, sprains, and bruises. It may also be used for other conditions as determined by your doctor.
Diclofenac Patch is an NSAID. Exactly how it works is not known. It may block certain substances in the body that are linked to inflammation. NSAIDs treat the symptoms of pain and inflammation. They do not treat the disease that causes those symptoms.
Contact your doctor or health care provider right away if any of these apply to you.
Some medical conditions may interact with Diclofenac Patch. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:
Some MEDICINES MAY INTERACT with Diclofenac Patch. Tell your health care provider if you are taking any other medicines, especially any of the following:
This may not be a complete list of all interactions that may occur. Ask your health care provider if Diclofenac Patch may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.
Use Diclofenac Patch as directed by your doctor. Check the label on the medicine for exact dosing instructions.
Ask your health care provider any questions you may have about the proper use of Diclofenac Patch.
All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:
Minor burning, itching, or irritation at the application site.
Severe allergic reactions (rash; hives; itching; trouble breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); bloody or black, tarry stools; change in the amount of urine produced; chest pain; confusion; depression; fainting; fast or irregular heartbeat; fever, chills, or persistent sore throat; mental or mood changes; numbness of an arm or leg; one-sided weakness; red, swollen, blistered, or peeling skin; ringing in the ears; seizures; severe headache or dizziness; severe or persistent irritation at the application site; severe or persistent stomach pain or nausea; severe vomiting or diarrhea; shortness of breath; sudden or unexplained weight gain; swelling of the hands, legs, or feet; symptoms of liver problems (eg, dark urine, pale stools, persistent loss of appetite, yellowing of the skin or eyes); unusual bruising or bleeding; unusual joint or muscle pain; unusual tiredness or weakness; vision or speech changes; vomit that looks like coffee grounds; wheezing.
This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.
Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Diclofenac Patch may be harmful if swallowed.
Store Diclofenac Patch at 77 degrees F (25 degrees C) in the sealed pouch. Brief storage between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Throw away any unused patches 3 months after opening the pouch. The pouch is not child-resistant. Keep Diclofenac Patch out of the reach of children and away from pets.
This information is a summary only. It does not contain all information about Diclofenac Patch. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.
Generic Name: diltiazem (Oral route)
dil-TYE-a-zem
In the U.S.
Available Dosage Forms:
Therapeutic Class: Cardiovascular Agent
Pharmacologic Class: Calcium Channel Blocker
Chemical Class: Benzothiazepine
Diltiazem is used alone or together with other medicines to treat severe chest pain (angina) or high blood pressure (hypertension). High blood pressure adds to the workload of the heart and arteries. If it continues for a long time, the heart and arteries may not function properly. This can damage the blood vessels of the brain, heart, and kidneys, resulting in a stroke, heart failure, or kidney failure. High blood pressure may also increase the risk of heart attacks. These problems may be less likely to occur if blood pressure is controlled .
Diltiazem is a calcium channel blocker. It works by affecting the movement of calcium into the cells of the heart and blood vessels. As a result, diltiazem relaxes blood vessels and increases the supply of blood and oxygen to the heart while reducing its workload .
This medicine is available only with your doctor's prescription .
In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:
Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.
Appropriate studies have not been performed on the relationship of age to the effects of diltiazem in the pediatric population. Safety and efficacy have not been established .
Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of diltiazem in the elderly. However, elderly patients are more likely to have age-related kidney, liver, or heart problems, which may require an adjustment in the dose for patients receiving diltiazem .
| Pregnancy Category | Explanation | |
|---|---|---|
| All Trimesters | C | Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women. |
Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.
Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.
Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.
Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.
Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.
Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.
The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:
This section provides information on the proper use of a number of products that contain diltiazem. It may not be specific to Dilacor XR. Please read with care.
In addition to the use of this medicine, treatment for your high blood pressure may include weight control and changes in the types of foods you eat, especially foods high in sodium. Your doctor will tell you which of these are most important for you. You should check with your doctor before changing your diet .
Many patients who have high blood pressure will not notice any signs of the problem. In fact, many may feel normal. It is very important that you take your medicine exactly as directed and that you keep your appointments with your doctor even if you feel well .
Remember that this medicine will not cure your high blood pressure, but it does help control it. You must continue to take it as directed if you expect to lower your blood pressure and keep it down. You may have to take high blood pressure medicine for the rest of your life. If high blood pressure is not treated, it can cause serious problems such as heart failure, blood vessel disease, stroke, or kidney disease .
Swallow the extended-release tablet or extended-release capsule whole. Do not open, crush, or chew it. It is best to take the extended-release capsule on an empty stomach .
The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
Ask your healthcare professional how you should dispose of any medicine you do not use.
It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly and to check for unwanted effects .
Low blood pressure (hypotension) may occur while taking this medicine. Check with your doctor right away if you have the following symptoms: blurred vision; confusion; severe dizziness, faintness, or lightheadedness when getting up from a lying or sitting position suddenly; sweating; or unusual tiredness or weakness .
Check with your doctor right away if you have pain or tenderness in the upper stomach; pale stools; dark urine; loss of appetite; nausea; unusual tiredness or weakness; or yellow eyes or skin. These could be symptoms of a serious liver problem .
Serious skin reactions can occur with this medicine. Check with your doctor right away if you have any of the following symptoms while taking this medicine: blistering, peeling, or loosening of the skin; chills; cough; diarrhea; itching; joint or muscle pain; red skin lesions, often with a purple center; skin rash; sore throat; sores, ulcers, or white spots in the mouth or on the lips; or unusual tiredness or weakness .
Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur:
Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:
Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.
Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
See also: Dilacor XR side effects (in more detail)
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Methergin may be available in the countries listed below.
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