Levitra Interactions
- Abarelix
Alpha-blockers
- Amoxapine
- Amprenavir
Anti-retroviral protease inhibitors
- Apomorphine
- Arsenic Trioxide
- Astemizole
Barbiturates
- Bepridil
Beta-agonists
- Bosentan
- Carbamazepine
- Chloroquine
- Ciprofloxacin
- Cisapride
- Clarithromycin
Class IA antiarrhythmics
Class III antiarrhythmics
- Clozapine
- Cyclobenzaprine
- Delavirdine
- Dexamethasone
- Diltiazem
- Dolasetron
- Droperidol
- Efavirenz
- Erythromycin
- Flecainide
- Fluconazole
- Fluoxetine
- Fluvoxamine
- Fosphenytoin
- Gatifloxacin
- Gemifloxacin
- grapefruit juice
- Grepafloxacin
- Halofantrine
Halogenated anesthetics
- Haloperidol
- Imatinib, STI-571
- Indinavir
- Isoniazid, INH
- Itraconazole
- Ketoconazole
- Levofloxacin
- Levomethadyl
Local Anesthetics
- Maprotiline
- Mefloquine
- Methadone
- Methscopolamine
- Mibefradil
- Mifepristone, RU-486
- Moxifloxacin
- Nefazodone
- Nevirapine
- Nicardipine
Nitrates
- Norfloxacin
- Octreotide
- Ofloxacin
- Palonosetron
- Pentamidine
Phenothiazines
- Phenytoin
- Pimozide
- Probucol
- Propafenone
- Rifabutin
- Rifampin
- Rifapentine
- Risperidone
- Ritonavir
- Sertindole
- Sparfloxacin
- Tacrolimus
- Telithromycin
- Terfenadine
Tricyclic antidepressants
- Troglitazone
- Troleandomycin
- Verapamil
- Voriconazole
- Zafirlukast
- Zileuton
- Ziprasidone
Levitra (Vardenafil) Interactions
Consistent with its known effects on the nitric oxide/cGMP pathway, vardenafil may potentiate the hypotensive effects of nitrates. In vivo studies show that vardenafil potentiates the blood pressure lowering effects of nitrates when sublingual nitroglycerin is taken 1, 4, and 8 hours after vardenafil (20 mg). These effects were not observed when vardenafil was taken 24 hours before nitroglycerin. Potentiation of the hypotensive effects of nitrates by vardenafil for patients with ischemic heart disease has not been studied. Deaths have been reported in men who were using a similar agent, sildenafil, while taking nitrate or nitrite therapy for angina. Vardenafil administration to patients who are concurrently using organic nitrates or nitrites in any form is contraindicated.
Concurrent use of phosphodiesterase (PDE5) inhibitors and alpha-blockers may lead to symptomatic hypotension in some patients. Vardenafil, other PDE5 inhibitors, and alpha-blockers are systemic vasodilators which can lower blood pressure. If vasodilators are used in combination, an additive effect on blood pressure is anticipated. Patients should be stable on alpha-blocker therapy before starting PDE5 inhibitor therapy. If hemodynamic instability is evident on alpha-blocker therapy alone, there is an increased risk of symptomatic hypotension with concomitant PDE5 inhibitor therapy. For patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be started at the lowest recommended dose. If a patients is currently receiving an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increases in the alpha-blocker dose may be associated with further hypotension when taking a PDE5 inhibitor. Other variables, such as intravascular volume depletion and other antihypertensive drugs, may affect the safety of concomitant use of PDE5 inhibitors and alpha-blockers. Studies have been conducted to determine the effects of vardenafil on the potentiation of the blood-pressure-lowering effects of the alpha-blockers terazosin and tamsulosin. When vardenafil 10 or 20 mg was administered to healthy subjects taking terazosin (10 mg daily), an alpha-1-blocker, there was significant augmentation of the hypotensive effects of terazosin on standing systolic blood pressure. In contrast, coadministration of a single 10 or 20 mg dose of vardenafil to healthy subjects taking 0.4 mg once daily of tamsulosin, a selective antagonist of alpha-1a receptors, resulted in no significant decreases in blood pressure.
Coadministration of vardenafil and other organic nitrates has been shown to potentiate the hypotension effects of nitrates. Many methscopolamine-containing products list methscopolamine nitrate as an ingredient. Coadministration of methscopolamine nitrate and vardenafil has not been studied. Therefore, the concomitant use of vardenafil and products which contain methscopolamine nitrate is not recommended.
The effects of vardenafil on QT prolongation were evaluated in 59 healthy males using moxifloxacin (400 mg) as an active control. Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produced similar increases in QTc interval (e.g., 4 - 6 msec calculated by individual QT correction) as moxifloxacin (7 msec). The effect of vardenafil on the QT interval should be considered when prescribing the drug. The manufacturer recommends that vardenafil not be used in patients taking Class IA antiarrhythmics or Class III antiarrhythmics. In addition to Class IA and Class III antiarrhythmics, other drugs which have been established to have a causal association with QT prolongation and TdP include: astemizole, arsenic trioxide, certain quinolones (grepafloxacin and sparfloxacin ), cisapride, chloroquine, clarithromycin, droperidol, erythromycin, halofantrine, haloperidol, levomethadyl, methadone, pentamidine, certain phenothiazines (chlorpromazine, mesoridazine, and thioridazine), pimozide, probucol, and terfenadine. Other agents associated with a lower, but possible risk for QT prolongation and TdP based on varying levels of documentation include: abarelix, alfuzosin, amoxapine, apomorphine, beta-agonists, certain quinolones (ofloxacin, ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, norfloxacin), cyclobenzaprine, clozapine, dolasetron, flecainide, halogenated anesthetics, local anesthetics, maprotiline, mefloquine, octreotide, palonosetron, some phenothiazines (fluphenazine, perphenazine, prochlorperazine, and trifluoperazine), propafenone, risperidone, sertindole, tacrolimus, telithromycin, tricyclic antidepressants when given in excessive doses or overdosage, troleandomycin (based on interactions with macrolides), or ziprasidone. This list is not inclusive of all agents that can cause QT interval prolongation. Additionally, some of the listed drugs (e.g., amiodarone, erythromycin, quinidine) are inhibitors of CYP3A4 and may reduce the clearance of vardenafil, however, no interaction studies have been performed. In addition to avoiding concurrent drug interactions, the potential for TdP can be reduced by avoiding the use of QT prolonging drugs in patients at substantial risk for TdP. Examples of general risk factors for TdP include congenital long QT syndrome, female sex, elderly patients, significant bradycardia, hypokalemia, hypomagnesemia, and underlying cardiac disease (e.g., arrhythmias, cardiomyopathy, acute myocardial ischemia).
Vardenafil is metabolized by hepatic cytochrome P450 3A4 (CYP3A4) and to a lesser extent CYP2C9. Inhibitors of CYP3A4 can reduce vardenafil clearance. Increased systemic exposure to vardenafil may result in an increase in vardenafil-induced adverse effects. In vivo studies report that several strong CYP3A4 inhibitors can significantly increase the AUC and Cmax of vardenafil when co-administered with vardenafil. Examples of strong CYP3A4 inhibitors include the macrolide erythromycin; the azole antifungals itraconazole and ketoconazole; and the anti-retroviral protease inhibitors amprenavir, atazanavir, fosamprenavir, indinavir, ritonavir, and tipranavir; dosage adjustments are required when vardenafil is administered with these agents (see Dosage). Specifically, ritonavir and indinavir have the greatest effect on vardenafil AUC and Cmax. Co-administration of ritonavir (600 mg bid) with vardenafil resulted in a 49-fold increase in the AUC of vardenafil, a 13-fold increase in vardenafil Cmax, and a prolonged vardenafil half-life of 26 hours. Indinavir (800 mg tid) increased the AUC and Cmax of vardenafil by 16-fold and 7-fold, respectively, and 2-fold increase in vardenafil half-life. Conversely, vardenafil reduces the AUC and Cmax of ritonavir by about 20% and the AUC and Cmax of indinavir by 30% and 40%, respectively. Use vardenafil and fosamprenavir together with caution and reduce the dosage of vardenafil to no more than 2.5 mg every 24 hours with increased monitoring for adverse events. Coadminister vardenafil with other protease inhibitors, including fosamprenavir boosted with ritonavir, with caution and reduce the dosage of vardenafil to no more than 2.5 mg every 72 hours with increased monitoring for adverse events. Ketoconazole (400 mg qd) increased the AUC and Cmax of vardenafil 10-fold and 4-fold, respectively, while erythromycin (500 mg tid) increased the AUC and Cmax of vardenafil 4-fold and 3-fold, respectively. Other potent CYP3A4 inhibitors such as delavirdine, efavirenz (induces or inhibits), mibefradil, imatinib, STI-571, other macrolides (i.e., clarithromycin, troleandomycin), or other systemic azole antifungals (e.g., fluconazole and voriconazole) would be expected to have effects on vardenafil clearance when co-administered. Other inhibitors of CYP3A4 may reduce the clearance of vardenafil, however, no interaction studies have been performed. Other CYP3A4 inhibitors may include amiodarone, diltiazem, fluoxetine, fluvoxamine, isoniazid, INH, nefazodone, nicardipine, verapamil, zafirlukast, and zileuton. Cimetidine (400 mg bid) had no effect on vardenafil AUC or Cmax.
Vardenafil is metabolized by cytochrome P450 (CYP) 3A4. It can be expected that concomitant administration of CYP3A4 enzyme-inducers will decrease plasma levels of vardenafil, however, no interaction studies have been performed. CYP3A4 inducers include barbiturates, bosentan, carbamazepine, dexamethasone, phenytoin or fosphenytoin, nevirapine, rifabutin, rifampin, rifapentine, and troglitazone.
Vardenafil is metabolized via the CYP3A4 isozyme. Grapefruit juice (food) has been reported to decrease the metabolism of drugs metabolized via this enzyme. Grapefruit juice contains a furano-coumarin compound, 6,7 - dihydroxybergamottin that inhibits CYP3A4 in enterocytes in the GI tract. Vardenafil levels may increase; it is possible that vardenafil-induced side effects could also be increased in some individuals.
Mifepristone, RU-486 inhibits CYP3A4 in vitro. Coadministration of mifepristone may lead to an increase in serum levels of drugs metabolized via CYP3A4, such as vardenafil. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration.
Vardenafil is metabolized to a small degree by cytochrome P450 2C9 (CYP2C9). It is not known to what extent vardenafil clearance can be decreased by drugs that significantly inhibit CYP2C9. Drugs that inhibit CYP2C9 include, but not limited to, amiodarone, chloramphenicol, clopidogrel, fluconazole, fluoxetine, fluvastatin (weak), fluvoxamine (weak), isoniazid, INH (particularly in a slow-acetylator of INH), the M1 (active) metabolite of leflunomide, metronidazole, modafinil, ritonavir, sulfonamides (e.g., sulfonamide antibiotics like sulfadiazine or sulfamethoxazole), voriconazole and zafirlukast.
Vardenafil does not potentiate the hypotensive effects of alcohol.
No pharmacokinetic interactions were observed between vardenafil and the following drugs: digoxin, glyburide, Maalox® (aluminum hydroxide; magnesium hydroxide), ranitidine, and warfarin. Additionally, the warfarin study showed vardenafil had no effect on the prothrombin time or other pharmacodynamic parameters of warfarin. Vardenafil does not potentiate the increase in bleeding time caused by aspirin (two 81 mg tablets).
Vardenafil (20 mg) did not affect the AUC or Cmax of slow-release nifedipine (30 or 60 mg qd) which is metabolized by CYP3A4. Nifedipine did not alter plasma levels of vardenafil. In patients whose hypertension was controlled with nifedipine, vardenafil produced mean additional supine systolic/diastolic blood pressure reductions of 6/5 mm Hg compared to placebo.
[ Last revised: 10/14/2005 1:02:00 PM ]
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