Ketoconazole Calcium-channel blockers

Drugs that may affect repaglinide include CYP 450 inhibitors (eg, clarithromycin, erythromycin, ketoconazole, miconazole), CYP 450 inducers (eg, barbiturates, carbamazepine, rifampin), beta blockers, calcium channel blockers, chloramphenicol, corticosteroids, coumarins, estrogens, gemfibrozil, isoniazid, itraconazole, levonorgestrel and ethinyl estradiol, MAOIs, nicotinic acid, NSAIDs, oral contraceptives, phenothiazines, phenytoin, probenecid, salicylates, simvastatin, sulfonamides, sympathomimetics, thiazides and other diuretics, and thyroid products. 

Drugs that may be affected by atazanavir include the following antiarrhythmics, atenolol, benzodiazepines, calcium channel blockers, cisapride, clarithromycin, ergot derivatives, HMG-CoA reductase inhibitors, immunosuppressants, indinavir, irinotecan, itraconazole, ketoconazole, oral contraceptives, PDE5 inhibitors, pimozide, rifabutin, saquinavir, tenofovir, tricyclic antidepressants, voriconazole, warfarin. 

Drugs that might be affected by lopinavir/ritonavir include ergot derivatives, oral contraceptives, antiarrhythmics, HMG-CoA reductase inhibitors, HIV protease inhibitors, atovaquone, calcium channel blockers, ketoconazole, itraconazole, pimozide, cisapride, clarithromycin, disulfiram, metronidazole, immunosuppressants, midazolam, triazolam, narcotic analgesics, rifabutin and rifabutin metabolite, sildenafil, warfarin, bupropion, clozapine, desipramine, piroxicam, quinidine, theophylline, and zolpidem. 

Drugs that may affect cyclosporine include allopurinol, amiodarone, androgens (eg, danazol, methyltestosterone), anticonvulsants (eg, carbamazepine, phenobarbital, phenytoin), azole antifungals (eg, fluconazole, ketoconazole), beta-blockers, bosentan, bromocriptine, calcium channel blockers, colchicine, oral contraceptives, corticosteroids, fluoroquinolones (eg, ciprofloxacin), foscarnet, HMG-CoA reductase inhibitors, imipenem-cilastatin, macrolide antibiotics, methotrexate, metoclopramide, nafcillin, nefazodone, orlistat, potassium-sparing diuretics, probucol, rifamycins (rifampin, rifabutin), serotonin reuptake inhibitors (SSRIs eg, fluoxetine, sertraline),... 

Coadminister known CYP3A4 inhibitors (eg, erythromycin, itraconazole, ketoconazole, fluconazole, calcium channel blockers, cimetidine) with caution in patients with widespread or erythrodermic disease. 

Omeprazole, like cimetidine, can impair benzodiazepine metabolism and lead to adverse effects (SEDA-18, 43). Other drugs, including antibiotics (erythromycin, chloramphenicol, isoniazid), antifungal drugs (ketoconazole, itraconazole, and analogues), some SSRIs (fluoxetine, paroxetine), other antidepressants (nefazodone), protease inhibitors (saquinavir), opioids (fentanyl), calcium channel blockers (diltiazem, verapamil), and disulfiram also compete for hepatic oxidative pathways that metabolize most benzodiazepines, as well as zolpidem, zopiclone, and buspirone (SEDA-22,39) (SEDA-22,41). 

FLUCONAZOLE, ITRACONAZOLE, KETOCONAZOLE, POSACONAZOLE, VORICONAZOLE CALCIUM CHANNEL BLOCKERS Plasma concentrations of dihydropyridine calcium channel blockers are t by fluconazole, itraconazole and ketoconazole. Risk of t verapamil levels with ketoconazole and itraconazole. Itraconazole and possibly posaconazole may t diltiazem levels The azoles are potent inhibitors of CYP3A4 isoenzymes, which metabolize calcium channel blockers. They also inhibit CYP2C9-mediated metabolism of verapamil. Ketoconazole and itraconazole both inhibit intestinal P-gp, which may t bioavailability of verapamil. Diltiazem is mainly a substrate of CYP3A5 and CYP3A5P1, which are inhibited by itraconazole. 75% of the metabolism of diltiazem occurs in the liver and the rest in the intestine. Diltiazem is a substrate of P-gp (also an inhibitor but unlikely to be significant at therapeutic doses), which is inhibited by itraconazole, resulting in t bioavailability of diltiazem Monitor PR, BP and ECG, and warn patents to watch for symptoms/signs of heart failure... 

Benzodiazepines alprazolam, clonazepam, diazepam, midazolam, triazolam, zolpidem Calcium channel blockers diltiazem, nifedipine, nimodipine, verapamil Steroids androgens, estrogens, cortisol Others erythromycin, terfenadine, cyclosporine, dapsone, ketoconazole, lovastatin, lidocaine, alfentanil, amiodarone, astemizole, codeine, sildenafil... 

Aminoglutethimide, rifampin, barbiturates, charcoal, ketoconazole, smoking (cigarettes and marijuana), sulfinpyrazone, and sympathomimetics (beta-agonists)—all decrease the plasma levels of theophylline, whereas allopu-rinol, beta-blockers (nonselective), calcium-channel blockers, cimetidine, contraceptives, corticosteroids, disulfiram, ephedrine, interferon, macrolides, mexiletine, quinolones, and thiabendazole all increase the plasma levels of theophylline. 

CYP3A4 alprazolam, calcium channel blockers, cisapride, clarithromycin, cyclosporin A, erythromycin, HIV protease inhibitors, lidocaine, midazolam, simvastatin, terfenadine carbamazepine, dexamethsone, phenobarbital, phenytoin, rifampicin, St John s wort cimetidine, erythromycin, grapefruit juice, HIV protease inhibitors, itraconazole, ketoconazole... 

Plasma concentrations of dihydropyridine calcium channel blockers are T by fluconazole, itraconazole and ketoconazole. Risk of t verapamil levels with ketoconazole and itraconazole. Itraconazole and possibly posaconazole may t diltiazem levels... 

An in vitro study showed that ritonavir markedly reduced the transport of fexofenadine, thought to be via inhibition of P-glycoprotein. This would be predicted to markedly increase the bioavailability of fexofenadine, as occurs with verapamil, see Calcium-channel blockers + Antihistamines , p.861. However, the similar marked increases in fexofenadine levels that occurred with erythromycin , (p.589) and ketoconazole , (p.584) did not increase adverse effects and were not associated with any prolongation of the QT interval. This suggests that a clinically relevant interaction between ritonavir and fexofenadine is not expected. 

Itraconazole can markedly raise the serum levels of felodipine, which Increases Its adverse effects, In particular ankle and leg oedema. A few case reports suggest that isradipine and nifedipine can interact similarly with itraconazole, and that fluconazole can also interact with nifedipine. Ketoconazole can markedly raise the plasma levels of lercanidipine and nisoldipine. Caution is warranted with all calcium-channel blockers when azole antifungals, particularly itraconazole and ketoconazole, are used. 

Ankle swelling due to precapillary vasodilatation is a relatively common adverse effect of the dihydropyridine calcium-channel blockers, and this effect appears to be dose-related. Calcium-channel blockers are metabolised in the gut wall and liver by the cytochrome P450 CYP3A subfamily of isoenzymes, which are inhibited by itraconazole, ketoconazole and to a lesser extent by fluconazole, so that in the presence of these antifungals the levels of the calcium-channel blockers are raised and the adverse effects increased. 

The interaction between felodipine and itraconazole would appear to be established and elinieally important. It also seems that isradipine, lercanidipine, nifedipine and nisoldipine ean interaet similarly with fluconazole, itraconazole or ketoconazole and, because they are metabolised by CYP3A4, it is likely that other calcium-channel blockers will behave in the same way. If itraconazole, ketoconazole, or fluconazole is given to a patient on established treatment with any calcium-channel blocker be alert for the need to lower the dosage of the calcium-channel blocker. However, some manufaeturers (e.g. felodipine, lercanidipine ) actually contraindicate concurrent use of itraconazole or ketoconazole, and others (e.g. nisoldipine ) additionally contraindicate fluconazole. In the US the guidance differs slightly and only caution is considered necessary with felodipine. The manufacturers of nimodipine predict that fluconazole, itraconazole and ketoconazole will substantially raise nimodipine levels. They say that concurrent use should be avoided, but, if this is not possible then the patient s blood pressure should be carefully monitored."... 

Although the effect of these increases has not been assessed, such marked increases in levels could increase adverse effects. The manufacturers recommend caution when aprepitant is given with ketoconazole and other drugs that are strong inhibitors of CYP3A4. They specifically name ritonavir, clarithromycin, telithromycin, itraconazole, ne-fazodone, troleandomycin, and nelfinavir. For the effect of diltiazem (a moderate CYP3A4 inhibitor), see Calcium-channel blockers + Aprepi-tanf, p. 861. Other inhibitors of CYP3A4 are listed in Table 1.4 , (p.6). 

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