Ketoconazole Dofetilide

Dofetilide See below3 patients must be hospitalized for 3 days during initiation of therapy Cimetidine, hy d roch I o roth iaz i de, ketoconazole, medroxyprogesterone, promethazine, trimethoprim, verapamil (all inhibit dofetilide elimination)... 

Verapamil increases serum dofetilide levels, as do drugs that inhibit cationic renal secretion, such as ketoconazole and cimetidine, raise serum levels. 

Clinically important, potentially hazardous interactions with acenocoumarol, alfuzosin, aminophylline, anisindione, anticoagulants, buprenorphine, butorphanol, caffeine, carmustine, dobazam, cocoa, dicumarol, dofetilide, duloxetine, epirubicin, eszopiclone, fentanyl, floxuridine, fluorouracil, galantamine, gliclazide, hydromorphone, itraconazole, ketoconazole, lidocaine, meptazinol, midazolam, mizolastine, modobemide, morphine, narcotic analgesics, oxprenolol, oxycodone, pentazocine, phenytoin, posaconazole, prednisone, propranolol, sufentanil, tolazoline, warfarin, xanthines, zaleplon, zofenopril, zolmitriptan, zolpidem... 

Clinically important, potentially hazardous interactions with cyclosporine, diltiazem, dofetilide, erythromycin, grapefruit, ketoconazole, quinidine, ritonavir, simvastatin, sotalol, thioridazine, verapamil, ziprasidone... 

K41.1 (ergl) KCNH2 7q35-36 minK, MiRPl Brain, heart, kidney, liver, lung, ovary, pancreas, testis, prostate, uterus, small intestine Astemizole, BeKM-1, ergtoxin, sertindole, dofetilide, cisapride, pimozide, terfenadine, halofantrine, BRL32872, E-4031, CT haloperidol, imipramine, cocaine, ketoconazole None... 

Dofetilide has weak affinity for CYP3A4. Concomitant use of dofetilide with cime-tidine, hydrochlorothiazide (including combination products), verapamil, trimethoprim, prochlorperazine, megestrol, or ketoconazole is contraindicated due to significant increases in dofetilide serum concentrations (see Table 8.3). 

Ketoconazole markedly increases the plasma levels of dofetilide. This is likely to be associated with an increased risk of dofetilide-induced QT prolongation and torsade de pointes arrhythmias. 

The manufacturer of dofetilide notes that ketoconazole 400 mg daily, given with dofetilide 500 micrograms twice daily for 7 days, increased the dofetilide peak levels by 53% in men and 97% in women, and the AUC by 41% in men and 69% in women. Ketoconazole decreased the renal clearance of dofetilide by 31.3% and the non-renal clearance by 40.3%, resulting in a reduction in total clearance of 34.7%. ... 

Ketoconazole may inhibit the active renal tubular secretion mechanism by which dofetilide is eliminated, so reducing its loss from the body (see also Dofetilide -i- H2-receptor antagonists , above). Ketoconazole also inhibits the metabolism of dofetilide by the cytochrome P450 isoenzyme CYP3A4. Both of these mechanisms contribute to the increase in dofetilide plasma levels. There is a linear relationship between plasma dofetilide concentrations and prolongation of the QT interval, which increases the risk for torsade de pointes. ... 

An established interaction. Because of the likely increased risk of torsade de pointes, the manufacturer contraindicates the use of ketoconazole in patients on dofetilide. This would seem to be a prudent precaution. 

Dofetilide is partially metabolised by the liver, primarily by the cytochrome P450 isoenzyme CYP3A4. The manufacturer suggests that there is a potential for dofetilide plasma levels to be increased by inhibitors of CYP3A4, and this has been shown for ketoconazole , (p.255). They recommend caution with other CYP3A4 inhibitors. 

---