Fluvastatin Fluconazole

In a randomized, double-blind, crossover study in 12 healthy volunteers, fluconazole increased the plasma concentrations of fluvastatin and prolonged its elimination the mechanism was probably inhibition of the CYP2C9-mediated metabolism of fluvastatin (70). Care should be taken if fluconazole or other potent inhibitors of CYP2C9 are given to patients using fluvastatin. 

Kantola T, Backman JT, Niemi M, Kivisto KT, Neuvonen PJ. Effect of fluconazole on plasma fluvastatin and pravastatin concentrations. Eur J Clin Pharmacol 2000 56(3) 225-9. 

CYP2C9 Inhibition Amiodarone, cimetidine, trimetho-primsulfamethoxazole, fluoxetine, fluvoxamine, isoniazid, itraconazole, ketoconazole, fluconazole, metro-nidasole, sulfinpyrazone, ticlopidine Fluvastatin Rosuvastatin ( ) ... 

The effects of fluconazole on plasma fluvastatin and pravastatin concentrations have been studied in two separate, randomized, double-blind, two-phase, crossover studies... 

Healthy volunteers were given oral fluconazole (400 mg on day 1 and 200 mg on days 2-4) or placebo. On day 4, they took a single oral dose of fluvastatin 40 mg or pravastatin 40 mg. Fluconazole increased the plasma AUC and the half-life of fluvastatin by 80% but had no significant effects on the pharmacokinetics of pravastatin. The mechanism of the prolonged elimination of fluvastatin was probably inhibition of CYP2C9. Pravastatin, in contrast, appears not to be susceptible to interactions with fluconazole and other CYP2C9 inhibitors. 

Clinically important, potentially hazardous interactions with alfentanil, aminophylline, amisulpride, amoxicillin, ampicillin, anticonvulsants, astemizole, atorvastatin, benzodiazepines, bromocriptine, buprenorphine, bupropion, carbamazepine, cilostazol, ciprofloxacin, cisapride, clindamycin, colchicine, cyclosporine, dasatinib, digoxin, dihydroergotamine, diltiazem, disopyramide, enoxacin, eplerenone, ergotamine, eszopiclone, everolimus, fluconazole, fluoxetine, fluvastatin, gatifloxacin, HMG-CoA reductase inhibitors, imatinib, itraconazole, ketoconazole, lomefloxacin, lorazepam, lovastatin, methadone, methylprednisolone, methysergide, midazolam, mizolastine, moxifloxacin, nitrazepam, norfloxacin, ofloxacin, paroxetine, pimozide, pravastatin, quinolones, ranolazine, repaglinide, rupatadine, sertraline, sildenafil, simvastatin, sparfloxacin, sulpiride, tacrolimus, terfenadine, triazolam, troleandomycin, vardenafil, verapamil, vinblastine, warfarin, zaleplon, zolpidem, zuclopenthixol... 

Figure 17.4 Compounds which are mentioned throughtout the chapter and numbered in the main text as follows (1) DMZ, (2) diclofenac, (3) flurbiprofen, (4) warfarin, (5) fluconazole, (6) coumarin, (7) dapsone, (8) retinoic acid, (9) arachidonic acid, (10) troglitazone, (11) fluvastatin, (12) cerivastatin, (13) taxol, (14) gemfibrozil, (15) verapamil, (16) amodiaquine, (17) amiodarone, (18) metyrapone, (19) progesterone, (20) testosterone, (21) erythromycin, (22) ketoconazole, (23) nicotine, (24) IV -Nitrosonor-nicotine, (25) 4-(Methylnitrosamino)-l-(3-pyridyl)-l-butanone...

Cimetidine, fluconazole, fluvastatin, isoniazid, lovastatin, pravastatin, simvastatin, sulfaphenazole, tienilic acid, tolbutamide, warfarin... 

CYP2C9 20 10 Celecoxib Diclofenac Fluoxetine Fluvastatin Ibuprofen Irbesarten Naproxen Amitriptyline Phenytoin Tolbutamide Torsemide S-warfarin Rosiglitazone Amiodarone Fluconazole Fluvoxamine Fluvastatin Isoniazid Sertraline Sulfaphenazole Trimethoprin Zafirlukast Rifampin Clotrimazole Carbamazepine Hyperforin Phenobarbital Ritonavir... 

Fluconazole modestly increases the levels of fluvastatin and rosuvastatin, but not pravastatin. Miconazoie wouid be expected to interact simiiariy. Itraconazoie causes a marked rise in the serum ieveis of atorvastatin, iovastatin, pravastatin and simvastatin, but no change in fluvastatin or rosuvastatin ieveis. Ketoconazole wouid be expected to interact simiiariy. Rhabdomyolysis has been reported in some cases. Due to the risk of myopathy, the manufacturers of voriconazoie caution, and the manufacturers of posaco-nazoie contraindicate, concurrent use with atorvastatin, iovastatin and simvastatin. 

A randomised, double-blind study in 12 healthy subjects found that fluconazole (400 mg on day 1 followed by 200 mg daily for 3 days) increased the AUC of a single 40-mg dose of fluvastatin by 84% and increased its maximum plasma level by 44%. The pharmacokinetics of the fluconazole were unaffected. In a similar study, itraconazole 100 mg daily for 4 days did not significantly affect the pharmacokinetics of fluvastatin, apart from a small increase in its half-life. ... 

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