Rifabutin with fluconazole

The effects of fluconazole and clarithromycin on the pharmacokinetics of rifabutin and 25-O-desacetylrifabu-tin have been studied in ten HIV-infected patients who were given rifabutin 300 mg qds in addition to fluconazole 200 mg qds and clarithromycin 500 mg qds (73). There was a 76% increase in the plasma AUC of rifabutin when either fluconazole or clarithromycin was given alone and a 152% increase when both drugs were given together. The authors concluded that patients should be monitored for adverse effects of rifabutin when it is co-administered with fluconazole or clarithromycin. 

The adverse effects that most frequently result in discontinuation of rifabutin include GI intolerance, rash, and neutropenia. Rifabutin levels will be increased with concurrent administration of fluconazole and clarithromycin, resulting in anterior uveitis, polymyalgia syndrome, and a yellowish-tan discoloration of the skin (pseudojaundice). Other adverse reactions are similar to those of rifampin, such as hepatitis, red-orange discoloration of body fluids, and drug interactions due to effects on the hepatic P450 cytochrome enzyme system. 

Since indinavir is a substrate as well as an inhibitor of CYP3 A4, numerous and complex drug interactions can occur as described above. Indinavir levels decrease with concurrent use of rifabutin, fluconazole, St. John s wort, and rifampin. Caution is advised with other 3 A4 inducers also, including phenobarbital, phenytoin, carbamezepine, and dexamethasone. Dose reduction of indinavir should be considered if coadministered with delavirdine, ketoconazole, or itraconazole, while an increase in the dose of indinavir is indicated if the drug is coadministered with efavirenz or rifabutin. 

RIFAMPICIN, RIFABUTIN, RIFAPENTINE ITRACONAZOLE, KETOCONAZOLE, POSACONAZOLE, VORICONAZOLE i levels of these azoles, with significant risk of therapeutic failure. Rifampicin is a very potent inducer that can produce undetectable concentrations of ketoconazole Rifampicin is a powerful inducer of CYP3A4 and other CYP isoenzymes. Rifabutin is a less powerful inducer but more potent than rifapentine. Rifapentine is an inducer of CYP3A4 and CYP2C8/9. Rifampicin is also a powerful inducer of P-gp, thus 1 bioavailability of itraconazole Avoid co-administration of ketoconazole or voriconazole with these drugs. Watch for inadequate therapeutic effects of itraconazole. Higher doses of itraconazole may not overcome this interaction, so consider the use of less lipophilic fluconazole, which is less dependent on CYP metabolism. Avoid co-administration of posaconazole with rifabutin... 

A 35-year old Caucasian man with AIDS and multiple opportunistic infections, including Mycobacterium kansasii and Mycobacterium avium complex (MAC) disease developed moderate to severe primary sensorineural hearing loss after 4—5 months of therapy with oral azithromycin 500 mg/day. Other medications included ethambutol, isoniazid, rifabutin, ciprofloxacin, co-trimoxazole, fluconazole, zidovudine (later switched to stavudine), lamivudine, indinavir, methadone, mod-ified-release oral morphine, pseudoephedrine, diphenhydramine, megestrol acetate, trazodone, sorbitol, salbutamol by metered-dose inhaler and nebulizer, ipratropium, and oral morphine solution as needed. Significant improvement of the hearing impairment was documented 3 weeks after drug withdrawal. 

Clinically important, potentially hazardous interactions with amiodarone, anabolic steroids, antithyroid agents, barbiturates, bivalirudin, cimetidine, clofibrate, clopidogrel, cyclosporine, delavirdine, dextrothyroxine, disulfiram, fluconazole, glutethimide, imatinib, itraconazole, ketoconazole, metronidazole, miconazole, penicillins, phenylbutazones, piperacillin, quinidine, quinine, rifabutin, rifampin, rifapentine, rofecoxib, salicylates, sulfinpyrazone, sulfonamides, testosterone, thyroid, zileuton... 

Clinically important, potentially hazardous interactions with amprenavir, aprepitant, atazanavir, carbamazepine, chlorpheniramine, cimetidine, clarithromycin, clorazepate, CNS depressants, darunavir, delavirdine, dexamethasone, efavirenz, erythromycin, esomeprazole, fluconazole, fluoxetine, fosamprenavir, grapefruit juice, griseofulvin, imatinib, indinavir, itraconazole, ivermectin, ketoconazole, lopinavir, nelfinavir, nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, ritonavir, roxithromycin, saquinavir, St John s wort, telithromycin, tipranavir... 

UNTOWARD EFFECTS Rifabutin generally is well tolerated in persons with HIV infection primary reasons for discontinuation of therapy include rash (4%), GI intolerance (3%), and neutropenia (2%). Overall, neutropenia occurred in 25% of patients with severe HIV infection who received rifabutin. Uveitis and arthralgias have occurred in patients receiving rifabutin doses >450 mg daily in combination with clarithromycin or fluconazole. Patients should be cautioned to discontinue the drug if visual symptoms occur. Like rifampin, the drug causes an orange-tan discoloration. Rarely, thrombocytopenia, a flu-like syndrome, hemolysis, myositis, chest pain, and hepatitis have occurred. 

Anterior Segment Glucocorticoids also have been implicated in cataract formation. If vision is reduced, cataract surgery may be necessary. Rifabutin, if used in conjunction with clarithromycin or fluconazole for treatment of Mycobacterium avium complex (MAC) opportunistic infections in AIDS, is associated with an iridocyclitis and even hypopyon. This will resolve with glucocorticoids or by stopping the medication. 

Items 6-7 A patient with AIDS has a CD4 count of 45/ xL. He is being maintained on a three-drug regimen of indinavir, zalcitabine, and zidovudine. For prophylaxis against opportunistic infections, he is also receiving cidofovir, fluconazole, rifabutin, and trimethoprim-sulfamethoxazole. 

Because of indinavir s metabolism, a number of drug interactions are possible. Indinavir interacts with rifabutin or ketoconazole, leading to increased or decreased indinavir concentration, respectively, in the blood plasma. Administration of drug combinations of indinavir with antiviral nucleoside analogues, cimetidine, quinidine, trimethoprim/sulfamethoxazole, fluconazole, or isoniazid resulted in an increased activity of indinavir. Indinavir is ... 

Rifabutin levels are increased by fluconazole, posaconazole, voriconazole, and possibly itraconazole. Patients taking this combination are at increased risk of rifabutin toxicity, specifically uveitis, and should be closely monitored. Rifabutin markedly reduces the plasma levels of itraconazole, posaconazole, and voriconazole. These azoles should be used cautiously with rifabutin, if at all Rifabutin does not affect the metabolism of fluconazole. 

Trapnell CB, Narai PK, Li R, Lavelle JP. Increased pla a rifabutin levels with ccxicomi-tant fluconazole therapy in HIV-infected patients. y4 w/w/ mM [Pg.219]

Winter HR, Trapnell CB, Slattery JT, Jacobson M, Green an DL, Hootc i TM, Unadkat JD. The effect of cmrithromycin, fluconazole, and rifabutin on sulfamethoxazole hydroxylamine formation in individuals with human immunodeficiency virus infection (AACTG 283). Clm Pharmacol Ther (2004) 76,313-22. 

Twelve HIV-positive patients were given dapsone 100 mg daily for 2 weeks and then in random order either fluconazole 200 mg daily, rifabutin 300 mg daily or fluconazole with rifabutin, each for 2 weeks. Dapsone pharmaeokineties were unaffected by fluconazole. However, fluconazole inhibited the production of the jV-hydroxylamine metabolite of dapsone (AUC, urinary recovery, and formation clearance reduced by about 50%). ... 

Uveitis or arthraigias. Uveitis, and in some cases pseudojaundice, aphthous stomatitis and an arthralgia syndrome have been described in patients treated with both clarithromycin 1 to 2 g daily and rifabutin 300 to 600 mg daily The presence of fluconazole does not appear to affect the development of uveitis in patients taking clarithromycin with rifabutin, but it has been suggested that this was because only small doses (50 mg) were used. ... 

The reason for the uveitis is not known, but based on animal studies it has been suggested that it is associated with effective treatment of MAC and is due to release of a mycobacterial protein, rather than a toxic effect of the drugs. It has been suggested that lower body weight and concurrent clarithromycin may result in toxic rifabutin serum levels, although concurrent fluconazole which increases levels does not appear to be a fac-... 

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