Rifabutin drug interactions

Finch CK, Chrisman CR, Baciewicz AM, et al. Rifampin and rifabutin drug interactions an update. Arch Intern Med 2002 162 985-992. 

Kraft WK, McCrea JB, Winchell GA, Carides A, Low R, Woolf EJ, Kusma SE, Deutsch PJ, Greenberg HE, Waldman SA. Indinavir and rifabutin drug interactions in healthy volunteers. JC/mP/jawzaco/ (2004) 44, 305-13. 

Rifabutin Adults0 5 mg/kg (300 mg) Children Appropriate dosing unknown Hematologic toxicity, uveitis, gastrointestinal symptoms, polyarthralgias, hepatotoxicity, pseudojaundice (skin discoloration with normal bilirubin), rash, flulike syndrome, orange discoloration of bodily fluids (sputum, urine, sweat, tears) Drug interactions are less problematic than rifampin... 

Rifampin (RIF) 600 mg daily for 4 months can be used when INH resistance is suspected or when the patient cannot tolerate INH. Rifabutin 300 mg daily may be substituted for RIF for patients at high risk of drug interactions. 

Because trimetrexate is metabolized by a P450 enzyme system, drugs that induce or inhibit this drug metabolizing enzyme system may elicit important drug interactions that may alter trimetrexate plasma concentrations, which include erythromycin, rifampin, rifabutin, ketoconazole, fluconazole, cimetidine, nitrogen substituted imidazole drugs (eg, clotrimazole, ketoconazole, miconazole). 

Rifabutin appears as effective as rifampin in the treatment of drug-susceptible tuberculosis and is used in the treatment of latent tuberculosis infection either alone or in combination with pyrazinamide. Clinical use of rifabutin has increased in recent years, especially in the treatment of HIV infection. It is a less potent inducer of cytochrome 450 enzymes pathways than rifampin and results in less drug interaction with the protease inhibitors and nonnucleoside reverse transcriptase inhibitors. Rifabutin is therefore commonly substituted for rifampin in the treatment of tuberculosis in HIV-infected patients. Another important use of rifabutin in the HIV-infected population is prevention and treatment of disseminated MAC. 

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. 

Significant drug interactions include cyclosporins (increased cyclosporine levels), phenytoin, rifampin, and rifabutin (decreased voriconazole levels). Because of its low toxicity profile, this drug may gain importance in the chronic treatment of infections with invasive dimorphic fungi and resistant Candida spp. 

Rifabutin Oral similar to rifampin but less cytochrome P450 induction and fewer drug interactions ... 

Delavirdine is extensively metabolized to inactive metabolites by the CYP3A and CYP2D6 enzymes and also inhibits CYP3A4 and 2C9. Therefore, there are numerous potential drug-drug interactions to consider (Tables 49-3 and 49-4). The concurrent use of delavirdine with fosamprenavir and rifabutin is not recommended because of decreased delavirdine levels. 

The most common adverse effects associated with nelfinavir are diarrhea and flatulence. Diarrhea often responds to antidiarrheal medications but can be dose-limiting. Nelfinavir is an inhibitor of the CYP3A system, and multiple drug interactions may occur (Tables 49-3 and 49-4). An increased dosage of nelfinavir is recommended when co-administered with rifabutin (with a decreased dose of rifabutin), whereas a decrease in saquinavir dose is suggested with concurrent nelfinavir. Co-administration with efavirenz should be avoided due to decreased indinavir levels. Nelfinavir has a favorable safety and pharmacokinetic profile for pregnant women compared with that of other Pis (Table 49-5) there is no evidence of human teratogenicity. 

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. 

Iatsimirskaia E, Tulebaev S, Storozhuk E, et al. Metabolism of rifabutin in human enterocyte and liver microsomes kinetic paramters, identification of enzyme systems, and drug interactions with macrolides and antifungal agents. Clin Pharmacol Ther 1997 61 554-562. 

Li AP, Reith MK, Rasmussen A et al. (1997) In vitro evaluation of drug-drug interaction potential A comparison of rifampin, rifapentine, and rifabutin in cytochrome P450 3A induction potential in primary human hepatocytes. Chemico-Biological Interactions 107 17-30... 

Committee on Safety of Medicines and the Medicines Control Agency. Revised indication and drug interaction of rifabutin. Curr Prob Pharmacovig 1997 23 14. 

Rifampin s potent induction of hepatic enzymes, especially cytochrome P450 (CYP) 3A4, may enhance the ehmination of many other drugs, most notably the protease inhibitors used to treat HIV (Table 110-7). HIV-positive patients may beneht from the use of rifabutin instead of rifampin (see below). ° Also, women who use oral contraceptives must use another form of contraception during therapy because increased clearance of the hormones may lead to unexpected pregnancies. Patient records should be reviewed for potential drug interactions before dispensing rifampin. Rifampin may turn urine and other secretions orange-red and may permanently stain some types of contact lenses. 

Datri 001 Study Group (1993). Clarithromycin plus rifabutin for MAC prophylaxis Evidence for a drug interaction. In Abstracts of the First National Conference on Human Retrovirus, p. 106. American Society for Microbiology, Washington, DC. 

DRUG INTERACTIONS Chloramphenicol inhibits hepatic CYPs and thereby prolongs the half-hves of CYP substrates, including coumadin, phenytoin, chlorpropamide, HIV protease inhibitors, rifabutin, and tolbutamide. Severe toxicity and death have occurred due to these drug interactions. Concurrent administration ofphenobarbital or rifampin, which potently induce CYPs, shortens chloramphenicors t j and may result in subtherapeutic drug concentrations. 

In HIV-infected patients, the substitution of rifabutin for rifampin minimizes drug interactions witii tiie HIV protease inhibitors and nonnucleoside reverse transcriptase inhibitors. 

Drug interactions are a special concern in patients receiving highly active antiretroviral therapy (H AART). The rifamycins accelerate the metabohsm of protease inhibitors and nonnucleoside reverse transcriptase inhibitors. Rifabutin has the least effect on serum levels and is indicated in this setting. 

THERAPEUTIC USES Rifabutin is effective for the prevention of MAC infection in HIV-infected individuals and can decrease the frequency of MAC bacteremia. Azithromycin or clarithromycin is more effective and less likely to interact with HAART drugs. Rifabutin also is commonly substituted for rifampin in the treatment of tuberculosis in HIV-infected patients, as it has a less profound CYP-dependent drug interaction. Rifabutin also is used in combination with clarithromycin and ethambutol for the therapy of MAC disease. 

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