indication

For the prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection.

pharmacology

Rifabutin is an antibiotic that inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme. It is bactericidal and has a very broad spectrum of activity against most gram-positive and gram-negative organisms (including Pseudomonas aeruginosa) and specifically Mycobacterium tuberculosis. Because of rapid emergence of resistant bacteria, use is restricted to treatment of mycobacterial infections and a few other indications. Rifabutin is well absorbed when taken orally and is distributed widely in body tissues and fluids, including the CSF. It is metabolized in the liver and eliminated in bile and, to a much lesser extent, in urine, but dose adjustments are unnecessary with renal insufficiency.

mechanism of action

Rifabutin acts via the inhibition of DNA-dependent RNA polymerase in gram-positive and some gram-negative bacteria, leading to a suppression of RNA synthesis and cell death.

toxicity

LD₅₀ = 4.8 g/kg (mouse, male)

biotransformation

Hepatic. Of the five metabolites that have been identified, 25-O-desacetyl and 31-hydroxy are the most predominant. The former metabolite has an activity equal to the parent drug and contributes up to 10% to the total antimicrobial activity.

absorption

Rifabutin is readily absorbed from the gastrointestinal tract, with an absolute bioavailability averaging 20%.

half life

45 (± 17) hours

route of elimination

A mass-balance study in three healthy adult volunteers with 14C-labeled rifabutin showed that 53% of the oral dose was excreted in the urine, primarily as metabolites. About 30% of the dose is excreted in the feces.

drug interactions

Acenocoumarol: Rifabutin may decrease the anticoagulant effect of acenocoumarol by increasing its metabolism.

Amitriptyline: The rifamycin, rifabutin, may decrease the effect of the tricyclic antidepressant, amitriptyline, by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of amitriptyline if rifabutin is initiated, discontinued or dose changed.

Amoxapine: The rifamycin, rifabutin, may decrease the effect of the tricyclic antidepressant, amoxapine, by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of amoxapine if rifabutin is initiated, discontinued or dose changed.

Amprenavir: Amprenavir may increase the effect and toxicity of rifabutin.

Anisindione: Rifabutin, may decrease the anticoagulant effect of anisindione.

Atazanavir: Atazanavir may increase levels/toxicity of rifabutin.

Atorvastatin: Rifabutin may decrease the effect of atorvastatin by increasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of atorvastatin if rifabutin is initiated, discontinued or dose changed.

Atovaquone: Rifabutin decreases the effect of atovaquone

Bromazepam: Rifabutin may decrease the serum concentration of bromazepam by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of bromazepam if rifabutin is initiated, discontinued or dose changed.

Bupropion: Rifampin reduces bupropion levels

Buspirone: Rifabutin decreases the effect of buspirone

Cerivastatin: Rifabutin may decrease the effect of cerivastatin by increasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of cerivastatin if rifabutin is initiated, discontinued or dose changed.

Clarithromycin: The rifamycin, rifabutin, may decrease the effect of the macrolide, clarithromycin.

Clomipramine: The rifamycin, rifabutin, may decrease the effect of the tricyclic antidepressant, clomipramine, by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of clomipramine if rifabutin is initiated, discontinued or dose changed.

Clozapine: Rifabutin decreases the effect of clozapine

Cyclosporine: The rifamycin decreases the effect of cyclosporine

Dapsone: Decreased levels of dapsone

Delavirdine: Rifabutin decreases the effect of delavirdine

Desipramine: The rifamycin, rifabutin, may decrease the effect of the tricyclic antidepressant, desipramine, by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of desipramine if rifabutin is initiated, discontinued or dose changed.

Dicumarol: Rifabutin may decrease the anticoagulant effect of dicumarol.

Doxepin: The rifamycin, rifabutin, may decrease the effect of the tricyclic antidepressant, doxepin, by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of doxepin if rifabutin is initiated, discontinued or dose changed.

Doxycycline: The rifamycin decreases the effect of doxycycline

Erlotinib: Decreased levels/effect of erlotinib

Erythromycin: The rifamycin, rifabutin, may decrease the effect of the macrolide, erythromycin.

Ethinyl Estradiol: Rifabutin may decrease the contraceptive effect of ethinyl estradiol. Hormonal contraception should not be solely relied on alone during concomitant therapy with rifabutin.

Fluconazole: Fluconazole may increase levels/toxicity of rifabutin.

Fluvastatin: Rifabutin may decrease the effect of fluvastatin by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of fluvastatin if rifabutin is initiated, discontinued or dose changed.

Fosamprenavir: Amprenavir increases the effect and toxicity of rifabutin

Haloperidol: The rifamycin decreases the effect of haloperidol

Imipramine: The rifamycin, rifabutin, may decrease the effect of the tricyclic antidepressant, imipramine, by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of imipramine if rifabutin is initiated, discontinued or dose changed.

Indinavir: Rifabutin decreases the effect of indinavir

Itraconazole: Rifabutin decreases the effect of itraconazole

Josamycin: The rifamycin, rifabutin, may decrease the effect of the macrolide, josamycin.

Lovastatin: Rifabutin may decrease the effect of lovastatin by increasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of lovastatin if rifabutin is initiated, discontinued or dose changed.

Mestranol: This product may cause a slight decrease of the contraceptive effect

Methadone: The rifamycin decreases the effect of methadone

Norethindrone: Rifabutin may decrease the contraceptive effect of norethindrone. Hormonal contraception should not be solely relied on alone during concomitant therapy with rifabutin.

Nortriptyline: The rifamycin, rifabutin, may decrease the effect of the tricyclic antidepressant, nortriptyline, by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of nortriptyline if rifabutin is initiated, discontinued or dose changed.

Posaconazole: Modification of drug levels for both agents

Propafenone: Rifampin decreases the effect of propafenone

Protriptyline: The rifamycin, rifabutin, may decrease the effect of the tricyclic antidepressant, protriptyline, by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of protriptyline if rifabutin is initiated, discontinued or dose changed.

Ritonavir: Rifabutin decreases the effect of ritonavir

Saquinavir: Rifabutin decreases the effect of saquinavir

Simvastatin: Rifabutin may decrease the effect of simvastatin by increasing its metabolism. Monitor for changes in the therapeutic effect of simvastatin if rifabutin is initiated, discontinued or dose changed.

Sirolimus: The rifamycin decreases the effect of sirolimus

Sunitinib: Possible decrease in sunitinib levels

Tacrolimus: Carbamazepine may decrease the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Carbamazepine therapy is initiated, discontinued or altered.

Tamoxifen: The rifamycin decreases the effect of anti-estrogen

Telithromycin: Rifabutin may decrease the plasma concentration of Telithromycin. Consider alternate therapy.

Temsirolimus: Rifabutin may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.

Terbinafine: Rifabutin may increase the metabolism and clearance of Terbinafine. To avoid Terbinafine treatment failure, co-administration should be avoided.

Tipranavir: Tipranavir increases the concentration of Rifabutin. Adjust Rifabutin dose and monitor for adverse/toxic effects.

Toremifene: The rifamycin decreases the effect of anti-estrogen

Tramadol: Rifabutin may decrease the effect of Tramadol by increasing Tramadol metabolism and clearance.

Trazodone: The CYP3A4 inducer, Rifabutin, may decrease Trazodone efficacy by increasing Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Rifabutin is initiated, discontinued or dose changed.

Trimipramine: The rifamycin, rifabutin, may decrease the effect of the tricyclic antidepressant, trimipramine, by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of trimipramine if rifabutin is initiated, discontinued or dose changed.

Verapamil: Rifabutin, a CYP3A4 inducer, may decrease the serum concentration of Verapamil by increasing its metabolism (particularly in the intestinal mucosa) and decreasing its absorption. Monitor for changes in the therapeutic/adverse effects of Verapamil if Rifabutin is initiated, discontinued or dose changed.

Voriconazole: Rifabutin may decrease the serum concentration of voriconazole likely by increasing its metabolism via CYP3A enzymes. Voriconazole may increase the serum concentration of rifabutin likely by inhibiting its metabolism via CYP3A. Concomitant therapy is contraindicated.

Warfarin: Rifabutin may decrease the anticoagulant effect of warfarin by increasing its metabolism.

Zidovudine: The rifamycin decreases levels of zidovudine