Rifabutin, also known as Mycobutin, belongs to the class of medicines called antimycobacterials. Antimycobacterials prevent or treat infections caused by a certain type of bacterium, including the bacterium that causes tuberculosis (TB).
HIV/AIDS-Related Uses
Rifabutin was approved by the FDA on August 23, 1996, for use with other medications to prevent and treat Mycobacterium avium complex (MAC). Rifabutin is also used with other medications to treat tuberculosis (TB) in HIV infected patients who are taking certain anti-HIV medications and also in some HIV uninfected patients. MAC and TB are opportunistic infections that commonly affect patients with HIV or AIDS.
Dosage Form/Administration
Rifabutin comes in capsule form and is taken by mouth.
Contraindications
Individuals should tell a doctor about any medical problems before taking this medicine.
Possible Side Effects
Along with its desired effects, rifabutin can cause some serious unwanted effects. Serious side effects of this medicine include eye problems, including pain, redness, and loss of vision; skin itching, redness, or rash; stomach problems that are severe or last a long time, including diarrhea, heartburn, loss of appetite, nausea, or vomiting; and yellowing of the eyes or skin. Individuals should tell a doctor if they have any of these side effects.Other side effects may not be serious and may lessen or disappear with continued use of this medicine. Less serious side effects of this medicine include headache and trouble sleeping. Rifabutin may change urine, feces, spit, sweat, tears, or skin to a red-orange or red-brown color. Colored tears may permanently stain soft contact lenses. Individuals should tell a doctor if these side effects continue or are bothersome.
Drug and Food Interactions
A doctor should be notified of any other medications also being taken, including prescription, nonprescription (over-the-counter), or herbal medications.
Clinical Trials
Click here to search ClinicalTrials.gov for trials that use Rifabutin.
Manufacturer Information
Mycobutin
Pharmacia Corporation
100 Route 206 North
Peapack, NJ 07977
Phone: 888-768-5501
Fax: 908-901-8379
Rifabutin
Pharmacia Corporation
100 Route 206 North
Peapack, NJ 07977
Phone: 888-768-5501
Fax: 908-901-8379
Last Updated: April 30, 2007
Drug Description
Rifabutin is a semisynthetic ansamycin antibiotic derived from rifamycin S. It is structurally related to rifampin and is similar to rifampin in many of its properties, including its spectrum of activity against gram-negative and -positive organisms. [1]
References
[1] AHFS Drug Information 2007; p. 566
HIV/AIDS-Related Uses
Rifabutin was approved by the FDA on August 23, 1996, for the prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection. [1] [2] Rifabutin is also used alone or in combination with azithromycin for the prevention of disseminated MAC disease in AIDS patients. [3]
Rifabutin is used as an alternative to rifampin in multiple-drug regimens for the treatment of tuberculosis (TB) in HIV infected patients who are taking certain antiretroviral drugs. A rifabutin-containing regimen has less potential for interaction with antiretrovirals, potentially better absorption in patients with advanced HIV, and greater tolerability in patients with rifampin-induced hepatoxicity. [4] Rifabutin is currently being investigated to determine its optimal dosing schedule when administered concurrently with the antiretroviral drug nelfinavir. [5]
Rifabutin is also used alone or in combination with other drugs to prevent the development of clinical TB or for the treatment of latent TB infection in HIV infected patients. [6]
References
[1] USP DI 2005; p. 2545
[2] FDA Approved Therapies for the Treatment of Complications of HIV/AIDS. Available at: http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm118949.htm. Accessed 04/30/07.
[3] AHFS Drug Information 2007; p. 562
[4] AHFS Drug Information 2007; p. 563
[5] ClinicalTrials.gov Intensive Pharmacokinetics of the Nelfinavir-Rifabutin Interaction in Patients with HIV-Related Tuberculosis Treated with a Rifabutin-Based Regimen. Available at: http://www.clinicaltrials.gov/ct/show/NCT00018083. Accessed 04/30/07.
[6] AHFS Drug Information 2007; pp. 563-4
Dosing Information
Mode of Delivery
Oral. [1]
Dosage Form
Capsules containing rifabutin 150 mg. [2]
Storage
Store capsules between 15 C and 30 C (59 F to 86 F) in a tightly closed container. [3]
References
[1] USAN 2005; p. 2549
[2] USP DI 2005; p. 2549
[3] USP DI 2005; p. 2549
Pharmacology
Rifabutin inhibits DNA-dependent RNA polymerase and subsequent initiation of transcription, thereby inhibiting protein synthesis. Rifabutin is active against mycobacteria, gram-positive and -negative bacteria, Chlamydia trachomatis, and Toxoplasma gondii. [1]
Rifabutin is readily absorbed from the gastrointestinal (GI) tract, and mean peak plasma levels of 375 ng/ml are reached within an average of 3.3 hours. Taking rifabutin capsules with high-fat meals slows the rate of absorption but does not affect the extent of absorption. In one study, the mean absolute bioavailability of rifabutin averaged 20% in five HIV infected patients who received both oral and IV doses. Pharmacokinetic dose-proportionality was established in early symptomatic HIV infected patients over a dose range of 300 to 900 mg. Total recovery of radioactivity in the urine indicates that at least 53% of an orally administered dose is absorbed from the GI tract. [2]
Rifabutin is highly lipophilic and is widely distributed with increased intracellular tissue uptake. In five HIV infected patients given an IV dose of rifabutin, estimates of apparent steady state distribution volume exceeded total body water by 15-fold. Intracellular tissue levels are substantially higher than plasma concentrations. The lung-to-plasma concentration ratio at 12 hours was found to be approximately 6.5 in four surgical patients administered an oral dose. [3] Rifabutin crosses the blood-brain barrier; cerebrospinal fluid concentrations are approximately 50% of the corresponding serum concentrations. [4]
Rifabutin is in FDA Pregnancy Category B. No adequate or well-controlled studies have been done in humans; however, in laboratory animals, fetal abnormalities occurred after the animals were given doses of rifabutin that greatly exceeded the recommended human dose. It is not known whether rifabutin is distributed into human milk; however, the possibility of adverse effects to the nursing infant from rifabutin should be considered in determining whether to discontinue nursing or treatment with rifabutin. [5]
About 85% of rifabutin is bound to plasma proteins. Binding does not appear to be influenced by renal or hepatic dysfunction. [6] Rifabutin undergoes hepatic biotransformation to five known metabolites. The 25-O-desacetyl metabolite has activity equal to the parent drug and contributes up to 10% of the total antimicrobial activity. In a study of seven healthy adults, rifabutin was eliminated slowly from plasma, with a mean terminal half-life of 45 hours. Systemic levels of rifabutin following multiple dosing decreased by 38%; however, terminal half-life did not change, presumably reflecting distribution-limited elimination. Renal and biliary clearance of rifabutin as unchanged drug each contribute about 5% to mean systemic clearance. About 30% of a dose is eliminated in feces. In a study of three healthy adults, 53% of a radiolabeled oral dose was excreted in urine, primarily as metabolites. [7]
In clinical trials, patients with severe renal impairment (defined as creatinine clearance less than 30 ml/min) given oral rifabutin had a 71% increase in the area under the concentration-time curve (AUC) over that of individuals with no renal impairment. Patients with moderate renal impairment had an AUC increase of 41%. The manufacturer suggests dosage reduction in severely impaired patients. [8]
References
[1] USP DI 2005; p. 2545
[2] Pharmacia Mycobutin Prescribing Information, February 2006, p. 2. Available at: http://www.pfizer.com/download/uspi_mycobutin.pdf. Accessed 04/30/07.
[3] Pharmacia Mycobutin Prescribing Information, February 2006, p. 2. Available at: http://www.pfizer.com/download/uspi_mycobutin.pdf. Accessed 04/30/07.
[4] USP DI 2005; p. 2545
[5] Pharmacia Mycobutin Prescribing Information, February 2006, pp. 9-10. Available at: http://www.pfizer.com/download/uspi_mycobutin.pdf. Accessed 04/30/07.
[6] Pharmacia Mycobutin Prescribing Information, February 2006, p. 2. Available at: http://www.pfizer.com/download/uspi_mycobutin.pdf. Accessed 04/30/07.
[7] Pharmacia Mycobutin Prescribing Information, February 2006, p. 2. Available at: http://www.pfizer.com/download/uspi_mycobutin.pdf. Accessed 04/30/07.
[8] Pharmacia Mycobutin Prescribing Information, February 2006, p. 3. Available at: http://www.pfizer.com/download/uspi_mycobutin.pdf. Accessed 04/30/07.
Adverse Events/Toxicity
The most common adverse effects of rifabutin requiring medical attention are allergic reactions, including skin rash and itching; GI effects, including anorexia, diarrhea, dyspepsia, nausea, and vomiting; and hematologic abnormalities, including anemia, leukopenia, neutropenia, and thrombocytopenia. In clinical trials, only the incidence of neutropenia was significantly greater with rifabutin than with placebo; however, rifabutin has been clearly linked to thrombocytopenia in rare cases. [1] [2]
Uveitis, characterized by pain, redness, and possible temporary or permanent loss of vision, may occur with rifabutin use. [3] The risk of uveitis appears to be greatest in patients taking higher doses of rifabutin in combination with macrolide antibiotics or fluconazole. Patients who developed uveitis had mild to severe symptoms that resolved after treatment with corticosteroids and/or mydriatic eye drops, although resolution of symptoms occurred after several weeks in some patients. [4]
Less serious adverse affects include abdominal pain and bloating, chest pain, taste perversion, headache, and insomnia. In addition, rifabutin may discolor body fluids, giving a red-orange or red-brown color to urine, feces, saliva, skin, sweat, and tears. Discolored tears may stain soft contact lenses permanently. [5]
References
[1] USP DI 2005; p. 2547
[2] Pharmacia Mycobutin Prescribing Information, February 2006, pp. 10-2. Available at: http://www.pfizer.com/download/uspi_mycobutin.pdf. Accessed 04/30/07.
[3] AHFS Drug Information 2007; p. 564
[4] Pharmacia Mycobutin Prescribing Information, February 2006, p. 12. Available at: http://www.pfizer.com/download/uspi_mycobutin.pdf. Accessed 04/30/07.
[5] USP DI 2005; p. 2547
Drug and Food Interactions
Rifabutin generally can be administered without regard to meals. [1]
Rifabutin, like other rifamycins, can induce the hepatic microsomal cytochrome P450 (CYP) oxidase system, causing interactions with drugs that are metabolized by these enzymes, including itraconazole and clarithromycin. Rifabutin appears to induce hepatic microsomal enzymes to a lesser degree than rifampin; however, rifabutin's structural similarity to rifampin may cause reduced activity of drugs that are affected by rifampin. [2]
By inducing CYP oxidases, rifabutin may accelerate the metabolism of some HIV protease inhibitors (e.g., amprenavir, indinavir, nelfinavir, ritonavir, saquinavir) and nonnucleoside reverse transcriptase inhibitors (e.g., delavirdine, efavirenz, nevirapine); these antiretrovirals may, in turn, slow the metabolism of rifabutin. The result may be subtherapeutic concentrations of the concurrent antiretrovirals and greatly increased concentrations of rifabutin. [3] [4] CDC guidelines recommend specific rifabutin dosing regimens for HIV infected individuals on antiretroviral therapy. [5]
Because rifabutin is metabolized through CYP3A enzymes, inhibitors of these enzymes, such as fluconazole or clarithromycin, may increase rifabutin plasma concentrations. Because these high plasma levels may increase the risk of adverse reactions, the dosage of rifabutin may need to be reduced. [6]
Rifabutin also may decrease the efficacy of oral contraceptives that contain estrogen by inducing the hepatic metabolism of estrogen. [7]
References
[1] AHFS Drug Information 2007; p. 563
[2] USP DI 2005; p. 2546
[3] USP DI 2005; p. 2546
[4] AHFS Drug Information 2007; pp. 565-6
[5] USP DI 2005; pp. 2548-9
[6] Pharmacia Mycobutin Prescribing Information, February 2006, p. 8. Available at: http://www.pfizer.com/download/uspi_mycobutin.pdf. Accessed 04/30/07.
[7] Pharmacia Mycobutin Prescribing Information, February 2006, p. 9. Available at: http://www.pfizer.com/download/uspi_mycobutin.pdf. Accessed 04/30/07.
Contraindications
Rifabutin is contraindicated in patients with a history of hypersensitivity to rifabutin or to any of the rifamycins. In addition, rifabutin must not be administered as a single agent for the prevention of MAC infection in patients with active TB because of the likelihood of developing TB that is resistant to both rifabutin and rifampin. [1]
References
[1] Pharmacia Mycobutin Prescribing Information, February 2006, pp. 7-8. Available at: http://www.pfizer.com/download/uspi_mycobutin.pdf. Accessed 04/30/07.
Clinical Trials
Click here to search ClinicalTrials.gov for trials that use Rifabutina.
Chemistry
CAS Name
(9S,12E,14S,15R,16S,17R,18R,19R,20S,21S,22E, 24Z)-6-16,18,20-Tetrahydroxy-1'-isobutyl-14- methoxy-7,9,15,17,19,21,25-heptamethylspiro(9,4- (epoxypentadeca(1,11,13)trienimino)-2H- furo(2',3':7,8)naphth(1,2-d)imidazole-2,4'- piperidine)-5,10,26(3H,9H-trione,16-acetate [1]
CAS Number
72559-06-9 [2]
Molecular Formula
C46-H62-N4-O11
Elemental Composition
C65.23%, H7.38%, N6.61%, O20.78%
Molecular Weight
847.02
Physical Description
Violet-red crystalline powder. [3]
Solubility
Highly soluble in chloroform, soluble in methanol, slightly soluble in ethanol, and minimally soluble in water (0.19 mg/ml). [4] [5]
References
[1] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 04/30/07.
[2] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 04/30/07.
[3] Merck Index 2006; p. 1416
[4] Merck Index 2006; p. 1416
[5] Pharmacia Mycobutin Prescribing Information, February 2006, p. 1. Available at: http://www.pfizer.com/download/uspi_mycobutin.pdf. Accessed 04/30/07.
Further Reading
Mycobutin Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Aaron L, Saadoun D, Calatroni I, Launay O, Memain N, Vincent V, Marchal G, Dupont B, Bouchaud O, Valeyre D, Lortholary O. Tuberculosis in HIV-infected patients: a comprehensive review. Clin Microbiol Infect. 2004 May;10(5):388-98. Review.
Breen RA, Swaden L, Ballinger J, Lipman MC. Tuberculosis and HIV co-infection: a practical therapeutic approach.
Drugs. 2006;66(18):2299-308.
Karakousis PC, Moore RD, Chaisson RE. Mycobacterium avium complex in patients with HIV infection in the era of highly active antiretroviral therapy. Lancet Infect Dis. 2004 Sep;4(9):557-65. Review.
Weiner M, Benator D, Peloquin CA, Burman W, Vernon A, Engle M, Khan A, Zhao Z; Tuberculosis Trials Consortium. Evaluation of the drug interaction between rifabutin and efavirenz in patients with HIV infection and tuberculosis.
Clin Infect Dis. 2005 Nov 1;41(9):1343-9. Epub 2005 Sep 29.
Manufacturer Information
Mycobutin
Pharmacia Corporation
100 Route 206 North
Peapack, NJ 07977
Phone: 888-768-5501
Fax: 908-901-8379
Rifabutin
Pharmacia Corporation
100 Route 206 North
Peapack, NJ 07977
Phone: 888-768-5501
Fax: 908-901-8379
Last Updated: April 30, 2007