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Brand Name: Mycobutin  |
Drug Class: Opportunistic Infection and Other Drugs
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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] |
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.[2][3] Rifabutin is also used alone or in combination with azithromycin for the prevention of disseminated MAC disease in AIDS patients.[4]
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.[5] Rifabutin is currently being investigated to determine its optimal dosing schedule when administered concurrently with the antiretroviral drug nelfinavir.[6]
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.[7] |
Non HIV/AIDS-Related Uses |
| Rifabutin is designated an orphan drug by the FDA for the treatment of disseminated MAC disease.[8] It is also used as an alternative to rifampin in multidrug regimens for the prevention and treatment of pulmonary tuberculosis.[9] |
Dosing Information |
Mode of Delivery |
| Oral.[10] |
Dosage Form |
| Capsules containing rifabutin 150 mg.[11] |
Storage |
| Store capsules between 15 C and 30 C (59 F to 86 F) in a tightly closed container.[12] |
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.[13]
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.[14]
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.[15] Rifabutin crosses the blood-brain barrier; cerebrospinal fluid concentrations are approximately 50% of the corresponding serum concentrations.[16]
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.[17]
About 85% of rifabutin is bound to plasma proteins. Binding does not appear to be influenced by renal or hepatic dysfunction.[18] 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.[19]
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.[20] |
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.[21][22]
Uveitis, characterized by pain, redness, and possible temporary or permanent loss of vision, may occur with rifabutin use.[23] 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.[24]
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.[25] |
Drug And Food Interactions |
Rifabutin generally can be administered without regard to meals.[26]
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.[27]
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.[28][29] CDC guidelines recommend specific rifabutin dosing regimens for HIV infected individuals on antiretroviral therapy.[30]
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.[31]
Rifabutin also may decrease the efficacy of oral contraceptives that contain estrogen by inducing the hepatic metabolism of estrogen.[32] |
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.[33] |
Clinical Trials |
| Click here to search ClinicalTrials.gov for trials that use Rifabutin. |
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[34] |
CAS Number |
| 72559-06-9[35] |
Molecular Formula |
| C46-H62-N4-O11[36] |
Elemental Composition |
| C65.23%, H7.38%, N6.61%, O20.78%[37] |
Molecular Weight |
| 847.02[38] |
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Physical Description |
| Violet-red crystalline powder.[39] |
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Solubility |
| Highly soluble in chloroform, soluble in methanol, slightly soluble in ethanol, and minimally soluble in water (0.19 mg/ml).[40][41] |
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Further Reading |
Mycobutin Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
PMID/15113314 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.
PMID/17181373 Breen RA, Swaden L, Ballinger J, Lipman MC. Tuberculosis and HIV co-infection: a practical therapeutic approach.
Drugs. 2006;66(18):2299-308.
PMID/15336223 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.
PMID/16206114 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.
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Manufacturer Information |
Rifabutin
Pharmacia Corporation
100 Route 206 North
Peapack, NJ 07977
(888) 768-5501
Mycobutin
Pharmacia Corporation
100 Route 206 North
Peapack, NJ 07977
(888) 768-5501
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References |
[1] AHFS Drug Information - 2007; p. 566
[2] USP DI - 2005; p. 2545
[3] FDA - Drugs Used to Treat Complications of HIV/AIDS. Available at: http://www.fda.gov/oashi/aids/stat_app.html. Accessed 04/30/07.
[4] AHFS Drug Information - 2007; p. 562
[5] AHFS Drug Information - 2007; p. 563
[6] 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.
[7] AHFS Drug Information - 2007; pp. 563-4
[8] FDA - Cumulative List of Orphan Products Designated and/or Approved. Available at: http://www.fda.gov/orphan/designat/alldes.rtf. Accessed 04/30/07.
[9] AHFS Drug Information - 2007; p. 563
[10] USAN - 2005; p. 2549
[11] USP DI - 2005; p. 2549
[12] USP DI - 2005; p. 2549
[13] USP DI - 2005; p. 2545
[14] Pharmacia - Mycobutin Prescribing Information, February 2006, p. 2. Available at: http://www.pfizer.com/download/uspi_mycobutin.pdf. Accessed 04/30/07.
[15] Pharmacia - Mycobutin Prescribing Information, February 2006, p. 2. Available at: http://www.pfizer.com/download/uspi_mycobutin.pdf. Accessed 04/30/07.
[16] USP DI - 2005; p. 2545
[17] Pharmacia - Mycobutin Prescribing Information, February 2006, pp. 9-10. Available at: http://www.pfizer.com/download/uspi_mycobutin.pdf. Accessed 04/30/07.
[18] Pharmacia - Mycobutin Prescribing Information, February 2006, p. 2. Available at: http://www.pfizer.com/download/uspi_mycobutin.pdf. Accessed 04/30/07.
[19] Pharmacia - Mycobutin Prescribing Information, February 2006, p. 2. Available at: http://www.pfizer.com/download/uspi_mycobutin.pdf. Accessed 04/30/07.
[20] Pharmacia - Mycobutin Prescribing Information, February 2006, p. 3. Available at: http://www.pfizer.com/download/uspi_mycobutin.pdf. Accessed 04/30/07.
[21] USP DI - 2005; p. 2547
[22] Pharmacia - Mycobutin Prescribing Information, February 2006, pp. 10-2. Available at: http://www.pfizer.com/download/uspi_mycobutin.pdf. Accessed 04/30/07.
[23] AHFS Drug Information - 2007; p. 564
[24] Pharmacia - Mycobutin Prescribing Information, February 2006, p. 12. Available at: http://www.pfizer.com/download/uspi_mycobutin.pdf. Accessed 04/30/07.
[25] USP DI - 2005; p. 2547
[26] AHFS Drug Information - 2007; p. 563
[27] USP DI - 2005; p. 2546
[28] USP DI - 2005; p. 2546
[29] AHFS Drug Information - 2007; pp. 565-6
[30] USP DI - 2005; pp. 2548-9
[31] Pharmacia - Mycobutin Prescribing Information, February 2006, p. 8. Available at: http://www.pfizer.com/download/uspi_mycobutin.pdf. Accessed 04/30/07.
[32] Pharmacia - Mycobutin Prescribing Information, February 2006, p. 9. Available at: http://www.pfizer.com/download/uspi_mycobutin.pdf. Accessed 04/30/07.
[33] Pharmacia - Mycobutin Prescribing Information, February 2006, pp. 7-8. Available at: http://www.pfizer.com/download/uspi_mycobutin.pdf. Accessed 04/30/07.
[34] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 04/30/07.
[35] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 04/30/07.
[36] Merck Index - 2006; p. 1416
[37] Merck Index - 2006; p. 1416
[38] Pharmacia - Mycobutin Prescribing Information, February 2002, p. 1. Available at: http://www.pfizer.com/download/uspi_mycobutin.pdf. Accessed 04/30/07.
[39] Merck Index - 2006; p. 1416
[40] Merck Index - 2006; p. 1416
[41] Pharmacia - Mycobutin Prescribing Information, February 2006, p. 1. Available at: http://www.pfizer.com/download/uspi_mycobutin.pdf. Accessed 04/30/07.
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Updated April 30, 2007
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