Mycobutin Information
Mycobutin () Description
Mycobutin () Capsules contain the antimycobacterial agent rifabutin, which is a semisynthetic ansamycin antibiotic derived from rifamycin S. Mycobutin () Capsules for oral administration contain 150 mg of rifabutin, USP, per capsule, along with the inactive ingredients microcrystalline cellulose, magnesium stearate, red iron oxide, silica gel, sodium lauryl sulfate, titanium dioxide, and edible white ink.
The chemical name for rifabutin is 1',4-didehydro-1-deoxy-1,4-dihydro-5'-(2-methylpropyl)-1-oxorifamycin XIV (Chemical Abstracts Service, 9th Collective Index) or (9, 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 24)-6,16,18,20-tetrahydroxy-1'-isobutyl-14-methoxy-7,9,15,17,19,21,25-heptamethyl-spiro [9,4-(epoxypentadeca[1,11,13]trienimino)-2-furo[2',3':7,8]naphth[1,2-d] imidazole-2,4'-piperidine]-5,10,26-(3,9)-trione-16-acetate. Rifabutin has a molecular formula of CHNO, a molecular weight of 847.02 and the following structure:
Rifabutin is a red-violet powder soluble in chloroform and methanol, sparingly soluble in ethanol, and very slightly soluble in water (0.19 mg/mL). Its log P value (the base 10 logarithm of the partition coefficient between n-octanol and water) is 3.2 (n-octanol/water).
Mycobutin () Clinical Pharmacology
(see also )
Rifabutin induces the enzymes of the cytochrome P450 3A subfamily (CYP3A) and therefore may reduce the plasma concentrations of drugs that are principally metabolized by those enzymes. Rifabutin is also metabolized by CYP3A. Thus, some drugs that inhibit CYP3A may significantly increase plasma concentrations of rifabutin.
Mycobutin () Clinical Studies
Two randomized, double-blind clinical trials (study 023 and study 027) compared Mycobutin () (300 mg/day) to placebo in patients with CDC-defined AIDS and CD4 counts ≤ 200 cells/µL. These studies accrued patients from 2/90 through 2/92. Study 023 enrolled 590 patients, with a median CD4 cell count at study entry of 42 cells/µL (mean 61). Study 027 enrolled 556 patients with a median CD4 cell count at study entry of 40 cells/µL (mean 58).
Endpoints included the following:
Mycobutin () Microbiology
Rifabutin has demonstrated in vitro activity against complex (MAC) organisms isolated from both HIV-positive and HIV-negative people. While gene probe techniques may be used to identify these two organisms, many reported studies did not distinguish between these two species. The vast majority of isolates from MAC-infected, HIV-positive people are , whereas in HIV-negative people, about 40% of the MAC isolates are .
Various in vitro methodologies employing broth or solid media, with and without polysorbate 80 (Tween 80), have been used to determine rifabutin MIC values for mycobacterial species. In general, MIC values determined in broth are several fold lower than that observed with methods employing solid media. Utilization of Tween 80 in these assays has been shown to further lower MIC values.
However, MIC values were substantially higher for egg-based compared to agar-based solid media.
Rifabutin activity against 211 MAC isolates from HIV-positive people was evaluated in vitro utilizing a radiometric broth and an agar dilution method. Results showed that 78% and 82% of these isolates had MIC values of ≤0.25 µg/mL and ≤1.0 µg/mL, respectively, when evaluated by these two methods. Rifabutin was also shown to be active against phagocytized, complex in a mouse macrophage cell culture model.
Rifabutin has in vitro activity against many strains of . In one study, utilizing the radiometric broth method, each of 17 and 20 rifampin-naive clinical isolates tested from the United States and Taiwan, respectively, were shown to be susceptible to rifabutin concentrations of ≤0.125 µg/mL.
Cross-resistance between rifampin and rifabutin is commonly observed with and complex isolates. Isolates of resistant to rifampin are likely to be resistant to rifabutin. Rifampicin and rifabutin MIC values against 523 isolates of complex were determined utilizing the agar dilution method (Ref. Heifets, Leonid B. and Iseman, Michael D. 1985. Determination of in vitro susceptibility of Mycobacteria to Ansamycin. Am. Rev. Respir. Dis. 132 (3):710–711).
Rifabutin in vitro MIC values of ≤0.5 µg/mL, determined by the agar dilution method, for and have been reported; however, the clinical significance of these results is unknown.
Mycobutin () Indications And Usage
Mycobutin () Capsules are indicated for the prevention of disseminated complex (MAC) disease in patients with advanced HIV infection.
Mycobutin () Contraindications
Mycobutin () Capsules are contraindicated in patients who have had clinically significant hypersensitivity to rifabutin or to any other rifamycins.
Mycobutin () Warnings
Mycobutin () Capsules must not be administered for MAC prophylaxis to patients with tuberculosis. Tuberculosis in HIV-positive patients is common and may present with atypical or extrapulmonary findings. Patients are likely to have a nonreactive purified protein derivative (PPD) despite active disease. In addition to chest X-ray and sputum culture, the following studies may be useful in the diagnosis of tuberculosis in the HIV-positive patient: blood culture, urine culture, or biopsy of a suspicious lymph node.
When Mycobutin () is used concomitantly with clarithromycin for MAC treatment, a decreased dose of Mycobutin () is recommended due to the increase in plasma concentrations of Mycobutin () (see ). Due to the possible occurrence of uveitis, patients should also be carefully monitored when Mycobutin () is given in combination with clarithromycin (or other macrolides) and/or fluconazole (and related compounds). If uveitis is suspected, the patient should be referred to an ophthalmologist and, if considered necessary, treatment with Mycobutin () should be suspended (see also ).
Patients who develop complaints consistent with active tuberculosis while on prophylaxis with Mycobutin () should be evaluated immediately, so that those with active disease may be given an effective combination regimen of anti-tuberculosis medications. Administration of Mycobutin () as a single agent to patients with active tuberculosis is likely to lead to the development of tuberculosis that is resistant both to Mycobutin () and to rifampin.
There is no evidence that Mycobutin () is effective prophylaxis against. Patients requiring prophylaxis against both and complex may be given isoniazid and Mycobutin () concurrently.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of , and surgical evaluation should be instituted as clinically indicated.
In accordance with the commonly accepted criteria for the treatment of mycobacterial infections, Mycobutin () should always be given in combination with other anti-mycobacterial drugs not belonging to the family of rifamycins.
For patients with severe liver insufficiency a dose reduction should be considered. Mild hepatic impairment does not require a dose modification.
Severe renal impairment (creatinine clearance below 30 mL/min) requires a dosage reduction of 50%. Mild to moderate renal impairment does not require any dosage adjustment.
Protease inhibitors act as substrates or inhibitors of CYP450 IIIA4 mediated metabolism. Therefore, due to significant drug-drug interactions between protease inhibitors and rifabutin, their concomitant use should be based on the overall assessment of the patient and a patient-specific drug profile (see ). For further recommendations regarding protease inhibitors, please refer to current, official product monographs or contact the specific manufacturer.
Mycobutin () Precautions
Patients should be advised of the signs and symptoms of both MAC and tuberculosis, and should be instructed to consult their physicians if they develop new complaints consistent with either of these diseases. In addition, since Mycobutin () may rarely be associated with myositis and uveitis, patients should be advised to notify their physicians if they develop signs or symptoms suggesting either of these disorders.
Urine, feces, saliva, sputum, perspiration, tears, and skin may be colored brown-orange with rifabutin and some of its metabolites. Soft contact lenses may be permanently stained. Patients to be treated with Mycobutin () should be made aware of these possibilities.
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes, after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
There is no reason to believe that Mycobutin () has any adverse effect on the ability to drive and/or use machines.
Long-term carcinogenicity studies were conducted with rifabutin in mice and in rats. Rifabutin was not carcinogenic in mice at doses up to 180 mg/kg/day, or approximately 36 times the recommended human daily dose. Rifabutin was not carcinogenic in the rat at doses up to 60 mg/kg/day, about 12 times the recommended human dose.
Rifabutin was not mutagenic in the bacterial mutation assay (Ames Test) using both rifabutin-susceptible and resistant strains. Rifabutin was not mutagenic in and was not genotoxic in V-79 Chinese hamster cells, human lymphocytes in vitro, or mouse bone marrow cells in vivo.
Fertility was impaired in male rats given 160 mg/kg (32 times the recommended human daily dose).
Mycobutin () Adverse Reactions
Mycobutin () Capsules were generally well tolerated in the controlled clinical trials. Discontinuation of therapy due to an adverse event was required in 16% of patients receiving Mycobutin () , compared to 8% of patients receiving placebo in these trials. Primary reasons for discontinuation of Mycobutin () were rash (4% of treated patients), gastrointestinal intolerance (3%), and neutropenia (2%).
The following table enumerates adverse experiences that occurred at a frequency of 1% or greater, among the patients treated with Mycobutin () in studies 023 and 027.
Mycobutin () Animal Toxicology
Liver abnormalities (increased bilirubin and liver weight) occurred in all species tested, in rats at doses 5 times, in monkeys at doses 8 times, and in mice at doses 6 times the recommended human daily dose. Testicular atrophy occurred in baboons at doses 4 times the recommended human dose, and in rats at doses 40 times the recommended human daily dose.
Mycobutin () Overdosage
No information is available on accidental overdosage in humans.
Mycobutin () Dosage And Administration
It is recommended that Mycobutin () Capsules be administered at a dose of 300 mg once daily. For those patients with propensity to nausea, vomiting, or other gastrointestinal upset, administration of Mycobutin () at doses of 150 mg twice daily taken with food may be useful. For patients with severe renal impairment (creatinine clearance less than 30 mL/min), the dose of Mycobutin () should be reduced by 50%. No dosage adjustment is required for patients with mild to moderate renal impairment. Reduction of the dose of Mycobutin () may also be needed for patients receiving concomitant treatment with certain other drugs (see ).
Mycobutin () How Supplied
Mycobutin () Capsules (rifabutin capsules, USP) are supplied as hard gelatin capsules having an opaque red-brown cap and body, imprinted with Mycobutin () /PHARMACIA & UPJOHN in white ink, each containing 150 mg of rifabutin, USP.
Mycobutin () is available as follows:
NDC 0013-5301-17 Bottles of 100 capsules
Mycobutin ()
Mycobutin () Principal Display Panel - Mg Capsule Label
