Mycobutin (Page 2 of 6)

Clinically Significant Disseminated MAC Disease

In association with the decreased incidence of bacteremia, patients on MYCOBUTIN showed reductions in the signs and symptoms of disseminated MAC disease, including fever, night sweats, weight loss, fatigue, abdominal pain, anemia, and hepatic dysfunction.

Survival

The one-year survival rates in Study 023 were 77% for the group receiving MYCOBUTIN and 77% for the placebo group. In Study 027, the one-year survival rates were 77% for the group receiving MYCOBUTIN and 70% for the placebo group.

These differences were not statistically significant.

Microbiology

Mechanism of Action

Rifabutin inhibits DNA-dependent RNA polymerase in susceptible strains of Escherichia coli and Bacillus subtilis but not in mammalian cells. In resistant strains of E. coli , rifabutin, like rifampin, did not inhibit this enzyme. It is not known whether rifabutin inhibits DNA-dependent RNA polymerase in Mycobacterium avium or in M. intracellulare which comprise M. avium complex (MAC).

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

In Vitro Studies

Rifabutin has demonstrated in vitro activity against M. avium 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 M. avium , whereas in HIV-negative people, about 40% of the MAC isolates are M. intracellulare.

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 MIC99 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, M. avium complex in a mouse macrophage cell culture model.

Rifabutin has in vitro activity against many strains of Mycobacterium tuberculosis. 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 M. tuberculosis and M. avium complex isolates. Isolates of M. tuberculosis resistant to rifampin are likely to be resistant to rifabutin. Rifampicin and rifabutin MIC99 values against 523 isolates of M. avium complex were determined utilizing the agar dilution method (Heifets, Leonid B. and Iseman, Michael D. Determination of in vitro susceptibility of Mycobacteria to Ansamycin. Am. Rev. Respir. Dis. 1985; 132(3):710–711).

Table 1 Susceptibility of M. Avium Complex Strains to Rifampin and Rifabutin
% of Strains Susceptible/Resistant to Different Concentrations of Rifabutin (μg/mL)
Susceptibility to Rifampin(µg/mL) Number of Strains Susceptible to 0.5 Resistant to 0.5 only Resistant to 1.0 Resistant to 2.0
Susceptible to 1.0 30 100.0 0.0 0.0 0.0
Resistant to 1.0 only 163 88.3 11.7 0.0 0.0
Resistant to 5.0 105 38.0 57.1 2.9 2.0
Resistant to 10.0 225 20.0 50.2 19.6 10.2
TOTAL 523 49.5 36.7 9.0 4.8

Rifabutin in vitro MIC99 values of ≤0.5 µg/mL, determined by the agar dilution method, for M. kansasii , M. gordonae and M. marinum 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 Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection.

CONTRAINDICATIONS

MYCOBUTIN Capsules are contraindicated in patients who have had clinically significant hypersensitivity to rifabutin or to any other rifamycins.

WARNINGS

Tuberculosis

MYCOBUTIN Capsules must not be administered for MAC prophylaxis to patients with active tuberculosis. 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 an effective prophylaxis against M. tuberculosis. Patients requiring prophylaxis against both M. tuberculosis and Mycobacterium avium complex may be given isoniazid and MYCOBUTIN concurrently.

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.

MAC Treatment with Clarithromycin

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 PRECAUTIONS-Drug Interactions, Table 2).

Hypersensitivity and Related Reactions

Hypersensitivity reactions may occur in patients receiving rifamycins. Signs and symptoms of these reactions may include hypotension, urticaria, angioedema, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia or flu-like syndrome (weakness, fatigue, muscle pain, nausea, vomiting, headache, fever, chills, aches, rash, itching, sweats, dizziness, shortness of breath, chest pain, cough, syncope, palpitations). There have been reports of anaphylaxis with the use of rifamycins.

Monitor patients receiving MYCOBUTIN therapy for signs and/or symptoms of hypersensitivity reactions. If these symptoms occur, administer supportive measures and discontinue MYCOBUTIN.

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