Rifabutin warnings and precautions

# Warnings
MYCOBUTIN Capsules must not be administered for MAC prophylaxis to patients with active 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 PRECAUTIONS-Drug Interactions). 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 ADVERSE REACTIONS).
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 M. tuberculosis. Patients requiring prophylaxis against both M. tuberculosis and Mycobacterium avium complex may be given isoniazid and MYCOBUTIN concurrently.
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including MYCOBUTIN (rifabutin capsules, USP), and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, 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 3A4 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 PRECAUTIONS-Drug Interactions). For further recommendations regarding protease inhibitors, please refer to current, official product monographs or contact the specific manufacturer.

# Precautions

## General
Because treatment with MYCOBUTIN Capsules may be associated with neutropenia, and more rarely thrombocytopenia, physicians should consider obtaining hematologic studies periodically in patients receiving prophylaxis with MYCOBUTIN.

## Information for Patients
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.

## Drug Interactions
Multiple dosing of rifabutin has been associated with induction of hepatic metabolic enzymes of the CYP450 3A4 subfamily. Rifabutin's predominant metabolite (25-desacetyl rifabutin; LM 565), may also contribute to this effect. Metabolic induction due to rifabutin is likely to produce a decrease in circulating levels of concomitantly administered drugs (especially those metabolized by the CYP450 IIIA pathway). Kinetic data suggest that enzymatic induction by rifabutin is complete within 5 days and is dose-independent over the 300 to 600 mg dose-range. Similarly, concomitant medications that competitively inhibit the CYP450 IIIA activity may increase circulating levels of rifabutin.

## Malabsorption
Gastric pH alteration due to progressing HIV disease has been linked with malabsorption of some drugs used in HIV-positive patients (e.g., rifampin, isoniazid). Drug serum concentration data from AIDS patients with varying disease severity (based on CD4+ counts) suggest that rifabutin absorption is not influenced by progressing HIV disease.

## Effects on Other Drugs
Rifabutin induces CYP3A enzymes and therefore may reduce the plasma concentrations of drugs metabolized by those enzymes. This effect may reduce the efficacy of standard doses of such drugs, which include itraconazole, clarithromycin, and saquinavir (see CLINICAL PHARMACOLOGY-Drug-Drug Interactions).

## Effects on Rifabutin
Some drugs that inhibit CYP3A may significantly increase the plasma concentration of rifabutin. Because high plasma levels of rifabutin may increase the risk of adverse reactions, carefully monitor patients receiving coadministration of such drugs, which include fluconazole and clarithromycin (see CLINICAL PHARMACOLOGY-Drug-Drug Interactions). In some cases, the dosage of MYCOBUTIN may need to be reduced when it is coadministered with such a drug (see below).
The following table summarizes the results and magnitude of the pertinent drug interactions assessed with rifabutin. The clinical relevance of these interactions and subsequent dose modifications should be judged in light of the population studied, severity of the disease, patient's drug profile, and the likely impact on the risk/benefit ratio.

## Other drugs
The structurally similar drug, rifampin, is known to reduce the plasma concentrations of a number of other drugs (see prescribing information for rifampin). Although rifabutin is a weaker enzyme inducer than rifampin, it may be expected to have some effect on those drugs as well.

## Carcinogenesis, Mutagenesis, Impairment of Fertility
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 Schizosaccharomyces pombe P1 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).

## Pregnancy Category: B
There are no adequate and well-controlled studies in pregnant or breastfeeding women.
Reproduction studies have been carried out in rats and rabbits given rifabutin using dose levels up to 200 mg/kg (40 times the recommended human daily dose). No teratogenicity was observed in either species. In rats, given 200 mg/kg/day, there was a decrease in fetal viability. In rats, at 40 mg/kg/day (8 times the recommended human daily dose), rifabutin caused an increase in fetal skeletal variants. In rabbits, at 80 mg/kg/day (16 times the recommended human daily dose), rifabutin caused maternotoxicity and increase in fetal skeletal anomalies. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, rifabutin should be used in pregnant women only if the potential benefit justifies the potential risk to the fetus.

## Nursing Mothers
It is not known whether rifabutin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

## Pediatric Use
Safety and effectiveness of rifabutin for prophylaxis of MAC in children have not been established. Limited safety data are available from treatment use in 22 HIV-positive children with MAC who received MYCOBUTIN in combination with at least two other antimycobacterials for periods from 1 to 183 weeks. Mean doses (mg/kg) for these children were: 18.5 (range 15.0 to 25.0) for infants one year of age, 8.6 (range 4.4 to 18.8) for children 2 to 10 years of age, and 4.0 (range 2.8 to 5.4) for adolescents 14 to 16 years of age. There is no evidence that doses greater than 5 mg/kg daily are useful. Adverse experiences were similar to those observed in the adult population, and included leukopenia, neutropenia, and rash. In addition, corneal deposits have been observed in some patients during routine ophthalmologic surveillance of HIV-positive pediatric patients receiving MYCOBUTIN as part of a multiple-drug regimen for MAC prophylaxis. These are tiny, almost transparent, asymptomatic peripheral and central corneal deposits which do not impair vision. Doses of MYCOBUTIN may be administered mixed with foods such as applesauce.

## Geriatric Use
Clinical studies of MYCOBUTIN did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see CLINICAL PHARMACOLOGY).