MYCOBUTIN* (rifabutin capsules) 150 mg

BRIEF SUMMARY

CONTRAINDICATIONS

Rifabutin is contraindicated in patients who have had clinically significant hypersensitivity to this drug, or to any other rifamycins.

WARNINGS

MYCOBUTIN prophylaxis must not be administered 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.

Patients who develop complaints consistent with active tuberculosis while on MYCOBUTIN prophylaxis should be evaluated immediately, so that those with active disease may be given an effective combination regimen of anti-tuberculosis medications. Administration of single-agent MYCOBUTIN 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 Mycobacterium tuberculosis. Patients requiring prophylaxis against both M. tuberculosis and Mycobacterium avium complex may be given isoniazid and MYCOBUTIN concurrently. PRECAUTIONS

Because MYCOBUTIN may be associated with neutropenia, and more rarely thrombocytopenia, physicians should consider obtaining hematologic studies períodically in patients receiving MYCOBUTIN prophylaxis.

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.

Drug Interactions

In 10 healthy adult volunteers and 8 HIV-positive patients, steady-state plasma levels of zidovudine (ZDV), an antiretroviral agent which is metabolized mainly through glucuronidation, were decreased after repeated MYCOBUTIN dosing; the mean decrease in Cmax and AUC was 48% and 32%, respectively. In vitro studies have demonstrated that MYCOBUTIN does not affect the inhibition of HIV by ZDV.

Steady-state kinetics in 12 HIV-positive patients show that both the rate and extent of systemic availability of didanosine (ddi), was not altered after repeated dosing of MYCOBUTIN.

MYCOBUTIN has liver enzyme-inducing properties. The related drug rifampin is known to reduce the activity of a number of other drugs, including dapsone, narcotics (including methadone), anticoagulants, corticosteroids, cyclosporine, cardiac glycoside preparations, quinidine, oral contraceptives, oral hypoglycemic agents (sulfonylureas), and analgesics. Rifampin has also been reported to decrease the effects of concurrently administered ketoconazole, barbiturates, diazepam, verapamil, beta-adrenergic blockers, clofibrate, progestins, disopyramide, mexiletine, theophylline, chloramphenicol, and anticonvulsants. Because of the structural similarity of rifabutin and rifampin, MYCOBUTIN may be expected to have some effect on these drugs as well. However, unlike rifampin, MYCOBUTIN appears not to affect the acetylation of isoniazid. When rifabutin was compared with rifampin in a study with 8 healthy normal volunteers, rifabutin appeared to be a less potent enzyme inducer than rifampin. The significance of this finding for clinical drug interactions is not known. Dosage adjustment of drugs listed above may be necessary if they are given concurrently with MYCOBUTIN. Patients using oral contraceptives should consider changing to nonhormonal methods of birth control.

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:

Pregnancy Category B: 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. Doses of MYCOBUTIN may be administered mixed with foods such as applesauce.

ADVERSE REACTIONS

MYCOBUTIN was 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.

CLINICAL ADVERSE EXPERIENCES REPORTED IN 21% OF PATIENTS TREATED WITH MYCOBUTIN MYCOBUTIN (n = 566) %

ADVERSE EVENT

BODY AS A WHOLE

Abdominal Pain

Asthenia

Chest Pain

Fever

Headache Pain

DIGESTIVE SYSTEM

Anorexia

Diarrhea

Dyspepsia

Eructation

Flatulence

Nausea

Nausea and Vomiting Vomiting

MUSCULOSKELETAL SYSTEM Myalgia

NERVOUS SYSTEM Insomnia

SKIN AND APPENDAGES Rash

SPECIAL SENSES

Taste Perversion

UROGENITAL SYSTEM

Discolored Urine

2

1

11

3 30

PLACEBO (n = 580) %

CLINICAL ADVERSE EVENTS REPORTED IN <1% OF PATIENTS WHO RECEIVED MYCOBUTIN

Considering data from the 023 and 027 pivotal trials, and from other clinical studies, MYCOBUTIN appears to be a likely cause of the following adverse events which occurred in less than 1% of treated patients: flu-like syndrome, hepatitis, hemolysis, arthralgia, myositis, chest pressure or pain with dyspnea, and skin discoloration. The following adverse events have occurred in more than one patient receiving MYCOBUTIN, but an etiologic role has not been established: seizure, paresthesia, aphasia, confusion, and non-specific T wave changes on electrocardiogram.

When MYCOBUTIN was administered at doses from 1050 mg/day to 2400 mg/day, generalized arthralgia and uveitis were reported. These adverse experiences abated when MYCOBUTIN was discontinued.

The following table enumerates the changes in laboratory values that were considered as laboratory abnormalities in studies 023 and 027.

PERCENTAGE OF PATIENTS WITH LABORATORY ABNORMALITIES

LABORATORY ABNORMALITIES

Increased Alkaline Phosphatase1

Increased SGOT2

Chemistry:

Increased SGPT2

Hematology:

Anemia3

Eosinophilia

Leukopenia

Neutropenia

Thrombocytopenia

MYCOBUTIN (n = 566) %

INCLUDES GRADE 3 OR 4 TOXICITIES AS SPECIFIED:

1all values> 450 U/L

2all values> 150 U/L

3all hemoglobin values < 8.0 g/dL

PLACEBO

(n = 580) %

4all WBC values < 1,500/mm3

Sall ANC values < 750/mm3

"all platelet count values < 50,000/mm3

The incidence of neutropenia in patients treated with MYCOBUTIN was significantly greater than in patients treated with placebo (p = 0.03). Although thrombocytopenia was not significantly more common among MYCOBUTIN treated patients in these trials, MYCOBUTIN has been clearly linked to thrombocytopenia in rare cases. One patient in study 023 developed thrombotic thrombocytopenic purpura, which was attributed to MYCOBUTIN.

CAUTION: Federal law prohibits dispensing without prescription. Manufactured by:

FARMITALIA CARLO ERBA

ASCOLI PICENO, ITALY

For:

ADRIA LABORATORIES COLUMBUS, OHIO 43216

Pharmacia

Adria

LC9312

April 1994

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