May 5, 2016
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Rifamate

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Rifamate




Warnings
Precautions

WARNINGS

RIFAMATE (rifampin and isoniazid capsules USP) is a combination of two drugs, each of which has been associated with liver dysfunction.

Rifampin

Rifampin has been shown to produce liver dysfunction. There have been fatalities associated with jaundice in patients with liver disease or receiving rifampin concomitantly with other hepatotoxic agents. Because RIFAMATE contains both rifampin and isoniazid, it should only be given with caution and under strict medical supervision to patients with impaired liver function. In these patients, careful monitoring of liver function, especially serum glutamic pyruvic transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) should be carried out prior to therapy and then every 2 to 4 weeks during therapy. If signs of hepatocellular damage occur, RIFAMATE should be withdrawn.

In some cases, hyperbilirubinemia resulting from competition between rifampin and bilirubin for excretory pathways of the liver at the cell level can occur in the early days of treatment. An isolated report showing a moderate rise in bilirubin and/or transaminase level is not in itself an indication for interrupting treatment; rather, the decision should be made after repeating the tests, noting trends in the levels, and considering them in conjunction with the patient's clinical condition.

Rifampin has enzyme-inducing properties, including induction of delta amino levulinic acid synthetase. Isolated reports have associated porphyria exacerbation with rifampin administration.

Isoniazid

(See the BOXED WARNING).

Since RIFAMATE contains isoniazid, ophthalmologic examinations (including ophthalmoscopy) should be done before treatment is started and periodically thereafter, even without occurrence of visual symptoms.

PRECAUTIONS

General

RIFAMATE should be used with caution in patients with a history of diabetes mellitus, as diabetes management may be more difficult.

Rifampin

For the treatment of tuberculosis, rifampin is usually administered on a daily basis. Doses of rifampin greater than 600 mg given once or twice weekly have resulted in a higher incidence of adverse reactions, including the “flu syndrome” (fever, chills and malaise), hematopoietic reactions (leukopenia, thrombocytopenia, or acute hemolytic anemia), cutaneous, gastrointestinal, and hepatic reactions, shortness of breath, shock, anaphylaxis, and renal failure. Recent studies indicate that regimens using twice-weekly doses of rifampin 600 mg plus isoniazid 15 mg/kg are much better tolerated.

Rifampin is not recommended for intermittent therapy; the patient should be cautioned against intentional or accidental interruption of the daily dosage regimen since rare renal hypersensitivity reactions have been reported when therapy was resumed in such cases. Rifampin has enzyme induction properties that can enhance the metabolism of endogenous substrates including adrenal hormones, thyroid hormones, and vitamin D.

Isoniazid

All drugs should be stopped and an evaluation of the patient should be made at the first sign of a hypersensitivity reaction.

Use of RIFAMATE, because it contains isoniazid should be carefully monitored in the following:

  1. Patients who are receiving phenytoin (diphenylhydantoin) concurrently. Isoniazid may decrease the excretion of phenytoin or may enhance its effects. To avoid phenytoin intoxication, appropriate adjustment of the anticonvulsant dose should be made.
  2. Daily users of alcohol. Daily ingestion of alcohol may be associated with a higher incidence of isoniazid hepatitis.
  3. Patients with current chronic liver disease or severe renal dysfunction.

Laboratory Tests

Adults treated for tuberculosis with RIFAMATE should have baseline measurements of hepatic enzymes, bilirubin, serum creatinine, a complete blood count (CBC) and platelet count (or estimate), and blood uric acid.

Patients should be seen at least monthly during therapy and should be specifically questioned concerning symptoms associated with adverse reactions. All patients with abnormalities should have follow-up, including laboratory testing, if necessary. Routine laboratory monitoring for toxicity in people with normal baseline measurements is generally not necessary.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Increased frequency of chromosomal aberrations was observed in vitro in lymphocytes obtained from patients treated with combinations of rifampin, isoniazid, and pyrazinamide and combinations of streptomycin, rifampin, isoniazid, and pyrazinamide.

Rifampin

A few cases of accelerated growth of lung carcinoma have been reported in man, but a causal relationship with the drug has not been established. Hepatomas were increased in female (C3Hf/DP) mice dosed for 60 weeks with rifampicin followed by an observation period of 46 weeks, at 20 to 120 mg/kg (equivalent to 0.1 to 0.5 times the maximum dosage used clinically, based on body surface area comparisons). There was no evidence of tumorigenicity in male C3Hf/DP mice or, in similar studies in BALB/c mice, or in two year studies in Wistar rats.

There was no evidence of mutagenicity in both prokaryotic (Salmonella typhi, Escherichia coli) and eukaryotic (Saccharomyces cerevisiae) bacteria, Drosophila melanogaster, or ICR/Ha Swiss mice. An increase in chromatid breaks was noted when whole blood cell cultures were treated with rifampin.

Isoniazid

Isoniazid has been reported to induce pulmonary tumors in a number of strains of mice.

Pregnancy

Teratogenic Effects

Category C

Although animal reproduction studies have not been conducted with RIFAMATE teratogenic effects (including cleft palate and spina bifida) have been observed in rodents treated with rifampin at doses 0.2 to 2 times the maximum recommended human dose, based on body surface area comparisons. There are no adequate and well-controlled studies of RIFAMATE in pregnant women. RIFAMATE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Rifampin

Congenital malformations, primarily spina bifida were increased in the offspring of pregnant rats given rifampin during organogenesis at oral doses of 150 to 250 mg/kg/day (about 1 to 2 times the maximum recommended human dose based on body surface area comparisons). Cleft palate was increased in a dose-dependent fashion in fetuses of pregnant mice treated at oral doses of 50 to 200 mg/kg (about 0.2 to 0.8 times the maximum recommended human dose based on body surface area comparisons). Imperfect osteogenesis and embryotoxicity were also reported in pregnant rabbits given rifampin at oral doses up to 200 mg/kg/day (about 3 times the maximum recommended daily human dose based on body surface area comparisons). Although there are no adequate and well-controlled studies in pregnant women, rifampin has been reported to cross the placental barrier and appear in cord blood.

Isoniazid

It has been reported that in both rats and rabbits, isoniazid may exert an embryocidal effect when administered orally during pregnancy, although no isoniazid-related congenital anomalies have been found in reproduction studies in mammalian species (mice, rats, and rabbits).

Pregnancy

Non-Teratogenic Effects

When administered during the last few weeks of pregnancy, rifampin can cause postnatal hemorrhages in the mother and infant for which treatment with vitamin K may be indicated.

Rifampin

When administered during the last few weeks of pregnancy, rifampin can cause postnatal hemorrhages in the mother and infant. In this case, treatment with vitamin K may be indicated for postnatal hemorrhage.

Nursing Mothers

Because of the potential for tumorigenicity shown for rifampin in animal studies, and since rifampin and isoniazid are known to cross the placental barrier and to pass into maternal breast milk, a decision should be made whether to discontinue nursing or to discontinue RIFAMATE, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients under the age of 15 have not been established. (See CLINICAL PHARMACOLOGY, General; See also DOSAGE AND ADMINISTRATION).

Geriatric Use

Clinical studies of RIFAMATE 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. Caution should therefore be observed in using rifampin and isoniazid in elderly patients. (See WARNINGS).

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 4/15/2016

Warnings
Precautions

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