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RIFATER (rifampin, isoniazid and pyrazinamide) is a combination of the three drugs, rifampin, isoniazid, and pyrazinamide. Each of these individual drugs has been associated with liver dysfunction.

Rifampin

Rifampin has been shown to produce liver dysfunction. Fatalities associated with jaundice have occurred in patients with liver disease and in patients taking rifampin with other hepatotoxic agents. Because RIFATER (rifampin, isoniazid and pyrazinamide) 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 If signs of hepatocellular damage occur, RIFATER (rifampin, isoniazid and pyrazinamide) should be withdrawn.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 RIFATER (rifampin, isoniazid and pyrazinamide) contains isoniazid, ophthalmologic examinations (including ophthalmoscopy) should be done before treatment is started and periodically thereafter, even without occurrence of visual symptoms.

Pyrazinamide

Since RIFATER (rifampin, isoniazid and pyrazinamide) contains pyrazinamide, patients started on RIFATER (rifampin, isoniazid and pyrazinamide) should have baseline serum uric acid and liver function determinations. Patients with preexisting liver disease or those patients at increased risk for drug related hepatitis (eg, alcohol abusers) should be followed closely.

Because it contains pyrazinamide, RIFATER (rifampin, isoniazid and pyrazinamide) should be discontinued and not be resumed if signs of hepatocellular damage or hyperuricemia accompanied by an acute gouty arthritis appear. If hyperuricemia accompanied by an acute gouty arthritis occurs without liver dysfunction, the patient should be transferred to a regimen not containing pyrazinamide.

General

RIFATER (rifampin, isoniazid and pyrazinamide) should be used with caution in patients with a history of diabetes mellitus, as diabetes management may be more difficult.

Rifampin

For treatment of tuberculosis, rifampin is usually administered on a daily basis. Doses of rifampin ( > 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 RIFATER (rifampin, isoniazid and pyrazinamide) , 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.

Pyrazinamide

Pyrazinamide inhibits renal excretion of urates, frequently resulting in hyperuricemia which is usually asymptomatic. If hyperuricemia is accompanied by acute gouty arthritis, RIFATER (rifampin, isoniazid and pyrazinamide) , because it contains pyrazinamide, should be discontinued.

Laboratory Tests

Adults treated for tuberculosis with RIF ATER 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

There are no known human data on long-term potential for carcinogenicity, mutagenicity, or impairment of fertility. 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. An increase in the incidence of hepatomas in female mice (of a strain known to be particularly susceptible to the spontaneous development of hepatomas) was observed when rifampin was administered in doses two to ten times the average daily human dose for 60 weeks followed by an observation period of 46 weeks. No evidence of carcinogenicity was found in male mice of the same strain, mice of a different strain, or rats under similar experimental conditions.

Rifampin has been reported to possess immunosuppressive potential in rabbits, mice, rats, guinea pigs, human lymphocytes in vitro, and humans. Antitumor activity in vitro has also been shown with rifampin.

There was no evidence of mutagenicity in bacteria, Drosophila melanogaster, or 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.

Pyrazinamide

In lifetime bioassays in rats and mice, pyrazinamide was administered in the diet at concentrations of up to 10,000 ppm. This resulted in estimated daily doses of 2 g/kg for the mouse, or 40 times the maximum human dose, and 0.5 g/kg for the rat, or 10 times the maximum human dose. Pyrazinamide was not carcinogenic in rats or male mice and no conclusion was possible for female mice.

Pyrazinamide was not mutagenic in the Ames bacterial test, but induced chromosomal aberrations in human lymphocyte cell cultures.

Pregnancy

Teratogenic Effects

Category C. Animal reproduction studies have not been conducted with RIFATER (rifampin, isoniazid and pyrazinamide) . It is also not known whether RIFATER (rifampin, isoniazid and pyrazinamide) can cause fetal harm when administered to a pregnant woman. RIFATER (rifampin, isoniazid and pyrazinamide) should be given to a pregnant woman only if clearly needed.

Rifampin

Rifampin has been shown to be teratogenic in rodents given oral doses of rifampin 15 to 25 times the human dose. Although rifampin has been reported to cross the placental barrier and appear in cord blood, the effect of rifampin, alone or in combination with other antituberculosis drugs, on the human fetus is not known. Isolated cases of fetal malformations have been reported; however, there are no adequate and well-controlled studies in pregnant women. An increase in congenital malformations, primarily spina bifida and cleft palate, has been reported in the offspring of rodents given oral doses of 150 to 250 mg/kg/day of rifampin during pregnancy. The incidence of these anomalies was dose-dependent. When rifampin was given to pregnant rabbits in doses up to 20 times the usual daily human dose, imperfect osteogenesis and embryotoxicity were reported.

The possible teratogenic potential in women capable of bearing children should be carefully weighed against the benefits of RIFATER (rifampin, isoniazid and pyrazinamide) therapy.

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). RIFATER (rifampin, isoniazid and pyrazinamide) , because it contains isoniazid, should be prescribed during pregnancy only when therapeutically necessary. The benefit of preventive therapy should be weighed against a possible risk to the fetus. Preventive treatment generally should be started after delivery because of the increased risk of tuberculosis for new mothers.

Pyrazinamide

Animal reproductive studies have not been conducted with pyrazinamide. It is also not known whether pyrazinamide can cause fetal harm when administered to a pregnant woman. RIFATER (rifampin, isoniazid and pyrazinamide) , because it contains pyrazinamide, should be given to a pregnant woman only if clearly needed.

Pregnancy - Non-Teratogenic Effects

It is not known whether RIFATER (rifampin, isoniazid and pyrazinamide) can affect reproduction capacity.

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

Since rifampin, isoniazid, and pyrazinamide are known to pass into maternal breast milk, a decision should be made whether to discontinue nursing or to discontinue RIFATER (rifampin, isoniazid and pyrazinamide) , 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 RIFATER (rifampin, isoniazid and pyrazinamide) 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)

Last reviewed on RxList: 12/17/2010
This monograph has been modified to include the generic and brand name in many instances.