RIFAMATE (rifampin and isoniazid capsules USP) is a combination of two drugs, each of which has been associated with liver dysfunction. Liver function tests should be performed prior to therapy with RIFAMATE and periodically during treatment.
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. Since an increased risk may exist for individuals with liver disease, benefits must be weighed carefully against the risk of further liver damage.
Several studies of tumorigenicity potential have been done in rodents. In one strain of mice known to be particularly susceptible to the spontaneous development of hepatomas, rifampin given at a level 2–10 times the maximum dosage used clinically resulted in a significant increase in the occurrence of hepatomas in female mice of this strain after one year of administration.
There was no evidence of tumorigenicity in the males of this strain, in males or females of another mouse strain, or in rats.
See the boxed warning.
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 been observed to increase the requirements for anticoagulant drugs of the coumarin type. The cause of the phenomenon is unknown. In patients receiving anticoagulants and rifampin concurrently, it is recommended that the prothrombin time be performed daily or as frequently as necessary to establish and maintain the required dose of anticoagulant.
Urine, feces, saliva, sputum, sweat, and tears may be colored red-orange by rifampin and its metabolites. Soft contact lenses may be permanently stained. Individuals to be treated should be made aware of these possibilities.
It has been reported that the reliability of oral contraceptives may be affected in some patients being treated for tuberculosis with rifampin in combination with at least one other antituberculosis drug. In such cases, alternative contraceptive measures may need to be considered.
It has also been reported that rifampin given in combination with other antituberculosis drugs may decrease the pharmacologic activity of methadone, oral hypoglycemics, digitoxin, quinidine, disopyramide, dapsone, and corticosteroids. In these cases, dosage adjustment of the interacting drugs is recommended.
Therapeutic levels of rifampin have been shown to inhibit standard microbiological assays for serum folate and vitamin B12. Alternative methods must be considered when determining folate and vitamin B12 concentrations in the presence of rifampin.
Since rifampin has been reported to cross the placental barrier and appear in cord blood and in maternal milk, neonates and newborns of rifampin-treated mothers should be carefully observed for any evidence of untoward effects.
All drugs should be stopped and an evaluation of the patient should be made at the first sign of a hypersensitivity reaction.
Use of isoniazid should be carefully monitored in the following:
- 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.
- Daily users of alcohol. Daily ingestion of alcohol may be associated with a higher incidence of isoniazid hepatitis.
- Patients with current chronic liver disease or severe renal dysfunction.
Periodic ophthalmoscopic examination during isoniazid therapy is recommended when visual symptoms occur.
Usage in Pregnancy and Lactation
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. An increase in congenital malformations, primarily spina bifida and cleft palate, has been reported in the offspring of rodents given oral doses of 150–250 mg/kg/day of rifampin during pregnancy.
The possible teratogenic potential in women capable of bearing children should be carefully weighed against the benefits of therapy.
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). 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.
Since isoniazid is known to cross the placental barrier and to pass into maternal breast milk, neonates and breast-fed infants of isoniazid-treated mothers should be carefully observed for any evidence of adverse effects.
Isoniazid has been reported to induce pulmonary tumors in a number of strains of mice.