Rifater (rifampin, isoniazid and pyrazinamide) Tablets
Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER) –
Carcinogenesis, Mutagenesis, 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. 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. 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.
- Category C. Although animal reproduction studies have not been conducted with Rifater 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 Rifater in pregnant women. Rifater 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.
Pregnancy Non-Tertatogenic Effects
- When administered during the last few weeks of pregnancy, rifampin can cause post-natal hemorrhages in the mother and infant for which treatment with vitamin K may be indicated.
- Rifampin is contraindicated in patients who are also receiving ritonavir-boosted saquinavir due to an increased risk of severe hepatocellular toxicity.
- Rifampin is contraindicated in patients who are also receiving atazanavir, darunavir, fosamprenavir, saquinavir, or tipranavir due to the potential of rifampin to substantially decrease plasma concentrations of these antiviral drugs, which may result in loss of antiviral efficacy and/or development of viral resistance.
- 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.
Information for Patients
- The patient should be advised that the reliability of oral or other contraceptives may be affected; consideration should be given to using alternative contraceptive measures.
- Enzyme Induction: Healthy subjects who received rifampin 600 mg once daily concomitantly with saquinavir 1000 mg/ritonavir 100 mg twice daily (ritonavir-boosted saquinavir) developed severe hepatocellular toxicity. Therefore, concomitant use of these medications is contraindicated.
- Rifampin has been reported to substantially decrease the plasma concentrations of the following antiviral drugs: atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir. These antiviral drugs must not be co-administered with rifampin.
- Rifampin has been reported to accelerate the metabolism of the following drugs: …digitoxin…clarithromycin, fluoroquinolones, doxycycline, levothyroxine,quinine, tacrolimus,tricyclic antidepressants (eg, amitriptyline, nortriptyline), and zidovudine.
- Patients using oral or other systemic hormonal contraceptives should be advised to change to nonhormonal methods of birth control during rifampin therapy.
- When the two drugs were taken concomitantly, decreased concentrations of atovaquone and increased concentrations of rifampin were observed.
Transient abnormalities in liver function tests (e.g., elevations in serum bilirubin, BSP, alkaline phosphatase, serum transaminases) have been observed.
- Rare reports of disseminated intravascular coagulation have been observed.
Central Nervous System
- Psychoses have been rarely reported.
- Rare reports of adrenal insufficiency in patients with compromised adrenal function have been observed.
- Acute tubular necrosis
- Erythema multiforme including Stevens-Johnson Syndrome, toxic epidermal necrolysis,vasculitis. Anaphylaxis has been reported rarely.
- Anaphylactic reactions, Stevens-Johnson syndrome.