Rifamate Information
Rifamate (Rifampin,isoniazid) Warning
Severe and sometimes fatal hepatitis associated with isoniazid therapy may occur and may develop even after many months of treatment. The risk of developing hepatitis is age related. Approximate case rates by age are: 0 per 1,000 for persons under 20 years of age, 3 per 1,000 for persons in the 20–34 year age group, 12 per 1,000 for persons in the 35–49 year age group, 23 per 1,000 for persons in the 50–64 year age group, and 8 per 1,000 for persons over 65 years of age. The risk of hepatitis is increased with daily consumption of alcohol. Precise data to provide a fatality rate for isoniazid-related hepatitis is not available; however, in a U.S. Public Health Service Surveillance Study of 13,838 persons taking isoniazid, there were 8 deaths among 174 cases of hepatitis.
Therefore, patients given isoniazid should be carefully monitored and interviewed at monthly intervals. Serum transaminase concentration becomes elevated in about 10–20 percent of patients, usually during the first few months of therapy, but it can occur at any time. Usually enzyme levels return to normal despite continuance of drug, but in some cases progressive liver dysfunction occurs. Patients should be instructed to report immediately any of the prodromal symptoms of hepatitis, such as fatigue, weakness, malaise, anorexia, nausea, or vomiting. If these symptoms appear or if signs suggestive of hepatic damage are detected, isoniazid should be discontinued promptly, since continued use of the drug in these cases has been reported to cause a more severe form of liver damage.
Patients with tuberculosis should be given appropriate treatment with alternative drugs. If isoniazid must be reinstituted, it should be reinstituted only after symptoms and laboratory abnormalities have cleared. The drug should be restarted in very small and gradually increasing doses and should be withdrawn immediately if there is any indication of recurrent liver involvement. Treatment should be deferred in persons with acute hepatic diseases.
Rifamate (Rifampin,isoniazid) Description
Rifamate (Rifampin,isoniazid) is a combination capsule containing 300 mg rifampin and 150 mg isoniazid. The capsules also contain as inactive ingredients: colloidal silicon dioxide, FD&C Blue No. 1, FD&C Red No. 40, gelatin, magnesium stearate, sodium starch glycolate, and titanium dioxide.
Rifampin is a semisynthetic antibiotic derivative of rifamycin B. The chemical name for rifampin is 3-(4-methyl-1-piperazinyliminomethyl) rifamycin SV.
Isoniazid is the hydrazide of isonicotinic acid. It exists as colorless or white crystals or as a white, crystalline powder that is water soluble, odorless, and slowly affected by exposure to air and light.
Rifamate (Rifampin,isoniazid) Clinical Pharmacology
Rifampin inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme. This is the mechanism of action by which rifampin exerts its therapeutic effect. Rifampin cross-resistance has only been shown with other rifamycins.
In a study of 14 normal human adult males, peak blood levels of rifampin occurred 1 1/2 to 3 hours following oral administration of two Rifamate (Rifampin,isoniazid) capsules. The peaks ranged from 6.9 to 14 mcg/ml with an average of 10 mcg/ml.
In normal subjects the T1/2 (biological half-life) of rifampin in blood is approximately 3 hours. Elimination occurs mainly through the bile and, to a much lesser extent, the urine.
Isoniazid acts against actively growing tubercle bacilli.
After oral administration isoniazid produces peak blood levels within 1 to 2 hours which decline to 50% or less within 6 hours. It diffuses readily into all body fluids (cerebrospinal, pleural, and ascitic fluids), tissues, organs, and excreta (saliva, sputum, and feces). The drug also passes through the placental barrier and into milk in concentrations comparable to those in the plasma. From 50 to 70% of a dose of isoniazid is excreted in the urine in 24 hours.
Isoniazid is metabolized primarily by acetylation and dehydrazination. The rate of acetylation is genetically determined. Approximately 50% of Blacks and Caucasians are "slow inactivators"; the majority of Eskimos and Orientals are "rapid inactivators."
The rate of acetylation does not significantly alter the effectiveness of isoniazid. However, slow acetylation may lead to higher blood levels of the drug, and thus an increase in toxic reactions.
Pyridoxine deficiency (B) is sometimes observed in adults with high doses of isoniazid and is considered probably due to its competition with pyridoxal phosphate for the enzyme apotryptophanase.
Rifamate (Rifampin,isoniazid) Indications And Usage
For pulmonary tuberculosis in which organisms are susceptible, and when the patient has been titrated on the individual components and it has therefore been established that this fixed dosage is therapeutically effective.
This fixed-dosage combination drug is not recommended for initial therapy of tuberculosis or for preventive therapy.
In the treatment of tuberculosis, small numbers of resistant cells, present within large populations of susceptible cells, can rapidly become the predominating type. Since rapid emergence of resistance can occur, culture and susceptibility tests should be performed in the event of persistent positive cultures.
This drug is not indicated for the treatment of meningococcal infections or asymptomatic carriers of . to eliminate meningococci from the nasopharynx.
Rifamate (Rifampin,isoniazid) Contraindications
Previous isoniazid-associated hepatic injury; severe adverse reactions to isoniazid, such as drug fever, chills, and arthritis; acute liver disease of any etiology. A history of previous hypersensitivity reaction to any of the rifamycins or to isoniazid, including drug-induced hepatitis.
Rifamate (Rifampin,isoniazid) Warnings
Rifamate (Rifampin,isoniazid) (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 (Rifampin,isoniazid) 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.
Rifamate (Rifampin,isoniazid) Precautions
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 B. Alternative methods must be considered when determining folate and vitamin B 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:
Periodic ophthalmoscopic examination during isoniazid therapy is recommended when visual symptoms occur.
Rifamate (Rifampin,isoniazid) Adverse Reactions
Nervous system reactions:
Gastrointestinal disturbances:
Hepatic reactions:
Renal reactions:
Hematologic reactions:
Allergic and immunological reactions:
Although rifampin has been reported to have an immunosuppressive effect in some animal experiments, available human data indicate that this has no clinical significance.
Metabolic reactions:
Miscellaneous reactions:
The most frequent reactions are those affecting the nervous system and the liver.
Nervous system reactions:
Other neurotoxic effects, which are uncommon with conventional doses, are convulsions, toxic encephalopathy, optic neuritis and atrophy, memory impairment, and toxic psychosis.
Gastrointestinal reactions:
Hepatic reactions:
Hematologic reactions:
Hypersensitivity reactions:
Metabolic and endocrine reactions:
Miscellaneous reactions:
Rifamate (Rifampin,isoniazid) Dosage And Administration
In general, therapy should be continued until bacterial conversion and maximal improvement have occurred.
Adults: Two Rifamate (Rifampin,isoniazid) (rifampin and isoniazid capsules USP) capsules (600 mg rifampin, 300 mg isoniazid) once daily, administered one hour before or two hours after a meal.
Concomitant administration of pyridoxine (B) is recommended in the malnourished, in those predisposed to neuropathy (e.g., diabetic), and in adolescents.
Rifamate (Rifampin,isoniazid) How Supplied
Capsules (opaque red), imprinted "Rifamate (Rifampin,isoniazid) " on both ends of the capsule, containing 300 mg rifampin and 150 mg isoniazid; bottles of 60 (NDC 0068-0509-60).
Storage: Keep tightly closed. Store in a dry place. Avoid excessive heat.
Rifamate (Rifampin,isoniazid)
