Hoechst Marion Roussel
Action And Clinical Pharmacology: Rifampin inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically, it interacts with bacterial RNA polymerase. This is the probable mechanism of action by which rifampin exerts its therapeutic effect.
Pharmacokinetics: Absorption is more rapid when rifampin is administered 1 hour before meals. Peak blood levels in normal adults vary widely from individual to individual. Peak levels occur between 2 and 4 hours following the oral administration of a 600 mg dose with average peak values of 7 to 10 g/mL.
Rifampin is distributed throughout the body and is detectable in many organs and body fluids, including the cerebrospinal fluid. The highest concentrations are present in the liver and bile.
In normal subjects, the biological half-life of rifampin is approximately 3 hours with variations from 1 to 5 hours. Rifampin is eliminated from the blood equally in the urine and feces as unchanged drug and metabolites.
The principal metabolite in man is the biologically active desacetylrifampin. Desacetylation of rifampin in the body does not substantially modify its antimycobacterial activity. In Kirschner’s medium, the MIC against M. tuberculosis varied from 0.1 to 2 g/mL.
Indications And Clinical Uses: As a treatment of tuberculosis.
To achieve a complete kill of the bacillary population and to avoid selection of drug-resistant mutants, rifampin must be used concomitantly with at least one other active antituberculous drug. The selection of the specific drug for partner is determined by the in vitro sensitivity of the causative organisms, comparative safety and effectiveness, the patient’s previous clinical history and the absorption/distribution pattern of the drug.
It is also indicated for the prophylaxis of bacterial meningitis or carriage of N. meningitidis or H. influenza b in persons exposed to a primary case.
Contra-Indications: Jaundice associated with reduced bilirubin excretion. History of previous sensitivity to any of the rifamycins. Premature and newborn infants in whom the liver is not yet capable of functioning with full efficiency. Rifampin passes into the breast milk and therefore should not be used during lactation.
Manufacturers’ Warnings In Clinical States: 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. Periodic liver function monitoring is mandatory.
Periodic blood counts should also be carried out in patients receiving long-term treatment.
Pregnancy: The effect of combinations of rifampin with other antituberculous drugs on the human fetus is not known. No obvious effect on the fetus was detected after the administration of rifampin to 15 pregnant patients. An increase in congenital malformations, primarily spina bifida and cleft palate, has been reported in the offspring of mice and rats given oral doses of rifampin 100 mg/kg/day during pregnancy.
Rifampin should not be used in pregnant women or women with childbearing potential. If rifampin therapy is judged to be essential, such treatment should be implemented only after carefully weighing the potential benefits of therapy against the risks which may be involved. In women with childbearing potential, treatment with rifampin should be undertaken only when the possibility of pregnancy during therapy is judged to be remote.
Precautions: Rifampin increases the requirements for anticoagulant drugs of the coumarin type. This effect is not observed until the fifth day following initiation of treatment. The decrease in prothrombin time usually lasts between 5 and 7 days, and is the result of rifampin’s ability to cause induction of drug metabolizing enzyme systems of the liver. As a result, the rate of metabolism of those drugs which are substrates for these enzymes can be altered, resulting in reduced pharmacological effects of the drugs involved. In patients receiving anticoagulants, it is recommended that daily prothrombin times be performed until the dose of the anticoagulant required has been established.
The intermittent administration of high doses of rifampin >120 mg/dose has been reported to be associated with a hypersensitivity reaction, characterized by fever and myalgia. The incidence of this reaction is greater when rifampin is given on a once-a-week basis than on a twice or thrice weekly basis. It is recommended that when resuming treatment with rifampin after short or prolonged interruptions, it be given in small, gradually increasing doses. During the transitional period, the renal and hemapoietic systems should be closely monitored. The drug should be stopped immediately if renal failure, thrombocytopenia purpura or hemolytic anemia develop and should not be reinstituted.
Safe conditions for the use of ethambutol alone or in combination with rifampin have not been established for children under the age of 13 years. Although renal insufficiency does not alter blood levels of rifampin, marked increases in ethambutol levels are observed under similar conditions; this, therefore, should be taken into consideration in such patients receiving rifampin/ethambutol combination therapy. Caution is recommended when instituting therapeutic regimens in which isoniazid is to be used concurrently with rifampin, in patients with impaired liver function, the elderly and malnourished.
From experimental studies, it would appear that BSP and rifampin compete with one another at the liver cell-bile canaliculus boundary. Clinically, this phenomena can be reflected by spurious BSP levels. It is recommended that the BSP test be carried out at least 5 hours after the last dose of rifampin.
Urine, feces, saliva, sputum, sweat and tears may be colored red-orange by rifampin and its metabolites. Individuals to be treated should be made aware of these possibilities in order to prevent undue anxiety.
Patients should be advised that soft contact lenses may be permanently stained.
It has been reported that oral contraceptives have failed to prevent conception in some patients receiving rifampin in association with other antituberculosis drugs. It is therefore necessary that alternative or additional contraceptive measures be recommended.
Current evidence indicates that administration of rifampin is associated with induction of some drug metabolizing enzyme systems of the liver. As a result, the rate of metabolism of those drugs which are substrates for these enzymes can be altered, resulting in reduced pharmacological effects of the drugs involved. Clinically significant changes have been reported for the oral anticoagulants, hypoglycemic agents, dapsone, digitalis preparations and corticosteroids (as well as for oral contraceptives and ethambutol). Readjustment in the dosage and monitoring of the effects of these drugs may therefore be necessary when they are used concomitantly with rifampin.
Microbiological techniques for assaying the serum concentrations of folic acid and vitamin B12 are not suitable for use during treatment with rifampin.
Upon completion of the treatment with rifampin, a renewed readjustment of the dosage should be made.
Adverse Reactions: Rifampin is usually well tolerated at recommended dosage levels.
Gastrointestinal disturbances such as heartburn, epigastric distress, anorexia, nausea, vomiting, gas, cramps and diarrhea have been noted in some patients. Headache, drowsiness, fatigue, ataxia, dizziness, inability to concentrate, mental confusion, visual disturbances, muscular weakness, fever, pains in extremities and generalized numbness have also been noted. Pruritus, urticaria, skin rashes, eosinophilia, sore mouth, sore tongue, dyspnea and acute renal failure have occasionally been encountered. The following menstrual disturbances: breakthrough bleeding, spotting, amenorrhea, monthly prolongation of both menstrual interval and menses have been reported.
Thrombocytopenia, purpura, leukopenia, hemolytic anaemia and decreased hemoglobin have been observed. Thrombocytopenia has occurred when rifampin and ethambutol were administered concomitantly according to an intermittent dose schedule twice weekly and in high doses. Elevations in BUN and serum uric acid have been reported.
Transient abnormalities in liver function tests (elevations of serum bilirubin, BSP, alkaline phosphatase and serum transaminases) have been observed, particularly during the first few weeks of treatment.
A few cases of jaundice with evidence of hepatocellular damage have been reported in patients receiving rifampin. In some of them it was possible, under careful laboratory control, to resume treatment after an interval without recurrence of abnormalities.
Clinical trials have furnished no evidence to suggest that rifampin has any harmful effects on the cochleovestibular system.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: For acute overdosage, general supportive measures should be employed, along with gastric lavage. No specific antidote is known.
Dosage And Administration: Treatment of tuberculosis: Adults: 600 mg in a single daily dose. Should intolerance occur, the daily dosage may be reduced to 450 mg. In patients with impaired liver function, a daily dose of 8 mg/kg should not be exceeded. A daily dosage of 10 mg/kg is recommended for frail and elderly persons.
Children: 10 to 20 mg/kg not to exceed 600 mg/day. Data is not available for the determination of dosage for children under 5 years of age.
In treatment of pulmonary tuberculosis, rifampin must be used in conjunction with at least one other antituberculous agent. In general, therapy should be continued until bacterial conversion has been established and maximum clinical improvement has occurred.
To ensure optimum absorption, rifampin should be taken on an empty stomach (1 hour before breakfast).
Prophylaxis versus H. influenzae type b: Adults: 600 mg every 24 hours for 4 days. Children (>1 month): 20 mg/kg (up to 600 mg) every 24 hours for 4 days. Neonates
Prophylaxis versus N. meningitidis: Adults: 600 mg every 12 hours for 2 days. Children (>1 month): 10 mg/kg (up to 600 mg) every 12 hours for 2 days. Neonates
Availability And Storage: 150 mg: Each maroon, opaque capsule contains: rifampin 150 mg. Nonmedicinal ingredients: cornstarch, D&C Red No. 28, FD&C Blue No. 1, FD&C Red No. 40, gelatin, magnesium stearate, talc and titanium dioxide. Tartrazine-free. Bottles of 100.
300 mg: Each maroon and scarlet, opaque capsule contains: rifampin 300 mg. Nonmedicinal ingredients: cornstarch, D&C Red No. 28, FD&C Blue No. 1, FD&C Red No. 40, gelatin, magnesium stearate, talc and titanium dioxide. Tartrazine-free. Bottles of 100.
RIFADIN® Hoechst Marion Roussel Rifampin Antituberculous Antibiotic