Rifampin ()

RIFAMPIN

General Monograph, Antibiotic

Pharmacology: Rifampin is a semisynthetic derivative of rifamycin B, an antibiotic produced by Streptomyces mediterranei. Rifampin is active against microorganisms of the genus Mycobacterium, including M. tuberculosis, M. kansasii, M. marinum, M. avium-intracellulare (M. avium complex) and M. leprae. Rifampin is also active against some gram-negative bacteria including N. meningitidis and H. influenzae type b, in addition to some gram-positive bacteria including S. aureus and S. epidermidis. Because of rapid emergence of resistant strains, it is generally recommended that rifampin be used in combination with other antibacterial agents.

Rifampin inhibits DNA-dependent RNA poymerase which leads to suppression of RNA synthesis in susceptible bacteria. The site of action appears to be the b subunit of the enzyme.

Rifampin may be bacteriostatic or bactericidal, depending on the concentration of the drug and the relative susceptibility of the organism. Rifampin is most effective when cell division is occurring.

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: Rifampin is readily absorbed and peak blood concentrations are reached between 2 and 4 hours following the oral administration of a 600 mg dose. Absorption of rifampin tends to be delayed if the drug is taken after food (see Dosage).

Rifampin is distributed throughout the body and is detectable in many organs and body fluids, including the cerebrospinal fluid, where concentrations are increased if the meninges are inflamed. High concentrations are found in the liver, bile and urine. Approximately 80% of rifampin in the serum is bound to protein. Rifampin crosses the placenta and is excreted in breast milk (see Warnings).

In normal subjects the serum half-life of rifampin is approximately 3 hours, with variations from 1 to 5 hours. Neither the peak concentration nor the half-life of rifampin is significantly altered in patients with impaired or absent renal function; these parameters are, however, increased in patients with impaired liver function or bile flow obstruction.

The principal metabolite of rifampin is desacetylated rifampin. To a large extent, desacetylated rifampin retains the antimycobacterial properties of rifampin, and is detectable in the blood, bile and urine following an oral dose of rifampin. Rifampin and its metabolite are excreted principally by the liver into the bile; however, the maximum excretory capacity of the liver is surpassed at doses larger than 5 mg/kg. In contrast, the amount of rifampin excreted by the kidney in the urine is proportional to the concentration of the drug in the blood and high urinary concentrations result with recommended dosages.

Indications: Active tuberculosis, whether it is in the primary or chronic phase. To prevent or delay the emergence of drug resistance, rifampin must be used in combination with at least one other effective antitubercular drug. Choice of appropriate drug combinations should be based on in vitro sensitivity studies, comparative safety as well as the patient’s previous clinical history.

Rifampin is sometimes used in multiple-drug regimens for the treatment of infections caused by M. avium complex, M. kansasii, M. marinum, M. leprae (leprosy), L. pneumophila (Legionnaires’ disease) and some gram-negative and gram-positive bacteria.

Rifampin is used for prophylaxis of selected individuals exposed to persons with invasive disease due to N. meningitidis and H. influenzae type b.

Contraindications: Jaundice. Hypersensitivity to rifamycins. Premature and newborn infants in whom liver function is not yet mature.

Warnings: Rifampin has been shown to produce hepatic dysfunction. There have been fatalities associated with jaundice in patients with pre-existing liver disease or in patients receiving rifampin in combination with other hepatotoxic agents. Predisposing factors include chronic liver disease and alcoholism. Therefore, the benefits must be weighed carefully against the risk in individuals with impaired liver function. It is essential that liver function be regularly assessed in patients with impaired liver function.

Pregnancy: Rifampin crosses the placenta. Reproductive and fetal toxicity studies in rats and mice with rifampin alone have indicated teratogenic effects, most commonly spina bifida and cleft palate, at doses of 100 mg/kg and above. Although the effect of rifampin alone or in combination with other antitubercular drugs on the human fetus is not known, the drug has been used (combined with isoniazid and/or ethambutol) to treat clinical tuberculosis in pregnant women.

Generally, rifampin should not be used in pregnant women. However, 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, particularly during the first 3 months of pregnancy. In women with childbearing potential, treatment with rifampin should be undertaken only when the possibility of pregnancy during therapy is judged to be remote. Oral contraceptive therapy has failed at times and alternative or additional contraceptive measures are essential in women who are receiving rifampin.

When administered during the last few weeks of pregnancy, rifampin has been shown to cause postnatal hemorrhage in the mother and infant; therefore, vitamin K should be given during labor to mothers receiving rifampin and to their offspring immediately after birth. In the newborn, careful surveillance for bleeding symptoms and decrease of coagulation factors is mandatory.

Lactation: Rifampin transfers into breast milk in limited amounts and is thought to represent a low risk to the nursing infant.

Precautions: Urine, feces, saliva, sputum, sweat and tears may be colored reddish orange by rifampin and its metabolites. To prevent undue anxiety, patients should be made aware of this possibility.

Soft contact lenses should not be worn during rifampin therapy as they may become permanently stained.

For prophylaxis of individuals exposed to persons with invasive disease due to N. meningitidis and H. influenzae type b, rifampin should be given only to selected individuals. Contact the local public health unit or refer to specific guidelines (i.e., Guidelines for control of meningococcal disease, Canada Communicable Disease Report 1994; 20:17-27) for further recommendations on which contacts should receive prophylaxis.

Daily treatment with rifampin is often better tolerated than intermittent therapy, since rare hypersensitivity reactions may occur. Resumption of treatment after termination of a course of long-term therapy with the drug involves risks and therefore, should if possible, be avoided. If intermittent administration is unavoidable, the risk of adverse reactions may be minimized if the drug-free interval or rest period is less than or closely resembles the interval of the previous drug treatment period. When resuming treatment with rifampin, the drug should be reintroduced gradually, beginning with a daily dose of 75 mg and increasing the dose by 75 mg daily until the required dosage is reached (see Dosage). During the transitional period, renal and hepatic function should be closely monitored. Corticosteroids may be useful in preventing adverse reactions since antigen-antibody complexes are suspected causes. If, as may happen in exceptional cases, the patient develops thrombocytopenia, purpura, hemolytic anemia or renal failure, treatment should be stopped at once and not reinstituted at a later date.

Rifampin should be used with caution in patients with porphyria as it could induce delta-aminolaevulinic acid synthetase activity.

Drug Interactions : Since the chemotherapy of tuberculosis involves the use of at least two drugs, the possible adverse reactions of each drug should be borne in mind, as well as the interactions that may occur. 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 in malnourished patients.

Rifampin is a potent inducer of hepatic drug metabolism (cytochrome P-450). As a consequence, the rate of metabolism of numerous drugs can be accelerated, which can result in reduced pharmacological effects of the drugs involved or toxicity when rifampin is discontinued. Adjustments in the dosage and monitoring of the effects of these drugs is therefore necessary when used concomitantly with rifampin. This is particularly important when rifampin administration is either initiated or withdrawn. The effect on enzyme induction may develop gradually over several days after starting rifampin and may take even longer to dissipate after withdrawal of rifampin.

Interactions of significance involving enzyme induction include: Anticoagulants, Oral: Reduced hypothrombinemic effect may occur. Avoid rifampin in patients on warfarin if possible. If rifampin is used, monitor INR or PT closely and adjust warfarin dose accordingly.

Antihyperglycemics: Reduced antihyperglycemic response may occur.

Calcium Channel Blockers: Rifampin reduces the bioavailability and protein binding of verapamil and induces the metabolism of diltiazem, nifedipine and verapamil, possibly resulting in loss of efficacy.

Clarithromycin: Rifampin reduces the serum levels of clarithromycin.

Corticosteroids: There may be exacerbation of the disease for which steroids are being administered (e.g., Addison’s disease, allograft failure, asthma).

Cyclosporine: Possible loss of therapeutic effect (e.g., graft-versus-host disease or graft rejection). Monitor cyclosporine concentration carefully and adjust dose accordingly.

Fluconazole: Concomitant administration of fluconazole and rifampin resulted in a 25% decrease in AUC and a 20% shorter half-life of fluconazole. The dosage of fluconazole should be increased by 25% when fluconazole is administered with rifampin.

Isoniazid: Hepatotoxicity has been reported to occur more frequently when rifampin and isoniazid are given concurrently. The incidence may be higher in slow isoniazid acetylators, those receiving high doses of isoniazid, prior general anesthesia and those with pre-existing liver disease.

Ketoconazole: In addition to enhanced metabolism of ketoconazole, rifampin concentrations may be reduced when concurrently administered with ketoconazole as a result of decreased rifampin absorption. Separate rifampin and ketoconazole doses by 12 hours.

Oral Contraceptives and Estrogens: Unplanned pregnancies and menstrual irregularities may occur. The effect of oral contraceptives can no longer be relied upon and it is necessary that alternative or additional contraceptive measures be used.

Other Agents: beta-blockers, chloramphenicol, cyclic antidepressants, diazepam, digoxin, disopyramide, itraconazole, methadone, mexiletine, phenytoin, propafenone, quinidine, theophyllines, tocainide and zidovudine.

Adverse Effects: CNS: headache, drowsiness, fatigue, ataxia, dizziness, inability to concentrate, mental confusion, visual disturbances.

Dermatological: Pruritus, urticaria, skin rashes, have occasionally been encountered.

Gastrointestinal: Sore mouth, sore tongue, dyspepsia, epigastric distress, anorexia, nausea, vomiting, gas, cramps and diarrhea have been noted. Isolated cases of pseudomembranous colitis have been reported.

Hematologic: Thrombocytopenia, eosinophilia, hemolytic anemia, purpura, transient leukopenia 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.

Hepatic: Transient abnormalities in liver function tests (elevations of serum bilirubin, alkaline phosphatase and serum aminotransferases) have been observed. In isolated cases, induction of porphyria has been noted.

A few cases of jaundice with evidence of hepatocellular damage have been reported in patients receiving rifampin. In some of them it was possible to resume rifampin treatment without recurrence of abnormalities. However, hepatitis and fatalities associated with jaundice have also been reported (see Warnings).

Hypersensitivity: Hypersensitivity reactions, especially a flu-like syndrome (fever, chills, dizziness, pain in extremities, dyspnea), have been noted. Hematuria, renal insufficiency and acute renal failure have also occurred infrequently. These hypersensitivity reactions are usually associated with high-dose intermittent rifampin therapy (900 to 1 200 mg twice weekly) or resumption of treatment after termination of a course of long-term therapy (see Precautions).

Miscellaneous: Disturbances of menstruation including breakthrough bleeding, spotting, amenorrhea, and prolongation of both the menstrual interval and menses have been reported in women taking rifampin either alone or in conjunction with oral contraceptives. Elevations in serum urea and serum uric acid have been reported.

Overdose: Symptoms: Overdosage of rifampin produces symptoms that are principally extensions of common side effects. These include nausea, vomiting, lethargy. Brownish-red or orange discoloration of the skin, urine, sweat, saliva, tears, and feces is proportional to amount ingested.

Following massive overdosage of rifampin, liver involvement, manifested by enlargement (possibly with tenderness), jaundice and increased bilirubin levels and liver enzymes, can develop within a few hours. Hepatotoxicity may be more marked in patients with prior hepatic impairment.

Treatment: For acute overdosage, general supportive measures should be employed. Empty the stomach using ipecac syrup or gastric lavage. Activated charcoal may be administered to reduce further absorption.

Dosage: To ensure optimal absorption, rifampin should be taken on an empty stomach (1 hour before a meal). Should gastric intolerance occur, the daily dosage may be taken after meals and/or reduced.

M. tuberculosis (in combination with at least one other antituberculosis agent): Adults: 10 mg/kg once daily, to a maximum of 600 mg. Children: 10 to 20 mg/kg once daily, to a maximum of 600 mg. The duration of therapy for uncomplicated pulmonary or extrapulmonary tuberculosis should be a minimum of 6 months.

Prophylaxis of N. meningitidis: Adults: 600 mg every 12 hours for 2 days. Children: ³1 month: 10 mg/kg (maximum 600 mg) every 12 hours for 2 days;
Prophylaxis of H. influenzae Type b: Adults: 600 mg every 24 hours for 4 days. Children: >1 month: 20 mg/kg (max 600 mg) every 24 hours for 4 days; 1 month or less: 10 mg/kg every 24 hours for 4 days.

M. avium complex: In combination with other agents, the adult dose is 600 mg daily until culture-negative for 1 year.

M. kansasii: In combination with other agents, the adult dose is 600 mg daily until culture-negative for 1 year.

M. leprae (leprosy): In combination with dapsone, the adult dose is 600 mg once monthly for at least 6 months.

M. marinum: In combination with ethambutal, the adult dose is 600 mg daily for at least 3 months.

Prosthetic Valve Endocarditis caused by S. aureus or S. epidermidis: In combination with other agents, the adult dose is 300 mg every 8 hours for 14 days.

RIFAMPIN General Monograph, Antibiotic

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