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: 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. The average peak value is 7 g/mL.
In one study, cumulation was noted upon multiple dosage of rifampin, 10 mg/kg/day, to newborns. Peak values appeared to be delayed in the newborns which were not seen in children up to 18 months of age. It is suggested that the drug is less readily eliminated from the newborn, probably because of the low flow of bile during the first days of life. In all of these children and infants the mean serum level of rifampin corresponded to one third to one tenth the levels in adults receiving proportionally the same dose.
Absorption is more rapid when rifampin is administered 1 hour before meals.
Distribution: 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.
The apparent volume of distribution is 1.6 L/kg in adults and 1.1 L/kg in children. Binding to serum proteins amounts to 84 to 91%.
Rifampin crosses the blood brain barrier in the case of inflamed meninges only, but concentrations in the cerebrospinal fluid may remain above the MIC for M. tuberculosis for up to 2 months with continuous therapy of 600 mg/day orally.
Rifampin crosses the human placenta and is secreted in human breast milk. However, a breast fed infant would not receive more than 1% of the usual therapeutic dose.
Biological Half-life: In normal subjects the biological half-life of rifampin is approximately 3 hours with variations from 1 to 5 hours. Biliary obstruction causes a longer half-life but kidney blockage does not appear to cause a change.
Excretion: Rifampin is eliminated from the blood equally in the urine and feces as unchanged drug and metabolites. Approximately half of the original dose eliminated by the bile is unchanged drug. The proportion of unchanged drug to metabolite is less in the urine than in the bile. In the presence of complete renal shutdown, the drug is excreted entirely in the bile.
The principal metabolite in man is the biologically active desacetyl-rifampin. Its excretion appears to be a dynamically changing picture at all times.
Desacetylation of rifampin in the body does not substantially modify its antimycobacterial activity.
Indications And Clinical Uses: Active pulmonary tuberculosis, whether it is in the primary or chronic phase.
Contra-Indications: Jaundice associated with reduced bilirubin excretion. Known or suspected sensitivity to any of the rifamycins or their excipients.
Premature and newborn infants in whom the liver is not yet capable of functioning with full efficiency.
Lactation: Rifampin passes into 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 the drug 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. If such treatment is necessary, the dosage must be reduced so that 6 to 8 mg/kg body weight is not exceeded. 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 100 mg/kg/day during pregnancy.
Rifampin should not be used in pregnant women or women with childbearing potential. If therapy is judged to be essential, such treatment should be implemented only after carefully weighing the potential benefits of therapy against the risks, particularly if used during the first 3 months of pregnancy.
The possibility of pregnancy should be ruled out prior to treatment with rifampin; patients should be advised to avoid pregnancy.
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.
Precautions: To delay the emergence of drug resistance, which can be a serious problem, rifampin must be used concomitantly with at least one other antituberculous drug. The selection of the specific drug for concurrent therapy is determined by the in vitro sensitivity tests on the organisms and the patient’s previous clinical history.
The possibility of a drug interaction, as well as the individual properties and special precautions relating to drugs used in concomitant therapy should be taken into consideration. For example, when rifampin is prescribed in addition to PAS preparations containing bentonite (aluminum hydrosilicate, closely related to kaolin), absorption of rifampin can be impaired; therefore, rifampin should be taken first, followed by the bentonite-containing preparation after an interval of 8 to 12 hours. Similarly, a reduction in the bioavailability of rifampin after oral dosing has been observed when given concomitantly with opiates and anticholinergic drugs. To avoid this interaction, rifampin should be taken a few hours before these preparations.
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 unavoidable, possible 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 re-introduced gradually, beginning with a daily dose of 75 mg and increasing the dose by 75 to 150 mg on the first day. The desired therapeutic dose should be reached within 3 to 4 days. During the transitional period, renal function should be closely monitored. Corticosteroids may be useful in attenuating possible immunological reactions. 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 re-instituted at a later date.
Rifampin has been observed to increase the requirements for anticoagulant drugs of the coumarin type. This effect was not observed until the fifth day following the initiation of treatment. The decrease in prothrombin time lasts 5 to 7 days on the average. The cause of this phenomenon is unknown. In patients receiving anticoagulants it is recommended that daily prothrombin times be performed until the dose of the anticoagulant required has been established.
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 bromsulphalein (BSP) and rifampin compete with one another at the liver cell-bile canaliculus boundary. In clinical studies, BSP elevation was reported following rifampin administration. Therefore, the rationale of using the BSP as a test of liver function during therapy is nullified.
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.
Drug Interactions: Current evidence indicates that administration of rifampin may be associated with 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. The activity of the following drugs may be impaired, and their dosage must therefore be re-assessed during and after treatment with rifampin: oral anticoagulants; oral antidiabetic agents; digitalis preparations; antiarrhythmic agents; tocainide; propafenone; quinidine; mexiletine; methadone (withdrawal signs may set in); hydantoins (phenytoin, ethotoin); hexobarbital; nortriptyline; benzodiazepines; corticosteroids (Addison patients may develop a crisis; exacerbation of pemphigus may occur; treatment for corticoid-dependent asthma may become more difficult or impossible); sex hormones (menstrual disorders may appear); oral contraceptives (their effect can no longer be relied upon); theophyllines (aminophylline, theophylline); dapsone; chloramphenicol; azole antifungal agents (ketoconazole, itraconazole); cyclosporin A; azathioprine (transplants may be rejected); b-blockers; nifedipine; verapamil; enalapril; cimetidine.
Rifampin should be used with caution in patients with porphyria as it could induce delta-aminolaevulinic acid synthetase activity.
Microbiological techniques for assaying the serum concentrations of folic acid and vitamin B12 are not suitable for use during treatment with rifampin.
Rifampin causes temporary competitive inhibition of bromosulphalein excretion. To guard against false positive results, the bromosulphalein test should be performed in the morning before administration of rifampin.
Adverse Reactions: Rifampin is usually well tolerated at recommended dosage levels. The adverse reactions are stated in terms of occurrence rate: frequent (>10%), occasional (>1% and 0.001% and
Gastrointestinal: Occasionally anorexia, nausea, abdominal pains, gaseous distension; rarely vomiting or diarrhea; isolated cases of erosive gastritis and pseudomembranous colitis.
CNS: Occasionally tiredness, drowsiness, headache, lightheadedness, dizziness; rarely ataxia, mental confusion; isolated cases of muscular weakness and visual disturbances. Clinical trials have furnished no evidence to suggest that rifampin has any harmful effects on the cochleovestibular system.
Skin and Appendages: Occasionally flushing, itching with or without skin rash, urticaria and reddening of the eyes; isolated cases of severe signs and symptoms such as exudative conjunctivitis or generalized hypersensitivity reactions involving the skin (e.g. exfoliative dermatitis, Lyell’s syndrome) and pemphigoid reactions.
Endocrine: In rare instances disturbances in the menstrual cycle; induction of a crisis in Addison patients (see Precautions, Drug Interactions).
Hematologic: Eosinophilia, thrombocytopenia, purpura, transient leukopenia, hemolytic anemia 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.
Thrombocytopenia and thrombocytopenic purpura are encountered more frequently under intermittent therapy than on continuous daily treatment, during which they occur only in isolated cases.
Hepatic: Frequently an asymptomatic increase in liver enzymes; rarely hepatitis or jaundice; here account must be noted of the liver toxicity of chemotherapeutic agents (e.g. isoniazid or pyrazinamide) employed in combination with rifampin. Induction of porphyria in isolated cases has been reported.
Unwanted effects chiefly occurring during intermittent therapy or upon resumption of treatment after temporary interruption: In patients taking rifampin other than on a daily basis or in those resuming treatment with the drug after a temporary interruption, an influenza-like syndrome (“flu syndrome”) may occur, this being very probably of immunopathological origin. It is characterized by fever, shivering and possibly headache, dizziness and musculoskeletal pain. In rare cases the “flu-syndrome” may be followed by thrombocytopenia, purpura, dyspnea, asthma-like attacks, hemolytic anemia, shock and acute renal failure. These serious complications may, however, also set in suddenly with no preceding “flu syndrome”, chiefly when treatment is resumed after a temporary interruption or when rifampin is given only once a week in high doses (25 mg/kg or more). When rifampin is administered in lower doses (600 mg) 2 to 3 times a week, the syndrome is only rarely encountered, its incidence then being comparable to that observed during daily medication.
Symptoms And Treatment Of Overdose: For acute overdosage, general supportive measures should be employed, along with gastric lavage. No specific antidote is known.Symptoms: Reddish-brown or orange discoloration of the skin, sputum, lacrimal fluid, sweat, feces (“red man syndrome”); nausea, vomiting, abdominal pains; enlargement of the liver, jaundice, elevated liver enzyme levels; possibly acute pulmonary edema, lethargy, clouding consciousness, convulsions. tag_Treatment
Treatment: Gastric lavage together with instillation of an activated charcoal suspension via the stomach tube; general supportive measures to maintain vital functions; forced diuresis; hemodialysis; in the presence of severe liver damage, cholecystostomy if necessary. Bear in mind that other drugs used in combination with rifampin may also have been taken in an over dosage and necessitate additional specific measures.
Dosage And Administration: 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 antituberculosis agent, each prescribed in its usual dosage. 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).
When administering combined treatment with isoniazid, one should not exceed the dosage recommended for the latter.
Availability And Storage: Each opaque, brownish-red, hard gelatin capsule containing an orange to reddish-brown powder, branded in black ink “CG” and the identification code letters “CS” (or “300”) contains: rifampin 300 mg. Nonmedicinal ingredients: calcium stearate, gelatin, iron oxides and titanium dioxide. Energy: 0.8 kJ (0.2 kcal). Bottles of 100. Protect from heat (store at 2 to 30°C), light and humidity. Keep out of reach of children. (Shown in Product Recognition Section)
RIMACTANE® Novartis Pharmaceuticals Rifampin Antituberculous Antibiotic
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