Rifampin 300 mg

Rifampin is a known inducer of cytochrome P450 isoenzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. As a consequence, the rate of metabolism of numerous drugs can be accelerated, which can result in reduced pharmacologic effects of the drugs involved or toxicity when rifampin is discontinued. Adjustments in the dose and monitoring of the effects of these drugs is necessary when they are 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 This is particularly important when rifampin administration is either initiated or withdrawn.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. See Table 1.

Cross-reactivity and false positive results may occur with urine screening tests for opiates that use Kinetic Interaction of Microparticles in Solution (KIMS) methods when the patient tested is taking rifampin. If opiate abuse is suspected, the results should be confirmed by other diagnostic tests (e.g., gas chromatography/mass spectrometry).

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.

Acute tubular necrosis, renal insufficiency, interstitial nephritis, increased blood urea nitrogen and serum uric acid concentrations, light chain proteinuria, hematuria, and acute renal failure have occurred infrequently with rifampin.

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.

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 1200 mg twice weekly) or resumption of treatment after termination of a course of long-term therapy (see Precautions). True hypersensitivity reactions are rare (may occur in 0.07-0.3% of patients) [American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Resp Crit Care Med 2003;167(4):603-62].

Immunologic reactions such as thrombocytopenia, hemolytic anemia, acute renal failure and thrombotic thrombocytopenia purpura have been reported.

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.

headache, drowsiness, fatigue, ataxia, dizziness, inability to concentrate, mental confusion, visual disturbances.

All secretions (sweat, urine, sputum, tears) may be colored reddish orange by rifampin and its metabolites (see Precautions).

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.

A few patients receiving rifampin experienced a drug-induced lupus-like syndrome consisting principally of malaise, myalgias, arthritis, and peripheral edema and accompanied by positive antinuclear antibody test results.

Monitor for signs and symptoms of immune reconstitution inflammatory syndrome (fever, malaise, local reactions in organs) during tuberculosis therapy after initiation of antiretroviral therapy in patients co-infected with HIV [Canadian tuberculosis standards. 6^th ed. http://www.phac-aspc.gc.ca/tbpc-latb/pubs/pdf/tbstand07_e.pdf].

Pruritus, urticaria, skin rashes have occasionally been encountered.

Transient elevations of serum bilirubin and alkaline phosphatase have been observed. Severe cholestatic hepatitis is rare. 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).

Older patients receiving multiple medications may be at an increased risk for drug-drug interactions due to the ability of rifampin to induce hepatic microsomal enzymes. The effectiveness of medications may be compromised with concomitant rifampin.

General management of acute overdose of rifampin includes supportive measures. Closely observe vital signs. Single-dose activated charcoal may be administered soon after ingestion to reduce further absorption. Severe nausea and vomiting can be relieved by the administration of antiemetic medication.

Common side effects of acute overdose of rifampin include gastrointestinal symptoms, e.g., epigastric pain, nausea, vomiting and diarrhea. Other side effects include flushing, angioedema and obtundation. Anterior uveitis and neurologic effects consisting of generalized numbness, extremity pain, ataxia and muscular weakness are occasionally observed. Children who have received an overdose of rifampin have developed facial or periorbital edema. Brownish-red or orange discoloration of the skin, urine, sweat, saliva, tears, and feces is proportional to amount ingested.

Following a massive overdose 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 such as patients with chronic liver disease, and in the elderly.

Urine, feces, saliva, sputum, sweat and tears may be colored reddish orange by rifampin and its metabolites but this is not harmful to the patient. To prevent undue anxiety, patients should be made aware of this possibility (see Adverse Reactions).

Soft contact lenses should not be worn during rifampin therapy and for several days after completing 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 (e.g., Guidelines for control of meningococcal disease. Can Commun Dis Rep 2005;31S1:1-20 at http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/05pdf/31s1_e.pdf) for further recommendations on which contacts should receive prophylaxis.

Daily treatment with rifampin is often better tolerated than intermittent therapy, since rare hypersensitivity reactions are more likely to occur during intermittent therapy. 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 this 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 and Administration). 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.

The 2-month regimen of rifampin and pyrazinamide for the treatment of latent tuberculosis infection is associated with increased risk of severe liver injury and death. As a result, the IDSA and CDC now recommend that this regimen not be offered as first-line therapy to persons with latent tuberculosis infection. If this regimen is to be used, a TB expert should be consulted.

Baseline measurements of bilirubin, hepatic enzymes, serum creatinine and a complete blood count are recommended for adults treated for tuberculosis with rifampin. Routine laboratory monitoring for toxicity in people with normal baseline results is generally not necessary. Baseline testing is generally not necessary for children unless a complicating condition is known or clinically suspected.

All patients, including children, should be clinically evaluated for adverse reactions at least monthly during therapy. Patients should also be instructed to report signs of adverse reactions such as hepatitis immediately (e.g., fatigue, weakness, malaise, anorexia, nausea or vomiting, dark urine, yellowing of the skin).

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

Rifampin has been shown to produce liver dysfunction. There have been fatalities associated with jaundice in patients with preexisting liver disease or in patients receiving rifampin in combination with other hepatotoxic agents. Therefore, the benefits must be weighed carefully against the risk in individuals with impaired liver function. Perform serum aminotransferases levels in these patients at baseline and every 2 to 4 weeks while on therapy. Monitor clinical symptoms of gastrointestinal toxicity (e.g., nausea, vomiting) and hypersensitivity reactions (e.g., fever, rash). Monitor clinical status and appropriate levels of interacting drugs, if possible. Monitor platelet count if indicated.

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 antituberculosis drugs on the human fetus is not known, the drug has been used in combination with isoniazid and/or ethambutol to treat active tuberculosis disease in pregnant women. The Canadian Thoracic Society (CTS), the American Thoracic Society (ATS), the US Centers for Disease Control and Prevention (CDC) and the Infectious Diseases Society of America (IDSA) consider rifampin to be safe for use in 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 K₁ 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.

Rifampin transfers into breast milk in limited amounts and is thought to represent a low risk to the nursing infant. Rifampin is compatible with breast-feeding according to the American Academy of Pediatrics.

Rifampin is readily absorbed and peak plasma concentrations are reached between 2 and 4 hours following a single oral administration of a 600 mg dose. Absorption of rifampin can be reduced by up to 30% if the drug is taken after food (see Dosage and Administration) and is delayed.

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 (CSF concentrations are reported to be 10 to 20% of plasma rifampin concentrations). 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 and Precautions, Special Populations, Nursing Women).

The half-life of rifampin is initially 2 to 5 hours, but because of enhanced biliary excretion, it decreases by 40% during the first two weeks of therapy. 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 undergoes enterohepatic circulation, but the metabolite does not. 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 doses. From 6 to 30% of a dose is excreted in the urine. Hemodialysis and peritoneal dialysis do not significantly reduce plasma concentrations of rifampin.