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Rifampin

Rifampin is a rifamycin B-derivative antibiotic that is active against mycobacteria and some gram-positive and -negative bacteria.

Drug Interactions

Antiretroviral Agents

Rifamycin derivatives (e.g., rifampin, rifabutin) can accelerate the metabolism of certain antiretroviral agents (i.e., HIV protease inhibitors, nonnucleoside reverse transcriptase inhibitors [NNRTIs]) by induction of cytochrome P-450 (CYP) oxidases, which may result in subtherapeutic plasma concentrations of some of these protease inhibitors and NNRTIs. 194 Rifampin also can affect the pharmacokinetics of some nucleoside reverse transcriptase inhibitors (e.g., zidovudine).

In addition, HIV protease inhibitors and some NNRTIs (e.g., delavirdine) reduce the metabolism of rifamycins, leading to increased plasma concentrations of rifamycins and an increased risk of toxicity. The potential for alterations in the plasma concentrations of antimycobacterial agent(s) and/or antiretroviral agent(s) must be considered when antimycobacterial agents are indicated for the management of latent or active tuberculosis or the prophylaxis or treatment of Mycobacterium avium complex (MAC) infections in HIV-infected patients who are receiving or are being considered for antiretroviral therapy.

Because the management of these patients is complex and must be individualized, experts in the management of mycobacterial infections in HIV-infected patients should be consulted.

HIV Protease Inhibitors

Because rifampin is a potent inducer of the CYP3A4 isoenzyme and can markedly reduce plasma concentrations of amprenavir, atazanavir, indinavir, lopinavir, or nelfinavir, concomitant use of rifampin and these HIV protease inhibitors is contraindicated.

Because concomitant use of rifampin and ritonavir results in decreased ritonavir concentrations, the manufacturer of ritonavir suggests that other antimycobacterial agents (e.g., rifabutin) be used instead of rifampin in patients receiving ritonavir.

Although pharmacokinetic data and clinical experience are limited, some experts state that concomitant use of ritonavir (with or without saquinavir) and usual dosages of rifampin for the treatment of tuberculosis (600 mg daily or 2 or 3 times weekly) is a possibility. These experts state that rifampin can be used for the treatment of active tuberculosis in patients receiving an antiretroviral regimen that includes ritonavir and one or more nucleoside reverse transcriptase inhibitors.

Because rifampin can markedly reduce plasma concentrations of saquinavir, the manufacturer of saquinavir and some experts state that rifampin should not be used in patients receiving saquinavir hard gelatin (Invirase®) or liquid-filled (soft gelatin) capsules (Fortovase®).

Although pharmacokinetic data and clinical experience with the combination are limited, some experts state that concomitant use of saquinavir hard gelatin or liquid-filled capsules with usual dosages of rifampin for the treatment of tuberculosis (600 mg daily or 2 or 3 times weekly) is a possibility, provided the antiretroviral regimen also includes ritonavir. These experts state that rifampin can be used for the treatment of active tuberculosis in patients receiving an antiretroviral regimen that includes both saquinavir and ritonavir. For specific information on the pharmacokinetic interactions between HIV protease inhibitors and rifampin, see Antimycobacterial Agents under Drug Interactions: Anti-infective Agents, in the individual monographs in 8:18.08.08.

Nonnucleoside Reverse Transcriptase Inhibitors

Concomitant use of rifampin and delavirdine results in a substantial decrease in concentrations of the nonnucleoside reverse transcriptase inhibitor. Because of this pharmacokinetic interaction, concomitant use of rifampin and delavirdine is contraindicated. Concomitant use of efavirenz and rifampin can result in decreased plasma concentrations and area under the plasma concentration-time curve (AUC) of the nonnucleoside reverse transcriptase inhibitor. The manufacturer of efavirenz states that the clinical importance of this pharmacokinetic interaction is unknown.

Although there is no published clinical experience, some experts state that rifampin can be used for the treatment of active tuberculosis in patients receiving an antiretroviral regimen that includes efavirenz and 2 nucleoside reverse transcriptase inhibitors without a modification of rifampin dosage; however, other experts recommend that consideration be given to increasing efavirenz dosage to 800 mg once daily when the drug is used in patients receiving rifampin.

Concomitant use of nevirapine and rifampin results in a substantial decrease in peak plasma concentrations and AUC of nevirapine, and the manufacturer of the nonnucleoside reverse transcriptase inhibitor and some experts state that the drugs should not be used concomitantly. Some experts state that data are insufficient to date to assess whether dosage adjustments are necessary when rifampin is used concomitantly with nevirapine, and that the drugs should be used concomitantly only when clearly indicated and only with careful monitoring.

Nucleoside Reverse Transcriptase Inhibitors

In a multiple-dose study in HIV-infected patients, concomitant use of zidovudine (200 mg every 8 hours) and rifampin (600 mg once daily) given for 14 days resulted in a 43% decrease in peak plasma concentrations of zidovudine, a 47% decrease in the AUC, and a 13% decrease in the plasma half-life of the antiretroviral agent.

Drugs Undergoing Hepatic Metabolism

Rifampin induces certain cytochrome P-450 liver enzymes responsible for the metabolism of a number of drugs. Concurrent administration of rifampin and any of the following drugs may result in decreased plasma concentrations of the drugs; dosage adjustments may be required and, in some cases, concomitant use is contraindicated.

Rifampin

Anticoagulants

In patients receiving rifampin and oral anticoagulants concurrently, prothrombin times should be performed daily or as frequently as necessary to establish and maintain the required anticoagulant dosage.

Antifungal Agents

Concomitant use of rifampin and itraconazole may lead to decreased serum concentrations of itraconazole. In at least one patient receiving both rifampin and itraconazole, serum concentrations of the antifungal agent were undetectable. It has been recommended that rifampin and itraconazole not be used concomitantly.

Concomitant use of rifampin and ketoconazole also has resulted in decreased serum concentrations of ketoconazole, and the manufacturer of ketoconazole recommends that the drugs not be used concomitantly. In one patient receiving ketoconazole concomitantly with rifampin and isoniazid, serum concentrations of both rifampin and ketoconazole were decreased. Although administration of ketoconazole 12 hours after the rifampin dose resulted in therapeutic serum concentrations of rifampin, serum concentrations of ketoconazole were subtherapeutic regardless of when the doses were given. In addition, isoniazid and rifampin appeared to have an additive effect in reducing serum ketoconazole concentrations.

Immunosuppressants

Concomitant use of rifampin in transplant recipients (e.g., kidney, heart) who were receiving an immunosuppressive regimen that included cyclosporine has resulted in decreased serum concentrations of cyclosporine. If rifampin is used in transplant recipients or other individuals receiving cyclosporine, serum concentrations of the immunosuppressant should be monitored closely and appropriate dosage modifications made. Some clinicians suggest that rifampin should not be used in patients receiving cyclosporine. Concomitant use of rifampin in a renal transplant recipient receiving tacrolimus has resulted in substantially decreased tacrolimus concentrations.

Oral Contraceptives

When administered concurrently with oral contraceptives containing estrogen, rifampin has decreased the effectiveness of the contraceptives and has caused a high incidence of menstrual disorders (e.g., spotting, breakthrough bleeding); patients should be advised that the reliability of oral contraceptives may be affected by rifampin and an alternative form of contraception should be considered in patients receiving the drug.

Verapamil

Marked (e.g., greater than 90%) reductions in bioavailability and peak serum concentrations of verapamil, accompanied by diminution or elimination of the drug’s electrocardiographic and therapeutic effects, have occurred after concurrent administration of rifampin and oral but not IV verapamil; alternatives to rifampin should be considered in patients in whom oral verapamil therapy is deemed essential.

Aminosalicylic Acid

Certain aminosalicylic acid preparations may impair GI absorption of rifampin, resulting in decreased serum concentrations of the drug. This effect appears to result from bentonite, an excipient used in preparations of aminosalicylic acid granules (not commercially available in the US).

Antacids

Results of a pharmacokinetic study in healthy, fasting adults indicate that 20 mL of an aluminum and magnesium hydroxide antacid (Mylanta®) does not affect peak plasma concentrations or area under the concentration-time curve (AUC) of rifampin. However, the manufacturer of rifampin states that concomitant administration of rifampin and an antacid may reduce the absorption of rifampin and recommends that daily doses of rifampin be given at least 1 hour before ingestion of an antacid. • Atovaquone Concomitant use of rifampin and atovaquone have resulted in increased concentrations of rifampin.

Rifampin

Clofazimine

Concomitant use of clofazimine in leprosy patients receiving rifampin alone or in conjunction with dapsone reportedly may decrease the rate of absorption of rifampin, delay the time to reach peak plasma rifampin concentrations, and result in a slight decrease in the area under the plasma concentration-time curve (AUC) of the drug. However, in a study in lepromatous leprosy patients receiving dapsone (100 mg daily) and rifampin (600 mg daily), concomitant use of clofazimine (100 mg daily) did not affect plasma rifampin concentrations or the AUC, plasma half-life, or urinary elimination of rifampin.

Enalapril

Concomitant use of rifampin and enalapril has resulted in decreased concentrations of enalaprilat, the active metabolite of enalapril; dosage adjustments should be required

Halothane

Because of an increased risk of hepatotoxicity, concomitant use of rifampin and halothane should be avoided.

Isoniazid

Because of an increased risk of hepatotoxicity, patients receiving rifampin and isoniazid concomitantly should be closely monitored for signs and symptoms of hepatotoxicity.

Other Anti-infective Agents

A drug-induced lupus-like syndrome manifested principally by malaise, myalgias, arthritis, and peripheral edema has been reported in a few patients receiving rifampin or rifabutin concomitantly with ciprofloxacin and/or clarithromycin. (See Cautions: Lupus-like Syndrome.) Serum rifampin concentrations available in one patient during such concomitant therapy were elevated compared with expected levels, presumably as a result of inhibition of rifampin metabolism by ciprofloxacin and/or clarithromycin, and careful surveillance for drug-induced lupus syndrome is advised when these drugs are used concomitantly with a rifamycin.

Rifampin

Probenecid

There is some evidence that probenecid may compete with rifampin for hepatic uptake resulting in higher blood concentrations of the antituberculosis agent. However, this effect is not predictable, and the use of probenecid to increase the therapeutic efficacy of rifampin is not justified.

Pyrazinamide

Severe liver injuries, including some fatalities, have been reported in patients receiving a 2-month daily regimen of rifampin and pyrazinamide for the treatment of latent tuberculosis infection. The 2-month daily rifampin and pyrazinamide regimen should be used with caution in selected individuals only and with close clinical and laboratory monitoring. (See Cautions: Precautions and Contraindications.)

Sulfapyridine

Plasma concentrations of sulfapyridine may decrease if rifampin is used concomitantly, possibly due to alterations in the colonic bacteria responsible for the reduction of sulfasalazine to sulfapyridine and mesalamine.

Laboratory Test Interferences

Rifampin may cause cross-reactivity and false-positive results in urine screening tests for opiates that use Kinetic Interaction of Microparticles in Solution (KIMS) methods (e.g., Abuscreen OnLine opiates assay; Roche Diagnostic Systems). If opiate abuse is suspected, the finding should be confirmed by other diagnostic tests (e.g., gas chromatography/mass spectrometry).

Rifampin interferes with microbiologic assays for serum folate and vitamin B12. Alternative test methods should be considered for patients receiving rifampin.

Rifampin reduces hepatic uptake of sulfobromophthalein sodium. To avoid false-positive sulfobromophthalein test results, the test should be completed prior to administration of the daily dose of rifampin. In vitro studies indicate that serum rifampin concentrations greater than 100 mcg/mL, which might occur in acute overdosage, may cause false elevations in total serum bilirubin concentration determined by the modified Malloy method utilizing diazotized sulfanilic acid as a reagent.

Acute Toxcicity

The LD50 of rifampin in mice, rats, and rabbits is 0.885, 1.72, and 2.12 g/kg, respectively. In humans, acute overdosage with rifampin doses up to 9-12 g in adults and one or two 100-mg/kg doses in children 1-4 years of age have not been fatal; however, fatalities in adults have been reported following ingestion of 14- to 60-g doses of the drug. Alcohol or a history of alcohol abuse was involved in some of these cases of fatal and nonfatal overdosage.

Manifestations

Overdosage of rifampin produces symptoms that are principally extensions of common adverse reactions. These include nausea, vomiting, abdominal pain, pruritus, headache, lethargy, and brownish-red or orange discoloration of skin, urine, sweat, saliva, tears, and feces in proportion to the amount of drug ingested. Transient elevations in hepatic enzymes and/or bilirubin may occur.

Following massive overdosage of rifampin, hepatic involvement can develop within a few hours and is manifested by liver enlargement (possibly with tenderness), jaundice, rapid increases in total and direct serum bilirubin and liver enzymes, and loss of consciousness.

Hepatotoxicity may be more marked in patients with prior hepatic impairment. In addition, hypotension, sinus tachycardia, ventricular arrhythmias, seizures, and cardiac arrest have been reported in some cases of fatalities resulting from rifampin overdosages.

However, an effect upon the hematopoietic system, electrolyte concentrations, or acid-base balance is unlikely. In one patient who ingested 12 g of rifampin, vomiting occurred 4 times within 1 hour of ingestion, and gastric lavage with 20 L of water was initiated 5 hours after ingestion. Plasma concentrations of rifampin in this patient were 400, 64, and 0.1 mcg/mL at 12, 24, and 72 hours, respectively, after the dose; urinary concentrations of the drug were 313, 625, and 78 mcg/mL at 30, 36, and 40 hours, respectively, after the dose.

Results of liver function tests were only transiently increased for about 5 days after the overdosage and the patient’s recovery was uneventful. Inadvertent administration of 1 or 2 rifampin doses of 100 mg/kg for chemoprophylaxis of Haemophilus influenzae type b infection (5 times the usual daily dose) in a group of children 1-4 years of age resulted in a glowing red discoloration of the skin, periorbital or facial edema, pruritus of the head, vomiting, headache, and diarrhea. Signs and symptoms of overdosage occurred within 0.5-4 hours after administration of the first or second excessive dose and lasted an average of 28 hours (range: 1-72 hours).

Treatment

Treatment of rifampin overdosage consists of intensive supportive and symptomatic therapy. In acute rifampin overdosage, the stomach should be emptied by gastric lavage. Activated charcoal slurry then may be instilled into the stomach to adsorb any drug remaining in the GI tract. An antiemetic may be required to control severe nausea and vomiting. Active diuresis, with measured intake and output, may promote excretion of the drug. If serious hepatic impairment occurs which lasts more than 24-48 hours, bile drainage or hemodialysis may be indicated. Reversal of liver enlargement and improvement of impaired hepatic function usually occur within 72 hours in patients with previously adequate hepatic function.

Mechanism of Action

Rifampin may be bacteriostatic or bactericidal in action, depending on the concentration of the drug attained at the site of infection and the susceptibility of the infecting organism. Rifampin usually is rapidly bactericidal against Mycobacterium leprae in vivo.

Rifampin suppresses initiation of chain formation for RNA synthesis in susceptible bacteria by inhibiting DNA-dependent RNA polymerase. The beta subunit of the enzyme appears to be the site of action.

Rifampin is most active against susceptible bacteria when they are undergoing cell division; however, the drug also has some effect when bacteria are in the metabolic resting state. Although rifampin is reported to have an immunosuppressive effect in some animal experiments, this effect is probably not clinically important in humans. Spectrum Rifampin is active in vitro and in vivo against Mycobacterium tuberculosis, M. bovis, M. marinum, M. kansasii, and some strains of M. fortuitum, M. avium, and M. intracellulare. Rifampin also is active against both dapsone-susceptible and dapsone-resistant M. leprae in experimental leprosy in mice.

Rifampin also is active in vitro against some gram-positive bacteria, including Staphylococcus aureus and Bacillus anthracis, and some gram-negative bacteria, including Neisseria meningitidis, Haemophilus influenzae, Brucella melitensis, and Legionella pneumophila. At very high concentrations, rifampin is active in vitro against Chlamydia trachomatis, poxviruses, and adenoviruses. In vitro, most strains of N. meningitidis are inhibited by rifampin concentrations of 0.1-1 mcg/mL.

Clinical isolates of Ehrlichia phagocytophila have been inhibited in vitro by rifampin concentrations of 0.125 mcg/mL or less. Results of in vitro susceptibility testing of 11 B. anthracis isolates that were associated with cases of inhalational or cutaneous anthrax that occurred in the US (Florida, New York, District of Columbia) during September and October 2001 in the context of an intentional release of anthrax spores (biologic warfare, bioterrorism) indicate that these strains had rifampin MICs of 0.5 mcg/mL or less. Based on interpretive criteria established for staphylococci, these strains are considered susceptible to rifampin.

In Vitro Susceptibility Testing

The National Committee for Clinical Laboratory Standards (NCCLS) states that, if results of in vitro susceptibility testing indicate that a clinical isolate is susceptible to rifampin, then an infection caused by this strain may be appropriately treated with the dosage of the drug recommended for that type of infection and infecting species, unless otherwise contraindicated. If results indicate that a clinical isolate has intermediate susceptibility to rifampin, then the strain has a minimum inhibitory concentration (MIC) that approaches usually attainable blood and tissue concentrations and response rates may be lower than for strains identified as susceptible.

Therefore, the intermediate category implies clinical applicability in body sites where the drug is physiologically concentrated or when a high dosage of the drug can be used. This intermediate category also includes a buffer zone which should prevent small, uncontrolled technical factors from causing major discrepancies in interpretation, especially for drugs with narrow pharmacotoxicity margins.

If results of in vitro susceptibility testing indicate that a clinical isolate is resistant to rifampin, the strain is not inhibited by systemic concentrations of the drug achievable with usual dosage schedules and/or MICs fall in the range where specific microbial resistance mechanisms are likely and efficacy has not been reliable in clinical studies. In vitro susceptibility testing of certain fastidious bacteria (e.g., Haemophilus, Streptococcus) requires use of specialized culture media, testing procedures, and interpretive criteria not required for most other bacteria.

Although results of susceptibility testing may indicate that strains of Staphylococcus, Enterococcus, or S. pneumoniae may be susceptible to rifampin, the drug should not be used alone in the treatment of infections caused by these organisms. (See Uses: Streptococcal and Staphylococcal Infections.)

Disk Susceptibility Tests

When the disk-diffusion procedure is used to test susceptibility to rifampin, a disk containing 5 mcg of rifampin is used. When the disk-diffusion procedure is performed according to NCCLS standardized procedures using NCCLS interpretive criteria, Staphylococcus or Enterococcus with growth inhibition zones of 20 mm or greater are susceptible to rifampin, those with zones of 17-19 mm have intermediate susceptibility, and those with zones of 16 mm or less are resistant to the drug.

When disk-diffusion susceptibility testing is performed according to NCCLS standardized procedures using Haemophilus test medium (HTM), Haemophilus with growth inhibition zones of 20 mm or greater are susceptible to rifampin, those with zones of 17-19 mm have intermediate susceptibility, and those with zones of 16 mm or less are resistant to the drug.

When the NCCLS standardized disk-diffusion procedure using Mueller-Hinton agar (supplemented with 5% sheep blood)is used to determine susceptibility of S. pneumoniae, S. pneumoniae with growth inhibition zones of 19 mm or greater are susceptible to rifampin, those with zones of 17-18 mm are have intermediate susceptibility, and those with zones of 16 mm or less are resistant to the drug. NCCLS states that disk-diffusion susceptibility tests are unreliable for determining susceptibility of Neisseria meningitidis to rifampin; dilution susceptibility tests should be used to determine susceptibility of this organism.

Dilution Susceptibility Tests

When dilution susceptibility testing is performed according to NCCLS standardized procedures using NCCLS interpretive criteria, Staphylococcus or Enterococcus with MICs of 1 mcg/mL or less are susceptible to rifampin, those with MICs of 2 mcg/mL have intermediate susceptibility, and those with MICs of 4 mcg/mL or greater are resistant to the drug. These same interpretive criteria apply when the appropriate NCCLS standardized procedures are used to test susceptibility of Haemophilus or S. pneumoniae to rifampin.

When dilution susceptibility testing is used, N. meningitidis with MICs of 1 mcg/mL or less are susceptible to rifampin, those with MICs of 2 mcg/mL have intermediate susceptibility, and those with MICs of 4 mcg/mL or greater are resistant to the drug.

Rifampin is not likely to eradicate N. meningitidis from the nasopharynx of asymptomatic carriers when the organism is reported to be resistant using in vitro susceptibility procedures. The in vitro susceptibility of mycobacteria to rifampin depends on the culture media used.

Rifampin susceptibility powders are available for both direct and indirect methods of determining susceptibility of strains of mycobacteria.

When determined in Middlebrook and Cohn 7H10 agar (7H10 agar) or other non-egg-containing media (e.g., Dubos), the minimum inhibitory concentration (MIC) of rifampin for most susceptible mycobacteria is 0.1-2 mcg/mL. When egg-containing media (e.g., Lowenstein-Jensen) are used, the MIC for most susceptible mycobacteria is 4-32 mcg/mL.

Resistance

Natural and acquired resistance to rifampin have been observed in vitro and in vivo in strains of M. tuberculosis, M. kansasii, Neisseria meningitidis,and most bacteria which are usually susceptible to the drug. In vitro, resistance to rifampin develops in a one-step process, probably as the result of modification of the beta subunit of RNA polymerase. Resistant strains of initially susceptible organisms develop rapidly if rifampin is used alone in the treatment of clinical tuberculosis.

When rifampin is combined with other antituberculosis agents in the treatment of the disease, emergence of resistant strains may be delayed or prevented. In patients with tuberculosis or the meningococcal carrier state, the small number of resistant strains of M. tuberculosis or N. meningitidis present within large populations of susceptible strains can rapidly become predominant.

Strains of Staphylococcus aureus and Streptococcus pyogenes (group A b-hemolytic streptococci) with rifampin resistance have been isolated from at least one patient who received rifampin monotherapy.

Strains of M. leprae resistant to rifampin have been reported rarely. Resistant strains of initially susceptible M. leprae have developed within 3-5 years in patients receiving rifampin alone for the treatment of leprosy.

Cross-resistance has been demonstrated only between rifampin and other rifamycin derivatives.

Pharmacokinetics

Absorption

Rifampin is well absorbed from the GI tract. If rifampin is administered with food, peak plasma concentrations of the drug may be slightly reduced (by about 30%) and delayed. Following a single 600-mg oral dose of rifampin in healthy fasting adults in one study, peak plasma concentrations of the drug averaged 7 mcg/mL and were attained within 2-4 hours.

However, there is considerable interpatient variation, and peak plasma concentrations of the drug may range from 4-32 mcg/mL. In a single-dose study in healthy fasting males, the extent of absorption (as measured by area under the plasma concentration-time curve) of isoniazid, rifampin, or pyrazinamide in dosages of 250 mg, 600 mg, or 1500 mg, respectively, was similar whether the drugs were administered individually as capsules (rifampin) and tablets (isoniazid and pyrazinamide) or as a fixed combination (Rifater®) containing isoniazid 50 mg, rifampin 120 mg, and pyrazinamide 300 mg per tablet.

The effect of food on the pharmacokinetics of Rifater® has not been determined to date. Following IV infusion over 30 minutes of a single 300- or 600-mg dose of rifampin in healthy adult men, peak plasma concentrations of the drug average 9 or 17. mcg/mL, respectively, and plasma concentrations remain detectable for 8 or 12 hours, respectively.

Plasma concentrations of the drug attained with the 600-mg dose are disproportionately higher (up to 50% higher) than expected based on those attained with the 300-mg dose. When 600-mg doses of rifampin are given once daily by IV infusion over 3 hours for 7 days, plasma concentrations of the drug average 5.8 mcg/mL 8 hours after completion of the infusion on the first day of therapy and 2.6 mcg/mL 8 hours after completion of the infusion on the 7th day of therapy.

In several studies in children receiving rifampin orally in a dosage of 10 mg/kg, peak serum rifampin concentrations ranged from 3.5-15 mcg/mL. In one study in fasting children 6-58 months of age who received 10 mg/kg of rifampin given orally (as an extemporaneously prepared oral suspension in simple syrup or as a dry powder mixed in applesauce), peak serum concentrations were attained 1 hour after the dose and averaged 10.7 or 11.5 mcg/mL, respectively.

When a rifampin dose of approximately 300 mg/m2 was given by IV infusion over 30 minutes to children 3 months to 12.8 years of age, peak serum rifampin concentrations at the end of the infusion averaged 26 mcg/mL. Following multiple doses in these children, peak concentrations of the drug ranged from 11.7-41.5 mcg/mL 1-4 days after initiation of therapy and 13.6.-37.4 mcg/mL 5-14 days after initiation of therapy. Plasma concentrations of rifampin are higher and more prolonged in patients with impaired hepatic function, especially in the presence of obstructive jaundice. There is no cumulative effect in patients with impaired renal function.

Distribution

Rifampin is widely distributed into most body tissues and fluids including the liver, lungs, bile, pleural fluid, prostate, seminal fluid, ascitic fluid, CSF, saliva, tears, and bone. CSF concentrations of rifampin in patients with inflamed meninges are reported to be 10-20% of concurrent plasma concentrations of the drug. At a concentration of 10 mcg/mL, rifampin is 84-91% bound to plasma proteins.

Rifampin crosses the placenta.

Rifampin is distributed into milk.

Elimination

The plasma half-life of rifampin following a single 600- or 900-mg oral dose in healthy adults is approximately 3.4-3. hours.

During the first several weeks of continued daily administration of 600-mg oral doses of rifampin, there is a progressive decrease in plasma concentrations and half-life of the drug due to increased biliary excretion. In one study in adults with tuberculosis, the plasma half-life of rifampin was 1.7 hours after 3 months of daily 600-mg oral doses of the drug.

The plasma half-life of the drug is increased in patients with renal impairment. In one study in individuals who received a single 900-mg oral dose of rifampin, the mean plasma half-life of the drug was 3.6 hours in healthy individuals, 5 hours in those with glomerular filtration rates of 30-50 mL/minute, 7.3 hours in those with rates less than 30 mL/minute, and 11 hours in anuric patients.

The plasma half-life of rifampin in children 6-58 months of age averages 2.9 hours following oral administration of a single 10-mg/kg dose of the drug. Plasma half-life of the drug in children 3 months to 12. years of age following IV doses of the drug was 1.04-3.81 hours during the first few days of therapy and decreased to 1.17-3.19 hours after 5-14 days of therapy.

Rifampin is metabolized in the liver to a deacetylated derivative which also possesses antibacterial activity. The drug and its deacetylated metabolite are excreted mainly via bile.

Rifampin undergoes enterohepatic circulation and is largely reabsorbed, but the metabolite is not.

Within 24 hours, 3-30% of a single 600-mg oral dose of rifampin is excreted in urine as unchanged drug and active metabolite. Approximately 60% of the oral dose is excreted in feces via biliary elimination.

Plasma concentrations of rifampin are not appreciably affected by hemodialysis or peritoneal dialysis.

Chemistry and Stability

Chemistry

Rifampin is a semisynthetic derivative of rifamycin B, an antibiotic derived from Streptomyces mediterranei. Rifampin occurs as a red-brown, crystalline powder and is very slightly soluble in water and slightly soluble in alcohol. The drug has a pKa of 7.9. Commercially available rifampin sterile powder for injection contains sodium formaldehyde sulfoxylate; sodium hydroxide may have been added to adjust pH. Oral rifampin is commercially available alone, in fixed combination with isoniazid, and in fixed combination with isoniazid and pyrazinamide.

Stability

Rifampin capsules should be stored in tight, light-resistant containers at a temperature of 30°C or less, preferably between 15-30°C. The capsules should not be exposed to excessive heat.

Tablets containing the fixed combination of rifampin, isoniazid, and pyrazinamide (Rifater®) should be protected from excessive humidity and stored at 15-30°C. Commercially available rifampin powder for injection should be protected from light and excessive heat (i.e., temperatures greater than 40°C. Following reconstitution with sterile water for injection, rifampin solutions containing 60 mg/mL are stable for 24 hours at room temperature.

The manufacturer states that reconstituted solutions of rifampin that have been further diluted in 100 or 500 mL of 5% dextrose injection should be used within 4 hours of preparation. (See Reconstitution and Administration: IV Infusion, in Dosage and Administration.) The manufacturer states that stability of the drug may be slightly lower if reconstituted solutions of the drug are further diluted in 0.9% sodium chloride rather than in 5% dextrose injection.

A precipitate indicating incompatibility has been observed during simulated Y-site administration of rifampin (6 mg/mL in 0.9% sodium chloride) and diltiazem that is undiluted (5 mg/mL) or diluted (1 mg/mL in 0.9% sodium chloride).

Preparations

Rifampin Oral Capsules 150 mg Rifadin®, Aventis Rifampin Capsules, Eon 300 mg Rifadin®, Aventis Rifampin Capsules, Eon Rimactane®, (with parabens) Sandoz Parenteral For injection 600 mg Rifadin® IV, (with sodium formaldehyde sulfoxylate) Aventis Rifampin for Injection, Bedford Rifampin Combinations Oral Capsules 300 mg with Isoniazid 150 mg Rifamate®,Aventis Tablets 120 mg with Isoniazid 50 mg Rifater®, (with povidone and and Pyrazinamide 300 mg propylene glycol) Aventis

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