Rifampin Information
Rifampin ()
Rifampin () Description
Rifampin () for Injection USP contains Rifampin () 600 mg, sodium formaldehyde sulfoxylate 10 mg, and sodium hydroxide to adjust pH to 7.8 to 8.8. Rifampin () for Injection is for intravenous infusion only.
Rifampin () is a semisynthetic antibiotic derivative of rifamycin SV. Rifampin () USP is a red-brown crystalline powder very slightly soluble in water at neutral pH, freely soluble in chloroform, and soluble in ethyl acetate and in methanol. The chemical name for Rifampin () is 5,6,9,17,19,21-Hexahydroxy-23-methoxy-2,4,12,16,18,20,22-heptamethyl-8-[-(4-methyl-1-piperazinyl)formimidoyl]-2,7-(epoxypentadeca[1,11,13]trienimino)naphtho[2,1-]furan-1,11-(2)-dione 21-acetate. Its structural formula is:
Molecular Formula=CHNO M.W. = 822.96
Rifampin () Clinical Pharmacology
After intravenous administration of a 300 or 600 mg dose of Rifampin () infused over 30 minutes to healthy male volunteers (n=12), mean peak plasma concentrations were 9.0 ± 3.0 and 17.5 ± 5.0 mcg/mL, respectively. Total body clearances after the 300 and 600 mg IV doses were 0.19 ± 0.06 and 0.14 ± 0.03 L/hr/kg, respectively. Volumes of distribution at steady state were 0.66 ± 0.14 and 0.64 ± 0.11 L/kg for the 300 and 600 mg IV doses, respectively. After intravenous administration of 300 or 600 mg doses, Rifampin () plasma concentrations in these volunteers remained detectable for 8 and 12 hours, respectively (see Table).
Plasma concentrations after the 600 mg dose, which were disproportionately higher (up to 30% greater than expected) than those found after the 300 mg dose, indicated that the elimination of larger doses was not as rapid.
After repeated once-a-day infusions (3 hr duration) of 600 mg in patients (n=5) for 7 days, concentrations of IV Rifampin () decreased from 5.81 ± 3.38 mcg/mL 8 hours after the infusion on day 1 to 2.6 ± 1.88 mcg/mL 8 hours after the infusion on day 7.
Rifampin () is widely distributed throughout the body. It is present in effective concentrations in many organs and body fluids, including cerebrospinal fluid. Rifampin () is about 80% protein bound. Most of the unbound fraction is not ionized and therefore diffuses freely into tissues.
Rifampin () is rapidly eliminated in the bile and undergoes progressive enterohepatic circulation and deacetylation to the primary metabolite, 25-desacetyl-Rifampin () . This metabolite is microbiologically active. Less than 30% of the dose is excreted in the urine as Rifampin () or metabolites. Serum concentrations do not differ in patients with renal failure at a studied dose of 300 mg and consequently, no dosage adjustment is required.
Intravenous Administration
2
Prior to initiation of therapy, appropriate specimens should be collected for identification of the infecting organism and susceptibility tests.
Two standardized susceptibility methods are available for testing Rifampin () against organisms. The agar proportion method (CDC or CLSI M24-A) utilizes Middlebrook 7H10 medium impregnated with Rifampin () at a final concentration of 1 mcg/mL to determine drug resistance. After three weeks of incubation MIC values are calculated by comparing the quantity of organisms growing in the medium containing drug to the control cultures. Mycobacterial growth in the presence of drug, of at least 1% of the growth in the control culture, indicates resistance.
The radiometric broth method employs the BACTEC 460 machine to compare the growth index from untreated control cultures to cultures grown in the presence of 2 mcg/mL of Rifampin () . Strict adherence to the manufacturer’s instructions for sample processing and data interpretation is required for this assay.
Susceptibility test results obtained by the two different methods can only be compared if the appropriate Rifampin () concentration is used for each test method as indicated above. Both procedures require the use of H37Rv ATCC 27294 as a control organism.
The clinical relevance of susceptibility test results for mycobacterial species other than using either the radiometric or the proportion method has not been determined.
Dilution Techniques: Quantitative methods that are used to determine minimum inhibitory concentrations provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure uses a standardized dilution method (broth, agar, or microdilution) or equivalent with Rifampin () powder. The MIC values obtained should be interpreted according to the following criteria for
A report of “susceptible” indicates that the pathogen is likely to be inhibited by usually achievable concentrations of the antimicrobial compound in the blood. A report of “intermediate” indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where the maximum acceptable dose of drug can be used. This category also provides a buffer zone that prevents small-uncontrolled technical factors from causing major discrepancies in interpretation. A report of “resistant” indicates that usually achievable concentrations of the antimicrobial compound in the blood are unlikely to be inhibitory and that other therapy should be selected.
Measurement of MIC or minimum bactericidal concentrations (MBC) and achieved antimicrobial compound concentrations may be appropriate to guide therapy in some infections. (See section for further information on drug concentrations achieved in infected body sites and other pharmacokinetic properties of this antimicrobial drug product.)
Standardized susceptibility test procedures require the use of laboratory control microorganisms. The use of these microorganisms does not imply clinical efficacy (see ); they are used to control the technical aspects of the laboratory procedures. Standard Rifampin () powder should give the following MIC values:
Diffusion Techniques: Quantitative methods that require measurement of zone diameters provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure that has been recommended for use with disks to test the susceptibility of microorganisms to Rifampin () uses the 5 mcg Rifampin () disk. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for Rifampin () .
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5 mcg Rifampin () disk should be interpreted according to the following criteria for :
Interpretation should be as stated above for results using dilution techniques.
As with standard dilution techniques, diffusion methods require the use of laboratory control microorganisms. The use of these microorganisms does not imply clinical efficacy (see ); they are used to control the technical aspects of the laboratory procedures. The 5 mcg Rifampin () disk should provide the following zone diameters in these quality control strains:
Rifampin () Indications And Usage
In the treatment of both tuberculosis and the meningococcal carrier state, the small number of resistant cells present within large populations of susceptible cells can rapidly become the predominant type. Bacteriologic cultures should be obtained before the start of therapy to confirm the susceptibility of the organism to Rifampin () and they should be repeated throughout therapy to monitor the response to treatment. Since resistance can emerge rapidly, susceptibility tests should be performed in the event of persistent positive cultures during the course of treatment. If test results show resistance to Rifampin () and the patient is not responding to therapy, the drug regimen should be modified.
Rifampin () is indicated in the treatment of all forms of tuberculosis.
A three-drug regimen consisting of Rifampin () , isoniazid, and pyrazinamide is recommended in the initial phase of short-course therapy which is usually continued for 2 months. The Advisory Council for the Elimination of Tuberculosis, the American Thoracic Society, and Centers for Disease Control and Prevention recommend that either streptomycin or ethambutol be added as a fourth drug in a regimen containing isoniazid (INH), Rifampin () , and pyrazinamide for initial treatment of tuberculosis unless the likelihood of INH resistance is very low. The need for a fourth drug should be reassessed when the results of susceptibility testing are known. If community rates of INH resistance are currently less the 4%, an initial treatment regimen with less than four drugs may be considered.
Following the initial phase, treatment should be continued with Rifampin () and isoniazid for at least 4 months. Treatment should be continued for longer if the patient is still sputum or culture positive, if resistant organisms are present, or if the patient is HIV positive.
Rifampin () for injection is indicated for the initial treatment and retreatment of tuberculosis when the drug cannot be taken by mouth.
Rifampin () is indicated for the treatment of asymptomatic carriers of to eliminate meningococci from the nasopharynx. (See .)
Rifampin () should not be used indiscriminately, and therefore, diagnostic laboratory procedures, including serotyping and susceptibility testing, should be performed for establishment of the carrier state and the correct treatment. So that the usefulness of Rifampin () in the treatment of asymptomatic meningococcal carriers is preserved, the drug should be used only when the risk of meningococcal disease is high.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Rifampin () and other antibacterial drugs, Rifampin () should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Rifampin () Contraindications
Rifampin () is contraindicated in patients with a history of hypersensitivity to Rifampin () or any of the components, or to any of the rifamycins. (See .)
Rifampin () is contraindicated in patients who are also receiving ritonavir-boosted saquinavir due to an increased risk of severe hepatocellular toxicity. (See )
Rifampin () is contraindicated in patients who are also receiving atazanavir, darunavir, fosamprenavir, saquinavir, or tipranavir due to the potential of Rifampin () to substantially decrease plasma concentrations of these antiviral drugs, which may result in loss of antiviral efficacy and/or development of viral resistance.
Rifampin () Warnings
Rifampin () has been shown to produce liver dysfunction. Fatalities associated with jaundice have occurred in patients with liver disease and in patients taking Rifampin () with other hepatotoxic agents. Patients with impaired liver function should be given Rifampin () only in cases of necessity and then with caution and under strict medical supervision. In these patients, careful monitoring of liver function, especially SGPT/ALT and SGOT/AST should be carried out prior to therapy and then every 2 to 4 weeks during therapy. If signs of hepatocellular damage occur, Rifampin () should be withdrawn.
In some cases, hyperbilirubinemia resulting from competition between Rifampin () and bilirubin for excretory pathways of the liver at the cell level can occur in the early days of treatment. An isolated report showing a moderate rise in bilirubin and/or transaminase level is not in itself an indiction for interrupting treatment; rather, the decision should be made after repeating the tests, noting trends in the levels, and considering them in conjunction with the patient’s clinical condition.
Rifampin () has enzyme-inducing properties, including induction of delta amino levulinic acid synthetase. Isolated reports have associated porphyria exacerbation with Rifampin () administration.
The possibility of rapid emergence of resistant meningococci restricts the use of Rifampin () for injection to short-term treatment of the asymptomatic carrier state.
Rifampin () Precautions
Rifampin () should be used with caution in patients with a history of diabetes mellitus, as diabetes management may be more difficult.
Prescribing Rifampin () in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
For the treatment of tuberculosis, Rifampin () is usually administered on a daily basis. Doses of Rifampin () greater than 600 mg given once or twice weekly have resulted in a higher incidence of adverse reactions, including the “flu syndrome” (fever, chills and malaise), hematopoietic reactions (leukopenia, thrombocytopenia, or acute hemolytic anemia), cutaneous, gastrointestinal, and hepatic reactions, shortness of breath, shock, anaphylaxis, and renal failure. Recent studies indicate that regimens using twice-weekly doses of Rifampin () 600 mg plus isoniazid 15 mg/kg are much better tolerated.
Rifampin () is not recommended for intermittent therapy; the patient should be cautioned against intentional or accidental interruption of the daily dosage regimen since rare renal hypersensitivity reactions have been reported when therapy was resumed in such cases.
Rifampin () has enzyme induction properties that can enhance the metabolism of endogenous substrates including adrenal hormones, thyroid hormones, and vitamin D. Rifampin () and isoniazid have been reported to alter vitamin D metabolism. In some cases, reduced levels of circulating 25-hydroxy vitamin D and 1,25-dihydroxy vitamin D have been accompanied by reduced serum calcium and phosphate, and elevated parathyroid hormone.
For intravenous infusion only. Must not be administered by intramuscular or subcutaneous route.
Patients should be counseled that antibacterial drugs including Rifampin () should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Rifampin () is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Rifampin () or other antibacterial drugs in the future.
The patient should be told that Rifampin () may produce a reddish coloration of the urine, sweat, sputum, and tears, and the patient should be forewarned of this. Soft contact lenses may be permanently stained.
The patient should be advised that the reliability of oral or other systemic hormonal contraceptives may be affected; consideration should be given to using alternative contraceptive measures.
Patients should be instructed to notify their physicians promptly if they experience any of the following: fever, loss of appetite, malaise, nausea and vomiting, darkened urine, yellowish discoloration of the skin and eyes, and pain or swelling of the joints.
Compliance with the full course of therapy must be emphasized, and the importance of not missing any doses must be stressed.
Adults treated for tuberculosis with Rifampin () should have baseline measurements of hepatic enzymes, bilirubin, serum creatinine, a complete blood count, and a platelet count (or estimate). Baseline tests are unnecessary in pediatric patients unless a complicating condition is known or clinically suspected.
Patients should be seen at least monthly during therapy and should be specifically questioned concerning symptoms associated with adverse reactions. All patients with abnormalities should have follow-up, including laboratory testing, if necessary. Routine laboratory monitoring for toxicity in people with normal baseline measurements is generally not necessary.
Healthy subjects who received Rifampin () 600 mg once daily concomitantly with saquinavir 1000 mg/ritonavir 100 mg twice daily (ritonavir-boosted saquinavir) developed severe hepatocellular toxicity. Therefore, concomitant use of these medications is contraindicated. (See .)
Enzyme Induction: Rifampin () is known to induce certain cytochrome P-450 enzymes. Administration of Rifampin () with drugs that undergo biotransformation through these metabolic pathways may accelerate elimination of coadministered drugs. To maintain optimum therapeutic blood levels, dosages of drugs metabolized by these enzymes may require adjustment when starting or stopping concomitantly administered Rifampin () .
Rifampin () has been reported to substantially decrease the plasma concentrations of the following antiviral drugs: atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir. These antiviral drugs must not be co-administered with Rifampin () . (See .)
Rifampin () has been reported to accelerate the metabolism of the following drugs: anticonvulsants (e.g., phenytoin), digitoxin, antiarrhythmics (e.g., disopyramide, mexiletine, quinidine, tocainide), oral anticoagulants, antifungals (e.g., fluconazole, itraconazole, ketoconazole), barbiturates, beta-blockers, calcium channel blockers (e.g., diltiazem, nifedipine, verapamil), chloramphenicol, clarithromycin, corticosteroids, cyclosporine, cardiac glycoside preparations, clofibrate, oral or other systemic hormonal contraceptives, dapsone, diazepam, doxycycline, fluoroquinolones (e.g., ciprofloxacin), haloperidol, oral hypoglycemic agents (sulfonylureas), levothyroxine, methadone, narcotic analgesics, progestins, quinine, tacrolimus, theophylline, tricyclic antidepressants (e.g., amitriptyline, nortriptyline) and zidovudine. It may be necessary to adjust the dosages of these drugs if they are given concurrently with Rifampin () .
Patients using oral or other systemic hormonal contraceptives should be advised to change to nonhormonal methods of birth control during Rifampin () therapy.
Rifampin () has been observed to increase the requirements for anticoagulant drugs of the coumarin type. In patients receiving anticoagulants and Rifampin () concurrently, it is recommended that the prothrombin time be performed daily or as frequently as necessary to establish and maintain the required dose of anticoagulant.
Other Interactions: When the two drugs were taken concomitantly, decreased concentrations of atovaquone and increased concentrations of Rifampin () were observed.
Concurrent use of ketoconazole and Rifampin () has resulted in decreased serum concentrations of both drugs. Concurrent use of Rifampin () and enalapril has resulted in decreased concentrations of enalaprilat, the active metabolite of enalapril. Dosage adjustments should be made if indicated by the patient’s clinical condition.
Concomitant antacid administration may reduce the absorption of Rifampin () . Daily doses of Rifampin () should be given at least 1 hour before the ingestion of antacids.
Probenecid and cotrimoxazole have been reported to increase the blood level of Rifampin () .
When Rifampin () is given concomitantly with either halothane or isoniazid, the potential for hepatotoxicity is increased. The concomitant use of Rifampin () and halothane should be avoided. Patients receiving both Rifampin () and isoniazid should be monitored close for hepatotoxicity.
Plasma concentrations of sulfapyridine may be reduced following the concomitant administration of sulfasalazine and Rifampin () . This finding may be the result of alteration in the colonic bacteria responsible for the reduction of sulfasalazine to sulfapyridine and mesalamine.
Cross-reactivity and false-positive urine screening tests for opiates have been reported in patients receiving Rifampin () when using the KIMS (Kinetic Interaction of Microparticles in Solution) method (e.g., Abuscreen OnLine opiates assay; Roche Diagnostic Systems). Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish Rifampin () from opiates.
Therapeutic levels of Rifampin () have been shown to inhibit standard microbiological assays for serum folate and Vitamin B. Thus, alternate assay methods should be considered. Transient abnormalities in liver function tests (e.g., elevation in serum bilirubin, alkaline phosphatase, and serum transaminases) and reduced biliary excretion of contrast media used for visualization of the gallbladder have also been observed. Therefore, these tests should be performed before the morning dose of Rifampin () .
There are no known human data on long-term potential for carcinogenicity, mutagenicity, or impairment of fertility. A few cases of accelerated growth of lung carcinoma have been reported in man, but a causal relationship with the drug has not been established. An increase in the incidence of hepatomas in female mice (of a strain known to be particularly susceptible to the spontaneous development of hepatomas) was observed when Rifampin () was administered in doses 2 to 10 times the average daily human dose for 60 weeks, followed by an observation period of 46 weeks. No evidence of carcinogenicity was found in male mice of the same strain, mice of a different strain, or rats, under similar experimental conditions.
Rifampin () has been reported to possess immunosuppressive potential in rabbits, mice, rats, guinea pigs, human lymphocytes , and humans. Antitumor activity has also been shown with Rifampin () .
There was no evidence of mutagenicity in bacteria, , or mice. An increase in chromatid breaks was noted when whole blood cell cultures were treated with Rifampin () . Increased frequency of chromosomal aberrations was observed in lymphocytes obtained from patients treated with combinations of Rifampin () , isoniazid, and pyrazinamide and combinations of streptomycin, Rifampin () , isoniazid, and pyrazinamide.
Rifampin () Adverse Reactions
Thrombocytopenia has occurred primarily with high dose intermittent therapy, but has also been noted after resumption of interrupted treatment. It rarely occurs during well supervised daily therapy. This effect is reversible if the drug is discontinued as soon as purpura occurs. Cerebral hemorrhage and fatalities have been reported when Rifampin () administration has been continued or resumed after the appearance of purpura.
Rare reports of disseminated intravascular coagulation have been observed.
Leukopenia, hemolytic anemia, and decreased hemoglobin have been observed.
Agranulocytosis has been reported very rarely.
Headache, fever, drowsiness, fatigue, ataxia, dizziness, inability to concentrate, mental confusion, behavioral changes, muscular weakness, pains in extremities, and generalized numbness have been observed.
Psychoses have been rarely reported.
Rare reports of myopathy have also been observed.
Menstrual disturbances have been observed.
Rare reports of adrenal insufficiency in patients with compromised adrenal function have been observed.
Occasionally, pruritus, urticaria, rash, pemphigoid reaction, erythema multiforme including Stevens-Johnson Syndrome, toxic epidermal necrolysis, vasculitis, eosinophilia, sore mouth, sore tongue, and conjunctivitis have been observed.
Anaphylaxis has been reported rarely.
Rifampin () Overdosage
Nausea, vomiting, abdominal pain, pruritus, headache, and increasing lethargy will probably occur within a short time after ingestion; unconsciousness may occur when there is severe hepatic disease. Transient increases in liver enzymes and/or bilirubin may occur. Brownish-red or orange discoloration of the skin, urine, sweat, saliva, tears, and feces will occur, and its intensity is proportional to the amount ingested.
Liver enlargement, possibly with tenderness, can develop within a few hours after severe overdosage; bilirubin levels may increase and jaundice may develop rapidly. Hepatic involvement may be more marked in patients with prior impairment of hepatic function. Other physical findings remain essentially normal. A direct effect upon the hematopoietic system, electrolyte levels, or acid-base balance is unlikely.
Facial or periorbital edema has also been reported in pediatric patients. Hypotension, sinus tachycardia, ventricular arrhythmias, seizures and cardiac arrest were reported in some fatal cases.
The LD of Rifampin () is approximately 885 mg/kg in the mouse,
1720 mg/kg in the rat, and 2120 mg/kg in the rabbit.
The minimum acute lethal or toxic dose is not well established. However, nonfatal acute overdoses in adults have been reported with doses ranging from 9 to 12 gm Rifampin () . Fatal acute overdoses in adults have been reported with doses ranging from 14 to 60 gm. Alcohol or a history of alcohol abuse was involved in some of the fatal and nonfatal reports. Nonfatal overdoses in pediatric patients ages 1 to 4 years old of 100 mg/kg for one to two doses has been reported.
Intensive support measures should be instituted and individual symptoms treated as they arise. The airway should be secured and adequate respiratory exchange established. Since nausea and vomiting are likely to be present, gastric lavage within the first 2 to 3 hours after ingestion is probably preferable to induction of emesis. Following evacuation of the gastric contents, the instillation of activated charcoal slurry into the stomach may help absorb any remaining drug from the gastrointestinal tract. Antiemetic medication may be required to control severe nausea and vomiting.
Active diuresis (with measured intake and output) will help promote excretion of the drug.
For severe cases, extracorporeal hemodialysis may be required. If this is not available, peritoneal dialysis can be used along with forced diuresis.
Rifampin () Dosage And Administration
Rifampin () for Injection is administered by IV infusion only (see ). IV doses are the same as those for oral.
See for dosing information in patients with renal failure.
Rifampin () How Supplied
Rifampin () for Injection USP, containing 600 mg of Rifampin () , is supplied in sterile vials, individually boxed. .
Store at room temperature 15° to 30°C (59° to 86°F).
Rifampin () References
Manufactured by: Manufactured for:
Ben Venue Laboratories, Inc. Bedford Laboratories™
Bedford, OH 44146 Bedford, OH 44146
January 2011 RFP-P05
Rifampin () Vial Label
