Rifampin

RIFAMPIN- rifampin injection, powder, lyophilized, for solution
Akorn

Rx ONLY

To reduce the development of drug-resistant bacteria and maintain the effectiveness of rifampin for injection USP and other antibacterial drugs, rifampin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

Rifampin for injection USP contains rifampin 600 mg, sodium formaldehyde sulfoxylate dihydrate 10 mg, and sodium hydroxide to adjust pH. Rifampin for injection is a sterile, lyophilized powder for intravenous infusion only.

Rifampin is a semisynthetic antibiotic derivative of rifamycin SV. Rifampin is a red-brown crystalline powder very slightly soluble in water at neutral pH, freely soluble in chloroform, soluble in ethyl acetate and in methanol. Its molecular weight is 822.95 and its chemical formula is C43 H58 N4 O12 . The chemical name for rifampin is either:

3-[[(4-Methyl-1-piperazinyl)imino]methyl]rifamycin

or

5,6,9,17,19,21-hexahydroxy-23-methoxy-2,4,12,16,20,22–heptamethyl-8-[N-(4-methyl-1-piperazinyl)formimidoyl]-2,7- (epoxypentadeca[1,11,13]trienimino)naphtho[2,1-b]furan-1,11(2H)-dione 21-acetate.

Its structural formula is:

Chemical StructureChemical Structure

CLINICAL PHARMACOLOGY

Intravenous Administration

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 (mean ± standard deviation, mcg/mL)

Rifampin
Dosage IV

30 min

1 hr

2 hr

4 hr

8 hr

12 hr

300 mg

8.9±2.9

4.9±1.3

4.0±1.3

2.5±1.0

1.1±0.6

<0.4

600 mg

17.4±5.1

11.7±2.8

9.4±2.3

6.4±1.7

3.5±1.4

1.2±0.6

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.

Pediatrics

Intravenous Administration

In pediatric patients 0.25 to 12.8 years old (n=12), the mean peak serum concentration of rifampin at the end of a 30 minute infusion of approximately 300 mg/m2 was 25.9 ± 1.3 mcg/mL; individual peak concentrations 1 to 4 days after initiation of therapy ranged from 11.7 to 41.5 mcg/mL; individual peak concentrations 5 to 14 days after initiation of therapy were 13.6 to 37.4 mcg/mL. The individual serum half-life of rifampin changed from 1.04 to 3.81 hours early in therapy to 1.17 to 3.19 hours 5 to 14 days after therapy was initiated.

Microbiology

Mechanism of Action

Rifampin inhibits DNA-dependent RNA polymerase activity in susceptible Mycobacterium tuberculosis organisms. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme.

Resistance

Organisms resistant to rifampin are likely to be resistant to other rifamycins. In addition, resistance to rifampin has been determined to occur as single-step mutations of the DNA-dependent RNA polymerase. Since resistance can emerge rapidly, appropriate susceptibility tests should be performed in the event of persistent positive cultures.

Activity in vitro and in vivo

Rifampin has bactericidal activity in vitro against slow and intermittently growing M tuberculosis organisms.

Rifampin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Aerobic Gram-Negative Microorganisms:
Neisseria meningitidis

“Other” Microorganisms:
Mycobacterium tuberculosis

The following in vitro data are available, but their clinical significance is unknown.

Rifampin exhibits in vitro activity against most strains of the following microorganisms; however, the safety and effectiveness of rifampin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.

Aerobic Gram-Positive Microorganisms:
Staphylococcus aureus (including Methicillin-Resistant S. aureus/ MRSA)
Staphylococcus epidermidis

Aerobic Gram-Negative Microorganisms:
Haemophilus influenzae

“Other” Microorganisms:
Mycobacterium leprae

β-lactamase production should have no effect on rifampin activity.

Susceptibility Testing

For specific information regarding susceptibility test criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: www.fda.gov/STIC.

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.

Tuberculosis

Rifampin is indicated in the treatment of all forms of tuberculosis.

A three-drug regimen consisting of rifampin, isoniazid, and pyrazinamide [e.g., RIFATER® ]1 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 than 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 [eg, RIFAMATE® ]2 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.

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