RIFAMPICIN
DESCRIPTION:
R-CIN (rifampicin) capsules for oral administration contain 150 mg or 300 mg of
rifampicin per capsule. The 150 mg and 300 mg capsules also contain, as inactive
ingredients: corn starch, D&C Red No. 28, FD&C Blue No. 1, FD&C Red No. 40,
gelatin, magnesium stearate, and titanium dioxide.
R-CIN IV (rifampicin for injection) contains rifampicin 600 mg, sodium
formaldehyde sulfoxylate 10 mg, and sodium hydroxide to adjust pH.
Rifampicin is a semisynthetic antibiotic derivative of rifamycin SV. Rifampicin 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 C43H58N4O12. The chemical
name for rifampicin 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.
ACTIONS/CLINICAL PHARMACOLOGY:
ORAL ADMINISTRATION
Rifampicin is readily absorbed from the gastrointestinal tract. Peak serum
concentrations in healthy adults and pediatric populations vary widely from
individual to individual. Following a single 600 mg oral dose of rifampicin in
healthy adults, the peak serum concentration averages 7 Mcgm-g/mL but may vary
from 4 to 32 Mcgm-g/mL. Absorption of rifampicin is reduced by about 30% when the
drug is ingested with food.
Rifampicin is widely distributed throughout the body. It is present in effective
concentrations in many organs and body fluids, including cerebrospinal fluid.
Rifampicin is about 80% protein bound. Most of the unbound fraction is not ionized
and, therefore, diffuses freely into tissues.
In healthy adults, the mean biological half-life of rifampicin in serum averages
3.35 +/- 0.66 hours after a 600 mg oral dose, with increases up to 5.08 +/-2.45
hours reported after a 900 mg dose. With repeated administration, the half-life
decreases and reaches average values of approximately 2 to 3 hours. The half-
life does not differ in patients with renal failure at doses not exceeding 600
mg daily, and consequently, no dosage adjustment is required. Following a single
900 mg oral dose of rifampicin in patients with varying degrees of renal
insufficiency, the mean half-life increased from 3.6 hours in healthy adults to
5.0, 7.3, and 11.0 hours in patients with glomerular filtration rates of 30 to
50 mL/min, less than 30 mL/min, and in anuric patients, respectively. Refer to
the WARNINGS section for information regarding patients with hepatic
insufficiency.
Rifampicin is rapidly eliminated in the bile, and an enterohepatic circulation
ensues. During this process, rifampicin undergoes progressive deacetylation so
that nearly all the drug in the bile is in this form in about 6 hours. This
metabolite is microbiologically active. Intestinal reabsorption is reduced by
deacetylation, and elimination is facilitated. Up to 30% of a dose is excreted
in the urine, with about half of this being unchanged drug.
INTRAVENOUS ADMINISTRATION
After intravenous administration of a 300 or 600 mg dose of rifampicin infused
over 30 minutes to healthy male volunteers (n=12), mean peak plasma
concentrations were 9.0 +/- 3.0 and 17.5 +/- 5.0 Mcgm-g/mL, respectively. Total
body clearance 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, rifampicin plasma
concentrations in these volunteers remained detectable for 8 and 12 hours,
respectively (see Table).
PLASMA CONCENTRATIONS (MEAN +/- STANDARD DEVIATION, MCGM-G/ML)
Rifampicin
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.
repeated once-a-day infusions (3 hr duration) of 600 mg in patients (n=5) for 7
days, concentrations of IV rifampicin decreased from 5.81 +/- 3.38 Mcgm-g/mL 8
hours after the infusion on day 1 to 2.6 +/- 1.88 Mu-g/mL 8 hours after the
infusion on day 7.
Rifampicin is widely distributed throughout the body. It is present in effective
concentrations in many organs and body fluids, including cerebrospinal fluid.
Rifampicin is about 80% protein bound. Most of the unbound fraction is not ionized
and therefore diffuses freely into tissues.
Rifampicin is rapidly eliminated in the bile and undergoes progressive
enterohepatic circulation and deacetylation to the primary metabolite, 25-
desacetyl-rifampicin. This metabolite is microbiologically active. Less than 30%
of the dose is excreted in the urine as rifampicin 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
ORAL ADMINISTRATION.
In one study, pediatric patients 6 to 58 months old were given rifampicin
suspended in simple syrup or as dry powder mixed with applesauce at a dose of 10
mg/kg body weight. Peak serum concentrations of 10.7 +/- 3.7 and 11.5 +/-5.1
Mcgm-g/mL were obtained 1 hour after preprandial ingestion of the drug
suspension and the applesauce mixture, respectively. After the administration of
either preparation, the t 1/2 of rifampicin averaged 2.9 hours. It should be noted
that in other studies in pediatric populations, at doses of 10 mg/kg body
weight, mean peak serum concentrations of 3.5 Mcgm-g/mL to 15 Mcgm-g/mL have
been reported.
INTRAVENOUS ADMINISTRATION.
In pediatric patients 0.25 to 12.8 years old (n=12), the mean peak serum
concentration of rifampicin at the end of a 30 minute infusion of approximately
300 mg/m(squared) was 25.9 +/- 1.3 Mcgm-g/mL; individual peak concentrations 1
to 4 days after initiation of therapy ranged from 11.7 to 41.5 Mcgm-g/mL;
individual peak concentrations 5 to 14 days after initiation of therapy were
13.6 to 37.4 Mu-g/mL. The individual serum half- life of rifampicin 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
Rifampicin inhibits DNA-dependent RNA polymerase activity in susceptible cells.
Specifically, it interacts with bacterial RNA polymerase but does not inhibit
mammalian enzyme. Rifampicin at therapeutic levels has demonstrated bactericidal
activity against both intracellular and extracellular MYCOBACTERIUM TUBERCULOSIS
organisms.
Organisms resistant to rifampicin are likely to be resistant to other rifamycins.
Rifampicin has bactericidal activity against slow and intermittently growing M
TUBERCULOSIS organisms. It also has significant activity against NEISSERIA
MENINGITIDIS isolates (see INDICATIONS AND USAGE).
IN THE TREATMENT OF BOTH TUBERCULOSIS AND THE MENINGOCOCCAL CARRIER STATE (SEE
INDICATIONS AND USAGE), THE SMALL NUMBER OF RESISTANCE CELLS PRESENT WITHIN
LARGE POPULATIONS OF SUSCEPTIBLE CELLS CAN RAPIDLY BECOME PREDOMINANT. IN
ADDITION, RESISTANCE TO RIFAMPICIN 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.
Rifampicin 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.
Rifampicin exhibits in vitro activity against most strains of the following
microorganisms; however, the safety and effectiveness of rifampicin 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
(beta)-lactamase production should have no effect on rifampicin activity.
SUSCEPTIBILITY TESTS
Prior to initiation of therapy, appropriate specimens should be collected for
identification of the infecting organism and in vitro susceptibility tests.
In vitro testing for MYCOBACTERIUM TUBERCULOSIS isolates:
Two standardized in vitro susceptibility methods are available for testing
rifampicin against M TUBERCULOSIS organisms. The agar proportion method (CDC or
NCCLS (REF.1) M24-P) utilizes Middlebrook 7H10 medium impregnated with rifampicin
at a final concentration of 1.0 Mcgm-g/mL to determine drug resistance. After
three weeks of incubation MIC99 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 2.0 Mcgm-g/mL of rifampicin. 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 rifampicin concentration is used for each test method
as indicated above. Both procedures require the use of M TUBERCULOSIS H37Rv ATCC
27294 as a control organism.
The clinical relevance of in vitro susceptibility test results for mycobacterial
species other than M TUBERCULOSIS using either the radiometric or the proportion
method has not been determined.
In vitro testing for NEISSERIA MENINGITIDIS isolates:
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 (REF. 2,4) (broth, agar, or microdilution) or
equivalent with rifampicin powder. The MIC values obtained should be interpreted
according to the following criteria for NEISSERIA MENINGITIDIS:
MIC (MCGM-G/ML) INTERPRETATION
(=)1 (S) Susceptible
2 (I) Intermediate
(>/=)4 (R) Resistant
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 ACTIONS/CLINICAL PHARMACOLOGY 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 INDICATIONS AND USAGE); they are used to control the technical
aspects of the laboratory procedures. Standard rifampicin powder should give the
following MIC values:
MICROORGANISM MIC (MCGM-G/ML)
STAPHYLOCOCCUS AUREUS ATCC 29213 0.008-0.06
ENTEROCOCCUS FAECALIS ATCC 29212 1-4
ESCHERICHIA COLI ATCC 25922 8-32
PSEUDOMONAS AERUGINOSA ATCC 27853 32-64
HAEMOPHILUS INFLUENZAE ATCC 49247 0.25-1
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 (REF. 3,4) that has
been recommended for use with disks to test the susceptibility of microorganisms
to rifampicin uses the 5 Mcgm-g rifampicin disk. Interpretation involves correlation
of the diameter obtained in the disk test with the MIC for rifampicin.
Reports from the laboratory providing results of the standard single-disk
susceptibility test with a 5 Mcgm-g rifampicin disk should be interpreted
according to the following criteria for NEISSERIA MENINGITIDIS:
ZONE DIAMETER (MM) INTERPRETATION
(>/=)20 (S) Susceptible
17-19 (I) Intermediate
(=)16 (R) Resistant
Interpretation should be 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 INDICATIONS AND USAGE); they are used to control
the technical aspects of the laboratory procedures. The 5 Mcgm-g rifampicin disk
should provide the following zone diameters in these quality control strains:
MICROORGANISM ZONE DIAMETER (MM)
S. AUREUS ATCC 25923 26-34
E. COLI ATCC 25922 8-10
H. INFLUENZAE ATCC 49247 22-30
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 rifampicin 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 rifampicin and the
patient is not responding to therapy, the drug regimen should be modified.
TUBERCULOSIS
Rifampicin is indicated in the treatment of all forms of tuberculosis.
A three-drug regimen consisting of rifampicin, isoniazid, and pyrazinamide (eg,
RIFATER(R)) 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), rifampicin, 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 unknown. 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 rifampicin and
isoniazid (eg, RIFAMATE(R)) 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.
R-CIN IV is indicated for the initial treatment and retreatment of
tuberculosis when the drug cannot be taken by mouth.
MENINGOCOCCAL CARRIERS
Rifampicin is indicated for the treatment of asymptomatic carriers of NEISSERIA
MENINGITIDIS to eliminate meningococci from the nasopharynx. RIFAMPICIN IS NOT
INDICATED FOR THE TREATMENT OF MENINGOCOCCAL INFECTION BECAUSE OF THE
POSSIBILITY OF THE RAPID EMERGENCE OF RESISTANT ORGANISMS. (See WARNINGS.)
Rifampicin 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 rifampicin in the treatment of asymptomatic
meningococcal carriers is preserved, the drug should be used only when the risk
of meningococcal disease is high.
CONTRAINDICATIONS:
Rifampicin is contraindicated in patients with a history of hypersensitivity to
any of the rifamycins. (See WARNINGS.)
WARNINGS:
Rifampicin has been shown to produce liver dysfunction. Fatalities associated with
jaundice have occurred in patients with liver disease and in patients taking
rifampicin with other hepatotoxic agents. Patients with impaired liver function
should be given rifampicin 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, rifampicin should be withdrawn.
In some cases, hyperbilirubinemia resulting from competition between rifampicin
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 indication 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.
Rifampicin has enzyme-inducing properties, including induction of delta amino
levulinic acid synthetase. Isolated reports have associated porphyria
exacerbation with rifampicin administration.
The possibility of rapid emergence of resistant meningococci restricts the use
of R-CIN to short-term treatment of the asymptomatic carrier state. R-CIN IS
NOT TO BE USED FOR THE TREATMENT OF MENINGOCOCCAL DISEASE.
PRECAUTIONS:
GENERAL
For the treatment of tuberculosis, rifampicin is usually administered on a daily
basis. Doses of rifampicin 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 rifampicin 600
mg plus isoniazid 15 mg/kg are much better tolerated.
Intermittent therapy may be used if the patient cannot (or will not) self-
administer drugs on a daily basis. Patients on intermittent therapy should be
closely monitored for compliance and cautioned against intentional or accidental
interruption of prescribed therapy, because of the increased risk of serious
adverse reactions.
Rifampicin has enzyme induction properties that can enhance the metabolism of
endogenous substrates including adrenal hormones, thyroid hormones, and vitamin
D. Rifampicin 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.
R-CIN IV
FOR INTRAVENOUS INFUSION ONLY. MUST NOT BE ADMINISTERED BY INTRAMUSCULAR OR
SUBCUTANEOUS ROUTE. Avoid extravasation during injection: local irritation and
inflammation due to extravascular infiltration of the infusion have been
observed. If these occur, the infusion should be discontinued and restarted at
another site.
INFORMATION FOR PATIENTS
The patient should be told that rifampicin 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 patients 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 take rifampicin either 1 hour before or 2 hours
after a meal with a full glass of water.
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.
LABORATORY TESTS
A complete blood count (CBC) and liver function tests should be obtained prior
to instituting therapy and periodically throughout the course of therapy.
Because of a possible transient rise in transaminase and bilirubin values, blood
for baseline clinical chemistries should be obtained before rifampicin dosing.
DRUG INTERACTIONS
Enzyme Induction: Rifampicin is known to induce certain cytochrome P-450 enzymes.
Administration of rifampicin 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 rifampicin.
Rifampicin has been reported to accelerate the metabolism of the following drugs:
anticonvulsants (eg, phenytoin), antiarrhythmics (eg, disopyramide, mexiletine,
quinidine, tocainide), oral anticoagulants, antifungals (eg, fluconazole,
itraconazole, ketoconazole), barbiturates, beta-blockers, calcium channel
blockers (eg, diltiazem, nifedipine, verapamil), chloramphenicol,
corticosteroids, cyclosporine, cardiac glycoside preparations, clofibrate, oral
or other systemic hormone contraceptives, dapsone, diazepam, doxycycline,
fluoroquinolones (eg ciprofloxacin), haloperidol, oral hypoglycemic agents
(sulfonylureas), levothyroxine, methadone, narcotic analgesics, nortriptyline,
progestins, tacrolimus, theophylline and zidovudine. It may be necessary to
adjust the dosages of these drugs if they are given concurrently with rifampicin.
Patients using oral or other systemic hormonal contraceptives should be advised
to change to nonhormonal methods of birth control during rifampicin therapy.
Rifampicin has been observed to increase the requirements for anticoagulant drugs
of the coumarin type. In patients receiving anitcoagulants and rifampicin
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.
Diabetes may become more difficult to control.
Concurrent use of ketoconazole and rifampicin has resulted in decreased serum
concentrations of both drugs. Concurrent use of rifampicin 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.
Other Interactions: Concomitant antacid administration may reduce the absorption
of rifampicin. Daily doses of rifampicin should be given at least 1 hour before the
ingestion of antacids.
Probenecid and cotrimoxazole have been reported to increase the blood level of
rifampicin.
When rifampicin is given concomitantly with either halothane or isoniazid, the
potential for hepatotoxicity is increased. The concomitant use of rifampicin and
halothane should be avoided. Patients receiving both rifampicin and isoniazid
should be monitored close for hepatotoxicity.
Plasma concentrations of sulfapyridine may be reduced following the concomitant
administration of sulfasalazine and rifampicin. This finding may be the result of
alteration in the colonic bacteria responsible for the reduction of
sulfasalazine to sulfapyridine and mesalamine.
DRUG/LABORATORY INTERACTIONS
Therapeutic levels of rifampicin have been shown to inhibit standard
microbiological assays for serum folate and vitamin B12. Thus, alternate assay
methods should be considered. Transient abnormalities in liver function tests
(eg, 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 rifampicin.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
There are no known human data on long-term potential for carinogenicity,
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 rifampicin 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.
Rifampicin has been reported to possess immunosuppressive potential in rabbits,
mice, rats, guinea pigs, human lymphocytes in vitro, and humans. Antitumor
activity in vitro has also been shown with rifampicin.
There was no evidence of mutagenicity in bacteria, DROSOPHILA MELANOGASTER, or
mice. An increase in chromotid breaks was noted when whole blood cell cultures
were treated with rifampicin. Increased frequency of chromosomal aberrations was
observed in vitro in lymphocytes obtained from patients treated with
combinations of rifampicin, isoniazid, and pyrazinamide and combinations of
streptomycin, rifampicin, isoniazid, and pyrazinamide.
PREGNANCY-TERATOGENIC EFFECTS
Category C. Rifampicin has been shown to be teratogenic in rodents given oral
doses of rifampicin 15 to 25 times the human dose. Although rifampicin has been
reported to cross the placental barrier and appear in cord blood, the effect of
R-CIN, alone or in combination with other antituberculosis drugs, on the human
fetus is not known . Neonates of rifampicin-treated mothers should be carefully
observed for any evidence of adverse effects. Isolated cases of fetal
malformations have been reported; however, there are no adequate and well-
controlled studies in pregnant women. Rifampicin should be used during pregnancy
only if the potential benefit justifies the potential risk to the fetus.
Rifampicin in oral doses of 150 to 250 mg/kg produced teratogenic effects in mice
and rats. Malformations were primarily cleft palate in the mouse and spina
bifida in the rat. The incidence of these anomalies was dose-dependent. When
rifampicin was given to pregnant rabbits in doses up to 20 times the usual daily
human dose, imperfect osteogenesis and embryotoxicity were reported.
PREGNANCY--NON-TERATOGENIC EFFECTS
When administered during the last few weeks of pregnancy, rifampicin can cause
post-natal hemorrhages in the mother and infant for which treatment with vitamin
K may be indicated.
NURSING MOTHERS
Because of the potential for tumorigenicity shown for rifampicin in animal
studies, a decision should be made whether to discontinue nursing or discontinue
the drug, taking into account the importance of the drug to the mother.
PEDIATRIC USE
See ACTIONS/CLINICAL PHARMACOLOGY--Pediatrics; see also DOSAGE AND
ADMINISTRATION.
DRUG INTERACTIONS:
Enzyme Induction: Rifampicin is known to induce certain cytochrome P-450 enzymes.
Administration of rifampicin 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 rifampicin.
Rifampicin has been reported to accelerate the metabolism of the following drugs:
anticonvulsants (eg, phenytoin), antiarrhythmics (eg, disopyramide, mexiletine,
quinidine, tocainide), oral anticoagulants, antifungals (eg, fluconazole,
itraconazole, ketoconazole), barbiturates, beta-blockers, calcium channel
blockers (eg, diltiazem, nifedipine, verapamil), chloramphenicol,
corticosteroids, cyclosporine, cardiac glycoside preparations, clofibrate, oral
or other systemic hormone contraceptives, dapsone, diazepam, doxycycline,
fluoroquinolones (eg ciprofloxacin), haloperidol, oral hypoglycemic agents
(sulfonylureas), levothyroxine, methadone, narcotic analgesics, nortriptyline,
progestins, tacrolimus, theophylline and zidovudine. It may be necessary to
adjust the dosages of these drugs if they are given concurrently with rifampicin.
Patients using oral or other systemic hormonal contraceptives should be advised
to change to nonhormonal methods of birth control during rifampicin therapy.
Rifampicin has been observed to increase the requirements for anticoagulant drugs
of the coumarin type. In patients receiving anitcoagulants and rifampicin
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.
Diabetes may become more difficult to control.
Concurrent use of ketoconazole and rifampicin has resulted in decreased serum
concentrations of both drugs. Concurrent use of rifampicin 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.
Other Interactions: Concomitant antacid administration may reduce the absorption
of rifampicin. Daily doses of rifampicin should be given at least 1 hour before the
ingestion of antacids.
Probenecid and cotrimoxazole have been reported to increase the blood level of
rifampicin.
When rifampicin is given concomitantly with either halothane or isoniazid, the
potential for hepatotoxicity is increased. The concomitant use of rifampicin and
halothane should be avoided. Patients receiving both rifampicin and isoniazid
should be monitored close for hepatotoxicity.
Plasma concentrations of sulfapyridine may be reduced following the concomitant
administration of sulfasalazine and rifampicin. This finding may be the result of
alteration in the colonic bacteria responsible for the reduction of
sulfasalazine to sulfapyridine and mesalamine.
DRUG/LABORATORY INTERACTIONS
Therapeutic levels of rifampicin have been shown to inhibit standard
microbiological assays for serum folate and vitamin B12. Thus, alternate assay
methods should be considered. Transient abnormalities in liver function tests
(eg, 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 rifampicin.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
GASTROINTESTINAL
Heartburn, epigastric distress, anorexia, nausea, vomiting, jaundice,
flatulence, cramps, and diarrhea have been noted in some patients. Although
CLOSTRIDIUM DIFFICILE has been shown in vitro to be sensitive to rifampicin,
pseudomembranous colitis has been reported with the use of rifampicin (and other
broad spectrum antibiotics). Therefore, it is important to consider this
diagnosis in patients who develop diarrhea in association with antibiotic use.
Rarely, hepatitis or a shock-like syndrome with hepatic involvement and abnormal
liver function tests has been reported.
HEMATOLOGIC
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 rifampicin administration has been continued or resumed after
the appearance of purpura.
Rare reports of disseminated intravascular coagulation have been observed.
Transient leukopenia, hemolytic anemia, and decreased hemoglobin have been
observed.
CENTRAL NERVOUS SYSTEM
Headache, fever, drowsiness, fatigue, ataxia, dizziness, inability to
concentrate, mental confusion, behavioral changes, muscular weakness, pain in
extremities, and generalized numbness have been observed.
Rare reports of myopathy have also been observed.
OCULAR
Visual disturbances have been observed.
ENDOCRINE
Menstrual disturbances have been observed.
Rare reports of adrenal insufficiency in patients with compromised adrenal
function have been observed.
RENAL
Elevations in BUN and serum uric acid have been reported. Rarely, hemolysis,
hemoglobinuria, hematuria, interstitial nephritis, acute tubular necrosis, renal
insufficiency, and acute renal failure have been noted. These are generally
considered to be hypersensitivity reactions. They usually occur during
intermittent therapy or when treatment is resumed following intentional or
accidental interruption of a daily dosage regimen, and are reversible when
rifampicin is discontinued and appropriate therapy instituted.
DERMATOLOGIC
Cutaneous reactions are mild and self-limiting and do not appear to be
hypersensitivity reactions. Typically, they consist of flushing and itching with
or without a rash. More serious cutaneous reactions which may be due to
hypersensitivity occur but are uncommon.
HYPERSENSITIVITY REACTIONS
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.
MISCELLANEOUS
Edema of the face and extremities has been reported. Other reactions reported to
have occurred with intermittent dosage regimens include "flu syndrome" (such as
episodes of fever, chills, headache, dizziness, and bone pain), shortness of
breath, wheezing, decrease in blood pressure and shock. The "flu syndrome" may
also appear if rifampicin is taken irregularly by the patient or if daily
administration is resumed after a drug free interval.
OVERDOSAGE:
SIGNS AND SYMPTOMS
Nausea, vomiting, and increased lethargy will probably occur within a short time
after ingestion; unconsciousness may occur when there is severe hepatic disease.
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, may 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.
ACUTE TOXICITY
The LD50 of rifampicin is approximately 885 mg/kg in the mouse, 1720 mg/kg in the
rat, and 2120 mg/kg in the rabbit.
rifampicin have been reported. In one patient who swallowed 12 g of rifampicin,
vomiting occurred four times within 1 hour of ingestion. Gastric lavage with 20
liters of water was initiated 5 hours after ingestion. Twelve hours after
ingestion of rifampicin, a plasma concentration of 400 Mcgm-g of rifampicin/mL was
measured by microbiological assay. The plasma concentration fell to 64 Mcgm-g/mL
on the following day, and to 0.1 Mcgm-g/mL on the third day. Urinary rifampicin
concentration was 313 Mcgm-g/mL approximately 30 hours after ingestion of the
drug, 625 Mcgm-g/mL after 36 hours, and 78 Mcgm-g/mL after 40 hours. By the
fourth day following the dose, only 0.1 Mcgm-g/mL rifampicin was present in the
urine. There was biochemical evidence of mild impairment of liver function.
Liver function tests had returned to normal within 5 days, and the patient's
recovery was described as uneventful.
One case of fatal overdose is known: a 26-year old man died after self-
administering 60 g of rifampicin.
TREATMENT
Since nausea and vomiting are likely to be present, gastric lavage 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. Hemodialysis may be of value in some patients. In patients with
previously adequate hepatic function, reversal of liver enlargement and of
impaired hepatic excretory function probably will be noted within 72 hours, with
a rapid return toward normal thereafter.
DOSAGE AND ADMINISTRATION:
Rifampicin can be administered by the oral route or by IV infusion (see
INDICATIONS AND USAGE).
See ACTIONS/CLINICAL PHARMACOLOGY for dosing information in patients with renal
failure.
TUBERCULOSIS
Adults: 600 mg in a single daily administration, oral or IV
Pediatric Patients: 10-20 mg/kg, not to exceed 600 mg/day, oral or IV
It is recommended that oral rifampicin be administered once daily, either 1 hour
before or 2 hours after a meal with a full glass of water.
Rifampicin is indicated in the treatment of all forms of tuberculosis. A three-
drug regimen consisting of rifampicin, isoniazid, and pyrazinamide (eg,
RIFATER(R)) 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 the Centers for Disease Control
and Prevention recommend that either streptomycin or ethambutol be added as a
fourth drug in a regimen containing isoniazid (INH), rifampicin 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 rifampicin and
isoniazid (eg, RIFAMATE(R)) for at least four 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.
PREPARATION OF SOLUTION FOR IV INFUSION: Reconstitute the lyophilized powder by
transferring 10 mL of sterile water for injection to a vial containing 600 mg of
rifampicin for injection. Swirl vial gently to completely dissolve the antibiotic.
The reconstituted solution contains 60 mg rifampicin per mL and is stable at room
temperature for 24 hours. Prior to administration, withdraw from the
reconstituted solution a volume equivalent to the amount of rifampicin calculated
to be administered and add to 500 mL of infusion medium. Mix well and infuse at
a rate allowing for complete infusion within 3 hours. Alternatively, the amount
of rifampicin calculated to be administered may be added to 100mL of infusion
medium and infused in 30 minutes.
Dilutions in dextrose 5% for injection (D5W) are stable at room temperature for
up to 4 hours and should be prepared and used within this time. Precipitation of
rifampicin from the infusion solution may occur beyond this time. Dilutions in
normal saline are stable at room temperature for up to 24 hours and should be
prepared and used within this time. Other infusion solution are not recommended.
MENINGOCOCCAL CARRIERS
Adults: For adults, it is recommended that 600 mg rifampicin be administered twice
daily for two days.
Pediatric Patients: Pediatric patients 1 month of age or older: 10 mg/kg (not to
exceed 600 mg per dose) every 12 hours for two days.
Pediatric patients under 1 month of age: 5 mg/kg every 12 hours for two days.
PREPARATION OF EXTEMPORANEOUS ORAL SUSPENSION
For pediatric and adult patients in whom capsule swallowing is difficult or
where lower doses are needed, a liquid suspension may be prepared as follows:
R-CIN 1% w/v suspension (10 mg/mL) can be compounded using one of four syrups-
Simple Syrup (Syrup NF), Simple Syrup (Humco Laboratories), Syrpalta(R) Syrup
(Emerson Laboratories), or Raspberry Syrup (Humco Laboratories).
1. Empty the contents of four R-CIN 300 mg capsules or eight R-CIN 150 mg
capsules onto a piece of weighing paper.
2. If necessary, gently crush the capsule contents with a spatula to produce a
fine powder.
3. Transfer the rifampicin powder blend to a 4-ounce amber glass or plastic (high
density polyethylene (HDPE), polypropylene, or procarbonate) prescription
bottle.
4. Rinse the paper and spatula with 20 mL of one of the above-mentioned syrups,
and add the rinse to the bottle. Shake vigorously.
5. Add 100 mL of syrup to the bottle and shake vigorously.
This compound procedure results in a 1% w/v suspension containing 10 mg
rifampicin/mL. Stability studies indicate that the suspension is stable when
stored at room temperature (25 +/- 3 deg C) or in a refrigerator (2-8 deg C) for
four weeks. This extemporaneously prepared suspension must be shaken well prior
to administration.