PYRAZINAMIDE
*************************************************
* *
* WARNING *
* Severe and sometimes fatal hepatitis *
* associated with isoniazid therapy may occur *
* and may develop even after many months of *
* treatment. The risk of developing hepatitis *
* is age related. Approximate case rates by *
* age are: 0 per 1,000 for persons under 20 *
* years of age, 3 per 1,000 for persons in *
* the 20 to 34 year age group, 12 per 1,000 *
* for persons in the 35 to 49 year age group, *
* 23 per 1,000 for persons in the 50 to 64 *
* year age group, and 8 per 1,000 for persons *
* over 65 years of age. The risk of hepatitis *
* is increased with daily consumption of *
* alcohol. Precise data to provide a fatality *
* rate for isoniazid-related hepatitis is not *
* available; however, in a U.S. Public Health *
* Service Surveillance Study of 13,838 *
* persons taking isoniazid, there were 8 *
* deaths among 174 cases of hepatitis. *
* Therefore, patients given isoniazid should *
* be carefully monitored and interviewed at *
* monthly intervals. Serum transaminase *
* concentration becomes elevated in about 10% *
* to 20% of patients, usually during the *
* first few months of therapy, but it can *
* occur at any time. Usually enzyme levels *
* return to normal despite continuance of *
* drug, but in some cases progressive liver *
* dysfunction occurs. Patients should be *
* instructed to report immediately any of the *
* prodromal symptoms of hepatitis, such as *
* fatigue, weakness, malaise, anorexia, *
* nausea, or vomiting. If these symptoms *
* appear or if signs suggestive of hepatic *
* damage are detected, isoniazid should be *
* discontinued promptly since continued use *
* of the drug in these cases has been *
* reported to cause a more severe form of *
* liver damage. *
* Patients with tuberculosis should be given *
* appropriate treatment with alternative *
* drugs. If isoniazid must be reinstituted, *
* it should be reinstituted only after *
* symptoms and laboratory abnormalities have *
* cleared. The drug should be restarted in *
* very small and gradually increasing doses *
* and should be withdrawn immediately if *
* there is any indication of recurrent liver *
* involvement. Treatment should be deferred *
* in persons with acute hepatic diseases. *
* *
*************************************************
RIFATER (rifampin/isoniazid/pyrazinamide) tablets are combination tablets
containing 120 mg rifampin, 50 mg isoniazid, and 300 mg pyrazinamide for use in
antibacterial therapy. The tablets also contain as inactive ingredients:
povidone, carboxymethylcellulose sodium, calcium stearate, sodium lauryl
sulfate, sucrose, talc, acacia, titanium dioxide, kaolin, magnesium carbonate,
colloidal silicon dioxide, dried aluminum hydroxide gel, ferric oxide, black
iron oxide, carnauba wax, white beeswax, colophony, hard paraffin, lecithin,
shellac, and propylene glycol. The RIFATER triple therapy combination was
developed for dosing convenience.
Rifampin is a semisynthetic antibiotic derivative of rifamycin B. Rifampin is a
red-brown crystalline powder very slightly soluble in water at neutral pH,
freely soluble in chloroform, soluble in ethyl acetate and methanol. Its
molecular weight is 822.95 and its chemical formula is C43H58N4O12. The chemical
name for rifampin is either:
3-(((4-methyl-1-piperazinyl) imino)-methyl)-rifamycin;
or
5,6,9,17,19,21-hexahydroxy-23methoxy- 2,4,12,16,18,20,22 heptamethyl-8-(N-(4-
methyl- 1-piperazinyl) formimidoyl)-2,7-(epoxypentadeca
(1,11,13)trienimino)naphthol(2,1-b)furan-1, 11(2H)-dione 21-acetate.
Click here to view chemical structure(s).
Isoniazid is the hydroxide of isonicotinic acid. It is a colorless or white
crystalline powder or white crystals. It is odorless and slowly affected by
exposure to air and light. It is freely soluble in water, sparingly soluble in
alcohol and slightly soluble in chloroform and in ether. Its molecular weight is
137.14 and its chemical formula is C6H7N3O. The chemical name for isoniazid is
4-pyridinecarboxylic acid, hydrazide.
Click here to view chemical structure(s).
Pyrazinamide, the pyrazine analogue of nicotinamide, is a white, crystalline
powder, stable at room temperature, and sparingly soluble in water. The chemical
name for pyrazinamide is pyrazinecarboxamide and its molecular weight is 123.11.
Its chemical formula is C5H5N3O.
Click here to view chemical structure(s).
ACTIONS/CLINICAL PHARMACOLOGY:
GENERAL
RIFAMPIN. Rifampin is readily absorbed from the gastrointestinal tract. Peak
serum levels in normal adults and children vary widely from individual to
individual. Following a single 600 mg oral dose of rifampin in healthy adults,
the peak serum level averages 7 mcgm/mL but may vary from 4 to 32 mcgm/mL.
Absorption of rifampin is reduced when the drug is ingested with food.
In normal subjects, the biological half-life of rifampin in serum averages about
3 hours after a 600 mg oral dose, with increases up to 5.1 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. The half-life of rifampin at a
dose of 720 mg daily has not been established in patients with renal failure.
Following a single 900 mg oral dose of rifampin in patients with varying degrees
of renal insufficiency, the half-life increased from 3.6 hours in normal
subjects to 5.0, 7.3 and 11.0 hours in patients with glomerular filtration rates
of 30-50 mL/min, less than 30 mL/min, and in anuric patients, respectively.
Refer to WARNINGS section for information regarding patients with hepatic
insufficiency.
After absorption, rifampin is rapidly eliminated in the bile, and an
enterohepatic circulation ensues. During this process, rifampin undergoes
progressive deacetylation so that nearly all the drug in the bile is in this
form in about 6 hours. This metabolite has antibacterial activity. Intestinal
reabsorption is reduced by deacetylation, and elimination is facilitated. Up to
30% of a dose is excreted in the urine, with about half as unchanged drug.
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 is diffused freely in tissues.
ISONIAZID. After oral administration, isoniazid is readily absorbed from the GI
tract and produces peak blood levels within 1 to 2 hours. It diffuses readily
into all body fluids (cerebrospinal, pleural, and ascitic fluids), tissues,
organs, and excreta (saliva, sputum, and feces). Isoniazid is not substantially
bound to plasma proteins. The drug also passes through the placental barrier and
into milk in concentrations comparable to those in the plasma. The plasma half-
life of isoniazid in patients with normal renal and hepatic function ranges from
1-4 hours, depending on the rate of metabolism. From 50% to 70% of a dose of
isoniazid is excreted in the urine within 24 hours, mostly as metabolites.
Isoniazid is metabolized in the liver mainly by acetylation and dehydrazination.
The rate of acetylation is genetically determined. Approximately 50% of African
Americans and Caucasians are "slow inactivators" and the rest are "rapid
inactivators"; the majority of Eskimos and Asians are "rapid inactivators." The
rate of acetylation does not significantly alter the effectiveness of Isoniazid.
However, slow acetylation may lead to higher blood levels of the drug, and thus,
an increase in toxic reactions.
Pyridoxine (B6) deficiency is sometimes observed in adults with high doses of
isoniazid and is probably due to its competition with pyridoxal phosphate for
the enzyme apotryptophanase.
PYRAZINAMIDE. Pyrazinamide is well absorbed from the gastrointestinal tract and
attains peak plasma concentrations within 2 hours. Plasma concentrations
generally range from 30 to 50 mcgm/mL with doses of 20 to 25 mg/kg. It is widely
distributed in body tissues and fluids including the liver, lungs, and
cerebrospinal fluid (CSF). The CSF concentration is approximately equal to
concurrent steady-state plasma concentrations in patients with inflamed
meninges. Pyrazinamide is approximately 10% bound to plasma proteins. The plasma
half-life of pyrazinamide is 9 to 10 hours in patients with normal renal and
hepatic function. The half-life of the drug may be prolonged in patients with
impaired renal or hepatic function. Pyrazinamide is hydrolyzed in the liver to
its major active metabolite, pyrazinoic acid. Pyrazinoic acid is hydroxylated to
the main excretory product, 5-hydroxypyrazinoic acid.
Within 24 hours, approximately 70% of an oral dose of pyrazinamide is excreted
in urine, mainly by glomerular filtration. About 4% to 14% of the dose is
excreted as unchanged drug; the remainder is excreted as metabolites.
RIFATER
In a single-dose bioavailability study of five RIFATER tablets (Treatment A,
n=23) versus RIFADIN 600 mg, isoniazid 250 mg, and pyrazinamide 1500 mg
(Treatment B, n=24) administered concurrently in normal subjects, there was no
difference in extent of absorption, as measured by the area under the plasma
concentration versus time curve (AUC), of all three components. However, the
mean peak plasma concentration of rifampin was approximately 18% lower following
the single-dose administration of RIFATER tablets as compared to RIFADIN
administered in combination with pyrazinamide and isoniazid. Mean (+/- SD)
pharmacokinetic parameters are summarized in the following table.
APPARENT ORAL BIOAVAIL-
CMAX HALF-LIFE CLEARANCE ABILITY
PARAMETER (MCGM/ML) (HR) (L/HR) (%)
-----------------------------------------------------------------------------
Treatment A B A B A B A
-----------------------------------------------------------------------------
Isoniazid 3.09 3.14 2.80 2.80 24.02 25.72 100.6
+/-0.88 +/-0.92 +/-1.02 +/-1.11 +/-15.29 +/-18.38 +/-16.6
-----------------------------------------------------------------------------
Rifampin 11.04 13.61 3.19 3.41 9.62 8.30 88.8
+/-3.08 +/-3.96 +/-0.63 +/-0.86 +/-3.00 +/- 2.50 +/-16.5
-----------------------------------------------------------------------------
Pyrazinamide 28.02 29.21 10.04 10.08 3.82 3.70 96.8
+/-4.52 +/-4.35 +/-1.54 +/-1.29 +/-0.65 +/- 0.59 +/-7.6
-----------------------------------------------------------------------------
The effect of food on the pharmacokinetics of RIFATER tablets was not studied.
MICROBIOLOGY
Rifampin, isoniazid, and pyrazinamide at therapeutic levels have demonstrated
bactericidal activity against both intracellular and extracellular Mycobacterium
Tuberculosis organisms.
MECHANISM OF ACTION
RIFAMPIN. 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.
Organisms resistant to rifampin are likely to be resistant to other rifamycins.
ISONIAZID. Isoniazid kills actively growing tubercle bacilli by inhibiting the
biosynthesis of mycolic acids which are major components of the cell wall of
Mycobacterium Tuberculosis.
PYRAZINAMIDE. The exact mechanism of action by which pyrazinamide inhibits the
growth of Mycobacterium Tuberculosis organisms is unknown. In Vitro and In Vivo
studies have demonstrated that pyrazinamide is only active at a slightly acidic
pH (pH 5.5).
SUSCEPTIBILITY TESTING
Prior to initiation of therapy, appropriate specimens should be collected for
identification of the infecting organism and In Vitro susceptibility tests.
Two standardized In Vitro susceptibility methods are available for testing
isoniazid, rifampin, and pyrazinamide against Mycobacterium Tuberculosis
organisms. The agar proportion method (CDC or NCCLS M24-P) utilizes Middlebrook
7H10 medium impregnated with isoniazid at 0.2 and 1.0 mcgm/mL and rifampin at
1.0 mcgm/mL for the final concentrations of drug. The final concentration for
pyrazinamide is 25.0 mcgm/mL at pH 5.5. After 3 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 >/=1% of the control 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 0.2 and 1.0 mcgm/mL of isoniazid and 2.0 mcgm/mL of rifampin. Strict
adherence to the manufacturer's instructions for sample processing and data
interpretation is required for this assay. The radiometric broth method has not
been approved for the testing of pyrazinamide.
Susceptibility test results obtained by the two different methods can only be
compared if the appropriate rifampin or isoniazid concentrations are used for
each test method as indicated above. Both test procedures require the use of
Mycobacterium Tuberculosis H37Rv, ATCC 27294, as a control organism.
The clinical relevance of In Vitro susceptibility test results for mycobacterial
species other than Mycobacterium Tuberculosis using either the radiometric broth
method or the proportion method has not been determined.
CLINICAL TRIALS
A total of 250 patients were enrolled in an open label, prospective, randomized,
parallel group, active controlled trial, for the treatment of pulmonary
tuberculosis. There were 241 patients evaluable for efficacy, 123 patients
received isoniazid, rifampin and pyrazinamide as separate tablets and capsules
for 56 days, and 118 patients received 4 to 6 RIFATER tablets based on body
weight for 56 days. RIFATER tablets and the drugs dosed as separate tablets and
capsules were administered based on body weight during the intensive phase of
treatment according to the following table.
DOSE OF ISONIAZID, RIFAMPIN AND PYRAZINAMIDE
ADMINISTERED AS SEPARATE DRUGS
-----------------------------------------------------------------------------
Isoniazid Rifampin Pyrazinamide
Patient Weight (mg) (mg) (mg)
-----------------------------------------------------------------------------
<50 kg 300 450 1500
-----------------------------------------------------------------------------
>/=50 kg 300 600 2000
-----------------------------------------------------------------------------
DOSE OF ISONIAZID, RIFAMPIN AND PYRAZINAMIDE ADMINISTERED AS RIFATER
-----------------------------------------------------------------------------
Patient Number of Isoniazid Rifampin Pyrazinamide
Weight Tablets (mg) (mg) (mg)
-----------------------------------------------------------------------------
=44 kg 4 200 480 1200
-----------------------------------------------------------------------------
45 to 54 kg 5 250 600 1500
-----------------------------------------------------------------------------
>/=55 kg 6 300 720 1800
During the continuation phase, both treatment groups received 450 mg of rifampin
and 300 mg of isoniazid per day for 4 months if the patient weighed <50 kg or
600 mg of rifampin and 300 mg of isoniazid per day for 4 months if the patient
weighed >/=50 kg. Patients were followed for occurrence of relapses for up to 30
months after the end of therapy.
There were no significant differences in the negative bacteriological sputum
results (available in a subset of patients) between the two treatments at 2 and
6 months during the trial and during the follow-up period. See table below.
Negative Sputums/No. of Patients (Percent Negative)
-----------------------------------------------------------------------------
Treatment 2 Months 6 Months Follow-up Period*
-----------------------------------------------------------------------------
RIFATER 91/96 (95%) 100/104 (96%) 99/101 (98%)
-----------------------------------------------------------------------------
Separate* 99/108 (92%) 95/96 (99%) 105/106 (99%)
-----------------------------------------------------------------------------
* The median follow-up time for all the RIFATER patients was 756 days with a
range of 42 to 1325 days and 745 days with a range of 50 to 1427 days for
the patients dosed with separate tablets and capsules.
* Isoniazid, rifampin, and pyrazinamide dosed as separate tablets and
capsules.
For adverse events, see ADVERSE REACTIONS section.
INDICATIONS AND USAGE:
RIFATER is indicated in the initial phase of the short-course treatment of
pulmonary tuberculosis. During this phase, which should last 2 months. RIFATER
should be administered on a daily, continuous basis (see DOSAGE AND
ADMINISTRATION section).
Following the initial phase and treatment with RIFATER, treatment should be
continued with rifampin and isoniazid (eg, RIFAMATE) for at least 4 months.
Treatment should be continued for a longer period of time if the patient is
still sputum or culture positive, if resistant organisms are present, or if the
patient is HIV positive.
In the treatment of tuberculosis, the small number of resistant cells present
within large populations of susceptible cells can rapidly become the predominant
type. Since resistance can emerge rapidly, susceptibility tests should be
performed in the event of persistent positive cultures during the course of
treatment. Bacteriologic smears or cultures should be obtained before the start
of therapy to confirm the susceptibility of the organism to rifampin, isoniazid,
and pyrazinamide and they should be repeated throughout therapy to monitor
response to the treatment. If test results show resistance to any of the
components of RIFATER and the patient is not responding to therapy, the drug
regimen should be modified.
CONTRAINDICATIONS:
RIFATER is contraindicated in patients with a history of hypersensitivity to
rifampin, isoniazid, pyrazinamide, or any of the components. Other
contraindications include patients with severe hepatic damage; severe adverse
reactions to isoniazid, such as drug fever, chills, and arthritis; patients with
acute liver disease of any etiology; and patients with acute gout.
WARNINGS:
*************************************************
* *
* WARNING *
* Severe and sometimes fatal hepatitis *
* associated with isoniazid therapy may occur *
* and may develop even after many months of *
* treatment. The risk of developing hepatitis *
* is age related. Approximate case rates by *
* age are: 0 per 1,000 for persons under 20 *
* years of age, 3 per 1,000 for persons in *
* the 20 to 34 year age group, 12 per 1,000 *
* for persons in the 35 to 49 year age group, *
* 23 per 1,000 for persons in the 50 to 64 *
* year age group, and 8 per 1,000 for persons *
* over 65 years of age. The risk of hepatitis *
* is increased with daily consumption of *
* alcohol. Precise data to provide a fatality *
* rate for isoniazid-related hepatitis is not *
* available; however, in a U.S. Public Health *
* Service Surveillance Study of 13,838 *
* persons taking isoniazid, there were 8 *
* deaths among 174 cases of hepatitis. *
* Therefore, patients given isoniazid should *
* be carefully monitored and interviewed at *
* monthly intervals. Serum transaminase *
* concentration becomes elevated in about 10% *
* to 20% of patients, usually during the *
* first few months of therapy, but it can *
* occur at any time. Usually enzyme levels *
* return to normal despite continuance of *
* drug, but in some cases progressive liver *
* dysfunction occurs. Patients should be *
* instructed to report immediately any of the *
* prodromal symptoms of hepatitis, such as *
* fatigue, weakness, malaise, anorexia, *
* nausea, or vomiting. If these symptoms *
* appear or if signs suggestive of hepatic *
* damage are detected, isoniazid should be *
* discontinued promptly since continued use *
* of the drug in these cases has been *
* reported to cause a more severe form of *
* liver damage. *
* Patients with tuberculosis should be given *
* appropriate treatment with alternative *
* drugs. If isoniazid must be reinstituted, *
* it should be reinstituted only after *
* symptoms and laboratory abnormalities have *
* cleared. The drug should be restarted in *
* very small and gradually increasing doses *
* and should be withdrawn immediately if *
* there is any indication of recurrent liver *
* involvement. Treatment should be deferred *
* in persons with acute hepatic diseases. *
* *
*************************************************
RIFATER is a combination of the three drugs, rifampin, isoniazid, and
pyrazinamide. Each of these individual drugs has been associated with liver
dysfunction.
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. Because RIFATER contains both rifampin
and isoniazid, it should only be given with caution and under strict medical
supervision to patients with impaired liver function. In these patients, careful
monitoring of liver function, especially serum glutamic pyruvic transaminase
(SGPT) and serum glutamic oxaloacetic transaminase (SGOT) should be carried out
prior to therapy and then every 2 to 4 weeks during therapy. If signs of
hepatocellular damage occur, RIFATER 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 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.
Rifampin has enzyme-inducing properties, including induction of delta amino
levulinic acid synthetase. Isolated reports have associated porphyria
exacerbation with rifampin administration.
ISONIAZID. See the boxed WARNING.
Since RIFATER contains isoniazid, ophthalmologic examinations (including
ophthalmoscopy) should be done before treatment is started and periodically
thereafter, even without occurrence of visual symptoms.
PYRAZINAMIDE. Since RIFATER contains pyrazinamide, patients started on RIFATER
should have baseline serum uric acid and liver function determinations. Patients
with preexisting liver disease or those patients at increased risk for drug
related hepatitis (eg, alcohol abusers) should be followed closely.
Because it contains pyrazinamide, RIFATER should be discontinued and not be
resumed if signs of hepatocellular damage or hyperuricemia accompanied by an
acute gouty arthritis appear. If hyperuricemia accompanied by an acute gouty
arthritis occurs without liver dysfunction, the patient should be transferred to
a regimen not containing pyrazinamide.
PRECAUTIONS:
GENERAL
RIFATER should be used with caution in patients with a history of diabetes
mellitus, as diabetes management may be more difficult.
RIFAMPIN. For treatment of tuberculosis, rifampin is usually administered on a
daily basis. Doses of rifampin (>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 and renal failure.
The patient should be advised that the reliability of oral contraceptives may be
affected; consideration should be given to using alternative contraceptive
measures.
ISONIAZID. All drugs should be stopped and an evaluation of the patient should
be made at the first sign of a hypersensitivity reaction.
Use of RIFATER, because it contains isoniazid, should be carefully monitored in
the following:
1. Patients who are receiving phenytoin (diphenylhydantoin) concurrently.
Isoniazid may decrease the excretion of phenytoin or may enhance its effects. To
avoid phenytoin intoxication, appropriate adjustment of the anticonvulsant dose
should be made.
2. Daily users of alcohol. Daily ingestion of alcohol may be associated with a
higher incidence of isoniazid hepatitis.
3. Patients with current chronic liver disease or severe renal dysfunction.
PYRAZINAMIDE. Pyrazinamide inhibits renal excretion of urates, frequently
resulting in hyperuricemia which is usually asymptomatic. If hyperuricemia is
accompanied by acute gouty arthritis, RIFATER, because it contains pyrazinamide,
should be discontinued.
INFORMATION FOR PATIENTS
FOOD INTERACTIONS: Because isoniazid has some monoamine oxidase inhibiting
activity, an interaction with tyramine-containing foods (cheese, red wine) may
occur. Diamine oxidase may also be inhibited, causing exaggerated response (eg,
headache, sweating, palpitations, flushing, hypotension) to foods containing
histamine (eg, skipjack, tuna, other tropical fish). Tyramine- and histamine-
containing foods should be avoided in patients receiving RIFATER.
RIFATER, BECAUSE IT CONTAINS 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.
Patients should be instructed to take RIFATER either 1 hour before or 2 hours
after a meal.
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, 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), liver function tests, and blood uric acid
determinations 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 RIFATER dosing.
DRUG INTERACTIONS
RIFAMPIN. Enzyme Induction: Rifampin is known to induce certain cytochrome P-450
enzymes. Coadministration of RIFATER, because it contains rifampin, with drugs
that undergo biotransformation through these metabolic pathways may accelerate
elimination. 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 accelerate the metabolism of the following drugs:
anticonvulsants (eg, phenytoin), antiarrhythmics (eg, disopyramide, mexiletine,
quinidine, tocainide), anticoagulants, antifungals (eg, fluconazole,
itraconazole, ketoconazole), barbiturates, beta-blockers, calcium channel
blockers (eg, diltiazem, nifedipine, verapamil), chloramphenicol, ciprofloxacin,
corticosteroids, cyclosporine, cardiac glycoside preparations, clofibrate, oral
contraceptives, dapsone, diazepam, haloperidol, oral hypoglycemic agents
(sulfonylureas), methadone, narcotic analgesics, nortriptyline, progestins, and
theophylline. It may be necessary to adjust dosages of these drugs if they are
given concurrently with RIFATER since it contains rifampin.
Rifampin has been observed to increase the requirements for anticoagulant drugs
of the coumarin type. In patients receiving anticoagulants and RIFATER
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.
Concurrent use of ketoconazole and rifampin has resulted in decreased serum
concentration of both drugs. Concurrent use of rifampin and enalapril has
resulted in decreased concentrations of enalaprilat, the active metabolite of
enalapril. Since RIFATER contains rifampin, dosage adjustments should be made if
RIFATER is concurrently administered with ketoconazole or enalapril if indicated
by the patient's clinical condition.
OTHER INTERACTIONS: Concomitant antacid administration may reduce the
absorption of rifampin. Daily doses of RIFATER, because it contains 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 RIFATER,
because it contains both rifampin and isoniazid, and halothane should be
avoided. Patients receiving both rifampin and isoniazid as in RIFATER should be
monitored closely for hepatotoxicity. See the boxed WARNING.
Plasma concentrations of sulfapyridine may be reduced following the concomitant
administration of sulfasalazine and RIFATER, because it contains rifampin. This
finding may be the result of alteration in the colonic bacteria responsible for
the reduction of sulfasalazine to sulfapyridine and mesalamine.
ISONIAZID. Enzyme Inhibition: Isoniazid is known to inhibit certain cytochrome
P-450 enzymes. Coadministration of isoniazid with drugs that undergo
biotransformation through these metabolic pathways may decrease elimination.
Consequently, dosages of drugs metabolized by these enzymes may require
adjustment when starting or stopping concomitantly administered RIFATER, because
it contains isoniazid, to maintain optimum therapeutic blood levels.
Isoniazid has been reported to inhibit the metabolism of the following drugs:
anticonvulsants (eg, carbamazepine, phenytoin, primidone, valproic acid),
benzodiazepines (eg, diazepam), haloperidol, ketoconazole, theophylline, and
warfarin. It may be necessary to adjust the dosages of these drugs if they are
given concurrently with RIFATER because it contains isoniazid. The impact of the
competing effects of rifampin and isoniazid on the metabolism of these drugs is
unknown.
OTHER INTERACTIONS: Concomitant antacid administration may reduce the
absorption of isoniazid. Ingestion with food may also reduce the absorption of
isoniazid. Daily doses of RIFATER, because it contains isoniazid, should be
given on an empty stomach at least 1 hour before the ingestion of antacids or
food.
Corticosteroids (eg, prednisolone) may decrease the serum concentration of
isoniazid by increasing acetylation rate and/or renal clearance. Para-
aminosalicylic acid may increase the plasma concentration and elimination half-
life of isoniazid by competition of acetylating enzymes.
PHARMACODYNAMIC INTERACTIONS: Daily ingestion of alcohol may be associated with
a higher incidence of isoniazid hepatitis. Isoniazid, when given concomitantly
with rifampin, has been reported to increase the hepatotoxicity of both drugs.
Patients receiving both rifampin and isoniazid as in RIFATER should be monitored
closely for hepatotoxicity.
The CNS effects of meperidine (drowsiness), cycloserine (dizziness, drowsiness),
and disulfiram (acute behavioral and coordination changes) may be exaggerated
when concomitant RIFATER, because it contains isoniazid, is given. Concurrent
RIFATER, because it contains isoniazid, and levodopa administration may produce
symptoms of excess catecholamine stimulation (agitation, flushing, palpitations)
or lack of levodopa effect.
Isoniazid may produce hyperglycemia and lead to loss of glucose control in
patients on oral hypoglycemics.
Fast acetylation of isoniazid may produce high concentrations of hydrazine which
facilitate deflorination of enflurane. Renal function should be monitored in
patients receiving both RIFATER and enflurane.
FOOD INTERACTIONS: Because isoniazid has some monoamine oxidase inhibiting
activity, an interaction with tyramine-containing foods (cheese, red wine) may
occur. Diamine oxidase may also be inhibited, causing exaggerated response (eg,
headache, sweating, palpitations, flushing, hypotension) to foods containing
histamine (eg, skipjack, tuna, other tropical fish). Tyramine- and histamine-
containing foods should be avoided by patients receiving RIFATER.
DRUG/LABORATORY TESTS INTERACTION
RIFAMPIN. Therapeutic levels of rifampin have been shown to inhibit standard
microbiological assays for serum folate and vitamin B12. Therefore, alternative
assay methods should be considered. Transient abnormalities in liver function
tests (eg, elevation in serum bilirubin, abnormal bromsulphalein (BSP)
excretion, alkaline phosphatase and serum transaminases), and reduced biliary
excretion of contrast media used for visualization of the gallbladder have also
been observed. Therefore, tests should be performed before the morning dose of
RIFATER.
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.
PYRAZINAMIDE. Pyrazinamide has been reported to interfere with ACETEST(R) and
KETOSTIX(R) urine tests to produce a pink-brown color.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Increased frequency of chromosomal aberrations was observed In Vitro in
lymphocytes obtained from patients treated with combinations of rifampin,
isoniazid, and pyrazinamide and combinations of streptomycin, rifampin,
isoniazid, and pyrazinamide.
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
rifampicin was administered in doses two to ten 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 In Vitro, and humans. Antitumor
activity In Vitro has also been shown with rifampin.
There was no evidence of mutagenicity in bacteria, Drosophilia Melanogaster, or
mice. An increase in chromatid breaks was noted when whole blood cell cultures
were treated with rifampin.
ISONIAZID. Isoniazid has been reported to induce pulmonary tumors in a number of
strains of mice.
PYRAZINAMIDE. In lifetime bioassays in rats and mice, pyrazinamide was
administered in the diet at concentrations of up to 10,000 ppm. This resulted in
estimated daily doses of 2 g/kg for the mouse, or 40 times the maximum human
dose, and 0.5 g/kg for the rat, or 10 times the maximum human dose. Pyrazinamide
was not carcinogenic in rats or male mice and no conclusion was possible for
female mice.
Pyrazinamide was not mutagenic in the Ames bacterial test, but induced
chromosomal aberrations in human lymphocyte cell cultures.
PREGNANCY--TERATOGENIC EFFECTS
Category C. Animal reproduction studies have not been conducted with RIFATER. It
is also not known whether RIFATER can cause fetal harm when administered to a
pregnant woman. RIFATER should be given to a pregnant woman only if clearly
needed.
RIFAMPIN. Although rifampin has been reported to cross the placental barrier and
appear in cord blood, the effect of rifampin, alone or in combination with other
antituberculosis drugs, on the human fetus is not known. An increase in
congenital malformations, primarily spina bifida and cleft palate, has been
reported in the offspring of rodents given oral doses of 150 to 250 mg/kg/day of
rifampin during pregnancy. The possible teratogenic potential in women capable
of bearing children should be carefully weighed against the benefits of RIFATER
therapy.
ISONIAZID. It has been reported that in both rats and rabbits, isoniazid may
exert an embryocidal effect when administered orally during pregnancy, although
no isoniazid-related congenital anomalies have been found in reproduction
studies in mammalian species (mice, rats, and rabbits). RIFATER, because it
contains isoniazid, should be prescribed during pregnancy only when
therapeutically necessary. The benefit of preventive therapy should be weighed
against a possible risk to the fetus. Preventive treatment generally should be
started after delivery because of the increased risk of tuberculosis for new
mothers.
PYRAZINAMIDE. Animal reproductive studies have not been conducted with
pyrazinamide. It is also not known whether pyrazinamide can cause fetal harm
when administered to a pregnant woman. RIFATER, because it contains
pyrazinamide, should be given to a pregnant woman only if clearly needed.
PREGNANCY--NON-TERATOGENIC EFFECTS
It is not known whether RIFATER can affect reproduction capacity.
RIFAMPIN. When administered during the last few weeks of pregnancy, rifampin can
cause postnatal hemorrhages in the mother and infant. In this case, treatment
with vitamin K may be indicated for postnatal hemorrhage.
NURSING MOTHERS
Since rifampin, isoniazid, and pyrazinamide are known to pass into maternal
breast milk, a decision should be made whether to discontinue nursing or to
discontinue RIFATER, taking into account the importance of the drug to the
mother.
PEDIATRIC USE
Safety and effectiveness in children or adolescents under the age of 15 have not
been established.