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Rifampin, Isoniazid, Pyrazinamide, and Ethambutol (Systemic)


VA CLASSIFICATION
Primary: AM500

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.

Not commercially available in Canada.



Category:


Antibacterial (antimycobacterial)—

Indications

Note: Because rifampin, isoniazid, pyrazinamide, and ethambutol combination is not commercially available in the U.S. or Canada, the bracketed information and the use of the superscript 1 in this monograph reflect the lack of labeled (approved) indications for this medication.

General considerations
Human immunodeficiency virus (HIV)-infected persons have an increased incidence of tuberculosis; therefore, testing for HIV infection is indicated for all patients with tuberculosis. Most HIV-infected adults with drug-susceptible tuberculosis respond well to antituberculosis regimen when appropriate treatment is given early{01}. For the treatment of HIV-infected persons with tuberculosis, see General Dosing Information.

The World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease (IUATLD) recommend the replacement of single-drug preparations by fixed-dose combination formulations (FDCs) as the primary treatment for tuberculosis{02}. The justification for this recommendation is:   • FDCs provide a simple approach to delivering the correct number of drugs at the correct dosage as all the necessary drugs are combined in a single tablet{02}; and
   • By altering the number of tablets according to the patient's body weight, complete treatment is delivered without the need for calculation of dose{02}.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Rifampin: 822.94{03}
    Isoniazid: 137.14{04}
    Pyrazinamide: 123.11{05}
    Ethambutol: 277.23{06}

Mechanism of action/Effect:

Rifampin inhibits DNA-dependent RNA polymerase activity in susceptible cells. Rifampin interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme{07}{08}{09}. At therapeutic levels, rifampin has demonstrated bactericidal activity against both intracellular and extracellular Mycobacterium tuberculosis organisms{07}{08}{09}. Rifampin has also bactericidal activity against slow and intermittently growing M. tuberculosis organisms{07}{08}{09}. Rifampin cross resistance has been shown only with other rifamycins{08}{10}.

Isoniazid kills actively growing tubercle bacilli by inhibiting the biosynthesis of mycolic acids which are major components of the cell wall of M. tuberculosis{09}{10}{11}.

The exact mechanism of action by which pyrazinamide inhibits the growth of M. 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){09}{12}{13}{14}{15}.

Ethambutol diffuses into actively growing M. tuberculosis such as tubercle bacilli{16}. Ethambutol appears to inhibit the synthesis of one or more metabolites, thus causing impairment of cell metabolism, arrest of multiplication, and cell death{16}. No cross resistance with other available antimicrobial agents has been demonstrated{16}.

Absorption:

Rifampin is well absorbed from the gastrointestinal tract{07}.

Isoniazid is readily absorbed following oral administration{09}{17}.

Pyrazinamide is well absorbed from the gastrointestinal tract{09}{12}.

Ethambutol is rapidly absorbed from the gastrointestinal tract following oral administration{16}.

Distribution:

Rifampin diffuses well to most body tissues and fluids, including the cerebrospinal fluid (CSF), where concentrations are increased if the meninges are inflamed; concentrations in the liver, gallbladder, bile, and urine are higher than those found in the blood. Therapeutic concentrations are achieved in the saliva, reaching 20% of serum concentrations. Rifampin crosses the placenta, with fetal serum concentrations at birth found to be approximately 33% of the maternal serum concentration; it penetrates into aqueous humor and is distributed into breast milk. Because it is lipid-soluble, rifampin may reach and kill susceptible intracellular, as well as extracellular, bacteria and Mycobacteria species.{07}{08}{09}

VolD—1.6 L per kg{18}.

Isoniazid is widely distributed to all fluids and tissues, including CSF, pleural and ascitic fluids, skin, sputum, saliva, lungs, and muscle. It crosses the placenta and is distributed into breast milk{11}{17}.

VolD—0.57 to 0.76 L per kg{19}{20}.

Pyrazinamide is widely distributed to most fluids and tissues, including liver, lungs, kidneys, and bile. Pyrazinamide has excellent penetration into CSF, ranging from 87 to 105% of the corresponding serum concentration{21}{22}.

VolD—0.57 to 0.74 L per kg{23}{24}{25}.

Ethambutol is distributed to most tissues and body fluids, except CSF. Ethambutol does not penetrate intact meninges, but 10 to 50% may penetrate the meninges of patients with tuberculous meningitis{16}.

VolD—1.6 L per kg{16}.

Protein binding:

Rifampin—High to very high (89%){18}.

Isoniazid—Very low (0 to 10%){17}.

Pyrazinamide—Low (10 to 20%){24}{25}.

Pyrazinoic acid—Low (approximately 31%){25}.

Ethambutol—Low (20 to 30%){16}.

Biotransformation:

Hepatic; rifampin is rapidly deacetylated by auto-induced microsomal oxidative enzymes to the active metabolite (25-O-desacetylrifampin). Other identified metabolites include rifampin quinone, desacetyl rifampin quinone, and 3-formylrifampin{18}. Isoniazid is acetylated by N-acetyltransferase to N-acetylisoniazid; it is then biotransformed to isonicotinic acid and monoacetylhydrazine{17}. Monoacetylhydrazine is associated with hepatotoxicity via formation of a reactive intermediate metabolite when N-hydroxylated by the cytochrome P450 mixed oxidase system{08}{09}. Pyrazinamide is hydrolyzed by a microsomal deamidase to pyrazinoic acid, an active metabolite, and then hydroxylated by xanthine oxidase to 5-hydroxypyrazinoic acid{13}{23}{24}. Up to 15% of ethambutol is metabolized to inactive metabolites{16}.

Time to peak serum concentration

Rifampin—1.5 to 4 hours after oral administration; peak concentration may be decreased and delayed following administration with food{07}{08}{09}.

Isoniazid—1 to 2 hours{08}{09}.

Pyrazinamide—1 to 2 hours{23}{24}.

Pyrazinoic acid—4 to 5 hours{23}{24}.

Ethambutol—2 to 4 hours{16}.

Peak serum concentration


Rifampin:

Adults: 7 to 9 micrograms per mL (mcg/mL) after a single 600-mg oral dose{18}.

Children (6 to 58 months of age): Approximately 11 mcg/mL after a dose of 10 mg per kg of body weight (mg/kg){18}.



Isoniazid:

3 to 7 mcg/mL (21.9 to 51 micromoles per L) after a single 300-mg oral dose{17}.



Pyrazinamide:

Approximately 19 mcg/mL after a single dose of 14 mg/kg{23}{24}.

Approximately 39 mcg/mL after a single dose of 27 mg/kg{23}{24}.



Pyrazinoic acid:

Approximately 3 mcg/mL after a single dose of 14 mg/kg{23}{24}.

Approximately 4.5 mcg/mL after a single dose of 27 mg/kg{23}{24}.



Ethambutol:

2 to 5 mcg/mL after a single dose of 25 mg/kg{16}.


Elimination:


Rifampin—
        Biliary/fecal; enterohepatic recirculation of rifampin, but not of its deacetylated active metabolite; 60 to 65% of dose appears in feces{07}{08}{09}.
        Renal; 6 to 15% excreted as unchanged drug and 15% excreted as active metabolite in urine; 7% excreted as inactive 3-formyl derivative{07}{08}{09}.
        Rifampin does not accumulate in patients with impaired renal function; its rate of excretion is increased during the first 6 to 10 days of therapy, probably because of auto-induction of hepatic microsomal oxidative enzymes; after high doses, excretion may be slower because of saturation of its biliary excretory mechanism{07}{08}{09}.


In dialysis—
        Rifampin is not removed from the blood by either hemodialysis or peritoneal dialysis{07}{08}{09}.




Isoniazid—
        Renal; approximately 75 to 95% excreted by kidneys within 24 hours, primarily as the inactive metabolites, N-acetylisoniazid and isonicotinic acid; of this amount, 93% of the isoniazid excreted in the urine may occur as the acetylated form in fast acetylators and 63% in slow acetylators, with the remainder, in both cases, occurring as the free or conjugated form{08}{09}.
        Biliary/fecal; small amounts are excreted in feces{08}{09}.


In dialysis—
        Significant amounts of isoniazid are removed from the blood by hemodialysis. A single 5-hour hemodialysis period removes up to 73% of the isoniazid in the blood{17}.
        Peritoneal dialysis is of limited benefit{08}{09}.




Pyrazinamide—
        Renal; approximately 3% of unchanged pyrazinamide, 33% of pyrazinoic acid, and 36% of remaining identifiable metabolites excreted in urine within 72 hours{23}.


In dialysis—
        A single 3- to 4-hour hemodialysis session reduces serum pyrazinamide concentrations by approximately 55% and pyrazinoic acid concentrations by 50 to 60%{24}{25}.




Ethambutol—
        Renal; by glomerular filtration and tubular secretion; up to 80% excreted within 24 hours (at least 50% excreted unchanged and up to 15% as inactive metabolites).
        Fecal; 20% excreted unchanged{16}.


In dialysis—
        ethambutol is removed from the blood by hemodialysis and peritoneal dialysis{16}.




Precautions to Consider

Cross-sensitivity and/or related problems

Patients hypersensitive to ethionamide, niacin (nicotinic acid), other rifamycins (rifabutin and rifapentine), or other medications chemically related to rifampin, isoniazid, pyrazinamide, or ethambutol may be hypersensitive to this medication also.

Pregnancy/Reproduction

Note: Tuberculosis during pregnancy should be managed on a case-by-case basis because of the complexity of management decisions. Pyridoxine is indicated for all pregnant women receiving isoniazid{01}.


Pregnancy—

Rifampin

Rifampin crosses the placenta{10}. It has rarely caused postnatal hemorrhages in the mother and infant when administered during the last few weeks of pregnancy; vitamin K may be indicated. Neonates should be carefully observed for evidence of adverse effects{10}.

Imperfect osteogenesis and embryotoxicity were reported in rabbits given up to 20 times the usual daily human dose. Studies in rodents have shown that rifampin given in doses of 150 to 250 mg per kg of body weight (mg/kg) a day causes congenital malformations, primarily cleft palate and spina bifida{07}{08}{09}.

FDA Pregnancy Category C{07}{08}{09}.



Isoniazid

Isoniazid crosses the placenta, resulting in fetal serum concentrations that may exceed maternal serum concentrations. Problems in humans have not been documented{08}{09}{10}.

Studies in rats and rabbits have shown that isoniazid may be embryocidal. However, isoniazid has not been shown to be teratogenic in mice, rats, or rabbits{08}{09}.

FDA Pregnancy Category C{08}{09}.



Pyrazinamide

Adequate and well-controlled studies in humans have not been done; the risk of teratogenicity has not been determined.

Animal reproduction studies have not been conducted with pyrazinamide{09}{12}.

FDA Pregnancy Category C{09}{12}.



Ethambutol

Ethambutol crosses the placenta, resulting in fetal plasma concentrations that are approximately 30% of maternal plasma concentrations. However, problems in humans have not been documented{16}.

Studies in mice given high doses of ethambutol have shown that ethambutol causes a low incidence of cleft palate, exencephaly, and vertebral column abnormalities. In addition, studies in rats given high doses of ethambutol have shown that ethambutol causes minor abnormalities of the cervical vertebrae. Studies in rabbits given high doses of ethambutol have shown that ethambutol may cause monophthalmia, limb reduction defects, hare lip and cleft palate{16}.

FDA Pregnancy Category C{16}.


Breast-feeding

Note: Women who are receiving isoniazid and are breast-feeding should receive pyridoxine{01}.


Rifampin, isoniazid, pyrazinamide, and ethambutol are distributed into breast milk{10}. However, problems in humans have not been documented{07}{08}{09}{12}{16}.

Pediatrics

Ethambutol may cause reversible optic neuritis; therefore, patients should be monitored regularly for visual acuity, visual fields, and red-green color discrimination. Because cooperation is essential for performance of these tests, use of ethambutol in young children whose visual acuity cannot be monitored requires careful consideration of risks and benefits{01}.


Geriatrics


Appropriate studies on the relationship of age to the effects of rifampin, isoniazid, pyrazinamide, and ethambutol combination have not been performed in the geriatric population. However, elderly patients are more likely to have an age-related decrease in renal function, which may require an adjustment of dosage in patients receiving ethambutol. Furthermore, patients older than 50 years of age are more likely to develop hepatitis while receiving isoniazid than are patients in younger age groups{08}{09}.


Pharmacogenetics

Isoniazid—Patients can be divided into two groups: slow and rapid acetylators of isoniazid. Approximately 50% of blacks and Caucasians are slow acetylators; the majority of Eskimos and Asians are rapid acetylators. The rate of acetylation does not significantly alter the effectiveness of isoniazid. However, slow acetylation may lead to higher blood levels of isoniazid and, thus, an increase in toxic reactions. Slow acetylators are characterized by a relative lack of hepatic N-acetyltransferase. Patients who are slow acetylators may be more prone to develop adverse effects, especially peripheral neuritis, and may require lower-than-usual doses. Rapid acetylators do not generally require higher doses, nor is isoniazid less effective in these patients{08}{09}.


Dental

Rifampin—The leukopenic and thrombocytopenic effects of rifampin may result in an increased incidence of certain microbial infections, delayed healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene, including caution in the use of regular toothbrushes, dental floss, and toothpicks. Rifampin may cause a hypersensitivity reaction of sore mouth or tongue{08}{09}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Acetaminophen    (concurrent use of acetaminophen with isoniazid may increase the potential for hepatotoxicity and, possibly, nephrotoxicity; isoniazid is thought to induce cytochrome P450, resulting in a greater proportion of acetaminophen being converted to toxic metabolite{27}{28}{29})


» Alcohol    (concurrent daily use of alcohol may result in increased incidence of isoniazid- and rifampin-induced hepatotoxicity and increased metabolism of isoniazid and rifampin; dosage adjustments of isoniazid and rifampin may be necessary; patients should be monitored closely for signs of hepatotoxicity and should be advised to restrict intake of alcoholic beverages{08}{09})


» Alfentanil    (chronic preoperative or perioperative use of isoniazid, a hepatic enzyme inhibitor, may decrease the plasma clearance and prolong the duration of action of alfentanil{08}{09})


Allopurinol or
Colchicine or
Probenecid or
Sulfinpyrazone    (pyrazinamide may increase serum uric acid concentrations and decrease the efficacy of gout therapy; dosage adjustments of these medications may be necessary to control hyperuricemia and gout when antigout medications are used concurrently with pyrazinamide; probenecid may compete with rifampin for hepatic uptake when used concurrently, resulting in increased and more prolonged rifampin serum concentrations and/or toxicity; however, the effect on rifampin serum concentrations is inconsistent, and concurrent use of probenecid to increase rifampin serum concentrations is not recommended{30})


» Aminophylline or
» Oxtriphylline or
» Theophylline    (rifampin may increase metabolism of theophylline, oxtriphylline, and aminophylline by induction of hepatic microsomal enzymes, resulting in increased theophylline clearance{31}{32}{33}; concurrent use with isoniazid may reduce the metabolism of theophylline, increasing theophylline plasma concentrations{34})


» Amprenavir or
» Indinavir or
» Nelfinavir or
» Ritonavir or
» Saquinavir    (rifampin accelerates the metabolism of protease inhibitors, such as amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir through induction of hepatic P450 cytochrome oxidases, resulting in subtherapeutic levels of the protease inhibitors; in addition, protease inhibitors retard the metabolism of rifampin, resulting in increased serum levels of rifampin and the likelihood of increased toxicity; concurrent use of HIV protease inhibitors with rifampin is only recommended under specific circumstances [see General Dosing Information]{35}{36})


Anesthetics, hydrocarbon inhalation, except isoflurane    (long-term use of hepatic enzyme–inducing agents, such as rifampin, prior to anesthesia, except isoflurane, may increase anesthetic metabolism, leading to increased risk of hepatotoxicity{37})


Antacids, especially aluminum-containing    (antacids may delay and decrease absorption and serum concentrations of orally administered isoniazid; concurrent use should be avoided, or patients should be advised to take oral isoniazid at least 1 hour before aluminum-containing antacids{38})


» Anticoagulants, coumarin- or indandione-derivative    (concurrent use with rifampin may enhance the metabolism of these anticoagulants by induction of hepatic microsomal enzymes, resulting in considerable decrease in the activity and effectiveness of the anticoagulants; prothrombin time determinations may be required as frequently as daily; dosage adjustments of anticoagulants may be required before and after rifampin therapy; concurrent use with isoniazid may result in increased anticoagulant effect because of the inhibition of enzyme metabolism of anticoagulants{37}{39})


» Antidiabetic agents, oral    (concurrent use with rifampin may enhance the metabolism of tolbutamide, chlorpropamide, and glyburide by induction of hepatic microsomal enzymes, resulting in lower serum sulfonylurea concentrations; although not documented, other oral antidiabetic agents may also interact with rifampin; dosage adjustment may be required{40})


» Azole antifungals    (concurrent use may increase the metabolism of the azole antifungals, lowering their plasma concentrations; depending on the clinical situation, the dose of an azole antifungal may need to be increased during concurrent use with rifampin; concurrent use of ketoconazole with isoniazid has been reported to decrease serum concentrations of ketoconazole; isoniazid should be used with caution when given concurrently with ketoconazole{41}{42})


Barbiturates    (concurrent use with rifampin may enhance the metabolism of hexobarbital by induction of hepatic microsomal enzymes, resulting in lower serum concentrations; there are conflicting data on rifampin's effect on phenobarbital; dosage adjustment may be required{37})


Benzodiazepines    (isoniazid may decrease the hepatic metabolism of benzodiazepines, such as diazepam, chlordiazepoxide, flurazepam, and prazepam, that are metabolized by phase I reactions [N-demethylation and hydroxylation]; it may also impair the oxidation of triazolam, by increasing plasma benzodiazepine concentrations; isoniazid may decrease first-pass metabolism and elimination of midazolam in the liver, probably by competitive inhibition at the cytochrome P450 binding sites, increasing steady-state plasma concentrations of midazolam{38}{43}; concurrent use with rifampin may enhance the elimination of diazepam, resulting in decreased plasma concentrations; whether this effect applies to other benzodiazepines has not been determined; dosage adjustment may be necessary{44})


Beta-adrenergic blocking agents, systemic    (concurrent use of metoprolol or propranolol with rifampin has resulted in reduced plasma concentrations of these two beta-adrenergic blocking agents due to enhanced metabolism of hepatic microsomal enzymes by rifampin; although not documented, other beta-adrenergic blocking agents may also interact with rifampin{31})


Bone marrow depressants (see Appendix II)     (concurrent use of bone marrow depressants with rifampin may increase the leukopenic and/or thrombocytopenic effects; if concurrent use is required, close observation for myelotoxic effects should be considered)


» Carbamazepine    (concurrent use with isoniazid increases serum carbamazepine levels and toxicity, probably through inhibition of carbamazepine metabolism{45}{46}; also, carbamazepine may induce microsomal metabolism of isoniazid, increasing formation of an INH-reactive intermediate metabolite, which may lead to hepatotoxicity{43})


Cheese, such as Swiss or Cheshire, or
Fish, such as tuna, skipjack, or Sardinella    (concurrent ingestion with isoniazid may result in redness or itching of the skin, hot feeling, rapid or pounding heartbeat, sweating, chills or clammy feeling, headache, or lightheadedness; this is thought to be due to the inhibition of plasma monoamine oxidase and diamine oxidase by isoniazid, interfering with the metabolism of histamine and tyramine found in fish and cheese{47}{48})


» Chloramphenicol    (concurrent use with rifampin may enhance the metabolism of chloramphenicol by induction of hepatic microsomal enzymes, resulting in significantly lower serum chloramphenicol concentrations; dosage adjustment may be necessary{49}{50})


Clofazimine    (concurrent use with rifampin has resulted in reduced absorption of rifampin, delaying its time to peak concentration and increasing its half-life{18})


Clofibrate    (concurrent use with rifampin may enhance the metabolism of clofibrate by induction of hepatic microsomal enzymes, resulting in significantly lower serum clofibrate concentrations{51})


» Contraceptives, estrogen-containing, oral    (concurrent use with rifampin may decrease the effectiveness of estrogen-containing oral contraceptives because of stimulation of estrogen metabolism or reduction in enterohepatic circulation of estrogens, resulting in menstrual irregularities, intermenstrual bleeding, and unplanned pregnancies; patients should be advised to use an additional method of contraception throughout the whole cycle while taking rifampin and estrogen-containing oral contraceptives concurrently{07}{08}{09})


» Corticosteroids, glucocorticoid and mineralocorticoid     (concurrent use with rifampin may enhance the metabolism of corticosteroids by induction of hepatic microsomal enzymes, resulting in a considerable decrease in corticosteroid plasma concentrations; dosage adjustment may be required; rifampin has also counteracted endogenous cortisol and produced acute adrenal insufficiency in patients with Addison's disease{30}{37}{52}; concurrent use of prednisolone, and other related corticosteroids, with isoniazid may increase hepatic metabolism and/or excretion of isoniazid, leading to decreased plasma concentrations and effectiveness of isoniazid, especially in patients who are rapid acetylators; isoniazid dosage adjustments may be required{38})


Cycloserine    (concurrent use may result in increased incidence of central nervous system [CNS] effects such as dizziness or drowsiness; dosage adjustments may be necessary and patients should be monitored closely for signs of CNS toxicity{38})


Cyclosporine    (concurrent use with pyrazinamide may decrease the serum concentration of cyclosporine, possibly leading to inadequate immunosuppression; cyclosporine serum concentrations should be monitored; rifampin may enhance metabolism of cyclosporine by induction of hepatic microsomal enzymes and intestinal cytochrome P450 enzymes; dosage adjustment may be required{31}{53}{54}{55})


Dapsone    (concurrent use with rifampin may decrease the effect of dapsone because of increased metabolism resulting from stimulation of hepatic microsomal enzyme activity; dapsone concentrations may be decreased by half; dapsone dosage adjustments are not required during concurrent therapy with rifampin for leprosy{30})


» Delavirdine or
» Efavirenz or
» Nevirapine    (rifampin accelerates the metabolism of nonnucleoside reverse transcriptase inhibitors (NNRTIs), such as delavirdine, efavirenz, and nevirapine through induction of hepatic P450 cytochrome oxidases, resulting in subtherapeutic levels of NNRTIs; in addition NNRTIs retard the metabolism of rifampin, resulting in increased serum levels of rifampin and the likelihood of increased toxicity; concurrent use of NNRTIs with rifampin is only recommended under specific circumstances [SeeGeneral Dosing Information]{35}{36})


» Digitalis glycosides    (concurrent use with rifampin may enhance the metabolism of digoxin or digitoxin by induction of hepatic microsomal enzymes, resulting in significantly lower serum digoxin or digitoxin concentrations; dosage adjustment may be necessary{31})


» Disopyramide or
» Mexiletine or
Propafenone or
» Quinidine or
» Tocainide    (concurrent use with rifampin may enhance the metabolism of these antiarrhythmics by induction of hepatic microsomal enzymes, resulting in significantly lower serum antiarrhythmic concentrations; serum antiarrhythmic concentrations should be monitored and dosage adjustment may be necessary{37}{56}{57}{58}{59})


» Disulfiram    (concurrent use in alcoholics may result in increased incidence of CNS effects such as dizziness, incoordination, irritability, or insomnia; reduced dosage or discontinuation of disulfiram may be necessary{38})


Enflurane    (isoniazid may increase formation of the potentially nephrotoxic inorganic fluoride metabolite when used concurrently with enfluran{38})


» Estramustine or
» Estrogens    (concurrent use of estramustine or estrogens with rifampin may result in significantly reduced estrogenic effect because of stimulation of estrogen metabolism or reduction in enterohepatic circulation of estrogens{60})


» Hepatotoxic medications, other (see Appendix II)    (concurrent use of rifampin and isoniazid and other hepatotoxic medications may increase the potential for hepatotoxicity and should be avoided)


» Methadone    (concurrent use with rifampin may decrease the effects of methadone because of stimulation of hepatic microsomal enzyme activity and/or impaired absorption, resulting in symptoms of methadone withdrawal if the patient is dependent on methadone; dosage adjustments may be necessary during and after rifampin therapy{37})


Neurotoxic medications, other (see Appendix II)    (concurrent use of other neurotoxic medications with isoniazid and ethambutol may produce additive neurotoxicity)


» Phenytoin    (concurrent use with isoniazid inhibits the metabolism of phenytoin, resulting in increased phenytoin serum concentrations and toxicity; phenytoin dosage adjustments may be necessary during and after isoniazid therapy, especially in slow acetylators of isoniazid{61}; concurrent use with rifampin may stimulate the hepatic metabolism of phenytoin, increasing its elimination and thus counteracting its anticonvulsant effects; careful monitoring of serum hydantoin concentrations and dosage adjustments may be necessary before and after rifampin therapy{62}{63})


Pyridoxine    (isoniazid may cause peripheral neuritis by acting as a pyridoxine antagonist or increasing renal excretion of pyridoxine; requirements for pyridoxine may be increased in patients receiving isoniazid concurrently{08}{09})


Trimethoprim    (concurrent use with rifampin may significantly increase the elimination and shorten the elimination half-life of trimethoprim{64})


» Verapamil, oral    (rifampin has been found to accelerate the metabolism of oral verapamil, resulting in a significant decrease in serum verapamil concentration and reversing its cardiovascular effects; concurrent use of intravenous verapamil with rifampin was found to have only minor effects on verapamil's clearance and no significant effect on cardiovascular function{31})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Coomb's (antiglobulin) tests, direct    (rarely, may become positive during rifampin therapy{64})


Dexamethasone suppression test    (rifampin may prevent the inhibitory action of a standard dexamethasone dose administered for the overnight suppression test, rendering the test abnormal; it is recommended that rifampin therapy be discontinued 15 days before the dexamethasone suppression test is administered{66})


Folate determinations, serum and
Vitamin B12 determinations, serum     (therapeutic concentrations of rifampin may interfere with standard microbiological assays for serum folate and vitamin B12; alternative methods must be considered when determining serum folate and vitamin B12 concentrations in patients taking rifampin{67})


Glucose, urine    (isoniazid may cause hyperglycemia with a secondary glycosuria, giving a positive response to copper sulfate tests; glucose enzymatic tests are not affected{68})


Ketone determinations, urine    (may react with sodium nitroprusside tests, such as Acetest or Chemstrip K; both pyrazinamide and pyrazinoic acid produce an interfering pink-brown color reaction with nitroprusside{69})


Sulfobromophthalein (BSP) uptake and excretion    (hepatic uptake and excretion of BSP in liver function tests may be delayed by rifampin, resulting in BSP retention; the BSP test should be performed prior to the daily dose of rifampin to avoid false-positive test results{07}{08}{09})


Urinalyses based on spectrometry or color reaction    (rifampin may interfere with urinalyses that are based on spectrometry or color reaction, due to rifampin's reddish-orange to reddish-brown discoloration of urine{65})

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Alkaline phosphatase and
Aspartate aminotransferase (AST [SGOT])    (values may be increased{07}{08}{09})


Bilirubin, serum and
Blood urea nitrogen (BUN) and
Uric acid, serum    (concentration may be increased{09}{70})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Alcoholism, active or in remission    (increased risk of hepatitis with daily consumption of alcohol{07}{08}{09})


Gout, history of    (pyrazinamide and ethambutol can increase serum uric acid concentrations and precipitate an acute attack of gout{71})


» Hepatic function impairment, severe    (rifampin, isoniazid, and pyrazinamide are metabolized in the liver and may also be hepatotoxic{07}{08}{09}{72})


» Hypersensitivity to isoniazid, ethambutol, ethionamide, pyrazinamide, niacin (nicotinic acid), or other chemically related medications
Hypersensitivity to rifampin, rifabutin, and/or rifapentine
» Optic neuritis    (ethambutol may cause retrobulbar optic neuritis{12})


» Renal function impairment    (ethambutol is excreted primarily through the kidneys, patients with a renal function impairment may require a reduction in dosage; there may be an increased risk of isoniazid toxicity in patients who have severe renal failure [creatinine clearance < 10 mL/min or 0.17 mL/sec]{08}{09}{12})


Seizure disorders    (isoniazid may be neurotoxic and cause seizures{08}{09})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Hepatic function determinations    (ALT [SGPT], AST [SGOT], alkaline phosphatase, and serum bilirubin determinations may be indicated prior to and monthly or more frequently during treatment; however, elevated serum enzyme values may not be predictive of clinical hepatitis and may return to normal despite continued treatment; patients with impaired hepatic function should not receive rifampin, isoniazid, pyrazinamide, and ethambutol combination unless it is crucial to therapy{07}{08}{09}{11})


» Ophthalmologic examinations    (symptoms of optic neuritis may occur in either adults or children during treatment due to adverse effects of isoniazid and/or ethambutol; tests for visual fields and acuity and red-green discrimination may be required prior to and monthly during treatment, especially if treatment is prolonged or if dosage is greater than 15 mg per kg of body weight [mg/kg] daily{07}{08}{09}{12})


Uric acid concentrations, serum    (may be required during treatment, since elevated serum uric acid concentrations frequently occur due to ethambutol and/or pyrazinamide, possibly resulting in precipitation of acute gout{09}{12})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Hepatitis (dark urine; yellow eyes or skin)
    
hepatitis prodromal symptoms (loss of appetite; nausea and vomiting; unusual tiredness or weakness)
    
peripheral neuritis (clumsiness or unsteadiness; numbness, tingling, burning, or pain in hands and feet )

Note: Severe and sometimes fatal hepatitis associated with isoniazid therapy may occur and may develop even after many months of treatment{08}{09}. The risk of developing hepatitis is age related. It is more prevalent in patients over 50 years of age{08}{09}. If signs and symptoms of hepatotoxicity occur, rifampin, isoniazid, pyrazinamide, and ethambutol combination should be discontinued promptly{08}{09}.


Incidence less frequent
    
“Flu-like” syndrome (chills; difficulty in breathing; dizziness; fever; headache; muscle and bone pain; shivering)
    
gouty arthritis, acute (chills; pain and swelling of joints, especially big toe, ankle, or knee; tense, hot skin over affected joints)
    
hypersensitivity (itching; redness; skin rash)
{07}{08}{09}{12}{16}
Incidence rare
    
Blood dyscrasias (sore throat; unusual bleeding or bruising)
    
interstitial nephritis (bloody or cloudy urine; greatly decreased frequency of urination or amount of urine)
    
neurotoxicity (seizures; mental depression; mood or other mental changes )
    
retrobulbar optic neuritis (blurred vision or loss of vision, with or without eye pain)
{07}{08}{09}{12}{16}


Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Confusion
    
gastrointestinal disturbances (diarrhea; nausea and vomiting; stomach pain)
    
headache
{07}{08}{09}{12}{16}
Incidence less frequent
    
Fungal overgrowth (sore mouth or tongue){07}{08}{09}



Those not indicating need for medical attention
Incidence more frequent
    
Reddish-orange to reddish-brown discoloration of urine, feces, saliva, sputum, sweat, and tears {07}{08}{09}

Note: Tears discolored by rifampin may also discolor soft contact lenses.






Overdose
For specific information on the agents used in the management of rifampin, isoniazid, pyrazinamide, and ethambutol overdose, see:    • Pyridoxine (Systemic) in monograph;
   • Diazepam in Benzodiazepines (Systemic) monograph; and/or
   • Thiopental in Barbiturates (Systemic) monograph.

For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

There is no experience with rifampin, isoniazid, pyrazinamide, and ethambutol combination overdose in humans. Therefore, the information below applies to rifampin and/or isoniazid overdose only. Experience with pyrazinamide overdose is limited.

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and Chronic
    
Gastrointestinal disturbances (nausea and vomiting)
    
mental obtundation ( mental changes)
    
metabolic acidosis
    
neurotoxicity (coma; disorientation ; dizziness; hyperreflexia; lethargy; seizures; slurred speech)
    
periorbital or facial edema (swelling around the eyes or the whole face)
    
pruritus, generalized ( itching over the whole body)
    
Redman syndrome (red-orange discoloration of skin, mucous membranes, and sclera){73}{74}{75}

Note: Patients may be asymptomatic for 30 minutes to 2 hours after an acute overdose. Early symptoms include nausea and vomiting, dizziness, slurred speech, lethargy, disorientation, and hyperreflexia. Seizures usually occur within 1 to 3 hours after ingestion, and are often repetitive and refractory to treatment with usual anticonvulsants. Lactic acid accumulation produces an anion-gap metabolic acidosis within a few hours, which is often severe and refractory to treatment with sodium bicarbonate. Hyperglycemia, glycosuria, and ketonuria have also been reported{73}{74}{75}.



Treatment of overdose


To decrease absorption:
Because seizures may occur soon after ingestion, induction of emesis with ipecac is not recommended. Gastric lavage may be performed within 2 to 3 hours of ingestion, and activated charcoal and a cathartic may be administered if the patient's seizures are controlled and the airway protected{73}{74}{75}.



Specific treatment:
Administering intravenous pyridoxine in a gram-for-gram dose, equivalent to the amount of isoniazid ingested; dose should be administered as a 5 or 10% solution in water for injection over 30 to 60 minutes. If the amount of isoniazid ingested is unknown, administering 5-gram doses of pyridoxine every 5 to 30 minutes until seizures stop or consciousness is regained{73}{74}{75}.

Controlling seizures with diazepam, which acts synergistically with pyridoxine. Phenytoin should be used with caution, if at all, since isoniazid inhibits phenytoin metabolism. Thiopental has been effective in treating refractory seizures{73}{74}{75}.

Carefully administering sodium bicarbonate if pyridoxine and diazepam do not control seizure activity. Use caution against overcorrection and watch for hypokalemia or hyperkalemia{73}{74}{75}.



Supportive care:
Supportive measures such as establishing intravenous lines, hydration, correction of electrolyte imbalance, oxygenation, and support of ventilatory function are essential for maintaining the vital functions of the patient. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation{73}{74}{75}.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Rifampin, Isoniazid, Pyrazinamide, and Ethambutol (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to rifampin, isoniazid, pyrazinamide, ethionamide, niacin (nicotinic acid), rifabutin, rifapentine, or other chemically related medications

Pregnancy—Rifampin, isoniazid, and ethambutol cross the placenta





Breast-feeding—Rifampin, isoniazid, pyrazinamide, and ethambutol are distributed into breast milk




Use in children——Ethambutol generally is not recommended in children whose visual acuity cannot be monitored (younger than 6 years of age)






Use in the elderly—Patients 50 years of age and older have the highest incidence of hepatitis with use of isoniazid
Other medications, especially daily alcohol consumption, alfentanil, aminophylline, amprenavir, coumarin- or indandione-derivative anticoagulants, oral antidiabetic agents, azole antifungals, carbamazepine, chloramphenicol, oral estrogen-containing contraceptives, corticosteroids, delavirdine, digitalis glycosides, disopyramide, disulfiram, efavirenz, estramustine, estrogens, other hepatotoxic medications, indinavir, methadone, mexiletine, nelfinavir, nevirapine, oxtriphylline, phenytoin, quinidine, ritonavir, saquinavir, theophylline, tocainide, or oral verapamil
Other medical problems, especially alcoholism, active or in remission, hepatic function impairment, optic neuritis, or renal function impairment

Proper use of this medication
Taking this medication with food or antacids, but not within 1 hour of aluminum-containing antacids, if gastrointestinal irritation occurs

» Compliance with full course of therapy, which may take months or years

» Taking pyridoxine concurrently to prevent or minimize symptoms of peripheral neuritis

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next scheduled dose; not doubling doses; intermittent dosing may result in more frequent and/or severe side effects

» Proper storage

Precautions while using this medication
» Regular visits to physician to check progress, as well as ophthalmologic examinations if signs of optic neuritis occur

» Checking with physician if no improvement within 2 to 3 weeks

» Using an alternate method of contraception if taking estrogen-containing oral contraceptives concurrently

» Avoiding alcoholic beverages while taking this medication

» Checking with physician if vascular reactions occur following concurrent ingestion of cheese or fish with isoniazid-containing medication

» Checking with physician if blurred vision or loss of vision occurs

» Medication causes urine, feces, saliva, sputum, sweat, and tears to turn reddish-orange to reddish-brown and may also permanently discolor soft contact lenses; avoiding the wearing of soft contact lenses

» Need to report to physician promptly prodromal signs of hepatitis or peripheral neuritis

» Using caution in use of regular toothbrushes, dental floss, and toothpicks; deferring dental work until blood counts have returned to normal; checking with physician or dentist concerning proper oral hygiene

Possible interference with diagnostic tests

» Diabetics: May interfere with urine ketone determinations


Side/adverse effects
Hepatitis caused by isoniazid is more likely to occur in patients 50 years of age and older

Reddish-orange to reddish-brown discoloration of urine, stools, saliva, sputum, sweat, and tears may be alarming to patient, although medically insignificant; however, tears discolored by rifampin may also discolor soft contact lenses

Signs of potential side effects, especially hepatitis, hepatitis prodromal symptoms, peripheral neuritis, “flu-like” syndrome, acute gouty arthritis, hypersensitivity, blood dyscrasias, interstitial nephritis, neurotoxicity, and optic neuritis


General Dosing Information
Rifampin, isoniazid, pyrazinamide, and ethambutol combination is indicated in the initial phase of the short-course treatment of tuberculosis. During this phase, which should last 2 to 3 months, rifampin, isoniazid, pyrazinamide, and ethambutol combination should be administered on a daily, continuous basis{02}.

Following the initial phase of treatment with rifampin, isoniazid, pyrazinamide, and ethambutol combination, treatment should be continued with rifampin and isoniazid for at least 4 months{02}. 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 human immunodeficiency virus (HIV)-positive{01}.

The duration of treatment with an antituberculosis regimen is at least 6 months, and treatment may be continued for 2 years. Uncomplicated pulmonary tuberculosis is often successfully treated within 6 to 12 months{76}.

The duration of antituberculosis therapy is based on the patient's clinical and radiographic responses, smear and culture results, and susceptibility studies of Mycobacterium tuberculosis isolates from the patient or the suspect source case. With directly observed therapy (DOT), clinical evaluation is an integral component of each visit for administration of medication. Careful monitoring of the clinical and bacteriologic responses to therapy on a monthly basis in sputum-positive patients is important{76}.

If therapy is interrupted, the treatment schedule should be extended to a later completion date. Although guidelines cannot be provided for every situation, the following factors need to be considered in establishing a new date for completion:   • The length of interruption;
   • The time during therapy (early or late) in which interruption occurred; and
   • The patient's clinical, radiographic, and bacteriologic status before, during, and after interruption. Consultation with an expert is advised{01}{76}.


Untoward effects of isoniazid therapy, including severe hepatitis, in otherwise healthy infants, children, and adolescents are rare. Routine determination of serum aminotransferase concentrations is not recommended. However, for children with severe tuberculosis, especially meningitis or disseminated disease, aminotransferase concentrations should be monitored approximately monthly during the first several months of treatment. Other indications for testing include the following:   • concurrent or recent liver disease;
   • high daily dose of isoniazid (more than 10 mg/kg per day) in combination with rifampin, pyrazinamide, or both;
   • pregnancy or first 6 weeks postpartum;
   • clinical evidence of hepatotoxic effects;
   • hepatobiliary tract disease from other causes; or
   • concurrent use of other hepatotoxic drugs (especially anticonvulsants){01}.


In most other circumstances, monthly clinical evaluations for 3 months, followed by evaluation every 1 to 3 months to observe for signs or symptoms of hepatitis and other adverse effects of drug therapy without routine monitoring of aminotransferase levels, is an appropriate schedule for follow-up. In all cases, regular physician-patient contact to assess drug adherence, efficacy, and toxic effects is an important aspect of management{01}.

Protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) are antiretroviral agents that may inhibit or induce cytochrome P450 isoenzymes (CYP450){35}. Rifamycins (rifampin, rifabutin, and rifapentine) are antituberculosis agents that induce CYP450 and may decrease substantially blood levels of the antiretroviral drugs{35}. These pharmacologic interactions are called "drug-drug" because, in addition to the effect rifamycins have on protease inhibitors and NNRTIs, the antiretroviral agents may affect the blood levels of rifamycins{35}.

The Centers for Disease Control and Prevention (CDC) provides the following recommendations for the management of these interactions that can result when patients receive PIs and NNRTIs for the treatment of HIV infection together with rifamycins for the treatment of tuberculosis{35}:   • The other class of antiretroviral agents, i.e., nucleoside reverse transcriptase inhibitors (NRTIs), are not metabolized by CYP450. Concurrent use of NRTIs and rifamycins is not contraindicated and does not require dose adjustments{36}{77}.
   • Rifampin can be used for the treatment of active tuberculosis in three situations:   —in a patient whose antiretroviral regimen includes the NNRTI efavirenz and two NRTIs{36}{78};
   —in a patient whose antiretroviral regimen includes the protease inhibitor ritonavir and one or more NRTIs{36}{79}; or
   —in a patient whose antiretroviral regimen includes the combination of two protease inhibitors (ritonavir and either saquinavir hard-gel capsule [HGC] or saquinavir soft-gel capsule [SGC]){36}{80}.

   • In addition, the CDC recommends substantially reducing the dose of rifabutin (150 mg two or three times per week) when it is administered to patients taking ritonavir with or without saquinavir HGC or saquinavir SGC) and increasing the dose of rifabutin (either 450 mg or 600 mg daily or 600 mg two or three times per week) when rifabutin is used concurrently with efavirenz{36}{81}{82}.
   • Of the available PIs, ritonavir has the highest potency in inhibiting CYP450{35}. The inhibition of this pathway increases plasma concentrations of other coadministered PIs, an interaction exploited in different combinations (e.g., ritonavir at low doses [400 mg twice per day] in combination with saquinavir [400 mg twice per day] substantially increases blood levels of saquinavir){36}{83}.
   • For patients treated with two PIs, the complexity of drug interactions is amplified, and recommendations about dose modifications are difficult when rifamycins also are administered. However, if ritonavir (taken in doses ranging from 100 mg to 600 mg twice per day) is combined with any other PI for HIV therapy, and the administration of rifabutin also becomes necessary, the need to use substantially reduced doses of rifabutin (150 mg two or three times per week) is certain. In comparison, for a patient who is undergoing treatment with saquinavir SGC (a relatively weak CYP450 inhibitor and two NRTIs, the usual dosage (300 mg daily or two or three times per week) of rifabutin should not be decreased{35}{36}{84}.
   • When both an inhibitor and an inducer of CYP450 are used with rifamycins (e.g., a PI in combination with a NNRTI), a different complex interaction occurs and the appropriate drug-dose adjustments necessary to ensure optimum levels of both antiretroviral drugs and rifamycins are unknown{36}.
   • Alternatively, for patients undergoing therapy with complex combinations of PIs or NNRTIs, the use of antituberculosis regimens containing no rifamycins can be considered. Isoniazid does not have an interactive effect with either the PI or NNRTIs, and the use of a 9-month regimen of isoniazid is recommended as the preferred option for treatment for latent M. tuberculosis infection. However, 2-month regimens of a rifamycin and pyrazinamide also are recommended for latent M. tuberculosis infection treatment{36}.
   • If these regimen options are chosen for HIV-infected patients with latent M. tuberculosis infection, the drug-drug interactions and dose adjustments for antiretroviral drugs and rifamycins apply. However, for HIV-infected patients with active tuberculosis, use of a treatment regimen that does not contain a rifamycin, although possible, may be sub-optimal and usually is not recommended{36}.
   • The management of HIV-infected patients taking PIs or NNRTIs and undergoing treatment for active tuberculosis with rifabutin or rifampin should be directed by, or conducted in consultation with, a physician with experience in the care of patients with these two diseases. This care should include close attention to the possibility of tuberculosis treatment failure, antiretroviral treatment failure, paradoxical reactions of tuberculosis, unique and synergistic side effects for all drugs used, and drug toxicities associated with increased serum concentrations of rifamycins{36}.


Health care or correctional institutions experiencing outbreaks of tuberculosis that are resistant to isoniazid and rifampin, or that are resuming therapy for a patient with a prior history of antitubercular therapy, may need to begin five- or six-drug regimens as initial therapy. These regimens should include the four-drug regimen and at least three medications to which the suspected multidrug-resistant strain may be susceptible{85}.


Oral Dosage Forms

Note: Because rifampin, isoniazid, pyrazinamide, and ethambutol combination is not commercially available in the U.S. or Canada, the bracketed information and the use of the superscript 1 in this monograph reflect the lack of labeled (approved) indications for this medication.

The World Health Organization (WHO) recommends the fixed-dose combination of rifampin 150 mg, isoniazid 75 mg, pyrazinamide 400 mg, and ethambutol 275 mg for the daily administration in the initial phase of tuberculosis treatment{02}. The WHO-recommended fixed-dose combination is not commercially available in the U.S. or Canada.

RIFAMPIN, ISONIAZID, PYRAZINAMIDE, AND ETHAMBUTOL tablets

Usual Adult Dose
[ Tuberculosis]1
Patients weighing between 30 and 37 kg: Oral, 2 tablets once a day{02}.

Patients weighing between 38 and 54 kg: Oral, 3 tablets once a day{02}.

Patients weighing between 55 and 70 kg: Oral, 4 tablets once a day{02}.

Patients weighing 71 kg or more: Oral, 5 tablets once a day{02}.


Usual Pediatric Dose
[ Tuberculosis]1
Infants and children under 30 kg of body weight: Use is not recommended.

Children weighing 30 kg or more: See Usual adult dose{02}.


Strength(s) usually available
U.S.—
Not commercially available.

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by the manufacturer. Protect from excessive humidity.

Auxiliary labeling:
   • Continue taking the medicine for full time of treatment.
   • Avoid alcoholic beverages.
   • May discolor body fluids.

1 Not included in Canadian product labeling.


Developed: 3/13/2002



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