Ethambutol and Isoniazid (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 ethambutol and isoniazid 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.


Accepted

[Tuberculosis (treatment)]1—The fixed-dose combination of ethambutol and isoniazid (400 mg ethambutol and 150 mg isoniazid) is indicated in the treatment of all forms of tuberculosis, in the continuation phase of antitubercular treatment {01}.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Note: Preliminary data suggest that patients coinfected with the human immunodeficiency virus (HIV) and mycobacteria (Mycobacterium tuberculosis or Mycobacterium avium ) have altered pharmacokinetic profiles for antimycobacterial agents {02} {03}. In particular, malabsorption of these agents appears to occur frequently and could seriously affect the efficacy of treatment {02} {03}.


Physicochemical characteristics:
Molecular weight—
    Ethambutol: 277.24
    Isoniazid: 137.14 {05}

Mechanism of action/Effect:

Ethambutol is a synthetic, bacteriostatic antitubercular agent {04}. Ethambutol diffuses into actively growing mycobacteria cells such as tubercle bacilli {04}. It appears to inhibit the synthesis of one or more metabolites, thus impairing cell metabolism, arresting multiplication, and resulting in cell death {04}.

Isoniazid is a synthetic, bactericidal antitubercular agent {05}. It kills actively growing tubercle bacilli by inhibiting the biosynthesis of mycolic acid, which is a major component of the cell wall of M. tuberculosis {05}.

Absorption:

Both ethambutol and isoniazid are rapidly absorbed from the gastrointestinal tract following oral administration {04} {05}. However, isoniazid may undergo significant first-pass metabolism {05}. Absorption and bioavailability are reduced when ethambutol and isoniazid are administered with food {04} {05}.

Distribution:

Ethambutol—Widely distributed to most tissues and body fluids except cerebrospinal fluid (CSF) {04}. CSF concentrations are 10 to 50% of the corresponding serum concentrations {04}. Ethambutol is distributed into breast milk {04}. Ethambutol does not penetrate intact meninges, but 10 to 50% may penetrate the meninges of patients with tuberculous meningitis {04}.

Vol D—1.6 L per kg {04}.

Isoniazid—Widely distributed to all fluids and tissues, including CSF, pleural and ascitic fluids, skin, sputum, saliva, lungs, muscle, and caseous tissue {05}. Isoniazid crosses the placenta and is distributed into breast milk {05}.

Vol D—0.57 to 0.76 L per kg {05}.

Protein binding:

Ethambutol—Low (20 to 30%) {04}.

Isoniazid—Very low (0 to 10%) {05}.

Biotransformation:

Ethambutol—Hepatic; up to 15% metabolized to inactive metabolites {04}.

Isoniazid—Hepatic; isoniazid is acetylated by N-acetyltransferase to N-acetylisoniazid; it is then biotransformed to isonicotinic acid and monoacetylhydrazine {05}. Monoacetylhydrazine is associated with hepatotoxicity via formation of a reactive intermediate metabolite when N-hydroxylated by the cytochrome P450 mixed oxidase system {05}. The rate of acetylation is genetically determined; slow acetylators are characterized by a relative lack of hepatic N-acetyltransferase {05}.

Half-life:


Ethambutol:

Normal renal function: 3 to 4 hours {04}.

Impaired renal function: Up to 8 hours {04}.



Isoniazid:



Adults (including elderly patients):

Fast acetylators: 0.5 to 1.6 hours {05}.

Slow acetylators: 2 to 5 hours {05}.

Acute and chronic liver disease: May be prolonged (6.7 hours vs 3.2 hours in controls) {05}.



Children (age 1.5 to 15 years):

2.3 to 4.9 hours {05}.



Neonates:

7.8 and 19.8 hours in two newborns who received isoniazid transplacentally {05}. The long half-life may be due to the limited acetylation capacity of neonates {05}.


Time to peak concentration:

Ethambutol—2 to 4 hours {04}.

Isoniazid—1 to 2 hours {05}.

Peak serum concentration

Ethambutol—2 to 5 mcg per mL after a single oral dose of 25 mg per kg of body weight (mg/kg) {04}.

Isoniazid—3 to 7 mcg per mL after a single 300-mg oral dose {05}.

Elimination:


Ethambutol—
        Renal; By glomerular filtration and tubular secretion; up to 80% excreted within 24 hours (at least 50% excreted unchanged and 8 to 15% as inactive metabolites) {04}.
        Fecal; 20 to 22% excreted unchanged {04}.
        In dialysis—Ethambutol is removed from the blood by hemodialysis and peritoneal dialysis {04}.



Isoniazid—
        Renal; approximately 75 to 95% excreted by the 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 {05}.
        Small amounts are excreted in feces {05}.
        In dialysis—Significant amounts of isoniazid are removed from the blood by hemodialysis {05}. A single 5-hour hemodialysis period has removed up to 73% of the isoniazid in the blood {05}.
        Peritoneal dialysis is of limited benefit {05}.



Precautions to Consider

Cross-sensitivity and/or related problems

Patients hypersensitive to ethambutol, ethionamide, isoniazid, niacin (nicotinic acid), pyrazinamide, or other chemically related medications may be hypersensitive to this medication also {05}.

Carcinogenicity/Tumorigenicity

Isoniazid has been shown to cause pulmonary tumors in a number of strains of mice {05}. However, isoniazid has not been shown to be carcinogenic or tumorigenic in humans {05}.

Pregnancy/Reproduction

Note: Tuberculosis in pregnancy should be managed in concert with an expert in the management of tuberculosis {07}. Women who have only pulmonary tuberculosis are not likely to infect the fetus until after delivery, and congenital tuberculosis is extremely rare {07}. In utero infections with tubercle bacilli, however, can occur after maternal bacillemia at different stages in the course of tuberculosis {07}. Miliary tuberculosis can seed the placenta and thereby gain access to the fetal circulation {07}. In women with tuberculosis endometritis, transmission of infection to the fetus can result from fetal aspiration of bacilli at the time of delivery {07}. A third mode of transmission is through ingestion of infected amniotic fluid in utero {07}.
If active disease is diagnosed during pregnancy, a 9-month regimen of isoniazid and rifampin, supplemented by an initial course of ethambutol if drug resistance is suspected, is recommended {07}. Isoniazid, ethambutol, and rifampin appear to be relatively safe for the fetus {07}. The benefit of ethambutol and rifampin for therapy of active disease in the mother outweighs the risk to the infant {07}. One of these medications can be discontinued after 1 or 2 months, depending on results of susceptibility tests {07}. If rifampin or isoniazid is discontinued, treatment is continued for a total of 18 months; if ethambutol is discontinued, treatment is continued for a total of 9 months {07}.
For all pregnant women receiving isoniazid, pyridoxine should be prescribed {07}. Streptomycin and pyrazinamide should not be used unless they are essential to the control of the disease {07}.
Prompt initiation of chemotherapy is mandatory to protect both the mother and the fetus {07}.
Asymptomatic pregnant women with positive tuberculin skin tests and normal chest radiographs should receive preventive therapy with isoniazid for 9 months if they are HIV seropositive or have recently been in contact with an infectious person {07}. For these individuals, preventive therapy should begin after the first trimester {07}. In other circumstances in which none of these risk factors is present, although no harmful effects of isoniazid to the fetus have been observed, preventive therapy can be delayed until after delivery {07}.


Pregnancy—
The effects of combinations of ethambutol with other antituberculous medications on the fetus are not known {04}. However, there are published reports of five women who received ethambutol during pregnancy without apparent adverse effect on the fetus {04}.

Studies in mice given high doses of ethambutol have shown that ethambutol causes a low incidence of cleft palate, exencephaly, and vertebral column abnormalities {04}. In addition, studies in rats given high doses of ethambutol have shown that ethambutol causes minor abnormalities of the cervical vertebrae {04}. Studies in rabbits given high doses of ethambutol have shown that ethambutol may cause monophthalmia, limb reduction defects, harelip, and cleft palate {04}.

Isoniazid crosses the placenta {05}. However, problems in humans have not been documented.

Studies in rats and rabbits have shown that isoniazid may be embryocidal {05}. However, isoniazid has not been shown to be teratogenic in mice, rats, or rabbits {05}.

FDA Pregnancy Category C {05}.

Breast-feeding

Ethambutol is distributed into breast milk in concentrations approximating maternal serum concentrations. However, problems in humans have not been documented.

Isoniazid and its acetyl metabolite are distributed into breast milk {05} {16}. An estimated 0.75 to 2.3% of the daily adult dose could be ingested by the nursing infant. Problems, including liver toxicity, in nursing newborns have not been documented and breast-feeding should not be discouraged {16}. However, because isoniazid concentrations are so low in breast milk, breast-feeding cannot be relied upon for adequate tuberculosis prophylaxis or therapy for nursing infants.

Pediatrics

Note: Possible isoniazid resistance should always be considered, particularly in children from population groups in which drug resistance is high, especially in children from countries with a high prevalence of drug-resistant tuberculosis {07}. For contacts who are likely to have been infected by an index case with isoniazid-resistant but rifampin-susceptible organisms, and in whom the consequences of the infection are likely to be severe (e.g., children up to 4 years of age), rifampin (10 mg per kg of body weight, maximum 600 mg, given daily in a single dose) should be given in addition to isoniazid (10 mg per kg of body weight, maximum 300 mg, given daily in a single dose) until susceptibility test results for the isolate from the index case are available {07}. If the index case is known or proven to be excreting organisms resistant to isoniazid, then isoniazid should be discontinued and rifampin given for a total of 9 months {07}. Isoniazid alone should be given if no proof of exposure to isoniazid-resistant organisms is found {07}. Optimal therapy for children with tuberculosis infection caused by organisms resistant to isoniazid and rifampin is unknown {07}. In deciding on therapy in this situation, consultation with an expert is advised {07}.
Adjuvant therapy with corticosteroids in treating tuberculosis is controversial {07}. Corticosteroids have been used in children with tuberculous meningitis to reduce vasculitis, inflammation, and, as a result, intracranial pressure {07}. Data indicate that dexamethasone may lower mortality rates and lessen long-term neurologic impairment {07}. The administration of corticosteroids should be considered in all children with tuberculous meningitis, and also may be considered in children with pleural and pericardial effusions (to hasten reabsorption of fluid), severe miliary disease (to mitigate alveolocapillary block), and endobronchial disease (to relieve obstruction and atelectasis) {07}. Corticosteroids should be given only when accompanied by appropriate antituberculosis therapy {07}. Consultation with an expert in the treatment of tuberculosis should be obtained when corticosteroid therapy is considered {07}.


Appropriate studies on the relationship of age to the effects of ethambutol have not been performed in children up to 13 years of age {04}. Ethambutol generally is not recommended in children whose visual acuity cannot be monitored (younger than 6 years of age). However, ethambutol should be considered for all children infected with organisms resistant to other medications, and in whom susceptibility to ethambutol has been demonstrated or is likely.

Studies performed in children have not demonstrated pediatrics-specific problems that would limit the usefulness of isoniazid in children {05}. However, newborn infants may have a limited acetylation capacity, prolonging the elimination half-life of isoniazid {05}.

Children do not require routine hepatic function determinations unless they have pre-existing hepatic disease {05}.

Pyridoxine supplementation usually is not required in children if dietary intake is adequate {05}.


Geriatrics


Appropriate studies on the relationship of age to the effects of ethambutol and isoniazid have not been performed in the geriatric population {04} {05}. 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 {04}. Furthermore, patients older than 50 years of age are more likely to develop hepatitis while receiving isoniazid than are patients in younger age groups {05}.


Pharmacogenetics

Patients can be divided into two groups: slow and rapid acetylators of isoniazid {05}. Approximately 50% of blacks and Caucasians are slow acetylators; the majority of Eskimos and Asians are rapid acetylators {05}. The rate of acetylation does not significantly alter the effectiveness of isoniazid {05}. However, slow acetylation may lead to higher blood levels of isoniazid and, thus, an increase in toxic reactions {05}. Slow acetylators are characterized by a relative lack of hepatic N-acetyltransferase {05}. Patients who are slow acetylators may be more prone to develop adverse effects, especially peripheral neuritis, and may require lower-than-usual doses {05}. Rapid acetylators generally do not require higher doses, nor is isoniazid less effective in these patients {05}.

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)


» Alcohol    (concurrent daily use of alcohol may result in increased incidence of isoniazid-induced hepatotoxicity and increased metabolism of isoniazid; dosage adjustments of isoniazid may be necessary; patients should be monitored closely for signs of hepatotoxicity and should be advised to restrict intake of alcoholic beverages {05})


» Alfentanil    (long-term preoperative or perioperative use of isoniazid, a hepatic enzyme inhibitor, may decrease the plasma clearance and prolong the duration of action of alfentanil)


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 taking aluminum-containing antacids)


Anticoagulants, coumarin- or indandione-derivative    (concurrent use with isoniazid may result in increased anticoagulant effect because of the inhibition of enzymatic metabolism of anticoagulants {05})


» Carbamazepine    (concurrent use with isoniazid increases serum carbamazepine concentrations and toxicity, probably through inhibition of carbamazepine metabolism; also, carbamazepine may induce microsomal metabolism of isoniazid, increasing formation of an INH-reactive intermediate metabolite, which may lead to hepatotoxicity {05})


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 {05})


Corticosteroids, glucocorticoid    (concurrent use of prednisolone, and probably 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 {05})


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)


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


Enflurane    (isoniazid may increase formation of the potentially nephrotoxic inorganic fluoride metabolite when used concurrently with enflurane {05})


» Ketoconazole    (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 {05})


» 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 {05})


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)


» Rifampin    (concurrent use of rifampin with isoniazid may increase the risk of hepatotoxicity, especially in patients with pre-existing hepatic impairment and/or in fast acetylators of isoniazid; patients receiving rifampin and isoniazid concurrently should be monitored closely for signs of hepatotoxicity during the first 3 months of therapy)


Theophylline    (concurrent use may reduce the metabolism of theophylline, increasing theophylline plasma concentrations {05})



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

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Aspartate aminotransferase (AST [SGOT])    (values may be transiently and asymptomatically increased in approximately 10 to 20% of patients tested {05})


Bilirubin, serum    (concentrations may be transiently and asymptomatically increased in approximately 10 to 20% of patients tested {05})


Uric acid, serum    (concentrations may be increased {04})


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, or
» Hepatic function impairment    (increased risk of hepatitis with daily consumption of alcohol or hepatic function impairment {05})


Gouty arthritis, acute    (ethambutol may increase uric acid concentrations {04})


Hypersensitivity to ethambutol, ethionamide, isoniazid, niacin (nicotinic acid), pyrazinamide, or other chemically related medications{04}{05}
» Optic neuritis    (ethambutol may cause retrobulbar optic neuritis {04})


» Renal failure, severe    (there may be an increased risk of toxicity in patients who have severe renal failure [creatinine clearance < 10 mL/min] {04})


» Renal function impairment    (because ethambutol is excreted primarily through the kidneys, patients with renal function impairment may require a reduction in dosage {04})


Seizure disorders    (isoniazid may be neurotoxic and cause seizures {05})



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    (AST [SGOT], ALT [SGPT], and serum bilirubin determinations may be required prior to initiation of pharmacotherapy and monthly or more frequently during treatment; however, elevated serum enzyme values may not be predictive of clinical hepatitis and values may return to normal despite continued treatment; therefore, routine measurement of hepatic function generally is not recommended unless there is pre-existing hepatic disease; patients should be instructed to report promptly any prodromal symptoms of hepatitis; if signs and symptoms of hepatotoxicity occur, isoniazid should be promptly discontinued; if isoniazid therapy must be reinstituted, very small and gradually increasing doses should be used, and then only after signs and symptoms of hepatotoxicity have cleared; isoniazid should be withdrawn immediately if any further evidence of hepatotoxicity occurs {05})


Ophthalmologic examinations    (tests for visual fields and acuity and red-green discrimination may be required prior to and monthly during treatment, especially if treatment is prolonged {04})


Uric acid concentrations, serum    (may be required during treatment since elevated serum uric acid concentrations frequently occur, possibly precipitating acute gout {04})




Side/Adverse Effects

Note: Isoniazid has been reported to cause severe, and sometimes fatal, age-related hepatitis {05}. If signs and symptoms of hepatotoxicity occur, isoniazid should be discontinued promptly {05}. The incidence of clinical hepatitis in young, healthy adults is 0.3%, but incidence can increase to 2.6% for those who drink alcohol daily, have chronic liver disease, or are elderly {05}.
Patients with advanced HIV disease have been reported to have an increased incidence of adverse reactions to antitubercular medications. This was not found in HIV-seropositive but nonsymptomatic patients being treated for tuberculosis.
Pyridoxine deficiency sometimes is observed in adults receiving high doses of isoniazid and probably results from isoniazid's competition with pyridoxal phosphate for the enzyme apotryptophanase {05}.
Peripheral neuritis usually can be prevented by the administration of 10 to 25 mg of pyridoxine per day {05}. It is recommended for patients at risk of neuritis, including those older than 65 years of age, pregnant women, and patients with diabetes mellitus, chronic renal failure, alcoholism, or malnutrition, and those taking anticonvulsant medications {05}.
Retrobulbar optic neuritis is thought to be dose-related, occurring most frequently with ethambutol daily doses of 25 mg per kg of body weight (mg/kg) and after 2 months of therapy; however, optic neuritis has occurred after only a few days of treatment {04}. Most cases are reversible after several weeks or months {04}. Visual changes may be unilateral or bilateral; therefore, each eye must be tested separately and both eyes tested together {04}.

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 {05}(dark urine; yellow eyes or skin)
    
hepatitis prodromal symptoms {05}(loss of appetite; nausea; unusual tiredness or weakness; vomiting)
    
peripheral neuritis {05}(clumsiness or unsteadiness; numbness, tingling, burning, or pain in hands and feet)

Incidence less frequent
    
Gouty arthritis, acute {04}(chills; pain and swelling of joints, especially big toe, ankle, or knee; tense, hot skin over affected joints)

Incidence rare
    
Blood dyscrasias (fever; sore throat; unusual bleeding or bruising; unusual tiredness or weakness)
    
hypersensitivity (fever; joint pain; skin rash)
    
neurotoxicity (mental depression; mood or other mental changes; seizures)
    
optic neuritis {04}(blurred vision or loss of vision, with or without eye pain)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Gastrointestinal disturbances (diarrhea; nausea; stomach pain; vomiting)
    
confusion
    
disorientation
    
headache





Overdose
The information below applies to the clinical effects and treatment of isoniazid overdose only.
For specific information on the agents used in the management of isoniazid overdose, see

   • Pyridoxine (Systemic) 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 ).

Clinical effects of isoniazid 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 effects
    
Gastrointestinal disturbances ( severe nausea; vomiting)
    
neurotoxicity {05}( dizziness; slurred speech; lethargy; disorientation ; hyperreflexia; seizures; coma)

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 {05}. 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 often is severe and refractory to treatment with sodium bicarbonate. Hyperglycemia, glycosuria, and ketonuria also have been reported {05}.




Treatment of isoniazid overdose


To decrease absorption:
Because seizures may occur soon after ingestion, induction of emesis with ipecac is not recommended {05}. 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 {05}.



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 {05}. 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 {05}.

Controlling seizures with diazepam, which acts synergistically with pyridoxine {05}. Phenytoin should be used with caution, if at all, since isoniazid inhibits phenytoin metabolism {05}. Thiopental has been effective in treating refractory seizures {05}.

Carefully administering sodium bicarbonate if pyridoxine and diazepam do not control seizure activity {05}. Use caution against overcorrection and watch for hypokalemia or hyperkalemia {05}.



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 {05}. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation {05}.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Ethambutol and Isoniazid (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

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

Pregnancy—Ethambutol crosses the placenta. However, problems in humans have not been documented

Isoniazid crosses the placenta; fetal serum concentrations may exceed maternal serum concentrations





Breast-feeding—Both ethambutol and isoniazid are distributed into breast milk





Use in children—Appropriate studies have not been done in children up to 13 years of age. Ethambutol generally is not recommended in children whose visual acuity cannot be monitored (younger than 6 years of age); children may be less susceptible to pyridoxine deficiency and hepatotoxicity than adults, unless they have pre-existing hepatic disease; newborn infants may have prolonged elimination






Use in the elderly—Patients older than age 50 have the highest incidence of hepatitis
Other medicines, especially daily alcohol use, alfentanil, carbamazepine, disulfiram, ketoconazole, phenytoin, or rifampin
Other medical problems, especially alcoholism, active or in remission, hepatic function impairment, optic neuritis, renal failure, severe, 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 6 months to 2 years

» Taking pyridoxine concurrently to prevent or minimize symptoms of peripheral neuritis; not usually required in children if dietary intake is adequate

» Making sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are not alert or able to see well

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» 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 in either adults or children

Checking with physician if no improvement within 2 to 3 weeks or if symptoms become worse

Checking with physician if vascular reactions occur following concurrent ingestion of cheese or fish with isoniazid

» Avoiding alcoholic beverages while taking this medication

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

» Patients with diabetes: False-positive reactions with copper sulfate urine glucose tests may occur


Side/adverse effects
Hepatitis may be more likely to occur in patients older than 50 years of age

Signs of potential side effects, especially hepatitis, hepatitis prodromal symptoms, peripheral neuritis, acute gouty arthritis, blood dyscrasias, hypersensitivity, neurotoxicity, and optic neuritis


General Dosing Information
Ethambutol and isoniazid in a fixed-dose combination (400 mg ethambutol and 150 mg isoniazid) is intended to promote compliance {01}. Ethambutol reduces the incidence of the emergence of mycobacterial resistance to isoniazid when both medications are used concurrently {04}.

Ethambutol and isoniazid in a fixed-dose combination should not be used in the initial phase of tuberculosis treatment {01}. Ethambutol and isoniazid in a fixed-dose combination can be substituted for thioacetazone and isoniazid combination in patients with side effects due to thioacetazone {01}.

This medication may be taken with meals if gastrointestinal irritation occurs. Antacids may be taken; however, ethambutol and isoniazid combination should be taken at least 1 hour before aluminum-containing antacids since oral absorption may be decreased if it is taken with food or antacids.

Drug-susceptibility testing should be performed on all initial isolates from patients with tuberculosis {14}. However, test results may not be available for several weeks, making selection of an initial regimen difficult, especially in areas where drug-resistant tuberculosis has been documented {14}. Current recommendations for therapy and dosage schedules for the treatment of drug-susceptible tuberculosis should be followed {14}.

Drug-resistant and multidrug-resistant tuberculosis is a growing problem {13}. The emergence of resistance may be due either to patient noncompliance or the transmission of already resistant strains {13}. In geographic areas or facilities in which drug-resistant tuberculosis is highly prevalent, the initial treatment regimen used while results of drug-susceptibility tests are pending may need to be expanded {14}. This decision should be based on analysis of surveillance data {14}.

When results from drug-susceptibility tests become available, the regimen should be adjusted appropriately {14}. The optimal therapy for drug-resistant tuberculosis, particularly multidrug-resistant tuberculosis, is less well studied and standardized {13}. Therefore, if drug resistance is present, clinicians unfamiliar with the management of patients with drug-resistant tuberculosis should seek expert consultation {14}.

For any regimen to be effective, adherence must be ensured {14}. The most effective method of ensuring adherence is the use of directly observed therapy (DOT) after the patient has been discharged from the hospital {14}. This practice should be coordinated with the public health department {14}.

Treatment with an antituberculosis regimen should continue at least 6 months and may be continued as long as 2 years {06}. Uncomplicated pulmonary tuberculosis often is treated successfully within 6 to 12 months {06}. Several different regimens currently are recommended {06}.

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 {07}. With DOT, clinical evaluation is an integral component of each visit for administration of medication {07}. Careful monitoring of the clinical and bacteriologic responses to therapy on a monthly basis in sputum-positive patients is important {07}.

If therapy is interrupted, the treatment schedule should be extended to a later completion date {07}. Although guidelines cannot be provided for every situation the following factors need to be considered in establishing a new date for completion {07}:    • The length of interruption {07};
   • The time during therapy (early or late) in which interruption occurred {07}; and
   • The patient's clinical, radiographic, and bacteriologic status before, during, and after interruption {07}. Consultation with an expert is advised {07}.


A high incidence of drug resistance has serious implications, not only for the treatment of the individual patients, with only approximately a 60% cure rate, but also for the management of contacts to these cases {08}. There is no consensus on the choice of preventive therapy for contacts of multidrug-resistant tuberculosis patients {08}. However, a combination of ciprofloxacin and pyrazinamide has been suggested for exposed health care workers {08}.

The inhibitory activities of additional antibacterial drugs have been tested on resistant strains of M. tuberculosis {08}. Ciprofloxacin, amikacin, kanamycin, and pyrazinamide have shown good activity {08}. A pronounced inhibitory effect was seen for amikacin and kanamycin also against most streptomycin-resistant strains, supporting the use of alternative aminoglycoside drugs in the therapy of streptomycin-resistant tuberculosis {08}. In vitro susceptibility tests including these agents can help in identifying effective drug combinations for the treatment of patients with resistant tuberculosis {08}.

Patients with impaired renal function generally do not require a reduction in dose if the plasma creatinine concentration is less than 6 mg per 100 mL. If renal impairment is more severe or if patients are slow acetylators, a reduction in dose and/or serum determinations may be required. Slow acetylators may require dosage adjustments to ensure isoniazid serum concentrations of less than 1 mcg per mL measured 24 hours after the preceding dose. In anuric patients, one half the usual maintenance dose is recommended.


Oral Dosage Forms

ETHAMBUTOL AND ISONIAZID TABLETS

Usual adult and adolescent dose
[Tuberculosis (treatment)]1
Oral, 800 mg ethambutol and 300 mg isoniazid, as a single daily dose {01}.


Usual pediatric dose
[Tuberculosis (treatment)]1
Children up to 13 years of age: Dosage has not been established {04}. However, regimens containing ethambutol should be considered for all children with organisms resistant to other medications and in whom susceptibility to ethambutol has been demonstrated or is likely {04}. Ethambutol generally is not recommended in children whose visual acuity cannot be monitored (younger than 6 years of age) {04}.

Children 13 years of age and older: See Usual adult and adolescent dose {01}.


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

Canada—
Not commercially available.

Africa, Asia, and Latin America—


Ethambutol 400 mg and isoniazid 150 mg. (Rx)[Generic]{01}

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 {04} {05}. Store in a well-closed, light-resistant container {04} {05}.

Auxiliary labeling:
   • Continue medicine for full time of treatment {01} {04} {05}.
   • Avoid alcoholic beverages {04} {05}.



Developed: 02/02/1999



References
  1. World Health Organization (WHO). Treatment of tuberculosis: guidelines for national programs. 2nd ed. 1997. World Health Organization/TB/97.220.
  1. Peloquin CA, Nitta AT, Burman WJ, et al. Low antituberculosis drug concentrations in patients with AIDS. Ann Pharmacother 1996; 30: 919-25.
  1. Bradford WZ, Martin JN, Reingold AL, et al. The changing epidemiology of acquired drug-resistant tuberculosis in San Francisco, USA. Lancet 1996; 348: 928-31.
  1. Myambutol (Lederle). In: PDR physicians' desk reference. 52nd ed. 1998. Montvale, NJ: Medical Economics Data; 1998. p. 1402-3.
  1. Rifamate (Hoechst Marion Roussel). In: PDR physicians' desk reference. 52nd ed. 1998. Montvale, NJ: Medical Economics Data; 1998. p. 1233-4.
  1. The American Thoracic Society (ATS). Ad Hoc Committee on the Scientific Assembly on Microbiology, Tuberculosis, and Pulmonary Infections. Treatment of tuberculosis and tuberculosis infection in adults and children. Clin Infect Dis 1995; 21: 9-27.
  1. American Academy of Pediatrics (AAP). Tuberculosis. In: Peter G, ed. 1997 Red book: report of the Committee on Infectious Diseases. 24th ed. Elk Grove Village, IL: American Academy of Pediatrics; 1997. p. 541-62.
  1. Pineda-Garcia L, Ferrera A, Galvez CL, et al. Drug-resistant Mycobacterium tuberculosis and atypical mycobacteria isolated from patients with suspected pulmonary tuberculosis in Honduras. Chest 1997; 111: 148-53.
  1. Burman WJ, Dalton CB, Cohn DL, et al. A cost-effectiveness analysis of directly observed therapy vs self-administered therapy for treatment of tuberculosis. Chest 1997; 112; 63-70.
  1. Burman WJ, Cohn DL, Rietmijer CA, et al. Short-term incarceration for the management of noncompliance with tuberculosis treatment. Chest 1997; 112: 57-62.
  1. Snider GL. Tuberculosis then and now: a personal perspective on the last 50 years. Ann Intern Med 1997; 126(3): 237-43.
  1. Centers for Disease Control and Prevention (CDC). Tuberculosis morbidity—United States, 1995. MMWR Morb Mortal Wkly Rep 1996; 45(18): 365-70.
  1. Telzak EE, Sepkowitz K, Alpert P, et al. Multidrug-resistant tuberculosis in patients without HIV infection. N Engl J Med 1995; 333(14): 907-11.
  1. Centers for Disease Control and Prevention (CDC). Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care facilities, 1994. MMWR Morb Mortal Wkly Rep 1994; 43(RR-13): 1-132.
  1. Hoffman ND, Kelly C, Futterman D. Tuberculosis infection in human immunodeficiency virus-positive adolescents and young adults: a New York City cohort. Pediatrics 1996; 97(2): 198-203.
  1. Panel comment, 11/98.
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