Pharmacology: Ethambutol is a bacteriostatic agent which diffuses into actively growing mycobacterium cells such as tubercle bacilli, where it inhibits the synthesis of one or more essential metabolites, causing impairment of cell metabolism, arrest of multiplication, and cell death.
It is active in vitro against strains of M. tuberculosis and other Mycobacterium species, but not other bacteria, fungi or viruses.
Resistance develops rapidly if ethambutol is used alone. It seems to develop in a step-wise manner and may be delayed or prevented by using ethambutol in combination with other antituberculosis agents. Cross-resistance has not been reported with other antituberculosis agents.
The minimum inhibitory concentration for susceptible strains is 1 to 8 g/mL, depending on the culture medium used.
Pharmacokinetics: Ethambutol is about 75 to 80% absorbed after an oral dose. Absorption is rapid and does not seem to be affected by food.
Following a single oral dose of 25 mg/kg of body weight, ethambutol attains a peak serum level of 2 to 5 g/mL 2 to 4 hours after administration. No drug accumulation has been observed with consecutive single daily doses of 25 mg/kg in patients with normal kidney function, although marked accumulation has been demonstrated in patients with renal insufficiency. Serum concentrations are undetectable 24 hours after the last dose except in some patients with abnormal renal function.
Ethambutol distributes widely into body fluids and tissues. Concentrations in erythrocytes may reach 2 to 3 times the plasma concentrations. It also appears in the lungs, kidneys, urine, and saliva, and to lesser extents in pleural and ascitic fluids. Ethambutol crosses the placenta. CSF concentrations reaching 10 to 50% of serum concentrations may occur with inflamed meninges. Ethambutol is not highly bound to plasma proteins. Its volume of distribution is about 1.6 L/kg.
The half-life of ethambutol is about 3 to 4 hours in patients with normal renal function; it may be as long as 7 to 8 hours in patients with renal insufficiency and 18 to 20 hours in the anephric patient.
Within 24 hours after oral administration, approximately 50% of the initial dose is excreted unchanged in the urine, while an additional 8 to 15% appears as inactive metabolites. The main metabolic path appears to be an initial oxidation of the alcohol to an aldehydic intermediate, followed by conversion to a dicarboxylic acid. From 20 to 22% of the initial dose is excreted in the feces as unchanged drug.
Indications: For the treatment of pulmonary tuberculosis. Ethambutol should only be used in conjunction with at least one other antituberculosis agent.
A 4 drug regimen including ethambutol may be used for initial treatment in persons with known exposure to isoniazid-resistant organisms, those who have previously received antitubercular drugs (i.e., retreatment of relapse cases) and in persons from parts of the world where drug-resistant tuberculosis is prevalent. Isoniazid resistance is common in Latin America, Africa, Southeast Asia, and other areas. Other factors to consider in the selection of antituberculosis therapy are results of in vitro susceptibility testing, considerations of comparative safety, local resistance patterns and severity of the disease.
In the treatment of relapse cases (i.e., retreatment) mycobacterial resistance to other drugs used in initial therapy is frequent. In these patients, ethambutol should be combined with at least one drug not previously administered to the patient and to which in vitro bacterial susceptibility has been indicated.
Ethambutol is also used in conjunction with other agents in the treatment of infections caused by M. avium complex and other mycobacteria.
Known hypersensitivity to the drug; known optic neuritis unless considerations of risk versus benefit (clinical judgment) determine that it may be used.
Warnings: Ethambutol may cause optic neuritis with decreased visual acuity, visual field constriction, loss of red-green color vision, or scotomata. Ocular toxicity may be related to dose and duration of treatment; however, it has occurred rarely after only a few days of therapy. Approximately 6% of patients receiving the drug have exhibited decreases in visual acuity. The effects are generally reversible when detected early and the drug discontinued promptly. Recovery of visual acuity generally occurs over a period of weeks to months after the drug has been discontinued. Some patients have then received ethambutol again, without recurrent loss of visual acuity. In rare cases, recovery may be delayed for up to 1 year or more, and the effects may be irreversible in some cases.
Visual acuity and color vision should be thoroughly tested before beginning treatment with ethambutol and periodically during drug therapy. Monthly examination is recommended for patients receiving doses greater than 15 mg/kg.
The changes in visual acuity may be unilateral or bilateral; hence, each eye must be tested separately and both eyes tested together. Snellen eye charts are recommended for testing of visual acuity. Ophthalmoscopy, finger perimetry and color discrimination should also be included in the baseline evaluation. If corrective lenses are used prior to treatment, they must be worn during visual acuity testing. During 1 to 2 years of ethambutol therapy, a refractive error may develop which must be corrected (by testing visual acuity through a pinhole) in order to obtain accurate results.
In patients with pre-existing visual defects such as cataracts, recurrent inflammatory conditions of the eye, optic neuritis and diabetic retinopathy, the evaluation of changes in visual acuity is more difficult, and care should be taken to ensure that the variations in vision are not due to the underlying disease condition. In such patients, consideration should be given to the expected benefits of ethambutol therapy and the possibility of visual deterioration.
Patients developing ocular toxicities during treatment may show subjective symptoms before, or at the same time as, decreases in visual acuity. All patients receiving ethambutol should be questioned periodically about blurred vision and other subjective eye symptoms. Progressive decreases in visual acuity during therapy must be considered to be due to ethambutol.
Patients should be advised to promptly report any changes in visual acuity to their physician.
Precautions: Use with caution in patients with decreased renal function due to the risk of drug accumulation; ethambutol dosage should be reduced.
Ethambutol may inhibit the response to BCG vaccine.
Periodic assessment of systemic functions, including renal, hepatic and hematopoietic should be made during long-term therapy.
Pregnancy: Reproductive studies in mice or rabbits have shown slight increases in fetal mortality when ethambutol was given at doses 10 times greater than the maximum human use dose. A low incidence of fetal abnormality was seen among animals receiving 4 to 10 times the maximum human use dose. The possibility that these findings are drug-related cannot be ruled out. Clinical experience has not shown an increase in the risk of abnormalities when the drug was administered throughout pregnancy. Although it appears that the possibility of fetal harm is remote, because of the findings in animals, ethambutol should be used during pregnancy only if clearly needed. Loss of fertility and testicular regression among male rats administered ethambutol has been reported. No effects on the testes were seen in other rat studies, or among other species treated with very high doses, for extended periods of time. There have been no reports of an antifertility effect in humans.
Lactation: Ethambutol is excreted in the milk of nursing mothers.
Children: Ethambutol is not recommended for use in children under 13 years of age, although it has been used in children older than 6 years of age. It should only be used in children whose visual acuity and color vision can be accurately determined and monitored.
Adverse Effects: Ophthalmologic: optic neuritis, decreased visual acuity, constriction of visual fields, central and peripheral scotomata, color vision defects (especially red-green color discrimination).
Dermatologic: dermatitis, pruritus.
Hypersensitivity: anaphylactoid reactions, fever, malaise. Rarely, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Renal: rarely, interstitial nephritis, nephrotoxicity (may be related to other antituberculous therapy).
Hematologic: rare case reports of thrombocytopenia, and neutropenia.
Gastrointestinal: anorexia, nausea, vomiting, abdominal pain, metallic taste.
CNS: headache, dizziness, mental confusion, possible hallucinations. Peripheral neuritis has been reported infrequently.
Hepatic: rarely, jaundice. Since ethambutol is recommended for therapy in conjunction with one or more other antituberculous drugs, these changes may be related to concurrent therapy.
Other: Elevated serum uric acid levels and precipitation of gout have been reported. Joint pain has also been reported.
Symptoms: anorexia, nausea, vomiting, gastrointestinal upset, abdominal pain, fever, malaise, headache, dizziness, mental confusion, disorientation and possible hallucinations.
Treatment: No specific antidote. Stop ethambutol administration. Remove drug by emesis or gastric lavage. Anaphylactoid reactions may necessitate emergency treatment.
Dosage: M. tuberculosis: Ethambutol should not be used alone in initial treatment or in retreatment. The drug should be administered on a once every 24 hour basis only. In general, therapy should be continued until bacteriological conversion has become permanent and maximal clinical improvement has occurred.
The duration of therapy should be a minimum of 6 to 9 months for initial treatment cases. Cases of drug-resistant tuberculosis, immunocompromised patients and retreatment cases may require 12 to 18 months or longer of therapy.
Initial Treatment: As part of a multi-drug regimen in adult patients who have not received previous antituberculous therapy, administer ethambutol 15 mg/kg as a single oral dose every 24 hours. The maximum recommended daily dose is 2.5 g.
Retreatment: In adult patients who have received previous antituberculous therapy, administer ethambutol 25 mg/kg as a single oral dose once every 24 hours. Concurrently administer at least one other antituberculosis agent not previously used and to which the organisms have been demonstrated to be susceptible by appropriate in vitro tests. After 60 days of therapy, or when bacteriologic cultures become negative, decrease the dose to 15 mg/kg once every 24 hours. During the period when a patient is on a daily dose of 25 mg/kg, monthly eye examinations are advised.
Twice Weekly Therapy: After an initial period of daily therapy, ethambutol may be given as part of a multiple-drug regimen at an adult dose of 50 mg/kg (up to 2.5 g) twice a week for the remainder of the chosen treatment period. The duration of the initial daily therapy period will depend on the number and combination of antituberculosis agents used as well as the patient’s clinical status. Alternatively, ethambutol has been used in combination with other agents at a dose of 25 to 30 mg/kg 3 times weekly.
Children (see Precautions, Children): In children whose visual acuity can be accurately monitored, 10 to 15 mg/kg is given once daily in conjunction with other antituberculosis agents. Specialized pediatric references should be consulted for detailed dosing information.
M. avium complex (M. avium and M. intracellulare): In combination with other agents, the adult dose is 15 to 25 mg/kg/day, continued until patient has been culture-negative for 1 year.
M. kansasii: In combination with rifampin plus isoniazid, the adult dose is 15 to 25 mg/kg/day for a minimum of 12 months.
M. marinum: In combination with rifampin, the adult dose is 15 to 25 mg/kg/day for a minimum of 3 months.
Ethambutol may be used in a dosage of 15 mg/kg/day in combination with other antimycobacterial agents for the treatment of other nontuberculous mycobacterial infections such as those caused by M. xenopi and M. genavense.
Dosage in Renal Failure: If creatinine clearance is 0.17 to 0.83 mL/s, give 50% of the normal dose once daily. Alternately, extend the dosing interval to once every 24 to 36 hours. If creatinine clearance is less than 0.17 mL/s, reduce the dose to 25% of the normal dose once daily, or extend the interval to once every 48 hours.
ETHAMBUTOL HCl General Monograph Antimycobacterial
Posted by RxMed