Dosage and Administration
Ethambutol can be taken with or without food. If taken concomitantly with aluminum hydroxide, the absorption of ethambutol is reduced. Separate the administration of aluminum hydroxide and ethambutol by at least 4 hours.
For treatment of tuberculosis in HIV-positive patients, once or twice weekly has been associated with higher failure and relapse rates. Daily and three times a week administration is recommended in this population.
Treatment of Active M. tuberculosis Disease: Ethambutol should not be used alone in initial treatment or in retreatment. The drug should be administered not more than once every 24 hours (i.e., daily doses should not be divided) or tissue concentrations may not reach therapeutic levels.
Adults: Initial Treatment: As part of a multi-drug regimen in adult patients who have not received previous antituberculosis therapy, administer ethambutol 18 to 26 mg/kg as a single oral dose (up to 1.6 g) every 24 hours [Canadian tuberculosis standards. 6th ed. http://www.phac-aspc.gc.ca/tbpc-latb/pubs/pdf/tbstand07_e.pdf]. With directly observed therapy (DOT) the dose is 50 mg/kg twice weekly (up to 4.0 g) or 25 to 30 mg/kg three times weekly (up to 2.4 g). Discontinue ethambutol if organism if susceptible to isoniazid, rifampin and pyrazinamide. Duration of therapy is generally 2 months; however, a longer duration of therapy may be required if organism is resistant to rifampin.
Adults: Retreatment: In adult patients who have received previous antituberculosis therapy, administer ethambutol 25 mg/kg as a single oral dose once every 24 hours, as part of a multi-drug treatment regimen. 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.
Children: The dose for children is 15 to 20 mg/kg (maximum 1 g) daily or 50 mg/kg (maximum 2.5 g) twice weekly [Canadian tuberculosis standards. 6th ed. http://www.phac-aspc.gc.ca/tbpc-latb/pubs/pdf/tbstand07_e.pdf]. Intermittent therapy should include directly observed drug administration.
M. avium Complex ( M. avium and M. intracellulare ) Pulmonary Disease: For patients with nodular/bronchiectatic disease, the dose of ethambutol is 25 mg/kg three times weekly in combination with clarithromycin 1000 mg or azithromycin 500 mg and rifampin 600 mg, which are also given three times weekly. For patients with fibrocavitary MAC lung disease or severe nodular/bronchiectatic disease, the dose is 15 mg/kg daily in combination with clarithromycin 500 to 1000 mg daily or azithromycin 250 mg daily and rifampin 600 mg daily or rifabutin 150 to 300 mg daily. Consider amikacin or streptomycin three times weekly early in therapy. Treat patients until culture-negative for 1 year [An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175(4):367-416].
Disseminated M. avium Complex Disease: In combination with clarithromycin 1000 mg daily or azithromycin 500 mg daily with or without rifabutin 300 mg daily, the adult dose of ethambutol is 15 mg/kg daily. Discontinue therapy after symptoms have resolved and cell-mediated immune function has been restored [An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175(4):367-416].
M. kansasii : In combination with rifampin 600 mg daily plus isoniazid 300 mg daily, the adult dose is 15 mg/kg daily for a minimum of 12 months. Treat patients until culture-negative for 1 year.
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.
Table 1: EthambutolDose in Adult Patients with Renal Impairment | Creatinine Clearance | Interval Adjustment |
| >50 mL/min | Q24H |
| 10–50 mL/min | Q24–36H |
| <10 mL/min | Q48H |
For patients on hemodialysis, 15-25 mg/kg per dose 3 times a week is recommended [The effect of hemodialysis on isoniazid, rifampin, pyrazinamide, and ethambutol. Am J Resp Crit Care Med 1999;159(5 Pt 1):1580-4].
Adverse Reactions
rarely, interstitial nephritis, nephrotoxicity (may be related to other antituberculosis therapy).
anorexia, nausea, vomiting, abdominal pain, metallic taste.
anaphylactoid reactions, fever, malaise, Stevens-Johnson syndrome (rare), toxic epidermal necrolysis (rare).
rare case reports of thrombocytopenia and neutropenia.
Elevated serum uric acid levels and precipitation of gout have been reported. Joint pain has also been reported.
Monitor for signs and symptoms of immune reconstitution inflammatory syndrome (fever, malaise, local reactions in organs) during tuberculosis therapy after initiation of antiretroviral therapy in patients co-infected with HIV [Canadian tuberculosis standards. 6th ed. http://www.phac-aspc.gc.ca/tbpc-latb/pubs/pdf/tbstand07_e.pdf].
headache, dizziness, mental confusion, possible hallucinations, peripheral neuritis (infrequent), mania, psychosis.
Retrobulbar optic neuritis is dose-dependent, renal function-dependent and is associated with prolonged duration of ethambutol treatment. Patients with retrobulbar optic neuritis complain of bilateral blurry vision, visual acuity impairment and color vision defects (especially red-green color discrimination). Advise patients to report symptoms of blurry vision and to discontinue ethambutol until further testing on visual acuity is performed (see Warnings and Precautions).
pneumonitis, pulmonary infiltrates.
jaundice (rare), hepatitis.
Since ethambutol is recommended for therapy in conjunction with one or more other antituberculosis drugs, these changes may be related to concurrent therapy.
Indications and Clinical Use
Ethambutol is used in the following clinical settings to treat infections caused by susceptible organisms:
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Adjunctive treatment of tuberculosis. Used with isoniazid, rifampin and pyrazinamide, while awaiting susceptibility data. Discontinue ethambutol if the organism is susceptible to isoniazid, rifampin and pyrazinamide. In treatment failure or relapse cases, mycobacterial resistance to other drugs used in initial therapy is frequent. Ethambutol monoresistance is rare; however, this does not change the duration and effectiveness of standard regimens [Canadian tuberculosis standards. 6th ed. http://www.phac-aspc.gc.ca/tbpc-latb/pubs/pdf/tbstand07_e.pdf].
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Adjunctive treatment of infections caused by nontuberculous mycobacteria such as M. avium complex (M. avium, M. intracellulare) and M. kansasii [An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Resp Crit Care Med 2007;175(4):367-416].
Overdosage
For management of a suspected drug overdose, CPhA recommends that you contact your regional Poison Control Centre. See the eCPS Directories section for a list of Poison Control Centres.
Warnings and Precautions
Use with caution in patients with decreased renal function, especially in the elderly, due to the risk of drug accumulation. Extend ethambutol dosing interval according to the degree of renal impairment (see Table 1: Dose in Adult Patients with Renal Impairment).
Ethambutol is often a component of a 4-drug empiric regimen used to treat active tuberculosis in children. Use ethambutol with caution in children who are too young for ophthalmologic monitoring. Ethambutol is not routinely used if visual acuity cannot be monitored. Monitor weight and adjust dose accordingly.
There have been no reports linking ethambutol with a higher incidence of congenital birth defects. The American Thoracic Society (ATS), the US Centers for Disease Control and Prevention (CDC) and the Infectious Diseases Society of America (IDSA) consider ethambutol to be safe for use in pregnancy [MMWR 2003;52:24].
Ethambutol is excreted in breast milk. According to the American Academy of Pediatrics, ethambutol is generally considered to be compatible with breast-feeding.
Contraindications
Patients who develop severe hypersensitivity reactions to ethambutol.
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Patients with known optic neuritis unless considerations of risk versus benefit (clinical judgement) determine that it may be used.
Action and Clinical Pharmacology
Ethambutol is about 75 to 80% absorbed after an oral dose. Absorption is rapid and not affected by food.
Two to four hours following a single oral dose of 25 mg/kg of body weight, ethambutol attains a peak serum level of 2 to 5 µg/mL. 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 kidney 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 and saliva, and to a lesser extent in pleural and ascitic fluids. 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 1.6-3.2 L/kg. Ethambutol crosses the placenta. Ethambutol distributes into milk in concentrations similar to its plasma concentration. It also distributes into cord blood and amniotic fluid.
The half-life of ethambutol is about 3 to 4 hours in patients with normal kidney function; it may be as long as ≥7 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 aldehyde intermediate, followed by conversion to a decarboxylic acid. From 20 to 22% of the initial dose is excreted in the feces as unchanged drug. Ethambutol is removed by peritoneal dialysis and to a lesser extent by hemodialysis.
