Myambutol (Ethambutol)

Ethambutol hydrochloride is an antimycobacterial medicine used as part of combination therapy. In Australia, it is used in standard tuberculosis treatment regimens under specialist prescribing and monitoring. It should not be used on its own for active tuberculosis because resistance can develop quickly.

Uses

Tuberculosis

Active tuberculosis

Ethambutol is used together with other anti-tuberculosis medicines to treat clinical tuberculosis.

Mycobacterium avium Complex (MAC) infections

Off-label notice (Australia): Ethambutol is approved in Australia for pulmonary tuberculosis. Use in MAC (including secondary prophylaxis) is off-label and should be guided by an experienced clinician.

Treatment of MAC infections

Ethambutol is used in combination with other antimycobacterial medicines to treat MAC infections. For disseminated MAC disease in people with HIV, treatment guidelines commonly recommend a macrolide plus ethambutol (15 mg/kg orally once daily), with or without rifabutin, depending on the clinical situation and the potential for drug interactions.

Prevention of recurrence

To help prevent recurrence of disseminated MAC infection (secondary prophylaxis), some guidelines recommend maintenance therapy after initial treatment is completed. Stopping treatment may be considered in selected patients who achieve sustained immune recovery (for example, CD4+ T-cell counts >100 cells/mm^3 for at least 6 months on effective antiretroviral therapy) and remain asymptomatic, based on specialist advice.

Administration

Ethambutol hydrochloride is taken by mouth.

Dosage

Active tuberculosis

Ethambutol should not be used alone to treat clinical tuberculosis. The manufacturer states that the usual adult dose, used with other anti-tuberculosis medicines in previously untreated patients, is 15 mg/kg once daily. In adults who have had previous anti-tuberculosis treatment, the usual dose recommended by the manufacturer is 25 mg/kg daily for 60 days, followed by 15 mg/kg daily.

The ATS/CDC/IDSA weight-based tables cited in some summaries recommend the following for daily therapy in adults and children 15 years or older: 800 mg (40-55 kg), 1.2 g (56-75 kg), and 1.6 g (76-90 kg). For a 3-times-weekly regimen, the listed doses are 1.2 g (40-55 kg), 2 g (56-75 kg), and 2.4 g (76-90 kg) (maximum 2.4 g). For a twice-weekly regimen, the listed doses are 2 g (40-55 kg), 2.8 g (56-75 kg), and 4 g (76-90 kg) (maximum 4 g). Intermittent regimens should only be used under expert guidance.

Paediatric dosage

The manufacturer states that ethambutol hydrochloride is not recommended for children under 13 years of age. Some TB guidance uses ethambutol in children when needed; typical guideline dosing includes 15-20 mg/kg daily (maximum 2.5 g) or 50 mg/kg twice weekly (maximum 2.5 g), with caution when visual acuity is difficult to monitor.

Dosage in renal impairment

In patients with impaired renal function, the dose and/or frequency of ethambutol hydrochloride should be adjusted according to the degree of renal impairment. Ethambutol may build up in renal insufficiency, so a reduced dose is recommended, and monitoring for ocular toxicity is especially important.

Precautions and Contraindications

Ethambutol is generally contraindicated in patients with optic neuritis unless clinical judgement determines that it may be used. It should be used with great care in patients with visual defects, older people, and patients in whom changes in visual acuity may be difficult to assess.

Patients should be advised to report visual disturbances immediately and to stop ethambutol until they have had a visual assessment. Ethambutol should be given in a reduced dose to patients with renal impairment. Ethambutol may trigger gout attacks.

Ocular monitoring

Visual acuity should be tested before starting ethambutol and periodically during treatment, and monthly when a patient is taking more than 15 mg/kg/day.

Pregnancy

Ethambutol has caused teratogenic effects in animals when used at high doses. Australian product information advises use during pregnancy only when the potential benefit justifies the potential risk to the fetus.

Breastfeeding

Ethambutol passes into breast milk. Australian product information states that use should be considered only if the expected benefit to the mother outweighs the potential risk to the infant.

Children

Australian product information: ethambutol is not recommended for use in paediatric patients under 13 years of age because safe conditions for use have not been established, and it is contraindicated in patients who are unable to recognise and report visual side effects or changes in vision. Some tuberculosis guidelines use ethambutol in younger children when needed, but monitoring for visual toxicity can be difficult; dosing and monitoring should be guided by an experienced clinician.

Possible side effects

Ocular effects

The most important side effect of ethambutol is retrobulbar neuritis (optic neuropathy), with reduced visual acuity, constriction of the visual field, central or peripheral scotoma, and loss of red-green colour discrimination. One or both eyes may be affected. The degree of visual impairment appears to depend on the dose and length of treatment; toxicity is seen most often at daily doses of 25 mg/kg or more and after at least 2 months of treatment.

The risk of ethambutol-associated optic neuropathy increases with higher doses and longer treatment, and may rarely occur after only a few doses (a possible idiosyncratic reaction). When ocular toxicity is detected early and ethambutol is stopped promptly, the visual effects are generally reversible over weeks or months. Rarely, recovery may be delayed for up to 1 year or more, or the effect may be irreversible.

Other adverse effects

Other reported side effects include confusion, disorientation, hallucinations, headache, dizziness, malaise, jaundice or temporary liver dysfunction, peripheral neuropathy, thrombocytopenia, pulmonary infiltrates, eosinophilia, and gastrointestinal problems such as nausea, vomiting, anorexia, and abdominal pain. Hypersensitivity reactions including skin rashes, pruritus, leucopenia, fever, and joint pain have occurred but appear to be rare with ethambutol. Increased serum uric acid concentrations and acute gout have occasionally occurred.

Drug interactions

Taking ethambutol with antacids containing aluminium hydroxide may reduce absorption. It is recommended to avoid taking them together for at least 4 hours after taking ethambutol.

Pharmacokinetics

After a single oral dose of 25 mg/kg, peak serum ethambutol concentrations of about 2 to 5 mcg/mL appear within 2 to 4 hours. Serum levels generally fall to undetectable levels by 24 hours after the last dose, except in some patients with abnormal renal function. Approximately 50% of a dose is excreted unchanged in the urine within 24 hours, and an additional 8 to 15% appears as metabolites. About 20 to 22% of the initial dose is excreted in the faeces as unchanged drug. Ethambutol may accumulate in patients with renal insufficiency.

Mechanism of action

Ethambutol is bacteriostatic. The medicine appears to inhibit the synthesis of one or more metabolites in susceptible mycobacteria, causing impaired cell metabolism, arrest of multiplication, and cell death.

Storage

Ethambutol hydrochloride tablets should be protected from light and moisture and stored in well-closed containers at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F).