Ethambutol

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ETHAMBUTOL (ETHAMBUTOL)

Composition:

Active substance: ethambutol;

One tablet contains ethambutol hydrochloride (calculated as 100% dry substance) – 400 mg;

Excipients: calcium hydrogen phosphate dihydrate, povidone, sodium lauryl sulfate, talc, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, round, flat-surfaced tablets with beveled edges and a score line.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Agents acting on mycobacteria. Antituberculosis agents. Ethambutol. ATC code J04A K02.

Pharmacological Properties

Pharmacodynamics

Ethambutol exerts a pronounced bacteriostatic effect against Mycobacterium tuberculosis as well as some atypical mycobacteria (M. avium, M. kansasii, M. xenopi). The drug suppresses the replication of mycobacteria resistant to streptomycin, isoniazid, para-aminosalicylic acid (PAS), ethionamide, kanamycin, and other anti-tuberculosis agents. The mechanism of ethambutol's action, after its penetration into mycobacteria, is associated with inhibition of RNA and protein synthesis, ability to interact with divalent biometal ions (copper, magnesium), disruption of ribosome structure, and suppression of lipid metabolism intensity. Primary resistance to the drug occurs in approximately 1% of patients. Rapid tolerance develops during monotherapy of tuberculosis.

Pharmacokinetics

When administered orally, 75–80% of the drug is absorbed from the gastrointestinal tract. Concomitant food intake enhances and accelerates the absorption process. Maximum ethambutol concentration in the blood is reached approximately 2 hours after administration, amounting to 4–5 µg/mL when the drug is given at a dose of 25 mg/kg and 8–9 µg/mL at a dose of 50 mg/kg. Protein binding in plasma depends on the administered dose and ranges from 10% to 40%. The elimination half-life (T½) is 3.3–3.5 hours. A distinctive feature of ethambutol's pharmacokinetics is its selective accumulation in erythrocytes (concentration being twice higher than in blood plasma). Ethambutol penetrates into cerebrospinal fluid, crosses the placenta, and enters breast milk. The drug is primarily excreted unchanged in the urine. Approximately 10–20% of ethambutol is excreted in feces as inactive metabolites (aldehydes, dicarboxylic acids). Administration of ethambutol in patients with impaired renal function may lead to its accumulation in the body.

Clinical characteristics.

Indications.

Treatment of all forms of pulmonary and extrapulmonary tuberculosis (in combination with other antituberculosis agents).

Contraindications.

• Hypersensitivity to the drug;
• Optic neuritis;
• Cataract;
• Inflammatory eye diseases;
• Diabetic retinopathy;
• Gout;
• Severe renal insufficiency, chronic renal failure;
• Conditions where visual function cannot be monitored (critical condition, mental disorders).

Interaction with other medicinal products or other types of interactions.

When used concomitantly:

with antituberculosis medicinal products – enhanced effects of antituberculosis agents. For the treatment of tuberculosis in combination therapy with ethambutol, the following may be used: isoniazid, para-aminosalicylic acid (PAS), streptomycin, cycloserine, pyrazinamide;

with isoniazid when used concomitantly with cyclosporine A – increased breakdown of cyclosporine A, increasing the risk of transplant rejection;

with digoxin – reduced efficacy of the latter;

with ciprofloxacin, aminoglycosides, asparaginase, carbamazepine, lithium preparations, imipenem, methotrexate, quinine – enhanced effects and increased neurotoxicity of the above-mentioned medicinal products;

with aluminum-containing preparations and other antacids – impaired absorption of ethambutol;

with disulfiram – increased concentration of ethambutol and enhanced toxicity;

with ethionamide, spermine, spermidine, magnesium – concomitant use is not recommended due to pharmacological antagonism (the drugs should preferably be alternated every other day);

with phentolamine – possible increase in arterial pressure;

with pyrazinamide – synergistic effect on uric acid excretion;

with ethanol – enhanced negative effect of ethambutol on vision; therefore, alcohol consumption should be avoided during treatment.

Ethambutol alters the metabolism of certain trace elements, primarily zinc.

Special precautions for use.

Disorders of the skin and subcutaneous tissue. Severe cutaneous adverse reactions (SCARs) have been reported in the post-marketing period associated with the use of ethambutol, including Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or result in death.

Patients should be informed about the signs and symptoms of SCARs, and careful monitoring for skin reactions is required during treatment.

If symptoms suggestive of these reactions occur, ethambutol should be discontinued immediately and alternative therapy considered (when necessary).

If a serious reaction such as SJS, TEN, or DRESS develops during ethambutol therapy, re-administration of ethambutol is absolutely contraindicated.

In children, the appearance of rash may be mistakenly attributed to the underlying infection or an alternative infectious process. Physicians should consider the possibility of an ethambutol-related reaction in children who develop rash and fever during ethambutol therapy.

The drug should be prescribed only in combination with other anti-tuberculosis agents.

Dosage of ethambutol should be reduced in patients with renal impairment, as the drug accumulates in the body.

Regular ophthalmological examinations are required before and during treatment, including fundoscopy, intraocular pressure, refraction, visual fields, visual acuity, and color vision testing (particularly differentiation of red and green, blue and green colors).

Daily ophthalmological monitoring is necessary for patients with impaired renal function.

Ophthalmological examination should be performed for each eye separately and for both eyes together, as changes in visual acuity may be monocular or bilateral.

Patients must inform their physician about any changes in visual function.

In case of visual disturbances, ethambutol should be discontinued immediately to prevent optic nerve atrophy. Visual changes are usually reversible and resolve within several weeks after discontinuation of treatment, sometimes within several months. In rare cases, visual changes are irreversible due to optic nerve atrophy. In case of visual impairment, hydroxocobalamin or cyanocobalamin should be used.

Ethambutol should be administered with caution in patients with hyperuricemia.

Ethambutol therapy may increase serum urate concentrations due to reduced renal excretion of uric acid.

Periodic monitoring of peripheral blood parameters, liver and kidney function is recommended.

In patients previously treated with antituberculosis agents, bacterial resistance to ethambutol develops more frequently.

Prolonged or repeated use of ethambutol may lead to the development of secondary infections. Medical advice should be sought if infection is suspected.

If symptoms of tuberculosis do not resolve within 2–3 weeks or if clinical deterioration occurs, medical consultation is recommended.

The full course of treatment must be completed regardless of the presence or absence of disease symptoms to prevent relapse or development of resistance.

Ethanol enhances the toxic effect of ethambutol on the visual organs; therefore, alcohol consumption should be avoided during treatment.

At the beginning of therapy, cough may be intensified and sputum production increased. To reduce these symptoms, prescribe vitamin B complex and expectorants.

If adverse effects occur, dose adjustment with dose reduction is required; if this is not possible, switch to intermittent administration (every other day or twice weekly).

This medicinal product contains sodium (sodium lauryl sulfate), which should be taken into account in patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Ethambutol is contraindicated during pregnancy.

If ethambutol use is necessary, breastfeeding should be discontinued, as ethambutol is excreted in breast milk.

Ability to affect reaction speed when driving or operating machinery.

During treatment with this medicinal product, driving vehicles or engaging in other potentially hazardous activities requiring high concentration and rapid psychomotor reactions is not recommended.

Method of administration and dosage.

Adults – For initial treatment, administer Ethambutol orally at a dose of 15 mg/kg body weight once daily. When conducting a repeat course, administer the drug once daily at a dose of 25 mg/kg for 2 months, then continue with a dose of 15 mg/kg for the remainder of the treatment period. When using the drug at a dose of 25 mg/kg body weight, monthly ophthalmological examinations are recommended. The maximum daily dose during initial treatment should not exceed 2 g.

Children aged 13 years and older – Administer Ethambutol orally at a dose of 15–25 mg/kg daily. The maximum daily dose for children is 1 g.

The duration of treatment depends on the form of tuberculosis and ranges from 6 to 12 months.

Taking Ethambutol after meals improves its tolerability.

In renal functional impairment, Ethambutol dosage should be adjusted according to creatinine clearance:

Children.

The use of the drug in children under 13 years of age is contraindicated.

Overdose.

Symptoms. Development of neurological disorders, optic nerve damage (which may lead to blindness), worsening of visual acuity or intensification of other adverse reactions, loss of appetite, nausea, vomiting, diarrhea, fever, headache, dizziness, confusion, hallucinations, polyneuritis, respiratory depression, asystole.

Treatment. There is no specific antidote; treatment is symptomatic. Due to the rapid absorption of the drug, immediately after ingestion, induce vomiting or perform gastric lavage, administer enterosorbents, and give intravenous infusions of Ringer's solution, Sorbilact, or Reosorbilact. Carry out forced diuresis. Administer vitamin B complex. Monitor and support vital functions; perform resuscitation measures if necessary. Forced diuresis, peritoneal dialysis, or hemodialysis are indicated. In case of allergic reactions, desensitizing agents should be used. In life-threatening conditions, blood transfusion is indicated to remove erythrocytes where ethambutol accumulates.

Adverse Reactions

Eye disorders: retrobulbar optic neuritis, optic neuropathy, unilateral or bilateral decrease in visual acuity, including irreversible blindness, disturbances in color vision (mainly green and red), development of central or peripheral scotoma, visual field defects, retinal hemorrhage. The occurrence of visual disturbances depends on the duration of treatment and pre-existing or concurrent eye diseases.

Immune system disorders: anaphylactic/anaphylactoid reactions, including anaphylactic shock.

Skin and subcutaneous tissue disorders: rash, pruritus, hyperemia, dermatitis, burning or stinging sensation, Stevens-Johnson syndrome, Lyell’s syndrome (toxic epidermal necrolysis), drug reaction with eosinophilia and systemic symptoms (DRESS) (see section "Special Warnings and Precautions for Use"), vasculitis.

Nervous system disorders: headache, dizziness, confusion, disorientation, hallucinations, seizures, delirium, depression, peripheral neuritis, paresthesia in extremities, numbness, paresis.

Blood and lymphatic system disorders: leukopenia, neutropenia, thrombocytopenia, eosinophilia, lymphadenopathy.

Respiratory, thoracic and mediastinal disorders: pulmonary infiltrates with or without eosinophilia, pneumonitis, bronchospasm.

Cardiac disorders: pericarditis, myocarditis, arterial hypotension, tachycardia.

Gastrointestinal disorders: loss of appetite, metallic taste in the mouth, nausea, vomiting, dyspepsia, heartburn, abdominal pain, diarrhea, anorexia, pseudomembranous colitis (when used concomitantly with rifampicin and isoniazid).

Hepatobiliary disorders: liver function abnormalities – increased liver transaminase activity, hepatitis, jaundice.

Renal and urinary disorders: increased creatinine levels, increased urea levels, interstitial nephritis.

Musculoskeletal and connective tissue disorders: arthralgia.

Metabolism and nutrition disorders: decreased serum uric acid clearance, manifestations of uric acid diathesis, gout exacerbation; hyperuricemia.

General disorders: increased body temperature, chills, general weakness, edema.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://аіsf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 10 tablets per blister, 5 blisters per carton; 120 tablets in a container and carton; 1000 tablets in containers.

Prescription status. Prescription only.

Manufacturer. Public Joint-Stock Company "Scientific and Production Center "Boryspil Chemical and Pharmaceutical Plant".

Manufacturer's address and location of operations. 17 Miru Street, Kyiv, 03134, Ukraine.