Ecoks 400

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ECOX 400 (ECOX 400)

Composition:

Active substance: ethambutol;

1 tablet contains ethambutol hydrochloride 400 mg;

Excipients: microcrystalline cellulose, povidone, stearic acid, corn starch, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, talc, magnesium stearate, hypromellose, ethylcellulose, polyethylene glycol 6000, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex, film-coated tablets with a score line on one side.

Pharmacotherapeutic group.

Antibacterials for systemic use. Antituberculosis agents. Ethambutol. ATC code J04AK02.

Pharmacological Properties

Pharmacodynamics. Ethambutol is a synthetic chemotherapeutic agent exerting a bacteriostatic effect against typical and atypical Mycobacterium tuberculosis. The mechanism of action of the drug is associated with rapid penetration into the cell, where it disrupts lipid metabolism and RNA synthesis, binds magnesium and copper ions, and interferes with ribosomal structure and protein synthesis in bacterial cells. It is active against mycobacteria resistant to other antituberculosis drugs, thus classifying it as a second-line agent. It affects both intracellular and extracellular forms of bacteria. Approximately 1% of patients exhibit primary resistance to the drug. It is active only against rapidly dividing cells. Ethambutol inhibits the growth and reproduction of Mycobacterium tuberculosis resistant to streptomycin, isoniazid, PAS, ethionamide, and kanamycin. When used as monotherapy, resistance of mycobacteria to ethambutol develops relatively rapidly.

Pharmacokinetics. After oral administration, ethambutol is rapidly absorbed from the gastrointestinal tract. Bioavailability is approximately 80%. It is 20–30% bound to plasma proteins. The minimum inhibitory concentration (MIC) is 1 μg/mL. Following a single oral dose of 25 mg/kg body weight, peak serum concentration of 2–5 μg/mL is reached within 2–4 hours; after 24 hours, serum concentration falls below 1 μg/mL. Ethambutol accumulates in lung tissue, reaching concentrations 5–9 times higher than those in serum, and penetrates well into many other tissues and organs. Its intracellular concentration in erythrocytes is twice that in serum.

Ethambutol is metabolized in the liver to dicarboxylic acid derivatives. The elimination half-life is 3–4 hours, but it is prolonged to 8 hours in renal impairment. Within 24 hours, more than 50% of the administered dose is excreted unchanged in urine, and 8–15% is excreted as inactive metabolites. Approximately 20–22% of the initial dose is excreted unchanged in feces.

Ethambutol crosses the placental barrier. The concentration of ethambutol in fetal blood is approximately 30% of the drug concentration in maternal blood.

Clinical characteristics.

Indications.

Treatment of various forms of tuberculosis (only in combination with other antituberculosis agents).

Contraindications.

Hypersensitivity to the components of the drug, optic neuritis, cataract, diabetic retinopathy, inflammatory eye diseases, gout, severe renal failure.

Interaction with other medicinal products and other types of interactions.

The drug is administered in combination with other antituberculosis agents, as well as simultaneously with broad-spectrum antibacterial agents, fluoroquinolones, sulfonamides, etc.

Aluminium hydroxide and similar antacid agents impair absorption of ethambutol from the gastrointestinal tract; therefore, they should not be taken simultaneously with ethambutol.

Pharmacological antagonism occurs with ethionamide, spermine, spermidine, and magnesium. Ethambutol and pyrazinamide act synergistically on uric acid excretion. Combined treatment with ethambutol and isoniazid, when used concomitantly with cyclosporine A, leads to enhanced degradation of the latter, increasing the risk of transplant rejection. Ethambutol reacts with phentolamine in blood and may cause an increase in arterial pressure. It enhances the neurotoxicity of aminoglycosides, asparaginase, ciprofloxacin, and methotrexate.

Ethambutol reduces the therapeutic efficacy of digoxin. Ethambutol enhances the neurotoxicity of carbamazepine, imipenem, lithium salts, and quinine. Concurrent treatment with disulfiram may lead to increased ethambutol concentration in blood serum and enhanced toxicity. Ethanol intensifies the toxic effect of ethambutol on the visual organ; therefore, alcohol consumption should be avoided during treatment.

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

Special precautions for use.

Ethambutol should be prescribed with caution to patients with moderate to severe renal impairment; the dose of ethambutol should be reduced in such patients because the drug accumulates in the body.

Visual acuity, refraction, visual fields, intraocular pressure, and fundus should be systematically monitored before and during treatment. Ophthalmological monitoring must be performed daily in patients with renal impairment. Ethambutol should not be prescribed if visual function cannot be assessed (e.g., in critical condition or psychiatric disorders).

Ophthalmological monitoring should be performed for each eye separately and for both eyes together, as changes in visual acuity may be unilateral or bilateral. If visual disturbances occur, ethambutol therapy should be discontinued to prevent optic nerve atrophy. Visual disturbances 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. Patients must be informed to report any visual changes to their physician. Hydroxocobalamin or cyanocobalamin should be administered if visual disturbances occur. Ethambutol therapy requires continuous monitoring of peripheral blood parameters, as well as liver and kidney function.

At the beginning of treatment, coughing may intensify and sputum volume may increase.

Ethambutol therapy may increase uric acid levels in blood due to reduced renal excretion of uric acid. The drug should be prescribed with caution in patients with elevated blood uric acid levels.

If adverse effects occur, dose adjustment—specifically dose reduction—is required; if this is not feasible, switching to intermittent dosing (every other day or twice weekly) should be considered. Vitamins of group B and expectorants may be prescribed to alleviate these symptoms.

Disorders of the skin and subcutaneous tissue

In the post-marketing period, severe cutaneous adverse reactions (SCARs) associated with ethambutol use have been reported, 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 these reactions, and careful monitoring for skin reactions should be performed during treatment.

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

Ethambutol therapy must never be resumed in patients who have experienced a serious reaction such as SJS, TEN, or DRESS during ethambutol treatment.

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

Use during pregnancy or breastfeeding.

The drug is contraindicated during pregnancy and breastfeeding.

Ability to affect reaction rate when operating vehicles or other machinery.

During treatment, driving vehicles and engaging in other potentially hazardous activities requiring increased attention and psychomotor speed is not permitted.

Method of administration and dosage.

Adults and children aged 13 years and older.

Initial treatment: administer the drug at a dose of 15 mg/kg body weight once daily.

Repeat course of treatment: administer the drug at a dose of 25 mg/kg once daily, then switch to administration of the drug at a dose of 15 mg/kg once daily.

During the period when the patient is taking the drug at a dose of 25 mg/kg body weight, monthly ophthalmologist examinations are recommended.

In renal functional impairment: administer the drug according to creatinine clearance value:

Maximum daily dose for adults – 2 g.

Maximum daily dose for children – 1 g.

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

Taking Ekoks 400 after a meal improves its tolerability.

Children.

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

Overdose.

Symptoms: dizziness, headache, polyneuritis, optic neuritis, optic nerve atrophy, possible development of blindness, deterioration of visual acuity, development of neurological disorders, confusion, hallucinations, loss of appetite, nausea, vomiting, diarrhea, fever, respiratory depression, asystole, collapse.

Treatment: there is no specific antidote; the drug should be discontinued, vomiting should be induced or gastric lavage should be performed, enteral sorbents should be administered, intravenous infusion of Ringer's solution, Sorbilact, Reosorbilact should be given, forced diuresis should be carried out. Vitamins of group B should be prescribed. Monitoring and measures to support vital functions should be implemented; resuscitation measures should be performed if necessary.

Forced diuresis, peritoneal dialysis, or hemodialysis are indicated. In life-threatening conditions, blood transfusion is indicated, since this procedure also removes erythrocytes in which ethambutol accumulates in significant amounts.

Side effects

Eye disorders: optic neuritis (unilateral or bilateral), manifested by impaired perception of red and green colors, narrowing of visual fields, decreased visual acuity up to complete blindness; development of central or peripheral scotoma; retinal hemorrhage.

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

Skin and subcutaneous tissue disorders: skin rashes, pruritus, dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome.

Frequency unknown:

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) (see section "Special precautions").

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

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

Respiratory system disorders: lung infiltrates with or without eosinophilia, pneumonitis.

Cardiac disorders: pericarditis, myocarditis.

Gastrointestinal disorders: loss of appetite, metallic taste in the mouth, nausea, vomiting, diarrhea, abdominal pain, heartburn.

Hepatobiliary disorders: increased levels of liver transaminases, hepatitis, jaundice.

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

Metabolic and nutritional disorders: uric acid diathesis, exacerbation of gout; hyperuricemia.

General disorders: increased body temperature, chills, weakness, edema, joint pain.

Shelf life. 4 years.

Storage conditions.

Store at a temperature not exceeding 30 °C in the original packaging.

Keep out of reach of children.

Packaging.

10 tablets per blister, 10 blisters per cardboard package.

Prescription category. Prescription only.

Manufacturer.

Macleods Pharmaceuticals Limited.

Address:

Phase II, Plot No. 12, 15, 21, 23, 24, 25, 26, 27, 28 and 30, Survey No. 366, Premier Industrial Estate, Kachigam, Daman, 396210, India.