Inbutol®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT INBUTOL® (INBUTOL)

Composition:

Active substance: 1 ml of solution contains 100 mg of ethambutol hydrochloride;

Excipient: water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless or slightly yellowish liquid. pH 3.5–7.0.

Pharmacotherapeutic group. Antituberculosis agents. ATC code J04A K02.

Pharmacological Properties.

Pharmacodynamics.

Inbutol exerts a specific antibacterial tuberculostatic effect against Mycobacterium tuberculosis and Mycobacterium bovis, as well as against some atypical (opportunistic, nontuberculous) mycobacterial species, Mycobacterium avium. It shows no activity against other bacteria, viruses, or fungi. The drug acts bacteriostatically. It suppresses the growth and multiplication of tuberculous mycobacteria resistant to other antituberculosis agents (streptomycin, isoniazid, para-aminosalicylic acid (PAS), ethionamide, kanamycin).

Primary resistance of Mycobacterium tuberculosis and Mycobacterium bovis to ethambutol is rare; secondary resistance develops slowly (except in cases of monotherapy), therefore the drug must be used in combination with other antituberculosis agents. The mechanism of ethambutol's bacteriostatic action is associated with inhibition of DNA and RNA enzymes, thereby suppressing protein synthesis, growth, and replication of tuberculous mycobacteria. Sensitivity of various mycobacteria to ethambutol ranges from 0.25 to 100 mcg/mL. A significant advantage of ethambutol is its bacteriostatic activity against atypical and avian strains of mycobacteria. Inbutol penetrates actively growing mycobacterial cells, inhibiting RNA synthesis of one or more metabolites and disrupting cellular metabolism—resulting in cessation of replication and cell death. It is active only against actively dividing cells.

Pharmacokinetics.

After intravenous administration of 10 mL of a 10% solution (1000 mg), the drug's effect begins immediately. Maximum drug concentration in the blood is achieved right after administration and is maintained for 2–4 hours. Plasma protein binding is 20–30%. The drug penetrates well into tissues, organs, and biological fluids, except ascitic and pleural fluids. It is detectable in cerebrospinal fluid in cases of tuberculous meningitis. The highest concentrations are found in the kidneys, lungs, saliva, and urine. It passes into breast milk. It does not cross the intact blood-brain barrier. Partially metabolized in the liver (15%) into inactive metabolites. The main metabolic pathway involves initial oxidation of the alcohol group to an aldehyde intermediate metabolite, followed by its conversion into a dicarboxylic acid. The elimination half-life is approximately 6 hours, and prolonged to 8 hours in case of impaired renal function. Excreted via urine at 80–90% (50% unchanged, 15% as inactive metabolites) and via feces at 10–20% (unchanged). The drug is removed by hemodialysis and peritoneal dialysis.

Clinical characteristics.

Indications.

Treatment of all forms and localizations of active tuberculosis, especially in newly detected acute processes.

Contraindications.

• Hypersensitivity to the active substance or to any excipient;
• optic neuritis, cataract, diabetic retinopathy, inflammatory eye diseases;
• other existing serious eye diseases;
• eye lesions that interfere with monitoring visual acuity;
• patients in whom reliable monitoring of visual acuity is impossible or no longer feasible for other reasons (severe condition, mental disorders);
• gout, severe renal insufficiency.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of the drug with other medicinal products may result in:

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

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

with digoxin – reduced efficacy of the latter;

with disulfiram – increased ethambutol concentration and enhanced toxicity;

with pyrazinamide – synergistic effect on uric acid excretion;

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

with ethionamide – pharmacological antagonism; therefore, concomitant use is not recommended (the drugs should preferably be administered on alternate days).

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

Ethanol enhances the negative effect of ethambutol on vision; therefore, alcohol consumption should be avoided during treatment.

Chronic alcoholics receiving disulfiram have an increased risk of visual function impairment when using ethambutol.

Effect on laboratory test results

Ethambutol interacts with phentolamine in blood serum and may cause false-positive results in testing for the diagnosis of pheochromocytoma.

Special precautions for use.

Use with caution in patients with impaired renal function.

In patients undergoing intermittent hemodialysis, dose adjustment with an increase in dose or switching to an intermittent administration regimen is required.

If adverse effects occur, dose reduction is necessary; if this is not possible, switch to intermittent administration (every other day or twice weekly). At the beginning of treatment, cough may worsen and sputum volume may increase. To reduce these symptoms, prescribe vitamin B complex and expectorants.

Treatment with ethambutol may increase blood urate levels due to reduced renal excretion of uric acid. Use with caution in patients with elevated blood uric acid levels.

Ophthalmologic monitoring should be performed before and during ethambutol treatment: examination of the fundus, intraocular pressure, refraction, visual fields, visual acuity, and color vision (particularly differentiation of red and green, blue and green colors).

Patients should be instructed to inform their physician about any changes in visual function.

In patients with impaired renal function, ophthalmologic monitoring should be performed daily.

Ophthalmologic 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 treatment should be discontinued to prevent optic nerve atrophy. Visual changes are usually reversible and resolve within several weeks after discontinuation of treatment; in some cases, resolution may take several months. In rare cases, visual changes are irreversible due to optic nerve atrophy. In case of visual disturbances, administer hydroxocobalamin or cyanocobalamin. Vision recovery may take several weeks or even months.

Ethambutol use requires continuous monitoring of peripheral blood parameters, and liver and kidney function.

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

Prolonged or repeated use of ethambutol may lead to development of secondary infections. If infection is suspected, medical advice should be sought.

If symptoms of tuberculosis do not resolve within 2–3 weeks or if clinical deterioration occurs, patients should consult a physician.

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.

Disorders of the skin and subcutaneous tissue

In the post-marketing period, serious skin adverse reactions (SSARs) associated with ethambutol use have been reported, including drug-induced eosinophilia with systemic symptoms (DRESS), which may be life-threatening or fatal.

Patients should be informed about the signs and symptoms of such 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 considered (if necessary).

Ethambutol treatment must never be resumed in patients who have experienced a serious reaction such as DRESS while receiving ethambutol.

In children, rash may be mistakenly attributed to primary 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.

Use during pregnancy or breastfeeding.

The medicinal product is contraindicated during pregnancy and breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

During treatment, patients should not drive or engage in other potentially hazardous activities requiring high attention concentration and rapid psychomotor reactions.

Dosage and Administration

The optimal dose of ethambutol for adults in the treatment of tuberculosis is 15–20 mg/kg body weight daily when administered every day, or 20–35 mg/kg body weight daily when administered intermittently (every other day). In cases of disseminated disease with massive bacterial excretion or in the treatment of tuberculous meningoencephalitis, the dose may be increased to 30–35 mg/kg body weight daily. The maximum daily dose for adults is 1–1.6 g, depending on body weight. For children aged 5 years and older, the drug should be administered at a dose of 15–20 mg/kg body weight daily; for intermittent administration, up to 25 mg/kg body weight daily. The maximum daily dose for children is 1–1.2 g, depending on body weight.

The optimal dose for adults when using the intravenous form of ethambutol (Inbutol®) in the treatment of tuberculosis is 10 mL of a 10% solution daily when administered every day, or 20 mL of a 10% solution daily when administered intermittently (every other day).

The total cumulative dose depends on the severity of the disease and is determined individually by the physician. The duration of treatment depends on therapeutic efficacy and patient tolerance, averaging 2–4 months.

For patients with impaired renal function and serum creatinine levels above 1.3 mg/dL, urine analysis should be monitored to assess excretion rate. If the excretion rate exceeds 50 mL/min, the dose of Inbutol® at 20 mg/kg does not need to be adjusted. If the excretion rate is less than 50 mL/min, the dose should be reduced to 12 mg/kg. If the excretion rate is less than 20 mL/min, serum levels of Inbutol® should be measured to maintain a concentration of approximately 5 µg/mL.

As an alternative regimen for patients with renal insufficiency or those undergoing dialysis, Inbutol® should be administered at a dose of 40 mg/kg body weight twice weekly. For patients undergoing dialysis, the drug should be administered 6 hours before the start of dialysis.

The drug should be administered by intravenous infusion after dilution of the required volume in 100 or 200 mL of 0.9% sodium chloride solution or 5% glucose solution. The recommended infusion duration is 60–90 minutes, depending on the volume.

Children.

The drug should not be administered to children under 5 years of age due to unreliable visual function testing. Use with caution in children under 10 years of age.

Overdose.

Symptoms: dizziness, headache, polyneuritis, optic neuritis (potentially leading to blindness), decreased visual acuity, development of neurological disturbances, confusion, hallucinations, loss of appetite, nausea, vomiting, diarrhea, fever, respiratory depression, asystole.

Treatment: There is no specific antidote. Discontinue the drug immediately. Induce vomiting or perform gastric lavage, and administer enterosorbents. Administer Ringer's solution, Sorbilact, or Reosorbilact intravenously by infusion. Perform forced diuresis. Prescribe vitamin B complex. Monitor and support vital functions; perform resuscitation if necessary.

Forced diuresis, peritoneal dialysis, or hemodialysis are indicated. In life-threatening situations, exchange transfusion is recommended, as it removes erythrocytes in which ethambutol accumulates significantly. Treatment is symptomatic. There is no specific antidote.

Adverse reactions.

Cardiovascular system: pericarditis, myocarditis, arterial hypotension, tachycardia.

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

Central nervous system: dizziness, headache, weakness, depression, confusion, hallucinations, seizures, disorientation, peripheral neuritis – paresthesia in limbs, tingling sensation, numbness, paresis.

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 concomitant eye diseases.

Respiratory system, thoracic organs and mediastinum: pulmonary infiltrates with or without eosinophilia, pneumonitis, increased cough, difficulty in sputum expectoration and increased sputum viscosity.

Gastrointestinal disorders: loss of appetite, metallic taste in mouth, nausea, vomiting, dyspepsia, heartburn, abdominal pain, diarrhea, pseudomembranous colitis (with concomitant use of rifampicin and isoniazid).

Urinary system: increased creatinine levels, interstitial nephritis.

Skin and subcutaneous tissue: rash, pruritus, hyperemia, dermatitis, drug-induced eosinophilia with systemic symptoms (DRESS) (see section "Special precautions").

Musculoskeletal system: joint pain.

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

Immune system: anaphylactic and anaphylactoid reactions, including anaphylactic shock, Stevens-Johnson syndrome, Lyell's syndrome (toxic epidermal necrolysis), bronchospasm, vasculitis.

Hepatobiliary system: increased liver transaminase activity, jaundice, hepatitis.

General disorders: increased body temperature, chills, general weakness, edema,
changes at the injection site.

Shelf life.

2 years.

Storage conditions.

Store at temperature not exceeding 25 °C. Keep out of reach of children.

Incompatibility.

The solution should not be mixed with other medicinal products in the same container.

Packaging.

10 ml, 20 ml in vials.

Prescription status. Prescription only.

Manufacturer.

Yuria-Pharm LLC.

Manufacturer's address and location of business activity.

108, Kobzarska St., Cherkasy, 18030, Cherkasy region, Ukraine. Tel.: (044) 281-01-01.