Ethambutol dt 100

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Ethambutol DT 100 (Ethambutol DT 100)

Composition:

Active substance: ethambutol hydrochloride;

One dispersible tablet contains ethambutol hydrochloride 100 mg;

Excipients: silicon dioxide colloidal anhydrous, microcrystalline cellulose, maize starch, sodium starch glycolate (type A), sodium croscarmellose, aspartame, povidone, low-substituted hydroxypropylcellulose, talc purified, siliconized microcrystalline cellulose, orange flavor (propylene glycol, orange oil, aldehyde C10, linalool), magnesium stearate.

Pharmaceutical form. Dispersible tablets.

Main physicochemical characteristics: round, flat tablets ranging from white to almost white, uncoated, with a score line on one side and smooth on the other.

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

Pharmacological properties.

Pharmacodynamics.

Ethambutol is used in the chemotherapy of tuberculosis in combination with other antituberculosis agents. It inhibits the synthesis of mycobacterial nucleic acids and thereby suppresses cell division.

Ethambutol exerts a bacteriostatic effect on the growth of mycobacteria (M. tuberculosis, M. bovis, M. smegmatis, M. phlei), including atypical forms (M. kansasii, M. aquae, M. avium). There is no activity against other bacteria, viruses, or fungi. At concentrations above 8 mcg/mL, ethambutol exerts a bactericidal effect. Primary resistance to ethambutol occurs rarely. There is no cross-resistance to other antituberculosis agents. When ethambutol is used as monotherapy, resistance develops in approximately 50% of patients within 6 months.

The table below presents data on the in vitro susceptibility of mycobacteria to ethambutol. The majority of tested strains of M. tuberculosis were sensitive to a concentration of 5 mcg/mL.

Most strains of M. kansasii, M. smegmatis, M. marinum, and M. avium were sensitive to low concentrations of ethambutol.

Strains of M. fortuitum, M. ulcerans, and M. thamnopheus were resistant even to high concentrations of ethambutol. Ethambutol is primarily bacteriostatic, although a bactericidal effect has been observed at high concentrations.

In vitro effectiveness of ethambutol against mycobacteria

* Number of susceptible strains compared to the indicated concentration.

** Includes strains resistant to INH, SM, PAS, and ETA.

Pharmacokinetics.

Absorption

After a single dose of ethambutol at 25 mg/kg body weight, peak serum concentration (Cmax) of 2–5 μg/mL is reached within 2–4 hours. Approximately 20–30% of ethambutol binds to plasma proteins over a concentration range of 0.5 to 2.0 μg/mL. Bioavailability is approximately 80%.

With daily administration of the drug at this dosage over a prolonged period, a similar serum level is observed. This serum level is no longer detectable 24 hours after the last dose, except in some patients with impaired renal function.

Distribution

Ethambutol distributes into most body tissues, including the lungs, and has been detected in pulmonary alveoli. As described in the literature, the steady-state volume of distribution ranges from 0.8 to 1.6 L/kg.

Ethambutol concentrations in erythrocytes are one to two times higher than in plasma. Erythrocytes may serve as a reservoir from which the drug slowly transfers into plasma.

Ethambutol does not cross the blood-brain barrier in healthy individuals, but in patients with meningitis, a dose-dependent concentration in cerebrospinal fluid (CSF) of up to 2.0 μg/mL has been observed.

Ethambutol can cross the placenta. Concentrations in breast milk correspond to the current serum concentration in the mother. Breastfed infants receive 3.5 to 6% of the maternal daily dose of 15 mg/kg.

Metabolism

8–15% of ethambutol is excreted as two metabolites—the derivative of dicarboxylic acid and an intermediate aldehyde—both products of ethambutol oxidation. Neither metabolite possesses antituberculosis activity and both are likely metabolized in the liver. Neither prolonged administration nor increased plasma concentrations lead to changes in metabolite production.

Elimination

The elimination half-life from plasma is 3.5–4.6 hours after a single 15 mg/kg dose. Renal clearance is approximately 6 mL/min/kg. Within 24 hours after ethambutol administration, approximately 50% of the initial dose is excreted unchanged in urine. Approximately 20–22% of the initial dose is excreted unchanged in feces.

After a single daily dose of 25 mg/kg, no drug accumulation was observed in patients with normal renal function, whereas significant accumulation was observed in patients with renal impairment.

Clinical characteristics.

Indications.

The medicinal product Ethambutol DT 100 may be used in combination with other antituberculosis agents for the treatment of all forms of tuberculosis caused by susceptible mycobacteria.

Contraindications.

Hypersensitivity to the active substance or to any other component of the medicinal product.

The product is contraindicated in case of previously damaged optic nerve or existing eye diseases.

Interaction with other medicinal products and other forms of interaction.

Aluminium hydroxide reduces the absorption of ethambutol; therefore, the medicinal product Ethambutol DT 100 should be taken at least 1 hour before taking agents that reduce gastric acidity.

Due to the neurotoxic effect of ethambutol, concomitant use with other neurotoxic agents (e.g., disulfiram) should be avoided.

Special precautions for use.

Since the medicinal product Ethambutol DT 100 may cause adverse reactions affecting the eyes, vision testing should be performed regularly.

The medicinal product Ethambutol DT 100 may cause visual impairment, which may manifest as retrobulbar neuritis. This effect may be dose- and duration-dependent. It is usually reversible: vision recovers after discontinuation of therapy. However, cases of irreversible blindness have been reported.

Careful ophthalmological examination should include fundoscopy, finger perimetry, and color vision testing, as the effect of ethambutol often first appears as loss of red-green color vision. In patients with pre-existing eye disorders such as cataracts, recurrent ocular infections, optic neuritis, or diabetic retinopathy, it may be difficult to determine the cause of visual disturbances. Therefore, it should be noted that such changes may be related to the underlying conditions. In such patients, the anticipated benefit of therapy with Ethambutol DT 100 should be carefully weighed against the potential risk of visual impairment.

Visual acuity, visual field, and color perception should be assessed before initiating therapy and regularly at 4-week intervals during treatment. In patients who develop visual disturbances during treatment, subjective symptoms may precede the appearance of objective signs or may occur simultaneously. All patients should be advised to seek immediate medical attention in case of any change in visual acuity, and should regularly monitor for blurred vision and other subjective ocular symptoms.

Changes in visual acuity may be monocular or bilateral. In such cases, each eye should be examined separately as well as both eyes together. If, after thorough examination, a degree of visual change is confirmed and no other causes are identified, treatment with Ethambutol DT 100 should be discontinued. The patient should then undergo frequent follow-up examinations. Progressive decline in visual acuity, visual field, and color perception during treatment should be considered related to the use of Ethambutol DT 100.

Experience with use in children under 13 years of age is limited. Particularly in young children, in whom objective vision testing is difficult, regular monitoring should be ensured.

Patients with renal impairment require weekly vision testing. The dose should be reduced according to the degree of renal function impairment.

Cases of hepatotoxicity and even liver failure have been reported. Therefore, liver function tests should be monitored regularly before and during therapy.

As with other potent medicinal products, renal and liver function tests, as well as a complete blood count, should be performed or monitored before and during treatment.

Ethambutol may reduce the excretion of urates, such as uric acid, leading to hyperuricemia. Acute gout attacks have been reported.

Disorders of the skin and subcutaneous tissue

Severe cutaneous adverse reactions (SCARs) have been reported in association with ethambutol use, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or fatal. Patients should be informed about the signs and symptoms of severe skin reactions when starting the drug and should be closely monitored.

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

If a patient develops a severe reaction such as SJS, TEN, or DRESS due to ethambutol, re-administration of ethambutol to this patient is absolutely contraindicated.

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

Paradoxical reaction

After initial improvement, ethambutol may cause paradoxical reactions with new exacerbation of tuberculosis symptoms. In patients receiving ethambutol, clinical or radiological worsening of existing tuberculosis lesions or development of new lesions has been observed. Such reactions typically occur within the first weeks or months of initiating tuberculosis treatment.

The cause of this paradoxical reaction is not fully understood. However, it may be related to an excessive immune response. If a paradoxical reaction is suspected, symptomatic treatment should be initiated, and immunosuppressive therapy may be necessary to control the excessive immune response.

Furthermore, it is recommended to continue the planned combination therapy. Patients should seek immediate medical attention if symptoms worsen. Symptoms depend on the affected tissue. General symptoms may include cough, fever, fatigue, dyspnea, headache, loss of appetite, weight loss, or asthenia (see section "Adverse reactions").

Excipients

Phenylketonuria

Ethambutol DT 100 contains 20 mg of aspartame.

Aspartame is a phenylalanine derivative and may be harmful to patients with phenylketonuria.

Sodium

This medicinal product contains sodium. Caution should be exercised when administering to patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

Pregnancy

Animal studies have shown adverse effects on the fetus (teratogenic potential of ethambutol).

However, no controlled studies in pregnant women have been conducted. Ethambutol crosses the placental barrier and results in fetal plasma concentrations equivalent to approximately 30% of the maternal plasma concentration. Cases of eye developmental abnormalities have been reported in infants born to women treated with anti-tuberculosis regimens containing ethambutol.

The medicinal product Ethambutol DT 100 is contraindicated during pregnancy.

Breastfeeding

Ethambutol is also excreted in breast milk. Concentrations correspond to those in maternal plasma. Breastfeeding should be discontinued before and during ethambutol treatment.

Fertility

There are no data on the effect of ethambutol on fertility.

Ability to affect reaction speed when driving or operating machinery.

The medicinal product Ethambutol DT 100 may affect vision and color perception. This may impair the ability to drive or operate machinery.

Method of administration and dosage.

Etambutol DT 100 should be taken as a single daily dose. Concurrent intake with food does not significantly impair absorption.

Combination with other anti-tuberculosis agents is prescribed by a physician depending on the specific clinical situation.

Preparation of the mixture for administration

1. With dry hands, place the recommended dose into a drinking container.
2. Add drinking water to the container. The minimum volume of water required for dispersing the dose is indicated below:

1. The mixture should be shaken or stirred until the tablets are completely dissolved.
2. Drink the entire contents of the container.

According to current clinical experience, for ethambutol in the intensive (initial) phase, the recommended dose is 15–25 mg/kg body weight per day.

In the maintenance phase, the recommended daily dose is 15–25 mg/kg body weight.

Treatment regimen and dosage recommendations

The dose of ethambutol for the treatment of susceptible tuberculosis in adults and children over 14 years of age is 15–25 mg/kg. The recommended ethambutol dose for this patient category is as follows:
25 to <30 kg – 600 mg;
30 to <35 kg – 800 mg;
35 to <65 kg – 1200 mg;
65 kg and above, including 80–95 kg – 1600 mg.

Special dosage instructions

Renal impairment

In cases of significant renal impairment, accumulation of ethambutol may occur, as the primary route of ethambutol elimination is via the kidneys. In such cases, the interval between ethambutol doses should be appropriately extended. Dosage adjustment is not required until creatinine clearance falls below 75 mL/min.

Patients with impaired renal function

* Serum levels should be within the range of minimal inhibitory concentrations of 2-5 mcg/mL, 2-4 hours after administration.

Children

The use of ethambutol in children under 13 years of age is not recommended, as safe conditions of use have not yet been established. If treatment with ethambutol in children under 13 years of age is considered absolutely necessary, adult doses adjusted according to body weight may be used. In such cases, treatment should be carried out with particular caution and under close supervision (see also section "Special precautions", "Administration and dosage").

Overdose.

Symptoms

Gastrointestinal disturbances, vomiting, fever, headache, anorexia, dizziness, hallucinations, and visual disturbances.

Treatment

There is no specific antidote; treatment should be supportive. Induced vomiting and gastric lavage may be effective if initiated within a few hours after overdose. If treatment is delayed, hemodialysis or peritoneal dialysis is considered effective.

Side effects

Adverse reactions are classified by MedDRA system organ classes and frequency.

By frequency, adverse reactions are categorized as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from available data).

Blood and lymphatic system disorders

Rare: leukopenia, neutropenia, thrombocytopenia.

Immune system disorders

Rare: hypersensitivity (rash, fever, joint pain), anaphylactic/anaphylactoid reactions.

Nervous system disorders

Uncommon: dizziness, disorientation, confusion, hallucinations, headache, malaise.

Rare: peripheral neuritis (numbness, tingling, burning, or weakness in hands or legs).

Eye disorders

Rare: dose-dependent retrobulbar optic neuritis (blurred vision, eye pain, red-green color blindness, vision loss), visual field loss, scotoma, congenital eye anomaly, blindness.

Gastrointestinal disorders

Uncommon: abdominal pain, loss of appetite, nausea and vomiting.

Hepatobiliary disorders

Uncommon: increased levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), hepatotoxicity, including fatal outcomes in very rare cases.

Skin and subcutaneous tissue disorders

Uncommon: pruritus.

Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis.

Not known: drug reaction with eosinophilia and systemic symptoms (DRESS) (see section "Special precautions").

Renal and urinary disorders

Uncommon: hyperuricemia, which may lead to acute gouty arthritis (chills; joint pain and swelling, especially in the big toe, ankle, or knee; skin over the joint is tight and hot).

General disorders

Very common/common¹: paradoxical reaction to treatment (recurrence or new appearance of symptoms, physical and radiological signs in a patient whose condition had previously improved on adequate tuberculosis treatment, i.e., paradoxical reaction diagnosed after excluding poor treatment compliance, drug resistance, adverse reactions to tuberculosis treatment, and secondary bacterial or fungal infections).

¹ In published literature, the frequency is reported to range from 6% to 30%.

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 30°C in the original packaging, in a dry place. Keep out of reach of children. Protect from light. Avoid exposure to temperatures above 30°C.

Packaging.

10 tablets per blister, 10 blisters per cardboard package.

Prescription category. Prescription only.

Manufacturer.

Oxalis Labs.

Manufacturer's address and location of operations.

Village Theda, P.O. Lodhiamaira, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India.