Bitub®

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

Composition:

Active substance: isoniazid;

1 ml of solution contains 100 mg of isoniazid;

Excipients: methionine, sodium succinate, succinic acid, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear colorless or slightly yellowish liquid.

Pharmacotherapeutic group. Antituberculosis agents. ATC code J04A C01.

Pharmacological properties.

Pharmacodynamics.

Isoniazid inhibits DNA-dependent RNA polymerase and suppresses synthesis of mycolic acids in the cell wall of Mycobacterium tuberculosis. The drug exhibits high bacteriostatic activity against Mycobacterium tuberculosis, inhibiting their growth at a concentration of 0.03 mcg/mL. It is particularly active against rapidly multiplying microorganisms. It has weak effects on causative agents of other infectious diseases.

Pharmacokinetics.

After parenteral administration, the drug rapidly penetrates into body tissues and biological fluids. It crosses the blood-brain barrier, especially during inflammation of the meninges. It penetrates into bones. Isoniazid is metabolized in the liver depending on individual genetic characteristics, either at a higher or lower rate. It is excreted by the kidneys. The half-life in individuals with a higher metabolic rate is 0.5–1.5 hours, and in those with a lower metabolic rate, 4–6 hours. The drug is mainly excreted via bile; 30% of the dose is excreted in urine.

Clinical characteristics.

Indications.

Treatment of all forms and localizations of active tuberculosis in adults and children (as a first-line agent).

Contraindications.

Hypersensitivity to isoniazid or to excipients of the drug.

Epilepsy and other disorders associated with a predisposition to seizures, severe psychoses, poliomyelitis (including in medical history), toxic hepatitis in medical history due to administration of hydrazide derivatives of isonicotinic acid (e.g., phthivazide), pronounced atherosclerosis, acute hepatic and/or renal failure.

Administration of isoniazid in doses exceeding 10 mg/kg body weight per day is contraindicated during pregnancy, in case of cardiopulmonary insufficiency, stage II–III arterial hypertension, ischemic heart disease, disorders of the nervous system, bronchial asthma, chronic renal failure, hepatitis in the phase of exacerbation, liver cirrhosis, psoriasis, eczema in the phase of exacerbation, hypothyroidism, myxedema.

Interaction with other medicinal products and other types of interactions.

Indirect anticoagulants, benzodiazepines, phenytoin, carbamazepine, theophylline, monoamine oxidase inhibitors (MAO) – isoniazid potentiates the effects of these drugs (including toxic effects).

Isoniazid may reduce the therapeutic effect of levodopa.

Concomitant use of isoniazid:

With itraconazole – a significant decrease in itraconazole serum concentration and lack of therapeutic effect are possible. Concomitant use is not recommended.

With ketoconazole – may reduce ketoconazole levels in serum: monitoring of drug concentration in blood is required and dose adjustment may be necessary.

With acetaminophen – increases its toxicity due to generation and accumulation of toxic metabolites in the liver, which may lead to serious adverse reactions.

With glucocorticoids – increases metabolism and elimination of isoniazid.

Phenytoin, theophylline, carbamazepine – isoniazid inhibits metabolism of the listed drugs, leading to increased plasma concentrations and potential enhancement of toxic effects.

Phenytoin – isoniazid enhances the antiarrhythmic effect of phenytoin.

Potentially hepatotoxic and neurotoxic agents (including alcohol, rifampicin) – increases the likelihood of developing toxic hepatitis and neuropathy (with paracetamol, the risk of hepatotoxicity increases).

Valproate – concomitant use increases valproate plasma concentration.

Stavudine – increases the risk of developing distal sensory neuropathy.

Vitamin B6 and glutamic acid – when used in combination, reduce the likelihood of isoniazid adverse effects.

Since isoniazid clearance is doubled when co-administered with zalcitabine in HIV-infected patients, monitoring of isoniazid and zalcitabine concentrations is required to ensure treatment efficacy.

When isoniazid is prescribed to patients with slow inactivation of the drug who are simultaneously receiving para-aminosalicylic acid, tissue concentration of the drug may be increased, thereby increasing the risk of adverse effects.

Isoniazid may slow hepatic metabolism of primidone, triazolam, chlorzoxazone, disulfiram, which may lead to increased toxicity.

To enhance efficacy, Bitub® should be used in combination with other antituberculosis drugs (such as Rifonat®, Inbutol®, Paskonat®), and in case of mixed infection – simultaneously with broad-spectrum antibiotics: fluoroquinolones (e.g., Leflocin®, Maxicin®), sulfonamides (in particular, Soluseptol®), macrolides (e.g., clarithromycin, azithromycin, roxithromycin).

Special precautions.

Medical supervision is required during treatment, along with regular monitoring of liver function tests and ophthalmological examinations. During the first month, examinations should be performed at least twice; thereafter, once a month.

To reduce adverse effects, if they occur, pyridoxine (intramuscularly, 1−2 mL of a 5% solution per day), thiamine chloride (intramuscularly, 1 mL of a 5% solution per day), or thiamine bromide (intramuscularly, 1 mL of a 6% solution per day), glutamic acid, or disodium ATP should be administered.

To prevent possible hepatotoxic effects of isoniazid, it should be administered in combination with hepatoprotectors (e.g., silymarin, ursodeoxycholic acid).

Alcoholic beverages should be avoided during treatment.

Since resistance to isoniazid develops rapidly when used as monotherapy (in 70% of cases), the drug should be prescribed only in combination with other antituberculosis agents to delay this process. In mixed infections, broad-spectrum antibiotics, fluoroquinolones, and sulfonamides should be administered concurrently with isoniazid.

A positive glucosuria test may occur in patients with diabetes mellitus.

Use during pregnancy or breastfeeding.

The use of the drug is contraindicated during pregnancy at doses exceeding 10 mg/kg per day. When administering Bitub® to pregnant women (at a daily dose up to 10 mg/kg body weight), it should be noted that isoniazid crosses the placenta and may cause myelomeningocele and hypospadias, hemorrhages (due to vitamin K deficiency), as well as delayed psychomotor development in the fetus.

Isoniazid is excreted in breast milk; therefore, considering the potential risk of hepatitis and peripheral neuritis in infants, a decision should be made either to discontinue breastfeeding or to stop using the drug.

Ability to affect reaction rate while driving or operating machinery.

Drivers and operators of complex machinery should be aware of the potential for adverse neurological effects that may impair concentration and reaction speed.

Administration and Dosage.

Bitub® is administered intramuscularly, intravenously, by inhalation, and intracavernously.

Intravenous administration of Bitub® is indicated for the treatment of disseminated pulmonary tuberculosis, in cases of massive bacterial excretion, concomitant gastrointestinal disorders, in patients avoiding oral intake of the drug, and in cases of inefficacy with oral administration.

The daily intravenous dose is: for adults – 200–300 mg; for children – 100–300 mg (10–20 mg/kg body weight); for newborns – 3–5 mg/kg, but not exceeding 10 mg/kg body weight per day. The drug is administered intravenously as a 2.5–10% solution (if necessary, the preparation is diluted with water for injections or 0.9% sodium chloride solution) over 30–60 seconds, once daily. The treatment course consists of 30–150 injections and depends on the therapeutic efficacy and the patient's response to the drug. To prevent adverse effects during intravenous administration of Bitub®, vitamin B6 (pyridoxine) and glutamic acid are prescribed. Pyridoxine is administered intramuscularly (100–125 mg) 30 minutes after Bitub® administration or orally (60–100 mg) every 2 hours following intravenous injections of Bitub®. Glutamic acid is taken at a daily dose of 1–1.5 g. Bed rest for 1–1.5 hours is required after intravenous administration of the drug.

For intramuscular administration in adults and children, Bitub® is given as a ready-to-use undiluted 10% solution at a dose of 5–12 mg/kg once daily for 2–5 months. To reduce side effects with this route of administration, pyridoxine is prescribed orally at a dose of 60–100 mg simultaneously with Bitub® administration (pyridoxine may also be administered intramuscularly at a dose of 100–125 mg/kg 30 minutes after Bitub®).

For inhalation, Bitub® is administered as a ready-to-use undiluted 10% solution. The daily dose is 0.005–0.01 g (5–10 mg) per 1 kg body weight, given in 1–2 inhalations. Inhalations are performed daily for 1–6 months.

Patients with fibrocavitary pulmonary tuberculosis with bacterial excretion, as well as in the preoperative period, receive Bitub® as a ready-to-use undiluted 10% solution at a daily dose of 10–15 mg/kg once daily. The drug is administered primarily by intracavitary injection or via intratracheal instillation.

The maximum daily and total course dose of the drug is determined based on the clinical form of tuberculosis, the degree of inactivation, and individual tolerance to isoniazid.

Children.

The drug can be administered to children starting from the neonatal period.

Overdose.

Symptoms of overdose may appear 0.5–3 hours after drug administration and include gastrointestinal disturbances, nausea, vomiting, neurotoxic effects, dizziness, visual disturbances, slurred speech, and visual hallucinations. Severe intoxication may lead to respiratory depression and CNS depression, seizures, and coma. Typical laboratory findings in overdose include metabolic acidosis, ketonuria, and hyperglycemia.

Treatment: Gastric lavage, activated charcoal, intravenous administration of high-dose pyridoxine. Hemodialysis is effective.

Treatment of seizures: Administration of magnesium sulfate solution, diazepam.

Treatment of hepatic dysfunction: Methionine, lipamide, ATP, vitamin B12.

Adverse reactions.

Central and peripheral nervous system: insomnia, dizziness, headache, irritability, euphoria, sleep disturbances, sensory disturbances, paresthesia, hyperreflexia, peripheral neuritis, psychotic reactions (including toxic psychoses), ranging from minor personality changes to severe mental disorders, increased frequency of seizures in patients with epilepsy, convulsions, toxic encephalopathy, memory disorders.

Sensory organs: optic neuritis, optic nerve atrophy, hearing loss, tinnitus in patients with end-stage renal failure.

Gastrointestinal tract: dry mouth, anorexia, nausea, vomiting, constipation, acute pancreatitis.

Hepatobiliary system: liver function abnormalities, hepatitis, elevated serum transaminases (SGOT, SGPT), bilirubinemia, bilirubinuria, fulminant hepatic failure which may lead to necrosis.

Endocrine system and metabolism: pyridoxine deficiency, pellagra, hyperglycemia, metabolic acidosis.

Cardiovascular system: palpitations, chest pain and cardiac area pain, arterial hypertension, myocardial ischemia in elderly patients, urinary retention.

Hematological system: agranulocytosis, hemolytic anemia, sideroblastic anemia, aplastic anemia, thrombocytopenia, eosinophilia.

Genitourinary system: gynecomastia and menorrhagia.

Allergic reactions: Quincke's edema, respiratory distress, skin itching, dermatitis, fever, lymphadenopathy, vasculitis, skin rashes (exfoliative, maculopapular, purpura, erythema multiforme, lupus-like syndrome, rheumatic syndrome), Stevens-Johnson syndrome, toxic epidermal necrolysis, interstitial pneumonitis, edema of bronchial mucosa.

Possible local reactions at the site of administration.

Adverse effects usually resolve with dose reduction or temporary discontinuation of the drug.

Shelf life. 1.5 years.

Storage conditions.

Store in a light-protected place. Store at a temperature not exceeding 25 °C. Do not freeze. Keep out of reach of children.

Incompatibility. Unknown.

Packaging.

5 ml in a vial; 10 vials per pack; 30 vials per box; 5 ml in an ampoule; 5 ampoules in a blister pack; 2 blister packs per pack.

Prescription status. Prescription only.

Manufacturer.

LLC "Yuria-Pharm".

Manufacturer's address

Date of last review.