Terizidone + Pyridoxine-Mak (Capsules) Instructions for Use

ATC Code

J04AK03 (Terizidone)

Active Substances

Pyridoxine (Rec.INN registered by WHO)

Terizidone (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antituberculosis drug

Pharmacotherapeutic Group

Antitubercular agent

Pharmacological Action

Terizidone is a broad-spectrum antibiotic, a derivative of D-cycloserine.

Terizidone competitively blocks the enzymes that incorporate alanine into the alanyl-alanine dipeptide, the main component of the mycobacterial cell wall.

It does not have cross-resistance with other antituberculosis drugs.

Terizidone has antibacterial activity against Mycobacterium tuberculosis and bacteria causing urinary tract infections, including bacterial strains that become resistant to other antibiotics.

The minimum inhibitory concentration of terizidone for susceptible strains is 4-250 mg/l, including 10-40 mg/l for Mycobacterium tuberculosis, 8-32 mg/l for staphylococci, and 50-250 mg/l for clinically significant Gram-negative bacteria.

The following bacteria are susceptible to terizidone: Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium avium, as well as Staphylococcus aureus, Staphylococcus epidermidis.

Enterococcus faecalis, Escherichia coli, Citrobacter, Enterobacter, Morganella morganii, Klebsiella pneumoniae, Pseudomonas aeruginosa are also susceptible to this drug.

Pyridoxine acts as a coenzyme, participating in biochemical reactions, including the metabolism of amino acids and glycogen, in the synthesis of nucleic acids, hemoglobin, sphingomyelin and other sphingolipids, in the synthesis of the neurotransmitters serotonin, dopamine, norepinephrine and gamma-aminobutyric acid.

Pyridoxine has an antineurotoxic effect.

The use of pyridoxine reduces side effects from the central nervous system when used concomitantly with antituberculosis drugs.

Pharmacokinetics

Terizidone. After oral administration of 250 mg of terizidone, C_max is about 6.5 µg/ml, the peak plasma concentration of the drug is reached in 2-4 hours.

Terizidone is absorbed from the gastrointestinal tract quickly and almost completely – 70-90%.

Food intake does not affect the absorption rate.

It is widely distributed in body tissues and fluids, for example in the lungs, bile, penetrates into ascitic, pleural and synovial fluids, lymph, saliva.

It penetrates very well into the cerebrospinal fluid (concentration in the cerebrospinal fluid reaches 80-100% of the plasma concentration), a higher concentration is noted in patients with meningitis.

When taking a dose of 250 mg of terizidone orally, high concentrations of the drug are found in the blood and urine, which allows it to be used for the treatment of urinary tract infections, including chronic forms.

Renal excretion is slow and uniform, T_1/2 is 24 hours.

Slow renal excretion of the drug leads to the fact that the concentration of terizidone in the urine persists for 12 hours, 60-70% of the drug is excreted unchanged by glomerular filtration.

A small amount is excreted in the feces.

The value of the elimination constant is 0.0262 h.

Terizidone is metabolized in small amounts, which is the reason for its weak toxic effect on the kidneys.

In renal failure, the half-life is prolonged to 72 hours.

Pyridoxine. It is rapidly absorbed throughout the small intestine, with a larger amount absorbed in the jejunum.

It is metabolized in the liver to form pharmacologically active metabolites (pyridoxal phosphate and pyridoxamine phosphate).

Pyridoxal phosphate is 90% bound to plasma proteins.

It penetrates well into all tissues; it accumulates mainly in the liver, less in muscles and the central nervous system.

It crosses the placenta and is secreted into breast milk.

T_1/2 is 15-20 days.

It is excreted by the kidneys, and also during hemodialysis.

Indications

• tuberculosis (various forms and localizations) in the complex therapy of drug-resistant forms of tuberculosis.

ICD codes

Dosage Regimen

Capsules

The drug is taken orally, regardless of meals.

Adults and children over 14 years of age weighing less than 60 kg are prescribed 300 mg 2 times/day (600 mg/day); with a body weight of 60-80 kg – 300 mg 3 times/day (900 mg/day); adults weighing more than 80 kg – 600 mg 2 times/day (1200 mg/day).

In case of impaired renal function (creatinine clearance less than 30 ml/min), the dose of the drug and the frequency of administration are reduced: 250 mg once/day daily or 500 mg 3 times a week (for example, Monday, Wednesday, Friday). If the creatinine concentration is more than 2 mg/dl, the use of the drug is contraindicated.

The duration of the treatment course is 3-4 months.

The drug has no peculiarities of action upon first administration or upon its withdrawal.

It is not recommended to prematurely stop or temporarily interrupt the started course of treatment or to take the drug irregularly.

If a single dose is missed, the next dose of the drug should be taken at the scheduled time; a double dose should not be taken.

Adverse Reactions

The following gradation is used to assess the frequency of side effects: very common (>1/10), common (>1/100 but <1/10), uncommon (>1/1000 but <1/100), rare (>1/10,000 but <1/1000), very rare (<1/10,000, including reports of isolated cases).

From the central nervous system

Rare – headache, dizziness, increased excitability, tremor, insomnia, feeling of intoxication;

Very rare – convulsions (including epileptic), dysarthria, mental disorders such as mania or depression.

From the gastrointestinal tract

Rare: abdominal pain, flatulence and diarrhea.

Other

Very rare: allergic reactions, skin rash.

Due to the presence of pyridoxine in the composition (additionally) hypersecretion of hydrochloric acid, numbness and a feeling of tightness in the extremities (symptom of “stockings” and “gloves”).

Contraindications

• Hypersensitivity to the drug, including to cycloserine, or to the components that make up the finished dosage form;
• Organic diseases of the central nervous system, cerebral atherosclerosis, epilepsy, epileptic seizures (including in history);
• Mental disorders (anxiety, psychoses, depression, including in history);
• Chronic heart failure;
• Chronic renal failure;
• Alcoholism;
• Pregnancy, lactation period;
• Children under 14 years of age;
• Lactose intolerance, lactase deficiency and glucose-galactose malabsorption syndrome.

With caution: elderly age; coronary artery disease; impaired liver and kidney function; heart failure; gastric and duodenal ulcer.

Use in Pregnancy and Lactation

The use of the drug during pregnancy is possible only for strict indications or in life-threatening conditions, if the doctor is confident that the potential benefit of using the drug in pregnant women outweighs the possible harm to the fetus.

Concentrations in breast milk approach those found in plasma. The decision to discontinue breastfeeding or to stop treatment with the drug should be made taking into account the importance of drug treatment for the mother.

Use in Hepatic Impairment

Use with caution in case of impaired liver function.

Use in Renal Impairment

Use with caution in case of impaired renal function.

Pediatric Use

Contraindicated in children under 14 years of age.

Geriatric Use

Use with caution in the elderly.

Special Precautions

The use of the drug while taking alcohol is associated with an increased frequency of side effects, up to the development of convulsions, so during the drug intake it is necessary to avoid the consumption of alcoholic beverages.

The use of the drug simultaneously with cycloserine is prohibited due to possible overdose.

Terizidone can cause the development of cyanocobalamin and folic acid deficiency. In these cases, it is necessary to conduct an appropriate examination and treatment of the patient. It is recommended to take it together with glutamic acid at a dose of 500 mg 3 times a day.

During therapy with the drug, it is necessary to monitor blood and urine tests monthly, liver function indicators (plasma concentration of ALT, aspartate aminotransferase and bilirubin).

It is necessary to monitor the patient’s condition: medical personnel monitoring patients in the hospital, as well as family members of outpatients taking Terizidone, should be informed about the possibility of developing adverse reactions from the nervous system and instructed on the need to immediately inform the attending physician if depression or changes in the patient’s behavior occur.

In severe liver damage, Pyridoxine in high doses can cause deterioration of its function.

When determining urobilinogen using Ehrlich’s reagent, Pyridoxine may distort the test results.

Effect on the ability to drive vehicles and mechanisms

The ability of the drug to affect the speed of psychomotor reactions and the ability to drive vehicles or other technical means has not been studied. Caution should be exercised when engaging in potentially hazardous activities that require increased attention and rapid psychomotor reactions.

Overdose

Cases of drug overdose have not been described.

In case of overdose, increased neurotoxicity (epileptiform seizures), impaired gastrointestinal functions are possible.

Measures to assist in case of overdose

Symptomatic therapy, activated charcoal. To prevent neurotoxic effects, the administration of pyridoxine, anticonvulsant and sedative drugs is possible. Hemodialysis is effective.

Drug Interactions

Ethanol increases the risk and frequency of adverse reactions, including the development of epileptic seizures.

When used concomitantly with ethionamide, the risk of adverse reactions from the central nervous system, especially convulsive syndrome, increases.

When used concomitantly with phenytoin, an increase in the plasma concentration of phenytoin is possible.

When used concomitantly with isoniazid, the frequency of dizziness and drowsiness increases.

When used concomitantly with cycloserine, an overdose of the drug is possible. Pyridoxine, which is part of the drug, enhances the effect of diuretics; weakens the pharmacological effects of levodopa.

Isoniazid, penicillamine, cycloserine and estrogen-containing oral contraceptives weaken the therapeutic effect of pyridoxine.

The drug is compatible with cardiac glycosides (Pyridoxine promotes increased synthesis of contractile proteins in the myocardium), with glutamic acid and potassium and magnesium asparaginate.

Storage Conditions

In a dry, light-protected place at a temperature not exceeding 25°C (77°F). Keep out of the reach of children.

Shelf Life

Shelf life – 2 years.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.