Loksidone^® Plus (Capsules) Instructions for Use

Marketing Authorization Holder

Pharmasintez, JSC (Russia)

ATC Code

J04AK03 (Terizidone)

Active Substances

Pyridoxine (Rec.INN registered by WHO)

Terizidone (Rec.INN registered by WHO)

Dosage Forms

	Loksidone^® Plus	Capsules 150 mg+10 mg: 10, 20, 30, 60, 100 or 120 pcs.
		Capsules 250 mg+10 mg: 10, 20, 30, 60, 100 or 120 pcs.
		Capsules 300 mg+10 mg: 10, 20, 30, 60, 100 or 120 pcs.

Dosage Form, Packaging, and Composition

Capsules No. 1, hard gelatin, capsule body white, capsule cap yellow.

	1 caps.
Terizidone	150 mg
Pyridoxine hydrochloride	10 mg

Excipients: lactose 5 mg, colloidal silicon dioxide (aerosil) 4 mg, talc 5 mg.

Capsule composition: purified water 14-15 mg, sodium lauryl sulfate 0.24 mg, methylparaben 0.8 mg, propylparaben 0.2 mg, titanium dioxide 1.1252 mg – 2.05 mg, quinoline yellow 0.0562 mg, gelatin up to 100 mg.

10 pcs. – contour cell packs (1) – cardboard packs.
10 pcs. – contour cell packs (2) – cardboard packs.
10 pcs. – contour cell packs (3) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
60 pcs. – polymer jars (1) – cardboard packs.
100 pcs. – polymer jars (1) – cardboard packs.
120 pcs. – polymer jars (1) – cardboard packs.

Capsules No. 0, hard gelatin, capsule body green, capsule cap blue.

	1 caps.
Terizidone	250 mg
Pyridoxine hydrochloride	10 mg

Excipients: lactose 15 mg, colloidal silicon dioxide (aerosil) 6.7 mg, talc 8.3 mg.

Capsule composition: purified water 14-15 mg, sodium lauryl sulfate 0.24 mg, methylparaben 0.8 mg, propylparaben 0.2 mg, indigo carmine 0.15 mg, quinoline yellow 0.2656 mg, titanium dioxide 1.1252 mg – 2.6256 mg, gelatin up to 100 mg.

Capsules No. 00, hard gelatin, capsule body white, capsule cap red.

	1 caps.
Terizidone	300 mg
Pyridoxine hydrochloride	10 mg

Excipients: lactose 20 mg, colloidal silicon dioxide (aerosil) 8 mg, talc 10 mg.

Capsule composition: purified water 14-15 mg, sodium lauryl sulfate 0.24 mg, methylparaben 0.8 mg, propylparaben 0.2 mg, azorubine dye 0.7501 mg, titanium dioxide 0.375 mg – 2.05 mg, gelatin up to 100 mg.

Clinical-Pharmacological Group

Antituberculosis drug

Pharmacotherapeutic Group

Antitubercular agent

Pharmacological Action

Terizidone

Terizidone is a broad-spectrum antibiotic, a derivative of D-cycloserine. Terizidone competitively blocks 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 sensitive 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 sensitive to this drug.

Pyridoxine

Pyridoxine acts as a coenzyme, participating in biochemical reactions, including amino acid and glycogen metabolism, 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.

Pharmacokinetics

Terizidone

Terizidone is absorbed from the gastrointestinal tract (GIT) quickly and almost completely – 70-90%. Food intake does not affect the absorption rate. After oral administration of 250 mg of terizidone, the maximum plasma concentration (C_max) is about 6.5 µg/mL, the time to reach maximum concentration (T_max) is 2-4 hours.

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 concentration in the blood serum), a higher concentration is noted in patients with meningitis.

When terizidone is taken orally at a dose of 250 mg, 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, the half-life (T_1/2) is 24 hours. The delayed excretion of the drug by the kidneys leads to the fact that the concentration level 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 by the intestines. The elimination constant value is 0.0262 h^-1.

An insignificant amount of terizidone is metabolized, which is the reason for the low/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 the muscles and 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, as well as by hemodialysis.

Indications

Tuberculosis of various forms and localizations as part of complex therapy for drug-resistant forms of tuberculosis.

ICD codes

Open the list of ICD codes

ICD-10 code	Indication
A15	Respiratory tuberculosis, bacteriologically and histologically confirmed
A18	Tuberculosis of other organs

ICD-11 code	Indication
1B10.0	Respiratory tuberculosis, bacteriologically or histologically confirmed
1B12	Tuberculosis of other systems and organs

Dosage Regimen

The method of application and dosage regimen for a specific drug depend on its form of release and other factors. The optimal dosage regimen is determined by the doctor. It is necessary to strictly adhere to the compliance of the dosage form of a specific drug with the indications for use and dosage regimen.

Orally, regardless of food intake (dose is indicated for terizidone): adults and children over 14 years of age and body weight less than 60 kg – 300 mg 2 times a day (600 mg/day); with body weight 60-80 kg – 300 mg 3 times a day (900 mg/day).

Adults with body weight over 80 kg – 600 mg 2 times a 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 a 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 does not have peculiarities of action upon first administration or upon its withdrawal.

Under no circumstances should you prematurely stop or temporarily interrupt the started course of treatment or 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 gradations were used to assess the frequency of adverse reactions: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10000, <1/1000), very rare (<1/10000, 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.

Others 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 (“stocking” and “glove” symptom), decreased lactation.

Contraindications

Hypersensitivity to terizidone or cycloserine, pyridoxine, or any other component of the drug;
Organic diseases of the central nervous system, cerebral atherosclerosis;
Epilepsy, epileptic seizures (including history);
Mental disorders (anxiety, psychoses, depression, including history);
Severe renal failure (creatinine concentration more than 2 mg/dL);
Alcoholism;
Children under 14 years of age;
Pregnancy, lactation period;
Lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

With caution

Elderly age, coronary heart disease, impaired liver function, impaired renal function (creatinine clearance less than 30 ml/min), chronic heart failure, gastric and duodenal ulcers.

Use in Pregnancy and Lactation

The use of the drug during pregnancy is contraindicated.

Concentrations of terizidone in breast milk approach those in blood plasma. If the drug is used during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

The drug should be prescribed with caution to patients with impaired liver function.

Use in Renal Impairment

The drug should be prescribed with caution to patients with impaired renal function (creatinine clearance less than 30 ml/min). If the creatinine concentration is more than 2 mg/dL, the use of the drug is contraindicated.

Pediatric Use

Contraindicated in children under 14 years of age.

Geriatric Use

The drug should be prescribed with caution to elderly patients.

Special Precautions

The use of the drug against the background of 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 alcohol consumption.

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

Terizidone can cause cyanocobalamin and/or folic acid deficiency; in these cases, appropriate examination and treatment of the patient is necessary.

It is recommended to take it together with glutamic acid at a dose of 500 mg 3 times a day.

During treatment with the drug, blood and urine tests, liver function parameters (ALT, AST activity, plasma bilirubin concentration) should be monitored monthly.

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 large doses can cause deterioration of its function.

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

Effect on ability to drive vehicles and mechanisms

During the treatment period, it is necessary to refrain from driving vehicles and engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms Data on drug overdose are not available.

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

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

Drug Interactions

Terizidone

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

When used concomitantly with ethionamide, the risk of side effects from the central nervous system (especially convulsions) increases.

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

Concomitant use with isoniazid increases the frequency of dizziness and drowsiness.

Concomitant use with cycloserine may lead to drug overdose.

Pyridoxine

Enhances the effect of diuretics; weakens the pharmacological effects of levodopa.

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

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

Storage Conditions

In the original manufacturer’s packaging at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

Shelf life – 2 years.

Dispensing Status

Dispensed 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.

Medical Disclaimer