Tizidone Neo (Capsules) Instructions for Use

Marketing Authorization Holder

Simpex Pharma, Pvt. Ltd. (India)

ATC Code

J04AK03 (Terizidone)

Active Substances

Pyridoxine (Rec.INN registered by WHO)

Terizidone (Rec.INN registered by WHO)

Dosage Forms

	Tizidone Neo	Capsules 250 mg+10 mg: 30, 50 or 100 pcs.
		Capsules 300 mg+10 mg: 30, 50 or 100 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin, size No. 0, with a black body and a purple cap; capsule contents – granules from white to light yellow.

Excipients : lactose monohydrate – 72 mg, crospovidone – 9 mg, povidone K30 – 14 mg, talc – 5 mg, magnesium sulfate – 5 mg.

Composition of the gelatin capsule cap: titanium dioxide – 1.7871%, methylparaben – 0.8%, propylparaben – 0.2%, brilliant blue – 0.0049%, carmoisine – 0.0799%, water – 14-15%, sodium lauryl sulfate – traces, gelatin – up to 100%; body: methylparaben – 0.8%, propylparaben – 0.2%, brilliant blue – 0.716%, Ponceau 4R dye – 0.718%, sunset yellow FCF dye – 0.292%, water – 14-15%, sodium lauryl sulfate – traces, gelatin – up to 100%.

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (5) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.

Capsules hard gelatin, size No. 00, with a body and cap of white or almost white color; capsule contents – granules from white to light yellow.

Excipients : lactose monohydrate – 317 mg, crospovidone – 30 mg, povidone K30 – 36 mg, talc – 7 mg, magnesium sulfate – 5 mg.

Composition of the gelatin capsule cap: titanium dioxide – 3.5%, methylparaben – 0.8%, propylparaben – 0.2%, water – 14-15%, sodium lauryl sulfate – traces, gelatin – up to 100%; body: titanium dioxide – 3.5%, methylparaben – 0.8%, propylparaben – 0.2%, water – 14-15%, sodium lauryl sulfate – traces, gelatin – up to 100%.

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (5) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.

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 enzymes that incorporate alanine into the alanyl-alanine dipeptide, a key component of the mycobacterial cell wall.

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

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

The MIC 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.

Terizidone is active against 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 terizidone.

Pyridoxine hydrochloride 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, and in the synthesis of the neurotransmitters serotonin, dopamine, norepinephrine, and GABA.

Pyridoxine has an antineurotoxic effect.

The use of pyridoxine reduces side effects from the central nervous system.

Pharmacokinetics

Terizidone

It is absorbed from the gastrointestinal tract rapidly and almost completely – 70-90%. Food intake does not affect the absorption rate.

After oral administration of terizidone at a dose of 250 mg, C_max in plasma is about 6.5 µg/mL, 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 serum), with higher concentrations noted in patients with meningeal inflammation.

After oral administration of terizidone at a dose of 250 mg, high concentrations of the drug are found in the blood and urine, which allows its use for the treatment of urinary tract infections, including chronic forms.

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

The slow excretion of the drug by the kidneys results in the terizidone concentration level in the urine being maintained for 12 hours, with 60-70% of the drug excreted unchanged by glomerular filtration.

A small amount is excreted via the intestine.

The elimination rate constant value is 0.0262 h^-1.

An insignificant amount of terizidone is metabolized, which is the reason for its low/weak toxic effect on the kidneys.

In renal failure, T_1/2 is prolonged to 72 hours.

Pyridoxine hydrochloride

It is absorbed rapidly 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, and less in muscles and the CNS.

It crosses the placental barrier and is secreted into breast milk.

T_1/2 is 15-20 days.

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

Indications

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

ICD codes

Dosage Regimen

The drug is taken orally, regardless of meals.

Adults and children over 14 years of age with a body weight of 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 with a body weight over 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 initiated 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 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 (>1/10,000, <1/1000), very rare (<1/10,000, including reports of isolated cases).

From the nervous system rare – headache, dizziness, increased excitability, tremor, insomnia, feeling of intoxication; very rare – seizures (including epileptic), dysarthria, mental disorders such as manias or depressions.

From the digestive system rare – abdominal pain, flatulence and diarrhea.

Other very rare – allergic reactions, skin rash.

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

Contraindications

Organic diseases of the CNS, cerebral atherosclerosis; epilepsy, epileptic seizures (including in history); mental disorders (anxiety, psychoses, depression, including in history); severe renal failure (creatinine concentration more than 2 mg/dL); alcoholism; children and adolescents under 14 years of age; pregnancy, lactation period; hypersensitivity to terizidone or cycloserine, pyridoxine, or any other component of the drug.

With caution elderly age, coronary artery disease, impaired liver function, impaired renal function (creatinine clearance less than 30 mL/min), chronic heart failure, gastric and duodenal ulcer.

Use in Pregnancy and Lactation

The use of the drug during pregnancy is contraindicated.

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

Use in Hepatic Impairment

With caution impaired liver function.

Use in Renal Impairment

The use of the drug is contraindicated in severe renal failure (creatinine concentration more than 2 mg/dL).

With caution impaired renal function (creatinine clearance less than 30 mL/min).

Pediatric Use

The use of the drug is contraindicated in children and adolescents under 14 years of age.

Geriatric Use

The drug should be prescribed with caution to elderly patients.

Special Precautions

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

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

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

The patient’s condition should be monitored: medical personnel supervising 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 may cause deterioration of its function.

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

The use of the drug while consuming alcohol is associated with an increased frequency of side effects, up to the development of seizures, so alcohol consumption should be avoided during therapy with the drug.

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.

Drug Interactions

Terizidone

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

Concomitant use with ethionamide increases the risk of side effects from the CNS (especially seizures).

Concomitant use with phenytoin may increase the plasma concentration of phenytoin.

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

Concomitant use with cycloserine may lead to drug overdose.

Pyridoxine

It enhances the effect of diuretics.

It weakens the pharmacological effects of levodopa.

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

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

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.