Trialgin^® (Tablets) Instructions for Use

Marketing Authorization Holder

FPK PharmVILAR, JSC (Russia)

Manufactured By

PharmVILAR NPO, LLC (Russia)

ATC Code

N02BB72 (Metamizole sodium in combination with psycholeptics)

Active Substances

Phenobarbital (Rec.INN registered by WHO)

Caffeine (Ph.Eur. European Pharmacopoeia)

Metamizole sodium (Rec.INN registered by WHO)

Dosage Form

Trialgin®

50 mg+300 mg+10 mg tablets: 10 or 20 pcs.

Dosage Form, Packaging, and Composition

Tablets from white to white with a yellowish tint, round, flat-cylindrical, with a score and a bevel.

Excipients: potato starch – 36.31 mg, magnesium stearate – 3.69 mg.

10 pcs. – contour cell packs (1) – cardboard packs.
10 pcs. – contour cell packs (2) – cardboard packs.
20 pcs. – bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Combination analgesic-antipyretic

Pharmacotherapeutic Group

Analgesics; other analgesics and antipyretics; pyrazolones

Pharmacological Action

Combined drug. It has analgesic and antipyretic effects. The analgesic effect develops in 20-30 minutes and reaches a maximum in 45 minutes. The pharmacological properties of the drug are due to the action of the components included in its composition.

Metamizole sodium is a pyrazolone derivative with analgesic, antipyretic and antispasmodic effects. The mechanism of action is not fully understood. According to research results, metamizole and its active metabolite (4N-methylaminoantipyrine) have central and peripheral mechanisms of action. It non-selectively inhibits cyclooxygenase and reduces the formation of prostaglandins from arachidonic acid.

Phenobarbital belongs to the group of barbiturates. It interacts with the barbiturate site of the benzodiazepine-γ-aminobutyric acid (GABA)-receptor complex, thereby increasing the sensitivity of GABA receptors to GABA, leading to the opening of chloride channels, which increases their entry into the cell and leads to hyperpolarization. It suppresses the sensory areas of the cerebral cortex, reduces motor activity, inhibits cerebral functions, including the respiratory center. It does not have a significant effect on the cardiovascular system. Reduces the tone of the smooth muscles of the gastrointestinal tract. In small doses, it has a sedative effect.

Caffeine increases the reflex excitability of the spinal cord, excites the respiratory and vasomotor centers, dilates the blood vessels of skeletal muscles, brain, heart, kidneys, reduces platelet aggregation; reduces drowsiness, feeling of fatigue, increases mental and physical performance. In this combination, caffeine in a small dose has almost no stimulating effect on the central nervous system, but increases the tone of cerebral vessels and promotes accelerated blood flow.

Pharmacokinetics

Metamizole sodium

After oral administration, metamizole sodium is hydrolyzed to the pharmacologically active 4N-methylaminoantipyrine (MAA). The bioavailability of MAA after oral administration is 90%, which is somewhat higher than with parenteral administration. Simultaneous food intake does not have a significant effect on the pharmacokinetics of metamizole sodium. Clinical efficacy is determined mainly by MAA, and to a lesser extent by the metabolites 4N-aminoantipyrine (AA). The AUC value of AA is 25% of this value for MAA.

Metabolites 4N-acetylaminoantipyrine (AAA) and 4N-formylaminoantipyrine (FAA) do not have pharmacological activity.

All metabolites have nonlinear pharmacokinetics. The clinical significance of this phenomenon is unknown. With short-term use, the accumulation of metabolites does not play a big role.

Metamizole sodium penetrates the placenta. Metamizole metabolites pass into breast milk.

Plasma protein binding of MAA is 58%, AA – 48%, FAA – 18% and AAA – 14%.

After a single oral dose, 85% of the dose is found in the urine as metabolites, of which 3±1% is MAA, 6±3% is AA, 26±8% is AAA and 23±4% is FAA. Renal clearance after a single oral dose of 1 g of metamizole sodium for MAA is 5±2 ml/min, for AA – 38±13 ml/min, for AAA – 61±8 ml/min and for FAA – 49±5 ml/min.

The corresponding plasma T_1/2 for MAA is 2.7±0.5 h, for AA – 3.7±1.3 h, for AAA – 9.5±1.5 h and for FAA – 11.2±1.5 h.

Elderly

In elderly patients, AUC increases by 2-3 times. In patients with liver cirrhosis, the T_1/2 of MAA and FAA with a single dose of the drug increases approximately 3 times, while the T_1/2 of AA and AAA does not follow the same pattern. High doses should be avoided in such patients.

Renal impairment

According to available data, in renal failure, the excretion rate of some metabolites (AAA and FAA) decreases. High doses should be avoided in such patients.

Bioavailability

According to a clinical study, the pharmacokinetic parameters of 4-MAA after oral administration of 1 g of metamizole sodium (tablets) have the following values (mean values and standard deviations are given): C_max is 17.3+7.54 mg/l; time to reach C_max – 1.42±0.54 h; AUC – 80.9±34.1 [mg×h/l]. The absolute bioavailability of 4-MAA by AUC when taking tablets is 93%.

Phenobarbital

When taken orally, it is completely but relatively slowly absorbed. C_max is observed 1-2 hours after administration. About 50% binds to plasma proteins. It is evenly distributed in different organs and tissues; its lower concentrations are found in brain tissues. It penetrates well into breast milk and through the placental barrier. It is metabolized in the liver, induces liver microsomal enzymes: CYP3A4, CYP3A5, CYP3A7 (the rate of enzymatic reactions increases by 10-12 times), increases the detoxification function of the liver. It accumulates in the body. T_1/2 is 2-4 days. It is excreted by the kidneys in the form of a glucuronide, 25% – unchanged.

Caffeine

When taken orally, absorption is good and occurs throughout the intestine. Absorption occurs mainly due to lipophilicity, not water solubility. Time to reach C_max – 50-75 minutes after oral administration, C_max 1.6-1.8 mg/l. It is quickly distributed in all organs and tissues of the body; easily penetrates the blood-brain barrier and placenta. V_d in adults – 0.4-0.6 l/kg, in newborns – 0.78-0.92 l/kg. Binding to blood proteins (albumin) – 25-36%. More than 90% is metabolized in the liver, in children of the first years of life up to – 10-15%. In adults, about 80% of the caffeine dose is metabolized to paraxanthine, about 10% to theobromine and about 4% to theophylline. These compounds are subsequently demethylated to monomethylxanthines and then to methylated uric acids. T_1/2 in adults – 3.9-5.3 h (sometimes – up to 10 h). Excretion of caffeine and its metabolites is carried out by the kidneys (in adults, 1-2% is excreted unchanged).

Indications

• Pain syndrome of various origins: headache, toothache, muscle and joint pain,
• Neuralgia, for painful menstruation, for radiculitis.

As a symptomatic agent to reduce elevated body temperature and alleviate the symptoms of “malaise” (headache, body aches) in “cold” diseases.

ICD codes

Dosage Regimen

Orally, 1 tab. 1-4 times/day. The tablets should be swallowed whole with plenty of liquid.

The maximum daily dose is 4 tablets. The duration of administration is no more than 5 days.

Elderly patients, patients in severe general condition and with impaired creatinine clearance require a dose reduction, as they may have reduced excretion of metamizole sodium and phenobarbital metabolites.

Since the rate of drug elimination is reduced in patients with impaired renal or liver function, repeated administration of high doses should be avoided. With short-term use, dose reduction is not required. There is no experience with long-term use.

Adverse Reactions

To date, no side effects have been reported with the use of this combination. The frequency of the following possible side effects is unknown. When using the drug in accordance with the instructions, the occurrence of the following side effects is unlikely.

Immune system disorders: angioedema, anaphylactoid and anaphylactic reactions.

Blood and lymphatic system disorders: agranulocytosis, leukopenia, thrombocytopenia, aplastic anemia, pancytopenia.

Nervous system disorders: psychomotor agitation, anxiety, tremor, restlessness, dizziness, epileptic seizures, increased reflexes, insomnia; paradoxical reaction in the elderly (unusual agitation), increased fatigue, drowsiness, decreased speed of psychomotor reactions, drug dependence.

Cardiac disorders: palpitations, tachycardia, increased blood pressure, decreased blood pressure.

Respiratory, thoracic and mediastinal disorders: tachypnea, bronchospastic syndrome, analgesic bronchial asthma.

Gastrointestinal disorders: nausea, vomiting, exacerbation of peptic ulcer (caffeine), constipation.

Skin and subcutaneous tissue disorders: rash (including persistent), itching, urticaria.

If adverse reactions occur, including those not listed in the instructions, you should consult your doctor.

Contraindications

• Hypersensitivity to metamizole sodium and other pyrazolone derivatives, as well as to pyrazolidines, for example, phenylbutazone (including patients who have had agranulocytosis due to the use of these drugs), caffeine, phenobarbital or other components of the drug;
• Analgesic bronchial asthma or intolerance to analgesics (such as urticaria-angioedema), i.e., patients with bronchospasm or other forms of anaphylactoid reactions (for example, urticaria, rhinitis, angioedema) in response to the use of salicylates, paracetamol or non-steroidal anti-inflammatory drugs such as diclofenac, ibuprofen, indomethacin or naproxen;
• Impaired bone marrow hematopoiesis (for example, after cytostatic therapy) or diseases of the hematopoietic organs;
• Hereditary deficiency of glucose-6-phosphate dehydrogenase (hemolysis);
• Acute intermittent hepatic porphyria (risk of porphyria attacks);
• Severe liver and/or kidney diseases;
• Respiratory diseases accompanied by shortness of breath or airway obstruction;
• Myasthenia gravis;
• Alcohol intoxication, drug or narcotic dependence, including history;
• Pregnancy and breastfeeding period;
• Children under 18 years of age.

With caution

Impaired liver and/or kidney function, gastric and duodenal ulcers in remission, glaucoma, increased excitability, old age, epilepsy and a tendency to convulsive seizures.

Use in Hepatic Impairment

The drug should be used with caution in patients with impaired liver function, repeated administration of high doses should be avoided. With short-term use, dose reduction is not required.

The use of the drug in patients with severe liver diseases is contraindicated.

Use in Renal Impairment

The drug should be used with caution in patients with impaired renal function, repeated administration of high doses should be avoided. With short-term use, dose reduction is not required.

The use of the drug in patients with severe kidney diseases is contraindicated.

Pediatric Use

The use of the drug in children and adolescents under 18 years of age is contraindicated.

Geriatric Use

The drug should be used with caution in elderly patients. In addition, the dose should be reduced, as they may have reduced excretion of metamizole sodium and phenobarbital metabolites.

Special Precautions

The drug should not be taken for more than 5 days in a row.

Due to the content of caffeine in the drug

The drug should be prescribed with caution to patients with gout, hyperthyroidism and arrhythmia.

When using the drug, the consumption of products containing caffeine should be limited, since excessive intake of caffeine can lead to nervousness, irritability, insomnia and, in some cases, increased heart rate.

Due to the content of metamizole sodium in the drug

If elevated body temperature and symptoms of “malaise” in “cold” diseases persist while taking the drug for 48 hours, you should consult a doctor. With long-term (more than 5 days) use of the drug, monitoring of the peripheral blood picture and functional state of the liver is necessary.

Against the background of long-term use of high doses of the drug due to the content of metamizole sodium, the development of agranulocytosis or thrombocytopenia is possible, therefore, if an unmotivated increase in temperature, chills, sore throat, difficulty swallowing, stomatitis, as well as the development of vaginitis or proctitis are detected, the drug should be immediately discontinued. If pancytopenia develops, the drug should be discontinued immediately and a complete blood count should be monitored until its parameters return to normal. All patients should be advised to seek immediate medical attention if signs and symptoms resembling blood disorders (e.g., general weakness, infections, persistent fever, bruising, bleeding, pallor) occur during treatment. Discontinuation of therapy should not be delayed until laboratory results are obtained.

Against the background of the use of high doses of metamizole sodium, life-threatening severe skin reactions have been described: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). If signs of SJS or TEN appear (such as a progressive skin rash, often accompanied by blisters or ulceration of the mucous membrane), treatment with metamizole should be stopped immediately and never resumed.

Patients with atopic bronchial asthma and hay fever have an increased risk of developing allergic reactions.

Abdominal pain

It is unacceptable to use the drug to relieve acute abdominal pain (until their cause is clarified).

Due to the content of phenobarbital in the drug

Long-term use of the drug should be avoided due to the possibility of accumulation of phenobarbital in the body and the development of tolerance or drug dependence.

Excipients

One tablet of the drug contains 0.85 mmol (19.64 mg) of sodium, which must be taken into account in persons controlling sodium intake with food (on a low salt/sodium diet).

Effect on ability to drive vehicles and operate machinery

The drug does not affect or slightly affects coordination of movements, but contains substances (caffeine, Phenobarbital) that significantly affect the central nervous system, therefore, during the treatment period, caution must be exercised when driving vehicles, operating machinery and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

To date, no cases of overdose with the use of this combination have been registered.

Caffeine (more than 300 mg per dose or more than 1 g/day)

Symptoms: common symptoms are anxiety, nervousness, restlessness, insomnia, mental agitation, muscle twitching, confusion, convulsions. With severe overdose, hyperglycemia may occur. Cardiac disorders are manifested by tachycardia and arrhythmia.

Treatment: dose reduction or discontinuation of caffeine.

Metamizole sodium (more than 1 g per dose, more than 3 g/day)

Symptoms: acute overdose is manifested by nausea, vomiting, abdominal pain, impaired renal function/acute renal failure (for example, as a manifestation of interstitial nephritis) and, rarely, symptoms from the central nervous system (dizziness, drowsiness, coma, convulsions) and decreased blood pressure, leading to tachycardia and shock.

With high overdose, the excretion of rubazonic acid may turn the urine red.

Treatment: a specific antidote is not known. In case of recent overdose, primary detoxification (for example, gastric lavage) or sorption therapy (for example, activated charcoal) is performed to limit the intake of the drug into the body.

The main metabolite (4N-methylaminoantipyrine) is removed by hemodialysis, hemofiltration, hemoperfusion, and plasmafiltration.

Treatment of overdose, as well as prevention of serious complications, may require general and specialized intensive medical monitoring and treatment.

Phenobarbital

An overdose of phenobarbital is unlikely when taking Tetralgin N: one package of the drug (20 tablets) contains one maximum single dose of phenobarbital.

Drug Interactions

Sodium metamizole

It enhances the effects of ethanol. The simultaneous use of radiopaque agents, colloidal blood substitutes, and penicillin is not recommended.

Concomitant use with cyclosporine reduces its blood concentration, so when used simultaneously, the concentration of cyclosporine should be monitored.

Sodium metamizole increases the activity of oral hypoglycemic agents, indirect anticoagulants, glucocorticosteroids, and indomethacin.

Phenylbutazone, barbiturates, and other inducers of hepatic microsomal enzymes reduce the effectiveness of sodium metamizole when used concomitantly.

Concomitant use with other non-narcotic analgesics, tricyclic antidepressants, contraceptive hormonal agents, and allopurinol may lead to increased toxicity.

Sedative and anxiolytic medicines (tranquilizers) enhance the analgesic effect of sodium metamizole.

Thiamazole and cytostatics increase the risk of leukopenia. The effect is enhanced by codeine, H₂-histamine receptor blockers, and propranolol (slows down inactivation).

Myelotoxic medicines enhance the manifestation of the drug’s hematotoxicity. Concomitant use of sodium metamizole and methotrexate may enhance the hematotoxicity of the latter, especially in elderly patients.

Concomitant use of sodium metamizole and chlorpromazine may lead to severe hypothermia.

Phenobarbital

Interaction with other medicines is mainly due to the ability of phenobarbital to induce cytochrome P450 (primarily the CYP3A4 isoenzyme).

It reduces the antibacterial activity of antibiotics and sulfonamides, and the antifungal activity of griseofulvin (reduces absorption).

It reduces the effectiveness of indirect anticoagulants, glucocorticosteroids, doxycycline, estrogens, and other medicines metabolized by hepatic microsomal enzymes. The hypnotic effect is reduced by the simultaneous use of atropine, belladonna extract, dextrose, thiamine, nicotinic acid, analeptics, and psychostimulants.

When combined with reserpine, the anticonvulsant effect is reduced; under the influence of amitriptyline, nialamide, diazepam, chlordiazepoxide, it is enhanced. Acetazolamide, by alkalinizing the urine, reduces the renal reabsorption of phenobarbital and weakens its effect.

It enhances the effect of alcohol, neuroleptics, narcotic analgesics, muscle relaxants, sedatives, and hypnotics.

Caffeine

Caffeine is an adenosine antagonist (higher doses of adenosine may be required). When caffeine is used concomitantly with barbiturates, primidone, anticonvulsant agents (hydantoin derivatives, especially phenytoin), increased metabolism and increased clearance of caffeine are possible; with cimetidine, oral contraceptives, disulfiram, ciprofloxacin, norfloxacin – decreased metabolism of caffeine in the liver (slowing its elimination and increasing its blood concentration). Caffeine-containing beverages and other CNS-stimulating agents – excessive CNS stimulation is possible. Mexiletine – reduces caffeine elimination by 50%; nicotine – increases the rate of caffeine elimination. Monoamine oxidase inhibitors, furazolidone, procarbazine, and selegiline – large doses of caffeine (more than 300 mg/day) may cause the development of life-threatening cardiac arrhythmias or a significant increase in blood pressure. Caffeine reduces the absorption of calcium preparations in the gastrointestinal tract. It reduces the effectiveness of narcotic and hypnotic medicines. It increases the urinary excretion of lithium preparations. It accelerates the absorption and enhances the effect of cardiac glycosides, increasing their toxicity. Concomitant use with beta-blockers may lead to mutual suppression of therapeutic effects; with beta-adrenergic agonists – to additional CNS stimulation and other additive toxic effects. Caffeine may reduce the clearance of theophylline and possibly other xanthines, increasing the possibility of additive pharmacodynamic and toxic effects.

Storage Conditions

The drug should be stored in a dry place, protected from light and out of the reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

Do not use after the expiration date.

Dispensing Status

The drug is approved for use as an over-the-counter product.

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.