Trialgin2, tablets 20 pcs

An analgesic combined (NSAID+psychostimulant+barbiturate)

ATX Code

N02BB72

Pharmacodynamics:

A combination drug. It has analgesic and antipyretic effects. Analgesic effect develops after 20-30 minutes and reaches its maximum after 45 minutes. The pharmacological properties of the drug are caused by the action of the components included in it.

Sodium metamizole is a derivative of pyrazolone with analgesic, antipyretic and antispasmodic effect. The mechanism of action is not fully understood. According to studies, metamizole and its active metabolite (4N-methylaminoantipyrine) have a central and peripheral mechanism of action. It nonselectively 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 benzodiazepine-γ-aminobutyric acid (GABA)-receptor complex which increases the sensitivity of GABA receptors to GABA and leads to opening of chlorine channels, which increases their flow into the cell and leads to hyperpolarization. Suppresses sensory areas of the cerebral cortex reduces motor activity suppresses cerebral functions including the respiratory center. Does not significantly affect the cardiovascular system. Reduces the tone of the smooth muscles of the gastrointestinal tract. In small doses it has a sedative effect.

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

Pharmacokinetics:

Sodium metamizole

After oral administration, sodium metamizole is hydrolyzed to the pharmacologically active 4N-methylaminoantipyrine (MAA). Bioavailability of MAA after oral administration is 90%, which is slightly higher than with parenteral administration. Simultaneous intake of food has no significant effect on the pharmacokinetics of sodium metamizole. Clinical efficacy is determined mainly by MAA and to a lesser extent by the metabolites of 4N-aminoantipyrine (AA). The value of the area under the curve “concentration-time” (AUC) of AA is 25% of this value for MAA.

The metabolites 4N-acetylaminoantipyrine (AAA) and 4N-formylaminoantipyrine (FAA) have no pharmacological activity.

All metabolites have nonlinear pharmacokinetics. The clinical significance of this phenomenon is not known. Cumulation of metabolites does not play a major role in short-term use.

Sodium metamizole penetrates the placenta. Metabolites of metamizole penetrate into breast milk.

The binding to plasma proteins MAA is 58% AA is 48% FAA is 18% and AAA is 14%.

After a single oral administration, 85% of the dose is detected in the urine as metabolites of which 3±1% is MAA 6±3% is AA 26±8% is AA and 23±4% is FAA.

The renal clearance after a single oral administration of 1 g of sodium metamizole for MAA is 5±2 mL/min for AA is 38±13 mL/min for AA is 61±8 mL/min and FAA is 49±5 mL/min.

The corresponding plasma elimination half-lives for MAA are 27±05 h AA is 37±13 h AA is 95±15 h and FAA is 112±15 h.

Elderly

The AUC is increased by a factor of 2 to 3 in elderly patients.

In patients with cirrhosis, the half-lives of MAA and FAA are increased approximately 3-fold with single drug administration, whereas the half-lives of AA and AAA do not follow the same pattern. High doses should be avoided in these patients.

Renal dysfunction

In renal failure, the excretion rate of some metabolites (AAA and FAA) has been reported to be decreased. High doses should be avoided in these patients.

bioavailability

According to a clinical study, the pharmacokinetic parameters of 4-MAA when ingested with 1 g of sodium metamizole (tablets) are as follows (mean values and standard deviations are given): The maximum plasma concentration (Cmax) is 173±754 mg/L; the time to reach maximum plasma concentration (Tmax) is 142±054 h; the area under the concentration-time curve (AUC) is 809±341 [mg x h/L]. Absolute bioavailability of 4-MAA by AUC when tablets are taken is 93%.

Phenobarbital

It is completely but relatively slowly absorbed when taken orally. Maximum plasma concentration is observed 1-2 hours after ingestion.

About 50% is bound 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.

Metabolized in the liver induces microsomal liver enzymes: CYP3A4 CYP3A5 CYP3A7 (the rate of enzymatic reactions increases 10-12 times) increases the detoxification function of the liver. It accumulates in the body. The elimination half-life is 2-4 days.

It is excreted by the kidneys as glucuronide 25% – unchanged.

Caffeine

When taken orally, absorption is good throughout the intestine. Absorption is mainly due to lipophilicity rather than water solubility. Time to reach maximum concentration – 50-75 min after oral administration maximum concentration is 16-18 mg/l. It is quickly distributed in all organs and tissues of the body; easily penetrates through the blood-brain barrier and the placenta.

The volume of distribution in adults is 04-06 l/kg; in newborns it is 078-092 l/kg. Binding with blood proteins (albumin) is 25-36%. More than 90% is metabolized in the liver in children of the first years of life 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.

The elimination half-life in adults is 39-53 h (sometimes up to 10 h). Excretion of caffeine and its metabolites is through the kidneys (1-2% in adults is excreted unchanged).

Indications

Active ingredient

Composition

Per tablet:

active ingredients: anhydrous caffeine – 50 mg, metamizole sodium monohydrate – 300 mg, phenobarbital – 10 mg;

How to take, the dosage

In the oral cavity but 1 tablet. 1-4 times daily. Tablets should be swallowed whole with plenty of liquid.

The maximum daily dose is 4 tablets. It should not be taken more than 5 days.

Elderly patients, patients with severe general condition and impaired CK should reduce the dose because their excretion of the metabolites sodium metamizole and phenobarbital may be reduced.

Because patients with impaired renal or hepatic function have slower excretion rates, multiple high doses should be avoided. No dose reduction is required for short-term use. There is no experience with long-term use.

Interaction

Sodium metamizole

Accelerates the effects of ethanol.

The simultaneous use of colloidal blood substitutes and penicillin is not recommended.

The concomitant use of cyclosporine decreases the concentration of the latter in the blood; therefore, the concentration of cyclosporine should be monitored when they are used concomitantly.

Sodium metamizole increases activity of oral hypoglycemic drugs indirect anticoagulants glucocorticosteroids and indomethacin.

Phenylbutazone barbiturates and other inducers of microsomal liver enzymes decrease the effectiveness of sodium metamizole when used concomitantly.

Simultaneous use with other non-narcotic analgesics tricyclic antidepressants contraceptive hormonal drugs and allonurinol may increase their toxicity.

Medicated and anxiolytic drugs (tranquilizers) increase the analgesic effect of sodium metamizole.

Thiamazole and cytostatics increase the risk of leukopenia.

The effects are enhanced by codeine H2-histamine receptor blockers and propranololol (slows inactivation).

Myelotoxic drugs increase the manifestation of hematoxicity of the drug. Concomitant use of sodium methamisole and methotrexate may increase the hematotoxicity of the latter especially in elderly patients.

The concomitant use of sodium metamizole and chlorpromazine may cause severe hypothermia.

Phenobarbital

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

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

Decreases the effectiveness of indirect anticoagulants glucocorticosteroids doxycycline estrogens and other drugs metabolized by microsomal liver enzymes.

The hypnotic effect is reduced with concomitant administration of atropine extract of urticaria dextrose dextrose thiamine nicotinic acid analeptics and psychostimulants.

When combined with reserpine the anticonvulsant effect is decreased under the influence of amitriptyline nialamide diazepam chlordiazepoxide is increased.

Acetazolamide by alkalizing the urine reduces reabsorption of phenobarbital in the kidneys and weakens its effect.

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

Caffeine

Caffeine is an adenosine antagonist (large doses of adenosine may be required).

When caffeine and barbiturates and primidone anticonvulsants (hydantoin derivative especially phenytoin) are used together, caffeine metabolism and clearance may be increased; cimetidine oral contraceptives disulfiram ciprofloxacin norfloxacin decrease caffeine metabolism in liver (slowing its excretion and increasing concentrations in blood).

Caffeine-containing beverages and other central nervous system stimulating drugs – excessive stimulation of the central nervous system is possible.

Mexiletine – reduces caffeine excretion by 50%; nicotine – increases caffeine excretion rate.

Monoamine oxidase inhibitors furazolidone procarbazine and selegiline – large doses of caffeine (more than 300 mg/day) can cause life-threatening cardiac arrhythmias or markedly increased blood pressure.

Caffeine reduces absorption of calcium preparations in the gastrointestinal tract.

Decreases the effectiveness of narcotic and sleeping medications.

Increases urinary excretion of lithium preparations.

Accelerates absorption and enhances the effect of cardiac glycosides increases their toxicity.

The co-administration with beta-adrenoblockers may lead to mutual suppression of therapeutic effects; with β-adrenomimetics – to additional central nervous system stimulation and other additive toxic effects.

Caffeine may decrease clearance of theophylline and possibly other xanthines increasing the possibility of additive pharmacodynamic and toxic effects.

Special Instructions

The drug should not be taken for more than 5 consecutive days.

Due to the caffeine content of the drug, caution should be exercised when prescribing to patients with gout, hyperthyroidism, and arrhythmia.

Caffeine containing foods should be limited when using the product, as caffeine overdose can lead to nervousness, irritability, insomnia, and in some cases, palpitations.

With methamisole sodium in the drug

If fever and “malaise” symptoms from “colds” persist after taking the drug for 48 hours, see your doctor.

In case of prolonged (more than 5 days) use of the drug it is necessary to monitor the peripheral blood count and the functional state of the liver.

In case of prolonged use of high doses of the drug due to its sodium metamizole content agranulocytosis or thrombocytopenia may develop, therefore if unusual fever, chills, sore throat, difficult swallowing, stomatitis or development of vaginitis or proctitis are revealed the drug should be stopped immediately.

In case of pancytopenia the drug should be stopped immediately and the blood count should be monitored until the blood count returns to normal.

All patients should be advised to seek immediate medical attention if signs and symptoms resembling blood disorders occur during treatment (e.g., general weakness, persistent fever, bruising, bleeding, pallor). Discontinuation of therapy should not be delayed until laboratory results are available.

Severe life-threatening severe skin reactions: Stevens-Johnson syndrome (SJD) and toxic epidermal necrolysis (TEN) have been described with high doses of sodium metamizole. If signs of SDS or TEN (such as progressive skin rash often accompanied by blisters or mucosal ulceration) appear, treatment with methamisole should be stopped immediately and never resumed.

Patients with atopic bronchial asthma and pollinosis have an increased risk of allergic reactions.

Intestinal pain

The drug should not be used for acute abdominal pain (until the cause is known).

Because of the drug’s phenobarbital content

Phenobarbital long-term use should be avoided because of the possibility of phenobarbital cumulation in the body and the development of addiction or drug dependence.

Excipients

One tablet of the product contains 085 mmol (1964 mg) of sodium, which must be considered in people who control their sodium intake with food (who are on a low-salt/sodium diet).

The drug has no or little effect on motor control but does contain agents (caffeine phenobarbital) which significantly affect the central nervous system. That is why during the treatment period caution must be taken while driving vehicles, operating machinery and performing other potentially dangerous activities which require increased concentration and quick psychomotor reactions.

Contraindications

With caution

Hepatic and/or renal disorders, peptic ulcer and duodenal ulcer in remission, glaucoma, hyperexcitability, advanced age, epilepsy and proneness to seizures.

Side effects

To date, no side effects have been reported with this combination. The incidence of the following possible side effects is unknown. When using the drug according to the instructions, the occurrence of the following side effects is unlikely.

Immune system disorders: angioedema, anaphylactoid and anaphylactic reactions.

Hematopoietic disorders: agranulocytosis, leukopenia, thrombocytopenia, aplastic anemia, pancytopenia.

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

Cardiovascular system disorders: palpitations, tachycardia, increased BP, decreased BP.

Respiratory system, chest and mediastinal organs: tachypnea, bronchospastic syndrome, analgesic bronchial asthma.

Digestive system disorders: nausea, vomiting, aggravation of peptic ulcer disease (caffeine), constipation.

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

In case of adverse reactions, including those not mentioned in the instructions, consult a physician.

Overdose

To date, no cases of overdose have been reported with this combination.

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

Symptoms

Prevalent symptoms are anxiety nervousness anxiety insomnia mental agitation muscle twitching confusion convulsions. In severe overdose, hyperglycemia may occur. Cardiac disorders are manifested by tachycardia and arrhythmia.

Treatment

Dose reduction or caffeine withdrawal.

Sodium metamizole (more than 1 g per dose over 3 g per day)

Symptoms

. Acute overdose is manifested by nausea, vomiting, abdominal pain renal dysfunction/acute renal failure (e.g. as a manifestation of interstitial nephritis) and rarely central nervous system symptoms (dizziness drowsiness coma seizures) and decreased blood pressure leading to tachycardia and shock.

In high overdose, excretion of rubazonic acid may stain the urine red.

Treatment

A specific antidote is not known. In recent overdose, primary detoxification (e.g., gastric lavage) or sorption therapy (e.g., activated charcoal) is used to limit drug ingestion. The main metabolite (4M-methylaminoantipyrine) is removed by hemodialysis hemoperfusion and plasmafiltration.

The treatment of overdose as well as the prevention of serious complications may require general and special intensive medical monitoring and treatment.

Phenobarbital

Phenobarbital overdose is unlikely with Trialgin® administration: one package of the drug (20 tablets) contains one maximum single dose of phenobarbital.

Pregnancy use

The drug is contraindicated for use during pregnancy.

If it is necessary to use the drug during lactation, it is necessary to consider stopping breastfeeding.