Composition

active substances: metamizole sodium monohydrate, paracetamol, sodium caffeine benzoate, phenobarbital, codeine phosphate hemihydrate;

1 tablet contains metamizole sodium monohydrate 300 mg, paracetamol 200 mg, sodium caffeine benzoate 50 mg (in terms of caffeine 20 mg), phenobarbital 10 mg, codeine phosphate hemihydrate 9.5 mg (in terms of codeine base 7 mg);

excipients: potato starch, gelatin, calcium stearate.

Medicinal form

Tablets.

The main physical and chemical properties: tablets are white or white with a yellowish tinge, flat-cylindrical, with a chamfer. On one surface of the tablet, the trademark of the company is applied, on the other surface of the tablet - a dash.

Pharmacotherapeutic group

Analgesics. Other analgesics and antipyretics. Pyrazolones. Metamizole sodium, combinations with psycholeptics.

ATX code N02B B72.

Pharmacological properties

Pharmacodynamics.

A combined drug that has an analgesic, antipyretic and anti-inflammatory effect.

Metamizole sodium is a derivative of pyrazolone, belongs to non-steroidal anti-inflammatory drugs. It has analgesic and antipyretic properties, has an antispasmodic effect on the smooth muscles of the biliary and urinary tracts, and the muscles of the uterus.

Paracetamol is a non-narcotic analgesic, blocks cyclooxygenase (COX) mainly in the central nervous system (CNS), affects the centers of pain and thermoregulation, has an analgesic and antipyretic effect.

Caffeine stimulates the psychomotor centers of the brain, has an analeptic effect, facilitates the penetration of analgesics through the blood-brain barrier, prevents collapse by stimulating the vasomotor center, eliminates the sedative effects of other components of the drug.

Phenobarbital in the composition of the drug has a sedative, antispasmodic and muscle relaxant effect, potentiates the activity of analgesic components.

Codeine is a narcotic analgesic whose effects are similar to those of morphine, but with a much weaker analgesic effect and a milder sedative effect. Codeine is a weak analgesic of central action. Codeine acts by interacting with μ-opioid receptors, although it has a low affinity for them, the analgesic effect of codeine is due to its transformation into morphine. Codeine, especially in combination with other analgesics such as paracetamol, has been shown to be effective in the treatment of acute nociceptive pain. Codeine reduces the excitability of the cough center. In small doses, it does not cause depression of the respiratory center, does not disrupt the function of the ciliated epithelium, and does not reduce bronchial secretion.

Pharmacokinetics.

Metamizole sodium is well and quickly absorbed in the gastrointestinal tract (GI). It is hydrolyzed in the intestinal walls with the formation of an active metabolite; unchanged metamizole is absent in the blood. The connection of the active metabolite with blood plasma proteins is 50–60%. The therapeutic effect develops 20–40 minutes after oral administration and reaches a maximum after 2 hours. Metabolized in the liver, excreted by the kidneys.

Paracetamol is quickly absorbed in the gastrointestinal tract, binds to plasma proteins. The half-life from plasma is 1–4 hours. It is metabolized in the liver with the formation of glucuronide and paracetamol sulfate. It is excreted by the kidneys mainly in the form of conjugation products, less than 5% is excreted unchanged.

Caffeine is well absorbed along the entire intestine. It is metabolized in the liver. Excreted with urine (10% unchanged).

Phenobarbital is slowly but almost completely absorbed in the gastrointestinal tract (80%) and is evenly distributed in the organs and tissues of the body. Penetrates through histohematal barriers and into breast milk. Penetrates well through the placenta. Phenobarbital is almost 45% bound to blood plasma proteins. The maximum concentration in the blood is observed 1-2 hours after taking. The effect occurs within 30–60 minutes. It is metabolized in the liver, induces microsomal liver enzymes. It is slowly removed from the body, which creates the prerequisites for the accumulation of phenobarbital. The half-life is 2–4 days. It is excreted by the kidneys in the form of inactive metabolites, up to 25% of the dose - in unchanged form. Renal excretion of unchanged phenobarbital depends on urine pH and may increase in an alkaline environment.

Codeine and its salts are quickly absorbed in the gastrointestinal tract. When used internally, the maximum concentration of codeine in blood plasma is reached within 1 hour. Due to its lipophilicity, codeine quickly penetrates the blood-brain barrier, accumulates in adipose tissue and, to a lesser extent, in tissues with a high level of perfusion (lungs, liver, kidneys and spleen). The half-life from blood plasma is 3-4 hours. The ratio of the strength of the analgesic effect when administered orally / intramuscularly is approximately 1: 1.5. It is metabolized by O- and N-demethylation in the liver with the formation of morphine and norcodeine. Codeine and its metabolites are excreted by the kidneys, mainly in the form of conjugates with glucuronic acid. Most of the excretion products are excreted in the urine within 6 hours and up to 86% of the dose is excreted from the body within 24 hours. About 70% of the dose is excreted as free codeine, 10% as free and conjugated morphine, and another 10% as free or conjugated norcodeine. Only traces of excretion products are found in feces.

Testimony

Pronounced pain syndrome of various genesis (pain in the joints, muscles, sciatica, menstrual pain, neuralgia, headache and toothache, migraine). Cold and flu-like conditions accompanied by painful symptoms and inflammation.

The drug is indicated for use in children aged 12 years and older for the treatment of acute moderate pain that is not relieved by other pain relievers such as paracetamol or ibuprofen (as monopreparations).

Contraindications

Hypersensitivity to codeine or other opioid analgesics, to caffeine or other xanthine derivatives (theophylline, theobromine), to pyrazolone derivatives or to any of the components of the medicinal product; the period after surgery on the biliary tract, peptic ulcer disease of the stomach and duodenum in the acute stage; conditions in which inhibition of peristalsis should be avoided or in which abdominal distension develops; risk of paralytic ileus, chronic constipation, severe kidney and/or liver dysfunction, congenital hyperbilirubinemia (including Gilbert's syndrome), acute pancreatitis, diabetes, hyperthyroidism, acute respiratory depression, respiratory diseases with shortness of breath, obstructive syndrome, bronchial asthma (opioids should not be used during an asthmatic attack); organic diseases of the cardiovascular system (including atherosclerosis), decompensated heart failure, ischemic heart disease, acute myocardial infarction, heart rhythm disorders, increased blood pressure, pronounced arterial hypotension, tendency to vasospasm, thrombosis, thrombophlebitis, bone marrow dysfunction or diseases of the hematopoietic system, infectious neutropenia, cytostatic neutropenia; agranulocytosis caused by metamizole, other pyrazolones or pyrazolidines in history; glucose-6-phosphate dehydrogenase deficiency, porphyria, myasthenia gravis, glaucoma, traumatic brain injury, or conditions associated with increased intracranial pressure (in addition to the risk of respiratory depression and increased intracranial pressure, codeine may affect pupillary response and other vital responses when assessing neurological status); depression, depressive disorders with the patient's tendency to suicidal behavior, states of increased excitement, sleep disorders (including insomnia), epilepsy; alcohol, drug, medication addiction (including history); the state of alcohol intoxication.

The use of the drug is contraindicated if there is a suspicion of acute surgical pathology in the patient, before the diagnosis is established.

The use of the medicinal product is contraindicated in the following groups of patients:

children under 12 years of age;

children aged 12 to 18 years who are undergoing tonsillectomy and/or adenoidectomy to prevent obstructive sleep apnea;

children aged 12 to 18 years with compromised respiratory function;

women during pregnancy or breastfeeding;

patients of any age who have an ultra-rapid metabolism involving CYP2D6;

elderly patients.

Do not use simultaneously with β-blockers, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors and within 2 weeks after stopping the use of MAO inhibitors.

Interaction with other medicinal products and other types of interaction

Interactions related to metamizole sodium

Metamizole sodium should not be used simultaneously with radiopaque substances, colloidal blood substitutes and penicillin. Metamizole sodium enhances the effect of oral hypoglycemic drugs, indirect coagulants, glucocorticosteroids, indomethacin, phenytoin, ibuprofen by displacing them from binding to blood proteins. Metamizole sodium can induce enzymes of metabolic pathways, including CYP2B6 and CYP3A4. Concomitant use of metamizole sodium with bupropion, efavirenz, methadone, valproate, cyclosporine, tacrolimus, and sertraline may result in decreased plasma concentrations of these drugs, potentially reducing their therapeutic effect. Thus, it is recommended to be careful in case of simultaneous use of metamizole sodium with other medicinal products; clinical response and/or plasma drug levels should be monitored as appropriate.

Metamizole sodium enhances the sedative effect of alcohol. With the simultaneous use of sodium metamizole with diuretics (furosemide), a decrease in the diuretic effect is possible. Myelotoxic drugs cause increased hematotoxicity. Sarcolysin, thiamazole, drugs that suppress the activity of the bone marrow (in particular, gold preparations), when used with metamizole sodium, increase the likelihood of hematotoxicity, including the development of leukopenia. Metamizole on triium in high doses can cause an increase in the concentration of methotrexate in the blood plasma and increase its toxic effects (primarily on the gastrointestinal tract and hematopoietic system). With the simultaneous use of metamizole sodium with other nonsteroidal anti-inflammatory drugs (NSAIDs), their analgesic and antipyretic effects are potentiated and the likelihood of additive side effects increases. Adverse reactions associated with the use of metamizole sodium are enhanced with simultaneous use with other non-narcotic analgesics, tricyclic antidepressants, hormonal contraceptives and allopurinol. The use of metamizole sodium in combination with chlorpromazine or other phenothiazine derivatives can lead to the development of severe hypothermia. The analgesic effect of metamizole sodium is enhanced by sedatives, tranquilizers (diazepam, trimethosin, etc.). In the case of simultaneous use, the effectiveness of metamizole sodium is reduced by phenylbutazone, glutethimide, barbiturates and other inducers of microsomal liver enzymes, and enhanced by codeine, blockers of H2-histamine receptors, propranolol.

Interactions related to paracetamol

The rate of absorption of paracetamol may increase when used with metoclopramide or domperidone and decrease when used with cholestyramine. Cholestyramine should not be used within one hour of taking paracetamol.

Medicines that induce microsomal enzymes, such as anticonvulsants and oral steroid contraceptives, can accelerate the metabolism of paracetamol and cause a decrease in its concentration in the blood plasma and an increase in the rate of elimination. Barbiturates reduce the antipyretic effect of paracetamol. Medicines that stimulate the activity of microsomal enzymes, in particular barbiturates, and alcohol can increase the hepatotoxicity of paracetamol, especially in case of taking toxic doses. With the simultaneous use of paracetamol with hepatotoxic agents, the toxic effect of drugs on the liver increases. Simultaneous use of high doses of paracetamol with isoniazid increases the risk of developing hepatotoxic syndrome.

Probenecid inhibits the binding of paracetamol to glucuronic acid, which leads to a decrease in the clearance of paracetamol by 50%, therefore, with simultaneous use, the dose of paracetamol should be reduced.

Paracetamol can reduce the bioavailability of lamotrigine with a decrease in its effectiveness due to the induction of metabolism of the drug in the liver.

With simultaneous use of paracetamol and zidovudine, the risk of neutropenia increases.

Paracetamol can affect the half-life of chloramphenicol. The clinical significance of these data has not been clarified. Routine patient monitoring is not required when paracetamol is co-administered with chloramphenicol, but this potential interaction should be considered, particularly in malnourished patients.

It is recommended that paracetamol be administered with caution at the same time as flucloxacillin, as such administration is associated with metabolic acidosis with a high anion difference due to pyroglutamine acidemia, especially in patients with risk factors (see section "Particulars of use").

Anticoagulant effect of warfarin and other coumarins may increase with increased risk of bleeding with long-term regular daily use with paracetamol; periodic reception does not show a significant effect.

Paracetamol reduces the effectiveness of diuretics.

Do not use simultaneously with alcohol.

Interactions related to caffeine

In case of simultaneous use of caffeine with:

‒ anticonvulsant drugs [barbiturates (including pentobarbital, primidone), hydantoin derivatives (especially phenytoin)] – acceleration of metabolism and increase in caffeine clearance;

‒ fluvoxamine, mexiletine – increasing the concentration of caffeine in the blood plasma;

‒ nicotine – acceleration of caffeine removal;

‒ ketoconazole, disulfiram, ciprofloxacin, norfloxacin, enoxacin, pipemidine acid ‒ slowing down the excretion of caffeine and increasing its concentration in blood plasma;

‒ methoxalen - slowing down the excretion of caffeine with a possible increase in its effect and the development of a toxic effect;

‒ cimetidine, hormonal contraceptives, isoniazid - strengthening of the action of caffeine;

‒ β-adrenoblockers ‒ mutual reduction of the therapeutic effects of drugs (see section "Contraindications");

‒ opioid analgesics, anxiolytics (including diazepam), hypnotics and sedatives – reducing the effect of medicines;

‒ ergotamine – increased absorption of ergotamine from the gastrointestinal tract;

‒ clozapine - increased concentration of clozapine in blood plasma;

‒ calcium preparations – decrease in the absorption of medicines;

‒ theophylline and other xanthine derivatives – decrease in drug clearance, increase in the risk of additive pharmacodynamic and toxic effects;

‒ lithium drugs – increase in lithium clearance (simultaneous use is not recommended);

‒ α- and β-adrenomimetics (including phenylpropanolamine), psychostimulant irritative agents, thyrotropin agents, analgesics-antipyretics - enhancement of the effect of drugs;

‒ cardiac glycosides – strengthening the effect and increasing the toxicity of cardiac glycosides;

‒ MAO inhibitors, furazolidone, procarbazine and selegiline ‒ the development of dangerous cardiac arrhythmias or a marked increase in blood pressure is possible.

Caffeine can increase the tachycardic effect of some decongestants.

Caffeine may interfere with the effects of hydrocylamide.

Caffeine is an antagonist of anesthetics, tranquilizers and other drugs that depress the central nervous system, a competitive antagonist of adenosine drugs.

The simultaneous use of Pyatirchatka® IC with other drugs that contain caffeine, or the simultaneous use of caffeinated beverages can lead to excessive stimulation of the central nervous system. Patients should avoid excessive consumption of coffee or tea.

Interactions related to phenobarbital

Phenobarbital induces liver enzymes and thus can accelerate the metabolism of some drugs that are metabolized with the participation of these enzymes [including paracetamol, salicylates, indirect anticoagulants, cardiac glycosides (digitoxin), antimicrobials (chloramphenicol, doxycycline, metronidazole, rifampicin, sulfanilamide), antiviral, antifungal (griseofulvin, itraconazole), antiepileptic (anticonvulsant), psychotropic (tricyclic antidepressants), hormonal (estrogens, progestogens, corticosteroids, thyroid hormones), immunosuppressive (glucocorticosteroids, cyclosporine, cytostatics), antiarrhythmic, antihypertensive (β-adrenoblockers, calcium channel blockers), oral hypoglycemics medicines, etc.]. Possible effect of phenobarbital on the concentration of phenytoin, carbamazepine and clonazepam in the blood. Phenobarbital can accelerate the metabolism of oral contraceptives, which leads to the loss of their effect. Phenobarbital increases the toxicity of methotrexate. Phenobarbital enhances the effect of analgesics, anesthetics, neuroleptics, tranquilizers. In the case of simultaneous use of phenobarbital with other drugs that depress the central nervous system, mutual strengthening of the action (sedative-hypnotic effect) is possible, which may be accompanied by respiratory depression. Alcohol increases the effect of phenobarbital and can increase its toxicity. Drugs that have the properties of acids (ascorbic acid, ammonium chloride) and drugs containing valproic acid enhance the effect of barbiturates. Patients receiving concurrent treatment with valproate and phenobarbital should be monitored for signs of hyperammonemia. In half of the reported cases, hyperammonemia was asymptomatic and did not necessarily lead to encephalopathy. MAO inhibitors (including furazolidone, procarbazine, selegiline) prolong the effect of phenobarbital. Rifampicin may reduce the effect of phenobarbital. When used in combination with gold preparations, the risk of kidney damage increases. With long-term simultaneous use with NSAIDs, there is a risk of stomach ulcers and bleeding. Simultaneous use of phenobarbital with zidovudine increases the toxicity of both drugs.

Interactions related to codeine

Cases of serotonin syndrome (including altered mental status, autonomic nervous system disorders, and neuromuscular disorders) have been reported in patients receiving opioids, especially when used concomitantly with other serotonergic drugs (including selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, MAO inhibitors, see section "Contraindications"). Codeine should not be used in combination with MAOIs or within 2 weeks of stopping their use. The use of MAO inhibitors in combination with pethidine has been associated with severe CNS excitation/depression (including arterial hypertension/arterial hypotension). Despite the fact that such phenomena have not been documented in the case of codeine, it is not excluded that such an interaction may occur (see the section "Particulars of use").

Codeine enhances the effects of CNS depressants. With the simultaneous use of codeine with alcohol, it is possible to increase the hypotensive, sedative effects of alcohol and its depressing effect on respiratory activity; with anesthetics (including sodium oxybutyrate), antihistamines with sedative properties - increased CNS depression and/or respiratory depression, and/or increased arterial hypotension are possible; with neuroleptics (including phenothiazine tranquilizers) - increased sedative and hypotensive effects; with anxiolytics, sedatives and hypnotics - increased sedative effect, increased risk of respiratory depression.

The use of opioids in combination with sedative drugs, such as benzodiazepines or drugs with effects similar to benzodiazepines, increases the risk of sedation, respiratory depression, coma, or death due to increased a protective effect on the central nervous system. Doses of medicinal products and the duration of concomitant treatment should be limited (see the section "Peculiarities of use").

The use of codeine in combination with antihypertensive agents can increase the hypotensive effect.

Codeine slows down the absorption of mexiletine, which leads to a decrease in the antiarrhythmic effect of the latter. With simultaneous use of codeine and quinidine, the analgesic effect of codeine is likely to be significantly reduced due to the negative effect of quinidine on its metabolism.

When using codeine in large doses, the effect of cardiac glycosides (digoxin and others) may increase.

When using codeine in combination with chloramphenicol, it is possible to increase the concentration of codeine in blood plasma due to inhibition of its metabolism; with non-narcotic analgesics - strengthening of the analgesic effect; with anti-ulcer drugs - cimetidine can suppress the metabolism of codeine, which leads to an increase in the concentration of the latter in the blood plasma.

Concomitant use of codeine with antidiarrheal agents, anticholinergic agents (eg, atropine), or drugs with anticholinergic-like effects increases the risk of severe constipation, which may lead to paralytic ileus and/or urinary retention.

Codeine antagonizes the effect of cisapride, metoclopramide and domperidone on gastrointestinal motility.

Premedication with opioids should be avoided, as they reduce the concentration of ciprofloxacin in the blood plasma.

When used with ritonavir, it is possible to increase the concentration of opioid analgesics (in particular, codeine) in the blood plasma.

Tricyclic antidepressants can increase the suppressive effects of opioid analgesics.

The use of codeine in combination with opioid antagonists (eg, buprenorphine, naloxone, naltrexone) may accelerate the development of the withdrawal syndrome.

Opioid use may interfere with gastric emptying studies, as opioids delay gastric emptying, and hepatobiliary imaging with Technetium Tc 99m Disofenin, as opioid therapy may cause narrowing of the sphincter of Oddi and increased biliary pressure.

Features of use

Do not use medicine to relieve acute abdominal pain (until the cause is determined). Since metamizole sodium has anti-inflammatory and analgesic properties, it can mask signs of infection, symptoms of non-infectious diseases and complications with pain syndrome, which can complicate their diagnosis.

Agranulocytosis

Treatment with metamizole can cause the development of agranulocytosis, in particular, with a fatal outcome (see the section "Adverse reactions"). Metamizole-induced agranulocytosis can develop even in patients who have previously used metamizole without complications.

Metamizole-induced agranulocytosis is an idiosyncratic adverse reaction. Metamisolone-induced agranulocytosis is not dose-dependent and may develop at any stage of treatment, even shortly after discontinuation of treatment.

Patients should be advised to discontinue treatment with metamizole and seek immediate medical attention if any symptoms suggestive of agranulocytosis occur, including fever, chills, sore throat, and abnormal mucosal changes accompanied by pain, particularly in the mouth, nose, and throat, or in the genital or anal region.

If metamizole is used to treat fever, some early symptoms of agranulocytosis may remain unrecognized. In addition, symptoms may be masked in patients receiving antibiotic therapy.

If agranulocytosis is suspected, a clinical blood test (including a differential count of leukocytes) should be performed immediately, and treatment should be stopped while waiting for the results of laboratory tests. If the diagnosis is confirmed, treatment should not be resumed (see section "Contraindications").

The risk of medicinal damage to the liver

Cases of acute hepatitis, mainly hepatocellular in nature, have been reported in patients taking metamizole sodium, the manifestations of which appeared in the period from several days to several months after the start of treatment with the drug. Symptoms have included elevated serum liver enzymes, with or without jaundice, often in the context of hypersensitivity reactions to other drugs (eg, skin rash, blood dyscrasias, fever, and eosinophilia) or with manifestations of autoimmune hepatitis. Most patients recovered after discontinuation of metamizole sodium; however, isolated cases of progression of liver failure up to the need for liver transplantation are known.

The mechanism of liver damage induced by metamizole sodium is not clearly elucidated, but available evidence suggests an immunoallergic mechanism.

Patients should be instructed to notify their physician of symptoms suggestive of liver damage. If liver damage is suspected, patients should be discontinued take metamizole sodium; in patients, it is necessary to evaluate indicators of the functional state of the liver.

Cases of liver damage during treatment with metamizole sodium are very rare, but the exact frequency of this adverse reaction cannot be calculated. In some patients, recurrences of liver damage were observed after repeated use of metamizole sodium. If the patient has previously had liver damage during treatment with metamizole sodium, and no other causes of liver damage have been identified, medicinal products containing metamizole sodium should not be used again.

In patients with liver diseases, the risk of hepatotoxic effects of paracetamol increases. The risk of drug overdose is higher in patients with non-cirrhotic alcoholic liver damage.

Paracetamol should be used with extreme caution in patients with dehydration, glutathione deficiency, chronic malnutrition, impaired kidney function (glomerular filtration rate, GFR ≤ 50 ml/min), impaired liver function (see the section "Contraindications"), patients with a body weight < 50 kg, in case of concomitant use of drugs that affect liver function.

There are known cases of impaired liver function / liver failure in patients with glutathione deficiency.

In patients with reduced levels of glutathione (in particular, with severe infections such as sepsis), the risk of metabolic acidosis increases when taking paracetamol. Symptoms of metabolic acidosis are deep, accelerated or difficult breathing, nausea, vomiting, loss of appetite. You should consult a doctor immediately if these symptoms appear.

Cases of high anion gap metabolic acidosis caused by pyroglutamine acidemia have been reported in patients with severe disease such as renal failure and sepsis, or in patients with malnutrition or other conditions associated with glutathione deficiency (eg, alcoholism) who have been using paracetamol at therapeutic doses for a long time or who have been treated with a combination of paracetamol and flucloxacillin. In case of suspicion of metabolic acidosis with a high anion difference due to pyroglutamine acidemia, it is recommended to immediately cancel the use of paracetamol and carefully monitor the patient's condition. Monitoring of urinary 5-oxoproline levels may be useful in identifying pyroglutamic acidemia as the underlying cause of high anion gap metabolic acidosis in patients with multiple risk factors.

The drug should be prescribed with caution to patients with mild arthritis who take analgesics every day, and to patients who use warfarin or similar drugs that have an anticoagulant effect.

The use of the drug during an acute asthma attack is contraindicated (see the section "Contraindications"). Patients with atopic bronchial asthma and pollinosis have an increased risk of developing hypersensitivity reactions. The drug should be taken with caution in case of increased sensitivity to analgesics and NSAIDs, in the presence of allergic diseases, including in the anamnesis (due to the increased risk of developing anaphylactic shock in this category of patients).

The drug should be used with caution in gastric and duodenal ulcers in remission, liver and kidney dysfunction (see section "Contraindications"), thyroid gland diseases (including hypothyroidism, see section "Contraindications"), urinary tract diseases, hyperkinesis, chronic respiratory tract infections, pneumonia, respiratory function disorders, acute drug intoxication, during treatment with cytostatic drugs (only under the supervision of a doctor). It is necessary to reduce the dose of the drug in weakened patients, patients with arterial hypotension (see the section "Contraindications"), hypertrophy of the prostate gland, hypofunction/insufficiency of the adrenal glands (for example, Addison's disease), inflammatory bowel diseases, including nonspecific ulcerative colitis and Crohn's disease (codeine reduces peristalsis, increases intestinal tone and segmentation, and can increase pressure in the colon) (see section "Contraindications"), with stricture of the urethra, convulsive conditions, patients in a state of shock. The dose of the drug should be reduced for patients with renal insufficiency (see the section "Contraindications"). The drug should be used with caution in patients with a history of kidney disease (pyelonephritis, glomerulonephritis) and patients who have recently undergone surgery on the intestines (due to a possible decrease in gastrointestinal motility) or urinary tract (such patients are more prone to urinary retention caused directly by spasm of the urethral sphincter and constipation due to codeine use). The drug should be prescribed with caution to patients with pheochromocytoma (opioids can stimulate the release of catecholamines by inducing the release of endogenous histamine). Patients with diseases of the biliary tract (in particular, cholelithiasis) should avoid the use of opioid analgesics or use them in combination with antispasmodics.

The drug should be prescribed with caution to patients whose condition may worsen as a result of taking opioids and to patients taking CNS depressants.

The risk of developing serotonin syndrome

Cases of serotonin syndrome have been reported in patients taking opioids, especially in the case of simultaneous use with other serotonergic drugs, including SSRIs, SSRIs, tricyclic antidepressants, MAO inhibitors (see section "Contraindications"). If concomitant treatment with opioids is clinically justified, appropriate medical monitoring of the patient's condition is recommended. The use of pethidine and possibly other opioid analgesics in patients taking MAO inhibitors can be associated with very severe reactions, sometimes with a fatal outcome. If the use of codeine in patients taking MAO inhibitors is vital, the use of MAO inhibitors should be stopped 2 weeks before the start of codeine treatment (see the sections "Contraindications", "Interaction with other medicinal products and other types of interactions").

The risk associated with the simultaneous use of sedative drugs such as benzodiazepines or drugs with effects similar to benzodiazepines

The simultaneous use of codeine and sedative drugs, such as benzodiazepines or drugs with an effect similar to the action of benzodiazepines, can lead to sedation, respiratory depression, coma and death (see the section "Interaction with other drugs and other types of interactions"). Therefore, the appointment of codeine in combination with sedatives is possible only in the absence of alternative treatment options. If the simultaneous use of codeine and sedative drugs is necessary, the lowest effective doses should be used, and the duration of treatment should be as short as possible. During concomitant therapy, the patient's condition should be monitored. Patients receiving concomitant therapy and their caregivers should be informed of symptoms of respiratory depression and sedation.

Metabolism involving CYP2D6

Codeine is transformed into its active metabolite - morphine - in the liver with the participation of the CYP2D6 enzyme. If the patient is deficient in this enzyme or if the patient lacks CYP2D6 completely, an adequate analgesic effect will not be obtained. Up to 7% of the Caucasian population may have this metabolic feature. However, if the patient is an ultra-rapid metabolizer involving CYP2D6, there is an increased risk of developing side effects – symptoms of opioid toxicity – even with normal doses. In such patients, the conversion of codeine to morphine rapidly leads to higher than expected serum morphine levels. General symptoms of opioid toxicity: confusion, drowsiness, shallow breathing, narrowed pupils, nausea, vomiting, constipation, lack of appetite. In severe cases, symptoms of circulatory and respiratory depression are possible, which can be dangerous and very rarely fatal.

Data on the prevalence of ultra-rapid metabolizers involving CYP2D6 in different populations are shown below:

Population Prevalence, %

Africans/Ethiopians 29

African Americans 3.4–6.5

Mongoloids 1,2–2

Caucasians 3.6–6.5

Greeks 6

Hungarians 1.9

Northern Europeans 1–2

Postoperative use in children

The use of codeine in children after tonsillectomy and/or adenoidectomy for the prevention of obstructive sleep apnea has been reported to occasionally result in life-threatening adverse events, including death (see Contraindications). All children received doses of codeine in the appropriate dose range. However, there is evidence that these children were either ultrarapid or extensive metabolizers of codeine.

Children with compromised respiratory function

Codeine is contraindicated in children in whom respiratory function may be compromised by neuromuscular disorders, severe cardiac or respiratory disease, upper respiratory tract or lung infections, multiple trauma, or major surgery. These factors may increase the symptoms of morphine toxicity.

Severe skin adverse reactions

Life-threatening skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome), have been reported during treatment with phenobarbital. Severe cutaneous adverse reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug-induced reaction with eosinophilia and systemic symptoms (DRESS syndrome), which may be life-threatening or fatal, have been reported with metamizole sodium. Before starting therapy with Pyatirchatka® IS, patients should be informed about the signs and symptoms of severe skin reactions. During treatment, it is necessary to carefully monitor the condition patients regarding the appearance of these characteristic symptoms. The risk of developing Stevens-Johnson syndrome or toxic epidermal necrolysis is greatest in the first weeks of treatment. In the event of the appearance of symptoms indicating severe skin adverse reactions (for example, progressive skin rashes, often with blisters, and damage to the mucous membrane), you should immediately stop taking the drug and in the future in no case use drugs that contain metamizole sodium or phenobarbital (see the section "Contraindications"). Early diagnosis and immediate discontinuation of the medication that may have caused the symptoms of Stevens-Johnson syndrome or toxic epidermal necrolysis allow for the best results in treatment.

Long-term use of the drug should be avoided due to the possibility of phenobarbital accumulation and the development of addiction. A withdrawal syndrome is characteristic of barbiturates. In patients who may be physically dependent, discontinuation of treatment should be done gradually to avoid accelerating the development of withdrawal symptoms.

With long-term use of caffeine, the development of psychological dependence is possible.

Regular or long-term use of codeine can lead to the development of psychological and physical dependence. Codeine should be used with caution in patients with substance abuse (including history) or mental illness (see section "Contraindications"). Incorrect use of codeine can lead to overdose and/or death (see section "Overdose"). Opioid analgesics reduce salivation, which can cause the development of caries and candidiasis of the mucous membrane of the oral cavity.

The use of the medicinal product can affect the results of doping control tests in athletes, the results of laboratory tests on the content of glucose in the blood. The use of caffeine can cause a false increase in the level of uric acid in the blood, which is determined by the Bittner method. Caffeine may increase urinary levels of 5-hydroxyindoleacetic acid, vanillylmandelic acid, and catecholamines, which may lead to false positives in the diagnosis of pheochromocytoma and neuroblastoma.

During treatment, the urine may turn red (due to the excretion of metamizole sodium metabolite), which has no clinical significance.

The drug should be taken at the lowest effective dose for the shortest period of time necessary to control symptoms.

Do not exceed recommended doses. In case of overdose, a doctor should be consulted immediately, even if the patient feels well, because of the risk of irreversible liver damage (see section "Overdose").

Do not use the medicine longer than the prescribed period without consulting a doctor. When using the drug for more than 3 days, it is necessary to monitor the indicators of liver and kidney function.

With long-term use, as well as with the use of the drug in doses that significantly exceed the recommended therapeutic doses, it is possible to increase the manifestations of adverse reactions.

If the symptoms persist for more than 3 days or, on the contrary, the state of health worsens (fever or signs of secondary infection appear), or undesirable effects appear, it is necessary to suspend the use of the medicinal product and consult a doctor regarding its further use.

Do not take the medicine with other drugs containing metamizole sodium, paracetamol, caffeine, phenobarbital or codeine.

It is forbidden to drink alcoholic beverages during treatment with the drug.

During the use of the drug, excessive consumption of drinks containing caffeine (including tea, coffee) is not recommended, as this can increase the side effects of caffeine, such as dizziness, increased excitability, insomnia, restlessness, feelings of anxiety, irritability, headache, disturbances from the gastrointestinal tract, tachycardia.

Long-term use of any pain medication to treat headaches can make the headache worse. Patients should be informed that in this case they need to consult a doctor and stop the analgesic drug therapy. The development of headache caused by excessive drug therapy should be suspected in patients with frequent or daily headaches despite regular use of headache medications (or due to regular use of these agents).

During the use of the medicinal product, children need constant medical monitoring (see sections "Contraindications", "Children").

1 tablet of Pyatirchatka® IS contains 1 mmol (or 23 mg) of sodium, which is 1.15% of the WHO recommended maximum daily sodium intake for an adult (2 g). This medicine should be used with caution in patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

Pregnancy period

The use of the medicinal product during pregnancy is contraindicated rendered

Daily consumption of more than 200 mg of caffeine during pregnancy increases the risk of miscarriage or the risk of having a low birth weight baby.

Barbiturates increase the likelihood of developing fetal pathology. When using phenobarbital in the III trimester of pregnancy, the occurrence of physical dependence in the fetus is possible, which leads to the appearance of withdrawal syndrome in the newborn, which is manifested by convulsions, excitement, blood coagulation disorders. The use of phenobarbital during childbirth can cause respiratory depression in the newborn.

A possible connection between the occurrence of respiratory system and heart defects in infants and the use of codeine in the first trimester of pregnancy has been reported. Regular use of codeine during pregnancy can cause the development of physical dependence in the fetus, which leads to withdrawal symptoms in the newborn. The use of codeine during childbirth can suppress breathing in the newborn. The use of opioid analgesics can lead to gastric stasis during childbirth, increasing the risk of aspiration pneumonia in the mother.

Breastfeeding period

Use of the drug during breastfeeding is contraindicated.

Paracetamol and caffeine are excreted in breast milk, but in clinically insignificant amounts. Although pronounced manifestations of the toxic effects of caffeine have not been observed in infants who are breastfed, caffeine can have a stimulating effect on the infant.

Phenobarbital in significant quantities penetrates into breast milk and can depress the central nervous system in a child.

When used in usual therapeutic doses, codeine and its active metabolite can be present in breast milk in very low concentrations, which is unlikely to have a negative effect on the infant. However, if the patient is an ultra-rapid metabolizer involving CYP2D6, higher levels of morphine may pass into breast milk, and in very rare cases, this may cause potentially fatal symptoms of opioid toxicity in the infant.

The ability to influence the speed of reaction when driving vehicles or other mechanisms.

During treatment with the drug, you should refrain from driving vehicles or other mechanisms due to the possibility of such effects as confusion, drowsiness, dizziness, hallucinations, visual disturbances or convulsions. Opioid analgesics increase the effects of alcohol.

Method of application and dosage

The medicine should be taken internally.

The recommended dose for adults and children over 12 years old is 1 tablet 1-3 times a day. The maximum single dose is 2 tablets, daily – 3 tablets.

Do not exceed the recommended dose.

The duration of continuous use of the medicinal product is no more than 3 days. If the symptoms do not disappear, you should consult a doctor. In exceptional cases, on the recommendation and under the supervision of a doctor, the treatment period can be extended.

Children.

The drug is indicated for use in children aged 12 to 18 years for the treatment of acute moderate pain that is not relieved by other pain relievers such as paracetamol or ibuprofen (as monopreparations) (see section "Indications").

The use of the drug is contraindicated in children under 12 years of age, as there is a risk of developing serious and life-threatening adverse reactions due to the variable and unpredictable pathway of conversion of codeine to morphine in patients of this age group (see section "Contraindications").

Codeine should not be used in children aged 12 to 18 years who are undergoing tonsillectomy and/or adenoidectomy to prevent obstructive sleep apnea due to the risk of developing serious and life-threatening adverse reactions (see sections "Contraindications", "Particulars of use").

Codeine should not be used in children aged 12 to 18 years with compromised respiratory function due to the risk of serious and life-threatening adverse reactions (see sections "Contraindications", "Particulars of use").

Codeine should not be used in children aged 12 to 18 years who have ultra-rapid metabolism involving CYP2D6 (see sections "Contraindications", "Particulars of use").

Overdose

At the first symptoms of overdose, you should immediately seek medical help.

Metamizole sodium overdose

Symptoms: tinnitus, drowsiness, convulsive syndrome, delirium, impaired consciousness, weakness, hypothermia, pronounced decrease in blood pressure, tachycardia, palpitations, hemorrhagic syndrome, acute renal failure, oliguria, anuria, dysphagia, nausea, vomiting, gastralgia/gastritis, liver failure, paralysis of respiratory muscles, shortness of breath.

Treatment: induction of vomiting, gastric lavage, use of saline laxatives, enterosorbents, forced diuresis, symptomatic therapy aimed at supporting vital functions. In severe cases, hemodialysis, hemoperfusion, peritoneal dialysis is possible. In case of development of convulsive syndrome, diazepam and fast-acting barbiturates should be administered intravenously.

Paracetamol overdose In case of use of the drug in a dose that exceeds the recommended dose, you should immediately consult a doctor because of the risk of liver damage. An overdose of paracetamol can cause liver failure, which may require a liver transplant or be fatal.

Symptoms Taking more than 12g of paracetamol or more than 150mg of paracetamol per kilogram of body weight (whichever number is lower) can cause severe liver damage. The development of liver damage, which is evidenced by an increase in the level of transaminases in the blood plasma, can be clinically manifested 8‒36 hours after taking an excessive dose of paracetamol. Biochemical markers of liver damage reach their maximum values ​​only 3-4 days after an overdose, clinical symptoms of liver damage are maximally manifested 4-6 days after an overdose. Taking 5 g or more of paracetamol can lead to liver damage in patients with risk factors (long-term use of carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort or other drugs that induce liver enzymes; regular excessive alcohol consumption; insufficiency of the glutathione system, for example, eating disorders, cystic fibrosis, HIV infection, fasting, cystic fibrosis, cachexia).

Symptoms of paracetamol overdose in the first 24 hours: pallor, nausea, vomiting, loss of appetite, abdominal pain. Clinical signs of overdose may not appear. Liver damage occurs when increased amounts of a toxic metabolite of paracetamol (which is normally neutralized by glutathione at normal doses of paracetamol) irreversibly binds to liver tissue. Glucose metabolism disorders and metabolic acidosis may occur. In severe poisoning, liver failure can progress to encephalopathy, hemorrhage, hypoglycemia, coma, and death. Acute renal failure with acute tubular necrosis can be manifested by severe pain in the lower back, hematuria, proteinuria and can develop even in the absence of severe liver damage. Cardiac arrhythmia and pancreatitis have been reported.

With long-term use of paracetamol in large doses, pancytopenia, aplastic anemia, thrombocytopenia, leukopenia, agranulocytosis, neutropenia may develop on the part of hematopoietic organs. When taking large doses from the side of the central nervous system, dizziness, psychomotor excitement, disorientation are possible; from the urinary system - nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis).

Treatment. In case of overdose, urgent medical assistance is required! The patient should be taken to the hospital immediately, even if there are no early symptoms of overdose. Symptoms may be limited to nausea and vomiting and may not reflect the severity of overdose and the risk of organ damage. The concentration of paracetamol in the blood plasma should be measured 4 hours after taking the drug or later (earlier concentrations are unreliable). Intravenous administration of N-acetylcysteine ​​within 8 hours after taking an excessive dose of paracetamol is effective. The effectiveness of the antidote decreases sharply after this time, but further use of N-acetylcysteine ​​up to 24 hours after the overdose, and possibly longer, may be effective to some extent. In the absence of vomiting, oral administration of methionine within 10‒12 hours after an overdose may be effective. Treatment with activated charcoal within 1 hour of taking an overdose of paracetamol may be appropriate. There is insufficient evidence regarding the effectiveness of gastric lavage in case of an overdose caused by paracetamol alone.

Caffeine overdose

Taking Pyatirchatka® IS in an amount that causes clinically pronounced symptoms of caffeine overdose is likely to lead to liver damage caused by paracetamol overdose.

Symptoms An overdose of caffeine can cause such conditions as headache, dizziness, emotional agitation, restlessness, nervousness, irritability, agitation, anxiety, psychomotor agitation, incoherence of thoughts and speech, confusion, delirium, insomnia, increased tactile or pain sensitivity, tremors, muscle twitching, seizures (in acute overdose – tonic-clonic convulsions), ringing in the ears, fever, rapid breathing, facial flushing, flushing, arrhythmia, tachycardia, extrasystole, nausea, vomiting, sometimes with blood impurities; pain in the epigastric area, gastrointestinal disorders, increased frequency of urination, increased diuresis, dehydration.

Treatment. In case of overdose of caffeine, it is necessary to wash the stomach. The use of activated charcoal can be effective if taken within 1 hour of an overdose, but the possibility of using activated charcoal can be considered within 4 hours after taking an excessive dose of caffeine. Lung ventilation, fluid and salt balance should be maintained, hemodialysis is possible; with convulsive n apadah - inject diazepam, phenobarbital or phenytoin intravenously. There is no specific antidote, but β-adrenergic antagonists can be used as a supportive measure to reduce cardiotoxic effects.

Phenobarbital overdose

Symptoms of acute poisoning with barbiturates of mild or moderate severity: dizziness, increased fatigue, even a deep sleep from which the patient cannot be awakened. Hypersensitivity reactions may occur: angioedema, itching, rash (especially urticaria).

Symptoms of acute severe barbiturate poisoning: depression of the central nervous system, up to a deep coma, accompanied by tissue hypoxia; shallow breathing, first accelerated, then slowed breathing; suppression of breathing, until it stops; inhibition of cardiovascular activity, including heart rhythm disturbances, lowering of blood pressure, up to the collapsing state; decrease in body temperature, decrease in diuresis, rapid heartbeat or bradycardia, weakening or absence of reflexes, nystagmus, headache, ataxia, nausea, weakness.

If poisoning is not treated, death may occur due to vascular insufficiency, respiratory paralysis, or pulmonary edema.

Treatment: symptomatic therapy (primarily monitoring of the body's main vital functions: breathing, pulse, blood pressure); intensive therapy if necessary. It is necessary to stabilize and normalize breathing and blood circulation. To treat respiratory failure, it is necessary to carry out artificial respiration, to stop shock - infuse plasma and plasma substitutes. If a short time (no more than 6 hours) has passed after taking an excessive amount of phenobarbital, gastric lavage should be performed followed by the administration of a sorbent (activated carbon) and sodium sulfate. In order to quickly remove barbiturates from the body, it is possible to carry out forced diuresis with alkalis, as well as hemodialysis and/or hemoperfusion.

Codeine overdose

Symptoms of codeine overdose may be masked by clinical manifestations of severe liver damage caused by paracetamol overdose. In case of overdose, immediate medical assistance is required, even if there are no symptoms of overdose!

Symptoms The first manifestations of codeine overdose are nausea and vomiting. The clinical triad of opioid overdose is coma, punctate pupils (miosis), and respiratory depression with subsequent dilation of the pupils during the development of hypoxia. Acute respiratory depression can cause cyanosis, slowed or difficult breathing, drowsiness, ataxia, less often - pulmonary edema. Other symptoms of opioid overdose: apnea, shortness of breath, hypothermia, convulsions (especially in children), confusion, severe dizziness, severe drowsiness; nervousness, restlessness, emotional excitement, hallucinations, arterial hypotension and tachycardia (possible, but unlikely); bradycardia, circulatory failure, collapse, urinary retention, severe weakness. Signs of histamine release may be observed. Cases of rhabdomyolysis progressing to renal failure have been reported with opioid overdose. Overdose increases with simultaneous use of alcohol and psychotropic drugs. Severe depression of the central nervous system, in particular respiratory depression, can develop in the case of concomitant use of codeine with other drugs with a sedative effect (including alcohol) or a significant overdose.

Treatment. Treatment of codeine overdose includes general symptomatic and supportive measures, including measures to ensure patency of the respiratory tract and monitoring of vital signs until the patient's condition is stabilized. Severe respiratory depression should be treated with artificial ventilation and oxygen. Taking activated charcoal is advisable if no more than 1 hour has passed since the moment of codeine intake in an adult in a dose exceeding 350 mg, in a child in a dose exceeding 5 mg per kilogram of body weight. Naloxone should be administered if coma or respiratory depression develops. Naloxone is a competitive antagonist and has a short half-life, so repeated administration of large doses may be necessary for patients with severe poisoning. It is necessary to observe the patient's condition for at least 4 hours after the administration of naloxone, or 8 hours in the case of using the drug naloxone with prolonged action.

Side effects

Most often, side effects are temporary and disappear after stopping treatment.

Psychiatric disorders: cognitive disorders, decreased concentration, hallucinations, nightmares, increased excitability, psychomotor agitation and disorientation, feelings of fear, restlessness, irritability, nervousness, feelings of anxiety, sudden mood changes, euphoria, dysphoria, depression, confusion, drug dependence (with long-term use of high doses), development of tolerance.

From the side of the nervous system: increased intracranial pressure, headache, increased headache (with long-term use), dizziness, increased reflexes, impaired coordination of movements, ataxia, tremor, seizures (especially in children), hyperkinesis (in children), slowness of reactions, weakness, asthenia, drowsiness, insomnia, paresthesia.

On the part of the organ of vision: narrowing of the pupils, impaired visual acuity, light sensitivity, impaired vision (in particular, blurriness, doubling of the contours of visible objects), miosis, nystagmus, conjunctivitis.

On the part of the organ of hearing and the vestibular apparatus: vertigo.

From the side of the skin and subcutaneous tissue: ulcers on the mucous membrane of the oral cavity, photosensitivity, redness of the face, hyperemia of the skin, exfoliative dermatitis, hypersensitivity reactions such as rash (usually a generalized rash; erythematous rash, maculopapular rash, which is considered a symptom of the hypersensitivity syndrome associated with the oral use of codeine; urticaria), itching, increased sweating, purpura, facial swelling, angioedema; severe skin reactions: toxic epidermal necrolysis (Lyell syndrome), drug-induced dermatitis, exudative erythema multiforme, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, drug-induced reaction with eosinophilia and systemic symptoms (DRESS syndrome).

From the musculoskeletal system: uncontrolled muscle movements, muscle stiffness (when using large doses); with long-term use, there is a risk of disruption of osteogenesis and development of rickets. There have been reports of decreased bone mineral density, osteopenia, osteoporosis, and fractures in patients receiving long-term phenobarbital therapy. The mechanism of effect of phenobarbital on the metabolism of bone tissue has not been established.

From the side of the cardiovascular system: chest tightness, heart pain, orthostatic hypotension, decreased blood pressure, collapse, increased blood pressure, arrhythmia, tachycardia, bradycardia, extrasystole, palpitation, facial skin hyperemia, edema.

From the blood and lymphatic system: an increase in lymph nodes, pancytopenia, leukopenia, granulocytopenia (with long-term use), neutropenia, leukocytosis, agranulocytosis, lymphocytosis, thrombocytopenia, anemia, hemolytic anemia, megaloblastic anemia, sulfhemoglobinemia, methemoglobinemia (cyanosis, shortness of breath, pain in the heart area), bleeding, bruises Patients should stop using the drug and seek medical attention if signs or symptoms of unexplained or excessive bleeding from cuts and wounds occur, or if there is extensive or deep bruising.

From the side of the immune system: anaphylaxis, anaphylactic shock, splenomegaly and lymphadenopathy.

From the urinary system: renal colic, spasm of the urinary tract, difficulty urinating, delayed urination, oliguria, dysuria, antidiuretic effect, increased frequency of urination, aseptic pyuria, increased creatinine clearance, increased sodium and calcium excretion, red urine color; usually in patients with impaired kidney function and/or when using excessive doses - anuria, proteinuria, interstitial nephritis.

From the reproductive system: sexual dysfunction, erectile dysfunction, decreased libido and potency.

From the endocrine system: hypoglycemia, up to hypoglycemic coma, hyperglycemia.

Metabolic and nutritional disorders: anorexia, frequency unknown (it is impossible to estimate the frequency from the available data) - metabolic acidosis with a high anion difference.

From the gastrointestinal tract: dry mouth, heartburn, heaviness or pain in the epigastrium, discomfort and pain in the abdomen, nausea, vomiting, diarrhea or constipation, dyspepsia, stomach cramps, acute pancreatitis in patients with a history of cholecystectomy, exacerbation of peptic ulcer disease, development of paralytic intestinal obstruction.

From the side of the hepatobiliary system: impaired liver function, liver failure, liver necrosis, hepatitis, jaundice, spasm of the biliary tract, increased activity of liver enzymes, usually without the development of jaundice; drug damage to the liver, including acute hepatitis, jaundice, increased levels of liver enzymes (see the section "Particulars of use").

From the organs of the respiratory system, organs of the chest and mediastinum: nasal congestion, bronchospasm (in patients sensitive to acetylsalicylic acid and other NSAIDs), tachypnea, shortness of breath, difficulty breathing, respiratory depression (when using large doses of the drug).

General disorders: a feeling of malaise, increased fatigue, a decrease in body temperature, fever.

Description of individual adverse reactions

Metabolic acidosis with a high anion difference

Cases of metabolic acidosis with a high anion difference, which was caused by pyroglutamine acidemia, were observed in patients with risk factors who used paracetamol (see the section "Particulars of use"). Pyroglutamic acidemia may be caused by low glutathione levels in these patients.

If the use of the medicine Pyatirchatka® IS in the recommended doses combined with the consumption of products that contain caffeine, an excessive amount of caffeine entering the body increases the likelihood of developing caffeine-related side effects, such as insomnia, restlessness, anxiety, irritability, headache, gastrointestinal disturbances, palpitations.

In the case of long-term use of caffeine, its effect may decrease, drug addiction may develop.

With long-term use of phenobarbital, folate deficiency, impotence, and drug dependence may develop.

With long-term use of codeine, as a rule, some of the most common side effects develop - drowsiness, nausea, vomiting, confusion.

Regular long-term use of codeine leads to the development of dependence and tolerance and to the appearance of restlessness and irritability after stopping treatment. It should be remembered that tolerance decreases quickly after stopping codeine, so repeated use before the acceptable dose can be fatal.

Long-term use of the drug for the treatment of headache can lead to its exacerbation (see the section "Peculiarities of use").

With long-term uncontrolled use of high doses of the drug, convulsions, respiratory depression, liver dysfunction, hypoglycemia, up to hypoglycemic coma, addiction (weakening of the analgesic effect), withdrawal syndrome may develop.

Withdrawal syndrome

In the case of abrupt withdrawal of caffeine intake, inhibition of the central nervous system may increase with the appearance of a feeling of increased fatigue, the development of drowsiness, muscle tension, depression.

In the case of abrupt termination of the use of phenobarbital, a withdrawal syndrome can usually occur, which is accompanied by nightmares, nervousness.

Sudden discontinuation of codeine treatment may cause a withdrawal syndrome. Possible symptoms: tremor, insomnia, restlessness, irritability, anxiety, depression, lack of appetite, nausea, vomiting, diarrhea, increased sweating, lacrimation, rhinorrhea, sneezing, yawning, piloerection, mydriasis, weakness, fever, muscle cramps, dehydration, increased heart rate, respiratory rate, and blood pressure.

In case of any adverse reactions, it is necessary to consult a doctor.

Reporting of suspected adverse reactions

The reporting of adverse reactions after the registration of a medicinal product is important. This makes it possible to monitor the benefit/risk ratio when using this medicinal product. Medical and pharmaceutical workers, as well as patients or their legal representatives should be notified of all cases of suspected adverse reactions and lack of effectiveness of the medicinal product through the Automated Pharmacovigilance Information System at the link: https://aisf.dec.gov.ua.

Expiry date

3 years.

Storage conditions

Store in the original packaging at a temperature not higher than 25 ºС.

Keep out of the reach of children.

Packaging

10 tablets in a blister; 1 blister in a pack.

Leave category

By prescription.

Manufacturer

"INTERKHIM" Limited Liability Company.

The location of the manufacturer and the address of the place of its activity.

Ukraine, 65025, Odesa, 21st km. 40-A, Starokyivska road.