Pyatyrchatka® ic

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PYATYRCHATKA® IS

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 (equivalent to caffeine 20 mg), phenobarbital 10 mg, codeine phosphate hemihydrate 9.5 mg (equivalent to codeine base 7 mg);

Excipients: potato starch, gelatin, calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: tablets of white or white with a yellowish tint color, flat cylindrical shape, with bevel. The trade mark of the manufacturer is imprinted on one surface of the tablet, and a line on the other surface.

Pharmacotherapeutic group.

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

ATC code N02B B72.

Pharmacological properties.

Pharmacodynamics.

A combined medicinal product exerting analgesic, antipyretic, and anti-inflammatory effects.

Metamizole sodium is a pyrazolone derivative belonging to non-steroidal anti-inflammatory agents. It has analgesic and antipyretic properties and exerts a spasmolytic effect on the smooth musculature of the biliary and urinary tracts, as well as on uterine musculature.

Paracetamol is a non-narcotic analgesic that predominantly inhibits cyclooxygenase (COX) in the central nervous system (CNS). It affects pain and thermoregulation centers, providing analgesic and antipyretic effects.

Caffeine stimulates psychomotor centers in the brain, exerts analeptic action, facilitates penetration of analgesics through the blood-brain barrier, prevents collapse by stimulating the vasomotor center, and counteracts sedative effects of other components of the medicinal product.

Phenobarbital in the composition of the medicinal product exerts sedative, spasmolytic, and myorelaxant effects and potentiates the activity of analgesic components.

Codeine is a narcotic analgesic with effects similar to morphine, but with significantly weaker analgesic action and milder sedative effect. Codeine is a weak centrally-acting analgesic. It exerts its effect by interacting with μ-opioid receptors, although it has low affinity for these receptors. The analgesic effect of codeine is due to its conversion into morphine. It has been shown that codeine, especially in combination with other analgesics such as paracetamol, is effective in the treatment of acute nociceptive pain. Codeine reduces excitability of the cough center. In small doses, it does not cause respiratory center depression, does not impair ciliary epithelium function, and does not reduce bronchial secretion.

Pharmacokinetics.

Metamizole sodium is well and rapidly absorbed in the gastrointestinal tract (GI tract). It undergoes hydrolysis in the intestinal wall to form an active metabolite; unchanged metamizole is not present in the blood. The active metabolite is 50–60% bound to plasma proteins. Therapeutic effects develop within 20–40 minutes after oral administration and reach maximum intensity within 2 hours. It is metabolized in the liver and excreted by the kidneys.

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

Caffeine is well absorbed along the entire length of the intestine. It is metabolized in the liver and excreted in the urine (10% unchanged).

Phenobarbital is slowly but practically completely absorbed in the GI tract (80%) and evenly distributed in organs and tissues of the body. It penetrates histohematic barriers and into breast milk. It readily crosses the placenta. Phenobarbital is approximately 45% bound to plasma proteins. Maximum blood concentration is observed within 1–2 hours after administration. The effect begins within 30–60 minutes. It is metabolized in the liver and induces hepatic microsomal enzymes. It is slowly eliminated from the body, creating conditions for phenobarbital accumulation. The elimination half-life is 2–4 days. It is excreted by the kidneys as inactive metabolites, with up to 25% of the dose excreted unchanged. Excretion of unchanged phenobarbital by the kidneys depends on urine pH and may increase in alkaline conditions.

Codeine and its salts are rapidly absorbed in the GI tract. After oral administration, maximum plasma concentration of codeine is reached within 1 hour. Due to its lipophilicity, codeine rapidly penetrates the blood-brain barrier and accumulates in fatty tissue and, to a lesser extent, in tissues with high perfusion rates (lungs, liver, kidneys, and spleen). The elimination half-life from plasma is 3–4 hours. The ratio of analgesic effect potency after oral administration versus intramuscular injection is approximately 1 : 1.5. It is metabolized in the liver via O- and N-demethylation to form morphine and norcodeine. Codeine and its metabolites are excreted by the kidneys, primarily as glucuronide conjugates. Most excretion products are eliminated in urine within 6 hours, and up to 86% of the dose is eliminated from the body within 24 hours. Approximately 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.

Clinical characteristics.

Indications.

Severe pain syndrome of various origins (joint pain, muscle pain, radiculitis, menstrual pain, neuralgias, headache and toothache, migraine). Cold and febrile conditions accompanied by pain symptoms and inflammation.

The medicinal product is indicated for use in children aged 12 years and older for the treatment of acute moderate pain not relieved by other analgesics such as paracetamol or ibuprofen (as monotherapy).

Contraindications.

Hypersensitivity to codeine or other opioid analgesics, to caffeine or other xanthine derivatives (theophylline, theobromine), to pyrazolone derivatives, or to any component of the medicinal product; postoperative period after biliary tract surgery; peptic ulcer disease of the stomach and duodenum in the acute phase; conditions where inhibition of peristalsis should be avoided or in which abdominal distension develops; risk of paralytic intestinal obstruction, chronic constipation, severe impairment of renal and/or hepatic function, congenital hyperbilirubinemia (including Gilbert’s syndrome), acute pancreatitis, diabetes mellitus, hyperthyroidism, acute respiratory depression, respiratory diseases with dyspnea, obstructive syndrome, bronchial asthma (opioids should not be used during an asthmatic attack); organic cardiovascular diseases (including atherosclerosis), decompensated heart failure, ischemic heart disease, acute myocardial infarction, cardiac arrhythmias, elevated arterial pressure, severe arterial hypotension, predisposition to vascular spasm, thrombosis, thrombophlebitis, blood disorders (particularly agranulocytosis, leukopenia, cytostatic neutropenia, infectious neutropia, thrombocytopenia, severe anemia, hemolytic anemia), glucose-6-phosphate dehydrogenase deficiency, porphyria, myasthenia, glaucoma, head injuries 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 signs during neurological assessment); depression, depressive disorders with suicidal tendencies, states of increased excitation, sleep disorders (including insomnia), epilepsy; alcohol, drug, or medication dependence (including in medical history); state of alcohol intoxication.

The use of the medicinal product is contraindicated if there is suspicion of acute surgical pathology in the patient prior to diagnosis.

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

• children under 12 years of age;
• children aged 12 to 18 years 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 are ultra-rapid metabolizers via CYP2D6;
• elderly patients.

Do not use concomitantly with β-adrenergic blockers, tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), or within 2 weeks after discontinuation of MAOIs.

Interaction with other medicinal products and other forms of interaction.

Interactions related to sodium metamizole

Sodium metamizole should not be used simultaneously with radiographic contrast agents, colloidal plasma substitutes, or penicillin. Sodium metamizole enhances the effects of oral hypoglycemic agents, indirect coagulants, glucocorticosteroids, indomethacin, phenytoin, and ibuprofen by displacing them from protein binding sites in the blood. Sodium metamizole may induce metabolic pathway enzymes, including CYP2B6 and CYP3A4. Concurrent use of sodium metamizole with bupropion, efavirenz, methadone, valproate, cyclosporine, tacrolimus, and sertraline may lead to decreased plasma concentrations of these drugs, potentially resulting in reduced therapeutic efficacy. Therefore, caution is recommended when using sodium metamizole concomitantly with other medicinal products; clinical response and/or plasma drug levels should be monitored as necessary.

Sodium metamizole enhances the sedative effect of alcohol. Concurrent use of sodium metamizole with diuretics (furosemide) may reduce the diuretic effect. Myelotoxic medicinal products may enhance hematotoxicity. Sarcolysin, thiamazole, and medicinal products that suppress bone marrow activity (including gold preparations), when used with sodium metamizole, increase the risk of hematotoxicity, including leukopenia. High doses of sodium metamizole may increase methotrexate plasma concentration and enhance its toxic effects (particularly on the gastrointestinal tract and hematopoietic system). Concurrent use of sodium metamizole with other nonsteroidal anti-inflammatory drugs (NSAIDs) potentiates their analgesic and antipyretic effects and increases the likelihood of additive adverse effects. Adverse reactions associated with sodium metamizole are enhanced when used concomitantly with other non-opioid analgesics, tricyclic antidepressants, hormonal contraceptives, and allopurinol. Concurrent use of sodium metamizole with chlorpromazine or other phenothiazine derivatives may lead to pronounced hypothermia. Analgesic effects of sodium metamizole are enhanced by sedatives and tranquilizers (diazepam, trimethozine, etc.). Concurrent use reduces the efficacy of sodium metamizole: phenylbutazone, glutethimide, barbiturates, and other inducers of hepatic microsomal enzymes; efficacy is enhanced by: codeine, H2-histamine receptor blockers, propranolol.

Interactions related to paracetamol

The absorption rate of paracetamol may be increased when used with metoclopramide or domperidone and decreased when used with cholestyramine. Cholestyramine should not be used within one hour after paracetamol intake.

Medicinal products that induce microsomal enzymes, such as anticonvulsants and oral steroid contraceptives, may accelerate paracetamol metabolism, leading to reduced plasma concentration and increased elimination rate. Barbiturates reduce the antipyretic effect of paracetamol. Medicinal products that stimulate microsomal enzyme activity, including barbiturates, and alcohol may increase the hepatotoxicity of paracetamol, especially when toxic doses are taken. Concurrent use of paracetamol with hepatotoxic agents increases the toxic effects of drugs on the liver. Concurrent use of high-dose paracetamol with isoniazid increases the risk of hepatotoxic syndrome.

Probenecid inhibits the conjugation of paracetamol with glucuronic acid, resulting in a 50% reduction in paracetamol clearance; therefore, the dose of paracetamol should be reduced when used concomitantly.

Paracetamol may reduce lamotrigine bioavailability and its efficacy by inducing hepatic metabolism of the drug.

Concurrent intake of paracetamol and zidovudine increases the risk of neutropenia.

Paracetamol may affect the half-life of chloramphenicol. The clinical significance of these data is not established. Routine monitoring of patients is not required when paracetamol is used concomitantly with chloramphenicol, but this potential interaction should be considered, especially in poorly nourished patients.

Paracetamol should be prescribed with caution when used concomitantly with flucloxacillin, as this combination is associated with metabolic acidosis with a high anion gap, particularly in patients with risk factors (see section "Special precautions").

The anticoagulant effect of warfarin and other coumarins may be enhanced, increasing the risk of bleeding, with long-term regular daily use of paracetamol; occasional use does not show significant effects.

Paracetamol reduces the effectiveness of diuretics.

Do not use concomitantly with alcohol.

Interactions related to caffeine

When used concomitantly with:

‒ anticonvulsant medicinal products [barbiturates (including pentobarbital, primidone), hydantoin derivatives (especially phenytoin)] – accelerated metabolism and increased clearance of caffeine;

‒ fluvoxamine, mexiletine – increased plasma concentration of caffeine;

‒ nicotine – accelerated elimination of caffeine;

‒ ketoconazole, disulfiram, ciprofloxacin, norfloxacin, enoxacin, pipemidic acid – slowed elimination of caffeine and increased plasma concentration;

‒ methoxsalen – slowed elimination of caffeine with possible enhancement of its effect and development of toxic effects;

‒ cimetidine, hormonal contraceptives, isoniazid – enhanced effect of caffeine;

‒ β-adrenergic blockers – mutual reduction of therapeutic effects (see section "Contraindications");

‒ opioid analgesics, anxiolytics (including diazepam), hypnotics and sedatives – reduced effect of medicinal products;

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

‒ clozapine – increased plasma concentration of clozapine;

‒ calcium preparations – reduced absorption of medicinal products;

‒ theophylline and other xanthine derivatives – reduced clearance of medicinal products, increased risk of additive pharmacodynamic and toxic effects;

‒ lithium preparations – increased clearance of lithium (concomitant use is not recommended);

‒ α- and β-adrenomimetics (including phenylpropanolamine), psychostimulants, thyrotropic agents, analgesic-antipyretics – enhanced effect of medicinal products;

‒ cardiac glycosides – enhanced action and increased toxicity of cardiac glycosides;

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

Caffeine may enhance the tachycardic effect of some decongestants.

Caffeine may affect the effects of idrocilamide.

Caffeine is an antagonist of anesthetic agents, tranquilizers, and other CNS depressants, and a competitive antagonist of adenosine preparations.

Concurrent use of the medicinal product Pyatyrchatka® IS with other medicinal products containing caffeine or concomitant consumption of caffeine-containing beverages may lead to excessive CNS stimulation. Patients should avoid excessive consumption of coffee or tea.

Interactions related to phenobarbital

Phenobarbital induces liver enzymes and thus may accelerate the metabolism of certain medicinal products metabolized by these enzymes [including paracetamol, salicylates, indirect anticoagulants, cardiac glycosides (digoxin), antimicrobials (chloramphenicol, doxycycline, metronidazole, rifampicin, sulfonamides), antivirals, antifungals (griseofulvin, itraconazole), antiepileptics (anticonvulsants), psychotropics (tricyclic antidepressants), hormones (estrogens, progestogens, corticosteroids, thyroid hormones), immunosuppressants (glucocorticosteroids, cyclosporine, cytostatics), antiarrhythmics, antihypertensives (β-adrenergic blockers, calcium channel blockers), oral hypoglycemic agents, etc.]. Phenobarbital may affect the blood concentration of phenytoin, carbamazepine, and clonazepam. Phenobarbital may accelerate the metabolism of oral contraceptives, leading to loss of their effect. Phenobarbital increases the toxicity of methotrexate. Phenobarbital enhances the effects of analgesics, anesthetics, neuroleptics, and tranquilizers. When used concomitantly with other CNS depressants, mutual enhancement of action (sedative-hypnotic effect) is possible, which may be accompanied by respiratory depression. Alcohol enhances the effect of phenobarbital and may increase its toxicity. Medicinal products with acidic properties (ascorbic acid, ammonium chloride) and preparations containing valproic acid enhance the effect of barbiturates. Patients receiving valproate and phenobarbital concurrently should be monitored for signs of hyperammonemia. In half of 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 prolonged concurrent use with NSAIDs, there is a risk of gastric ulceration and bleeding. Concurrent use of phenobarbital with zidovudine enhances the toxicity of both medicinal products.

Interactions related to codeine

Cases of serotonin syndrome (including altered mental status, autonomic nervous system disorders, and neuromuscular disturbances) have been reported in patients taking opioids, particularly when used concomitantly with other serotonergic medicinal products (including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, MAO inhibitors; see section "Contraindications"). Codeine should not be used in combination with MAO inhibitors or within 2 weeks after discontinuation of their use. The use of MAO inhibitors in combination with pethidine has been associated with severe CNS excitation/depression (including arterial hypertension/hypotension). Although such events have not been documented with codeine, a similar interaction cannot be ruled out (see section "Special precautions").

Codeine enhances the effects of CNS depressants. Concurrent use of codeine with alcohol may enhance the hypotensive and sedative effects of alcohol and its respiratory depressant effect; with anesthetics (including sodium oxybate), antihistamines with sedative properties – possible enhancement of CNS depression and/or respiratory depression, and/or enhanced arterial hypotension; with neuroleptics (including phenothiazine tranquilizers) – enhanced sedative and hypotensive effects; with anxiolytics, sedatives, and hypnotics – enhanced sedative effect, increased risk of respiratory depression.

The use of opioids in combination with sedative medicinal products, such as benzodiazepines or benzodiazepine-like agents, increases the risk of sedation, respiratory depression, coma, or fatal outcome due to enhanced CNS depressant effects. Doses of medicinal products and duration of concomitant therapy should be limited (see section "Special precautions").

Concomitant use of codeine with antihypertensive agents may enhance hypotensive effects.

Codeine slows the absorption of mexiletine, leading to reduced antiarrhythmic effect. When used concomitantly with quinidine, the analgesic effect of codeine is likely to be significantly reduced due to the negative impact of quinidine on its metabolism.

When used in high doses, codeine may enhance the effects of cardiac glycosides (digoxin and others).

Concomitant use of codeine with chloramphenicol may increase codeine plasma concentration due to inhibition of its metabolism; with non-opioid analgesics – enhanced analgesic effect; with anti-ulcer medicinal products – cimetidine may inhibit codeine metabolism, leading to increased plasma concentration.

Concomitant use of codeine with antidiarrheal agents, anticholinergic agents (e.g., atropine), or medicinal products with anticholinergic-like effects increases the risk of severe constipation, which may lead to paralytic intestinal obstruction and/or urinary retention.

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

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

Concomitant use with ritonavir may increase the plasma concentration of opioid analgesics (including codeine).

Tricyclic antidepressants may enhance the depressant effects of opioid analgesics.

Concomitant use of codeine with opioid antagonists (e.g., buprenorphine, naloxone, naltrexone) may accelerate the onset of withdrawal syndrome.

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

Special precautions for use.

Do not use the medicinal product to relieve acute abdominal pain (prior to determining the cause). Since sodium metamizole has anti-inflammatory and analgesic properties, it may mask signs of infection, symptoms of non-infectious diseases, and complications associated with pain syndrome, which may complicate their diagnosis.

Hepatotoxicity risk

Cases of acute hepatitis, predominantly hepatocellular in nature, have been reported in patients receiving sodium metamizole, with manifestations appearing from several days to several months after initiation of treatment. Symptoms included elevated serum liver enzymes, with or without jaundice, often in the context of hypersensitivity reactions to other drugs (e.g., skin rash, blood dyscrasias, fever, and eosinophilia) or accompanied by features of autoimmune hepatitis. Most patients recovered after discontinuation of sodium metamizole; however, isolated cases of progression to liver failure requiring liver transplantation have been reported.

The mechanism of sodium metamizole-induced liver injury is not fully understood, but available data suggest an immune-allergic mechanism.

Patients should be instructed to promptly inform their physician if symptoms indicating liver injury occur. If liver injury is suspected, sodium metamizole should be discontinued, and liver function tests should be performed.

Cases of liver injury during treatment with sodium metamizole are very rare, but the exact incidence of this adverse reaction cannot be determined. In some patients, recurrence of liver injury has been observed upon re-exposure to sodium metamizole. If a patient has previously experienced liver injury during treatment with sodium metamizole and no other causes of liver injury have been identified, medicinal products containing sodium metamizole should not be re-administered.

Agranulocytosis may occur during treatment with sodium metamizole. Therefore, patients should be warned before starting treatment that if they develop chills, fever, sore throat, dysphagia, gingival bleeding, pallor, asthenia, vaginitis, proctitis, or skin and mucosal rashes without apparent cause, they should immediately discontinue the medicinal product and consult a physician.

In patients with liver disease, the risk of hepatotoxic effects of paracetamol is increased. The risk of overdose is higher in patients with non-cirrhotic alcoholic liver disease.

Paracetamol should be used with particular caution in dehydrated patients, those with glutathione deficiency, chronic malnutrition, impaired renal function (glomerular filtration rate, GFR ≤ 50 mL/min), impaired liver function (see section "Contraindications"), patients with body weight < 50 kg, and in cases of concomitant use of medicinal products affecting liver function.

Cases of impaired liver function / liver failure have been reported in patients with glutathione deficiency.

In patients with reduced glutathione levels (particularly those with severe infections such as sepsis), the risk of developing metabolic acidosis during paracetamol use is increased. Symptoms of metabolic acidosis include deep, rapid, or labored breathing, nausea, vomiting, and loss of appetite. Immediate medical attention should be sought if these symptoms occur.

Concomitant use of paracetamol with flucloxacillin is recommended with caution due to an increased risk of high anion gap metabolic acidosis, especially in patients with sepsis, malnutrition, and other conditions associated with glutathione deficiency, as well as in patients receiving the maximum daily dose of paracetamol. Close monitoring of patients, including measurement of urinary 5-oxoproline levels, is advised.

The medicinal product should be prescribed with caution to patients with mild forms of arthritis who take analgesics daily, and to patients receiving warfarin or similar anticoagulant agents.

Use of the medicinal product during an acute asthma attack is contraindicated (see section "Contraindications"). Patients with atopic bronchial asthma and pollen allergy have an increased risk of hypersensitivity reactions. The medicinal product should be taken with caution in patients with hypersensitivity to analgesics and NSAIDs, and in those with a history of allergic diseases (due to the increased risk of anaphylactic shock in this patient group).

The medicinal product should be used with caution in patients with peptic ulcer disease in remission, impaired liver or kidney function (see section "Contraindications"), thyroid disorders (including hypothyroidism, see section "Contraindications"), urinary tract disorders, hyperkinesia, chronic respiratory infections, pneumonia, respiratory function disorders, acute drug intoxication, and during treatment with cytostatic agents (only under medical supervision). The dose should be reduced in debilitated patients, patients with arterial hypotension (see section "Contraindications"), prostatic hypertrophy, adrenal insufficiency (e.g., Addison's disease), inflammatory bowel diseases including ulcerative colitis and Crohn's disease (codeine reduces gastrointestinal motility, increases intestinal tone and segmentation, and may increase colonic pressure) (see section "Contraindications"), urethral stricture, seizure disorders, and patients in shock. Dose reduction is required in patients with renal insufficiency (see section "Contraindications"). The medicinal product should be used with caution in patients with a history of kidney disease (pyelonephritis, glomerulonephritis) and in those who have recently undergone gastrointestinal or urinary tract surgery (due to possible reduced gastrointestinal motility or increased risk of urinary retention caused by urethral sphincter spasm and constipation due to codeine use). The medicinal product should be prescribed with caution in patients with pheochromocytoma (opioids may stimulate catecholamine release via induction of endogenous histamine release). Patients with biliary tract disorders (particularly cholelithiasis) should avoid opioid analgesics or use them in combination with spasmolytics.

The medicinal product should be prescribed with caution to patients whose condition may worsen due to opioid use and to patients receiving CNS depressants.

Risk of serotonin syndrome

Cases of serotonin syndrome have been reported in patients receiving opioids, particularly when used concomitantly with other serotonergic medicinal products, including SSRIs, SNRIs, tricyclic antidepressants, and MAO inhibitors (see section "Contraindications"). If concomitant opioid therapy is clinically justified, appropriate medical monitoring is recommended. Use of pethidine and possibly other opioid analgesics in patients receiving MAO inhibitors may lead to severe, sometimes fatal, reactions. If codeine use in patients taking MAO inhibitors is essential, MAO inhibitors should be discontinued at least 2 weeks before starting codeine treatment (see sections "Contraindications", "Interaction with other medicinal products and other forms of interaction").

Risk associated with concomitant use of sedative medicinal products such as benzodiazepines or benzodiazepine-like drugs

Concomitant use of codeine and sedative medicinal products such as benzodiazepines or benzodiazepine-like drugs may result in sedation, respiratory depression, coma, and death (see section "Interaction with other medicinal products and other forms of interaction"). Therefore, codeine may only be prescribed in combination with sedatives when no alternative treatment options are available. If concomitant use of codeine and sedative medicinal products is necessary, the lowest effective doses should be used, and treatment duration should be as short as possible. Patients should be monitored during concomitant therapy. Patients receiving concomitant therapy and their caregivers should be informed about symptoms of respiratory depression and sedation.

Metabolism involving CYP2D6

Codeine is converted to its active metabolite, morphine, in the liver by the CYP2D6 enzyme. If a patient has a deficiency or complete absence of this enzyme, adequate analgesic effect will not be achieved. Up to 7% of the Caucasian population may have this metabolic characteristic. However, if a patient is an ultra-rapid metabolizer via CYP2D6, there is an increased risk of adverse effects—symptoms of opioid toxicity—even at usual doses. In such patients, rapid conversion of codeine to morphine leads to higher-than-expected serum morphine levels. Common symptoms of opioid toxicity include confusion, drowsiness, shallow breathing, pinpoint pupils, nausea, vomiting, constipation, and loss of appetite. In severe cases, circulatory and respiratory depression may occur, which can be life-threatening and very rarely fatal.

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

Postoperative use in children

Cases have been reported where the use of codeine in children after tonsillectomy and/or adenoidectomy for prevention of obstructive sleep apnea rarely led to life-threatening adverse events, including fatal outcomes (see section "Contraindications"). All children received codeine doses within the recommended dosage range. However, evidence suggests these children were either ultra-rapid or extensive metabolizers of codeine.

Children with compromised respiratory function

Codeine is contraindicated in children whose respiratory function may be compromised by neuromuscular disorders, severe cardiac or respiratory diseases, upper respiratory tract infections or lung infections, multiple trauma, or major surgical procedures. These factors may exacerbate 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 phenobarbital treatment. Severe skin adverse reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have also been reported with sodium metamizole, which may be life-threatening or lead to fatal outcomes. Before initiating therapy with the medicinal product Pyryatinkka® IS, patients should be informed about the signs and symptoms of severe skin reactions. Patients must be closely monitored during treatment for the emergence of these characteristic symptoms. The risk of developing Stevens-Johnson syndrome or toxic epidermal necrolysis is highest during the first weeks of treatment. If symptoms indicating severe skin adverse reactions occur (e.g., progressive skin rashes, often with blisters, and mucosal involvement), the medicinal product must be discontinued immediately, and medicinal products containing sodium metamizole or phenobarbital must not be used thereafter (see section "Contraindications"). Early diagnosis and immediate discontinuation of the suspected causative medicinal product in cases of Stevens-Johnson syndrome or toxic epidermal necrolysis provide the best treatment outcomes.

Prolonged use of the medicinal product should be avoided due to the potential for phenobarbital accumulation and dependence development. Barbiturates are associated with a withdrawal syndrome. In patients who may have physical dependence, treatment discontinuation should be gradual to avoid precipitating withdrawal symptoms.

Prolonged use of caffeine may lead to psychological dependence.

Regular or prolonged use of codeine may lead to psychological and physical dependence. Codeine should be used with caution in patients with a history of substance abuse or psychiatric disorders (see section "Contraindications"). Misuse of codeine may lead to overdose and/or fatal outcomes (see section "Overdose"). Opioid analgesics reduce salivation, which may promote the development of dental caries and oral candidiasis.

Use of the medicinal product may affect doping control test results in athletes and laboratory tests for blood glucose levels. Caffeine use may cause falsely elevated blood uric acid levels when measured by the Bittner method. Caffeine may increase urinary levels of 5-hydroxyindoleacetic acid, vanillylmandelic acid, and catecholamines, potentially leading to false-positive diagnoses of pheochromocytoma and neuroblastoma.

During treatment, urine may turn red (due to excretion of a sodium metamizole metabolite), which is clinically insignificant.

The medicinal product should be taken at the lowest effective dose for the shortest duration necessary to control symptoms.

Recommended doses should not be exceeded. In case of overdose, immediate medical attention should be sought, even if the patient feels well, due to the risk of irreversible liver damage (see section "Overdose").

The medicinal product should not be used longer than recommended without consulting a physician. If used for more than 3 days, blood morphology (due to sodium metamizole myelotoxicity) and liver and kidney function parameters should be monitored.

With prolonged use or use at doses significantly exceeding recommended therapeutic doses, adverse reactions may intensify.

If symptoms persist for more than 3 days, worsen (e.g., fever or signs of secondary infection appear), or adverse effects occur, the medicinal product should be discontinued and medical advice sought regarding further use.

Do not take the medicinal product with other medications containing sodium metamizole, paracetamol, caffeine, phenobarbital, or codeine.

Alcoholic beverages are prohibited during treatment with this medicinal product.

Excessive consumption of caffeine-containing beverages (including tea and coffee) is not recommended during treatment, as this may intensify caffeine-related side effects such as dizziness, increased excitability, insomnia, restlessness, anxiety, irritability, headache, gastrointestinal disturbances, and tachycardia.

Prolonged use of any analgesic for headache treatment may lead to medication-overuse headache. Patients should be informed that in such cases, they should consult a physician and discontinue analgesic therapy. Medication-overuse headache should be suspected in patients with frequent or daily headaches despite regular use of headache medications (or due to regular use of these agents).

Continuous medical monitoring is required when administering the medicinal product to children (see sections "Contraindications", "Children").

One tablet of the medicinal product Pyryatinkka® IS contains 1 mmol (or 23 mg) of sodium, which corresponds to 1.15% of the WHO recommended maximum daily sodium intake for adults (2 g). This medicinal product should be used cautiously in patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding

Pregnancy

Use of the medicinal product during pregnancy is contraindicated.

Daily consumption of more than 200 mg of caffeine during pregnancy increases the risk of spontaneous abortion or low birth weight.

Barbiturates increase the risk of fetal malformations. Use of phenobarbital in the third trimester of pregnancy may lead to physical dependence in the fetus, resulting in neonatal withdrawal syndrome characterized by seizures, irritability, and coagulation disorders. Use of phenobarbital during labor may cause respiratory depression in the newborn.

A possible association has been reported between congenital respiratory and cardiac malformations in infants and codeine use during the first trimester of pregnancy. Regular use of codeine during pregnancy may lead to physical dependence in the fetus, resulting in neonatal abstinence syndrome. Use of codeine during labor may suppress respiration in the newborn. Use of opioid analgesics may cause gastric stasis during labor, increasing the risk of aspiration pneumonia in the mother.

Breastfeeding

Use of the medicinal product during breastfeeding is contraindicated.

Paracetamol and caffeine are excreted in breast milk in clinically insignificant amounts. Although pronounced toxic effects of caffeine have not been observed in breastfed infants, caffeine may exert a stimulatory effect on the infant.

Phenobarbital passes into breast milk in significant amounts and may cause CNS depression in the infant.

At usual therapeutic doses, codeine and its active metabolite may be present in breast milk at very low concentrations, unlikely to adversely affect the infant. However, if the patient is an ultra-rapid metabolizer via CYP2D6, higher morphine levels may accumulate in breast milk, and in very rare cases, this may cause potentially fatal opioid toxicity symptoms in the infant.

Ability to affect reaction speed when driving or operating machinery

Driving or operating machinery should be avoided during treatment due to possible effects such as confusion, drowsiness, dizziness, hallucinations, visual disturbances, or seizures. Opioid analgesics enhance the effects of alcohol.

Dosage and Administration

The medicinal product should be taken orally.

The recommended dose for adults and children aged 12 years and older is 1 tablet 1–3 times daily. The maximum single dose is 2 tablets; the maximum daily dose is 3 tablets.

Do not exceed the recommended dose.

The duration of continuous use of the medicinal product should not exceed 3 days. If symptoms persist, consult a physician. In exceptional cases, the treatment duration may be extended under medical supervision and upon physician's recommendation.

Children

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

The use of the medicinal product is contraindicated in children under 12 years of age due to the risk of developing serious and life-threatening adverse reactions resulting from the variable and unpredictable metabolism of codeine to morphine in this age group (see section "Contraindications").

Codeine must not be used in children aged 12 to 18 years undergoing tonsillectomy and/or adenoidectomy to prevent the occurrence of obstructive sleep apnea, due to the risk of serious and life-threatening adverse reactions (see sections "Contraindications", "Special Warnings and Precautions").

Codeine must 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", "Special Warnings and Precautions").

Codeine must not be used in children aged 12 to 18 years who are ultra-rapid metabolizers via CYP2D6 (see sections "Contraindications", "Special Warnings and Precautions").

Overdose

In case of first signs of overdose, seek immediate medical help.

Sodium metamizole overdose

Symptoms: tinnitus, drowsiness, convulsive syndrome, delirium, impaired consciousness, weakness, hypothermia, marked decrease in blood pressure, tachycardia, palpitations, acute agranulocytosis, hemorrhagic syndrome, acute renal failure, oliguria, anuria, dysphagia, nausea, vomiting, gastralgia/gastritis, hepatic failure, respiratory muscle paralysis, dyspnea.

Treatment: induce vomiting, gastric lavage, administration of saline laxatives and enterosorbents, forced diuresis, symptomatic therapy aimed at supporting vital functions. In severe cases, hemodialysis, hemoperfusion, or peritoneal dialysis may be considered. In case of convulsive syndrome, intravenous diazepam and fast-acting barbiturates should be administered.

Paracetamol overdose

In case of administration of a dose exceeding the recommended dose, seek immediate medical attention due to the risk of liver damage. Paracetamol overdose may lead to liver failure, which may require liver transplantation or result in a fatal outcome.

Symptoms. Ingestion of more than 12 g of paracetamol or more than 150 mg paracetamol per kg body weight (whichever amount is lower) may result in severe liver damage. Liver injury, indicated by elevated plasma transaminase levels, may clinically manifest 8–36 hours after ingestion of an excessive dose of paracetamol. Biochemical markers of liver injury reach their peak values only after 3–4 days following overdose, while clinical symptoms of liver injury become most apparent after 4–6 days. Ingestion of 5 g or more of paracetamol may lead to liver injury in patients with risk factors (chronic use of carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort, or other drugs inducing liver enzymes; regular excessive alcohol consumption; glutathione deficiency, e.g., eating disorders, cystic fibrosis, HIV infection, fasting, malnutrition, cachexia).

Symptoms of paracetamol overdose within the first 24 hours: pallor, nausea, vomiting, loss of appetite, abdominal pain. Clinical signs of overdose may not be apparent. Liver injury occurs when the increased amount of the toxic metabolite of paracetamol (normally neutralized by glutathione at therapeutic doses) irreversibly binds to liver tissue. Glucose metabolism disturbances and metabolic acidosis may occur. In severe poisoning, liver failure may progress to encephalopathy, hemorrhage, hypoglycemia, coma, and death. Acute renal failure with acute tubular necrosis may present as severe flank pain, hematuria, proteinuria, and may develop even in the absence of severe liver injury. Cardiac arrhythmias and pancreatitis have been reported.

With prolonged use of high-dose paracetamol, hematological disorders such as pancytopenia, aplastic anemia, thrombocytopenia, leukopenia, agranulocytosis, and neutropenia may develop. High doses may cause central nervous system effects such as dizziness, psychomotor agitation, disorientation; and urinary system effects such as nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis).

Treatment. In case of overdose, prompt medical intervention is required! The patient should be immediately hospitalized, even if early symptoms of overdose are absent. Symptoms may be limited to nausea and vomiting and may not reflect the severity of overdose or risk of organ damage. Paracetamol plasma concentration should be measured at least 4 hours after drug intake or later (earlier concentrations are unreliable). Intravenous administration of N-acetylcysteine is effective if initiated within 8 hours after ingestion of an excessive paracetamol dose. The efficacy of the antidote sharply decreases after this period, but continued administration of N-acetylcysteine up to 24 hours or even longer may still be partially effective. Oral administration of methionine may be effective if given within 10–12 hours after overdose, provided vomiting is absent. Activated charcoal treatment may be beneficial within 1 hour after ingestion of an excessive paracetamol dose. Evidence for the effectiveness of gastric lavage in cases of isolated paracetamol overdose is insufficient.

Caffeine overdose

Overdose of the medicinal product Pyatyrchatka® IS in quantities causing clinically evident symptoms of caffeine overdose is likely to result in liver injury due to paracetamol overdose.

Symptoms. Caffeine overdose may cause headache, dizziness, emotional excitation, restlessness, nervousness, irritability, agitation, anxiety, psychomotor agitation, disorganized thinking and speech, confusion, delirium, insomnia, increased tactile or pain sensitivity, tremor, muscle twitching, seizures (tonic-clonic seizures in acute overdose), tinnitus, fever, tachypnea, facial flushing, hot flashes, arrhythmia, tachycardia, extrasystoles, nausea, vomiting (sometimes with blood), epigastric pain, gastrointestinal disturbances, increased frequency of urination, increased diuresis, dehydration.

Treatment. Gastric lavage is required in case of caffeine overdose. Activated charcoal may be effective if administered within 1 hour after overdose, but its use may be considered up to 4 hours after caffeine overdose. Supportive measures include maintaining lung ventilation, fluid and electrolyte balance; hemodialysis may be considered. In case of seizures, intravenous diazepam, phenobarbital, or phenytoin should be administered. There is no specific antidote, but β-adrenergic receptor antagonists may be used as supportive therapy to reduce cardiotoxic effects.

Phenobarbital overdose

Symptoms of mild to moderate acute barbiturate poisoning: dizziness, increased fatigue, even deep sleep from which the patient cannot be awakened. Hypersensitivity reactions may occur: angioedema, pruritus, skin rash (including urticaria).

Symptoms of severe acute barbiturate poisoning: central nervous system depression up to deep coma, accompanied by tissue hypoxia; shallow breathing, initially rapid, then slowed; respiratory depression up to respiratory arrest; cardiovascular depression, including cardiac rhythm disturbances, decreased blood pressure up to collapse; hypothermia, decreased diuresis, tachycardia or bradycardia, diminished or absent reflexes, nystagmus, headache, ataxia, nausea, weakness.

If untreated, fatal outcome may occur due to circulatory failure, respiratory paralysis, or pulmonary edema.

Treatment: symptomatic therapy (primarily monitoring of vital functions: respiration, pulse, blood pressure); intensive care if necessary. Stabilization and normalization of respiration and circulation are required. Artificial ventilation is necessary to treat respiratory failure; plasma and plasma substitutes should be administered to counteract shock. If only a short time has passed since ingestion of excessive phenobarbital (no more than 6 hours), gastric lavage should be performed, followed by administration of a sorbent (activated charcoal) and sodium sulfate. Forced alkaline diuresis, hemodialysis, and/or hemoperfusion may be performed to accelerate barbiturate elimination.

Codeine overdose

Symptoms of codeine overdose may be masked by clinical manifestations of severe liver injury caused by paracetamol overdose. In case of overdose, immediate medical assistance is required, even if symptoms are absent!

Symptoms. The first signs of codeine overdose are nausea and vomiting. The clinical triad of opioid overdose includes coma, pinpoint pupils (miosis), and respiratory depression, with subsequent pupil dilation occurring upon development of hypoxia. Acute respiratory depression may lead to cyanosis, slowed or labored breathing, drowsiness, ataxia, and less frequently, pulmonary edema. Other symptoms of opioid overdose include apnea, dyspnea, hypothermia, seizures (especially in children), confusion, severe dizziness, marked drowsiness; nervousness, restlessness, emotional excitation, hallucinations, arterial hypotension, and tachycardia (possible but unlikely); bradycardia, circulatory failure, collapse, urinary retention, and profound weakness. Signs of histamine release may occur. Cases of rhabdomyolysis progressing to renal failure have been reported following opioid overdose. Overdose is potentiated by concomitant alcohol and psychotropic drug use. Severe central nervous system depression, including respiratory depression, may develop with concomitant use of codeine and other sedative agents (including alcohol) or significant dose escalation.

Treatment. Management of codeine overdose includes general symptomatic and supportive measures, including ensuring airway patency and monitoring vital functions until the patient's condition stabilizes. Severe respiratory depression should be treated with artificial ventilation and oxygen supplementation. Activated charcoal administration is advisable if less than 1 hour has passed since ingestion of more than 350 mg of codeine in adults or more than 5 mg/kg body weight in children. Naloxone should be administered in case of coma or respiratory depression. Naloxone is a competitive antagonist with a short half-life, so repeated administration of high doses may be required in patients with severe poisoning. The patient should be observed for at least 4 hours after naloxone administration or 8 hours in cases of prolonged-action naloxone formulations.

Side effects

Adverse effects are usually temporary and disappear after discontinuation of treatment.

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

Nervous system disorders: increased intracranial pressure, headache, worsening of headache (with prolonged use), dizziness, increased reflexes, impaired motor coordination, ataxia, tremor, seizures (especially in children), hyperkinesia (in children), slowed reaction time, weakness, asthenia, drowsiness, insomnia, paresthesia.

Eye disorders: pupil constriction, visual acuity disturbances, photophobia, visual disturbances (including blurred vision, double vision), miosis, nystagmus, conjunctivitis.

Ear and labyrinth disorders: vertigo.

Skin and subcutaneous tissue disorders: oral mucosal ulcers, photosensitivity, facial flushing, skin hyperemia, exfoliative dermatitis, hypersensitivity reactions such as rash (usually generalized rash; erythematous rash, maculopapular rash considered as a symptom of hypersensitivity syndrome associated with oral codeine administration), urticaria, pruritus, increased sweating, purpura, facial swelling, angioneurotic edema; severe skin reactions: toxic epidermal necrolysis (Lyell's syndrome), drug-induced dermatitis, erythema multiforme, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

Musculoskeletal and connective tissue disorders: uncontrolled muscle movements, muscle rigidity (with high-dose use); with prolonged use, there is a risk of impaired osteogenesis and rickets development. Cases of decreased bone mineral density, osteopenia, osteoporosis, and fractures have been reported in patients receiving long-term phenobarbital therapy. The mechanism of phenobarbital's effect on bone metabolism has not been established.

Cardiac and vascular disorders: chest tightness, chest pain, orthostatic hypotension, decreased blood pressure, collapse, increased blood pressure, arrhythmia, tachycardia, bradycardia, extrasystoles, palpitations, facial skin hyperemia, edema.

Blood and lymphatic system disorders: enlarged lymph nodes, pancytopenia, leukopenia, granulocytopenia (with prolonged use), neutropenia, leukocytosis, agranulocytosis, lymphocytosis, thrombocytopenia, anemia, hemolytic anemia, megaloblastic anemia, sulfhemoglobinemia, methemoglobinemia (cyanosis, dyspnea, chest pain), bleeding, bruising. Patients should discontinue the medication and consult a physician if signs or symptoms of unexplained or excessive bleeding from cuts or wounds occur, or if numerous or deep bruises appear.

Immune system disorders: anaphylaxis, anaphylactic shock, splenomegaly, lymphadenopathy.

Renal and urinary disorders: renal colic, ureteral spasm, difficulty urinating, urinary retention, oliguria, dysuria, antidiuretic effect, increased frequency of urination, sterile pyuria, increased creatinine clearance, increased excretion of sodium and calcium, red discoloration of urine; usually in patients with impaired renal function and/or with overdose – anuria, proteinuria, interstitial nephritis.

Reproductive system disorders: sexual dysfunction, erectile dysfunction, decreased libido and potency.

Endocrine disorders: hypoglycemia, up to hypoglycemic coma, hyperglycemia.

Metabolism and nutrition disorders: anorexia.

Gastrointestinal disorders: dry mouth, heartburn, epigastric fullness or pain, abdominal discomfort and pain, nausea, vomiting, diarrhea or constipation, dyspepsia, stomach cramps, acute pancreatitis in patients with history of cholecystectomy, exacerbation of peptic ulcer disease, development of paralytic intestinal obstruction.

Hepatobiliary disorders: liver function disturbances, liver failure, liver necrosis, hepatitis, jaundice, biliary tract spasm, elevated liver enzyme activity, usually without jaundice; drug-induced liver injury, including acute hepatitis, jaundice, elevated liver enzyme levels (see section "Special precautions for use").

Respiratory, thoracic and mediastinal disorders: nasal congestion, bronchospasm (in patients sensitive to acetylsalicylic acid and other NSAIDs), tachypnea, dyspnea, breathing difficulty, respiratory depression (with high-dose use of the drug).

General disorders: malaise, increased fatigue, decreased body temperature, fever.

If use of the medicinal product Pyatyrchatka® IS at recommended doses is combined with consumption of products containing caffeine, excessive intake of caffeine increases the likelihood of caffeine-related adverse effects such as insomnia, restlessness, anxiety, irritability, headache, gastrointestinal disorders, palpitations.

With prolonged use of caffeine, its effect may diminish, and drug dependence may develop.

With prolonged use of phenobarbital, folate deficiency, impotence, and drug dependence may develop.

With prolonged use of codeine, some of the most common adverse effects usually develop – drowsiness, nausea, vomiting, confusion.

Regular long-term use of codeine leads to dependence and tolerance, and may cause restlessness and irritability after discontinuation. It should be remembered that tolerance decreases rapidly after stopping codeine, so re-administration of a previously tolerated dose may be fatal.

Prolonged use of the drug for headache treatment may lead to worsening of headache (see section "Special precautions for use").

With prolonged uncontrolled use of high doses of the drug, seizures, respiratory depression, liver function impairment, hypoglycemia up to hypoglycemic coma, habituation (reduced analgesic effect), and withdrawal syndrome may occur.

Withdrawal syndrome

Sudden discontinuation of caffeine may lead to increased CNS depression, increased fatigue, drowsiness, muscle tension, and depression.

Sudden discontinuation of phenobarbital usually causes a withdrawal syndrome accompanied by nightmares and nervousness.

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

If any adverse reactions occur, it is mandatory to consult a physician.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after medicinal product registration is of great importance. It allows continuous monitoring of the benefit-risk ratio of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life: 3 years.

Storage conditions:

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging:

10 tablets in a blister; 1 blister per carton.

Prescription status: Prescription only.

Manufacturer:

Additional liability company "INTERSIM".

Manufacturer's address and location of business activity:

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