Pentalgin-fs

INSTRUCTION for medical use of the medicinal product Pentalgin-PS (Pentalgin-PS)

Composition:

Active substances: paracetamol, sodium metamizole monohydrate (analgin), caffeine, phenobarbital, codeine phosphate hemihydrate;

1 tablet contains paracetamol 300 mg, sodium metamizole monohydrate (analgin) 300 mg, caffeine 50 mg, phenobarbital 10 mg, codeine phosphate hemihydrate calculated as codeine phosphate 8 mg;

Excipients: potato starch, povidone, stearic acid, calcium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: tablets, white or yellowish-white, flat-surfaced, round-shaped with bevel, with a score line on one side.

Pharmacotherapeutic group. Analgesics and antipyretics. Sodium metamizole in combination with psychotropic agents. ATC code N02B B72.

Pharmacological properties.

Pharmacodynamics.

The drug exerts analgesic, antipyretic, anti-inflammatory, spasmolytic, and sedative effects. Pentalgin-FS is a combination drug that combines the properties of its active ingredients.

Metamizole sodium and paracetamol belong to the group of non-narcotic analgesics, exerting pronounced anti-inflammatory and antipyretic effects and possessing analgesic activity.

Codeine phosphate enhances the effect of non-narcotic analgesics (blocks opioid receptors, stimulates the antinociceptive system, and alters the emotional perception of pain).

Caffeine causes vasodilation of blood vessels in skeletal muscles, brain, heart, and kidneys; increases mental and physical performance, helps relieve fatigue and drowsiness; raises arterial blood pressure in arterial hypotension; increases permeability of histohematogenous barriers and enhances bioavailability of non-narcotic analgesics, thereby contributing to the enhancement of therapeutic effect.

Phenobarbital exerts a sedative effect.

Pharmacokinetics.

The pharmacokinetics of the combination drug Pentalgin-FS have not been studied.

Clinical characteristics.

Indications.

Moderate pain of various origins: headache, toothache, neuralgia, myalgia, arthralgia, dysmenorrhea; as an antipyretic agent.

Contraindications.

Hypersensitivity to codeine or other opioid analgesics, to pyrazolone derivatives, or to any component of the medicinal product; postoperative period after biliary tract surgery, active peptic ulcer disease of the stomach and duodenum, conditions where inhibition of peristalsis should be avoided or in which abdominal distension develops; risk of paralytic ileus, severe renal and/or hepatic impairment, congenital hyperbilirubinemia (including Gilbert’s syndrome), acute pancreatitis, diabetes mellitus, acute respiratory depression, respiratory disorders with dyspnea, obstructive syndrome, bronchial asthma (opioids should not be used during an asthmatic attack); organic cardiovascular diseases, including severe atherosclerosis; decompensated heart failure, acute myocardial infarction, cardiac arrhythmias, elevated arterial pressure, marked arterial hypotension, glucose-6-phosphate dehydrogenase deficiency, porphyria, hyperthyroidism; history of agranulocytosis caused by metamizole, other pyrazolones or pyrazolidines; bone marrow dysfunction or disorders of the hematopoietic system and blood (including leukopenia (including cytostatic and infectious neutropenia), thrombocytopenia, severe anemia (including hemolytic)); myasthenia gravis, 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 when assessing neurological status); depression, depressive disorders with suicidal tendencies, states of increased excitation, sleep disorders, epilepsy, alcohol, drug, or medication dependence (including history thereof), alcohol intoxication; elderly age. The use of the medicinal product is contraindicated if acute surgical pathology is suspected in the patient until a diagnosis is established.

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.

Do not use concomitantly with monoamine oxidase inhibitors (MAOIs) or within 2 weeks after discontinuation of MAOIs.

Interaction with other medicinal products and other types of interactions.

The toxic effect of sodium metamizole is enhanced when used concomitantly with other non-narcotic analgesics, tricyclic antidepressants, hormonal contraceptives, and allopurinol. Sarcosine, thiimazole, and medicinal products that suppress bone marrow activity, including gold preparations, increase the risk of hematotoxicity, including leukopenia, when used with sodium metamizole. The analgesic effect of sodium metamizole is enhanced by H2-histamine receptor blockers, propranolol, codeine, sedatives, and tranquilizers (diazepam, trimethozine, etc.), and reduced by phenylbutazone, glutethimide, barbiturates, and other inducers of hepatic microsomal enzymes. Myelotoxic medicinal products increase hematotoxicity. Sodium metamizole enhances the activity of oral hypoglycemic agents, indirect anticoagulants, glucocorticosteroids, indomethacin, phenytoin, and ibuprofen by displacing them from plasma protein binding. Sodium metamizole enhances the sedative effect of ethanol.

Pharmacokinetic induction of metabolic enzymes:

Metamizole may induce metabolic enzymes, including CYP2B6 and CYP3A4.

Concomitant use of metamizole with bupropion, efavirenz, methadone, valproate, cyclosporine, tacrolimus, or sertraline may lead to decreased plasma concentrations of these drugs with potential reduction in clinical efficacy. Therefore, caution is recommended when using them concomitantly with metamizole; if necessary, clinical response and/or drug levels should be monitored.

Concomitant use of sodium metamizole with other nonsteroidal anti-inflammatory drugs (NSAIDs) potentiates their analgesic and antipyretic effects and increases the risk of additive adverse effects. Use in combination with phenothiazine derivatives (including chlorpromazine) may lead to pronounced hypothermia. Caution is required when using the medicinal product concomitantly with sulfonylurea hypoglycemic agents (potentiation of hypoglycemic effect) and diuretics (furosemide). High doses of sodium metamizole may increase methotrexate plasma concentration and enhance its toxic effects (primarily on the gastrointestinal tract and hematopoietic system). Sodium metamizole must not be used concomitantly with radiographic contrast agents, colloidal plasma substitutes, or penicillin.

The absorption rate of paracetamol may be increased when used with metoclopramide and domperidone and decreased when used with cholestyramine. Barbiturates reduce the antipyretic effect of paracetamol. Anticonvulsant medicinal products (including phenytoin, barbiturates, carbamazepine), which stimulate hepatic microsomal enzyme activity, may enhance the hepatotoxic effect of paracetamol due to increased formation of hepatotoxic metabolites. Concomitant use of paracetamol with hepatotoxic agents increases the hepatotoxic effect of medicinal products. Concurrent use of high-dose paracetamol with isoniazid increases the risk of hepatotoxic syndrome. The anticoagulant effect of warfarin and other coumarins may be enhanced by long-term, regular daily use of paracetamol, increasing the risk of bleeding; occasional use does not produce a significant effect. Paracetamol reduces the efficacy of diuretics. Do not use concomitantly with alcohol. Paracetamol may reduce lamotrigine bioavailability with potential reduction in its effect due to possible induction of its hepatic metabolism. Concurrent use of paracetamol and zidovudine increases the risk. Caution is advised when using paracetamol concomitantly with flucloxacillin, as co-administration of these drugs is associated with an increased risk of metabolic acidosis with a high anion gap due to pyroglutamic acidosis, especially in patients with risk factors (see section "Special precautions for use").

Caffeine enhances the effect (improves bioavailability) of analgesic-antipyretic agents and ergotamine, potentiates the effects of xanthine derivatives, α- and β-adrenergic agonists, and psychostimulants. Concurrent use of caffeine with thyroid-stimulating agents increases thyroid effect. Other medicinal products whose effects may be altered by interaction with caffeine: hydroxyzine, mexiletine, ciprofloxacin, enoxacin, pipemidic acid, fluvoxamine, phenylpropanolamine, phenytoin, clozapine, lithium, theophylline, pentobarbital, diazepam, methoxsalen. Caffeine reduces the effect of opioid analgesics, anxiolytics, hypnotics, and sedatives; it is an antagonist of anesthetic agents and other medicinal products that depress the central nervous system (CNS), and a competitive antagonist of adenosine preparations. Concurrent use of caffeine with MAO inhibitors may cause a dangerous increase in blood pressure. Cimetidine, hormonal contraceptives, and isoniazid enhance the effect of caffeine.

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), antivirals, antifungals (griseofulvin, itraconazole), antiepileptics (anticonvulsants), psychotropics (tricyclic antidepressants, clonazepam), hormones (estrogens, progestogens, corticosteroids, thyroid hormones), immunosuppressants (glucocorticosteroids, cyclosporine, cytostatics), antiarrhythmics, antihypertensives (β-blockers, calcium channel blockers), oral hypoglycemic agents, and other medicinal products). Phenobarbital may accelerate the metabolism of oral contraceptives, leading to loss of their effect. Phenobarbital enhances the effect of analgesics, local anesthetics, and medicinal products that depress the CNS (anesthetics, neuroleptics, tranquilizers), and alcohol. Concurrent use of phenobarbital with medicinal products exhibiting sedative effects leads to enhanced sedative-hypnotic effect and may be accompanied by respiratory depression. Phenobarbital may affect the blood concentration of phenytoin, carbamazepine, and clonazepam. Medicinal products with acidic properties (ascorbic acid, ammonium chloride) enhance the effect of barbiturates. Patients receiving concomitant valproate and phenobarbital therapy 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 concomitant 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.

Codeine should not be used in combination with MAO inhibitors or within 2 weeks after discontinuation of MAO inhibitors. Use of MAO inhibitors in combination with meperidine 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. Tricyclic antidepressants may enhance the depressant effects of opioid analgesics. Concurrent use of codeine with alcohol may enhance the hypotensive and sedative effects of alcohol and the respiratory depressant effect of alcohol; with anesthetics, sodium oxybate, antihistamines with sedative properties – possible enhancement of CNS depression and/or respiratory depression, and/or arterial hypotension; with neuroleptics – enhanced sedative and hypotensive effects; with anxiolytics, sedatives, and hypnotics – enhanced sedative effect and increased risk of respiratory depression; with antihypertensive agents – enhanced hypotensive effect; with antiarrhythmics – codeine slows the absorption of mexiletine; concurrent use of codeine and quinidine may significantly reduce the analgesic effect of codeine due to the negative effect of quinidine on its metabolism; avoid premedication with opioids, as they reduce plasma concentration of ciprofloxacin; with antiulcer agents – cimetidine may inhibit codeine metabolism, leading to increased plasma concentration; with antidiarrheal agents, anticholinergic agents (e.g., atropine) – risk of severe constipation, which may lead to paralytic intestinal obstruction and/or urinary retention. Codeine antagonizes the effect of cisapride, metoclopramide, and domperidone on gastrointestinal motility. Use of codeine in combination with opioid antagonists (e.g., buprenorphine, naloxone, naltrexone) may accelerate the onset of withdrawal syndrome. Avoid premedication with opioids, as they reduce plasma concentration of ciprofloxacin. Use with ritonavir may increase plasma levels of opioid analgesics (including codeine). Concurrent use of mexiletine with codeine slows absorption of mexiletine.

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

Special precautions for use

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

Alcohol consumption is prohibited during treatment with this medicinal product.

The information below is specific to the active substances of the medicinal product.

Metamizole

Agranulocytosis

Treatment with metamizole may cause agranulocytosis, which can be fatal (see section "Adverse reactions"). Agranulocytosis may occur even after previous use of metamizole without complications.

Metamizole-induced agranulocytosis is an idiosyncratic adverse reaction. It is not dose-dependent and may occur at any time during treatment, even shortly after discontinuation of therapy.

Patients must be informed before starting treatment about the necessity to discontinue therapy and immediately seek medical help if any symptoms suggestive of agranulocytosis occur (e.g., fever, chills, sore throat, and pathological changes in mucous membranes, particularly in the mouth, nose, throat, genital area, or anal region).

If metamizole is used during fever, some symptoms of developing agranulocytosis may remain unnoticed. Similarly, symptoms may be masked in patients receiving antibiotic therapy.

In case of signs or symptoms suggestive of agranulocytosis, a complete blood count (including differential count) should be performed immediately, and treatment should be discontinued pending test results. If the diagnosis is confirmed, treatment must not be resumed (see section "Contraindications").

Severe skin reactions

Severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug-induced eosinophilia with systemic symptoms (DRESS syndrome), which may be life-threatening or fatal, have been reported during treatment with metamizole.

Patients should be informed about the signs and symptoms of skin reactions and closely monitored.

If signs or symptoms suggestive of these reactions occur, the medicinal product should be discontinued immediately and must never be restarted (see section "Contraindications").

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

The medicinal product should be used with caution in patients:

• elderly patients – may lead to increased frequency of adverse reactions, especially those affecting the gastrointestinal system;
• with existing allergic diseases (including pollinosis) or a history of such conditions – increased risk of allergic reactions;
• with impaired kidney function or history of kidney disease (pyelonephritis, glomerulonephritis);
• with inflammatory bowel diseases, including ulcerative colitis and Crohn’s disease;
• with marked arterial hypotension or cardiovascular insufficiency;
• with a history of alcoholism;
• who are concurrently using cytostatic medicinal products (only under medical supervision).

Do not use the medicinal product for longer than the recommended duration without consulting a physician. Do not exceed the specified doses. Prolonged use or use of doses significantly exceeding the recommended therapeutic doses may lead to increased adverse reactions. Liver function parameters should be monitored during treatment.

Drug-induced liver injury

Cases of drug-induced liver injury, mainly of hepatocellular type, have been observed in patients treated with metamizole, occurring several days or months after initiation of therapy. Signs and symptoms include elevated serum liver enzymes, with or without jaundice, often accompanied by hypersensitivity reactions to other drugs (e.g., skin rash, blood dyscrasias, fever, and eosinophilia), or features suggestive of autoimmune hepatitis. In most patients, the condition resolved after discontinuation of metamizole therapy. However, isolated cases of progression to acute liver failure requiring liver transplantation have been reported.

The mechanism of liver injury caused by metamizole is not fully understood, although available data suggest an immune-allergic mechanism.

Patients should be informed about the need to consult a physician if symptoms suggestive of liver injury occur. In such cases, metamizole should be discontinued and liver function should be evaluated.

If symptoms such as nausea and vomiting, fever, fatigue, loss of appetite, dark urine, pale stools, jaundice (yellowing of the skin or sclera), pruritus, skin rash, or upper abdominal pain occur, metamizole use should be discontinued and medical advice should be sought immediately. Metamizole must not be re-administered to patients who have experienced liver injury during previous treatment with metamizole, unless other causes of liver injury have been ruled out.

During treatment, red discoloration of urine (due to excretion of a metabolite of metamizole sodium) may occur, which is not clinically significant.

Phenobarbital

Life-threatening skin reactions, including Stevens-Johnson syndrome or toxic epidermal necrolysis (Lyell’s syndrome), have been reported with phenobarbital use. Therefore, if characteristic symptoms of these reactions occur (e.g., progressive skin rash, often with blisters, and mucosal lesions), the medicinal product should be discontinued immediately and never be used again, including any medicinal products containing phenobarbital. The risk of developing Stevens-Johnson syndrome or Lyell’s syndrome is highest during the first weeks of treatment. Early diagnosis and immediate discontinuation of the suspected causative medicinal product 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 withdrawal syndrome.

The medicinal product should be used with caution in patients with peptic ulcer disease of the stomach and duodenum in remission, hepatic or renal dysfunction (see section "Contraindications"), thyroid disorders (including hypothyroidism, see section "Contraindications"), urinary tract diseases, hyperkinesias, chronic respiratory infections, pneumonia, respiratory function disorders, acute drug intoxication, or during treatment with cytostatics (only under medical supervision).

Paracetamol

In patients with liver or kidney disease, medical advice should be sought before using the medicinal product (see section "Contraindications").

It should be noted that patients with liver disease have an increased risk of hepatotoxic effects of paracetamol.

Cases of impaired liver function/liver failure have been reported in patients with reduced glutathione levels, which may occur in severe malnutrition, anorexia, low body mass index, chronic alcoholism, or sepsis.

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe conditions such as severe renal failure and sepsis, or in patients with poor nutrition or other causes of glutathione deficiency (e.g., chronic alcoholism) treated with paracetamol at therapeutic doses for prolonged periods or in combination with flucloxacillin. In suspected HAGMA due to pyroglutamic acidosis, immediate discontinuation of paracetamol and careful patient monitoring are recommended. Measurement of 5-oxoproline levels in urine may be useful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.

In patients with reduced glutathione levels, the use of paracetamol increases the risk of developing metabolic acidosis. Symptoms of metabolic acidosis include deep, rapid, or labored breathing, nausea, vomiting, and loss of appetite. Immediate medical consultation is required if these symptoms occur.

The medicinal product may affect laboratory test results for blood glucose and uric acid levels.

Codeine

Use of the medicinal product during an acute asthma attack is contraindicated (see section "Contraindications"). Codeine should be used with caution or the dose reduced in patients with asthma or reduced respiratory reserve. Codeine use should be avoided during an acute asthma attack (see section "Contraindications"). Codeine should be used with caution in patients with impaired renal or hepatic function, gallbladder disorders (including cholelithiasis), history of drug abuse, respiratory function disorders, or history of asthma.

The dose of codeine should be reduced in debilitated patients, patients with arterial hypotension (see section "Contraindications"), hypothyroidism, prostate hypertrophy, adrenal insufficiency (e.g., Addison’s disease), inflammatory bowel diseases including ulcerative colitis and Crohn’s disease (codeine reduces peristalsis, increases intestinal tone and segmentation, and may increase pressure in the colon) (see section "Contraindications"), urethral stricture, seizure disorders, patients in shock, or those with myasthenia gravis. The dose of codeine should be reduced in patients with renal insufficiency. Codeine should be used with caution in patients who have recently undergone gastrointestinal surgery (due to possible reduction in gastrointestinal motility) or urinary tract surgery (such patients are more prone to urinary retention due to urethral sphincter spasm and constipation due to codeine use). Codeine should be used with caution in patients with pheochromocytoma (opioids may stimulate catecholamine release by inducing endogenous histamine release). In patients who may develop physical dependence, treatment should be discontinued gradually to avoid precipitating withdrawal symptoms.

Metabolism involving CYP2D6

Codeine is converted in the liver to its active metabolite, morphine, 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 CYP2D6 metabolism 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 with standard doses. In such patients, rapid conversion of codeine to morphine leads to higher serum morphine levels than expected.

General symptoms of opioid toxicity: 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:

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

There have been reports of life-threatening adverse events, including fatalities, associated with the use of codeine in children after tonsillectomy and/or adenoidectomy for the prevention of postoperative obstructive sleep apnea (see section "Contraindications"). All children received codeine doses within the recommended range. However, evidence suggests that 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 pulmonary infections, multiple trauma, or extensive surgical procedures. These factors may potentiate morphine toxicity symptoms.

Patients with biliary tract disorders (including cholelithiasis) should avoid the use of opioid analgesics or use them in combination with antispasmodics.

The use of pethidine and possibly other opioid analgesics in patients taking MAO inhibitors may lead to severe, sometimes fatal, reactions. If the use of codeine in patients receiving MAO inhibitors is essential, MAO inhibitors should be discontinued 14 days prior to initiating codeine therapy (see sections "Contraindications", "Interaction with other medicinal products and other types of interactions").

Alcohol consumption should be avoided during codeine treatment.

In elderly patients, metabolism and elimination of codeine may be slower (see section "Dosage and administration").

Codeine use requires regular benefit-risk assessment by a physician.

Caffeine

During treatment with this medicinal product, excessive consumption of tea, coffee, other stimulant beverages, alcohol, or use of medicinal products containing caffeine is not recommended.

Prolonged use of the drug may lead to psychological dependence. Abrupt discontinuation of treatment may result in increased central nervous system (CNS) depression (drowsiness, depression).

The drug's effect largely depends on the type of nervous system and may manifest either as excitation or inhibition of higher nervous activity.

Caffeine may cause a false increase in blood uric acid levels when measured by the Bittner method.

Caffeine may increase urinary levels of 5-hydroxyindoleacetic acid (5-HIAA), vanillylmandelic acid (VMA), and catecholamines, potentially leading to false-positive results in the diagnosis of pheochromocytoma and neuroblastoma.

Use with caution in patients with a history of peptic ulcer disease of the stomach or duodenum.

In case of overdose, seek immediate medical attention due to the risk of liver damage, even if the patient feels well.

Use during pregnancy or breastfeeding

Pregnancy

The use of this medicinal product during pregnancy is contraindicated.

There have been reports of a possible association between congenital respiratory and cardiac malformations in newborns 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 withdrawal symptoms in the newborn. Codeine use during labor may depress respiration in the newborn. Opioid analgesics may cause gastric stasis during labor, increasing the risk of aspiration pneumonia in the mother.

An increased risk of fetal abnormalities has been reported with barbiturate use. Phenobarbital use during the third trimester of pregnancy may lead to physical dependence, resulting in a withdrawal syndrome in the newborn, manifested by seizures, irritability, and coagulation disorders. Phenobarbital use during labor may cause respiratory depression in the newborn.

Breastfeeding

The use of this medicinal product during breastfeeding is contraindicated.

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

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

Ability to influence the speed of reactions when driving or operating machinery

During treatment with this medicinal product, patients should refrain from driving or operating machinery due to the possible occurrence of effects such as confusion, drowsiness, dizziness, hallucinations, visual disturbances, or seizures. The effects of alcohol are enhanced by opioid analgesics.

Dosage and Administration.

Pentalgin-FS should be taken orally. For adults and children aged 12 years and older, Pentalgin-FS is administered as a single dose of 1 tablet for short-term pain relief. For prolonged pain syndromes (neuralgia, arthralgia, myalgia) and severe conditions, administer 1 tablet 3 times daily. The duration of therapy should generally not exceed 5 days when used as an analgesic and 3 days when used as an antipyretic.

Maximum daily dose – 3 tablets.

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 monoproducts) (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 related to 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 due to the risk of developing obstructive sleep apnea and other serious and life-threatening adverse reactions (see sections "Contraindications", "Special Warnings and Precautions for Use").

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 for Use").

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 for Use").

Overdose.

Symptoms of sodium metamizole overdose: nausea, vomiting, dysphagia, gastralgia/gastritis, hypothermia, palpitations, tachycardia, dyspnea, tinnitus, oliguria, anuria, weakness, drowsiness, delirium, impaired consciousness, convulsive syndrome, possible development of acute agranulocytosis, hemorrhagic syndrome, acute renal and hepatic failure, paralysis of respiratory muscles.

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

Paracetamol overdose. If a patient has taken a dose exceeding the recommended amount, immediate medical attention is required due to the risk of liver damage. Liver injury may occur in adults who have ingested 10 g or more of paracetamol, and in children who have ingested more than 150 mg/kg body weight. Ingestion of 5 g or more of paracetamol may lead to liver damage in patients with risk factors (chronic use of carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John's wort, or other drugs inducing liver enzymes; chronic excessive alcohol consumption; glutathione system deficiency, e.g., eating disorders, HIV infection, fasting, cystic fibrosis, cachexia).

Symptoms of paracetamol overdose within the first 24 hours: pallor, nausea, vomiting, loss of appetite, and abdominal pain. Liver damage may become evident 12–48 hours after overdose. Glucose metabolism disturbances and metabolic acidosis may occur. In severe poisoning, hepatic 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 damage. Cardiac arrhythmias and pancreatitis have also been reported.

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

In case of overdose, prompt medical assistance is required. The patient should be immediately transported to a hospital, even if early symptoms of overdose are absent. Symptoms may be limited to nausea and vomiting or may not reflect the severity of overdose or risk of organ damage.

Treatment: Activated charcoal should be considered if the excessive dose of paracetamol was ingested within the past hour. Plasma paracetamol concentration should be measured 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be administered within 24 hours after paracetamol ingestion, but maximum protective effect is achieved when administered within 8 hours. The efficacy of the antidote decreases significantly after this time. If necessary, intravenous N-acetylcysteine should be administered according to current guidelines. In the absence of vomiting, oral methionine may be used as an alternative in remote areas outside hospital settings.

Symptoms of caffeine overdose: nervousness, restlessness, insomnia, excitement, irritability, affective state, anxiety, dizziness, tremor, muscle twitching, convulsions, tinnitus, facial flushing, hyperthermia, rapid breathing, increased frequency of urination, gastrointestinal disturbances, epigastric pain, vomiting, arrhythmias (including tachycardia, extrasystoles), psychomotor agitation. Clinically significant symptoms of caffeine overdose may also be associated with paracetamol-induced liver injury.

Treatment: In case of caffeine overdose, administration of β-adrenoreceptor antagonists may alleviate cardiotoxic effects.

Symptoms of phenobarbital overdose: nausea, headache, ataxia, nystagmus, weakness, respiratory depression with risk of respiratory arrest, cardiovascular depression including arrhythmias, decreased arterial blood pressure up to collapse, bradycardia, hypothermia, reduced diuresis, CNS depression progressing to coma.

Treatment: gastric lavage, symptomatic therapy (primarily monitoring of vital functions such as respiration, pulse, and blood pressure).

Codeine overdose. Severe CNS depression, including respiratory depression, may occur with concomitant use of other sedative agents (including alcohol) or significant overdose. The clinical triad of opioid overdose includes coma, pinpoint pupils, and respiratory depression (which may lead to cyanosis), followed by pupil dilation as hypoxia develops. Other symptoms of opioid overdose: hypothermia, confusion, convulsions (especially in children), severe dizziness, marked drowsiness, arterial hypotension and tachycardia (possible but unlikely), nervousness or restlessness, emotional excitement, hallucinations, bradycardia, circulatory failure, slow or labored breathing, profound weakness. Dyspnea, apnea, collapse, and urinary retention may occur; pulmonary edema is rare; signs of histamine release may be observed. Cases of rhabdomyolysis progressing to renal failure have been reported in opioid overdose.

Overdose effects are potentiated by concomitant alcohol and psychotropic drug use.

Treatment: general symptomatic and supportive measures, including actions to support the respiratory center and monitoring of vital signs until stabilization.

Administration of activated charcoal is advisable if less than 1 hour has passed since ingestion of codeine in adults at doses exceeding 350 mg or in children at doses exceeding 5 mg/kg body weight. Naloxone should be administered in cases of coma or respiratory depression. Naloxone is a competitive antagonist with a short half-life; therefore, repeated administration of high doses may be necessary in patients with severe poisoning. The patient should be observed for at least 4 hours after naloxone administration or at least 8 hours if a prolonged-release naloxone formulation has been used.

Adverse Reactions

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

Nervous system disorders: increased intracranial pressure, headache, dizziness, impaired motor coordination, ataxia, tremor, seizures (especially in children), hyperkinesia (in children), slowed reaction time, weakness, asthenia, somnolence, insomnia (in children and elderly patients), development of tolerance or dependence.

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

Ear and labyrinth disorders: vertigo.

Psychiatric disorders: cognitive disturbances (including reduced attention, hallucinations), nightmares, paradoxical excitation, increased irritability, restlessness, anxiety, irritability, confusion, sudden mood changes, euphoria, dysphoria, depression.

Gastrointestinal disorders: anorexia, dry mouth, epigastric heaviness or pain, nausea, vomiting, diarrhea or constipation, development of paralytic ileus, gastric spasms, pancreatitis.

Hepatobiliary disorders: hepatitis, drug-induced liver injury, including acute hepatitis, jaundice, elevated liver enzymes (see section "Special precautions for use").

Metabolism and nutrition disorders: anorexia, metabolic acidosis with high anion gap.

Cardiovascular disorders: chest tightness, orthostatic hypotension, arterial hypotension, collapse, arterial hypertension, arrhythmias (tachycardia or bradycardia, extrasystoles, etc.), palpitations, facial skin hyperemia.

Blood and lymphatic system disorders: enlarged lymph nodes, leukopenia, granulocytopenia, thrombocytopenia, agranulocytosis, leukocytosis, lymphocytosis, anemia (including hemolytic anemia, megaloblastic anemia), sulfhemoglobinemia, methemoglobinemia (cyanosis, dyspnea, chest pain), bleeding, bruising.

Respiratory system disorders: bronchospasm in patients sensitive to acetylsalicylic acid and other NSAIDs, dyspnea, shortness of breath, respiratory depression (with high-dose administration).

Renal and urinary disorders: interstitial nephritis, urinary tract spasm, difficulty urinating, urinary retention, oliguria, anuria, dysuria, antidiuretic effect, increased urine output, red discoloration of urine, proteinuria, increased creatinine clearance, increased excretion of sodium and calcium, aseptic pyuria.

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

Endocrine disorders: hypoglycemia up to hypoglycemic coma, hyperglycemia.

Immune system disorders: anaphylaxis, hypersensitivity reactions, including skin pruritus, skin and mucous membrane rashes (usually generalized, erythematous, urticarial), maculopapular rash (considered a symptom of hypersensitivity syndrome associated with oral codeine administration), angioedema, dyspnea, bronchospasm provocation, shortness of breath (including tachypnea), fever, splenomegaly and lymphadenopathy, conjunctivitis.

Skin and subcutaneous tissue disorders: photosensitization, facial flushing, exfoliative dermatitis, allergic reactions such as rash, urticaria, pruritus, increased sweating, facial swelling, Stevens–Johnson syndrome (including other forms of erythema multiforme), toxic epidermal necrolysis (Lyell’s syndrome), drug-induced eosinophilia with systemic symptoms (DRESS syndrome).

Musculoskeletal and connective tissue disorders: uncontrolled muscle movements, muscle rigidity (with high-dose administration); prolonged use may impair osteogenesis and lead to rickets.

General disorders: malaise, increased fatigue, hypothermia or hyperthermia.

Prolonged use of the drug for headache treatment may lead to worsening of headache.

Prolonged uncontrolled use of high doses may result in seizures, respiratory depression, liver function impairment, hypoglycemia up to hypoglycemic coma, development of dependence (reduced analgesic effect), and withdrawal syndrome.

Prolonged use of phenobarbital may lead to drug dependence, folate deficiency, and impotence.

Prolonged use of codeine typically leads to tolerance and some of the most common adverse effects — somnolence, nausea, vomiting, confusion.

Regular prolonged 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 codeine discontinuation; therefore, re-administration of a previously tolerated dose may be fatal.

Metabolic acidosis with high anion gap

Cases of metabolic acidosis with high anion gap as a result of pyroglutamic acidosis have been observed in patients with risk factors who used paracetamol (see section "Special precautions for use"). In such patients, pyroglutamic acidosis may occur as a consequence of low glutathione levels.

Withdrawal syndrome

Abrupt discontinuation of phenobarbital may typically lead to withdrawal syndrome, characterized by nightmares and nervousness.

Sudden cessation of codeine therapy may cause withdrawal syndrome. Possible symptoms include: 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 adverse effects occur, patients should consult a physician regarding further use of the drug.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the drug. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store in a place inaccessible to children, in the original packaging at a temperature not exceeding 25 °C.

Packaging. 10 tablets in a blister; 1 blister per cardboard pack.

Prescription status. Prescription only.

Manufacturer. LLC "Pharma Start".

Manufacturer's address and location of business activity.

8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine.

If adverse effects occur or if you have any questions regarding the safety of the drug, please contact the Pharmacovigilance Department of LLC "ASINO UKRAINA" at: 8 Vatslava Havela Boulevard, Kyiv, 03124, tel/fax: +38 044 281 2333