Pentalgin fs extra capsules
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PENTALGIN PS EXTRA CAPSULES (pentalgin ps extra capsules)
Composition:
Active substances: paracetamol, metamizole sodium monohydrate, caffeine, phenobarbital, codeine phosphate hemihydrate;
1 capsule contains paracetamol 150 mg, metamizole sodium monohydrate 150 mg, caffeine
25 mg, phenobarbital 5 mg, codeine phosphate hemihydrate calculated as codeine phosphate 4 mg;
Excipients: potato starch, povidone, stearic acid, calcium stearate;
Capsule shell composition: gelatin, titanium dioxide (E 171).
Pharmaceutical form. Capsules.
Main physicochemical characteristics: hard gelatin capsules with white cap and body. The contents of the capsules are a fine granular mass of white or yellowish-white color. Presence of compressed columns or lumps which disintegrate upon pressure is acceptable.
Pharmacotherapeutic group.
Analgesics and antipyretics. Metamizole sodium in combination with psychotropic agents. ATC code N02BB72.
Pharmacological properties.
Pharmacodynamics.
The drug exerts analgesic, antipyretic, anti-inflammatory, spasmolytic, and sedative effects. Pentalgin FS Extra capsules are a combination drug that combines the properties of active ingredients.
Metamizole sodium and paracetamol are non-opioid analgesics that exert pronounced anti-inflammatory and antipyretic effects and possess analgesic activity.
Codeine phosphate enhances the effect of non-opioid analgesics (by blocking opioid receptors, stimulating the antinociceptive system, and altering 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-opioid analgesics, thereby contributing to the enhancement of therapeutic effect.
Phenobarbital exerts a sedative effect.
Pharmacokinetics.
The pharmacokinetics of the combination drug Pentalgin FS Extra capsules 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 the components of the drug; severe impairment of liver and/or kidney function; postoperative period after surgery on the biliary tract; active peptic ulcer disease of the stomach or duodenum; conditions in which inhibition of peristalsis should be avoided or in which abdominal distension develops; risk of paralytic ileus; congenital hyperbilirubinemia; pulmonary insufficiency; conditions associated with respiratory depression; acute respiratory depression, respiratory diseases with dyspnea, obstructive syndrome; bronchial asthma in the acute phase (opioids should not be used during an asthma attack); agranulocytosis in history caused by metamizole, other pyrazolones or pyrazolidines; bone marrow dysfunction or blood-forming system disorders and blood diseases, including leukopenia (including cytostatic and infectious neutropenia), thrombocytopenia; Gilbert's syndrome; acute pancreatitis; severe anemia (including hemolytic); leukopenia; decompensated heart failure; arrhythmia; acute myocardial infarction; arterial hypertension; severe arterial hypotension; organic cardiovascular diseases (including atherosclerosis); thrombosis; thrombophlebitis; 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 status assessment); head trauma; glaucoma; myasthenia; diabetes mellitus; depression, depressive disorders with a tendency towards suicidal behavior, states of increased excitability, sleep disorders, epilepsy; porphyria; hyperthyroidism; glucose-6-phosphate dehydrogenase deficiency; drug or alcohol dependence; alcohol intoxication; suspicion of acute surgical pathology before diagnosis is established; elderly age.
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 development of 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 with monoamine oxidase inhibitors (MAOIs) or within 2 weeks after discontinuation of MAOIs.
Interaction with other medicinal products and other forms of interaction.
When Pentagin FS extra capsules are used concomitantly with agents that have a depressant effect on the central nervous system (CNS), an increased sedative effect and respiratory center depression may occur. Barbiturates reduce the antipyretic effect of paracetamol. Long-term use of anticonvulsant drugs (including phenytoin, barbiturates, carbamazepine), which stimulate hepatic microsomal enzyme activity, may reduce the efficacy of paracetamol and enhance paracetamol's hepatotoxic effects due to increased conversion into hepatotoxic metabolites. Concurrent use of paracetamol with hepatotoxic agents increases the hepatotoxic effects of the drugs. Simultaneous use of high doses of paracetamol with isoniazid increases the risk of hepatotoxic syndrome. Paracetamol reduces the activity of diuretics. The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol, increasing the risk of bleeding; occasional use does not have a significant effect. The absorption rate of paracetamol may be increased by metoclopramide and domperidone and decreased by cholestyramine. Do not use simultaneously with alcohol. Paracetamol may reduce the bioavailability of lamotrigine, potentially reducing its efficacy due to possible induction of its hepatic metabolism. Concurrent use of paracetamol and zidovudine increases the risk of neutropenia. Caution should be exercised when using paracetamol concomitantly with flucloxacillin, as concurrent use 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").
Sodium metamizole, by displacing from protein binding oral hypoglycemic agents, indirect anticoagulants, phenytoin, ibuprofen, glucocorticosteroids, and indomethacin, increases their activity. Tricyclic antidepressants, non-narcotic analgesics, oral contraceptives, allopurinol impair the metabolism of sodium metamizole in the liver and increase its toxicity. Histamine H2-blockers, propranolol, codeine, sedatives, and tranquilizers (diazepam, trimethozine) enhance the effect of sodium metamizole, while phenylbutazone, glutethimide, barbiturates, and other inducers of hepatic microsomal enzymes reduce it. Myelotoxic medicinal products increase hematotoxicity. Sarcolysin, thiamazole, and drugs that suppress bone marrow activity, including gold preparations, when used with sodium metamizole, increase the likelihood of hematotoxicity, including the development of leukopenia. Sodium metamizole enhances the sedative effect of ethanol. X-ray contrast agents, colloidal plasma substitutes, and penicillin should not be used during treatment with sodium metamizole. Concurrent use of sodium metamizole with chlorpromazine or phenothiazine may lead to the development of pronounced hyperthermia.
Pharmacokinetic induction of metabolic enzymes:
Metamizole may induce metabolic enzymes, including CYP2B6 and CYP3A4.
Combined use of metamizole with bupropion, efavirenz, methadone, valproate, cyclosporine, tacrolimus, or sertraline may result in decreased plasma concentrations of these drugs with potential reduction in clinical efficacy. Therefore, caution is recommended when using them concomitantly with metamizole; clinical response and/or drug levels should be monitored if necessary.
When sodium metamizole is used concomitantly with other nonsteroidal anti-inflammatory drugs (NSAIDs), their analgesic and antipyretic effects are potentiated, and the probability of additive adverse effects increases. Caution is required when using the drug concomitantly with sulfonamide hypoglycemic agents (hypoglycemic effect is enhanced) and diuretics (furosemide). High doses of sodium metamizole may cause an increase in methotrexate plasma concentration and intensification of its toxic effects (primarily on the gastrointestinal tract and hematopoietic system).
Phenobarbital, included in the composition of the drug, is an inducer of hepatic microsomal enzymes and therefore may accelerate the clearance of drugs metabolized in the liver (including paracetamol, salicylates, indirect anticoagulants, cardiac glycosides (digoxin), antimicrobials (chloramphenicol, doxycycline, metronidazole, rifampicin), antivirals, antifungals (griseofulvin, itraconazole), antiepileptics, anticonvulsants, psychotropic drugs (tricyclic antidepressants, clonazepam), oral hypoglycemics, hormones (estrogens, progestogens, corticosteroids, thyroid hormones), immunosuppressants (glucocorticosteroids, cyclosporine), cytostatics, antiarrhythmics, antihypertensives (β-blockers, calcium channel blockers), and other medicinal products). Phenobarbital may accelerate the metabolism of oral contraceptives, leading to loss of their effect.
Phenobarbital enhances the action of analgesics, local anesthetics, and drugs that depress the CNS (anesthetics, neuroleptics, tranquilizers), and alcohol. Concurrent use of phenobarbital with drugs having a sedative effect leads to enhanced sedative-sleeping effect and may be accompanied by respiratory depression. Possible influence of phenobarbital on blood concentrations of phenytoin, carbamazepine, and clonazepam. Medicinal products with acidic properties (ascorbic acid, ammonium chloride) enhance the action of barbiturates. Patients receiving concurrent treatment with valproates and phenobarbital should be monitored for signs of hyperammonemia. In half of the registered 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. Concurrent use of phenobarbital with gold preparations increases the risk of kidney damage. Long-term concurrent use of phenobarbital with NSAIDs carries a risk of gastric ulcer formation and bleeding. Concurrent use of phenobarbital with zidovudine enhances the toxicity of both drugs.
Interactions possibly due to the presence of caffeine: enhanced action of analgesic-antipyretics, ergotamine; reduced effect of opioid analgesics, anxiolytics, hypnotics, and sedatives; acts as an antagonist of anesthetics and other CNS depressants; competitive antagonist of adenosine agents; enhances absorption and action of cardiac glycosides; with xanthine derivatives, α- and β-adrenomimetics, psychostimulants – potentiation of their effects; increased thyroid effect when caffeine is used concomitantly with thyrotropic agents (undesirable interaction with thyroid hormones); cimetidine, hormonal contraceptives, isoniazid enhance the action of caffeine.
Concurrent use of caffeine with MAO inhibitors may cause dangerous elevation of blood pressure. Other medicinal products whose action may be altered by interaction with caffeine: hydroxyzine, mexiletine, ciprofloxacin, enoxacin, pipemidic acid, fluvoxamine, phenylpropanolamine, phenytoin, clozapine, lithium, theophylline, pentobarbital, diazepam, methoxsalen.
Codeine, when used concomitantly with ethanol, enhances its psychotropic effects. Increased risk of intestinal obstruction when used concomitantly with antidiarrheals (loperamide, kaolin), anticholinergic agents (atropine) – risk of severe constipation, which may lead to paralytic intestinal obstruction and/or urinary retention; with antiulcer drugs – cimetidine may inhibit codeine metabolism, leading to increased plasma concentration; enhanced effect of antihypertensive agents. 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 development of withdrawal syndrome. Premedication with opioids should be avoided, as they reduce plasma concentration of ciprofloxacin. Ritonavir and cimetidine increase codeine plasma concentration. Concurrent use of the drug with ethanol and medicinal products containing ethanol significantly increases the risk of liver function impairment due to enhanced hepatotoxicity. Codeine should not be used in combination with MAO inhibitors or within 2 weeks after discontinuation of their use. 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 use, such 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, increased risk of respiratory depression; with antiarrhythmic agents – codeine slows down mexiletine absorption; when codeine and quinidine are used concomitantly, the analgesic effect of codeine is likely to be significantly reduced due to the negative effect of quinidine on its metabolism; avoid premedication with opioids, as they reduce plasma concentration of ciprofloxacin. Concurrent use of mexiletine with codeine slows down mexiletine absorption.
Use of opioids may interfere with gastric emptying studies, as opioids delay gastric emptying, as well as hepatobiliary imaging using Technetium Tc 99m Disofenin, since opioid therapy may cause Oddi sphincter narrowing and increased pressure in the biliary tract.
Special precautions for use.
It is not recommended to use other medicinal products containing paracetamol, sodium metamizole, caffeine, phenobarbital, or codeine simultaneously with Pentagin FS extra capsules.
Alcohol consumption is prohibited during treatment with this medicinal product.
The information below is relevant to the active substances of the medicinal product.
Metamizole
Agranulocytosis
Treatment with metamizole may cause agranulocytosis, which can lead to a fatal outcome (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 seek immediate 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 undetected. Similarly, symptoms may be masked in patients receiving antibiotic therapy.
In the presence of signs and symptoms suggestive of agranulocytosis, a complete blood count (including differential count) should be performed immediately, and treatment should be discontinued until test results are available. 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 identifying 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, which may complicate their diagnosis.
The medicinal product should be used with caution in patients:
- of advanced age – may lead to an increased frequency of adverse reactions, particularly 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 a history of kidney diseases (pyelonephritis, glomerulonephritis);
- with inflammatory bowel diseases, including ulcerative colitis and Crohn’s disease;
- with severe arterial hypotension or cardiovascular insufficiency;
- with a history of chronic alcohol use;
- when used concomitantly with cytotoxic 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 indicated doses. Prolonged use or use of doses significantly exceeding the recommended therapeutic doses may increase the severity of 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 resolves 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-colored urine, pale-colored stools, jaundice of the skin or sclera, pruritus, rash, or upper abdominal pain occur, metamizole should be discontinued and medical advice must 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 may occur (due to excretion of a metabolite of sodium metamizole), which is not clinically significant.
Phenobarbital
Life-threatening skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell’s syndrome), have been reported with phenobarbital use. Therefore, if characteristic symptoms occur (e.g., progressive skin rash, often with blisters, and mucosal lesions), the medicinal product should be discontinued immediately, and barbiturate-containing products must never be used again. 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 drug provide the best 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.
The medicinal product should be used with caution in patients with peptic ulcer disease of the stomach and duodenum in remission, impaired liver or kidney function (see section "Contraindications"), thyroid disorders (including hypothyroidism, see section "Contraindications"), urinary tract diseases, hyperkinesia, chronic respiratory infections, pneumonia, respiratory function disorders, acute drug intoxication, and during treatment with cytostatics (only under medical supervision).
Paracetamol
In patients with liver or kidney disease, consultation with a physician is required before using the medicinal product (see section "Contraindications").
It should be noted that the risk of hepatotoxic effects of paracetamol is increased in patients with liver disease.
Cases of liver function impairment/liver failure have been reported in patients with reduced glutathione levels, such as those with 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 malnutrition or other causes of glutathione deficiency (e.g., chronic alcoholism) treated with paracetamol at therapeutic doses for prolonged periods or in combination with other drugs. In suspected HAGMA due to pyroglutamic acidosis, immediate discontinuation of paracetamol and careful monitoring of the patient’s condition are recommended. Measurement of urinary 5-oxoproline levels may be useful in identifying pyroglutamic acidosis as the primary cause of HAGMA in patients with multiple risk factors.
In patients with reduced glutathione levels, the risk of developing metabolic acidosis increases with paracetamol use. 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 at a reduced dose in patients with asthma or reduced respiratory reserve. Codeine use should be avoided during acute asthma attacks (see section "Contraindications"). Codeine should be used with caution in patients with impaired kidney or liver function, gallbladder diseases (including cholelithiasis), history of drug abuse, respiratory function disorders, or a history of asthma.
The dose of codeine should be reduced in debilitated patients, patients with arterial hypotension (see section "Contraindications"), prostatic hypertrophy, adrenal hypofunction/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 colonic pressure) (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. Caution should be exercised when using the medicinal product in patients with a history of kidney diseases (pyelonephritis, glomerulonephritis). 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 caused by direct 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 have developed physical dependence, treatment discontinuation should be gradual to avoid withdrawal symptoms. Caution is recommended when using paracetamol concomitantly with flucloxacillin due to an increased risk of high anion gap metabolic acidosis, especially in patients with severe renal failure, sepsis, malnutrition, or other causes of glutathione deficiency (e.g., chronic alcoholism), and when maximum daily doses of paracetamol are used. Careful monitoring, including measurement of urinary 5-oxoproline levels, is recommended.
Metabolism via 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 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 at usual 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 ultra-rapid CYP2D6 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 |
| North 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 with compromised respiratory function due to neuromuscular disorders, severe cardiac or respiratory diseases, upper respiratory tract infections or lung infections, multiple trauma, or major surgical procedures. These factors may exacerbate morphine-related toxicity symptoms.
Patients with biliary tract disorders (particularly cholelithiasis) should avoid opioid analgesics or use them in combination with spasmolytics.
The use of pethidine and possibly other opioid analgesics in patients taking MAO inhibitors may lead to severe, sometimes fatal, reactions. If codeine use is essential in patients receiving MAO inhibitors, MAO inhibitors should be discontinued 14 days prior to initiating codeine therapy (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").
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 physician assessment of the benefit-risk ratio.
Caffeine
Excessive consumption of tea, coffee, other stimulant beverages, alcohol, or use of medicinal products containing caffeine is not recommended during treatment with this medicinal product.
Prolonged use of the drug may lead to psychological dependence. Sudden 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 as determined 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 and 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 is contraindicated during pregnancy.
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. The use of opioid analgesics may cause gastric stasis during labor, increasing the risk of aspiration pneumonia in the mother.
Barbiturates increase the risk of fetal abnormalities. Use of phenobarbital 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 is contraindicated during breastfeeding.
When used at normal therapeutic doses, codeine and its active metabolite may be present in breast milk at very low concentrations, unlikely to cause adverse effects in 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 suppress the central nervous system of the infant.
Ability to influence reaction speed when driving or operating machinery.
The use of Pentagin FS Extra capsules may impair performance of tasks requiring high speed of mental and physical reactions (e.g., driving vehicles, operating machinery, or handling instruments). Therefore, 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.
Method of Administration and Dosage.
The medication should be taken orally after meals, with sufficient amount of water. For mild and short-term pain, take 1–2 capsules of Pentalgin FS Extra at a single dose. For prolonged pain syndromes (neuralgia, arthralgia, myalgia) or fever, administer 2 capsules 1–3 times daily. The medication should be taken at intervals of no less than 4 hours between doses and should not be used for more than 5 days as an analgesic or more than 3 days as an antipyretic. Maximum daily dose – 6 capsules.
Children.
The medication is contraindicated in children under 12 years of age. For children aged 12 to 18 years, the medication may be prescribed to relieve acute moderate pain that cannot be controlled by other analgesics such as paracetamol or ibuprofen used as monotherapy.
The use of this medicinal product is contraindicated in children under 12 years of age due to the risk of developing serious and life-threatening adverse reactions caused by the variable and unpredictable metabolism of codeine into morphine in patients of this age group (see section "Contraindications").
Due to the presence of codeine in the formulation, the medication is contraindicated 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 for Use"). Its use is not recommended in children who may have impaired respiratory function.
Codeine should not be administered to 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 may be applied. In case of convulsive syndrome, intravenous administration of diazepam and fast-acting barbiturates may be required.
Paracetamol overdose. Symptoms of overdose within the first 24 hours are generally due to paracetamol and include pallor, anorexia, nausea, vomiting, abdominal pain, hepatonecrosis, elevated liver transaminase activity, and increased prothrombin index. If a patient has ingested a dose exceeding the recommended amount, immediate medical attention is required due to the risk of liver damage. Signs of liver injury typically appear 12–48 hours after overdose. Glucose metabolism disturbances and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress and lead to toxic encephalopathy with impaired consciousness, in some cases resulting in death; hemorrhages, hypoglycemia, and coma are possible. Acute renal failure with acute tubular necrosis may present as severe lumbar pain, hematuria, proteinuria, and may develop even in the absence of severe liver injury. Pancreatitis may also occur. Cardiac arrhythmias have also been reported. Liver damage in adults may occur after ingestion of 10 g or more of paracetamol, and in children after ingestion of more than 150 mg/kg body weight. Liver damage may also result from ingestion of 5 g or more of paracetamol in patients with risk factors (chronic use of carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, or other drugs inducing liver enzymes; alcohol abuse; glutathione deficiency (digestive disorders, cystic fibrosis, HIV infection, starvation)). With prolonged use of the drug at high doses, blood-forming organs may develop aplastic anemia, pancytopenia, neutropenia, agranulocytosis, leukopenia, thrombocytopenia. With large doses, central nervous system effects may include dizziness, psychomotor agitation, and disorientation. Urinary system effects – nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis). Excessive sweating, psychomotor agitation or central nervous system depression, drowsiness, and impaired consciousness may also occur.
In case of paracetamol overdose, prompt medical assistance is required. The patient should be immediately transported to a hospital. Symptoms may be limited to nausea and vomiting or may not reflect the severity of overdose or risk of organ damage.
Treatment. Administration of activated charcoal should be considered if an excessive dose of paracetamol was ingested within the past hour. Plasma paracetamol concentration should be measured at least 4 hours or later after ingestion (earlier concentrations are unreliable).
Paracetamol antidotes are acetylcysteine and methionine. Acetylcysteine treatment may be administered within 24 hours after paracetamol ingestion, but maximum protective effect is achieved when administered within 8 hours after ingestion. The efficacy of the antidote decreases sharply after this time. If necessary, intravenous N-acetylcysteine should be administered according to established dosing regimens. In the absence of vomiting, oral methionine may be used as an alternative in remote areas outside hospital settings. General supportive measures should also be implemented.
Symptoms of caffeine overdose: Large doses of caffeine may cause nervousness, restlessness, epigastric pain, vomiting, diuresis, rapid breathing, extrasystoles, tachycardia or cardiac arrhythmia, muscle twitching, tinnitus, facial flushing, hyperthermia, increased frequency of urination, gastrointestinal disturbances, and effects on the central nervous system (dizziness, insomnia, nervous excitement, irritability, affective state, anxiety, tremor, seizures). Clinically significant symptoms of caffeine overdose may also be associated with liver damage caused by paracetamol.
Treatment. There is no specific antidote for caffeine, but supportive measures such as administration of β-adrenergic antagonists may help alleviate cardiotoxic effects.
Symptoms of phenobarbital overdose: symptoms of phenobarbital overdose include ataxia, nystagmus, headache, tachycardia, weakness, decreased blood pressure, cardiac dysfunction, respiratory depression up to respiratory arrest. High doses of the drug may cause decreased body temperature, bradycardia, reduced diuresis, vascular collapse, CNS depression up to coma.
Treatment: Gastric lavage is required. Oxygen therapy is recommended. In case of seizures, diazepam should be administered. Symptomatic therapy (primarily monitoring of vital functions (respiration, pulse, blood pressure)) is essential.
Codeine overdose. Severe CNS depression, including respiratory depression, may develop 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 cause cyanosis), followed by pupil dilation as hypoxia develops. Other symptoms of opioid overdose: hypothermia, confusion, seizures (especially in children), severe dizziness, pronounced 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 is intensified by concomitant intake of alcohol and psychotropic agents.
Treatment: General symptomatic and supportive measures, including measures 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 8 hours in cases where long-acting naloxone formulations are used.
Side effects.
Allergic reactions in the form of skin rash occur rarely after single use. Usually, adverse effects are temporary and disappear after discontinuation of the drug:
Gastrointestinal system: nausea, dry mouth, epigastric discomfort and pain, diarrhea or constipation, vomiting, heartburn, hypersalivation, decreased appetite, development of paralytic intestinal obstruction, stomach spasms, pancreatitis.
Metabolism and nutrition disorders: metabolic acidosis with high anion gap.
Hepatobiliary system: hepatitis, drug-induced liver injury, including acute hepatitis, jaundice, elevated liver enzymes (see section "Special precautions").
Blood and lymphatic system disorders: enlarged lymph nodes, leukopenia, leukocytosis, lymphocytosis, pancytopenia, neutropenia, granulocytopenia, agranulocytosis, thrombocytopenia, hemorrhagic syndrome (including bruising or bleeding), anemia, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia (in patients with glucose-6-phosphate dehydrogenase deficiency), aplastic anemia, megaloblastic anemia, bleeding, bruising may develop with prolonged use of high doses.
Immune system disorders: anaphylaxis, hypersensitivity reactions, including angioneurotic edema; anaphylactic shock, fever, splenomegaly and lymphadenopathy, conjunctivitis.
Respiratory system: bronchospasm in patients sensitive to acetylsalicylic acid and other NSAIDs, dyspnea, shortness of breath (including tachypnea), respiratory depression (with high-dose use).
Nervous system disorders: dizziness, syncope, drowsiness, sleep disturbances, insomnia in children and elderly patients, tremor, ataxia, seizures (especially in children), paresthesia in extremities, impaired motor coordination, tinnitus, reduced psychomotor reaction speed and attention concentration, slowed reactions, asthenia, fatigue, increased intracranial pressure, headache, hyperkinesia (in children), paradoxical excitation, anxiety; in individual cases – cognitive disorders, confusion, depressive states, hallucinations, development of tolerance or dependence.
Psychiatric disorders: cognitive disorders (including reduced attention concentration, hallucinations), nightmares, paradoxical excitation, increased excitability, restlessness, anxiety, irritability, confusion, sudden mood swings, euphoria, dysphoria, depression.
Ear and labyrinth disorders: vertigo.
Eye disorders: pupil constriction, impaired visual acuity, miosis, photophobia, nystagmus, visual and accommodation disturbances, increased intraocular pressure.
Cardiovascular system: chest tightness, orthostatic hypotension, arrhythmia, tachycardia, bradycardia, extrasystoles, collapse, arterial hypo- or hypertension, chest pain, palpitations, facial skin hyperemia.
Musculoskeletal system: with prolonged use of drugs containing phenobarbital, there is a risk of impaired osteogenesis and rickets development, uncontrolled muscle movements, muscle rigidity (with high-dose use).
Urinary system: with high-dose use – acute renal failure, possible signs of nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis), micturition disorders, urinary tract spasms, difficult urination, urinary retention, oliguria, anuria, dysuria, antidiuretic effect, increased urine output, red discoloration of urine, proteinuria, increased creatinine clearance, increased sodium and calcium excretion, aseptic pyuria.
Skin and mucous membranes: photosensitization, facial flushing, exfoliative dermatitis, allergic reactions such as skin and mucous membrane rashes, maculopapular rash, pruritus, urticaria, multiform exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), drug reaction with eosinophilia and systemic symptoms (DRESS), increased sweating, facial swelling.
Reproductive system: sexual dysfunction, erectile dysfunction, decreased libido and potency.
Endocrine system: hypoglycemia up to hypoglycemic coma, hyperglycemia.
Other: weakness, increased sweating, dyspnea, folate deficiency, withdrawal syndrome.
Prolonged use of the medicinal product for headache treatment may lead to its worsening.
With prolonged uncontrolled use of high doses of the medicinal product, seizures and respiratory depression are possible; liver function impairment, hypoglycemia up to hypoglycemic coma, habituation (reduced analgesic effect), and withdrawal syndrome may develop.
With prolonged use of phenobarbital, drug dependence, folate deficiency, and impotence may develop.
With prolonged use of codeine, tolerance usually develops along with some of the most common side effects – drowsiness, nausea, vomiting, confusion.
Regular prolonged use of codeine leads to dependence and tolerance, and to restlessness and irritability after discontinuation of treatment. It should be remembered that tolerance decreases rapidly after stopping codeine, so re-administering 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"). In such patients, pyroglutamic acidosis may occur as a consequence of low glutathione levels.
Withdrawal syndrome
Withdrawal syndrome, typically accompanied by nightmares and nervousness, may occur upon abrupt discontinuation of phenobarbital.
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, coughing, 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 adverse reactions after medicinal product registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.
Shelf life.
3 years.
The drug must not be used after the expiry date stated on the packaging.
Storage conditions.
Store in the original packaging, out of reach of children, at a temperature not exceeding 25 °C.
Packaging.
10 capsules per blister, 1 or 2 blisters per cardboard box.
Prescription status.
Prescription only.
Manufacturer.
LLC "Pharma Start".
Manufacturer's address and location of business activity.
8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine.