Pentased

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PENTASED (PENTASED)

Composition:

Active substances: 1 tablet contains Paracetamol DS 90 % calculated as paracetamol 210 mg, propyphenazone 210 mg, caffeine 50 mg, phenobarbital 20 mg, codeine phosphate 10 mg;

Excipients: microcrystalline cellulose; maize starch; lactose monohydrate; magnesium stearate; sodium croscarmellose; sodium lauryl sulfate; polyethylene glycol 4000; talc; colloidal anhydrous silicon dioxide.

Pharmaceutical form. Tablets.

Main physicochemical properties: tablets of white or white with creamy shade, flat surface, with bevel and score line.

Pharmacotherapeutic group. Analgesics and antipyretics. Propyphenazone, combinations with psycholeptics. ATC code N02B B74.

Pharmacological Properties

Pharmacodynamics

An analgesic and antipyretic agent. The pharmacological effects of the drug are determined by the properties of its active ingredients.

Paracetamol is a non-narcotic analgesic that exerts analgesic and antipyretic effects due to inhibition of prostaglandin synthesis and other mediators of pain and inflammation, primarily in the central nervous system. It reduces the excitability of the hypothalamic thermoregulatory center.

Propyphenazone produces pronounced analgesic and antipyretic effects related to blockade of prostaglandin synthesis, mainly in the central nervous system; at high doses, it also exhibits anti-inflammatory and moderate spasmolytic effects.

Codeine has analgesic activity due to stimulation of opioid receptors in various regions of the central nervous system and peripheral tissues, resulting in activation of the antinociceptive system and reduced emotional perception of pain. It also produces central antitussive effects by suppressing excitability of the cough center.

Phenobarbital exerts a depressant effect on the central nervous system, providing sedative, hypnotic, and some myorelaxant actions, and reduces emotional response to pain sensations.

Caffeine stimulates psychomotor centers in the brain, has analeptic activity, enhances the effect of analgesics, relieves drowsiness and fatigue, and increases physical and mental performance.

Pharmacokinetics

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

Caffeine is well absorbed throughout the intestinal tract. It is metabolized in the liver. Excreted in urine (10% unchanged).

Phenobarbital is completely but slowly absorbed. It is metabolized in the liver and induces hepatic microsomal enzymes. The elimination half-life is 3–4 days. It is excreted by the kidneys as inactive metabolites, with 25–50% excreted unchanged. It readily crosses the placenta.

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 (lungs, liver, kidneys, and spleen). In the body, codeine is hydrolyzed by tissue esterases (with cleavage of the methyl group), followed by conjugation in the liver with glucuronic acid. Codeine metabolites possess their own analgesic activity. Codeine is excreted mainly in the form of metabolites in urine; a significantly smaller portion of metabolites conjugated with glucuronic acid is excreted in bile. In patients with renal insufficiency, accumulation of these active metabolites may occur, leading to a prolonged duration of drug action.

Propyphenazone is rapidly and completely absorbed after oral administration.

Propyphenazone is metabolized primarily in the liver, forming the main metabolite N-desmethylpropyphenazone.

The administered dose of propyphenazone is excreted in urine predominantly as glucuronic acid conjugates.

Propyphenazone crosses the placenta and is also excreted in breast milk.

In hepatic and renal insufficiency, metabolism and elimination of propyphenazone may be impaired.

Clinical characteristics.

Indications.

Mild to moderate pain of various origins: headache, toothache, neuralgia, muscle pain, joint pain, menstrual pain. Fever associated with colds and influenza.

Contraindications.

Individual hypersensitivity to the components of the drug, as well as to pyrazolone or related compounds (containing phenazone, propyphenazone, aminophenazone, metamizole), acetylsalicylic acid, phenylbutazone, opioid analgesics. Severe hepatic and/or renal insufficiency, glucose-6-phosphate dehydrogenase deficiency, anemia, leukopenia, granulocytopenia, agranulocytosis, respiratory disorders with dyspnea and obstructive syndrome (including bronchial asthma); conditions associated with respiratory depression; intracranial hypertension, arterial hypertension, severe arterial hypotension, acute myocardial infarction, alcohol intoxication, alcoholism, glaucoma; sleep disturbances and increased excitability, acute porphyria; congenital hyperbilirubinemia, drug or substance dependence (including in medical history), pancreatitis, diabetes mellitus, benign prostatic hyperplasia; blood disorders; organic cardiovascular diseases (decompensated heart failure, cardiac conduction disorders, severe atherosclerosis, tendency to vascular spasm, ischemic heart disease); epilepsy, hyperthyroidism; depression and/or depressive disorders with suicidal tendencies, myasthenia, advanced age; head trauma, postoperative period after biliary tract surgery. Do not use concomitantly with monoamine oxidase inhibitors (MAOIs) or within 2 weeks after discontinuation of MAOIs; contraindicated in patients taking tricyclic antidepressants or β-blockers.

Interaction with other medicinal products and other types of interactions.

When used simultaneously with drugs that depress the central nervous system (sedatives, hypnotics, tranquilizers, muscle relaxants, alcohol), mutual enhancement of adverse effects is possible (CNS depression, respiratory center depression, development of hypotension).

Concomitant use with microsomal oxidation inducers (barbiturates, carbamazepine, phenytoin, nicotine, rifampicin, salicylamide), tricyclic antidepressants, or alcohol consumption significantly increases the risk of hepatotoxic effects.

Concomitant use with products containing paracetamol may lead to paracetamol overdose. Concurrent use of paracetamol with hepatotoxic agents (alcohol, phenytoin, carbamazepine, isoniazid, and rifampicin) increases the toxic effects of these drugs on the liver. Paracetamol reduces the efficacy of diuretics. The absorption rate of paracetamol may be increased by domperidone.

Caution is advised when using paracetamol concomitantly with flucloxacillin, as such combined use has been associated with metabolic acidosis with a high anion gap due to pyroglutamic acidosis, particularly in patients with risk factors (see section "Special precautions").

Concomitant use with oral anticoagulants (acenocoumarol, warfarin) or nonsteroidal anti-inflammatory drugs may lead to gastrointestinal adverse effects.

The anticoagulant effect of warfarin and other coumarins may be enhanced during long-term, regular daily use of paracetamol, increasing the risk of bleeding. Occasional use has no significant effect.

Concomitant use of caffeine with:

• MAO inhibitors, furazolidone, procarbazine, and selegiline may cause dangerous cardiac arrhythmias or marked increase in blood pressure;
• barbiturates, primidone, anticonvulsants (hydantoin derivatives, especially phenytoin) – enhanced metabolism and increased clearance of caffeine;
• ketoconazole, disulfiram, ciprofloxacin, norfloxacin, enoxacin, pipemidic acid – slowed elimination and increased plasma concentration of caffeine;
• fluvoxamine – increased plasma levels of caffeine;
• mexiletine – reduced elimination of caffeine by 50%;
• nicotine – increased elimination rate of caffeine;
• methoxsalen – reduced elimination of caffeine from the body, potentially leading to enhanced effects and toxic reactions;
• clozapine – increased blood concentration of clozapine;
• beta-adrenergic blockers – mutual suppression of therapeutic effects;
• calcium-containing preparations – reduced absorption of these drugs.

Beverages and medicinal products containing caffeine, when used concomitantly with this drug, may cause excessive stimulation of the central nervous system.

Caffeine enhances the action (improves bioavailability) of analgesic-antipyretic agents, potentiates the effects of xanthine derivatives, α- and β-adrenergic agonists, psychostimulants, and MAO inhibitors (furazolidone, procarbazine, selegiline).

Caffeine reduces the effectiveness of anxiolytics, hypnotics, and sedatives; it acts as an antagonist of anesthetic agents and other drugs that depress the CNS, and as a competitive antagonist of adenosine and ATP preparations. Concurrent use of caffeine with ergotamine improves absorption of ergotamine from the gastrointestinal tract; with thyroid-stimulating agents – enhances thyroid effect. Caffeine reduces blood lithium concentration. Hormonal contraceptives and isoniazid enhance the effects of caffeine.

Codeine may suppress the effects of metoclopramide and domperidone on gastrointestinal motility. Codeine may enhance the effects of drugs that depress the central nervous system (including alcohol, anesthetics, hypnotics, sedatives, tricyclic antidepressants, phenothiazine tranquilizers), although this interaction has no clinical significance when recommended doses of the drug are used.

Phenobarbital induces liver enzymes and thus may accelerate the metabolism of certain drugs metabolized by these enzymes (including indirect anticoagulants, cardiac glycosides, antimicrobial, antiviral, antifungal, antiepileptic, anticonvulsant, oral hypoglycemic, hormonal, immunosuppressive, cytostatic, antiarrhythmic, antihypertensive agents). Phenobarbital enhances the effects of analgesics, local anesthetics, and drugs that depress the central nervous system (anesthetics, neuroleptics, tranquilizers), and alcohol.

Concomitant use of phenobarbital with other drugs exhibiting sedative properties leads to enhanced sedative-hypnotic effects and may be accompanied by respiratory depression. Acidic agents (ascorbic acid, ammonium chloride) enhance the effects of barbiturates. Possible influence on blood concentrations of phenytoin, as well as carbamazepine and clonazepam. MAO inhibitors prolong the effects of phenobarbital.

Rifampicin may reduce the effect of phenobarbital. Concurrent use with gold preparations increases the risk of kidney damage.

Long-term concomitant use with nonsteroidal anti-inflammatory drugs carries a risk of gastric ulceration and bleeding.

Concomitant use of phenobarbital with zidovudine enhances the toxicity of both drugs. Phenobarbital may accelerate the metabolism of oral contraceptives, leading to loss of contraceptive efficacy.

Long-term use of anticonvulsants may reduce the effectiveness of paracetamol.

Repeated administration of paracetamol may enhance the effects of anticoagulants (dicoumarol derivatives).

Concomitant use with antiarrhythmic agents: phenobarbital enhances the hypotensive effect of sotalol and accelerates the metabolism of mexiletine.

Propyphenazone may enhance the effects of oral antidiabetic agents, sulfonamide drugs, anticoagulants, and the ulcerogenic effect of corticosteroids.

The effectiveness of the drug may be reduced when used concomitantly with cholestyramine, cholinolytics, antidepressants, and alkaline substances.

Paracetamol accelerates the elimination of chloramphenicol; metoclopramide accelerates the absorption of paracetamol.

Caffeine accelerates the absorption of ergotamine.

Special precautions for use

Consult a physician regarding the possibility of using the medicine in patients with impaired kidney or liver function. Consult a physician before using the medicine if the patient is taking warfarin or similar agents with anticoagulant effects.

Cases of high anion gap metabolic acidosis (HAGMA) due to 5-oxoprolinuria (pyroglutamic acidosis) have been reported in patients with severe conditions such as severe renal insufficiency and sepsis, or in patients with malnutrition or other causes of glutathione deficiency (e.g., chronic alcoholism) who were treated with therapeutic doses of paracetamol over a prolonged period or with a combination of paracetamol and flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol is recommended, along with careful monitoring of the patient. Measurement of urinary 5-oxoproline levels may be useful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.

The risk of developing Stevens-Johnson syndrome and Lyell’s syndrome is highest during the first weeks of treatment.

Use with caution in patients with peptic ulcer disease of the stomach and duodenum (in the acute phase), in patients with pollen allergies, and in elderly patients.

Excessive consumption of caffeine-containing products (coffee, tea) during treatment may cause symptoms of overdose.

Prolonged uncontrolled use of the drug in high doses may lead to tolerance (reduced analgesic effect), drug dependence (due to the presence of codeine), and renal and/or hepatic insufficiency.

If treatment lasts more than 7 days, monitoring of peripheral blood parameters and liver function (liver transaminase activity) is required.

The drug may alter the results of doping control tests in athletes and may complicate the diagnosis of "acute abdomen." Alcohol consumption must be avoided during treatment.

Avoid prolonged use of the drug due to the risk of accumulation and dependence; withdrawal syndrome may occur. Use with caution in patients with hyperkinesia, hyperthyroidism, adrenal insufficiency, severe hypotension, decompensated heart failure, acute or persistent pain, acute drug intoxication, and inflammatory or obstructive gastrointestinal disorders. The risk of neutropenia and agranulocytosis is primarily associated with the presence of propiphenazone. If such a reaction occurs after taking the drug (elevated temperature, sore throat, oral ulcers and abscesses, perianal abscesses, and/or decreased granulocyte count in blood), the drug should be discontinued immediately. These adverse effects are usually reversible and disappear within 1–2 weeks. Note that patients with alcoholic liver damage have an increased risk of hepatotoxic effects of paracetamol; the drug may affect laboratory test results for blood glucose and uric acid levels.

Patients who take analgesics daily for mild forms of arthritis should consult a physician.

Do not exceed the recommended doses.

Do not take the drug with other products containing paracetamol.

If symptoms persist, consult a physician.

If headache becomes persistent, consult a physician.

During treatment with this medicine, it is not recommended to consume excessive amounts of beverages containing caffeine (such as coffee, tea), as this may lead to sleep disturbances, tremor, and discomfort behind the sternum due to palpitations.

This medicinal product contains lactose and therefore should not be used in patients with galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption syndrome (a rare hereditary condition).

Use during pregnancy or breastfeeding

The medicine should not be used during pregnancy or breastfeeding.

Ability to affect reaction speed when driving or operating machinery

During treatment with this medicine, patients should refrain from engaging in potentially hazardous activities requiring high concentration, mental alertness, and rapid psychomotor reactions.

Dosage and Administration.

For adults, administer 1-2 tablets 1-3 times daily, preferably after meals, taken with a small amount of water.

For children aged 12 years and older, administer ½-1 tablet 1-2 times daily.

The maximum daily dose is 6 tablets (in 3-4 divided doses) for adults and 3 tablets for children aged 12 years and older.

The duration of treatment depends on therapeutic efficacy and response, usually not exceeding 5 days when treating pain syndrome and not more than 3 days when treating fever.

Children. Use in children aged 12 years and older.

Overdose.

In case of overdose, each active ingredient may cause specific symptoms. Overdose is usually caused by paracetamol.

In patients with risk factors (long-term use of carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, or other drugs inducing liver enzymes; alcohol abuse; glutathione system deficiency, e.g., due to malnutrition, AIDS, fasting, cystic fibrosis, cachexia), ingestion of 5 g or more of paracetamol may lead to liver damage.

Symptoms: exceeding recommended doses may cause nausea, vomiting, gastralgia, increased sweating, pallor, tachycardia, arrhythmia, respiratory center depression, disorientation, arterial hypotension, anorexia, abdominal pain, hepatonecrosis, elevated liver transaminase activity, prolonged prothrombin index. It should be noted that paracetamol administration in doses exceeding 6 g may cause severe liver injury. Liver damage may manifest 12–48 hours after overdose. Disorders of glucose metabolism and metabolic acidosis may occur. In severe poisoning, liver failure may progress and lead to toxic encephalopathy with impaired consciousness, in some cases resulting in death. Acute renal failure with acute tubular necrosis may develop even in the absence of severe kidney injury. Cardiac arrhythmias have also been reported. Liver injury is possible in adults who have taken 10 g or more of paracetamol, and in children who have ingested more than 150 mg/kg body weight. High doses of caffeine may cause epigastric pain, vomiting, increased diuresis, rapid breathing, extrasystoles, tachycardia, or cardiac arrhythmia; and may affect the central nervous system (loss of consciousness, insomnia, nervous excitement, irritability, emotional lability, anxiety, tremor, seizures). Overdose of propyphenazone may cause CNS damage (seizures, coma). In case of phenobarbital overdose, possible symptoms include nausea, ataxia, nystagmus, respiratory depression up to respiratory arrest, headache, tachycardia, weakness, cardiovascular depression, including rhythm disturbances, decreased arterial pressure, up to collapse-like state. High doses of the drug may cause decreased body temperature, slowed pulse, reduced diuresis, CNS depression, up to coma.

In severe poisoning, liver failure may progress to encephalopathy, hemorrhages, hypoglycemia, coma, and may be fatal. Acute renal failure with acute tubular necrosis may present as severe lumbar pain, hematuria, proteinuria, and may develop even without severe liver injury. Cardiac arrhythmias and pancreatitis have also been reported.

In case of codeine overdose, acute respiratory center depression may occur, manifesting as cyanosis, slowed breathing, drowsiness, rarely pulmonary edema; dyspnea, apnea, arterial hypotension, seizures, and urinary retention may also develop.

Treatment: in case of paracetamol overdose, immediate medical assistance is required. The patient must be taken to hospital immediately. Symptoms may be limited to nausea and vomiting or may not reflect the severity of overdose or risk of organ damage. Administration of activated charcoal should be considered if excessive paracetamol dose was taken within the last hour. Paracetamol plasma concentration should be measured 4 hours or later after ingestion (earlier concentrations are unreliable).

Antidotes for paracetamol are acetylcysteine and methionine. Treatment with N-acetylcysteine 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 sharply decreases 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.

Treatment for codeine overdose: symptomatic therapy, including measures to support respiratory function: monitoring of vital signs (pulse, respiration, body temperature, blood pressure). Administer naloxone in case of coma or respiratory depression. The patient should be observed for at least 4 hours after administration or 8 hours in cases requiring supportive therapy.

Adverse reactions.

Discontinue use of the medicine and seek immediate medical attention if adverse reactions occur.

Therapeutic doses of the medicine are generally well tolerated. Adverse reactions are mainly due to the presence of paracetamol in the formulation.

Concurrent use of the medicine at recommended doses with products containing caffeine may intensify caffeine-related adverse effects such as dizziness, increased excitability, insomnia, restlessness, anxiety, irritability, headache, gastrointestinal disturbances, and tachycardia.

Gastrointestinal system: nausea, vomiting, constipation, feeling of heaviness and pain in the epigastric region; with prolonged use at high doses, hepatotoxic effects may develop, including hepatonecrosis (a dose-dependent effect), dyspepsia, heartburn, dry mouth, oral mucosal ulcers, acute pancreatitis in patients with a history of cholecystectomy.

Hepatobiliary system: liver function disturbances, including liver failure (hepatotoxicity is usually associated with paracetamol overdose), increased liver enzyme activity, jaundice.

Metabolism and nutrition: frequency "unknown" – 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"). Pyroglutamic acidosis may occur due to low glutathione levels in these patients.

Nervous system: dizziness, drowsiness, reduced speed of mental and motor reactions, impaired attention concentration, psychomotor excitation and disorientation, paradoxical excitation, headache, tremor, paresthesia, anxiety, fear sensation, irritability, sleep disturbances, insomnia, confusion, euphoria, dysphoria, hallucinations, anxiety, sedative state; with prolonged use at high doses, dependence may develop; ataxia, impaired motor coordination, nystagmus, increased fatigue, cognitive disorders, general weakness, depression, hyperkinesia (in children).

Cardiovascular system: palpitations, tachycardia, changes in blood pressure, arterial hypotension, arrhythmia, bradycardia, chest pain.

Blood and lymphatic system: anemia, including megaloblastic and hemolytic anemia, bruising or bleeding; sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), leukopenia, granulocytopenia, agranulocytosis, leukocytosis, lymphocytosis. With prolonged use at high doses – aplastic anemia, pancytopenia, agranulocytosis, neutropenia, thrombocytopenia.

Urinary system: urinary retention, kidney function disturbances, renal colic, interstitial nephritis, papillary necrosis. With prolonged use at high doses, nephrotoxic effects may develop (renal colic, interstitial nephritis, papillary necrosis).

Immune system: anaphylaxis, hypersensitivity reactions, including skin itching, skin and mucous membrane rashes (usually generalized, erythematous rash, urticaria), angioneurotic edema, multiform exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).

Skin and subcutaneous tissues: exfoliative dermatitis, purpura, allergic dermatitis, hemorrhages, photosensitization.

Respiratory system: bronchospasm in patients sensitive to NSAIDs.

Other: hypoglycemia, up to hypoglycemic coma, miosis, increased sweating; with prolonged use, there is a risk of impaired osteogenesis, folate deficiency, impotence, withdrawal syndrome, which usually may occur after abrupt discontinuation of the medicine and is accompanied by nightmares, nervousness, increased body temperature, enlarged lymph nodes, and breathing difficulties.

Shelf life.

2 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 cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Limited liability company "Kharkiv Pharmaceutical Enterprise "Zdorov'ya Narodu".

Manufacturer's address and location of business activity.

Ukraine, 61002, Kharkiv region, city of Kharkiv, Kulikovska Street, building 41.