Paracetamol Extratab (Tablets) Instructions for Use

Marketing Authorization Holder

Aliym, JSC (Russia)

Contact Information

ALIUM JSC (Russia)

ATC Code

N02BE51 (Paracetamol in combination with other drugs, excluding psycholeptics)

Active Substances

Ascorbic acid (Rec.INN registered by WHO)

Paracetamol (Rec.INN registered by WHO)

Dosage Form

Paracetamol Extratab

Tablets 500 mg+150 mg: from 5 to 75 pcs.

Dosage Form, Packaging, and Composition

Tablets from white to white with a yellowish tint, biconvex, oblong in shape, with rounded ends, with a score on one side; “slight marbling” is allowed.

Excipients: hypromellose (hydroxypropyl methylcellulose), macrogol 6000 (polyethylene glycol 6000), corn starch, stearic acid.

From 5 to 15 pcs. – contour cell packs (from 1 to 5 pcs.) – cardboard packs.

Clinical-Pharmacological Group

Analgesic-antipyretic

Pharmacotherapeutic Group

Analgesics; other analgesics and antipyretics; anilides

Pharmacological Action

Combined analgesic drug

Paracetamol has analgesic and antipyretic effects.

It blocks COX-1 and COX-2 predominantly in the CNS, affecting the centers of pain and thermoregulation.

In inflamed tissues, cellular peroxidases neutralize the effect of paracetamol on COX, which explains the almost complete absence of an anti-inflammatory effect.

The drug does not have a negative effect on water-salt metabolism (sodium and water retention) and the gastrointestinal mucosa, due to the lack of effect on the synthesis of prostaglandins in peripheral tissues.

The possibility of methemoglobin formation is unlikely.

Ascorbic acid (vitamin C) is not formed in the human body, it comes only with food.

Physiological functions: it is a co-factor of some hydroxylation and amidation reactions – transfers electrons to enzymes, supplying them with a reducing equivalent.

It participates in the hydroxylation of proline and lysine residues of procollagen with the formation of hydroxyproline and hydroxylysine (post-translational modification of collagen), oxidation of lysine side chains in proteins with the formation of hydroxytrimethyllysine (in the process of carnitine synthesis), oxidation of folic acid to folinic acid, metabolism of drugs in liver microsomes and hydroxylation of dopamine to form norepinephrine.

It increases the activity of amidating enzymes involved in the processing of oxytocin, ADH and cholecystokinin.

It participates in steroidogenesis in the adrenal glands.

The main role at the tissue level is participation in the synthesis of collagen, proteoglycans and other organic components of the intercellular substance of teeth, bones and capillary endothelium.

Pharmacokinetics

Paracetamol

Absorption is high. T_max – 0.5-2 h; C_max – 5-20 µg/ml. Plasma protein binding – 15%.

It penetrates the BBB. V_d varies from 0.8 to 1.36 l/kg of body weight.

Less than 1% of the paracetamol dose taken by a nursing mother penetrates into breast milk.

Therapeutically effective plasma concentration of paracetamol is achieved when it is prescribed at a dose of 10-15 mg/kg.

It is metabolized in the liver in three main ways: conjugation with glucuronides, conjugation with sulfates, oxidation by microsomal liver enzymes.

In the latter case, toxic intermediate metabolites are formed, which are subsequently conjugated with glutathione, and then with cysteine and mercapturic acid.

The main cytochrome P450 isoenzymes for this metabolic pathway are isoenzyme CYP2E1 (predominantly), CYP1A2 and CYP3A4 (secondary role).

In glutathione deficiency, these metabolites can cause damage and necrosis of hepatocytes.

Additional pathways of metabolism are hydroxylation to 3-hydroxyparacetamol and methoxylation to 3-methoxyparacetamol, which are subsequently conjugated with glucuronides or sulfates.

In adults, glucuronidation predominates; in newborns (including premature) and young children, sulfation predominates.

Conjugated metabolites of paracetamol (glucuronides, sulfates and conjugates with glutathione) have low pharmacological (including toxic) activity.

Elimination half-life (T_1/2) – 1-4 h.

It is excreted by the kidneys in the form of metabolites, mainly conjugates, only 3% unchanged.

In elderly patients, the clearance of the drug decreases and T_1/2 increases.

Ascorbic acid

Plasma protein binding – 25%.

The concentration of ascorbic acid in plasma is normally approximately 10-20 µg/ml.

It easily penetrates into leukocytes, platelets, and then into all tissues; the highest concentration is achieved in glandular organs, leukocytes, liver and the lens of the eye; it penetrates the placental barrier.

The concentration of ascorbic acid in leukocytes and platelets is higher than in erythrocytes and plasma.

In deficiency states, the concentration in leukocytes decreases later and more slowly and is considered a better criterion for assessing deficiency than plasma concentration.

It is metabolized mainly in the liver to dehydroascorbic acid and then to oxaloacetic acid and ascorbate-2-sulfate.

It is excreted by the kidneys, through the intestines, with sweat, breast milk unchanged and in the form of metabolites.

When prescribed in high doses, the excretion rate increases sharply.

Smoking and consumption of ethanol accelerate the destruction of ascorbic acid (conversion to inactive metabolites), sharply reducing reserves in the body.

It is excreted during hemodialysis.

Indications

• As an antipyretic for infectious and inflammatory diseases (ARVI, including influenza);
• As an analgesic for mild to moderate pain syndrome (headache, toothache) of non-inflammatory origin, for neuralgia, muscle and joint pain, algodysmenorrhea.

ICD codes

Dosage Regimen

Adults and children over 12 years of age (with body weight over 50 kg) take 1 tab. orally 3-4 times/day with an interval between doses of 4-8 hours.

Children from 6 to 12 years – 1/2 tab., maximum daily dose – 2 tab.

Maximum duration of treatment for children – 3 days.

Maximum duration of treatment for adults – no more than 5 days when prescribed as an analgesic and no more than 3 days – as an antipyretic.

Adverse Reactions

Paracetamol

From the digestive system rarely – nausea, very rarely – vomiting, diarrhea, pain in the epigastric region, jaundice, pancreatitis and increased activity of liver enzymes.

Allergic reactions rarely – skin rash, skin itching, urticaria, angioedema.

From the hematopoietic and lymphatic system very rarely – anemia, leukopenia.

Other weakness.

Ascorbic acid

Allergic reactions skin rash, skin hyperemia.

Laboratory parameters thrombocytosis, hyperprothrombinemia, erythrocytopenia, neutrophilic leukocytosis, hypokalemia, glucosuria.

Contraindications

• Severe kidney disease;
• Severe liver disease;
• Renal and/or hepatic failure;
• Glucose-6-phosphate dehydrogenase deficiency;
• Erosive and ulcerative lesions of the gastrointestinal tract in the acute phase;
• Gastrointestinal bleeding;
• Children under 6 years of age;
• Pregnancy;
• Lactation period (breastfeeding).

With caution erosive and ulcerative lesions of the gastrointestinal tract (in history), congenital hyperbilirubinemias (Gilbert, Dubin-Johnson and Rotor syndromes); blood diseases (thrombocytopenia, leukopenia, agranulocytosis), sideroblastic anemia, thalassemia; hemochromatosis, hyperoxaluria, urolithiasis; bronchial asthma; alcoholism.

Use in Pregnancy and Lactation

There are no data from studies on the efficacy and safety of the combination of paracetamol and ascorbic acid in pregnant and lactating women.

Thus, it is not possible to assess the possible risk-benefit ratio, and therefore the use of the drug in these categories of patients is not recommended.

Pediatric Use

Contraindication: children under 6 years of age.

Special Precautions

Do not exceed the recommended doses of the drug Paracetamol EXTRATAB.

If hyperthermia persists for more than 3 days and pain syndrome for more than 5 days, a doctor’s consultation is required.

After 5 days of using the drug Paracetamol EXTRATAB, control of the peripheral blood picture and functional state of the liver is necessary.

Paracetamol distorts the indicators of laboratory tests in the quantitative determination of the concentration of glucose and uric acid in plasma.

To avoid toxic liver damage, Paracetamol should not be combined with the intake of alcoholic beverages, and should not be taken by persons prone to alcohol abuse.

There is evidence that frequent use of drugs containing Paracetamol leads to worsening of symptoms of bronchial asthma.

Simultaneous use with other medicines should be agreed with a doctor.

Influence on the ability to drive vehicles and mechanisms

There are no data on the effect of the drug Paracetamol EXTRATAB on the ability to drive vehicles and other technical means.

Overdose

Paracetamol

Symptoms: within the first 24 hours after ingestion – pallor of the skin, nausea, vomiting; anorexia, abdominal pain; impaired glucose metabolism, metabolic acidosis.

Symptoms of impaired liver function may appear 12-48 hours after overdose.

In severe overdose – liver failure with progressive encephalopathy, coma, death; acute renal failure with tubular necrosis (including in the absence of severe liver damage); arrhythmia, pancreatitis.

Hepatotoxic effect in adults is manifested when taking 10 g or more.

Rarely, liver failure develops rapidly and may be complicated by renal failure (tubular necrosis).

Treatment: administration of SH-group donors and precursors of glutathione synthesis – methionine – within 8-9 hours after overdose and acetylcysteine – within 8 hours.

The need for additional therapeutic measures (further administration of methionine, intravenous administration of acetylcysteine) is determined depending on the concentration of paracetamol in the blood, as well as on the time elapsed after ingestion.

Ascorbic acid

Symptoms: diarrhea, nausea, irritation of the gastrointestinal mucosa, flatulence, abdominal pain of a spasmodic nature, frequent urination, nephrolithiasis, insomnia, irritability, hypoglycemia.

Treatment: symptomatic, forced diuresis.

Drug Interactions

When taking other medicines simultaneously with the drug Paracetamol EXTRATAB, you should consult your doctor.

Paracetamol reduces the effectiveness of uricosuric drugs.

With long-term and regular use, Paracetamol potentiates the action of warfarin and other coumarin derivatives and increases the risk of bleeding.

Simultaneous intake of cholestyramine leads to a decrease in the absorption of paracetamol (and a weakening of the effects of paracetamol).

Metoclopramide and domperidone increase the absorption of paracetamol.

Simultaneous use of paracetamol and NSAIDs (including metamizole sodium, acetylsalicylic acid, ibuprofen) increases the risk of “analgesic” nephropathy and renal papillary necrosis, end-stage renal failure.

Simultaneous use of paracetamol and chloramphenicol may be accompanied by an increase in T_1/2 of chloramphenicol up to 5 times.

Inducers of microsomal liver enzymes (phenytoin, ethanol, barbiturates, rifampicin, phenylbutazone, tricyclic antidepressants) increase the production of hydroxylated active metabolites, which causes the possibility of developing severe intoxications even with small overdoses.

Salicylamide increases the T_1/2 of paracetamol, which leads to the accumulation of paracetamol and, accordingly, increased formation of its toxic metabolites.

Simultaneous use of paracetamol and ethanol may increase the hepatotoxicity of paracetamol, as well as contribute to the development of acute pancreatitis.

Diflunisal increases the plasma concentration of paracetamol by 50% – risk of hepatotoxicity.

Other medicines containing Paracetamol, as well as other non-narcotic analgesics, should not be used simultaneously.

Simultaneous use of other medicines should be agreed with a doctor.

Ascorbic acid increases the concentration in the blood of benzylpenicillin and tetracyclines; at a dose of 1 g/day increases the bioavailability of ethinylestradiol (including as part of oral contraceptives); improves the absorption of iron preparations in the intestine (converts ferric iron to ferrous); may increase iron excretion when used simultaneously with deferoxamine; reduces the effectiveness of heparin and indirect anticoagulants.

Acetylsalicylic acid, oral contraceptives, fresh juices and alkaline drinks reduce the absorption and assimilation of ascorbic acid.

When used simultaneously with acetylsalicylic acid, the excretion of ascorbic acid in the urine increases and the excretion of acetylsalicylic acid decreases.

Acetylsalicylic acid reduces the absorption of ascorbic acid by approximately 30%.

Ascorbic acid increases the risk of crystalluria during treatment with salicylates and short-acting sulfonamides, slows down the excretion of acids by the kidneys, increases the excretion of drugs that have an alkaline reaction (including alkaloids), reduces the concentration in the blood of oral contraceptives.

Drugs of the quinoline series, calcium chloride, salicylates, corticosteroids with long-term use deplete the reserves of ascorbic acid.

When used simultaneously, Ascorbic acid reduces the chronotropic effect of isoprenaline.

With long-term use or use in high doses, Ascorbic acid may interfere with the interaction of disulfiram and ethanol; in high doses, it increases the excretion of mexiletine by the kidneys.

Barbiturates and primidone increase the excretion of ascorbic acid in the urine.

Ascorbic acid reduces the therapeutic effect of antipsychotic drugs (neuroleptics) – phenothiazine derivatives, tubular reabsorption of amphetamine and tricyclic antidepressants.

Storage Conditions

The drug should be stored out of the reach of children, in a dry, light-protected place at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 2 years.

Dispensing Status

The drug is approved for use as an over-the-counter product.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.