Efferalgan with vitamin c

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EFERALGAN WITH VITAMIN C

Composition:

Active substances: paracetamol, ascorbic acid;

1 effervescent tablet contains 330 mg of paracetamol, 200 mg of ascorbic acid (vitamin C);

Excipients: potassium hydrogencarbonate, anhydrous citric acid, sodium hydrogencarbonate, sorbitol (E 420), sodium benzoate (E 211), sodium docusate, povidone.

Pharmaceutical form. Effervescent tablets.

Main physicochemical properties: white tablets with a score line for division and bevelled edges, soluble in water with effervescence; minor chipping is acceptable.

Pharmacotherapeutic group.

Analgesics and antipyretics. Paracetamol, combination without psychotropic agents. ATC code N02BE51.

Pharmacological Properties.

Pharmacodynamics.

Paracetamol exerts analgesic, antipyretic, and anti-inflammatory effects. Clinical studies have demonstrated that when a preparation containing 330 mg of paracetamol in the form of effervescent tablets is administered, the analgesic effect occurs twice as fast compared to conventional paracetamol tablets.

Ascorbic acid (vitamin C), included in the composition of the preparation, replenishes the body's need for vitamin C, enhances antioxidant activity, reduces vascular permeability, and increases the body's resistance to adverse external factors.

Pharmacokinetics.

After oral administration, paracetamol in the form of effervescent tablets is rapidly and completely absorbed. Maximum plasma concentration is achieved within 20–30 minutes after administration. Paracetamol is rapidly distributed throughout all tissues. Concentrations in plasma, saliva, and blood are approximately equal. Plasma protein binding is weak.

Paracetamol is primarily metabolized in the liver. The two main metabolic pathways are conjugation forming glucuronides and sulfates. The latter pathway becomes rapidly saturated when doses exceeding therapeutic levels are administered. A minor metabolic pathway, catalyzed by cytochrome P450, leads to the formation of an intermediate compound (N-acetylbenzoquinoneimine), which under normal conditions is rapidly detoxified by reduced glutathione and excreted in urine after conjugation to cysteine and mercapturic acid. However, in severe poisoning, the amount of this toxic metabolite increases.

The drug is primarily excreted in urine. Approximately 90% of the administered dose is eliminated by the kidneys within 24 hours, mainly as glucuronide conjugates (60–80%) and sulfate conjugates (20–30%).

Less than 5% is excreted unchanged.

After oral administration, the elimination half-life is approximately 2 hours.

Almost all ascorbic acid (vitamin C) is absorbed in the small intestine.

Vitamin C is excreted in urine either unchanged or as dehydroascorbic acid, 2,3-diketogulonic acid, or oxalic acid.

Clinical characteristics.

Indications.

Symptomatic treatment of mild to moderate pain and/or fever.

Contraindications.

Hypersensitivity to any component of the drug.

Urolithiasis; use of high doses (over 1 g) of ascorbic acid.

Severe impairment of liver and/or kidney function, congenital hyperbilirubinemia, glucose-6-phosphate dehydrogenase deficiency, blood disorders, severe anemia, leukopenia.

Thrombosis, predisposition to thrombosis, thrombophlebitis, diabetes mellitus, urolithiasis. Alcoholism.

Special precautions.

Do not take the drug simultaneously with other products containing paracetamol. To avoid the risk of overdose, ensure that other medicinal products do not contain paracetamol.

If a child is receiving paracetamol treatment at a dose of 60 mg/kg/day, combination with another antipyretic agent is justified only if paracetamol is ineffective.

Use with caution in patients with body weight below 50 kg, chronic malnutrition (low hepatic glutathione stores), dehydration, or mild to moderate hepatic insufficiency.

Patients on a salt-free or low-salt diet should be aware that each effervescent tablet contains 330 mg of sodium (i.e., 14.3 mEq or mmol).

Use with caution, after consultation with a physician, in patients with mild to moderate renal or hepatic impairment.

In patients with non-cirrhotic alcoholic liver disease, the risk of hepatotoxic effects of paracetamol is increased. Patients who abuse alcohol should consult a physician before taking the drug, as the risk of hepatotoxic effects of paracetamol is increased.

In elderly patients, elimination of paracetamol from the body may be reduced.

The drug contains sorbitol (E 420); therefore, it is contraindicated in patients with rare hereditary fructose intolerance. Sorbitol may also cause a mild laxative effect.

Consult a physician before using the drug if the patient is taking warfarin or similar anticoagulant agents.

In patients with severe infections such as sepsis, which are associated with reduced glutathione levels, the risk of metabolic acidosis increases during paracetamol use.

Symptoms of metabolic acidosis include deep, rapid, or labored breathing, nausea, vomiting, and loss of appetite. Seek immediate medical attention if these symptoms occur.

Do not exceed the recommended doses. If symptoms persist, consult a physician.

With high-dose or prolonged use of the drug, monitor renal and liver function, blood pressure, and pancreatic function.

Ascorbic acid may interfere with various laboratory tests, e.g., blood glucose, bilirubin, transaminase activity, lactate dehydrogenase, etc.

Since ascorbic acid enhances iron absorption, its use in high doses may be hazardous in patients with hemochromatosis, thalassemia, polycythemia, leukemia, and sideroblastic anemia.

Patients with high body iron content should use the drug at the lowest possible doses.

Alcoholic beverages should not be consumed during treatment.

Treatment should be discontinued if acute viral hepatitis is diagnosed.

Interaction with other medicinal products and other forms of interaction.

Concomitant use with oral anticoagulants may increase anticoagulant effect and increase the risk of bleeding when paracetamol is taken at maximum doses (4 g/day) for at least 4 days. Regular monitoring of INR (International Normalized Ratio) is recommended. The dose of oral anticoagulant may need to be adjusted during and after paracetamol treatment.

Paracetamol intake may interfere with blood glucose measurement by the glucose oxidase-peroxidase method, leading to falsely elevated concentrations.

Paracetamol intake may interfere with blood urea measurement by the phosphotungstic acid method.

The absorption rate of paracetamol may be increased by concomitant use with metoclopramide and domperidone, and decreased when used with cholestyramine. Barbiturates reduce the antipyretic effect of paracetamol.

Anticonvulsants (including phenytoin, barbiturates, carbamazepine), which stimulate hepatic microsomal enzyme activity, may enhance the hepatotoxic effect of paracetamol due to increased conversion of the drug into hepatotoxic metabolites.

Concomitant use of paracetamol with isoniazid increases the risk of hepatotoxic syndrome.

Paracetamol reduces the effectiveness of diuretics.

Use paracetamol with caution when administered concomitantly with flucloxacillin, as co-administration 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").

Ascorbic acid enhances intestinal absorption of iron, increases blood levels of ethinylestradiol, penicillins, and tetracyclines; decreases blood levels of antipsychotics and phenothiazine derivatives. Glucocorticoids reduce ascorbic acid stores. Concurrent use of ascorbic acid and deferoxamine increases tissue iron toxicity, especially in cardiac muscle, potentially leading to circulatory decompensation. The drug should be administered only 2 hours after deferoxamine injection. High doses of ascorbic acid reduce the effectiveness of tricyclic antidepressants. Absorption of ascorbic acid is reduced when taken concomitantly with oral contraceptives, fruit or vegetable juices, or alkaline drinks.

Special precautions for use.

Use during pregnancy or breastfeeding.

Epidemiological study results from clinical trials allow excluding any developmental abnormalities or fetotoxic effects associated with paracetamol.

A large amount of data in pregnant women indicates no evidence of developmental malformations or foeto-/neonatal toxicity. Epidemiological studies on nervous system development in children exposed to paracetamol in utero have shown inconclusive results. Paracetamol may be used during pregnancy, when clinically necessary, at the lowest effective dose, for the shortest duration, and with the least possible frequency.

Traditional studies using currently accepted standards for assessing reproductive and developmental toxicity are lacking.

Therefore, when paracetamol is used at recommended doses, the drug may be prescribed during pregnancy, taking into account the benefit-risk ratio.

Paracetamol passes into breast milk, but in clinically insignificant amounts. Available published data do not contain contraindications regarding breastfeeding.

This medicinal product can be used during breastfeeding at therapeutic doses; however, with frequent use, the benefit-risk ratio should be considered.

Cases of metabolic acidosis with a high anion gap (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe conditions such as severe renal insufficiency and sepsis, or in patients with malnutrition or other sources of glutathione deficiency (e.g., chronic alcoholism), who were treated with paracetamol at therapeutic doses 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. 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.

Ability to influence reaction rate while driving or operating machinery.

Does not affect.

Method of Administration and Dosage

For oral use.

Completely dissolve the tablet in a large glass of water and take immediately.

The medication is intended for adults and children aged 8 years and older (with body weight over 27 kg). The recommended daily dose of paracetamol is approximately 60 mg/kg. The daily dose should be divided into 4 or 6 doses, i.e., approximately 15 mg/kg every 6 hours or 10 mg/kg every 4 hours.

Children should be administered doses based on their body weight; therefore, an appropriate dosage form must be selected. The approximate age-to-weight correlation is provided for reference only:

Children with body weight from 27 to 30 kg (approximately 8–10 years): the dose is 1 effervescent tablet per administration. The dose may be repeated after 6 hours if necessary, but not more than 5 effervescent tablets per day.

Children with body weight from 30 to 35 kg (approximately 10–12 years): the dose is 1–2 effervescent tablets per administration. The dose may be repeated after 6 hours if necessary, but not more than 6 effervescent tablets per day.

Children with body weight from 35 to 50 kg (approximately 12–15 years): the dose is 1–2 effervescent tablets per administration. The dose may be repeated after 6 hours if necessary, but not more than 7 effervescent tablets per day.

Adults and children with body weight over 50 kg (approximately 15 years and older): the dose is 1–2 effervescent tablets per administration. The dose may be repeated after 4 hours if necessary, but not exceeding 9 effervescent tablets per day.

Typically, no more than 3 g of paracetamol per day (i.e., more than 9 effervescent tablets per day) should be used. However, in cases of more severe pain, the maximum daily dose may be increased to 4 g (i.e., up to 12 effervescent tablets per day).

The interval between doses should be 4 hours.

Maximum Recommended Doses

Children with body weight less than 37 kg: total daily dose of paracetamol should not exceed 80 mg/kg/day.

Children with body weight from 38 kg to 50 kg: total daily dose of paracetamol should not exceed 3 g/day.

Adults and children with body weight over 50 kg: total daily dose of paracetamol should not exceed 4 g/day.

Frequency of Administration

Regular dosing helps avoid fluctuations in pain and fever levels:

• In children, the recommended regular interval between doses, both during the day and at night, is 6 hours, but not less than 4 hours;
• In adults, the interval between doses should be at least 4 hours.

Because the medication contains vitamin C, it should not be taken late in the day.

Renal Impairment

In cases of severe renal impairment (creatinine clearance less than 10 ml/min), the interval between doses should be at least 8 hours.

The duration of treatment is determined individually by a physician.

Children

The medication is indicated for children aged 8 years and older (with body weight over 27 kg).

Overdose

Symptoms of Paracetamol Overdose

There is a risk of poisoning in elderly patients and especially in young children (both therapeutic overdoses and accidental poisonings are common); poisoning can be fatal.

Symptoms

Nausea, vomiting, pallor, anorexia, and abdominal pain, which usually appear within the first 24 hours.

A single dose of 10 g in adults and 150 mg/kg body weight in children may cause glucose metabolism disturbances, hemorrhages, and hypoglycemia. Acute renal failure with acute tubular necrosis may develop even in the absence of severe kidney damage and may present as severe lumbar pain, hematuria, and proteinuria. Cardiac arrhythmias and pancreatitis have also been reported. With prolonged use of high doses, hematological side effects may include aplastic anemia, pancytopenia, agranulocytosis, neutropenia, leukopenia, and thrombocytopenia.

With large doses:

• Central nervous system: dizziness, psychomotor agitation, and disorientation;
• Urinary system: nephrotoxicity (renal colic, interstitial nephritis, papillary necrosis);
• Digestive system: hepatonecrosis.

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

Overdose of more than 10 g of paracetamol in a single dose in adults or 150 mg/kg body weight in a single dose in children causes hepatic cytolysis, which may lead to complete and irreversible necrosis, resulting in hepatocellular failure, metabolic acidosis, and encephalopathy, potentially leading to coma or death.

Concurrently, elevated levels of liver transaminases, lactate dehydrogenase, bilirubin, and increased prothrombin index may develop within 12–48 hours after overdose.

Symptoms of ascorbic acid (vitamin C) overdose: epigastric pain, nausea, vomiting, flatulence, diarrhea, itching, skin rash, increased nervous system excitability.

With prolonged use in high doses, possible effects include suppression of the islet apparatus of the pancreas, development of cystitis, accelerated formation of urinary stones (urates, oxalates, cystine stones), and myocardial dystrophy.

Emergency Measures

In case of overdose, immediate medical assistance is required, even if symptoms are not present. Urgent elimination of the ingested medication by gastric lavage in cases of oral intake. Administration of oral methionine or intravenous acetylcysteine may be effective within 48 hours after overdose. General supportive measures and symptomatic therapy should also be applied.

Adverse Reactions

The drug is generally well tolerated at recommended doses; however, the following adverse reactions may occur:

Allergic reactions: anaphylaxis, anaphylactic shock, angioedema (Quincke's edema), erythema multiforme, urticaria, skin rash and pruritus, mucosal lesions, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome).

Blood and lymphatic system disorders: anemia, sulfhemoglobinemia and methemoglobinemia (cyanosis, dyspnea, chest pain), hemolytic anemia; thrombocytosis, erythrocytopenia, thrombosis, neutrophilic leukocytosis, hyperprothrombinemia, thrombocytopenia, leukopenia and neutropenia. In patients with glucose-6-phosphate dehydrogenase deficiency, hemolysis of erythrocytes may occur, as well as bruising or bleeding.

Respiratory system disorders: bronchospasm in patients sensitive to acetylsalicylic acid and other NSAIDs.

Gastrointestinal disorders: dyspeptic symptoms, nausea, vomiting, epigastric pain, heartburn, diarrhea.

Hepatobiliary disorders: increased liver enzyme activity, usually without development of jaundice, hepatonecrosis (dose-dependent effect), liver function disturbances.

Endocrine system disorders: hypoglycemia, up to hypoglycemic coma.

Renal and urinary system disorders: glomerular damage, crystalluria, formation of oxalate, cystine, and urate kidney stones and stones in the urinary tract, renal colic.

Nervous system disorders: headache, sensation of warmth, increased excitability, sleep disturbances.

Metabolism and nutrition disorders: disturbances in zinc and copper metabolism.

Cardiovascular system disorders: fluctuations in arterial blood pressure.

Metabolism and nutrition disorders: metabolic acidosis with high anion gap, reported with an incidence of "unknown" (cannot be estimated from available data).

Description of selected adverse reactions.

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 were taking paracetamol (see section "Special precautions"). Pyroglutamic acidosis may occur as a consequence of low glutathione levels in these patients.

If any adverse reactions occur, administration of this medicinal product and similar drugs should be discontinued immediately and medical advice should be sought.

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in a tightly closed tube and in the original cardboard packaging.

Keep out of reach of children.

Packaging.

10 tablets in a tube, 1 tube in a cardboard box.

10 tablets in a tube, 2 tubes in a cardboard box.

Prescription status.

Over-the-counter.

Manufacturer.

UPSA SAS, France.

Manufacturer's address and place of business.

979, avenue des Pyrenees, 47520 Le Passage, France.

304, avenue du Docteur Jean Bru, 47000 Agen, France.