EFFERALGAN 500 mg Orodispersible tab 2T/8

Orodispersible tablet.

Round, white tablet.

For an orodispersible tablet:

Paracetamol (paracetamol microencapsulated with ethylcellulose): 500 mg

Excipients with known effect :

One orodispersible tablet contains 4,8 mg of aspartame (E951) (source of phenylalanine), traces of benzyl alcohol, glucose, 39 mg of sodium, 25 mg of sodium benzoate (E211), 31 mg of sorbitol (E420) and sucrose.

Excipients:

Symptomatic treatment of mild to moderate pain and/or febrile states.

EFFERALGAN 500 mg, orodispersible tablet is indicated in adults and adolescents weighing more than 50 kg.

Dosage

The lowest effective dose should generally be used, for the shortest possible duration.

Body weight (approximate age)	Dose per administration	Interval of administration	Maximum daily dose
Adults and adolescents > 50 kg	500 mg to 1000 mg of paracetamol (1 to 2 tablets)	minimum 4 hours	3000 mg of paracetamol per day (6 tablets)

The daily dose is 3000 mg of paracetamol per day, i.e. 6 tablets per day. However, in case of more intense pain, and on medical advice, the Dosage maximum may be increased to 4 g per day, i.e. 8 tablets per day. An interval of 4 hours must always be respected between two doses.

Warning: Take into account all medicines containing paracetamol to avoid overdose, including if they are obtained without prescription (see section Warnings and precautions).

Special populations

The lowest possible effective daily dose should be considered without exceeding the recommended maximum doses (60 mg/kg/day, i.e. 3 g/day) in the following situations:

• Chronic malnutrition (low reserves of hepatic glutathione)

• Dehydration

Paediatric population

For adolescents, see the dosage table above.

This medicine must not be used in children and adolescents weighing less than 50 kg.

Renal impairment

In patients with renal impairment and unless medically advised, the minimum interval between each dose must be modified and the maximum daily dose must be reduced according to the following table:

Creatinine clearance	Interval between each dose	Maximum daily dose
CrCl 10-50 mL/min	6 hours	3000 mg (3g)/day
CL <10 mL/min	8 hours	2000 mg (2g)/day

Hepatic impairment and chronic alcoholism

The dose must be reduced or the dosing interval prolonged. The total daily dose must not exceed 2 g/day in the following situations:

• Hepatocellular insufficiency (mild to moderate),

• Gilbert's syndrome (familial non-haemolytic jaundice),

• Chronic alcoholism.

Chronic alcohol consumption may lower the toxicity threshold of paracetamol. In these patients, the interval between two doses must be at least 8 hours.

Elderly patients

No dosage adjustment is necessary in elderly people. However, concomitant risk factors should be taken into account, some of which occur more often in elderly subjects and which require dosage adjustment.

Method of administration

Oral use.

Let the tablet dissolve on the tongue, without water (see section Pharmacokinetics).

Two tablets must not be taken simultaneously but individually.

Hypersensitivity to the active substance or to any of the excipients listed in section Composition.

Severe hepatocellular insufficiency.

Prolonged or frequent use is not recommended (see section Dosage and administration). Long-term use, except under medical supervision, may be harmful.

To avoid a risk of overdose:

• check that paracetamol is not contained in the composition of other medicines (medicines obtained with or without prescription).

• respect the maximum recommended doses without exceeding the maximum number of tablets per day (see sections Dosage and administration "dosage table" and 4.9).

Taking several daily doses at once can seriously damage the liver; unconsciousness does not always occur. Immediate medical advice must be sought in case of overdose, even if the patient feels well, due to the risk of irreversible liver damage (see section Overdose).

Alcohol intake during this treatment is not advised.

Risk factors for liver disorders

EFFERALGAN 500 mg, orodispersible tablet, should only be administered with particular caution in the presence of the following risk factors, which could lower the threshold for hepatotoxicity. In these cases, the dosage must be adjusted and the maximum daily dose must absolutely not be exceeded in these patients (see section Dosage and administration) :

• mild to moderate hepatocellular insufficiency

• renal insufficiency

• Gilbert's syndrome (familial non-hemolytic jaundice)

• chronic alcoholism

• concomitant treatment with medicines affecting liver function

• glucose-6-phosphate dehydrogenase (G6PD) deficiency (which may lead to hemolytic anemia)

• chronic malnutrition (low hepatic glutathione reserves), anorexia, cachexia, fasting

• dehydration

Concomitant treatment with medicines affecting liver function, dehydration and chronic malnutrition (low hepatic glutathione reserves) are also risk factors for the development of hepatotoxicity and may possibly lower the threshold for hepatic toxicity. The maximum daily dose must certainly not be exceeded in these patients.

In case of discovery of acute viral hepatitis, treatment must be stopped.

EFFERALGAN 500 mg, orodispersible tablet, must not be used in children, adolescents, or adults weighing less than 50 kg because the dose cannot be adjusted correctly.

Concomitant use with other medicines

In adolescents treated at the maximum recommended dose of 60 mg/kg of paracetamol per day, combination with another antipyretic is not justified, except in case of ineffectiveness.

In case of persistent fever, medical advice is recommended.

High anion gap metabolic acidosis (HAGMA)

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with serious diseases such as severe renal failure and sepsis, or in patients suffering from malnutrition and other sources of glutathione deficit (for example, chronic alcoholism), who have been treated with paracetamol at a therapeutic dose for a prolonged period or with a combination of paracetamol and flucloxacillin. In case of suspected HAGMA due to pyroglutamic acidosis, it is recommended to immediately stop paracetamol and carry out close monitoring. Measurement of urinary 5-oxoproline may be useful to identify pyroglutamic acidosis as the underlying cause of HAGMA in patients presenting with multiple risk factors.

Severe skin reactions

Paracetamol may cause severe skin reactions. Patients must be informed of the early signs of these serious skin reactions, and the appearance of a skin rash or any other sign of hypersensitivity requires discontinuation of treatment.

Medication overuse headache

With long-term use, high doses, or incorrect use of analgesics in patients with chronic headaches, headaches may appear or worsen; they must not be treated with higher doses of this medicine. In such cases, the use of analgesics must be discontinued on medical advice.

Excipients with known effect

This medicine contains 4,8 mg of aspartame (E 951) per orodispersible tablet. Aspartame contains a source of phenylalanine. It may be harmful for people with phenylketonuria (PKU), a rare genetic disease characterised by the accumulation of phenylalanine that cannot be properly eliminated.

This medicine contains traces of benzyl alcohol per orodispersible tablet. Benzyl alcohol may cause allergic reactions. Due to the risk of accumulation and toxicity (metabolic acidosis), caution is required in pregnant and breast-feeding women, as well as in subjects with hepatic or renal impairment.

This medicine contains glucose. Patients with glucose-galactose malabsorption syndrome must not take this medicine.

This medicine contains 39 mg of sodium per orodispersible tablet, which is equivalent to 1,95 % of the WHO-recommended maximum daily dietary intake of 2 g of sodium per adult.

This medicine contains 25 mg of sodium benzoate (E 211) per orodispersible tablet.

This medicine contains 31 mg of sorbitol (E 420) per orodispersible tablet. Patients with hereditary fructose intolerance (HFI) must not receive this medicine. The additive effect of concomitantly administered products containing sorbitol (or fructose) and the dietary intake of sorbitol (or fructose) must be taken into account.

The sorbitol content of medicines for oral use may affect the bioavailability of other medicines for oral use administered concomitantly.

This medicine contains sucrose. Patients with fructose intolerance, glucose-galactose malabsorption syndrome or sucrase/isomaltase deficiency (rare hereditary diseases) must not take this medicine.

+ Probenecid

Probenecid intake inhibits the binding of paracetamol to glucuronic acid, thus causing a decrease in paracetamol clearance by a factor of approximately 2. The paracetamol dose should be reduced in patients taking probenecid concomitantly.

+ Salicylamide

Salicylamide may prolong the elimination half-life (t½) of paracetamol.

+ Enzyme inducers and alcohol

Paracetamol is mainly metabolised in the liver. Some paracetamol metabolites are hepatotoxic, and concomitant administration with potent enzyme inducers may therefore lead to hepatotoxic reactions, particularly when high doses of paracetamol are used. These potent enzyme inducers include, but are not limited to, barbiturates, isoniazid, carbamazepine, rifampicin, ethanol, and certain anticonvulsants.

+ Phenytoin

Patients receiving treatment with phenytoin should avoid large and/or chronic doses of paracetamol. Patients will be monitored for signs of hepatotoxicity.

+ Zidovudine

Concomitant intake of paracetamol and AZT (zidovudine) increases the tendency to neutropenia. Therefore, this medicine should be co-administered with AZT only on medical advice.

+ Cholestyramine

Cholestyramine reduces the absorption of paracetamol and therefore must not be administered within one hour of taking paracetamol.

+ Flucloxacillin

Precautions must be taken when paracetamol is used at the same time as flucloxacillin, as concomitant intake has been associated with high anion gap metabolic acidosis due to pyroglutamic acidosis, particularly in patients with risk factors (see section Warnings and precautions).

Concomitant intake of medicines that speed up gastric emptying, such as metoclopramide, accelerates the absorption and onset of effect of paracetamol.

Concomitant intake of medicines that slow down gastric emptying may delay the absorption and onset of effect of paracetamol.

No interaction studies have been carried out with food or milk.

Associations requiring precautions for use

Repeated intake of paracetamol for more than one week increases the effect of anticoagulants, in particular warfarin. Therefore, long-term administration of paracetamol in patients receiving anticoagulant treatment should only take place under medical supervision.

Concomitant use of paracetamol with coumarins including warfarin may lead to slight variations in INR values. In this case, increased monitoring of INR values should be carried out during the period of concomitant use and for one week following discontinuation of paracetamol treatment.

Occasional intake of paracetamol does not have a significant effect on bleeding tendency.

Interactions with paraclinical tests

Taking paracetamol may distort the measurement of blood uric acid by the phosphotungstic acid method and the measurement of blood glucose by the glucose oxidase-peroxidase method.

Taking paracetamol increases the plasma concentrations of acetylsalicylic acid and chloramphenicol.

Pregnancy

The large amount of data on pregnant women indicates no malformative, nor foeto/neonatal toxicity. Epidemiological studies on the neurodevelopment of children exposed to paracetamol in utero give inconclusive results. If clinically necessary, paracetamol may be used during pregnancy, however at the lowest possible dose for the shortest possible period of time and at the lowest possible frequency.

Breast-feeding

Paracetamol is excreted in small quantities in breast milk following oral administration. However, paracetamol is considered compatible with breastfeeding. Nevertheless, precautions should be taken when administering EFFERALGAN 500 mg, orodispersible tablet to breastfeeding women.

Fertility

Because of its potential mechanism of action on cyclo-oxygenases and prostaglandin synthesis, paracetamol could impair fertility in women, through an effect on ovulation that is reversible upon discontinuation of treatment.

Effects on male fertility have been observed in an animal study. The relevance of these effects in humans is not known.

Paracetamol has no or negligible effect on the ability to drive vehicles and use machines.

The following table presents the undesirable effects. Undesirable effects are classified by system organ class. Their frequencies are defined as follows:

• Very common (≥ 1/10),

• Common (≥ 1/100 to < 1/10),

• Uncommon (> 1/1 000 to < 1/100),

• Rare (≥ 1/10 000 to < 1/1 000),

• Very rare (< 1/10 000),

• Frequency not known (cannot be estimated from the available data).

System organ class	Rare (≥ 1/10 000 to < 1/1 000)	Very rare (< 1/10 000)	Frequency not known
Blood and lymphatic system disorders		Thrombocytopenia, Leukopenia, Neutropenia
Immune system disorders	Hypersensitivity1		Anaphylactic reaction (including hypotension)1, Anaphylactic shock1, Angioedema (Quincke's oedema)1
Respiratory, thoracic and mediastinal disorders			Bronchospasm
Metabolism and nutrition disorders			High anion gap metabolic acidosis due to pyroglutamic acidosis3
Gastrointestinal disorders	Abdominal pain, Diarrhoea
Hepatobiliary disorders			Increased liver enzymes
Skin and subcutaneous tissue disorders	Rash1, Purpura2, Urticaria1, Erythema1	Severe skin reactions1	Fixed pigmented erythema
1The occurrence of these effects requires permanent discontinuation of this medicine and related medicines. 2The occurrence of this effect requires immediate discontinuation of this medicine. The product may be reintroduced only on medical advice. 3In patients with risk factors who are taking paracetamol (see section Warnings and precautions). Pyroglutamic acidosis may occur in these patients due to low glutathione levels.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Centres of Pharmacovigilance - Website: https://signalement.social-sante.gouv.fr/.

There is a risk of overdose, particularly in patients suffering from liver disease, in cases of chronic alcoholism, in patients suffering from chronic malnutrition and in patients receiving enzyme inducers. An overdose can be fatal, especially in these cases.

Hepatotoxicity often occurs within 24 to 48 hours following administration. An overdose can be fatal. Immediate medical advice must be sought in case of overdose, even in the absence of symptoms.

Symptoms:

Nausea, vomiting, anorexia, pallor, malaise, sweating, abdominal pain generally appear within 24 first hours.

A single overdose of paracetamol in adults or children causes hepatic cytolysis that may lead to complete and irreversible necrosis, resulting in hepatocellular failure, metabolic acidosis (which may in some cases be of lactic or pyroglutamic acid origin) and encephalopathy that may progress to coma and death.

Simultaneously, an increase in hepatic transaminases (AST, ALT), lactate dehydrogenase, and bilirubin, and a decrease in prothrombin level may appear 12 to 48 hours after ingestion. Clinical symptoms of liver involvement are generally observed after 1 to 2 days and reach a maximum after 3 to 4 days.

An overdose may also cause acute pancreatitis, acute renal failure, and disseminated intravascular coagulation.

Emergency management:

• Stop treatment;

• Immediate transfer to a hospital setting;

• As soon as possible, from the 4th hour after ingestion, draw a blood tube to perform the initial plasma paracetamol assay. Values must be analysed using the appropriate nomogram;

• Rapid evacuation of the ingested product by gastric lavage, followed by administration of activated charcoal (adsorbent) within one hour of ingestion;

• Treatment of overdose conventionally includes administration of the antidote N-acetylcysteine as early as possible, intravenously or orally if possible. before the 10th hour;

• Symptomatic treatment;

• Liver tests must be performed at the start of treatment and repeated every 24 hours. In most cases, hepatic transaminases return to normal within 1 to 2 weeks with full restoration of liver function. However, in very severe cases, liver transplantation may be necessary.

Pharmacotherapeutic class: OTHER ANALGESICS AND ANTIPYRETICS, ANILIDES, ATC code: N02BE01.

N: Nervous system.

Mechanism of action

The mechanism of action may involve central and peripheral actions.

Absorption

The absorption of paracetamol by the oral route is complete and rapid. In a pharmacokinetic study, when the tablet was left on the tongue without water intake, the maximum observed concentration (5,81 mg/l) was 32 % lower than that observed with a conventional formulation taken with water, and the time required to reach this maximum concentration (1 hour 20 minutes) was delayed by 45 minutes.

Distribution

Paracetamol is rapidly distributed in all tissues. Concentrations are comparable in blood, saliva and plasma. Binding to plasma proteins is low.

Biotransformation

Paracetamol is metabolised mainly in the liver. The 2 major metabolic pathways are glucuronidation and sulphation. The latter pathway is rapidly saturable at dosages above therapeutic doses. A minor pathway, catalysed by cytochrome P450, results in the formation of a reactive intermediate (N-acetyl benzoquinone imine), which, under normal conditions of use, is rapidly detoxified by reduced glutathione and eliminated in the urine after conjugation with cysteine and mercapturic acid. However, during massive overdoses, the quantity of this toxic metabolite is increased.

Elimination

Paracetamol is eliminated mainly by metabolism, and the metabolites are then eliminated mainly by renal excretion. 90 % of the ingested dose is eliminated by the kidney within 24 hours, mainly in glucuronide-conjugated form (60 to 80 %) and sulphate-conjugated form (20 to 30 %). Less than 5 % is eliminated in unchanged form.

The elimination half-life is approximately 3 hours.

Pathophysiological variations

Insuffisyearce kidneyle : in cases of renal insufficiency, the elimination of paracetamol and its metabolites is delayed (see section Dosage and administration).

Hepatic impairment : paracetamol metabolism is impaired in patients with chronic hepatic impairment, as shown by increased plasma paracetamol concentrations and a longer elimination half-life (see section Dosage and administration).

Elderly patients : the conjugation capacity is not modified (see section Dosage and administration).

No conventional study based on currently accepted standards for assessing reproductive and developmental toxicity is available.

3 years.

This medicine does not require any particular storage precautions.

No special requirements.

Marketing authorisation (AMM)

CIP 3400934821523 (2T/8).

Not reimbursed by Social Security: free price. Collect.