EFFERALGAN VITAMIN C 500 mg/200 mg Effervescent tab 2T/8

Effervescent tablet.

Paracetamol.................................................................................................................................................500 mg

Ascorbic acid.........................................................................................................................................200 mg

For one effervescent tablet.

Excipients with known effect: one tablet contains 110 mg of sodium benzoate (E211), 387 mg of sodium, 300 mg of sorbitol (E420), and in the flavouring, 0,003 mg of ethanol and 0,0099 mg of benzyl alcohol.

Excipients:

Symptomatic treatment of mild to moderate pain and/or fever in adults and children from 27 kg (approximately 8 years).

Dosage

In children, it is imperative to respect the dosages defined according to weight of the child and therefore choose a suitable presentation. Approximate ages according to weight are given for information only.

The recommended daily dose of paracetamol is approximately 60 mg/kg/day, to be divided into 4 or 6 doses, i.e. approximately 15 mg/kg every 6 hours or 10 mg/kg every 4 hours.

Weight (approximate age)	Maximum dose per administration	Interval of administration	Daily dose maximum
Child 27 kg – 40 kg (approximately 8 to 12 years)	500 mg of paracetamol + 200 mg of vitamin C (1 tablet)	6 hours minimum	2000 mg of paracetamol per day, i.e. 2 g + 800 mg of vitamin C per day (4 tablets)
Child 41 kg – 49 kg (approximately 13 to 15 years)	500 mg of paracetamol + 200 mg of vitamin C (1 tablet)	minimum 4 hours	3000 mg of paracetamol per day, i.e. 3 g + 1200 mg of vitamin C per day, i.e. 1,2 g (6 tablets)
Adults and children from 50 kg (approximately 15 years)	500 mg to 1000 mg of paracetamol, i.e. 500 mg to 1 g + 200 mg to 400 mg of vitamin C (1 to 2 tablets)	minimum 4 hours	3000 mg of paracetamol per day, i.e. 3 g + 1200 mg of vitamin C per day, i.e. 1,2 g (6 tablets)

For children, the total dose of paracetamol must not exceed 80 mg/kg/day (see section Overdose).

Recommended maximum doses : see section Warnings and precautions.

Warning: Take into account all medicines containing paracetamol and ascorbic acid to avoid overdose, including those obtained without a prescription.

Only on medical advice and in the absence of concomitant risk factors, the paracetamol dose may be increased up to 4000 mg (4 g) per day, i.e. 8 tablets per day, in patients weighing at least 50 kg (from approximately 15 years of age).

Special populations

The maximum daily dose of paracetamol must not exceed 60 mg/kg/day nor exceed 3000 mg per day (3 g/day) in the following situations: 

•                      Adults under 50 kg,

•          In case of low reserves or deficiency of hepatic glutathione (e.g., chronic malnutrition, fasting, recent weight loss, anorexia, cachexia),

•                      Dehydration. 

Hepatic insufficiency (mild to moderate), chronic alcoholism and Gilbert's syndrome (familial non-haemolytic jaundice)

It is recommended to reduce the paracetamol dose and increase the minimum interval between two doses. The daily dose of paracetamol must not exceed 2000 mg/day (2 g/day).

Renal impairment

In case of renal impairment and unless otherwise advised by a doctor, it is recommended to reduce the maximum daily dose of paracetamol and increase the minimum interval between 2 doses according to the table below.

Adults:

Creatinine clearance	Administration interval	Maximum daily dose of paracetamol
10-50 mL/min	6 hours minimum	3000 mg/day (3 g/day)
<10 mL/min	minimum 8 hours	2000 mg/day (2 g/day)

Elderly

Clinical experience indicates that the recommended dosage is generally adequate in adults. However, concomitant risk factors, some of which occur more frequently in elderly subjects and which require dose adjustment, should be taken into account.

Method of administration

Oral use.

Let dissolve completely the tablet in a glass of water.

Do not swallow or chew the tablets.

Due to the presence of vitamin C, avoid taking it at the end of the day.

Duration of treatment

Frequent or prolonged use without medical supervision is not recommended.

If symptoms persist beyond 5 days in the case of pain or 3 days in the case of fever, if symptoms worsen or if new symptoms appear, treatment should be re-evaluated.

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

Severe hepatic insufficiency.

Oxalo-calcium renal lithiasis (urinary tract stones) for doses above 1 g/day.

Patients must be informed that they must not take other medicines containing paracetamol. Taking several doses at one administration can seriously damage the liver; if this occurs, the patient must immediately call a doctor.

In a child treated with 60 mg/kg/day of paracetamol, the combination with another antipyretic is only justified in case of ineffectiveness.

In case of acute viral hepatitis, treatment should be stopped.

Special warnings

To avoid a risk of overdose:

• Check that there is no paracetamol or ascorbic acid in the composition of other medicines (medicines obtained with or without a prescription).

• respect the recommended maximum doses.

Recommended maximum doses:

• in children under 40 kg, the total dose of paracetamol must not exceed 80 mg/kg/day (see section Overdose).

• in children from 41 kg to 50 kg, the total dose of paracetamol must not exceed 3 g per cheek (see section Overdose).

• in adults and children over 50 kg, THE TOTAL DOSE OF PARACETAMOL MUST NOT EXCEED 4 GRAMS PER DAY (see section Overdose)

Precautions for use

Due to a slightly stimulating effect caused by the presence of vitamin C, it is advisable not to take this medicine at the end of the day.

Paracetamol must be administered with caution in the following situations (see section Dosage and administration) :

• Adult weighing less than 50 kg

• Mild to moderate hepatic insufficiency

• Chronic alcoholism and recent withdrawal

• Renal impairment

• Gilbert's syndrome

• Concomitant treatment with medicines affecting liver function (e.g. potentially hepatotoxic medicines or cytochrome P450 enzyme-inducing medicines such as phenobarbital, phenytoin, carbamazepine, topiramate, rifampicin)

• Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency (which may lead to haemolytic anaemia)

• Dehydration

• In cases of low reserves or hepatic glutathione deficiency (e.g. chronic malnutrition, fasting, recent weight loss, anorexia, cachexia)

• Elderly

Consumption of alcoholic beverages during treatment is not recommended.

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

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with serious illness such as severe renal insufficiency and sepsis, or in patients suffering from malnutrition and other sources of glutathione deficiency (for example, chronic alcoholism), who were 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 stop paracetamol immediately 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 with multiple risk factors.

Vitamin C must be used with caution in patients with iron metabolism disorders, predisposed to the formation of urinary or renal stones, and in subjects deficient in Glucose-6 Phosphate Dehydrogenase.

Excipients with known effect:

This medicine contains 110 mg of sodium benzoate (E211) per effervescent tablet.

This medicine contains 387 mg of sodium per effervescent tablet, equivalent to 19,35 % of the maximum recommended daily dietary intake of sodium by the WHO. The maximum daily dose of this product (6 tablets) is equivalent to 116,4 % of the maximum recommended daily dietary intake of sodium by the WHO. EFFERALGAN VITAMINE C 500 mg/200 mg, effervescent tablet has a high sodium content. To be taken into account in people following a low-sodium diet.

This medicine contains 300 mg of sorbitol (E420) per effervescent tablet. Patients with hereditary fructose intolerance (HFI) must not take/receive this medicine.

This medicine contains 0,003 mg of ethanol per effervescent tablet. The small amount of alcohol contained in this medicine is not likely to produce a noticeable effect.

This medicine contains traces of benzyl alcohol per effervescent tablet. Benzyl alcohol may cause allergic reactions. Due to a risk of accumulation and toxicity (metabolic acidosis), precautions must be taken in pregnant and breastfeeding women, and in subjects with hepatic or renal impairment.

Interactions with paracetamol:

Associations requiring precautions for use

+ Vitamin K antagonists

Risk of increased effect of the vitamin K antagonist and of bleeding risk when paracetamol is taken at maximum doses (4 g/day) for at least 4 days.

More frequent INR monitoring. Possible adjustment of the vitamin K antagonist dose during paracetamol treatment and after its discontinuation.

+ 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).

Interactions with paraclinical tests

Taking paracetamol may distort blood glucose measurement by the glucose oxidase-peroxidase method in cases of abnormally high concentrations.

Taking paracetamol may distort the measurement of blood uric acid by the phosphotungstic acid method.

Interactions with vitamin C:

At doses above 2 g/day of vitamin C, ascorbic acid may interfere with the following laboratory tests: blood and urine creatinine and glucose assays (diabetes monitoring by glucose-oxidase test strips).

Associations requiring precautions for use

+ Deferiprone

By extrapolation from the interaction with deferoxamine: with high-dose intravenous ascorbic acid: abnormalities of cardiac function, even acute heart failure (generally reversible upon discontinuation of vitamin C).

+ Deferoxamine

With high-dose ascorbic acid and by intravenous route: abnormal cardiac function, or even acute heart failure (generally reversible upon discontinuation of vitamin C).

In cases of hemochromatosis, give vitamin C only after deferoxamine treatment has been started. Monitor cardiac function in case of combination.

Associations to be taken into account

+ Ciclosporin

Risk of decreased blood concentrations of ciclosporin, particularly in case of combination with vitamin E.

Pregnancy

Related to paracetamol

A large amount of data on pregnant women demonstrates the absence of any malformation or foetal/neonatal toxicity. Epidemiological studies on the neurodevelopment of children exposed to paracetamol in utero produce inconclusive results.

Linked to vitamin C

No teratogenesis study of vitamin C is available in animals.

In clinical practice, a substantial follow-up and a sufficiently large number of exposed pregnancies have not revealed any malformative or foetotoxic effect of vitamin C.

Consequently, the use of EFFERALGAN VITAMINE C 500 mg/200 mg, effervescent tablet should only be considered during pregnancy if clinically necessary. It should be used at the lowest effective dose, for the shortest possible duration and at the lowest possible frequency.

Breast-feeding

After administration, paracetamol is excreted in small amounts in breast milk.

In the absence of data on the passage of vitamin C into breast milk, the use of this medicine should be avoided during breastfeeding.

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.

EFFERALGAN VITAMINE C 500 mg/200 mg, effervescent tablet has no or negligible effect on the ability to drive vehicles and use machines.

Adverse effects are classified by system organ class. Their frequencies are defined as follows:

• Very common (≥ 1/10)

• Common (≥ 1/100 to < 1/10)

• Uncommon (≥ 1/1000 to < 1/100)

• Rare (≥ 1/10 000 to < 1/1000)

• Very rare (< 1/10 000) 

• Not known (frequency cannot be estimated from the available data)

 

RELATED TO PARACETAMOL

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	Hypersensitivity reactions1		Anaphylactic reaction (including hypotension)1, Anaphylactic shock1, Angioedema (Quincke's oedema)1
Respiratory, thoracic and mediastinal disorders			Bronchospasm (cases of bronchospasm have been identified with paracetamol, mostly in asthmatic patients sensitive to aspirin or to other non-steroidal anti-inflammatory drugs).
Metabolism and nutrition disorders			High anion gap metabolic acidosis3
Gastrointestinal disorders			Diarrhoea, Abdominal pain
Hepatobiliary disorders			Increased liver enzymes
Skin and subcutaneous tissue disorders	Erythema1, Urticaria1, Skin rash1, Purpura2	Severe skin reactions1	Fixed pigmented erythema
1Their occurrence requires immediate and permanent discontinuation of this medicine and related medicines. 2The occurrence of this effect requires immediate discontinuation of this medicine. The medicine may only be reintroduced on medical advice. 3 Cases of high anion gap metabolic acidosis due to pyroglutamic acidosis have been observed in patients with risk factors taking paracetamol (see section Warnings and precautions). Pyroglutamic acidosis may occur in these patients due to low glutathione levels.

RELATED TO VITAMIN C

System organ class	Rare (≥ 1/10 000 to < 1/1 000)	Very rare (< 1/10 000)	Frequency not known
Blood and lymphatic system disorders			At doses above 3 g/day of vitamin C, risk of haemolysis in subjects deficient in G6PD
Nervous system disorders			Dizziness
Gastrointestinal disorders			At doses above 1 g/day of vitamin C, possibility of: digestive disorders (gastric burning, diarrhoea, abdominal pain)
Skin and subcutaneous tissue disorders			Urticaria, Rashes
Renal and urinary disorders			Chromaturia At doses above 1 g/day of vitamin C, possibility of urinary disorders (oxalic, cystinic and/or uric lithiasis)

RELATED TO EFFERALGAN VITAMIN C 500 mg/200 mg, effervescent tablet

System organ class	Rare (≥ 1/10 000 to < 1/1 000)	Very rare (< 1/10 000)	Frequency not known
Blood and lymphatic system disorders			Agranulocytosis
Immune system disorders			Hypersensitivity, Anaphylactic reaction, Angioedema
Gastrointestinal disorders			Abdominal pain
Hepatobiliary disorders			Hepatitis
Skin and subcutaneous tissue disorders			Dermatitis, Pruritus, Rash, Urticaria

Reporting of suspected adverse reactions

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

The risk of severe poisoning (therapeutic overdose or accidental poisoning) may be particularly high in elderly subjects, young children, patients with hepatic or renal impairment, in cases of chronic alcoholism, in patients suffering from chronic malnutrition (see section Dosage and administration), fasting, recent weight loss, familial cholemia (Gilbert's syndrome), as well as patients receiving enzyme-inducing medicines. In these cases, poisoning may be fatal.

Paracetamol overdose:

Symptoms

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

An overdose may cause hepatic cytolysis which may lead to hepatocellular failure that may require liver transplantation, gastrointestinal bleeding, metabolic acidosis, encephalopathy that may progress to coma and death.

Cases of disseminated intravascular coagulation have been observed in the context of paracetamol overdose.

Simultaneously, an increase in hepatic transaminases, lactate dehydrogenase, and bilirubin, and a decrease in prothrombin level may be observed 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.

Overdose may also cause acute pancreatitis, hyperamylasemia, acute renal failure and pancytopenia.

Emergency management

• Stop the treatment.

• Immediate transfer to a hospital setting for emergency medical care, despite the absence of significant early symptoms.

• Rapid evacuation of the ingested product, by aspiration and gastric lavage, preferably within the 4 hours following ingestion.

• Blood sample to perform the initial plasma paracetamol assay. The plasma paracetamol concentration must be measured at least 4 hours after ingestion (an assay performed earlier is not reliable)

• Management of overdose classically involves administration of the antidote N-acetylcysteine as early as possible, by intravenous route or oral route if possible before the tenth hour. Although less effective, a protective effect of the antidote may be obtained up to 48 hours post-ingestion. In this case the antidote must be administered for longer.

• Symptomatic treatment.

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

• Taking other measures will depend on the severity, nature and evolution of the clinical symptoms of paracetamol poisoning and should follow standard intensive care protocols.

Vitamin C overdose:

At doses above 1 g/day of vitamin C, possible: digestive disorders (gastric burning, diarrhoea, abdominal pain), urinary disorders (oxalic, cystinic and/or uric lithiasis).

At doses above 2 g/day of vitamin C, ascorbic acid may interfere with the following laboratory tests: blood and urine creatinine and glucose assays (diabetes monitoring by glucose-oxidase test strips).

At doses above 3 g/day of vitamin C, risk of haemolysis in subjects deficient in G6PD.

Pharmacotherapeutic class: OTHER ANALGESICS AND ANTIPYRETICS-ANILIDES.

ATC code: N02BE01.

Paracetamol has a central and peripheral mechanism of action.

RELATED TO PARACETAMOL

Absorption

Oral absorption of paracetamol is complete and rapid. Maximum plasma concentrations are reached 30 to 60 minutes after ingestion.

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 sulfoconjugation. The latter pathway is rapidly saturable at doses above therapeutic doses. A minor pathway, catalysed by cytochrome P 450, is 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. In contrast, during massive overdoses, the quantity of this toxic metabolite is increased

Elimination

Elimination is primarily urinary. 90 % of the ingested dose is eliminated by the kidney within 24 hours, mainly in glucuronide-conjugated form (60 to 80 %) and sulfate-conjugated form (20 to 30 %).

Less than 5 % is eliminated unchanged.

The elimination half-life is approximately 2 hours.

Pathophysiological variations

Renal impairment (see section Dosage and administration) : elimination of paracetamol and its metabolites is delayed.

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

LINKED TO VITAMIN C

Digestive absorption is good. In case of intake above requirements, the excess is eliminated via the urinary route.

Related to paracetamol

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

3 years

To be kept in the outer packaging.

No special requirements.

Marketing authorisation (AMM)

CIP 3400936373242 (2T/8).

Not reimbursed by Social Security.