CLARADOL CAFFEINE 500 mg Tablet Blister/16

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

Caffeine ...................................................................................................................................... 50 mg

For one tablet.

Excipient(s) with known effect: sodium

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

Method of administration

Oral use.

The tablets are to be swallowed whole with a drink (for example water, milk, fruit juice).

Dosage

RESERVED FOR ADULTS AND CHILDREN WEIGHING MORE THAN 50 KG (FROM 15 YEARS OF AGE) due to the presence of caffeine.

The usual dosage is 1 to 2 tablets of 500 mg, to be repeated if needed after at least 4 hours.

It is generally not necessary to exceed 3 grams of paracetamol per day, i.e. 6 tablets.

However, in cases of more intense pain, the maximum dosage may be increased up to 4 grams per day, i.e. 8 tablets per day. Always respect an interval of 4 hours between doses.

Recommended maximum doses : see section Warnings and precautions.

Frequency of administration

Regular dosing helps avoid fluctuations in pain and/or fever: in adults, doses should be spaced at least 4 hours apart.

Renal impairment

In cases of severe renal impairment (creatinine clearance below 10 ml/min), the interval between two doses must be at least 8 hours. The dose of paracetamol must not exceed 3 g per day, i.e. 6 tablets.

This medicine is not suitable for children (under 15 years of age) due to its caffeine content.

Hypersensitivity to paracetamol, or to any of the excipients mentioned in the section Composition.

ΙSevere hepatocellular insufficiency (Child-Pugh score > 9).

Special warnings

To avoid a risk of overdose, check that paracetamol is not present in the composition of other medicines.

Recommended maximum doses:

• In adults and children over 50 kg (from 15 years), THE TOTAL DAILY DOSE OF PARACETAMOL MUST NOT EXCEED 4 GRAMS PER DAY (see section Overdose).

Precautions for use

Due to the presence of caffeine, this medicine may cause insomnia; it must not be taken late in the day.

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with serious conditions such as severe renal failure and sepsis, or in patients suffering from malnutrition or 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 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.

Related to caffeine:

Combinations not recommended

+ Enoxacin

Increase in plasma caffeine concentrations, which may lead to excitation and hallucinations due to decreased hepatic metabolism.

Associations to be taken into account

+ Ciprofloxacin, norfloxacin

Increase in plasma caffeine concentrations due to decreased hepatic metabolism.

+ Lithium

In case of abrupt cessation of coffee or caffeine-containing medicines consumption, risk of increased lithaemia.

+ Mexiletine

Increase in plasma concentrations of caffeine, due to inhibition of its hepatic metabolism by mexiletine.

Associations requiring precautions for use

+ Stiripentol

Possible increase in plasma caffeine concentrations, with risk of overdose, due to inhibition of its hepatic metabolism.

Related to paracetamol:

Associations requiring precautions for use

+Vitamin K antagonists

Risk of increased effect of vitamin K antagonists 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.

Other interactions related to the presence of paracetamol:

Medicines leading to delayed gastric emptying may lead to slower absorption of paracetamol and therefore to a delayed onset of action.

Medicines leading to accelerated gastric emptying (for example metoclopramide) may lead to faster absorption of paracetamol and therefore to a faster onset of action.

Concomitant use of medicines that cause induction of hepatic enzymes, for example certain hypnotic and antiepileptic medicines (phenobarbital, phenytoin, carbamazepine etc.) or rifampicin, may lead to liver damage, even at doses of paracetamol that would otherwise be without risk. In case of excessive alcohol consumption, taking paracetamol, even at therapeutic doses, may lead to liver damage.

The effects of the following medicines are intensified: the combination with chloramphenicol may prolong its half-life and thus potentially increase its toxicity.

Tropisetron and granisetron, serotonin 5HT-3 receptor antagonists, may completely inhibit the analgesic effect of paracetamol due to a pharmacodynamic interaction.

Concomitant use of paracetamol and AZT (zidovudine) increases the tendency towards a reduction in the white blood cell count (neutropenia). Therefore paracetamol must not be taken in combination with AZT, except on medical advice.

It is preferable to avoid continuous treatment combining more than one analgesic; there is little evidence of additional benefit for the patient, and the incidence of side effects is generally additive.

Caution should be exercised when paracetamol and flucloxacillin are used concomitantly, as simultaneous use 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.

Pregnancy

DATA RELATED TO PARACETAMOL

A large amount of data on pregnant women demonstrates the absence of any malformation or any fetal/neonatal toxicity. Epidemiological studies on the neurodevelopment of children exposed to paracetamol in utero produce inconclusive results. If clinically necessary, paracetamol may be used during pregnancy; however, it should be used at the lowest effective dose, for the shortest possible duration and at the lowest possible frequency.

Paracetamol may be used during pregnancy, but should only be taken on medical advice.

The use of paracetamol over a prolonged period, at high doses or in combination with other medicines during pregnancy is not recommended, as its safe use under these conditions has not been confirmed.

DATA RELATED TO CAFFEINE

Epidemiological studies do not show an increased risk of malformation due to caffeine. Late in pregnancy, at high doses, caffeine may cause fetal or neonatal cardiac arrhythmia.

Consequently, the use of caffeine should be considered during pregnancy only if necessary.

Breast-feeding

Data related to paracetamol

Paracetamol passes into breast milk in small amounts. Although no adverse effects have been observed so far, paracetamol should be used during breastfeeding on medical advice.

Data related to caffeine

Caffeine passes into breast milk, and the maximum concentration is observed 1 to 2 hours after intake. The half-life of caffeine is considerably increased in the breastfed newborn, by a factor of approximately 15.

Repeated and high doses of caffeine may cause agitation and irritability in the breastfed infant.

The maximum dose of caffeine that is unlikely to have an effect on the child is approximately 100 to 200 mg per day (i.e., one to two cups of coffee).

Consequently:

If taking this medicine appears essential, this dose should not be exceeded, dietary intake included, while spacing out doses as much as possible;

The medicine should be taken right after breastfeeding.

Fertility

Data related to paracetamol:

Data are limited regarding the fact that medicines that inhibit cyclo-oxygenase or prostaglandin synthesis could impair female fertility, through an effect on ovulation, reversible upon discontinuation of treatment. Paracetamol being suspected of inhibiting prostaglandin synthesis, it is possible that it could impair fertility, although this has not been demonstrated.

Some patients taking paracetamol may experience dizziness or drowsiness. Patients should be cautious if they engage in activities requiring alertness.

Related to paracetamol

The listed adverse effects are based on spontaneous reports, therefore an organisation according to the CIOMS III frequency categories is not possible.

Blood and lymphatic system disorders

Changes in blood count, including thrombocytopenia, thrombocytopenic purpura, leukopenia and pancytopenia.

Metabolism and nutrition disorders

High anion gap metabolic acidosis with "undetermined" frequency (cannot be estimated from available data)

Description of selected adverse reactions

High anion gap metabolic acidosis

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.

Gastrointestinal disorders

Nausea, vomiting, stomach ache, diarrhoea and abdominal pain.

Hepatobiliary disorders

Hepatic impairment, hepatitis, dose-dependent hepatic failure, hepatic necrosis (including fatal outcome). Non-compliant chronic use may lead to hepatic fibrosis, hepatic cirrhosis, including fatal outcome (see sections Warnings and precautions and Overdose).

Immune system disorders

Allergic reactions, anaphylactic reaction, and anaphylactic shock.

Nervous system disorders

Dizziness, drowsiness.

Renal and urinary disorders

Renal impairment, particularly in cases of overdose.

Respiratory, thoracic and mediastinal disorders

Bronchospasm and asthma, in particular analgesic asthma syndrome.

Skin and subcutaneous tissue disorders

Very rare cases of severe skin reactions have been reported.

Rash, pruritus, urticaria, allergic oedema and angioedema, acute generalised exanthematous pustulosis, fixed pigmented erythema, erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis (including fatal outcome)

Caffeine-related

Possibility of excitation, insomnia, palpitations.

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/

Intoxication is to be feared in the elderly and especially in young children (therapeutic overdose or frequent accidental intoxication), in whom it may be fatal. In case of paracetamol overdose, a doctor or poison control centre must be contacted immediately.

Acute paracetamol toxicity

The most important effect of acute paracetamol intoxication is hepatotoxicity: hepatocellular lesions are caused by binding of reactive paracetamol metabolites to hepatic cellular proteins. At therapeutic doses, these metabolites are bound by glutathione and form non-toxic conjugates. In the case of massive overdose, the liver's supply of –SH group donors (which promotes glutathione formation) is exhausted, toxic metabolites accumulate and cause hepatic cell necrosis, resulting in impaired liver function progressing to hepatic coma. Renal damage following necrosis of the renal tubules has also been described independently.

The overdose threshold may be lowered in patients taking certain medicines or alcohol, or who are severely malnourished.

Chronic paracetamol toxicity

Chronic toxicity includes various hepatic impairments (see "Symptoms of intoxication"). Data on chronic toxicity, and in particular on the nephrotoxicity of paracetamol, are controversial. Attention should be paid to the possible influence on the peripheral blood count during chronic use.

Symptoms

Nausea, vomiting, anorexia, pallor, abdominal pain, sweating and general malaise generally appear within the first 24 hours. The patient's condition may improve within 24 to 48 hours, although symptoms may not disappear completely.

Liver size increases rapidly, transaminases and bilirubin are elevated, prothrombin time becomes pathological, urine output falls, and mild azotaemia may develop. Hypokalaemia and metabolic acidosis (in particular lactic acidosis) may also develop in the context of acute and/or chronic overdose. Frequent clinical manifestations after 3 to 5 days are: jaundice, fever, fetor hepaticus, haemorrhagic diathesis, hypoglycaemia, and hepatic failure. Hepatic failure may progress to all stages of hepatic encephalopathy, to cerebral oedema, and to death.

Acute renal failure with acute necrosis of the renal tubules, strongly suggested by back pain, haematuria and proteinuria, which may develop even in the absence of severe hepatic impairment.

An overdose, starting from 10 g of paracetamol in a single dose in adults and 150 mg/kg of body weight in a single dose in children, causes hepatic cytolysis that may lead to complete and irreversible necrosis resulting in hepatocellular failure, metabolic acidosis, encephalopathy that may progress to coma and death.

Simultaneously, an increase in hepatic transaminases, lactic dehydrogenase, bilirubin and a decrease in the prothrombin level are observed, which may appear 12 to 48 hours after ingestion.

Emergency management

Intensive medical care with close monitoring of vital signs, laboratory tests and circulatory status should generally be initiated:

• Immediate transfer to a hospital setting. Rapid medical assistance is critical for both adults and children, even if no signs or symptoms are apparent.

• Draw a blood tube to perform the initial plasma paracetamol assay.

• Rapid evacuation of the ingested product by gastric lavage (within the first six hours).

• Treatment of overdose conventionally includes administration as early as possible of the antidote N-acetylcysteine, a donor of –SH groups (or methionine, cysteamine) by intravenous route or oral route if possible before tenth hour, insofar as they conjugate the reactive metabolites and thereby contribute to their normal detoxification. N-acetylcysteine may be protective to a certain degree up to 48 hours after ingestion.

• Symptomatic treatment.

Haemodialysis and haemoperfusion contribute to the elimination of the product

Pharmacotherapeutic class : ANALGESIC, ANTIPYRETIC, (N. Central nervous system)

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 dosages 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 intoxications, the amount of this toxic metabolite is increased.

Elimination

Elimination is mainly urinary. 90 % of the ingested dose is eliminated by the kidney in 24 hours, mainly in glucuronide conjugated form (60 to 80 %) and sulfoconjugated form (20 to 30 %). Less than 5 % is eliminated in unchanged form. The elimination half-life is approximately 2 hours.

Pathophysiological variations

Renal impairment: in cases of severe renal impairment (creatinine clearance below 10 ml/min), elimination of paracetamol and its metabolites is delayed.

Elderly subject: the conjugation capacity is not modified.

Caffeine

Caffeine is rapidly and completely absorbed. Its maximum plasma concentrations are generally reached between a few minutes and 60 minutes after ingestion. It is metabolised by the liver. Its elimination is urinary.

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

3 years.

No special precautions for storage.

No special requirements.