4.1. Therapeutic indications

Symptomatic treatment of mild to moderate pain and/or fever in adults and adolescents aged 12 years and above.

4.2. Posology and method of administration

Posology

Paediatric population

Dose depends on body weight and age. A single dose ranges from 10 to 15 mg/kg bodyweight. The maximum total daily dose is 60 mg/kg body weight for total daily dose.

• Children below 12 years of age: this product is not recommended in children aged less than 12 years.

• Adolescents of 12 to 15 years of age: one tablet at a time, every 4-6 hours as needed, the maximum being 4 tablets per day (paracetamol 2000 mg per 24 hours).

• Adolescents of 16 to 18 years and weighing more than 50 kg: as adults.

Adults

For adults and adolescents (aged 16 years and older) weighing more than 50 kg the usual single dose is 1-2 tablets at a time, to be repeated every 6 hours as needed, the maximum being 8 tablets per day (paracetamol 4000 mg per 24 hours).

For adults and adolescents (aged 16 years and older) and weighing less than 50 kg the recommended single dose is 1 tablet. The daily effective dose of paracetamol should not exceed 60 mg/kg/day (upto maximum 2g/day).

Renal impairment

In patients with renal insufficiency, the dose should be reduced:

Glomerular filtration rate

Dose

10-50 ml/min

500 mg every 6 hours

< 10 ml/min

500 mg every 8 hours

Hepatic impairment

In patients with impaired hepatic function or Gilbert´s syndrome, the dose must be reduced or the dosing interval prolonged.

Method of administration

Oral use. Place the tablets in a full tumbler of water and allow to dissolve completely before swallowing.

After dissolving the tablets, a slightly opalescent solution will be produced.

4.3. Contraindications

• Hypersensitivity to paracetamol or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Prolonged or frequent use is discouraged. Patients should be advised not to take other paracetamol containing products concurrently. Taking multiple daily doses in one administration can severely damage the liver; in such case unconsciousness does not occur. However, medical assistance should be sought immediately. Prolonged use except under medical supervision may be harmful. In adolescents treated with 60mg/kg daily of paracetamol, the combination with another antipyretic is not justified except in the case of ineffectiveness.

Patients should be advised to consult a doctor if they suffer from non-serious arthritis and need to take painkillers every day.

Renal and hepatic impairment

Caution is advised in the administration of paracetamol to patients with moderate and severe renal insufficiency, mild to moderate hepatic insufficiency (including Gilbert's syndrome), severe hepatic insufficiency (child-pugh>9), acute hepatitis, concomitant treatment with medicinal products affecting hepatic functions, glucose-6-phosphatedehydrogenase deficiency, hemolytic anemia, alcohol abuse dehydration and chronic malnutrition (see section 4.2).

Alcohol usage

The hazards of overdose are greater in those with non- cirrhotic alcoholic liver disease. Caution should be exercised in cases of chronic alcoholism. The daily dose should not exceed 2000 mg in such case. Alcohol should not be used during the treatment with paracetamol.

“Caution is advised in asthmatic patients sensitive to aspirin (acetylsalicylic acid), because light reaction bronchospasm with paracetamol (cross-reaction) has been reported in less than 5% of the patients tested.”

Other medications and withdrawal:

Abrupt discontinuation of long-term use of high-dosed analgesics, taken not as directed, may cause headache, tiredness, muscular pain, nervousness and vegetative symptoms. The withdrawal symptoms subside within a few days. Patients should be advised to consult their doctor if headaches become persistent.

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe illness such as severe renal impairment and sepsis, or in patients with malnutrition or other sources of glutathione deficiency (e.g. chronic alcoholism) who were treated with paracetamol at therapeutic dose for a prolonged period or a combination of paracetamol and flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, prompt discontinuation of paracetamol and close monitoring is recommended. The measurement of urinary 5-oxoproline may be useful to identify pyroglutamic acidosis as underlying cause of HAGMA in patients with multiple risk factors.

This medicinal product contains 463.01 mg sodium per tablet, equivalent to 23.15% of the WHO recommended maximum daily intake of 2g sodium for an adult.

Neither non-clinical nor clinical data are available to assess aspartame use in infants below 12 weeks of age.

Do not exceed the stated dose.

If symptoms persist consult a doctor.

Treatment with an antidote is advised if an overdose is suspected.

Immediate medical advice should be sought in the event of overdosage even if the patient feels well, because of the risk of delayed serious liver damage.

This product should not be used for more than 10 consecutive days without a prescription. Liver and kidney damage cannot be excluded with prolonged use or excessive doses (more than 2 gram per day).

4.5. Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions:

The anticoagulant effect of warfarin and other coumarins may be enhanced by regular use of paracetamol with increased risk of bleeding. The effect may occur already at daily doses of 2000 mg after 3 days. Occasional doses have no significant effect on bleeding tendency. Increased monitoring of INR values should be done during the duration of the combination and after its discontinuation.

Caution should be taken when paracetamol is used concomitantly with flucloxacillin as concurrent intake has been associated with high anion gap metabolic acidosis due to pyroglutamic acidosis, especially in patients with risks factors (see section 4.4)

Pharmacokinetic interactions:

Use of substances that induce liver enzymes, such as carbamazepine, phenytoin, phenobarbital, rifampicin and St John's wort (Hypericum perforatum) can increase the hepatotoxicity of paracetamol due to increased and more rapid formation of toxic metabolites. Therefore, caution should be taken in case of concomitant use of enzyme inducing substances.

Probenecid nearly halves the clearance of paracetamol by inhibiting its conjugation with glucuronic acid. This probably means that the dose of paracetamol can be halved when being given at the same time as probenecid.

Concurrent intake of medicinal products that accelerate gastric emptying, such as metoclopramide or domperidone, accelerates the absorption and onset of effect of paracetamol.

The absorption of paracetamol is reduced by cholestyramine. Cholestyramine should not be given within one hour if maximum analgesic effect is to be obtained.

Isoniazid affects the pharmacokinetics of paracetamol with possible potentiation of liver toxicity.

Paracetamol may affect the pharmacokinetics of chloramphenicol. Therefore an analysis of chloramphenicol in plasma is recommended in the event of combination treatment with chloramphenicol for injection.

Interference with laboratory tests:

Paracetamol may affect uric acid tests by wolframato phosphoric acid, and blood sugar tests by glucose-oxidase-peroxidase.

4.6. Fertility, pregnancy and lactation

Pregnancy

A large amount of data on pregnant women indicate neither malformative, nor feto/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results. If clinically needed, paracetamol can be used during pregnancy however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency.

Breast-feeding

After oral administration, paracetamol is excreted into breast milk in small quantities. No undesirable effects on nursing infants have been reported. Consequently, paracetamol may be used in breast-feeding women.

4.7. Effects on ability to drive and use machines

Paracetamol has no influence on the ability to drive and use machines.

4.8. Undesirable effects

The frequency using the following convention should be: 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), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Frequency

System

Symptoms

Rare

>1/10000 - < 1/1000

Blood and lymphatic system disorders

Platelet disorders, stem cell disorders, agranulocytosis, leucopenia, thrombocytopenia, haemolytic anaemia, pancytopenia, methaemoglobenaemia

Immune system disorders

Allergies (excluding angioedema).

Psychiatric disorders

Depression NOS, confusion, hallucinations.

Nervous system disorders

Tremor NOS, headache NOS.

Eye disorders

Abnormal vision.

Cardiac disorders

Oedema.

Gastrointestinal disorders

Haemorrhage NOS, abdominal pain NOS, diarrhoea NOS, nausea, vomiting.

Hepato-biliary disorders

Abnormal Hepatic function, hepatic failure, hepatic necrosis, jaundice.

Skin and subcutaneous tissue disorders

Pruritus, rash, sweating, purpura, angioedema, urticaria

General disorders and administration site conditions

Dizziness (excluding vertigo), malaise, pyrexia, sedation, drug interaction NOS.

Injury, poisoning and procedural complications

Overdose and poisoning

Very Rare

(< 10,000)

Respiratory, thoracic and mediastinal disorders

Bronchospasm

Hepato-biliary disorders

hepatotoxicity

General disorders and administration site conditions

hypersensitivity reaction (requiring discontinuation of treatment), serious skin reactions

Metabolism and nutrition disorders

Hypoglycemia

Renal and urinary disorders

Sterile pyuria (cloudy urine) and renal side effects

Not known

(cannot be estimated from the available data)

Metabolism and nutrition disorders

High anion gap metabolic acidosis

Interstitial nephritis has been reported incidentally after prolonged use of high doses. Some cases of epidermal necrolysis, Stevens Johnson syndrome, erythema multiforme, edema of the larynx, anaphylactic shock, anemia, liver alteration and hepatitis, renal alteration (severe renal impairment, haematuria, anuresis), gastro intestinal effects and vertigo have been reported.

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 using paracetamol (see section 4.4). Pyroglutamic acidosis may occur as a consequence of low glutathione levels in these patients.

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 reactions via the Yellow Card Scheme at: https://yellowcard.mhra.gov.uk/ or search for MHRA Yellow Card in the Google Play or Apple App.

4.9. Overdose

There is a risk of poisoning, particularly in elderly subjects, in young adolescents, in patients with liver disease, in cases of chronic alcoholism, in patients with chronic malnutrition. Overdosing may be fatal.

Liver damage is possible in adults who have taken 10g or more of paracetamol. Ingestion of 5g or more of paracetamol may lead to liver damage if the patient has risk factors (see below).

Risk factors

If the patient

• Is on long term treatment with carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin, St John's Wort or other drugs that induce liver enzymes.

• Or, Regularly consumes ethanol in excess of recommended amounts.

• Or, Is likely to be glutathione deplete e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia.

Symptoms

Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain.

Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported. Simultaneously, increased levels of hepatic transaminases (AST, ALT), lactate dehydrogenase and bilirubin are observed together with increased prothrombin levels that may appear 12 to 48 hours after administration.

Management

Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage. Management should be in accordance with established treatment guidelines.

Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be used up to 24 hours after ingestion of paracetamol, however, the maximum protective effect is obtained up to 8 hours post-ingestion. The effectiveness of the antidote declines sharply after this time. If required the patient should be given intravenous N-acetylcysteine, in line with the established dosage schedule. If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital.

High doses of sodium bicarbonate may be expected to induce gastrointestinal symptoms including belching and nausea. In addition, high doses of sodium bicarbonate may cause hypernatraemia; electrolytes should be monitored and patients managed accordingly.