Treatment of mild to moderate pain and/or fever.

Posology

Paracetamol 500 mg Tablets:

Adults, the elderly and children 16 years and over:

Take one or two tablets every 4-6 hours as required.

Children 10 to 15 years of age:

Take one tablet every 4-6 hours as required.

Not recommended for children under 10 years of age.

The dose should not be repeated more frequently than every 4 hours and not more than 4 doses should be taken in any 24 hours.

High doses of paracetamol should be avoided for prolonged periods of time as the risk of liver damage increases.

If pain persists for more than 5 days, fever for more than 3 days, or pain or fever gets worse or other symptoms appear, the clinical situation should be evaluated.

Renal impairment:

It is recommended when giving paracetamol to patients with renal impairment, to reduce the dose and to increase the minimum interval between each administration to at least 6 hours unless directed otherwise by a physician. See table:

Hepatic impairment:

In patients with hepatic impairment or Gilbert's Syndrome, the dose should be reduced or the dosing interval prolonged. The daily dose should not exceed 2 g/day unless directed by a physician.

Method of administration

Oral.

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

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 severly damage the liver; in such cases unconsciousness does not occur. However, medical assistance should be sought immediately. Prolonged use except under medical supervision may be harmful. In adolescents treated with 60 mg/kg daily of Paracetamol, the combination with another antipyretic is not justified except in the case of ineffectiveness.

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, haemolytic anaemia, alcool abuse dehydration and chronic malnutrition (see section 4.2).

The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease. Caution should be excercised in cases of chronic alcholism. The daily dose should not exceed 2 grams in such cases. Alcohol should not be used during the treatment with Paracetamol.

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

500 mg Only: In the case of high fever, or signs of secondary infection or persistence of symptoms a doctor should be consulted.

1000 mg Only: Abrupt discontinuation of long-term use of high dosed analgesics, taken not as directed, may cause headache, tiredness, muscular pain, nervousness and vegetative syptoms. The withdrawal symptoms subside within a few days. Patients should be advised to consult their doctor if headaches become persistent.

Immediate medical advice should be sought in the event of an overdosage even if the patient feels well because of the risk of irreversible liver damage (see section 4.9).

Pack Label:

Immediate medical advice should be sought in the event of an overdose, even if you feel well. Do not take with any other paracetamol-containing products.

Patient Information Leaflet:

Immediate medical advice should be sought in the event of an overdose, even if you feel well, because of the risk of delayed, serious liver damage.

Interference with laboratory tests: Paracetamol may affect uric acid tests by wolframatop phosphoric acid, and blood sugar tests by glucose-oxydase-peroxydase.

Hepatotoxic substances may increase the possibility of Paracetamol accumulation and overdose. The risk of hepatotoxicity of paracetamol may be increased by drugs which induce liver microsomal enzymes such as barbiturates, tricyclic antidepressants, and alcohol.

Probenecid causes an almost 2-fold reduction in clearance of Paracetamol by inhibiting its conjugtion with glucoronid acid. A reduction of the Paracetamol dose should be considered for concomitant treatment with probenecid.

The speed of absorption of paracetamol tablets may be increased by metoclopramide or domperidone and absorption reduced by colestyramine. Salicylamide may prolong the elimination t1/2 of Paracetamol.

Concomitant use of Paracetamol (4 g per day for at least 4 days) with oral anticoagulants may lead to slight variations of INR values. In this case, increased monitoring of INR values should be done during the duration of the combination and after its discontinuation.

Rifampicin and some antiepileptics such as carbamazepine, phenytoin, phenobarbial and primidone may interact with paracetamol tablets.

Isoniazid: Reduction of paracetamol clearance, with possible potentiation of its action and/or toxicity, by inhibiting its metabolism in the liver.

Lamotrigine: Decrease in the bioavailability of lamotrigine, with possible reduction of its effect, due to possible induction of its metabolism in the liver.

Co-administration of acetaminophen with zidovudine may result in nuetropenia or hepatotoxicity. However, these effects have not been consistently reported. The chronic/multiple-dose acetaminophen use in patients on zidovudine therapy should be avoided. However, if chronic acetaminophen and zidovudine are to be given concurrently, not only white blood count should be monitored, but also liver function tests, particularly in malnourished patients.

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.

Lactation:

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

Fertility:

There are no available data on the effect of paracetamol on fertility.

None.

The frequency using the following convention: 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), including isolated reports. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

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

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 national reporting system.

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Spain

Website: www.notificaRAM.es

Portugal

Site internet: http://extranet.infarmed.pt/page.seram.frontoffice.seramhomepage

E-mail: [email protected]

There is a risk of poisoning, particularly in ederly subjects, in young children, in patients with liver disease, in cases of chronic alcoholism and in patients with chronic malnutrition.

Overdose of Paracetamol is poteentially fatal in all populations.

Symptoms generally appear within the first 24 hours and comprise: nausea, vomiting, anorexia, pallor and abdominal pain. Immediate emergency measures are necessary in case of paracetamol overdose, even when no symptoms are present.

Overdose, 10 g or more of Paracetamol in adults or 150 mg/kg of body weight, causes liver cell necrosis likely to induce complete and irreversible necrosis, resulting in hepatocellular insufficiency, metabolic acidosis and encephalopathy which may lead to coma and death.

Simultaneously, incresed 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 admiistration.

Emergency Procedure:

▪ Immediate transfer to hospital.

▪ Blood sampling to determine initial paracetamol plasma concentration.

▪ IV (or oral if possible) administration of the antidote N-acetylcysteine as soon as possible or within 8 hours of the overdose.

▪ Activated charcoal may be used if the dose of Paracetamol ingested exceeds 12 g or 150 mg/kg and should be undertaken if within 1 hour of the overdose.

▪ Oral methionine is also effective provided that it is given within 10 to 12 hours of the overdose.

▪ Symptomatic treatment should be implemented.

▪ Haemodialysis or haemoperfusion is possible in cases of severe poisoning.

Pharmacotherapeutic group: Analgesics and antipyretics, anilides; ATC-code: N02B E01

Paracetamol is an antipyretic analgesic. The mechanism of action is probably similar to that of aspirin and dependant on the inhibition of prostaglandin synthesis. This inhibition appears, however, to be on a selective basis.

Absorption

The absorption of paracetamol by the oral route is rapid and complete. Maximum plasma concentrations are reached 30 to 60 minutes following ingestion.

Distribution

Paracetamol is distributed rapidly throughout all tissues. Concentration are comparable in blood, saliva and plasma. Protein binding is low.

Metabolism

Paracetamol is metabolised mainly in the liver following two major metabolic pathways: glucuronic acid and sulfuric acid conjugates. The latter route is rapidly saturated at doses higher than the therapeutic dose. A minor route, catalysed by the cytochrome P450, results in the formation of an intermediate reagent (N-acetyl-p-benzoquinoneimine) which under normal conditions of use is rapidly detoxified by glutathione and eliminated in the urine, after conjugation with cysteine and mercaptopuric acid. Conversely, when massive intoxication occurs, the quantity of this toxic metabolite is increased.

Elimination

Elimination is essentially through the urine. 90% of the ingested dose is eliminated via the kidneys within 24 hours, principally as glucuronide (60 60 80%) and sulphate conjugates (20 to 30%). Less than 5% is eliminated in unchanged form.

Elimination half-life is about 2 hours.

Special patient groups

Renal Insufficiency: In cases of severe renal insufficiency (creatinine clearance lower than 10 ml/min) the elimination of paracetamol and its metabolites is delayed.

Elderly Subjects: The capacity for conjugation is not modified.

Conventional studies using the currently accepted standards for the evaluation of toxicity to reproduction and development are not available.

Pregelatinised starch

Povidone

Magnesium stearate

Not applicable.

2 years.

Store in the original package in order to protect from light.

500 mg tablets

PVC/PVdC/aluminium blisters: 16, 20 & 100 tablets

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.