Paracetamol 500 mg Effervescent Tablets

Each effervescent tablet contains 500 mg of Paracetamol.

Excipients: Sodium content approximately 503 mg/tablet. Also contains sorbitol (E420) 131 mg /tablet. For full list of excipients see section 6.1

Effervescent Tablet

White to off white round, flat, beveled edged plain on both side.

Treatment of mild to moderate pain and/or fever.

This presentation is reserved for use only in adults and in adolescents aged 12 years and above.

Doses depend on body weight and age; a single dose ranges from 10 to 15 mg/kg body weight (= b.w.) to a maximum of 60 mg/kg b.w. for total daily dose.

Pediatric Patients:

• Children below 12 years of age: Paracetamol effervescent Tablet is not recommended in children aged less than 12 years.

• Adolescents of 12 to 15 years and weighing 41 to 50 kg the posology is one tablet per dose, repeated if necessary 6-4 hours later, without exceeding 4 tablets daily.

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

Adults:

The usual adults dose is one to two tablets of 500mg, repeated if necessary 4 hours later, without exceeding 3g of Paracetamol a day (i.e. 6 tablets).

Maximum daily dose:

• The maximum daily dose of Paracetamol must not exceed 3g.

• Maximum single dose is 1g (2 effervescent tablets)

Paracetamol 500 mg Effervescent Tablets are for oral administration. The tablets should be placed in a full tumbler of water and allowed to dissolve completely before swallowing.

Frequency of administration:

The specific dose interval depends on the symptoms and the maximum daily dose. Systematic administration enables to avoid pain or fever oscillation. Depending on the reoccurrence of symptoms (fever and/or pain), repeated administration is allowed. It should, however, preferably never fall below 6 hours and in no case fall below 4 hours. In adolescents administration should be regularly spaced, including nighttime, preferably at 6 hour intervals, otherwise at intervals of a minimum of 4 hours. If the pain persists for more than 5 days or the fever lasts for more than 3 days, or gets worse or other symptoms appear, you should stop the treatment and consult a doctor.

Renal Insufficiency:

In case of renal insufficiency the dose should be reduced:

Impaired liver function:

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

The daily effective dose should not exceed 60 mg/kg/day (upto maximum 2g/day) in the following situations :

• adults weighing less than 50 kg

• mild to moderate hepatic insufficiency, Gilberts's syndrome (familial non-haemolytic jaundice

• dehydration

• chronic malnutrition

• chronic alcoholism

Intake of paracetamol with food and drink does not affect the efficacy of the medicinal product.

Hypersensitivity to Paracetamol or any of the excipients.

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.

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).

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 2 grams in such case. 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 the patients tested.

This medicinal product contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

This medicinal product contains 503 mg of sodium per effervescent tablet. To be taken into consideration by patients on a controlled sodium diet.

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

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

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 conjugation with glucuronid acid. A reduction of the Paracetamol dose should be considered for concomitant treatment with probenecid.

• Salicylamide may prolong the elimination t1/2 of Paracetamol

• Metoclopramide and Domperidone: accelerate absorption of Paracetamol

• Cholestyramine: reduces absorption 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.

• 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 neutropenia 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.

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

Pregnancy:

Epidemiological data on the oral administration of therapeutic doses of Paracetamol indicate no adverse effects on pregnancy or on the health of the fetus/newborn child. Prospective data on overdose during pregnancy showed no increased risk of malformations. Reproduction studies investigating oral administration did not indicate any signs of malformation or fetotoxicity (see section 5.3).

Paracetamol is considered to be safe in normal therapeutic doses for short-term use as a minor analgesic/antipyretic in pregnancy.

Lactation:

Following oral administration, Paracetamol is excreted into breast milk in small quantities. To date, no adverse reactions or undesirable effects are known in association with lactation. Therapeutic doses of Paracetamol can be administered during breast-feeding.

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

The frequency using the following convention: very common (> 1/10); common (>1/100 to < 1/10); uncommon (>1/1000 to < 1/100); rare (>1/10000 to < 1/1000); very rare (< 1/10000), including isolated reports. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Some cases of epidermal necrolysis, Stevens Johnson syndrome, erythema multiforme, edema 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.

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.

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, 10g 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, 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.

Emergency Procedure:

• Immediate transfer to hospital

• Blood sampling to determine initial paracetamol plasma concentration.

• IV 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 12g or 150mg/kg and should be undertaken if within 1hour 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 the case of severe poisoning.

Pharmacotherapeutic group: other analgesics and antipyretics; anilides

ATC code: N02BE01

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. Concentrations are comparable in blood, saliva and plasma. Protein binding is low.

Metabolism

Paracetamol is metabolized mainly in the liver following two major metabolic pathways: glucuronic acid and sulphuric acid conjugates. The latter route is rapidly saturated at doses higher than the therapeutic dose. A minor route catalyzed 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 cystein 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 to 80%) and sulphate conjugates (20 to 30%). Less than 5% is eliminated in unchanged form.

Elimination half life is about 2 hours.

Physiopathological Variations

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.

In animal studies investigating the acute, sub chronic and chronic toxicity of paracetamol in the rat and mouse, gastrointestinal lesions, blood count changes, degeneration of the hepatic and renal parenchyma and necrosis were observed. These changes are, on the one hand, attributed to the mechanism of action and, on the other, to the metabolism of paracetamol. The metabolites that is probably responsible for the toxic effects and the corresponding organic changes have also been found in humans. Moreover, during long term use (i.e. 1 year) very rare cases of reversible chronic aggressive hepatitis have been described in the range of maximum therapeutic doses. At sub toxic doses, symptoms of intoxication can occur following a 3-week intake period. Paracetamol should therefore not be administered over a long period of time or at high doses.

Extensive investigations showed no evidence of any relevant genotoxic risk of paracetamol in the therapeutic, i.e. non-toxic, dose range.

Long-term studies in rats and mice yielded no evidence on relevant carcinogenic effects at non-hepatotoxic dosages of paracetamol.

Paracetamol crosses the placental barrier. Animal studies and clinical experience to date have not indicated any teratogenic potential.

Anhydrous citric acid

Sodium hydrogen carbonate

Sorbitol E420

Sodium carbonate anydrous

Povidone K 25 (E1201)

Simeticone

Saccharin sodium

Lemon flavour (containing maize maltodextrin, acacia gum (E414) and alpha-tocopherol (E307))

Macrogol 6000

Not applicable.

2 years

Store below 30°C. Keep the polypropylene tube tightly closed. Store in the original container to protect from the moisture and light.

White opaque plain polypropylene tube and white opaque tamper evident polyethylene cap with inbuilt desiccant. Contains 20 tablets, 10 tablets or 8 tablets in a tube.

Pack size: 60 (3 x 20) tablets per carton.

20 (1 x 20) tablets per carton

30 (3 x 10) tablets per carton

10 (1 x 10) tablets per carton

16 (2 x 8) tablets per carton

No special requirements.

Accord Healthcare Limited

Sage House

319 Pinner Road

North Harrow

Middlesex, HA1 4HF

United Kingdom

PL 20075/0083

06/11/2009

04/01/2011