SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Paracetamol Nordic 500 mg Granules

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

One sachet contains 500 mg paracetamol.

One sachet contains 25 mg aspartame (E 951).

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Granules.

White to off white, freely flowable granules

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Symptomatic treatment of mild to moderate pain and/or fever

4.2    Posology and method of administration

Adults:

500-1000 mg, maximum 3000 mg in 24 hours.

Maximum single dose is 1000 mg (2 sachets).

Paediatric Patients:

Paracetamol Nordic 500 mg Granules is not recommended in children below 12 years of age.

Adolescents of 12 to 15 years and weighing 41 to 50 kg: one sachet per dose. Not more than 4 sachets daily.

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

Paracetamol Nordic 500 mg Granules can be swallowed without water or other fluid. The sachet can be torn or cut open on the end where the notch is. The sachet should be emptied directly on the tongue in order to swallow the granules. If required, any remaining granules can be swallowed with water. Instructions for use:

The specific dose interval depends on the symptoms and the maximum daily dose.

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.

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, the patient should stop the treatment and consult a doctor.

In cases of renal insufficiency the dose should be reduced:

Glomerular filtration    Dose

10 - 50 ml/min    500 mg every 6 hours

< 10 ml/min    500 mg every 8 hours

The daily effective dose must be considered, without exceeding 60 mg/kg/day (without exceeding 3 g/day) in the following situations:

-    Adults and adolescents weighing less than 50 kg,

-    Hepatocellular insufficiency (mild to moderate). Gilberts’s syndrome (familial non-haemolytic jaundice)

-    Chronic alcoholism

-    Dehydration

-    Chronic malnutrition

4.3 Contraindications

Paracetamol Nordic 500 mg Granules are contraindicated in patients with hypersensitivity to paracetamol or any of the excipients.

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.

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.

Paracetamol Nordic contains aspartame, which is a source of phenylalanine. The phenylalanine in the granules may be harmful to people with phenylketonuria.

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

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).

4.5 Interaction with other medicinal products and other forms of interaction

The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by colestyramine. Colestyramine should not be given within an hour if maximal analgesic effect is to be obtained.

The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.

Use of substances that induce liver enzymes, such as rifampicin and some antiepileptics (phenytoin, phenobarbital, carbamazepine) have shown to reduce the paracetamol plasma AUC by 60% and can increase the hepatotoxicity of paracetamol overdose due to increased and more rapid formation of toxic metabolites.

Caution should be taken in case of concomitant use of enzyme inducing substances (see section 4.9).

Probenecide blocks the binding of paracetamol to glucuronic acid reducing paracetamol clearance by a factor of about 2. If probenecide is taken concurrently the paracetamol dose should be reduced.

Salicylamide may prolong the elimination half life of paracetamol.

Ethyl alcohol potentiates paracetamol toxicity, possibly by inducing hepatic production of paracetamol-derived hepatotoxic products.

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

Paracetamol may decrease the bioavailability of lamotrigine, with possible reduction of its effect, due to a possible induction of its metabolism in the liver

Interference with laboratory tests

Paracetamol may affect phosphotungstate uric acid tests and blood sugar tests by glucose-oxydase-peroxydase.

4.6 Fertility, Pregnancy and lactation

Pregnancy:

Epidemiological data from the use of oral therapeutic doses of paracetamol indicate no undesirable effects on the pregnancy or on the health of the foetus/newborn infant. Reproductive studies did not show any malformation or foetotoxic effects.

Consequently under normal conditions of use, paracetamol can be used throughout the duration of pregnancy, after a benefit-risk assessment.

Lactation:

Paracetamol is excreted in breast milk but not in a clinically significant amount. No negative effects on infants have been reported. Paracetamol may be used by breastfeeding women as long as the recommended dosage is not exceeded. In case of long term use caution should be exercised.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

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

Frequency	System	Symptoms
Rare >1/10000 - < 1/1000	Blood and lymphatic system disorders	Platelet disorders, stem cell disorders.
	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	Hepatic function abnormal, 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)	Hepato-biliary disorders	hepatotoxicity
	General disorders and administration site conditions	hypersensitivity reaction (requiring discontinuation of treatment)
	Blood and lymphatic system disorders	thrombocytopenia leukopenia neutropenia hemolytic anemia
	Metabolism and nutrition disorders	Hypoglycaemia
	Renal and urinary disorders	Sterile pyuria (cloudy urine) and renal side effects

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.

4.9 Overdose

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

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

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

Or

b,    Regularly consumes ethanol in excess of recommended amounts.

Or

c,    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.

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 local overdose 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. Management of patients who present with serious hepatic dysfunction beyond 24 h from ingestion should be discussed with the NPIS or a liver unit.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: other analgesics and antipyretics; anilides; ATC code: N02BE01

Paracetamol has both analgesic and antipyretic effects. However, it does not have an anti-inflammatory effect.

5.2 Pharmacokinetic properties

Absorption

After oral administration paracetamol is rapidly and almost completely absorbed. Peak plasma concentrations are reached after 30 minutes to 2 hours.

Distribution

The volume of distribution of paracetamol is approximately 1 L/kg bodyweight. At therapeutic doses protein binding is negligible.

Metabolism

In adults paracetamol is conjugated in the liver with glucuronic acid (~60%), sulphate (~35%) and cystein (~3%).

Elimination

Paracetamol is excreted in urine, predominantly as the glucuronide and the sulphate conjugate, and approximately 2-3% unchanged. The elimination half life varies between 1 and 4 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.

5.3 Preclinical safety data

In animal studies investigating the acute, subchronic 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 which are 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 subtoxic 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.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Basic butylated methacrylate copolymer Colloidal hydrated silica (E551)

Stearic acid Sodium laurilsulfate Xylitol (E967)

Saccharin sodium (E954)

Aspartame (E951)

Grapefruit flavour (containing potato maltodextrin, acacia gum (E 414), buthylhydroxyanisol (E 320))

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Each carton contains 5, 10 or 20 sachets (PETP/Alu/PE) of Paracetamol

Nordic 500 mg Granules

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7 MARKETING AUTHORISATION HOLDER

Imgroma B.V.

Verrijn Stuartweg 60 1112 AX Diemen The Netherlands

8    MARKETING AUTHORISATION NUMBER(S)

PL 41885/0001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

14/03/2011

10 DATE OF REVISION OF THE TEXT

14/05/2013