SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Supofen 200 mg/5ml oral suspension

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 ml contains 40 mg of paracetamol.

The full oral syringe (5 ml) contains 200 mg of paracetamol.

Excipient(s) with known effect:

Contains 0.68 mg/ml of methyl parahydroxybenzoate (E218), 0.12 mg/ml of propyl parahydroxybenzoate (E216) and 500 mg/ml of sucrose.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Oral suspension.

Viscous white to almost white liquid with homogenous appearance and orange flavour. The pH lies between 5-6.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

For the short-term symptomatic treatment of mild to moderate pain (e.g. headache, odontalgia and dysmenorrhea) and/or fever.

Supofen is used to treat mild to moderate pain and/or fever in infants (older than 3 months), children, adolescents and adults (including elderly).

4.2 Posology and method of administration

Supofen is used to treat mild to moderate pain and/or fever in infants (older than 3 months), children, adolescents and adults (including elderly). In children below 3 years of age paracetamol must be used only by physician’s recommendation.

It is imperative to respect the posology defined on the basis of the child's body weight and thus to select the appropriate dose in ml of the oral suspension. Approximate ages based on body weight are given for information.

The recommended daily dose of paracetamol is approximately 60 mg/kg/day which is divided into 4 or 6 administrations daily, i.e. 15 mg/kg every 6 hours or 10 mg/kg every 4 hours.

For example, to administer 15 mg/kg every 6 hours, the instructions are as follows:

5 ml oral suspension = 200 mg paracetamol

Alternatively this oral suspension can be given as follows:

Child’s Age	How Much	How often (in 24 hours)
3 - 6 months	1.5 ml	4 times
6 - 24 months	3 ml	4 times
2 - 3 years	4.5 ml	4 times
4 - 6 years	6 ml	4 times
7 - 9 years	9 ml	4 times
10 - 12 years	12.5 ml	4 times

To follow the above posology schemes, a dosing interval of at least 6 hours must be maintained.

Maximal daily dose must not be exceeded due to risk of serious hepatic damage (see section 4.4 and 4.9).

The bottle should be well shaken before using.

The exact quantity of Supofen should be delivered using the syringe provided in the cardboard box. The dosing syringe should be rinsed after use under the tap by hand operating several times (filling in with water).

In case of high fever, signs of secondary infection or persistence of symptoms for more than 2 days, the patient/caretaker should be advised to contact a doctor. (see section 4.4.)

For infants weighing less than 7 kg of body weight (6 month), the use of suppositories, if available, should be considered except in the case where the administration of this pharmaceutical form is not possible for clinical reasons (e.g. diarrhoea).

For children weighing more than 41 kg (older than 12 years), adolescents and adults other paracetamol dosage forms are available which may be considered more appropriate.

Supofen is a ready to use medicine and can be taken with food and drinks. The administration of food did not show influence on the effect of the medicine, yet taking paracetamol after meals may lead to a delay on the onset of its action.

Severe hepatic insufficiency:

Care should be taken in administering this product to patients with severe hepatic impairment.

Mild to moderate hepatic insufficiency:

In patients with mild to moderate hepatic insufficiency, or with Gilbert syndrome (familial non-haemolytic jaundice) the daily effective dose should not exceed 60 mg/kg/day (up to maximum of 2 g/day).

Renal insufficiency:

Paracetamol should be used with caution in the presence of renal insufficiency and increased interval between doses is recommended in case of severe renal insufficiency. When creatinine clearance is lower than 10 ml/min, the minimum interval between two intakes should be 8 hours.

Dialysed patients: it should be administrated a maintenance dose after haemodialysis but not after peritoneal dialysis.

Elderly: in accordance with pharmacokinetic data no dosage adjustments are required. However one should consider that these patients are more predisposed to situations of renal and/ or hepatic insufficiency.

4.3 Contraindications

Supofen is contra-indicated:

- In patients with hypersensitivity to the active substance or to any of the excipients listed in section 6.1;

4.4 Special warnings and precautions for use

Prolonged or frequent 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.

After long term treatment (>3 months) of analgesics with use every second day or more frequently, headache may develop or aggravate. Headache caused by overuse of analgesics (MOH - medication-overuse-headache) should not be treated by increasing the dose. In such cases the use of analgesics should be discontinued in consultation with a doctor.

Abrupt discontinuation following long-term high-dose, incorrect use of analgesics may lead to headaches, fatigue, muscle pain, nervousness and automatic symptoms. These withdrawal symptoms resolve within a few days. Until this time, further intake of analgesics should be avoided and not restarted without medical advice.

Hepatic and renal 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, haemolytic anaemia, 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.

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).

Alcohol should not be used during the treatment with paracetamol (see section 4.5).

Caution is advised in asthmatic patients sensitive to acetylsalycilic acid, because light reaction bronchospasm with paracetamol (cross-reaction) has been reported.

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

Paediatric population

In children and adolescents treated with 60 mg/kg daily of paracetamol, the combination with another antipyretic is not justified except in the case of ineffectiveness.

Important information about some of the ingredients of Supofen Contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicinal product. Doses over 10 ml of oral suspension contain more than 5 g of sucrose per dose which should be taken into account in patients with diabetes mellitus. Sucrose may be harmful to the teeth.

Contains methyl parahydroxybenzoate (E218) and propyl parahydroxybenzoate (E216). May cause allergic reactions (possibly delayed).

4.5 Interaction with other medicinal products and other forms of interaction

Paracetamol is extensively metabolised in the liver, and therefore it may interact with other medicinal products that use the same metabolic pathways or which are capable of inhibiting or inducing such pathways. Some of its metabolites are hepatotoxic, and thus concomitant administration with potent enzymatic inducers (rifampicin, certain anticonvulsant drugs, etc.) may cause hepatotoxic reactions, particularly when using high doses of paracetamol.

The following are some of the potentially most relevant interactions affecting the use of paracetamol:

Concomitant use of paracetamol with:	Possible side effects:
Ethyl alcohol	Potentiates paracetamol toxicity, possibly by inducing hepatic production of paracetamol-derived hepatotoxic products (see section 4.4)
Anticholinergic drugs (glycopyrronium, propantheline)	Reduce the absorption of paracetamol, with possible inhibition of its effect due to the reduced rate of gastric emptying.
Hormonal contraceptives/oestrogens	Reduce plasma paracetamol levels, with possible inhibition of its effect, due to possible induction of its metabolism.
Antiepileptic drugs (phenytoin, phenobarbital, methylphenobarbital, primidone)	Reduce of the bioavailability of paracetamol as well as potentiation of overdose hepatotoxicity due to the induction of hepatic metabolism.
Activated charcoal	Reduces the absorption of paracetamol when administered rapidly after an overdose.
Isoniazid	Reduction of clearance of paracetamol, with possible potentiation of its action and/or toxicity, by inhibiting its metabolism in the liver.
Metoclopramide and domperidone	Increases the absorption of paracetamol in the small intestine due the effects of these medications on gastric emptying.
Probenecid	Increases the plasma half-life of paracetamol, by reducing the breakdown and urinary excretion of its metabolites.
Propranolol	Increases plasma paracetamol levels, possibly by inhibiting its metabolism in the liver.
Ion exchange resins (cholestyramine)	Reduce the absorption of paracetamol, with possible inhibition of its effect due to the

	adsorption of paracetamol in the intestine.
Rifampicin	Increases paracetamol clearance and formation of its hepatotoxic metabolites due to a possible induction of its metabolism in the liver.

The following are some of the potentially most relevant interactions resulting in clinically relevant changes on the use of other medicinal products:

Concomitant use of paracetamol with:	Possible side effects:
Oral anticoagulants (acenocumarol, warfarin)	Possible potentiation of the anticoagulant effect, by inhibiting hepatic production of coagulation factors. However, because the apparently low clinical relevance of this interaction in the majority of patients, alternative analgesia with salicylates is considered when the patient is taking anticoagulant drugs. Nonetheless, the dose and duration of the treatment should be as low as possible, with periodic INR monitoring.
Chloramphenicol	Potentiation of chloramphenicol toxicity, possibly 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
Zidovudine	Although a possible increase in the toxicity of zidovudine (neutropenia, hepatotoxicity) has been described in isolated cases, there seems to be no kinetic type interaction between these two drugs.

Interactions with diagnostic tests

Paracetamol may affect the values of the following analytical determinations:	Possible effects:
Blood	Increase (biological) in

	transaminases (ALT and AST), alkaline phosphatase, ammonia, bilirubin, creatinine, lactate-dehydrogenase (LDH) and urea; increase (interference with test) in glucose, theophylline and uric acid. Increase in prothrombin time (in patients on maintenance warfarin therapy, but with no clinical significance). Reduction (interference with test) of glucose when using the oxidase-peroxidase method.
Urine	False increases in metadrenaline and uric acid may appear.
Urine 5-hydroxyindoleacetic acid (5-HIAA) determinations	Paracetamol may cause falsepositive results in qualitative screening tests using nitrosonaphthol reagent. The quantitative test is unaffected.
Bentiromide test for assessing pancreatic dysfunction	Paracetamol, like bentiromide, is also metabolized to an arylamine, and thus the apparent quantity of paraaminobenzoic acid (PABA) recovered is increased; it is recommended that paracetamol be discontinued at least three days prior to administration of bentiromide

4.6 Fertility, pregnancy and lactation

Pregnancy

Epidemiological data on the oral administration of therapeutic doses of paracetamol indicate no adverse effects on pregnancy or on the health of the foetus or newborn child. Prospective data on overdose during pregnancy showed no increase risk on malformation. Reproduction studies investigating oral administration did not indicate any signs of malformation or foetotoxicity (see section 3).

Paracetamol is considered to be safe in therapeutic doses for short-term use, and can be used throughout the duration of pregnancy after a benefit-risk assessment.

During pregnancy, paracetamol should not be taken for long periods, at high doses or in combination with other medicinal products as safety of use has not been established in such cases.

Lactation

Following oral administration, paracetamol is excreted in the breast milk in small quantities. To date, no undesirable effects on infant have been reported. Paracetamol may be used by breastfeeding woman as long as the recommended dosage is not exceeded.

4.7 Effects on ability to drive and use machines

Paracetamol does not interfere with the ability to drive or use machines. However, it should be taken into consideration that may be observed as side effects mild somnolence and vertigo during the treatment with paracetamol.

4.8 Undesirable effects

The effects listed below are rated with the following convention of frequency: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1000 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).

Blood and lymphatic system disorders:

-    Very rare: thrombocytopenia, leukopenia, pancytopenia.

Nervous system disorders:

-    Common: mild somnolence

-    Uncommon: vertigo, somnolence, nervousness.

Respiratory, thoracic and mediastinal disorders:

-    Uncommon: pharyngeal burning sensation.

-    Very rare: bronchospasm in predisposed patients.

Gastrointestinal disorders:

-    Common: nausea, vomiting.

-    Uncommon: diarrhoea, abdominal pain, constipation.

Hepatobiliary disorders

Biological signs of hepatotoxicity can become apparent due to an elevation of transaminases after a treatment with high doses paracetamol.

Skin and subcutaneous tissue disorders:

-    Rare: allergic dermatitis, including hypersensitivity reactions (namely hives, pruritus), erythema and angioedema.

- Uncommon: nephrotoxic effects. These effects have not been reported in association with therapeutic doses, except after prolonged administration.

Biological signs of hepatotoxicity can become apparent due to an elevation of transaminases after a treatment with high doses acetaminophen.

4.9 Overdose

The intake of high doses of paracetamol may lead to intoxication signs with a latency period of 24 to 48 hours. Patients may develop dysfunction of the hepatic function, hepatocellular necrosis and hepatic coma (which may be fatal).

Acute renal insufficiency may occur as a consequence of the hepatic insufficiency or, rarely, in its absence.

Patients receiving treatment with enzyme inducers or with history of alcoholism have increased susceptibility of developing hepatic toxicity.

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

The following symptoms of the paracetamol overdose may occur:

-    During phase I which lasts between 12 to 14 hours after the overdose, patients may, frequently, present paleness, nausea, vomiting, sweating, somnolence and malaise.

-    During phase II, after 24 to 48 hours, it is seen a subjective improvement of the symptoms but the first signs of hepatic injury start to appear: mild abdominal pain, hepatomegaly, increase of the transaminases and bilirubin levels, prolonged prothrombin time and oliguria.

-    During phase III, after 48 hours, the transminases levels reach their maximum, with jaudice, coagulopathy, hypoglycaemia, progression for hepatic coma.

It was reported the occurrence of cardiac arrhythmias.

In adults, the hepatotoxicity can occur after the ingestion of a single dose of 10-15 g (150-250 mg/kg) of paracetamol; doses of 20-25 g or higher are potentially fatal.

Fatalities are rare with doses lower than 15 g of paracetamol.

Treatment:

The adequate control of the paracetamol overdose requires an immediate treatment.

Despite the absence of early symptoms, patients should be taken to the hospital emergency for immediate treatment.

The emergency treatment in the cases of paracetamol overdose is the gastric emptying by gastric aspiration or lavage and administration of activated charcoal (only if the antidote is administrated by i.v. route, because by oral route the activated charcoal stops the antidote absorption), when the intoxication happened less than 4 hours ago and in a dosage equal or higher than 10 g.

Since the quantity of paracetamol ingested is, usually, uncertain, not being reliable for a therapeutic approach, the plasma concentration of paracetamol should be determined as soon as possible, but never before 4 hours after the ingestion (to ensure that the maximum concentration has already been reached). The specific treatment with the antidote, acetylcysteine, should be administrated immediately (one should not wait for the laboratorial results to begin the intoxication therapy) if less than 24 h have occurred since the ingestion. The results are great if acetylcysteine is administrated in the first 16h, particularly in the first 8 h. However, there are reports of the therapeutic success even when acetylcysteine administration was initiated 36 hours after the paracetamol ingestion. If the patient is incapable of retaining acetylcysteine due to vomiting, the placement of a duodenal probe allows acetylcysteine administration. Other alternative is the administration of methyonine per os, if the patient does not vomit and is conscious.

To patients with hepatic failure should be administrated an IV glucose solution to prevent hypoglycemia.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other analgesics and antipyretics, Anilides, Paracetamol.

ATC Code: N02BE01

Paracetamol has pharmacological properties, with proven efficacy, as analgesic and antipyretic, even though it has a weak anti-inflammatory effect. The mechanism of analgesic action has not been fully determined. Paracetamol may act predominantly by inhibiting prostaglandin synthesis in the central nervous system (CNS) and, to a lesser extent, through a peripheral action by blocking pain impulse generation. The peripheral action may also be due to inhibition of prostaglandin synthesis or to inhibition of the synthesis or actions of other substances that sensitise pain receptors to mechanical or chemical stimulation.

Paracetamol probably produces antipyresis by acting centrally on the hypothalamic heat regulating centre to produce peripheral vaso-dilation resulting in increased blood flow through the skin, sweating and heat loss. The central action probably involves inhibition of prostaglandin synthesis in the hypothalamus.

5.2 Pharmacokinetic properties

Absorption:

Paracetamol is absorbed in a quick and almost complete way from the gastrointestinal tract. After the administration of paracetamol, plasma peak is obtained within 10 to 60 minutes. After 8 h only a small quantity of the drug is detectable in plasma.

Distribution:

Paracetamol is quick and uniformly distributed in most of the body tissues. The binding of paracetamol to plasma proteins is low.

Biotransformation:

Paracetamol is metabolised by the microsomal enzyme system of the liver. About 80 - 85% of the body paracetamol is connected mainly with glucuronic acid and in lower extension with sulphuric acid. A small quantity of paracetamol is deacetylated, probably to p-aminophenol, which causes metahemoglobinaemia.

Data from studies performed in vitro and performed in animals show that small quantities of paracetamol are metabolised by the microsomal enzyme cytochrome P-450, giving a reactive intermediate metabolite, which is mostly metabolised by the conjugation route with the glutathione and finally excreted in urine with mercapturic acid. It was suggested that this intermediate metabolite is the responsible for the liver necrosis induction by paracetamol and that great doses of paracetamol may cause glutathione depletion which causes the inactivity of this toxic metabolite.

With high doses, the capacity of the metabolic routes, for the conjugation with the glucuronic acid and with the sulphuric acid may be exceeded, from what results an increase of paracetamol metabolism by alternative routes.

Drugs that possibly modify this metabolic processes (like for example: acetylcysteine, cysteine, mercaptoamine) have been studied as possible antidotes for the hepatotoxicity induced by paracetamol.

Elimination:

Paracetamol in plasma has a half-life of 1.25 - 3 hours. The plasma half-life of paracetamol may be prolonged in the case of ingestion of toxic doses or in patients with liver injuries.

Paracetamol is excreted by urine mainly as acetaminophen glucuronate and in small quantities as acetaminophen sulphate and mercaptate and as non-metabolised drug.

About 85% of paracetamol dose is excreted in urine in the free and conjugated form in the 24 hours after the ingestion. Paracetamol administration in patients with moderate or severe renal insufficiency may result in the accumulation of paracetamol conjugates.

5.3 Preclinical safety data

Paracetamol in hepatotoxic doses showed genotoxic and carcinogenic potential (liver and bladder tumours), in mice and rat. However, it is considered that this genotoxic and carcinogenic activity is related with changes in the metabolism of paracetamol when in high doses/ concentrations and does not represent a risk for the clinical use.

In non-hepatotoxic doses, paracetamol was not teratogenic in mice and did not originated anomalies in the intra-uterine development in rat. High doses of paracetamol, administrated by oral route, compromised the spermatogenesis and caused testicular atrophy.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Citric acid monohydrate Sodium citrate Sucrose

Methyl parahydroxybenzoate (E218) Propyl parahydroxybenzoate (E216) Xanthan gum Purified water Orange flavour:

Natural flavouring substance(s) Artificial flavouring substance(s) Ethanol

Butylated hydroxyanisole (E320)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years for the unopened bottle.

After first-opening the bottle, the oral suspension should be used in the next 6 months.

6.4 Special precautions for storage

This medicinal product does not require any special temperature storage conditions. Store in the original package in order to protect from light.

6.5 Nature and contents of container

85 ml of oral suspension in an amber glass bottle (type III) with a child-resistant closure (polyethylene, polypropylene) in a cardboard box also containing a 5 ml oral syringe (polyethylene, polystyrene) graduated every 0.25 ml.

6.6 Special precautions for disposal

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

7    MARKETING AUTHORISATION HOLDER

Laboratorios Basi - Industria Farmaceutica, S.A.

Rua do Padrao, 98 3000-312 Coimbra - Portugal Tel.: +351 239 827 021 Fax.: +351 239 492 845 e-mail: basi@basi.pt

8    MARKETING AUTHORISATION NUMBER(S)

PL 27632/0001

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

19/12/2012

10    DATE OF REVISION OF THE TEXT

19/12/2012