SUMMARY OF PRODUCT CHARACTERISTICS

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1. NAME OF THE MEDICINAL PRODUCT

(Invented name), film-coated tablet

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Paracetamol...... 500.00 mg Chlorphenamine maleate...... 4.00 mg

For one film-coated tablet

Excipients with known effect: Carmoisine (E122) For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Oblong purple film-coated tablet.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications This medicinal product is indicated for treatment, during the course of colds, rhinitis, rhinopharyngitis and flu-like conditions in adults and children aged over 15 years:  of clear nasal discharge and watering of the eyes,  of sneezing,  of headaches and/or fever.

4.2 Posology and method of administration

Posology Restricted to adults and children over the age of 15 years.

Weight Dose per Administration Maximum daily dose (age) administration interval Adults and 1 tablet 4 hours 4 tablets children >50 kg i.e., i.e., (>15 years) 500 mg of paracetamol 2,000 mg of paracetamol 4 mg of chlorphenamine 16 mg of chlorphenamine

Do not exceed the maximum posology of 4 tablets per 24 hours.

Patients with renal failure In the event of renal failure and unless otherwise medically advised, it is recommended that the dose be reduced and that the minimum interval between the 2 doses be increased, based on the following table:

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Creatinine Administration interval clearance ≥50 ml/min 4 hours 10–50 ml/min 6 hours

<10 ml/min 8 hours

The total dose of paracetamol should not exceed 3 g/day.

Patients with hepatic failure In patients with active or compensated chronic hepatic disease, particularly those with hepatocellular insufficiency, chronic alcoholism, chronic malnutrition (low reserves of hepatic glutathione), and dehydration, the dose of paracetamol should not exceed 3 g/day.

Special clinical situations The lowest possible effective daily dose of paracetamol should be used, without exceeding 60 mg/kg/day (without exceeding 3 g/day) in the following conditions:

 adults weighing less than 50 kg,  mild-to-moderate hepatocellular insufficiency,  chronic alcoholism,  chronic malnutrition,  dehydration.

Maximum recommended doses:  in adults and children over 50 kg, THE TOTAL PARACETAMOL DOSE SHOULD NOT EXCEED 4 GRAMS PER DAY (see section 4.9).  in adults and children over 50 kg, THE TOTAL DOSE OF CHLORPHENAMINE MALEATE SHOULD NOT EXCEED 16 MILLIGRAMS PER DAY (see section 4.9).

Method of administration Oral use. The tablets should be swallowed as they are with a drink (e.g. water, milk, fruit juice). Evening doses should be favoured because of the sedative effect of chlorphenamine maleate.

Frequency of administration 1 tablet, to be renewed if needed, after a minimum of 4 hours, without exceeding 4 tablets per day.

Duration of treatment If fever or pain persist for more than 3 days, or symptoms fail to improve after 5 days of treatment, the management of treatment should be reassessed.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. In children under 15 years of age.

Due to the presence of paracetamol:  Severe hepatocellular insufficiency or active decompensated hepatic disease.

Due to the presence of chlorphenamine maleate:

3  Risk of angle-closure glaucoma.  Risk of urinary retention related to urethroprostatic disorders.

4.4 Special warnings and precautions for use

In case of high or persistent fever, or if signs of superinfection occur or symptoms persist for more than 5 days, treatment must be reassessed.

In order to avoid a risk of overdose  check that there is no paracetamol or chlorphenamine maleate in the composition of the other medicinal products (medicinal products obtained with or without a prescription),  respect the maximum recommended doses (see section 4.2).

This medicinal product contains an azo colouring agent (E122) and may cause allergic reactions.

Related to the presence of paracetamol:

Paracetamol should be used with caution in the event of:  weight <50 kg,  mild-to-moderate hepatocellular insufficiency,  renal failure (see table in section 4.2),  glucose-6-phosphate dehydrogenase (G6PD) deficiency (which may lead to haemolytic anaemia),  chronic alcoholism, excessive alcohol consumption (3 or more alcoholic drinks per day),  anorexia, bulimia or cachexia,  chronic malnutrition (low reserves of hepatic glutathione),  dehydration, hypovolaemia (see section 4.2).

Very rare cases of serious skin reactions have been reported. Patients should be informed of the early signs of these serious skin reactions and the onset of a skin rash or any other signs of hypersensitivity leading to the discontinuation of treatment.

Related to the presence of chlorphenamine maleate:

This medicinal product should be used with caution in patients (particularly elderly patients) with:  a higher sensitivity to orthostatic hypotension, vertigo, and sedation,  chronic constipation (risk of paralytic ileus),  possible prostatic hypertrophy,  severe hepatic and/or renal failure, due to the risk of accumulation.

Due to the presence of chlorphenamine, it is not recommended to take alcoholic drinks, medicinal products containing alcohol or sedatives (barbiturates in particular) during treatment, because they potentiate the sedative effect of antihistamines (see section 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

Related to the presence of paracetamol:

Combinations requiring precautions for use

+ Antivitamin K Increased risk on the effect of antivitamin K and the risk of haemorrhage in the event that paracetamol is taken at maximum doses (4 g/day) for at least 4 days.

4 More frequent INR controls. Potential adjustment of the antivitamin K dosage during treatment with paracetamol and after its discontinuation.

+ Interactions with laboratory tests: Administration of paracetamol can cause errors in blood glucose tests using the glucose oxidase peroxidase method in the event of abnormally high concentrations. Administration of paracetamol can cause errors in blood uric acid assays using the phosphotungstic acid method.

Related to the presence of chlorphenamine maleate:

Combinations not recommended

+ Alcohol (drink or excipient) Increased sedative effect of H1 antihistamine by alcohol. Impaired alertness may make driving and use of machines dangerous. Avoid the consumption of alcoholic drinks and medicinal products containing alcohol.

+ Sodium oxybate Increased central nervous system depression. Impaired alertness may make driving and use of machines dangerous.

Combinations to be taken into consideration

+ Other atropinic medicinal products: imipraminic antidepressants, most atropinic H1 antihistamines, anticholinergic antiparkinson agents, atropinic antispasmodics, disopyramide, phenothiazine neuroleptics and clozapine. Addition of atropinic undesirable effects such as urinary retention, constipation, dryness of the mouth.

+ Other sedative medicinal products: morphine derivatives (analgesics, antitussives and substitution treatments), neuroleptics, barbiturates, benzodiazepines, anxiolytics other than benzodiazepines (meprobamate), hypnotics, sedative antidepressants (amitriptyline, doxepin, mianserin, mirtazapine, trimipramine), sedative H1 antihistamines, centrally-acting antihypertensives; other: baclofen and thalidomide. Increased central nervous system depression. Impaired alertness may make driving and use of machines dangerous.

4.6 Fertility, pregnancy and lactation

Pregnancy Studies in animals did not show evidence of a teratogenic or foetotoxic effect from paracetamol. Clinically, the results from epidemiology studies seem to rule out a specific malformation or foetotoxic effect from paracetamol or chlorphenamine.

Prospective data on pregnant women exposed to paracetamol overdoses did not show an increased risk of malformation. Therefore, the use of this medicinal product during pregnancy and breast-feeding should only be considered if necessary. The recommended dosage and duration of treatment must be strictly respected. In the case of administration at the end of pregnancy, take into account the possible repercussions of the atropinic and sedative properties of chlorphenamine for newborns.

5 Breastfeeding It is not known whether chlorphenamine is excreted in breast milk. Given the possibilities of the newborn’s sedation or paradoxical excitation, this medicinal product is not recommended during breast- feeding.

Fertility Due to a potential mechanism of action on cyclooxygenase and prostaglandin synthesis, paracetamol may alter fertility in women, by a reversible effect on ovulation upon discontinuation of treatment. Effects on male fertility have been observed in an animal study. The relevance of these effects in humans is unknown.

4.7 Effects on ability to drive and use machines

(Invented name), film-coated tablet has a major influence on the ability to drive and use machines. Attention is drawn, particularly for drivers of vehicles and operators of machines, to the risks of sleepiness associated with the use of this medicinal product, especially at the beginning of treatment. This phenomenon is increased by the consumption of alcoholic drinks, or alcohol-containing medicinal products or sedative medicinal products. It is better to start this treatment in the evening.

4.8 Undesirable effects

RELATED TO PARACETAMOL

The undesirable effects are listed by organ system. Their frequencies are defined as follows: o Very common (1/10) o Common (1/100 to <1/10) o Uncommon (1/1,000 to <1/100) o Rare (1/10,000 to <1/1,000) o Very rare (<1/10,000) o Unknown frequency (cannot be estimated from the available data)

Immune system disorders Rare: hypersensitivity reactions, such as anaphylactic shock, Quincke’s oedema, erythema, urticaria, skin rash. Their onset calls for the definitive discontinuation of this medicine and related medications.

Skin and subcutaneous tissue disorders Very rare: Serious skin reactions.

Blood and lymphatic system disorders Very rare: thrombocytopenia, leukopenia and neutropenia. Increased or decreased INR.

Hepatobiliary disorders Unknown frequency: Increased liver enzymes

Gastrointestinal disorders Unknown frequency: Diarrhoea, abdominal pains

RELATED TO CHLORPHENAMINE MALEATE

The pharmacological characteristics of chlorphenamine may cause undesirable effects of variable intensity, which may or may not be related to the dose (see section 5.2):

Neurovegetative effects  Sedation or drowsiness, more pronounced at the start of treatment.

6  Anticholinergic effects such as dryness of the mucosa, constipation, accommodation disorders, mydriasis, palpitations, risk of urinary retention,  Orthostatic hypotension,  Balance disorders, vertigo, decreased memory or concentration, more common in elderly patients,  Motor incoordination, tremors,  Mental confusion, hallucinations,  More rarely, excitation effects: agitation, nervousness and insomnia.

Hypersensitivity reactions  Erythema, pruritus, eczema, purpura, urticaria,  Oedema, more rarely Quincke’s oedema,  Anaphylactic shock.

Haematological effects  Leukopenia, neutropenia,  Thrombocytopenia,  Haemolytic anaemia.

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 listed in Appendix V.

4.9 Overdose

The risks of serious intoxication (therapeutic overdose or accidental poisoning) may be particularly high in elderly patients, young children, patients with hepatic failure, cases of chronic alcoholism, patients suffering from chronic malnutrition and patients receiving enzyme inducers. In these cases, intoxication can be fatal.

Paracetamol overdose:

Symptoms Nausea, vomiting, anorexia, paleness, dizziness, sweating and abdominal pain generally appear within the first 24 hours.

An overdose, from 10 g of paracetamol in one single administration in adults, and 150 mg/kg body weight in one single administration in children, causes hepatic cytolysis that could lead to complete and irreversible necrosis, leading to hepatocellular insufficiency, metabolic acidosis, encephalopathy, which could lead to coma and death.

Simultaneously, we have observed an increase in hepatic transaminases, lactate dehydrogenase, bilirubin and a decrease in prothrombin time, which could occur 12 to 48 hours after ingestion. The clinical symptoms of hepatic damage are generally observed after 1 to 2 days, and reach a maximum after 3 to 4 days.

Emergency procedure  Immediate transfer to hospital.  Collect a tube of blood for an initial plasma assay on paracetamol as soon as possible, from the 4th hour after ingestion.  Rapid evacuation of the ingested product by gastric lavage.

7  The treatment of an overdose traditionally includes administration of the N-acetylcysteine antidote via IV or orally as soon as possible, if possible, before the tenth hour.  Symptomatic treatment.  Hepatic tests must be carried out at the beginning of treatment and repeated every 24 hours. In most cases, hepatic transaminases return to normal in 1 to 2 weeks with a full return of hepatic function. However, in very serious cases, a hepatic transplant may be necessary.

Chlorphenamine maleate overdose:

Chlorphenamine maleate overdose may cause: convulsions (especially in children), disturbances of consciousness, coma.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: ANTIPYRETIC ANALGESIC ANTIHISTAMINE H1 RECEPTOR INHIBITOR, ATC code: R05X (R: respiratory system)

Mechanism of action This medicinal product consists of a combination of an antipyretic analgesic, paracetamol, and an antihistamine, chlorphenamine.

Chlorphenamine maleate: H1 antihistamine, with propylamine structure, having an anticholinergic activity, causing undesirable effects.

H1 antihistamines have the common property of opposing, by a more or less reversible competitive antagonism, the effects of histamines, particularly on the skin, bronchi, intestine, and blood vessels.

Passage of the blood-brain barrier is the cause of the sedative effects, of histaminergic and adrenolytic nature, the latter property which may also have an effect on the haemodynamic status (risk of orthostatic hypotension).

5.2 Pharmacokinetic properties

Of paracetamol

Absorption The absorption of paracetamol taken orally is complete and rapid. Maximum plasma concentrations are reached 30 to 60 minutes after ingestion.

Distribution Paracetamol rapidly diffuses in all tissues. Concentrations are comparable in blood, saliva and plasma. Binding to plasma proteins is weak.

Biotransformation

Paracetamol is essentially metabolised by the liver. The 2 major metabolic routes are glucuronic acid and sulphate conjugation. This second route can be rapidly saturated with dosages that exceed the therapeutic doses. A minor route, catalysed by cytochrome P450, is the formation of a reactive intermediary (N-acetyl-benzoquinone imine), which, under normal conditions of use, is rapidly

8 detoxified by reduced glutathione and eliminated in the urine after cysteine and mercapturic acid conjugation. However, during massive poisoning, the quantity of this toxic metabolite is increased.

Elimination Elimination is essentially urinary. 90% of the ingested dose is eliminated by the kidneys in 24 hours, primarily in glycoconjugate (60 to 80%) and sulphoconjugate (20 to 30%) form. Less than 5% of what is eliminated remains unchanged. The elimination half-life is approximately 2 hours.

Physiopathological variations Renal failure: in the event of severe renal failure (see section 4.2), the elimination of paracetamol and its metabolites is delayed.

Elderly patients: the conjugation ability is not modified (see section 4.2).

Of chlorphenamine maleate

Bioavailability The bioavailability of chlorphenamine maleate is between 25 and 50%. There is a significant first-pass hepatic effect.

Distribution The time to reach maximum plasma concentration is between 2 and 6 hours, but the effect is maximum 6 hours after the dose. The duration of effect varies from 4 to 8 hours. Binding to plasma proteins is 72%.

Biotransformation Metabolism is hepatic and leads to an inactive metabolite by demethylation.

Elimination Elimination is via the renal route, with a comparable proportion of the product eliminated in unchanged or metabolised form. The elimination half-life is between 14 and 25 hours.

Physiopathological variations  Hepatic or renal failure increases the half-life of chlorphenamine maleate.  Chlorphenamine maleate crosses the placenta and is excreted in breast milk.

5.3 Preclinical safety data

Not applicable.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Croscarmellose sodium, hypromellose, microcrystalline cellulose, povidone K90, glyceryl behenate, magnesium stearate, Coating agent*, polishing agent**

*Coating agent: Hypromellose (E464), propylene glycol (E1520), titanium dioxide (E171), carmoisine (E122), indigo carmine (E132)

**Polishing agent: Purified water, beeswax (E901), carnauba wax (E903), polysorbate 20 (E432), sorbic acid (E200)

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6.2 Incompatibilities

Not applicable.

6.3 Shelf life

30 months.

6.4 Special precautions for storage

Store below 30°C.

6.5 Nature and contents of container

4 film-coated tablets in blister (aluminium/PVC/aluminium/OPA). 8 film-coated tablets in blister (aluminium/PVC/aluminium/OPA). 12 film-coated tablets in blister (aluminium/PVC/aluminium/OPA). 16 film-coated tablets in blister (aluminium/PVC/aluminium/OPA). 20 film-coated tablets in blister (aluminium/PVC/aluminium/OPA). 24 film-coated tablets in blister (aluminium/PVC/aluminium/OPA). 28 film-coated tablets in blister (aluminium/PVC/aluminium/OPA). 32 film-coated tablets in blister (aluminium/PVC/aluminium/OPA). Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. MARKETING AUTHORISATION HOLDER

[To be completed nationally]

{Name and address} <{tel}> <{fax}> <{e-mail}>

8. MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: {DD month YYYY} Date of latest renewal: {DD month YYYY}

[To be completed nationally]

10 10. DATE OF REVISION OF THE TEXT

DD month YYYY [To be completed nationally]

11. DOSIMETRY

Not applicable.

12. INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS

Not applicable.

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