SUMMARY OF PRODUCT CHARACTERISTICS

DCP Day 210 proposed text

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1 NAME OF THE MEDICINAL PRODUCT Theraflu Cold and Congestion 500 mg/30 ml + 30 mg/30 ml

2 QUALITATIVE AND QUANTITATIVE COMPOSITION 30 ml syrup contain paracetamol 500 mg and pseudoephedrine hydrochloride 30 mg. Excipients with known effect: medium inverted syrup (invert sugar 4.7 g, 4.2 g), sodium 15 mg, ethanol 2.4 g, Allura red AC (E129) 19.5 mg, lecithin soya (E322) 1.51 mg. For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM Syrup. A clear red syrup with a characteristic of berry aroma.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications Short-term symptomatic treatment of nasal and sinus congestion associated with the symptoms of colds and flu, such as pain, headache and/or fever. Theraflu Cold and Congestion is indicated in adults and adolescents aged 15 years and over.

4.2 Posology and method of administration

Posology Adults, the elderly and adolescents aged 15 years and over One 30 ml measured dose. Repeat every four to six hours as needed up to 4 times a day. No more than four doses should be taken in 24 hours. Patients should seek medical advice if symptoms persist for more than 3 days or worsen. This syrup provides a warming sensation in the throat and back of the mouth. Paediatric population This product should not be given to children under 15 years. Hepatic insufficiency In patients with impaired hepatic function, the dose must be reduced or the dosing interval prolonged.

Method of administration For oral use. The measuring cup should be filled up to the 30 ml mark. After each use the measuring cup should be washed and dried.

4.3 Contraindications  Hypersensitivity to paracetamol, pseudoephedrine hydrochloride or to any of the excipients listed in section 6.1.  This medicine contains lecithin soya (E322) and should therefore not be taken in patients allergic to soya or peanut due to the risk of hypersensitivity reactions. Page 3 of 9

 Heart disease, hypertension and cardiovascular disease.  Hyperthyroidism.  Closed angle glaucoma.  Urinary retention.  Pheochromocytoma.  Patients who are taking or have taken monoamine oxidase inhibitors (MAOIs) within the last two weeks.  Patients taking tricyclic antidepressants (see section 4.5).  Patients taking beta-blocking drugs (see section 4.5).  Patients taking other sympathomimetic drugs such as decongestants, appetite suppressants and amphetamine-like psychostimulants (see section 4.5).  First trimester of pregnancy (see section 4.6).

4.4 Special warnings and precautions for use Caution is advised in the administration of paracetamol to patients with moderate and severe renal insufficiency, mild to moderate hepatocellular insufficiency (including Gilbert’s syndrome), severe hepatic insufficiency (Child-Pugh >9), acute hepatitis, concomitant treatment with medicinal products affecting hepatic functions, -6- phosphatedehydrogenase deficiency, haemolytic anaemia, dehydration, alcohol abuse and chronic malnutrition. Patients should not take any other paracetamol-containing products concurrently due to the risk of severe liver damage in case of overdose. Following long-term, high-dose, incorrect use of analgesics, headaches may occur which should not be treated using higher doses of analgesics. In general, habitual intake of analgesics, particularly a combination of several analgesic substances, can lead to permanent renal damage with the risk of renal failure. Abrupt discontinuation following long-term, high-dose, incorrect use of analgesics may lead to headaches, fatigue, muscle pain, nervousness and autonomic 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. Patients should not take other sympathomimetic containing products concomitantly, including other nasal or eye decongestant products. Alcoholic beverages should be avoided while taking this medicine. Paracetamol should be given with caution to patients with alcohol dependence (see section 4.5). The hazards of overdose are greater in those non-cirrhotic alcoholic liver disease. This medicine should be used with caution in patients with:  Cardiovascular disease,  Diabetes,  Prostatic hypertrophy, as they may be susceptible to urinary retention and dysuria,  Occlusive vascular disease (e.g. Raynaud's Phenomenon),  Psychosis,  Chronic cough, asthma, or emphysema. Elderly patients may be particularly sensitive to the central nervous system effects of pseudoephedrine. This medicine is recommended when all the symptoms (pain and/or fever, congestion) are present. It should be used only for a few days. Patients should seek medical advice if symptoms persist for more than 3 days or worsen. Page 4 of 9

In case of surgery, it is advisable to stop treatment a few days before. Risk of hypertensive crisis is increased if halogenated anaesthetics are used (see section 4.5). Paediatric population This product should not be given to children under 15 years. Warning concerning doping misuse Pseudoephedrine may induce positive results in certain anti-doping tests.

Information concerning excipients This medicinal product contains: Medium inverted sugar syrup contains 4.7 g invert sugar (mixture of and glucose) and 4.2 g sucrose. per 30 ml dose. Patients with rare hereditary problems of fructose intolerance, glucose- malabsorption or sucrose-isomaltase insufficiency should not take this medicine. Should also be taken into account by patients with diabetes mellitus. 0.65 mmol (or 15 mg) Sodium per 30 ml dose, to be taken into consideration by patients on a controlled sodium diet. Ethanol, this medicinal product contains 10 % v/v ethanol (alcohol), i.e. 2.4 g of ethanol per 30 ml dose, equivalent to 61 ml of beer or 26 ml . Harmful for those suffering from alcoholism. To be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease, or epilepsy. Allura red AC (E129), an azo colouring agent. It may cause allergic reactions.

4.5 Interaction with other medicinal products and other forms of interaction

Paracetamol The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol, with increased risk of bleeding. Occasional use of paracetamol has no significant effect. Metoclopramide or domperidone may increase the rate of absorption of paracetamol. The tuberculosis treatments rifampicin and isoniazid may increase the hepatotoxicity of paracetamol. The half-life of chloramphenicol may be prolonged by paracetamol. However, topical chloramphenicol may be used concomitantly when used to treat eye infections. Antiepileptics such as phenytoin, phenobarbital and carbamazepine (-inducing medicines) may increase the risk of liver damage. Paracetamol may decrease the bioavailability of lamotrigine, with possible reduction of its effect, due to a possible induction of its metabolism in the liver. Cholestyramine may reduce the absorption of paracetamol. Cholestyramine should not be given within one hour following paracetamol intake. Regular use of paracetamol simultaneously with zidovudine may cause neutropenia and increases the risk of liver damage. The gout treatment probenecid reduces the clearance of paracetamol, so the dose of paracetamol may be reduced in case of concomitant treatment. The hepatotoxicity of paracetamol may be potentiated by excessive intake of alcohol (see section 4.4). Paracetamol may affect phosphotungstate uric acid tests and blood sugar tests. Salicylates/acetylsalicylic acid may prolong the elimination half-life of paracetamol. Page 5 of 9

Pharmacological interactions involving paracetamol with a number of other drugs have been reported. These are considered to be of unlikely clinical significance in acute use at the dosage regimen. Pseudoephedrine Pseudoephedrine may potentiate the action of monoamine oxidase inhibitors (MAOIs, including moclobemide and brofaromine) and may induce hypertensive interactions. Use is contraindicated in patients who are taking or have taken MAOIs within the past two weeks (see section 4.3). Concomitant use of pseudoephedrine with other sympathomimetic agents or tricyclic antidepressants (e.g. amitriptyline) can increase the risk of cardiovascular side effects. Pseudoephedrine may reduce the efficacy of beta-blockers (see section 4.3) and other antihypertensive drugs (e.g. debrisoquine, guanethidine, reserpine, methyldopa). The risk of hypertension and other cardiovascular side effects may be increased. Pseudoephedrine may interact with halogenated anaesthetics such as cyclopropane, halothane, enflurane, isoflurane (see section 4.4). Concomitant use of pseudoephedrine with digoxin and cardiac glycosides may increase the risk of irregular heartbeat or heart attack. Ergot alkaloids (ergotamine and methylsergide): there may be an increased risk of ergotism. Concomitant use with linezolide may increase the risk of hypertension.

4.6 Fertility, pregnancy and lactation Pregnancy The effects of this product during pregnancy have not been specifically investigated. Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage, but patients should follow the advice of their doctor regarding its use. There are limited data on the use of pseudoephedrine in pregnant women. Vasoconstriction of uterine vessels and reduced uterine blood flow associated with use of pseudoephedrine may result in foetal hypoxia. Use of pseudoephedrine is contraindicated during the first trimester of pregnancy and not recommended during the rest of the pregnancy. In the current status of knowledge, the product is contraindicated during the first trimester of pregnancy and not recommended during the rest of the pregnancy (see section 4.3). Breast-feeding Both paracetamol and pseudoephedrine pass into breast milk in small quantities. Since no data is available on the combination of the two substances, this product should be avoided during breastfeeding. Fertility The effects of this product on fertility have not been specifically investigated. Preclinical studies with paracetamol do not indicate special hazard to fertility at therapeutically relevant doses. There are no adequate reproductive toxicology studies with pseudoephedrine.

4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. If affected by dizziness, patients should be advised not to drive or operate machinery.

4.8 Undesirable effects Paracetamol Page 6 of 9

Adverse events from historical clinical trial data are both infrequent and from limited patient exposure. Events reported from extensive post-marketing experience at therapeutic/labelled dose and considered attributable are tabulated below by MedDRA System Organ Class. Due to limited clinical trial data, the frequency of these adverse events is unknown (cannot be estimated from available data), but post- marketing experience indicates that adverse reactions to paracetamol are rare (1/10,000 to <1/1,000) and serious reactions are very rare (<1/10,000).

Body System Undesirable effect

Blood and Thrombocytopenia, agranulocytosis, lymphatic system pancytopenia, leucopenia, neutropenia. disorders These are not necessarily causally related to

paracetamol Immune system Hypersensitivity, including anaphylactic disorders reactions, angioedema, Steven Johnson syndrome and bronchospasm*. Hepatobiliary Hepatic dysfunction disorders Gastrointestinal Abdominal discomfort, diarrhoea, nausea and disorders vomiting *There have been cases of bronchospasm with paracetamol, but these are more likely in asthmatics sensitive to aspirin or other NSAIDs.

Pseudoephedrine

Body System Undesirable effect

Nervous system Central nervous system stimulation (e.g. disorders insomnia, rarely hallucinations) Cardiac disorders Cardiac effects (e.g. tachycardia) Vascular disorders Increase in blood pressure, although not in controlled hypertension Skin and Rash, pruritus, erythema, urticaria, allergic subcutaneous dermatitis. tissue disorders Renal and urinary Urinary retention, particularly in patients disorders with prostatic hypertrophy. 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.

4.9 Overdose Paracetamol In acute overdose, paracetamol may exert a hepatotoxic effect or even cause necrosis of the liver. Overdose of paracetamol, including high total dose levels reached over a prolonged period, may cause nephropathy with irreversible liver failure. Liver damage is possible in adults who have taken 10 g or more of paracetamol. Ingestion of 5 g or more of paracetamol may lead to liver damage if the patient has risk factors (see below). Page 7 of 9

Symptoms of paracetamol overdose in the first 24 hours are pallor, nausea, vomiting, and anorexia. Abdominal pain may be the first indication of liver damage, which is not usually apparent for 24 to 48 hours and sometimes may be delayed for up to 4 to 6 days after ingestion. Liver damage is generally at a maximum 72 to 96 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycemia, cerebral edema, and death. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported. 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 hours from ingestion should be discussed with the local National Poison Center or a liver unit. Additional information on special populations There is a risk of poisoning, particularly in elderly patients, young children, in patients with liver disease, in case of chronic alcoholism or in patients with chronic malnutrition. Overdosing may be fatal in these cases. Risk is higher if the patient:  is on long term treatment with carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin, St John’s Wort or other drugs that induce liver ,  regularly consumes ethanol in excess of recommended amounts,  is likely to be glutathione depleted e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia. Pseudoephedrine Due to the nature of this sympathomimetic agent, overdosage tends to lead to central nervous system stimulation. The symptoms are irritability, restlessness, excitement, tremor, convulsions, palpitations, hypertension and difficulty in micturition. The effects do not correlate well with the dose taken due to inter-individual sensitivity to sympathomimetic properties. Symptoms of sympathomimetic effect: CNS depression: e.g. sedation, apnea, cyanosis, coma CNS stimulation (which is more likely in children): e.g. insomnia, hallucinations, convulsions, tremor. Besides the symptoms already mentioned as undesirable effect, the following symptom can occur: hypertensive crisis, cardiac arrhythmias, muscle weakness and tenseness, euphoria, excitement, thirst, chest pain, dizziness, tinnitus, ataxia, blurred vision, hypotension. In case of a very severe overdose, action should be taken to control convulsions; diazepam can be used as an anticonvulsant and sedative. Measures should be taken to sustain respiration. Beta-blockers can be used to constrain the possible side effects of tachycardia, arrhythmia and hypokalaemia. If necessary the removal of the drug can be attempted by performing gastric lavage. To hasten the elimination of pseudoephedrine, dialysis or acid diuresis can be utilized. It may be necessary to catheterize the bladder. Page 8 of 9

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties Pharmacotherapeutic group: Cough and Cold Preparations; Other cold preparations. Analgesics; Paracetamol, combinations excl. psycholeptics. ATC code: R05X N02BE51 Paracetamol has both analgesic and antipyretic activity which is mediated principally through its inhibition of prostaglandin synthesis in the central nervous system. Pseudoephedrine is a sympathomimetic agent with alpha-agonistic activity. It is the dextroisomer of ephedrine, both agents are equally effective as nasal decongestants. They stimulate alpha-adrenergic receptors of vascular smooth muscle, thus constricting dilated arterioles within the nasal mucosa and reducing blood flow to the engorged area.

5.2 Pharmacokinetic properties Paracetamol Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. Plasma concentrations are measured as soon as 5 minutes post-intake, with peak plasma concentrations occurring between 15 to 60 minutes following oral dosing. Paracetamol is primarily metabolised in the liver via three pathways: glucuronidation, sulphation and oxidation. It is excreted in the urine, mainly as the glucuronide and sulphate conjugates. The mean elimination half-life is approximately 6 hours. Pseudoephedrine Pseudoephedrine is absorbed readily and completely from the gastrointestinal tract after oral administration. Peak plasma concentrations occurring between 15 minutes and 3 hours after oral administration. Less than 1% is demethylated in the liver to norpseudoephedrine (an active metabolite). Pseudoephedrine is excreted unmetabolized in the urine to 96.3% in 24 hours and has no significant active metabolites contributing to its efficacy (main metabolite norpseudophenylephedrine). The mean elimination half-life is approximately 5 hours; however this is dependent on the acidic nature of the urine. When the urine is more acidic, urinary elimination is increased and therefore the half-life decreased. Tubular reabsorption of pseudoephedrine is increased in alkaline urine.

5.3 Preclinical safety data Preclinical safety data on these active ingredients in the literature have not revealed any pertinent and conclusive findings which are of relevance to the recommended dosage and use in the product and which have not already been mentioned elsewhere in this Summary.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients Excipients: Medium inverted sugar syrup (invert sugar, sucrose) Mixed berry flavour (contains lecithin soya E322) Raspberry flavour (contains lecithin soya E322) Flavour 316282 anhydrous Sodium benzoate (E211) Disodium edetate Page 9 of 9

Sodium citrate (E331) Acesulfame potassium Propylene glycol Macrogol 1450 Ethanol 96% Purified water Allura red AC (E129)

6.2 Incompatibilities Not applicable.

6.3 Shelf life 2 years

6.4 Special precautions for storage This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container The syrup is packed in a polyethylene terephthalate (PET) bottle with a two-piece, child resistant “Push and Turn” polypropylene (PP) closure and a low density polyethylene (LDPE) foam liner. Contents 240 ml. A CE-marked measuring cup made of polypropylene (PP), with 30 ml graduation included.

6.6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORIZATION HOLDER {To be completed nationally}

8 MARKETING AUTHORIZATION NUMBER(S) {To be completed nationally}

9 DATE OF FIRST AUTHORIZATION/RENEWAL OF THE AUTHORIZATION {To be completed nationally}

10 DATE OF REVISION OF THE TEXT {To be completed nationally}