SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

LemoCalm Plus Cold and Flu Capsules

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains:

•    Paracetamol 300 mg

•    Caffeine 25 mg

•    Phenylephrine Hydrochloride 5 mg For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Capsule hard

Green cap with yellow body size one hard gelatin capsule filled with a white powder

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Symptomatic relief of symptoms of influenza, feverishness, chills and colds including feverish colds.

The symptomatic relief of nasal congestion and difficult breathing arising from this, sinusitis and its associated pain, acute nasal catarrh

4.2    Posology and method of administration

Posology:

Adults (including elderly) and children aged 16 years and over:

Two capsules every 4 - 6 hours as required. Do not exceed 12 capsules in any 24 hours.

Do not take continuously for more than 7 days without medical advice.

Children aged 12 years to 15 years:

Two capsules every 4 - 6 hours when necessary to a maximum of 4 doses in 24 hours. Do not exceed 8 capsules in any 24 hours.

Children under 12 years of age:

LemoCalm Plus Cold and Flu Capsules are not recommended for children under the age 12.

Method of administration:

For oral administration

4.3    Contraindications

•    Hypersensitivity to the active substances or to any of the excipients listed in section 6.1;

•    Concomitant use of other sympathomimetic decongestants;

•    Hepatic or severe renal impairment, cardiovascular disease, hypertension, diabetes mellitus, hyperthyroidism, phaeochromocytoma, closed angle glaucoma;

•    Patients taking tricyclic antidepressants, or beta blocking drugs and those who are taking or who have taken within the last two weeks monoamine oxidase inhibitors (see section 4.5).

4.4    Special warnings and precautions for use

Medical advice should be sought before using this product in patients with these conditions:

•    An enlargement of the prostate gland;

•    Occlusive vascular disease (e.g. Raynaud's phenomenon);

•    Cardiovascular disease.

This product should not be used by patients taking other sympathomimetics (such as decongestants, appetite suppressants and amphetamine-like psychostimulants) (see interactions).

Excessive intake of caffeine (e.g. coffee, tea and some canned drinks) should be avoided while taking this product.

Do not take other flu, cold or decongestant medicines with this product.

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 60 mg/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.

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).

Special Label Warnings

Contains paracetamol.

Do not take anything else containing paracetamol while taking this medicine Do not take with other flu, cold or decongestant products.Do not take more medicine than the label tells you to. If you do not get better, talk to your doctor.

Talk to a doctor at once if you take too much of this medicine, even if you feel well. Special Leaflet Warnings

Talk to a doctor at once if you take too much of this medicine even if you feel well. This is because too much paracetamol can cause delayed, serious liver damage

4.5 Interaction with other medicinal products and other forms of interaction

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. Medical advice should be sought before taking paracetamol-caffeine phenylephrine in combination with the following drugs:

Monoamine oxidase inhibitors (including moclobemide)	Hypertensive interactions occur between sympathomimetic amines such as phenylephrine and monoamine oxidase inhibitors (see contraindications).
Sympathomimetic amines	Concomitant use of phenylephrine with other sympathomimetics amines can increase the risk of cardiovascular side effects (see warnings and precautions).
Beta-blockers and other antihypertensives (including debrisoquine, guanethidine, reserpine, methyldopa)	Phenylephrine may reduce the efficacy of betablocking drugs and antihypertensive drugs. The risk of hypertension and other cardiovascular side effects may be increased (see contraindications).
Tricyclic antidepressants (eg amitriptyline)	May increase the risk of cardiovascular side effects with phenylephrine (see contraindications).
Digoxin and cardiac glycosides	Concomitant use of phenylephrine with digoxin or cardiac glycosides may increase the risk of irregular heartbeat or heart attack.
Ergot alkaloids	Ergotamine and methylsergide increased risk of ergotism.
Warfarin and other coumarins	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. The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular daily use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.
Probenecid	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.
Metoclopramide and Domperidone	Accelerate absorption of Paracetamol.
Cholestyramine	Reduces absorption of Paracetamol.
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 with paracetamol.
Interference with laboratory tests	Paracetamol may affect uric acid tests by wolframatop phosphoric acid, and blood sugar tests by glucose-oxydase-peroxydase.
Salicylamide	May prolong the elimination t1/2 of Paracetamol.

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 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.

However, this product is not recommended for use in pregnancy due to the phenylephrine and caffeine content. There is a potential increased risk of lower birth weight and spontaneous abortion associated with caffeine consumption during 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.

Caffeine in breast milk may have a stimulating effect on breast-fed infants.

Phenylephrine may be excreted in breast milk. This product should not be used while breast-feeding without medical advice.

4.7 Effects on ability to drive and use machines

Patients should be advised not to drive or operate machinery if affected by dizziness

4.8 Undesirable effects

(i) Paracetamol

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; not known: frequency cannot be estimated from the available data. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Frequency	System	Symptoms
Rare >1/10000 -	Blood and lymphatic system disorders	Platelet disorders, stem cell disorders.
< 1/1000	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	Hepato-biliary disorders	Hepatotoxicity.
(< 10 000)	General disorders and administration site conditions	Hypersensitivity reaction (requiring discontinuation of treatment).
	Blood and lymphatic system disorders	Thrombocytopenia, leukopenia, neutropenia, hemolytic anemia, agranulocytosis.
	Metabolism and nutrition disorders	Hypoglycaemia.
	Renal and urinary disorders	Sterile pyuria (cloudy urine) and renal side effects.
	Skin and subcutaneous tissue disorders	Very rare cases of serious skin reactions have been reported.

Not known: Edema of the larynx, anaphylactic shock, anaemia, bronchospasm*, liver alteration and hepatitis, renal alteration (severe renal impairment, nephrite interstitial, haematuria, anuresis), gastrointestinal effects and vertigo have been reported.

* There have been cases of bronchospasm with paracetamol, but these are more likely in asthmatics sensitive to aspirin or other NSAIDs.

(ii) Caffeine

Adverse reactions identified through post-marketing use with caffeine are listed below. The frequency of these reactions is unknown.

Central Nervous system	Nervousness and anxiety
	Irritablility, Restlessness and Excitability
	Dizziness

When the recommended paracetamol-caffeine dosing regimen is combined with dietary caffeine intake, the resulting higher dose of caffeine may increase the potential for caffeine-related adverse effects such as insomnia, irritability anxiety, restlessness, headaches, gastrointestinal disturbances and palpitations.

(iii) Phenylephrine hydrochloride

The following adverse events have been observed in clinical trials with phenylephrine and may therefore represent the most commonly occurring adverse events.

Body system	Undesirable effect
Psychiatric disorders	Nervousness
Nervous system disorders	headache, dizziness, insomnia
Cardiac disorders	Increases in blood pressure
Gatrointestinal disorders	nausea, vomiting, diarrhoea

Adverse reactions identified during post-marketing use are listed below. The frequency of these reactions is unknown._

Eye disorders	Mydriasis, acute angle closure glaucoma, most likely to occur in those with closed angle glaucoma.
Cardiac disorders	Tachycardia, palpitations.
Skin and subcutaneous disorders	Allergic reactions (eg. rash, urticarial, allergic dermatitis). Hypersensitivity reactions - including that cross-sensitivity may occur with other sympathomimetics.
Renal and urinary disorders	Dysuria, urinary retention. This is most likely to occur in those with bladder outlet obstruction, such as 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

4.9 Overdose

(i) Paracetamol

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.

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).

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. 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.

Management

Immediate treatment is essential in the management of paracetamol overdose.

Despite a lack of significant early symptoms, patients should be refered 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 established treatment guidelines.

Treatment with activated charcoal should be considered if the overdose has been taken within one 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.

(ii)    Caffeine

Symptoms

Overdose of caffeine may result in epigastric pain, vomiting, diurese, tachycardia or cardiac arrhythmia, CNS stimulation (insomnia, restlessness, excitement, agitation, jitteriness, tremors and convulsions).

It must be noted that for clinically significant symptoms of caffeine overdose to occur with this product, the amount ingested would be associated with serious paracetamol-related liver toxicity.

Management

No specific antidote is available, but supportive measures may be used.

(iii)    Phenylephrine hydrochloride

Symptoms

Phenylephrine overdosage is likely to result in effects similar to those listed under adverse reactions. Additional symptoms may include hypertension, and possibly reflex bradycardia. In severe cases confusion, hallucinations, seizures and arrhythmias may occur. However the amount required to produce serious phenylephrine toxicity would be greater than that required to cause paracetamol-related liver toxicity.

Management

Treatment should be as clinically appropriate. Severe hypertension may need to be treated with alpha blocking drugs such as phentolamine.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Paracetamol: An analgesic and antipyretic.

Caffeine: A mild stimulant.

Phenylephrine hydrochloride: A sympathomimetic decongestant.

5.2 Pharmacokinetic properties

Paracetamol: It is readily absorbed from the gastro-intestinal tract.

It is metabolised in the liver and excreted in the urine mainly as the glucuronide and sulphate conjugates.

Caffeine: It is absorbed readily after oral administration maximal plasma concentrations are achieved within one hour and the plasma half-life is about 3.5 hours. 65-80% of administered caffeine is excreted in the urine as 1-methyluric acid and 1-methylxanthine.

Phenylephrine hydrochloride: It has reduced bioavailability from the gastrointestinal

tract owing to first pass metabolism by monoamine oxidase in the gut and liver. It is excreted in the urine almost entirely as the sulphate conjugate.

5.3 Preclinical safety data

Pre-clinical 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 of the product and which have not already been mentioned elsewhere in this Summary.

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.

PHARMACEUTICAL PARTICULARS

6.1    List of excipients

•    Modified maize starch;

•    Colloidal anhydrous silica;

•    Magnesium stearate ;

•    Patent blue V (E131);

•    Titanium dioxide (E171);

•    Quinoline yellow (E 104);

•    Ferric oxide (E 172).

6.2    Incompatibilities

Not applicable

6.3 Shelf life

3 Years.

6.4 Special precautions for storage

Do not store above 25°C.

6.5    Nature and contents of container

PVC/aluminium blisters.

Pack sizes: 8,12, 16, 24 and 32.

6.6    Special precautions for disposal

Not applicable

7 MARKETING AUTHORISATION HOLDER

Bristol Laboratories Unit 3, Canalside Northbridge Road