LEM PLUS CAPSULES, COLD RELIEF CAPSULES - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Lem Plus Capsules

Aspar Cold Relief Capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Active Ingredients:

Each capsules contains:-

Paracetamol E.P.              300mg

Caffeine E.P.                      2­5mg

Phenylephrine Hydrochloride E.P. 5mg

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Hard gelatin green and yellow capsules.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For the symptomatic relief of aches, pains, headache, sore throat, fever and nasal congestion

associated with colds and influenza.

4.2 Posology and method of administration

Posology

Adults, the elderly and children 16 years and over : two capsules to be taken every four to six hours, when necessary up to four times daily.

Maximum dose of 8 capsules in 24 hours.

Do not take the medicine for more than 3 days without consulting a doctor.

Method of administration

Oral administration only.

4.3 Contraindications

Paracetamol: known hypersensitivity to paracetamol.

Caffeine: should be given with care to patients with a history of peptic ulcer.

Phenylephrine hydrochloride: should be avoided or only used with great caution in hyper-susceptible patients or those with hyperthyroidism, aneurism, hypertension, arteriosclerosis and cardiovascular disorders. As an alphaadrenoceptor stimulant it may provoke uterine changes which can result in foetal asphyxia.

4.4 Special Warnings and Special 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.

Keep out of sight and reach of children

Do not exceed the stated dose.

If symptoms persist, consult your Doctor.

Talk to a doctor at once if you take too much of this medicine, even if you feel well. Contains Paracetamol.

If you are under the care of your doctor or receiving prescribed medicines consult your doctor before taking this product.

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

The dosage (4 doses in 24 hours) interval should be consistent with other solid dose paracetamol: 4–6 hours. Accidental overdose by shortening the dosage interval is a real public health risk.

Care is advised in the administration of paracetamol to patients with renal or hepatic impairment.

The hazard of overdose is greater in those with non-cirrhotic alcoholic liver disease.

Special Label Warnings

Do not take with any other paracetamol-containing products. Do not take with other flu, cold or decongestant products.

Immediate medical advice should be sought in the event of an overdose, even if you feel well.

Special Leaflet Warnings

Immediate medical advice should be sought in the event of an overdose, even if you feel well, because of the risk of delayed, serious liver damage.

4.5 Interaction with other medicinal products and other forms of interaction

Paracetamol: Alcohol and hepatotoxic medications reduce the capacity of the liver to metabolise paracetamol. Chronic use of paracetamol enhances the effects of anticoagulants. Cholestyramine reduces absorption of paracetamol. Metoclopramide and domperidone accelerate absorption of paracetamol. Plasma levels of chloramphenicol may increase with concurrent administration of paracetamol.

Concurrent use of paracetamol with NSAID may increase the risk of adverse renal effects. Prolonged concurrent use of paracetamol and aspirin or other salicylate may increase the risk of renal damage (such as analgesic nephropathy and renal papillary necrosis).

Effervescent preparations of paracetamol which contain a high sodium concentration may increase the risk of cedema and/or hypematraemia when administered concurrently with adrenocorticoids, anabolic steroids, androgens or ACTH. Oral tetracyclines may form non-absorbable complexes with the buffering agents present in effervescent preparations, these medications should be taken 1–2 hours apart.

Interactions with laboratory tests: paracetamol may interfere with a number of test results; blood glucose, urate, bilrubin, lactate dehydrogenase and transaminase concentrations, urine 5-hydroxyindoleacetic acid determination, prothrombin time and pancreatic function using benitromide.

Caffeine: The effect of caffeine may be enhanced by izoniazid and meprobamate. It is claimed to enhance the action of ergotamine.

Phenylephrine Hydrochloride: The hypersensitive effect can be markedly enhanced by the administration of debrisoquine. Rare severe hypertension may be associated with 2, 4, beta adrenoceptor-blocking drugs.

4.6 Fertility, pregnancy and lactation

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.

This product should not be used while breast-feeding without medical advice. Caffeine in breast milk may have a stimulating effect on breast-fed infants. Phenylephrine may be excreted in breast milk.

4.7 Effects on ability to drive and use machines

Phenylephrine Hydrochloride: May cause drowsiness. If affected, do not drive or operate machinery. Avoid alcoholic drinks.

4.8 Undesirable effects

Adverse events of paracetamol from historical clinical trial data are both infrequent and from small patient exposure. Accordingly, events reported from extensive post-marketing experience at therapeutic/la­belled dose and considered attributable are tabulated below by system class. The frequency of these adverse events is not known (cannot be estimated from available data).

Paracetamol

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

Very rare cases of serious skin reactions have been reported.

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

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, restlessness, anxiety, irritability, headaches, gastrointestinal disturbances and palpitations.

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

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

Reporting of suspected adverse reactions after authorization 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

Paracetamol:

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).

If the patient:

A. is on long term treatment with carbamazepine, phenobarbital, 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 established treatment guidelines, see BNF overdose section.

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 24h from ingestion should be discussed with the NPIS or a liver unit.

Caffeine: Symptoms – emesis and convulsions may occur. No specific antidote. However, treatment is usually fluid therapy. Fatal poisoning is rare. If symptoms become apparent or overdose is suspected, consult a doctor immediately.

Phenylephrine Hydrochloride: Not Known – if overdose is suspected consult a doctor immediately.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Paracetamol is an effective analgesic and antipyretic agent but has only weak anti-inflammatory properties. Its mechanism of action is not fully understood. It has been suggested that it may act predominantly by inhibiting prostaglandin synthesis in the 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 an antipyretic action by a central effect on the hypothalamic heat-regulating centre to produce peripheral vasodilation resulting in increased blood flow through the skin, sweating and heat loss. The central action probably involves inhibition of prostaglandin synthesis in the hypothalamus. The drug has no effect on the cardiovascular and respiratory systems, and unlike salicylates it does not cause gastric irritation or bleeding.

Caffeine acts on the central nervous system on muscle including cardiac muscle and the kidneys. Its action on the cns is mainly on the higher centres and produces a condition of wakefulness and increased mental activity. It facilitates the performance of muscular work and increases the total amount of work that can be performed by a muscle. It may stimulate the respiratory centre, increasing the rate and depth of respiration. Its stimulant action on the medullary vasomotor centre is usually compensated by its prepheral vasodilator effect on the arterioles, so that blood pressure usually remains unchanged. The diuretic action of caffeine has been accounted for in many ways. It may increase renal blood flow and glomerular filtration rate, but its main action may be due to the regulation of the normal tubular absorption. The xanthines are rarely of great value in promoting increased renal function when this is depressed. Caffeine is claimed to enhance the action of ergotamines and is frequently given with ergotamine in the treatment of migraine.

Phenylephrine hydrochloride is a sympathomimetic with many direct effects on adrenergic receptors. It has predominantly alpha-adrenergic activity and is without stimulating effects on the cns. Its pressor activity is weaker than that of noradrenaline but of longer duration. After injection it has produced peripheral vasoconstriction and increased arterial pressure; it also causes reflex bradycardia. It increases blood flow to the skin and to the kidneys. It has been used in the treatment of hypotensive states eg. circulatory failure, spinal anaesthesia or hypertension following the use of chlorpromazine and other phenothiazines. Phenylephrine hydrochloride may be given for the relief of nasal congestion. Locally it is used as a nasal decongestant in rhinitis and sinusitis. In ophthalmology it is employed as a mydriatic and conjunctival decongestant in open angle glaucoma. It is sometimes used to temporarily lower intra-ocular pressure.

There is no pharmacological information with regard to the compound preparation. However, there is no evidence to suggest that any of the action described above are in any way impinged upon by the other active ingredients.

5.2 Pharmacokinetic properties

Paracetamol is readily absorbed from the gastro-intestinal tract with peak plasma concentrations occurring about 30 minutes to 2 hours after ingestion. It is metabolised in the liver (90–95%) and excreted in the urine mainly as the glucuronide and sulphate conjugates. Less than 5% is excreted as unchanged paracetamol. The elimination half-life varies from about 1 to 4 hours. Plasma-protein binding is negligible at usual therapeutic concentrations but increases with increasing concentrations.

A minor hydroxylated metabolite (n-acetyl-p-benzoquinoneimine) which is usually produced in very small amounts by mixed-function oxidases in the liver and which is usually detoxified by conjugation with liver glutathione may accumulate following paracetamol overdosage and cause liver damage. The time to peak concentrations of paracetamol is 0.5 to 2 hours, the time to peak effect I to 3 hours and the duration of action 3 to 4 hours.

Caffeine: is readily absorbed after oral, rectal or parenteral administration, but absorption from the gastrointestinal tract may be erratic. There is little evidence of accumulation in any particular tissue. Caffeine passes readily into the central nervous system and into saliva. Concentrations have also been detected in breast milk. Caffeine is metabolised almost completely and is excreted in the urine as 1-methyluric acid, 1-methylxanthine and other metabolites with only about 1% unchanged.

Phenylephrine hydrochloride: has reduced bioavailability from the gastrointestinal tract owing to first pass metabolism by monoamine oxidase in the gut and liver. When injected intramuscularly it takes 10 to 15 minutes to act and subcutaneous and intramuscular injections are effective for about an hour. Intravenous injections are effective for about 20 minutes.

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.

The toxicity of paracetamol has been extensively studied in numerous animal species. Pre-clinical studies in rats and mice have indicated single dose oral LD50 values of 3.7 g/kg and 338 mg/kg, respectively. Chronic toxicity in these species at large multiples of the human therapeutic dose, occurs as degeneration and necrosis of hepatic, renal and lymphoid tissue, and blood count changes. The metabolites believed responsible for these effects have also been demonstrated in man. Paracetamol should not, therefore, be taken for long periods of time, and in excessive doses. At normal therapeutic doses, paracetamol is not associated with genotoxic or carcinogenic risk. There is no evidence of embryo-or foetus-toxicity from paracetamol in animal studies. Conventional studies using the currently accepted standards for the evaluation of toxicity to reproduction and development are not available.

6 PHARMACEUTICAL PARTICULARS

6.1 List of Excipients

Starch BP

Colloidal

Anhydrous Silica

EP

(Aerosil 200)

Magnesium

Stearate EP

Indigotine-FD & C Blue2 (E132)

Yellow Iron Oxide (E172)

Titanium Dioxide (E171)

Gelatin

6.2 Incompatibilities

Paracetamol: None known

Caffeine: Iodine, silver salts, tannins and strong solution of caustic alkalis.

Phenylephrine Hydrochloride: Butacaine, alkalis, ferric salts and oxidising agents.

6.3 Shelf life

3 Years from the date of manufacture.

6.4 Special precautions for storage

Store in a diy place below 25°C. Protect from light.

Keep out of reach of children.

6.5 Nature and contents of container

Blister Pack

Capsules are packed individually in pre-moulded PVC film and sealed with aluminium foil.

Pack sizes of 10, 12, 20 and 24 capsules.

6.6 Special precautions for disposal

Return unused capsules to the Pharmacist.

7 MARKETING AUTHORISATION HOLDER

Aspar Pharmaceuticals Limited

Acrewood Way

St Albans,

AL4 0JY

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 08977/0037

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

27 June 2000