SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Lem Plus Capsules

Aspar Cold Relief Capsules

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Active Ingredients: Each capsule contains:-

Paracetamol E.P.	300
	mg
Caffeine E.P.	25m
	g
Phenylephrine Hydrochloride E.P.	5mg

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

Adults:    1 - 2 capsules every four hours up to a maximum of 4 doses in any

24 hours. The dosage should not be continued for more than 3 days without consulting a doctor. Dose not to be repeated more frequently than 4 hour intervals.

The Elderly:    One capsule every 4 hours.

Children under 12 Not recommended. years:

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 alpha-adrenoceptor stimulant it may provoke uterine changes which can result in foetal asphyxia.

4.4 Special warnings and precautions for use

*    Do not exceed the stated dose.

*    If symptoms persist for more than 3 days consult your Doctor.

*    If you are receiving a course of medicinal treatment, consult your doctor before taking

this product.

*    Do not take this medicine if you are taking any other product containing PARACETAMOL.

*    contains PARACETAMOL

*    Do not give to children under 12 years.

Paracetamol should be given with care to patients with impaired liver or kidney function, and to patients taking other drugs that affect the liver. Liver function tests may be required at periodic intervals during high dose or long term therapy, especially in patients with pre-existing hepatic disease. Care should be taken in giving paracetamol to patients with alcohol dependence. Care should be taken giving paracetamol to patients with glucose-6-phosphate dehydrogenase deficiency. Caution is advised in patients with cardiovascular disease or those on a sodium restricted diet who should not use buffered paracetamol without medical advice.

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 Pregnancy and lactation

Paracetamol crosses the placenta. There is no known hazard in normal dosage, but like all non-essential medications paracetamol should be avoided especially during the first trimester unless considered essential by the physician. Paracetamol is excreted in breast milk but there is no evidence that this is clinically significant.

Caffeine: During pregnancy the half-life of caffeine is prolonged. This is a possible contributory factor in hyperemesis gravidarum. It is recommended that no medicines should be taken during pregnancy unless recommended by a doctor.

Phenylephrine Hydrochloride: As an alpha-adrenoceptor stimulant it may provoke uterine changes which can result in foetal asphyxia.

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

(Frequency and Seriousness)

Paracetamol: Side effects are usually mild, though haematological reactions, blood dyscrasias and anaemia have been reported. Rashes and other allergic reactions occur occasionally. There are isolated reports of thrombocytopenic purpura, methaemoglobinaemia, and agranulocytosis. Rarely renal colic, sterile pyuria, uraemia, azotaemia, acute pancreatitis and hepatitis have occurred.

Caffeine: Nausea, insomnia, headache may be experienced. Excessive consumption of beverages containing caffeine may cause headaches, irritability and signs of anxiety neurosis. Large doses may cause restlessness, excitement, muscle tremor, tinnitus, scintillating scotoma, tachycardia and extrasystoles. Caffeine increases gastric secretions and may cause gastric ulceration.

Phenylephrine hydrochloride: high blood pressure with headache, vomiting and rarely palpitations, perforation of the nasal septum and possible cardiovascular effect on a diabetic patient. Also rare reports of allergic reactions.

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).

Risk factors

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

No additional preclinical data.

6.1 List of Excipients

Starch BP Colloidal Anhydrous Silica EP

(Aerosil 200)

Magnesium Stearate EP

Empty Hard Gelatin Capsule Shell contains:

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,

29-30 Capitol Way,

Colindale,

London NW9 0EQ