McNeil Healthcare (Ireland) Ltd

CALPOL Six Plus 250mg/5ml Oral Suspension

Each 5ml contains -

Paracetamol 250 mg.

Excipients: Contains Sucrose 2.1g/5ml, Sorbitol 1.89g/5ml, methyl parahydroxybenzoate (E218) 4mg/5ml and Sunset Yellow (E110) 0.25mg/5ml.

For a full list of excipients see section 6.1.

Oral Suspension.

An orange coloured and flavoured viscous oral suspension.

CALPOL products are indicated for the treatment of mild to moderate pain and as antipyretics.

CALPOL is indicated for the symptomatic relief of headache, migraine, neuralgia, toothache and teething pains, sore throat, influenza, feverishness and feverish colds.

For oral administration

Children aged 6 years - 12 years:

Children aged 12 - 16 years:

Two - three 5ml spoonfuls (large end) up to 4 times a day.

Adults and children over 16 years:

Two - four 5ml spoonfuls (large end) up to 4 times a day.

Children under 6 years

Not recommended

The Elderly

In the elderly the rate and extent of paracetamol absorption is normal, however, plasma half-life is longer and paracetamol clearance is longer than in young adults.

CALPOL is contra-indicated in patients with a known hypersensitivity to paracetamol.

CALPOL should be used with caution in patients with severe hepatic or renal dysfunction.

There is no evidence of paracetamol dependence.

Contains sucrose and sorbitol. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine.

Contains sunset yellow (E110) which may cause allergic reactions.

Contains methyl parahydroxybenzoate (E218) which may cause allergic reactions (possibly delayed).

The following precautions should be followed when taking this medicine:

Do not give with any other paracetamol-containing products

Never give more medicine than shown in the table

Do not overfill the spoon

Always use the spoon supplied with the pack.

Do not give more than 4 doses in any 24 hour period

Leave at least 4 hours between doses

Do not give this medicine to your child for more than 3 days without speaking to your doctor or pharmacist

As with all medicines, if your child is currently taking any medicine consult your doctor or pharmacist before taking this product

Keep out of reach and sight of children

Patients who have taken barbiturates, tricyclic antidepressants and alcohol may show diminished ability to metabolise large doses of paracetamol, the plasma half-life of which can be prolonged.

Alcohol can increase the hepatotoxicity of paracetamol overdosage and may have contributed to the acute pancreatitis reported in one patient who had taken an overdose of paracetamol.

Chronic ingestion of anticonvulsants or oral steroid contraceptives induce liver enzymes and may prevent attainment of therapeutic paracetamol levels by increasing first pass metabolism or clearance.

The speed of absorption of paracetamol may be increased by metoclopramide or domperdone and absorption reduced by cholestyramine.

The anticoagulant effect of warfarin and other coumains may be enhanced by prolonged regular use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.

The safe use of CALPOL during pregnancy has not been established directly. There is epidemiological evidence of safety of paracetamol in human pregnancy.

A pharmacokinetic study in 12 nursing mothers revealed that less than 1% of a 650 mg oral dose of paracetamol ingested by a nursing mother appears in human milk, therefore maternal ingestion of therapeutic doses does not present a risk to the infant.

None known

Paracetamol is well tolerated when taken at the recommended dosages, with most reports of adverse reactions relating to overdosage with the drug. At normal therapeutic doses, side effects are mild and infrequent with reports of adverse reactions rare. Skin rashes have been documented occasionally, as have case reports of hypersensitivity and idiosyncratic reactions (e.g. thrombocytopenic purpura, haemolytic anaemia and agranulocytosis).

Chronic hepatic necrosis has been reported in a patient who took daily therapeutic doses of paracetamol for about a year and liver damage has been reported after daily ingestion of excessive amounts for shorter periods. A review of a group of patients with chronic active hepatitis failed to reveal differences in the abnormalities of liver function in those who were long-term users of paracetamol nor was the control of their disease improved after paracetamol withdrawal.

Nephrotoxicity following therapeutic doses of paracetamol is uncommon, but papillary necrosis has been reported after prolonged administration.

Signs and symptoms

Pallor, anorexia, nausea and vomiting are frequent early symptoms of paracetamol overdosage, although in many cases there are no symptoms for many hours. Hepatic necrosis is a dose-related complication of paracetamol over-dosage. Hepatic enzymes may become elevated and prothrombin time prolonged within 12-48 hours, but clinical symptoms may not be apparent until 1 to 6 days after ingestion. Toxicity is likely in adults who have taken more than 10g, but may also occur at lower doses in certain patients (see treatment section).

Treatment

To protect the patient against delayed hepatotoxicity, paracetamol overdosage should be treated promptly by gastric lavage followed by intravenous N-acetylcysteine or oral methionine. Peak plasma paracetamol concentration may be delayed by up to 4 hours following overdose. Additional therapy (further methionine or intravenous N-acetylcysteine) is normally considered in the light of blood paracetamol content and time elapsed since ingestion. Fulminant hepatic failure which may follow paracetamol overdosage requires specialised management.

In paracetamol overdosage with liver cell damage, paracetamol half-life is often prolonged from around 2 hours in normal adults to 4 hours or longer. However, liver cell damage has been found in patients with a paracetamol half-life less than 4 hours. Diminution in ¹⁴CO₂ excretion after oral ¹⁴C-aminopyrine has been reported to correlate better with liver cell damage in paracetamol overdosage than do either plasma paracetamol concentration or half-life or conventional liver function test measurements. Concomitant renal failure due to acute tubular necrosis may accompany paracetamol-induced fulminate hepatic failure. The incidence is however, no more frequent in these patients than in others with fulminant hepatic failures from other causes.

It has been proposed that the threshold for treatment with N-acetylcysteine should be reduced by 30-50% in patients taking drugs which reduce hepatic enzymes, who abuse alcohol long-term, or who are chronically malnourished, as the patients may be more susceptible to the toxic effects of paracetamol.

Paracetamol is an analgesic and antipyretic. The therapeutic effects of paracetamol are thought to be related to inhibition of prostaglandin synthesis, as a result of inhibition of cyclo-oxygenase. There is some evidence that it is a more effective inhibitor of central as opposed to peripheral cyclo-oxygenase. Paracetamol has analgesic and antipyretic properties, but only weak anti-inflammatory properties. This may be explained by the concept that inflammatory tissues have higher levels of cellular peroxides than other tissues and that cellular peroxides prevent inhibition of cyclo-oxygenase by paracetamol.

Absorption

Absorption of paracetamol occurs mainly by passive transfer from the small intestine. Gastric emptying is the rate-limiting step in the absorption of orally-administered paracetamol. Any drug, disease or other condition which alters the rate of gastric emptying will therefore influence the rate of paracetamol absorption. Peak plasma paracetamol concentration usually occurs between 30 and 90 minutes after oral ingestion, depending on the formulation. Mean maximum plasma concentrations of paracetamol of 12.84 ug/ml were determined following the administration of CALPOL Six Plus suspension (containing 1g paracetamol) to adults.

Paracetamol is incompletely available to the systemic circulation after oral administration since a variable proportion is lost through first-pass metabolism. Oral bioavailability in adults appears to depend on the amount of paracetamol administered, increasing from 63% of the administered dose after 500 mg to nearly 90% of the dose after 1 or 2g (in tablet form).

Distribution

Paracetamol is distributed uniformly throughout most body fluids with an estimated volume of distribution of 0.95 1/kg.

Following therapeutic doses, paracetamol is not appreciably bound to plasma proteins.

Metabolism and elimination

The plasma half-life of paracetamol after therapeutic doses is in the range 1.5-2.5 hours. Paracetamol is metabolised by the liver and several metabolites of paracetamol have been identified in man. The two major metabolites excreted in the urine are the glucuronide and sulphate conjugates. About 10% of administered paracetamol is converted, via a minor pathway, by a cytochrome P-450 mixed function oxidase system to a reactive metabolite, acetamidoquinone. This metabolite is rapidly conjugated with reduced glutathione and excreted as cysteine and mercapturic acid conjugates. When large amounts of paracetamol are taken, hepatic glutathione may become depleted causing excessive accumulation within the hepatocyte of acetamidoquinone, which binds covalently to vital hepatocellular macromolecules. In overdose, this can lead to hepatic necrosis. Total body clearance of paracetamol following a single dose (1000 mg i.v) is approximately 5 ml/min/kg.

Renal excretion of paracetamol involves glomerular filtration and passive reabsorption and the sulphate and glucuronide conjugates are subject to active renal tubular secretion. Renal clearance of paracetamol depends on urine flow rate, but not pH.

Less than 4% of the administered drug is excreted as unchanged paracetamol. In healthy subjects, approximately 85-95% of a therapeutic dose is excreted in the urine within 24 hours.

Pharmacokinetics in Renal Impairment

The mean plasma half life of paracetamol is similar in normal and renally impaired subjects between 2-8 hours, but from 8-24 hours paracetamol is eliminated less rapidly. Marked accumulation of the glucuronide and sulphate conjugates occurs in chronic renal failure. There may be some extra renal elimination of retained paracetamol conjugates in patients with chronic renal failure, with limited regeneration of the parent compound. An increase in the interval between doses of paracetamol has been recommended for adults with chronic renal failure. Haemodialysis may result in reduced plasma levels of paracetamol. Supplementary doses of paracetamol may be necessary in order to maintain therapeutic blood levels.

Pharmacokinetics in Hepatic Impairment

The mean plasma paracetamol half-life is similar in normal subjects and those with mild liver disease, but is significantly prolonged (approximately 75%) in patients with severe liver disease. However, the clinical significance of the increase in half-life is unclear, since there is no evidence of drug accumulation or hepatotoxicity in patients with liver disease and glutathione conjugation is not impaired. The administration of 4g paracetamol daily for 13 days to 20 subjects with chronic stable liver disease, resulted in no deterioration of liver function, and in mild liver disease, there is no evidence that paracetamol is harmful when taken at recommended doses. However, in severe liver disease, the plasma paracetamol half-life is significantly prolonged.

Pharmacokinetics in the Elderly

Differences in pharmacokinetic parameters observed between fit young and fit elderly subjects are not thought to be of clinical significance. However, there is some evidence to suggest that serum paracetamol half-life is markedly increased (by approximately 84%) and clearance of paracetamol is decreased (by approximately 47%) in frail, immobile, elderly subjects when compared to fit young subjects.

Pharmacokinetics in children

Studies have shown that in neonates 0-2 days old and children 3-10 years old, paracetamol sulphate is the major metabolite of paracetamol, whereas data in adults and children of 12 years of age and over demonstrate that the major metabolite is the glucuronide conjugate. However, there are no significant age-related differences in the overall elimination rate of paracetamol or in the total amount of drug recovered in the urine.

The active ingredients of CALPOL are well known constituents of medicinal products and their safety profile is well documented.

CALPOL Six Plus Suspension contains the following excipients:

Sucrose Ph. Eur.

Sorbitol liquid, (non-crystallising) Ph. Eur. (E420)

Glycerol Ph. Eur. (E422)

Dispersible cellulose BP

Polysorbate 80 Ph. Eur.

Flavour (white sugar DA 13780)

Flavour (orange 510652E)

Methyl parahydroxybenzoate Ph. Eur. (E218)

F, D and C yellow No 6 soluble/Sunset Yellow FCF (E110)

Purified water Ph. Eur.

None known

3 years.

Do not store above 25°C.

Store in the original package to protect from light.

5 ml paper/aluminium foil/surlyn sachets.

Amber glass bottle closed with a two-piece plastic child-resistant, tamper-evident closure fitted with a polyethylene or polyvinylidine chloride (PVDC) laminate faced wad.

or

Amber glass bottle closed with a three-piece plastic child-resistant, tamper-evident closure fitted with a polyethylene or polyvinylidine chloride (PVDC) laminate faced wad.

Pack size: 60 ml and 70 ml

A spoon with a 2.5 ml and 5ml measure is supplied with all packs of this product.

Not all pack sizes may be marketed.

No special requirements

McNeil Healthcare (Ireland) Limited

Airton Road

Tallaght

Dublin 24

Ireland

PA 823/10/3

25 January 1985 / 25 January 2010

December 2011