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McNeil Healthcare (Ireland) Ltd

Airton Road, Tallaght, Dublin 24, Ireland
Telephone: +353 1 466 5200
Fax: +353 1 466 5316


Summary of Product Characteristics last updated on medicines.ie: 29/07/2015
SPC Calpol Six Plus Suspension


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1. NAME OF THE MEDICINAL PRODUCT

CALPOL Six Plus 250mg/5ml Oral Suspension


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2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5ml contains -

Paracetamol 250 mg.

Excipients with known effect:

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

For the full list of excipients, see section 6.1.


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3. PHARMACEUTICAL FORM

Oral Suspension.

An orange coloured and flavoured viscous oral suspension.


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4. CLINICAL PARTICULARS

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4.1 Therapeutic indications

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.


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4.2 Posology and method of administration

For oral administration

Children aged 6 years – 12 years:

Child's Age

How Much

How often (in 24 hours)

6 – 8 years

One 5 ml spoonful (large end)

4 times

8 – 10 years

One 5.0 ml spoonful (large end) and one 2.5ml spoonful (small end)

4 times

10 – 12 years

Two 5 ml spoonfuls (large end)

4 times

• 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

• Do not give to children under the age of 6 years.

• It is important to shake the bottle for at least 10 seconds before use.

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.


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4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.


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4.4 Special warnings and precautions for use

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

There is no evidence of paracetamol dependence.

Serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens - Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), have been reported very rarely in patients receiving paracetamol. Patients should be informed about the signs of serious skin reactions, and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

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 sight and reach of children


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4.5 Interaction with other medicinal products and other forms of interaction

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 domperidone and absorption reduced by cholestyramine.

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


4.6 Fertility, pregnancy and lactation

There are no adequate and well-controlled clinical studies in pregnant or breastfeeding women. Epidemiological studies indicate that paracetamol, when taken as directed, does not adversely affect the pregnant mother or fetus.

Pregnancy

When given to the mother in labeled doses, paracetamol crosses the placenta into fetal circulation as early as 30 minutes after ingestion and is effectively metabolized by fetal sulfate conjugation. When taken as directed, paracetamol does not adversely affect the pregnant mother or fetus

Breastfeeding

Paracetamol is excreted in breast milk in low concentrations (0.1% to 1.85% of the ingested maternal dose). Maternal ingestion of paracetamol in labeled doses does not present a risk to the nursing infant.


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4.7 Effects on ability to drive and use machines

CALPOL has no or negligible influence on the ability to drive and use machines.


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4.8 Undesirable effects

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.

Low level transaminase elevations may occur in some patients taking labelled doses of paracetamol; these are not accompanied with liver failure and usually resolve with continued therapy or discontinuation of paracetamol.

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

Adverse drug reactions identified during post-marketing experience with paracetamol are included in the table below. The frequencies are provided according to the following convention:

Very common ≥1/10

Common ≥1/100 and < 1/10

Uncommon ≥1/1,000 and <1/100

Rare ≥1/10,000 and <1/1,000

Very rare <1/10,000

Not known (cannot be estimated from the available data)

The ADRs identified are presented by frequency category based on 1) incidence in adequately designed clinical trials or epidemiology studies, if available or 2) when incidence is unavailable, frequency category is listed as Not known.

Adverse Drug Reactions Identified During Post-Marketing Experience with Therapeutic doses of Paracetamol by Frequency Category Estimated from Clinical Trials or Epidemiology Studies

System Organ Classification (SOC)

Frequency category

Adverse Event Preferred Term

Blood and lymphatic system disorders

Not known

Thrombocytopenic purpura

Not known

Haemolytic anaemia

Not known

Agranulocytosis

Immune system disorders

Not known

Anaphylactic reaction

Rare

Hypersensitivity

Hepatobilary disorders

Not known

Hepatic necrosis

Not known

Liver injury

Skin and subcutaneous tissue disorders

Rare

Rash

Not known

Urticaria

Not known

Pruritic rash

Renal and urinary disorders

Uncommon

Nephropathy toxic

Not known

Renal papillary necrosis

Investigations

Not known

Transaminases increased

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.


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4.9 Overdose

Please refer to local guidelines for the treatment of paracetamol overdose.

Signs and symptoms

Hepatic necrosis is a dose-related complication of paracetamol over-dosage.

In adults and adolescents (> 12 years of age), hepatic toxicity may occur following ingestion of greater than 7.5 to 10 grams over a period of 8 hours or less.

Early symptoms following a potentially hepatotoxic overdose may include: anorexia, nausea, vomiting, diaphoresis, pallor and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion.

The following are clinical events associated with paracetamol overdose that if seen with overdose are considered expected, including fatal events due to fulminant hepatic failure or its sequelae.

Adverse Drug Reactions Identified with Overdose of Paracetamol

Metabolism and Nutrition Disorders:

Anorexia

Gastrointestinal Disorders:

Vomiting, Nausea, Abdominal discomfort

Hepatobiliary Disorders:

Hepatic necrosis, Acute (fulminant) hepatic failure, Jaundice, Hepatomegaly, Liver tenderness

General Disorders and Administration Site Conditions:

Pallor, Hyperhidrosis, Malaise

Investigations:

Blood bilirubin increased, Hepatic enzymes increased, International normalised ratio increased, Prothrombin time prolonged, Blood phosphate increased, Blood lactate increased

The following clinical events are sequelae to acute hepatic failure and may be fatal. If these events occur in the setting of acute hepatic failure associated with paracetamol overdose (adults and adolescents: ≥12 years of age: >7.5 g within 8 hours; children <12 years of age: >150 mg/kg within 8 hours), they are considered expected.

Expected Sequelae to Acute Hepatic Failure Associated with Paracetamol Overdose

Infections and Infestations:

Sepsis, Fungal infection, Bacterial infection

Blood and Lymphatic System Disorders:

Disseminated intravascular coagulation, Coagulopathy, Thrombocytopenia

Metabolism and Nutrition Disorders:

Abnormalities of glucose metabolism, Hypoglycaemia, Hypophosphatemia, Metabolic Acidosis, Lactic Acidosis

Nervous System Disorders:

Coma (with massive paracetamol overdose or multiple drug overdose), Encephalopathy, Brain oedema

Cardiac Disorders:

Cardiomyopathy, Cardiac arrhythmias

Vascular Disorders:

Hypotension

Respiratory, Thoracic and Mediastinal Disorders:

Respiratory failure

Gastrointestinal Disorders:

Pancreatitis, Gastrointestinal haemorrhage

Renal and Urinary Disorders:

Acute renal failure with acute tubular necrosis

General Disorders and Administration Site Conditions:

Multi-organ failure

Treatment

Gastric lavage may be considered for any patient who has ingested around 7.5g or more of paracetamol in the preceding 4 hours 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.

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.


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5. PHARMACOLOGICAL PROPERTIES

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5.1 Pharmacodynamic properties

ATC Code: N02BE01 – Other analgesics and antipyretics

Paracetamol is a centrally acting, non-opiate, non-salicylate analgesic. Paracetamol is a clinically proven analgesic/antipyretic, and it is thought to produce analgesia by elevation of the pain threshold and antipyresis through action on the hypothalamic heat-regulating centre. Single-dose studies (12.5 mg/kg) of paracetamol in febrile children showed an onset of fever reduction within 15 to 30 minutes.


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5.2 Pharmacokinetic properties

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.


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5.3 Preclinical safety data

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


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6. PHARMACEUTICAL PARTICULARS

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6.1 List of excipient(s)

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.


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6.2 Incompatibilities

None known


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6.3 Shelf life

3 years.


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6.4 Special precautions for storage

Do not store above 25°C.

Store in the original package to protect from light.


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6.5 Nature and contents of container

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.


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6.6 Special precautions for disposal and other handling

No special requirements


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7. MARKETING AUTHORISATION HOLDER

McNeil Healthcare (Ireland) Limited

Airton Road

Tallaght

Dublin 24

Ireland


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8. MARKETING AUTHORISATION NUMBER(S)

PA 823/10/3


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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 25 January 1985

Date of last renewal: 25 January 2010


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10. DATE OF REVISION OF THE TEXT

July 2015



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Active Ingredients

 
   Paracetamol