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MHRA PAR – Calpol Suspension (PL 15513/0297-302) - 1 -

CALPOL SUSPENSION INFANT (PL 15513/0297, 299) CALPOL SUGAR FREE SUSPENSION INFANT (PL 15513/0298, 300)

CALPOL SUSPENSION INFANT SACHETS (PL 15513/0301) CALPOL SUGAR FREE SUSPENSION INFANT SACHETS (PL 15513/0302)

UKPAR

TABLE OF CONTENTS Lay Summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

0

Steps taken after authorisation – summary

Page 11

Summary of Product Characteristics Page 12

Product Information Leaflet

Page 27

Labelling Page 29




LAY SUMMARY

The MHRA granted McNeil Products Limited Marketing Authorisations (licences) for the medicinal products Calpol Suspension Infant (P and GSL), Calpol Sugar Free Suspension Infant (P and GSL), Calpol Suspension Infant Sachets and Calpol Sugar Free Suspension Infant Sachets on 2nd September 2009. These products, to be available by general sales licence (GSL) and as pharmacy medicines licence (P), contain paracetamol and are used to relieve pain and bring down fever (high temperature) - including post-immunisation fever and teething pain. The active ingredient paracetamol is part of a group of medicines called analgesics, which help ease pain. These applications are duplicates of previously granted applications for Calpol Infant Suspension (PL 15513/0004), Calpol Sugar Free Infant Suspension (PL 15513/0006), Calpol Infant Suspension (PL 15513/0122), Calpol Sugar Free Infant Suspension (PL 15513/0123), Calpol Infant Suspension Sachets (PL 15513/0154) and Calpol Sugar Free Infant Suspension Sachets (PL 15513/0155), which were originally approved on28th April 1997, , 28th April 1997, 3rd June 2005, 3rd June 2005, , 26th February 2007 and 26th February 2007, respectively. No new or unexpected safety concerns arose from this simple application and it was, therefore, judged that the benefits of taking Calpol Suspension Infant, Calpol Sugar Free Suspension Infant, Calpol Suspension Infant Sachets and Calpol Sugar Free Suspension Infant Sachets outweigh the risks, hence Marketing Authorisations have been granted.




SCIENTIFIC DISCUSSION

TABLE OF CONTENTS Introduction

Page 4

Pharmaceutical assessment

Page 5

Preclinical assessment

Page 8

Clinical assessment

Page 9

Overall conclusions and risk benefit assessment Page 10


INTRODUCTION The UK granted marketing authorisations for the medicinal products Calpol Suspension Infant, Calpol Sugar Free Suspension Infant, Calpol Suspension Infant Sachets and Calpol Sugar Free Suspension Infant Sachets on 2nd September 2009 (PL 15513/0297-302) to McNeil Products Limited. These products are available as:

• general sales licence (GSL) products – PL 15513/0299, 0300, 0301 and 0302. • pharmacy medicines licence (P) products – PL 15513/0297, 0298

The applications were submitted as simple abridged applications according to Article 10c (formerly Article 10.1(a)(i)) of Directive 2001/83/EC, cross-referring to Calpol Infant Suspension (PL 15513/0004), Calpol Sugar Free Infant Suspension (PL 15513/0006), Calpol Infant Suspension (PL 15513/0122), Calpol Sugar Free Infant Suspension (PL 15513/0123), Calpol Infant Suspension Sachets (PL 15513/0154) and Calpol Sugar Free Infant Suspension Sachets (PL 15513/0155), which were originally approved on28th April 1997, 28th April 1997, , 3rd June 2005, 3rd June 2005, 26th February 2007 and 26th February 2007, respectively. No new data were submitted nor was it necessary for these simple applications, as the data are identical to that of the previously granted cross-reference product. The active ingredient is paracetamol, which has analgesic and antipyretic effects similar to those of aspirin and is useful in the treatment of mild to moderate pain. It has weak anti-inflammatory effects. Calpol Suspension Infant, Calpol Sugar Free Suspension Infant, Calpol Suspension Infant Sachets and Calpol Sugar Free Suspension Infant Sachets are indicated for the treatment of mild to moderate pain (including teething pain) and as an antipyretic (including post immunisation fever).


PHARMACEUTICAL ASSESSMENT

LICENCE NO: PL 15513/0297-302 PROPRIETARY NAME: Calpol Suspension Infant, Calpol Sugar Free Suspension Infant, Calpol Suspension Infant Sachets and Calpol Sugar Free Suspension Infant Sachets ACTIVE(S): Paracetamol COMPANY NAME: McNeil Products Limited E.C. ARTICLE: Article 10c (formerly Article 10.1(a)(i)) of Directive 2001/83/EC LEGAL STATUS: GSL and P 1. INTRODUCTION These are simple, piggy back applications for Calpol Suspension Infant, Calpol Sugar Free Suspension Infant, Calpol Suspension Infant Sachets and Calpol Sugar Free Suspension Infant Sachets submitted under Article 10c (formerly Article 10.1(a)(i)) of Directive 2001/83/EC. The proposed MA holder is McNeil Products Limited, Foundation Park, Roxborough Way, Maidenhead, Berkshire, SL6 3UG, UK. The applications cross-refer to Calpol Infant Suspension (PL 15513/0004), Calpol Sugar Free Infant Suspension (PL 15513/0006), Calpol Infant Suspension (PL 15513/0122), Calpol Sugar Free Infant Suspension (PL 15513/0123), Calpol Infant Suspension Sachets (PL 15513/0154) and Calpol Sugar Free Infant Suspension Sachets (PL 15513/0155), which were originally approved on 28th April 1997, 28th April 1997, , 3rd June 2005, 3rd June 2005, 26th February 2007 and 26th February 2007, respectively. The current application is considered valid. 2. MARKETING AUTHORISATION APPLICATION FORM 2.1 Name(s) The proposed names of the products are Calpol Suspension Infant, Calpol Sugar Free Suspension Infant, Calpol Suspension Infant Sachets and Calpol Sugar Free Suspension Infant Sachets. The products have been named in line with current requirements. 2.2 Strength, pharmaceutical form, route of administration, container and pack sizes The products contain paracetamol, equivalent to 120 mg. It is to be stored in either: 1. glass amber bottles with polyethylene or polyvinylidene chloride child-resistant closures and a plastic measuring spoon, in pack sizes of 30 ml (PL 15513/0298), 70ml (PL 15513/0299 and 0300), 100ml (PL 15513/0299 and 0300) 140ml (PL 15513/0298), 200ml (PL 15513/0297 and 0298) and 1000ml (PL 15513/0298) 2. aluminium/paper sachets, stored in cardboard boxes, in pack sizes of 12 sachets and 20 sachets (PL 15513/0301 and 0302). The proposed shelf-life (36 months) and storage conditions (Do not store above 25 degrees, Keep bottle/sachets in outer carton) are consistent with the details registered for the cross-reference products. 2.3 Legal status On approval, the products will be available as general sales licence (GSL) and pharmacy licence (P) medicines.


2.4 Marketing authorisation holder/Contact Persons/Company McNeil Products Limited, Foundation Park, Roxborough Way, Maidenhead, Berkshire, SL6 3UG, UK The QP responsible for pharmacovigilance is stated and his CV is included. 2.5 Manufacturers The proposed manufacturing sites are consistent with those registered for the cross-reference products and evidence of GMP compliance has been provided. 2.6 Qualitative and quantitative composition The proposed composition is consistent with the details registered for the cross-reference products. 2.7 Manufacturing process The proposed manufacturing process is consistent with the details registered for the cross-reference products and the maximum batch size is stated. 2.8 Finished product/shelf-life specification The proposed finished product specification is in line with the details registered for the cross-reference products. 2.9 Drug substance specification The proposed drug substance specification is consistent with the details registered for the cross-reference products. 2.10 TSE Compliance No materials of animal or human origin are included in the product. This is consistent with the cross reference products. 3. EXPERT REPORTS The applicant has included detailed expert reports in Module 2 of the applications. Signed declarations and copies of the experts’ CVs are enclosed in Module 1.4 for the quality, non-clinical and clinical experts. All are considered to have sufficient experience for their responsibilities. 4. PRODUCT NAME & APPEARANCE See 2.1 for details of the proposed product names. The appearance of the products are identical to their respective cross-reference products. 5. SUMMARY OF PRODUCT CHARACTERISTICS The proposed summaries are consistent with the details registered for the cross-reference products.


6. PATIENT INFORMATION LEAFLET/CARTON PIL The patient information leaflets have been prepared in-line with the details registered for their respective cross-reference products. A package leaflet has been submitted to the MHRA along with results of consultations with target patient groups ("user testing"), in accordance with Article 59 of Council Directive 2001/83/EC. The results indicate that the package leaflet is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that it contains. Carton and blister The proposed artwork is comparable to the artwork registered for the cross-reference products and complies with statutory requirements. In line with current legislation, the applicant has also included the name of the product in Braille on the outer packaging and has included sufficient space for a standard UK pharmacy dispensing label. 7. PHARMACOVIGILANCE SYSTEM The Pharmacovigilance System, as described by the applicant, fulfils the requirements and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance, and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. 8. RISK MANAGEMENT PLAN A suitable justification has been provided for not submitting a risk management plan for these products. 9. ENVIRONMENTAL RISK ASSESSMENT A suitable justification has been provided for not submitting an environmental risk assessment for these products. 10. CONCLUSIONS The data submitted with these applications are acceptable. The grant of Marketing Authorisations is recommended.


PRECLINICAL ASSESSMENT No new preclinical data have been supplied with these applications and none are required for applications of this type.


CLINICAL ASSESSMENT

No new clinical data have been supplied with these applications and none are required for applications of this type.


OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT QUALITY The data for these applications are consistent with that previously assessed for their respective cross-reference products and as such have been judged to be satisfactory. PRECLINICAL No new preclinical data were submitted and none are required for applications of this type. EFFICACY The applications are identical to a previously granted applications for Calpol Infant Suspension (PL 15513/0004), Calpol Sugar Free Infant Suspension (PL 15513/0006), Calpol Infant Suspension (PL 15513/0122), Calpol Infant Suspension (PL 15513/0123), Calpol Infant Suspension Sachets (PL 15513/0154) and Calpol Sugar Free Infant Suspension Sachets (PL 15513/0155). No new or unexpected safety concerns arise from these applications. The SPC, PIL and labelling are satisfactory and consistent with that for the cross-reference products. RISK BENEFIT ASSESSMENT The quality of the product is acceptable and no new preclinical or clinical safety concerns have been identified. The applicant’s products are identical to their respective cross-reference products. Extensive clinical experience with paracetamol is considered to have demonstrated the therapeutic value of the compound. The risk benefit is, therefore, considered to be positive.


CALPOL SUSPENSION INFANT (PL 15513/0297, 299)

CALPOL SUGAR FREE SUSPENSION INFANT (PL 15513/0298, 300) CALPOL SUSPENSION INFANT SACHETS (PL 15513/0301)

CALPOL SUGAR FREE SUSPENSION INFANT SACHETS (PL 15513/0302)

STEPS TAKEN FOR ASSESMENT

1 The MHRA received the marketing authorisation application on 19/02/2008 (PL 15513/0297 and 0299), 15/02/2008 (PL 15513/0298, 0300, 0301 and 0302).

2 Following standard checks and communication with the applicant the MHRA considered the application valid on 28/02/2008 (PL 15513/0297 and 0299), 27/02/2008 (PL 15513/0298), 29/02/2008 (PL 15513/0300 and 0301) and 03/03/2008 (PL 15513/0302).

3 Following assessment of the application the MHRA requested further information on 04/02/2009 (PL 15513/0297, 0299, 0300, 0301 and 0302) and 02/02/2009 (PL 15513/0298).

4 The applicant responded to the MHRA’s requests, providing further information on 15/06/2009 (PL 15513/0297, 0299, 0300 and 0302) and 22/06/2009 (PL 15513/0301)

5 The application was determined on 02/09/2009 (all applications)




STEPS TAKEN AFTER ASSESSMENT

Date submitted

Application type

Scope Outcome




SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT CALPOL Suspension Infant

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

CALPOL Suspension Infant contains 120mg Paracetamol in each 5ml.

Excipients sucrose (contain 2.2 g of sucrose per 5 ml), sorbitol liquid (E420), methyl parahydroxybenzoate (E218), ethyl parahydroxybenzoate (E214), propyl parahydroxybenzoate (E216) and carmoisine (E122). See section 4.4 for further information. For full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Oral Suspension A pink strawberry flavoured suspension. 4 CLINICAL PARTICULARS 4.1 Therapeutic indications

CALPOL Suspension Infant is indicated for the treatment of mild to moderate pain (including teething pain) and as an antipyretic (including post immunisation fever).

4.2 Posology and method of administration

Children aged 1 to under 6 years: Oral. 5 to 10ml (120mg to 240mg paracetamol). Repeat every 4 hours, if necessary, up to a maximum of 4 doses per 24 hours. Infants 3 months to under 1 year: Oral. 2.5 to 5 ml (60mg to 120mg paracetamol). Repeat every 4 hours, if necessary, up to a maximum of 4 doses per 24 hours. Infants aged 2-3 months: Oral. A 2.5ml (60 mg paracetamol) dose is suitable for babies who develop post vaccination fever at 2 months followed, if necessary, by a second dose 4 to 6 hours later. The same 2 doses may be given for other causes of fever or mild to moderate pain provided the infant weighs over 4 kg and was not born before 37 weeks gestation. Medical advice should be sought promptly if further doses are required or if the cause of the infant’s fever or pain is not known, The Elderly: In the elderly, the rate and extent of paracetamol absorption is normal but plasma half-life is longer and paracetamol clearance is lower than in young adults.

4.3 Contraindications CALPOL Suspension Infant is contra-indicated in patients with known hypersensitivity to paracetamol, or any of the other constituents.


4.4 Special warnings and precautions for use Care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment. The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease. Due to the presence of sucrose and sorbitol, patients with rare hereditary problems of fructose intolerance, glucose- galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. Ethyl (E214), Propyl (E216) and Methyl (E218) parahydroxybenzoates may cause allergic reactions (possibly delayed). Carmosine (E122) may cause allergic reactions. The label contains the following statements: Do not exceed the stated dose. If symptoms persist consult your doctor. Keep out of the reach and sight of children. Do not give with any other paracetamol containing products. Leave at least 4 hours between doses. Immediate medical advice should be sought in the event of an overdose, even if the child seems well. (label) Immediate medical advice should be sought in the event of an overdose, even if the child seems well, because of the risk of delayed, serious liver damage. (leaflet) Talk to your doctor: If your child has an inherited intolerance to fructose or been diagnosed with an intolerance to some other sugars. (leaflet) The sucrose and sorbitol liquid (E420) content of this product means that this product is unsuitable for people with inherited intolerance to fructose. This medicine contains 2.2 g of sucrose per 5 ml. This should be taken into account in patients with diabetes mellitus. (leaflet)

4.5 Interaction with other medicinal products and other forms of interaction The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by colestyramine. 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. Chronic alcohol intake can increase the hepatotoxicity of paracetamol overdose and may have contributed to the acute pancreatitis reported in one patient who had taken an overdose of paracetamol. Acute alcohol intake may diminish an individual’s ability to metabolise large doses of paracetamol, the plasma half-life of which can be prolonged. The use of drugs that induce hepatic microsomal enzymes, such as anticonvulsants and oral contraceptives, may increase the extent of metabolism of paracetamol, resulting in reduced plasma concentrations of the drug and a faster elimination rate.

4.6 Pregnancy and lactation Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage, but patients should follow the advice of their doctor regarding its use. Paracetamol is excreted in breast milk but not in a clinically significant amount. Available published data do not contraindicate breast-feeding.


4.7 Effects on ability to drive and use machines None known.

4.8 Undesirable effects

Adverse effects of paracetamol are rare but hypersensitivity/anaphylactic reactions including skin rash may occur. There have been reports of blood dyscrasias including thrombocytopenia and agranulocystosis but these were not necessarily causality related to paracetamol. Most reports of adverse reactions to paracetamol relate to overdosage with the drug. 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 the disease improved after paracetamol withdrawal. Nephrotoxicity following therapeutic doses of paracetamol is uncommon, but apillary necrosis has been reported after prolonged administration.

4.9 Overdose

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.


5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Paracetamol has analgesic and antipyretic effects that do not differ significantly from those of aspirin. However it has only weak anti-inflammatory effects. It is only a weak inhibitor of prostaglandin biosynthesis although there is some evidence to suggest it may be more effective against enzymes in the central nervous system than in the periphery. This may in part account for its activity profile. ATC code: NO2BE01, other analgesics and antipyretics.

5.2 Pharmacokinetic properties Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract with peak plasma concentrations occurring 0.5-2 hours after dosing. The plasma half-life is approximately 2 hours after therapeutic doses in adults but is increased in neonates to about 5 hours. It is widely distributed through the body. Metabolism is principally by the hepatic microsomal enzymes and urinary excretion accounts for over 90% of the dose within 1 day. Virtually no paracetamol is excreted unchanged, the bulk being conjugated with glucoronic acid (60%), sulphuric acid (35%) or cysteine (3%). Children have less capacity for glucuronidation of the drug than adults.

5.3 Preclinical safety data

Mutagenicity There are no studies relating to the mutagenic potential of CALPOL Suspension Infant. In vivo mutagenicity tests of paracetamol in mammals are limited and show conflicting results. Therefore, there is insufficient information to determine whether paracetamol poses a mutagenic risk to man. Paracetamol has been found to be non-mutagenic in bacterial mutagenicity assays, although a clear clastogenic effect has been observed in mammalian cells in vitro following exposure to paracetamol (3 and 10 mM for 2h). Carcinogenicity There are no studies to the carcinogenic potential of CALPOL Suspension Infant. There is inadequate evidence to determine the carcinogenic potential of paracetamol in humans. A positive association between the use of paracetamol and cancer of the ureter (but not of other sites in the urinary tract) was observed in a case-control study in which approximate lifetime consumption of paracetamol (whether acute or chronic) was estimated. However, other similar studies have failed to demonstrate a statistically significant association between paracetamol and cancer of the urinary tract, or paracetamol and renal cell carcinoma. There is limited evidence for the carcinogenicity of paracetamol in experimental animals. Liver cell tumours can be detected in rats following chronic feeding of 500 mg/kg/day paracetamol. Teratogenicity There is no information relating to the teratogenic potential of CALPOL Suspension Infant. In humans, paracetamol crosses the placenta and attains concentrations in the foetal circulation similar to those in the maternal circulation. Intermittent maternal ingestion of therapeutic doses of paracetamol are not associated with teratogenic effects in humans. Paracetamol has been found to be foetotoxic to cultured rat embryo. Fertility There is no information relating to the effects of CALPOL Suspension Infant on fertility. A significant decrease in testicular weight was observed when male Sprague-Dawley rats were given daily high doses of paracetamol (500 mg/kg/body weight/day) orally for 70 days.


6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Sucrose Sorbitol Liquid (non crystallising) (E420) Glycerol Xanthan Gum Dispersible Cellulose Polysorbate 80 Acesulfame Potassium Propyl Parahydroxybenzoate (E216) Ethyl Parahydroxybenzoate (E214) Strawberry Flavour 500018E Methyl Parahydroxybenzoate (E218) Carmoisine (E122) Purified Water

6.2 Incompatibilities None known

6.3 Shelf life

36 months for the amber glass bottles. 6.4 Special precautions for storage

Do not store above 25ºC. Keep bottle in the outer carton. 6.5 Nature and contents of container

200 ml amber glass bottle closed with a two-piece plastic child resistant, tamper evident closure fitted with a polyethylene/polvinylidine chloride (PVDC) polyethylene laminate faced wad or a three piece plastic child resistant, tamper evident closure fitted with a polyethylene/polyvinylidene chloride (PVDC) polyethylene laminate faced wad.

6.6 Special precautions for disposal

No special requirements. 7 MARKETING AUTHORISATION HOLDER

McNeil Products Limited Foundation Park Roxborough Way Maidenhead Berkshire SL6 3UG UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 15513/0297 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 02/09/2009 10 DATE OF REVISION OF THE TEXT

02/09/2009


1. NAME OF THE MEDICINAL PRODUCT CALPOL Sugar Free Suspension Infant 2. QUALITATIVE AND QUANTITATIVE COMPOSITION

CALPOL Sugar Free Suspension Infant contains 120 mg Paracetamol in each 5 ml.

Excipients: maltitol liquid (E965), sorbitol liquid (E420), methyl parahydroxybenzoate (E218), ethyl parahydroxybenzoate (E214), propyl parahydroxybenzoate (E216) and carmoisine (E122). See section 4.4 for further information.

For full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM Oral Suspension. A pink strawberry flavoured suspension. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications CALPOL Sugar Free Suspension Infant is indicated for the treatment of mild to moderate pain

(including teething pain), and as an antipyretic (including post immunisation fever). 4.2 Posology and method of administration Children aged 1 to under 6 years: Oral. 5 to 10 ml (120 mg to 240 mg paracetamol). Repeat every 4 hours, if necessary, up to a

maximum of 4 doses per 24 hours. Infants 3 months to under 1 year: Oral. 2.5 to 5 ml (60 mg to 120 mg paracetamol). Repeat every 4 hours, if necessary, up to a

maximum of 4 doses per 24 hours. Infants aged 2 – 3 months:

Oral. A 2.5 ml (60 mg paracetamol) dose for babies who develop post-vaccination fever at 2 months followed, if necessary, by a second dose 4 to 6 hours later. The same 2 doses may be given for other causes of fever or mild to moderate pain provided the infant weighs over 4 kg and was not born before 37 weeks gestation. Medical advice should be sought promptly if further doses are required or if the cause of the infant’s fever or pain is not known.

The Elderly:

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

4.3 Contra-indications CALPOL Sugar Free Suspension Infant is contra-indicated in patients with known hypersensitivity

to paracetamol, or any of the other components. 4.4 Special warnings and precautions for use

Care is advised in the administration of paracetamol to patients with severe renal impairment or severe hepatic impairment. The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease. Concomitant use of other paracetamol-containing products should be avoided. Due to the presence of maltitol liquid (E965) and sorbitol liquid (E420), patients with rare hereditary problems of fructose intolerance should not take this medicine. Ethyl (E214), Propyl (E216) and Methyl (E218) parahydroxybenzoates may cause allergic reactions (possibly delayed).


Carmosine (E122) may cause allergic reactions. The label contains the following statements: Shake the bottle thoroughly (bottle only) Do not exceed the stated dose. If symptoms persist consult your doctor. Keep out of the reach and sight of children. Do not give with any other paracetamol-containing products. Do not give more than 2 doses. If further doses are required consult your doctor (age: 2 months). Do not give more than 4 doses in 24 hours. Do not give for more than 3 days without consulting a doctor (age: 3 months – 6 years). Leave at least 4 hours between doses. If your child is currently taking any other medicine consult your doctor or pharmacist before using this product. Do not store above 25°C. Keep container in outer carton. Contains paracetamol. Immediate medical advice should be sought in the event of an overdose, even if the child seems well. (label) Immediate medical advice should be sought in the event of an overdose, even if the child seems well, because of the risk of delayed, serious liver damage. (leaflet) Talk to your doctor: If your child has an inherited intolerance to fructose or been diagnosed with an intolerance to some other sugars. (leaflet) The sorbitol liquid (E420) and maltitol liquid (E965) content of this product means that this product is unsuitable for people with inherited intolerance to fructose. (leaflet).


4.6 Pregnancy & lactation

Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage, but patients should follow the advice of their doctor regarding its use. Paracetamol is excreted in breast milk but not in a clinically significant amount. Available published data do not contraindicate breast feeding.



4.8 Undesirable effects Adverse effects of paracetamol are rare but hypersensitivity/anaphylactic reactions including skin rash may occur. There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis but these were not necessarily causality related to paracetamol.

Most reports of adverse reactions to paracetamol relate to overdose with the drug. 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.

4.9 Overdose

Liver damage is possible in adults who have taken 10 g 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 carbamezipine, 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.


5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Paracetamol has analgesic and antipyretic effects similar to those of aspirin and is useful in the

treatment of mild to moderate pain. It has only weak anti-inflammatory effects. ATC code: NO2BE01, other analgesics and antipyretics. 5.2 Pharmacokinetic properties

Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. Peak plasma concentrations are reached 30-90 minutes post dose and the plasma half-life is in the range of 1 to 3 hours after therapeutic doses. Drug is widely distributed throughout most body fluids. Following therapeutic doses 90-100% of the drug is recovered in the urine within 24 hours almost entirely following hepatic conjugation with glucuronic acid (about 60%), sulphuric acid (about 35%) or cysteine (about 3%). Small amounts of hydroxylated and deacetylated metabolites have also been detected. Children have less capacity for glucuronidation of the drug than do adults. In overdosage there is increased N-hydroxylation followed by glutathione conjugation. When the latter is exhausted, reaction with hepatic proteins is increased leading to necrosis.


The active ingredient of this product is a well known constituent of medicinal products and its safety profile is well documented.


Maltitol liquid (E965) Sorbitol liquid (non crystallising) (E420) Glycerol Dispersible cellulose Xanthan gum Ethyl parahydroxybenzoate (E214) Methyl parahydroxybenzoate (E218) Propyl parahydroxybenzoate (E216) Polysorbate 80 Strawberry Flavour 500286E Carmoisine (E122) Purified water


6.3 Shelf life


Do not store above 25°C. Keep bottle in the outer carton. 6.5 Nature and contents of container

Amber glass bottle with plastic screw cap, a polyethylene or polyvinylidene chloride (PVDC) laminate faced wad. Or Amber glass bottle with a two-piece plastic child resistant, tamper evident closure fitted with a polyethylene or polyvinylidene chloride (PVDC) laminate faced wad. Or Amber glass bottle with a three-piece plastic child resistant, tamper evident closure fitted with a polyethylene or polyvinylidene chloride (PVDC) laminate faced wad.


Pack sizes 30 ml, 70ml, 140 ml, 200 ml and 1000ml. A spoon with a 5 ml and 2.5 ml measure is supplied with this pack. 1000 ml amber glass bottle with an aluminium cap fitted with a polyethylene wad.



McNeil Products Limited Foundation Park Roxborough Way Maidenhead Berkshire SL6 3UG UK 8 MARKETING AUTHORISATION NUMBER(S)


02/09/2009


1 NAME OF THE MEDICINAL PRODUCT CALPOL Suspension Infant


CALPOL Suspension Infant contains 120mg Paracetamol in each 5ml.

Excipients sucrose (contains 2.2 g of sucrose in each 5 ml), sorbitol liquid (E420), methyl parahydroxybenzoate (E218), ethyl parahydroxybenzoate (E214), propyl parahydroxybenzoate (E216) and carmoisine (E122). See section 4.4 for further information. For full list of excipients, see section 6.1.



CALPOL Suspension Infant is indicated for the treatment of mild to moderate pain (including teething pain) and as an antipyretic (including post immunisation fever).



4.3 Contraindications CALPOL Suspension Infant is contra-indicated in patients with known hypersensitivity to paracetamol, or any of the other constituents.

4.4 Special warnings and precautions for use

Care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment. The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease. Due to the presence of sucrose and sorbitol, patients with rare hereditary problems of fructose intolerance, glucose- galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.


Ethyl (E214), Propyl (E216) and Methyl (E218) parahydroxybenzoates may cause allergic reactions (possibly delayed). Carmosine (E122) may cause allergic reactions. The label contains the following statements: Do not exceed the stated dose. If symptoms persist consult your doctor. Keep out of the reach and sight of children. Do not give with any other paracetamol containing products. Leave at least 4 hours between doses. Immediate medical advice should be sought in the event of an overdose, even if the child seems well. (label) Immediate medical advice should be sought in the event of an overdose, even if the child seems well, because of the risk of delayed, serious liver damage. (leaflet) Talk to your doctor: If your child has an inherited intolerance to fructose or been diagnosed with an intolerance to some other sugars. (leaflet) The sucrose and sorbitol liquid (E420) content of this product means that this product is unsuitable for people with inherited intolerance to fructose. This medicine contains 2.2 g of sucrose per 5 ml. This should be taken into account in patients with diabetes mellitus. (leaflet)





4.8 Undesirable effects Adverse effects of paracetamol are rare but hypersensitivity/anaphylactic reactions including skin rash may occur. There have been reports of blood dyscrasias including thrombocytopenia and agranulocystosis but these were not necessarily causality related to paracetamol. Most reports of adverse reactions to paracetamol relate to overdosage with the drug. 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 the disease improved after paracetamol withdrawal. Nephrotoxicity following therapeutic doses of paracetamol is uncommon, but apillary necrosis has been reported after prolonged administration.

4.9 Overdose

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 the 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 concentrations 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.






Mutagenicity There are no studies relating to the mutagenic potential of CALPOL Suspension Infant. In vivo mutagenicity tests of paracetamol in mammals are limited and show conflicting results. Therefore, there is insufficient information to determine whether paracetamol poses a mutagenic risk to man. Paracetamol has been found to be non-mutagenic in bacterial mutagenicity assays, although a clear clastogenic effect has been observed in mammalian cells in vitro following exposure to paracetamol (3 and 10 mM for 2h). Carcinogenicity There are no studies to the carcinogenic potential of CALPOL Suspension Infant. There is inadequate evidence to determine the carcinogenic potential of paracetamol in humans. A positive association between the use of paracetamol and cancer of the ureter (but not of other sites in the urinary tract) was observed in a case-control study in which approximate lifetime consumption of paracetamol (whether acute or chronic) was estimated. However, other similar studies have failed to demonstrate a statistically significant association between paracetamol and cancer of the urinary tract, or paracetamol and renal cell carcinoma. There is limited evidence for the carcinogenicity of paracetamol in experimental animals. Liver cell tumours can be detected in rats following chronic feeding of 500 mg/kg/day paracetamol. Teratogenicity There is no information relating to the teratogenic potential of CALPOL Suspension Infant. In humans, paracetamol crosses the placenta and attains concentrations in the foetal circulation similar to those in the maternal circulation. Intermittent maternal ingestion of therapeutic doses of paracetamol are not associated with teratogenic effects in humans. Paracetamol has been found to be foetotoxic to cultured rat embryo. Fertility There is no information relating to the effects of CALPOL Suspension Infant on fertility. A significant decrease in testicular weight was observed when male Sprague-Dawley rats were given daily high doses of paracetamol (500 mg/kg/body weight/day) orally for 70 days.





6.3 Shelf-life

36 months. 6.4 Special precautions for storage

Do not store above 25ºC. Keep bottle in the outer container. 6.5 Nature and contents of container

70ml and 100 ml amber glass bottle closed with a two-piece plastic child resistant, tamper evident closure fitted with a polyethylene/polvinylidine chloride (PVDC) polyethylene laminate faced wad or a three piece plastic child resistant, tamper evident closure fitted with a polyethylene/polyvinylidene chloride (PVDC) polyethylene laminate faced wad. A spoon with a 5ml and 2.5ml measure is supplied with this pack.






02/09/2009


1 NAME OF THE MEDICINAL PRODUCT CALPOL Sugar Free Suspension Infant


CALPOL Sugar Free Suspension Infant contains 120mg Paracetamol in each 5ml.

Excipients: maltilol liquid (E965), sorbitol liquid (E420), methyl parahydroxybenzoate (E218), ethyl parahydroxybenzoate (E214), propyl parahydroxybenzoate (E216) and carmoisine (E122). See section 4.4 for further information. For full list of excipients, see section 6.1.



CALPOL Sugar Free Suspension Infant is indicated for the treatment of mild to moderate pain (including teething pain) and as an antipyretic (including post immunisation fever).



4.3 Contraindications CALPOL Sugar Free Suspension Infant is contra-indicated in patients with known hypersensitivity to paracetamol, or any of the other components.


CALPOL Sugar Free Suspension Infant should be used with caution in severe renal impairment or severe hepatic impairment. The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease. Concomitant use of other paracetamol-containing products should be avoided. Due to the presence of maltitol liquid (E965) and sorbitol liquid (E420), patients with rare hereditary problems of fructose intolerance should not take this medicine.


Ethyl (E214), Propyl (E216) and Methyl (E218) parahydroxybenzoates may cause allergic reactions (possibly delayed). Carmosine (E122) may cause allergic reactions. The label contains the following statements: Shake the bottle thoroughly. Keep out of the reach and sight of children. Do not exceed the stated dose. Do not take more than 4 doses in 24 hours. Leave at least 4 hours between doses. Do not give for more than 3 days without consulting a doctor. If you are currently taking any medicine consult your doctor or pharmacist before taking this product. If symptoms persist consult your doctor. Do not store above 25°C. Keep container in outer carton. Contains paracetamol. Immediate medical advice should be sought in the event of an overdose, even if the child seems well. (label)

Do not give with any other paracetamol-containing products. Immediate medical advice should be sought in the event of an overdose, even if the child seems well, because of the risk of delayed, serious liver damage. (leaflet) Talk to your doctor: If your child has an inherited intolerance to fructose or been diagnosed with an intolerance to some other sugars. (leaflet) The sorbitol liquid (E420) and maltilol liquid (E965) content of this product means that this product is unsuitable for people with inherited intolerance to fructose (leaflet).





4.8 Undesirable effects Adverse effects of paracetamol are rare but hypersensitivity/anaphylactic reactions including skin rash may occur. There have been reports of blood dyscrasias including thrombocytopenia and agranulocystosis but these were not necessarily causally related to paracetamol. Most reports of adverse reactions to paracetamol relate to overdose with the drug. 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 apillary necrosis has been reported after prolonged administration.

4.9 Overdose

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, 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. 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 concentrations 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.


5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Paracetamol has analgesic and antipyretic effects similar to those of aspirin and is useful in the treatment

of mild to moderate pain. It has only weak anti-inflammatory effects. ATC code: NO2BE01, other analgesics and antipyretics.

5.2 Pharmacokinetic properties Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. Peak plasma

concentrations are reached 30-90 minutes post dose and the plasma half-life is in the range of 1 to 3 hours after therapeutic doses. Drug is widely distributed throughout most body fluids. Following therapeutic doses 90-100% of the drug is recovered in the urine within 24 hours almost entirely following hepatic conjugation with glucuronic acid (about 60%), sulphuric acid (about 35%) or cysteine (about 3%). Small amounts of hydroxylated and deacetylated metabolites have also been detected. Children have less capacity for glucuronidation of the drug than do adults. In overdosage there is increased N-hydroxylation followed by glutathione conjugation. When the latter is exhausted, reaction with hepatic proteins is increased leading to necrosis.


Mutagenicity There are no studies relating to the mutagenic potential of CALPOL Sugar-Free Suspension Infant. In vivo mutagenicity tests of paracetamol in mammals are limited and show conflicting results. Therefore, there is insufficient information to determine whether paracetamol poses a mutagenic risk to man. Paracetamol has been found to be non-mutagenic in bacterial mutagenicity assays, although a clear clastogenic effect has been observed in mammalian cells in vitro following exposure to paracetamol (3 and 10 mM for 2h). Carcinogenicity There are no studies to the carcinogenic potential of CALPOL Sugar Free Suspension Infant. There is inadequate evidence to determine the carcinogenic potential of paracetamol in humans. A positive association between the use of paracetamol and cancer of the ureter (but not of other sites in the urinary tract) was observed in a case-control study in which approximate lifetime consumption of paracetamol (whether acute or chronic) was estimated. However, other similar studies have failed to demonstrate a statistically significant association between paracetamol and cancer of the urinary tract, or paracetamol and renal cell carcinoma. There is limited evidence for the carcinogenicity of paracetamol in experimental animals. Liver cell tumours can be detected in rats following chronic feeding of 500 mg/kg/day paracetamol. Teratogenicity There is no information relating to the teratogenic potential of CALPOL Sugar Free Suspension Infant. In humans, paracetamol crosses the placenta and attains concentrations in the foetal circulation similar to those in the maternal circulation. Intermittent maternal ingestion of therapeutic doses of paracetamol are not associated with teratogenic effects in humans. Paracetamol has been found to be foetotoxic to cultured rat embryo. Fertility There is no information relating to the effects of CALPOL Suagr Free Suspension Infant on fertility. A significant decrease in testicular weight was observed when male Sprague-Dawley rats were given daily high doses of paracetamol (500 mg/kg/body weight/day) orally for 70 days.





6.3 Shelf life


Do not store above 25ºC. Keep bottle in the outer carton. 6.5 Nature and contents of container

Amber glass bottle with a two-piece plastic child resistant, tamper evident closure fitted with a polyethylene or polyvinylidene chloride (PVDC) laminate faced wad. or Amber glass bottle with a three-piece plastic child resistant, tamper evident closure fitted with a polyethylene or polyvinylidene chloride (PVDC) laminate faced wad. Pack sizes 70ml and 100ml. A spoon with a 5 ml and 2.5 ml measure is supplied with this pack.






02/09/2009


1 NAME OF THE MEDICINAL PRODUCT CALPOL Suspension Infant Sachets


CALPOL Suspension Infant Sachets contains 120mg Paracetamol in each 5ml.

Excipients sucrose (contain 2.2 g of sucrose per 5 ml), sorbitol liquid (E420), methyl parahydroxybenzoate (E218), ethyl parahydroxybenzoate (E214), propyl parahydroxybenzoate (E216) and carmoisine (E122). See section 4.4 for further information. For a full list of excipients, see section 6.1.



CALPOL Suspension Infant Sachets is indicated for the treatment of mild to moderate pain (including teething pain) and as an antipyretic (including post immunisation fever).


Children aged 1 to under 6 years: Oral. 5 to 10ml (120mg to 240mg paracetamol). Repeat every 4 hours, if necessary, up to a maximum of 4 doses per 24 hours. Infants 3 months to under 1 year: Oral. 2.5 to 5 ml (60mg to 120mg paracetamol). Repeat every 4 hours, if necessary, up to a maximum of 4 doses per 24 hours. Infants aged 2-3 months: Oral. A 2.5ml (60 mg paracetamol) dose is suitable for babies who develop post vaccination fever at 2 months followed, if necessary, by a second dose 4 to 6 hours later. The same 2 doses may be given for other causes of fever or mild to moderate pain provided the infant weighs over 4 kg and was not born before 37 weeks gestation. Medical advice should be sought promptly if further doses are required or if the cause of the infant’s fever or pain is not known. The Elderly: In the elderly, the rate and extent of paracetamol absorption is normal but plasma half-life is longer and paracetamol clearance is lower than in young adults.

4.3 Contraindications CALPOL Suspension Infant Sachets is contra-indicated in patients with known hypersensitivity to paracetamol, or any of the other constituents.


Care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment. The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease. Due to the presence of sucrose and sorbitol, patients with rare hereditary problems of fructose intolerance, glucose- galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.


Ethyl (E214), Propyl (E216) and Methyl (E218) parahydroxybenzoates may cause allergic reactions (possibly delayed). Carmosine (E122) may cause allergic reactions. The label contains the following statements: Do not exceed the stated dose. If symptoms persist consult your doctor. Keep out of the reach and sight of children. Do not give with any other paracetamol containing products. Leave at least 4 hours between doses. Immediate medical advice should be sought in the event of an overdose, even if the child seems well. (label) Immediate medical advice should be sought in the event of an overdose, even if the child seems well, because of the risk of delayed, serious liver damage. (leaflet) Talk to your doctor: If your child has an inherited intolerance to fructose or been diagnosed with an intolerance to some other sugars. (leaflet) The sucrose and sorbitol liquid (E420) content of this product means that this product is unsuitable for people with inherited intolerance to fructose. This medicine contains 2.2 g of sucrose per 5 ml. This should be taken into account in patients with diabetes mellitus. (leaflet)





4.8 Undesirable effects Adverse effects of paracetamol are rare but hypersensitivity/anaphylactic reactions including skin rash may occur. There have been reports of blood dyscrasias including thrombocytopenia and agranulocystosis but these were not necessarily causality related to paracetamol. Most reports of adverse reactions to paracetamol relate to overdosage with the drug. 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 the disease improved after paracetamol withdrawal. Nephrotoxicity following therapeutic doses of paracetamol is uncommon, but apillary necrosis has been reported after prolonged administration.

4.9 Overdose

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.






Mutagenicity There are no studies relating to the mutagenic potential of CALPOL Suspension Infant Sachets. In vivo mutagenicity tests of paracetamol in mammals are limited and show conflicting results. Therefore, there is insufficient information to determine whether paracetamol poses a mutagenic risk to man. Paracetamol has been found to be non-mutagenic in bacterial mutagenicity assays, although a clear clastogenic effect has been observed in mammalian cells in vitro following exposure to paracetamol (3 and 10 mM for 2h). Carcinogenicity There are no studies to the carcinogenic potential of CALPOL Suspension Infant Sachets. There is inadequate evidence to determine the carcinogenic potential of paracetamol in humans. A positive association between the use of paracetamol and cancer of the ureter (but not of other sites in the urinary tract) was observed in a case-control study in which approximate lifetime consumption of paracetamol (whether acute or chronic) was estimated. However, other similar studies have failed to demonstrate a statistically significant association between paracetamol and cancer of the urinary tract, or paracetamol and renal cell carcinoma. There is limited evidence for the carcinogenicity of paracetamol in experimental animals. Liver cell tumours can be detected in rats following chronic feeding of 500 mg/kg/day paracetamol. Teratogenicity There is no information relating to the teratogenic potential of CALPOL Suspension Infant Sachets. In humans, paracetamol crosses the placenta and attains concentrations in the foetal circulation similar to those in the maternal circulation. Intermittent maternal ingestion of therapeutic doses of paracetamol are not associated with teratogenic effects in humans. Paracetamol has been found to be foetotoxic to cultured rat embryo. Fertility There is no information relating to the effects of CALPOL Suspension Infant Sachets on fertility. A significant decrease in testicular weight was observed when male Sprague-Dawley rats were given daily high doses of paracetamol (500 mg/kg/body weight/day) orally for 70 days.





6.3 Shelf life


Do not store above 25ºC. Keep sachets in the outer carton. 6.5 Nature and contents of container

12 and 20 units of 5ml paper/foil/surlyn sachets. Not all pack sizes are marketed. A spoon with a 5 ml and 2.5 ml measure is supplied with the pack.

6.6 Special precautions for disposal No special requirements.

7 MARKETING AUTHORISATION HOLDER




02/09/2009


1 NAME OF THE MEDICINAL PRODUCT CALPOL Sugar Free Suspension Infant Sachets


CALPOL Sugar Free Suspension Infant Sachets contains 120mg Paracetamol in each 5ml.

Excipients: maltilol liquid (E965), sorbitol liquid (E420), methyl parahydroxybenzoate (E218), ethyl parahydroxybenzoate (E214), propyl parahydroxybenzoate (E216) and carmoisine (E122). See section 4.4 for further information. For a full list of excipients, see section 6.1.



CALPOL Sugar Free Suspension Infant Sachets is indicated for the treatment of mild to moderate pain (including teething pain) and as an antipyretic (including post immunisation fever).



4.3 Contraindications CALPOL Sugar Free Suspension Infant Sachets is contra-indicated in patients with known hypersensitivity to paracetamol, or any of the other components.


CALPOL Sugar Free Suspension Infant Sachets should be used with caution in severe renal impairment or severe hepatic impairment. The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease. Concomitant use of other paracetamol-containing products should be avoided. Due to the presence of maltitol liquid (E965) and sorbitol liquid (E420), patients with rare hereditary problems of fructose intolerance should not take this medicine.


Ethyl (E214), Propyl (E216) and Methyl (E218) parahydroxybenzoates may cause allergic reactions (possibly delayed). Carmosine (E122) may cause allergic reactions. The label contains the following statements: Keep out of the reach and sight of children. Do not exceed the stated dose. Do not give more than 4 doses in 24 hours. Leave at least 4 hours between doses. If you are currently taking any medicine consult your doctor or pharmacist before taking this product. If symptoms persist consult your doctor. Do not store above 25°C. Keep container in outer carton. Contains paracetamol. Immediate medical advice should be sought in the event of an overdose, even if the child seems well. (label) Immediate medical advice should be sought in the event of an overdose, even if the child seems well, because of the risk of delayed, serious liver damage. (leaflet) Talk to your doctor: If your child has an inherited intolerance to fructose or been diagnosed with an intolerance to some other sugars. (leaflet) The sorbitol liquid (E420) and maltilol liquid (E965) content of this product means that this product is unsuitable for people with inherited intolerance to fructose. (leaflet) Do not give with any other paracetmol-containing products.





4.8 Undesirable effects Adverse effects of paracetamol are rare but hypersensitivity/anaphylactic reactions including skin rash may occur. There have been reports of blood dyscrasias including thrombocytopenia and agranulocystosis but these were not necessarily causally related to paracetamol. Most reports of adverse reactions to paracetamol relate to overdose with the drug. 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 the disease improved after paracetamol withdrawal. Nephrotoxicity following therapeutic doses of paracetamol is uncommon, but papillary necrosis has been reported after prolonged administration.

4.9 Overdose

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, 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. 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 the 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 concentrations 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.



Paracetamol has analgesic and antipyretic effects similar to those of aspirin and is useful in the treatment of mild to moderate pain. It has only weak anti-inflammatory effects. ATC code: NO2BE01, other analgesics and antipyretics.

5.2 Pharmacokinetic properties Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. Peak plasma concentrations are reached 30-90 minutes post dose and the plasma half-life is in the range of 1 to 3 hours after therapeutic doses. Drug is widely distributed throughout most body fluids. Following therapeutic doses 90-100% of the drug is recovered in the urine within 24 hours almost entirely following hepatic conjugation with glucuronic acid (about 60%), sulphuric acid (about 35%) or cysteine (about 3%). Small amounts of hydroxylated and deacetylated metabolites have also been detected. Children have less capacity for glucuronidation of the drug than do adults. In overdosage there is increased N-hydroxylation followed by glutathione conjugation. When the latter is exhausted, reaction with hepatic proteins is increased leading to necrosis.


Mutagenicity There are no studies relating to the mutagenic potential of CALPOL Sugar Free Suspension Infant Sachets. In vivo mutagenicity tests of paracetamol in mammals are limited and show conflicting results. Therefore, there is insufficient information to determine whether paracetamol poses a mutagenic risk to man. Paracetamol has been found to be non-mutagenic in bacterial mutagenicity assays, although a clear clastogenic effect has been observed in mammalian cells in vitro following exposure to paracetamol (3 and 10 mM for 2h). Carcinogenicity There are no studies to the carcinogenic potential of CALPOL Sugar Free Suspension Infant Sachets. There is inadequate evidence to determine the carcinogenic potential of paracetamol in humans. A positive association between the use of paracetamol and cancer of the ureter (but not of other sites in the urinary tract) was observed in a case-control study in which approximate lifetime consumption of paracetamol (whether acute or chronic) was estimated. However, other similar studies have failed to demonstrate a statistically significant association between paracetamol and cancer of the urinary tract, or paracetamol and renal cell carcinoma. There is limited evidence for the carcinogenicity of paracetamol in experimental animals. Liver cell tumours can be detected in rats following chronic feeding of 500 mg/kg/day paracetamol. Teratogenicity There is no information relating to the teratogenic potential of CALPOL Sugar Free Infant Suspension Sachets. In humans, paracetamol crosses the placenta and attains concentrations in the foetal circulation similar to those in the maternal circulation. Intermittent maternal ingestion of therapeutic doses of paracetamol are not associated with teratogenic effects in humans. Paracetamol has been found to be foetotoxic to cultured rat embryo. Fertility There is no information relating to the effects of CALPOL Sugar Free Infants Suspension Sachets on fertility. A significant decrease in testicular weight was observed when male Sprague-Dawley rats were given daily high doses of paracetamol (500 mg/kg/body weight/day) orally for 70 days.





6.3 Shelf life


Do not store above 25ºC. Keep sachets in the outer carton. 6.5 Nature and contents of container

5 ml sachet composed of a laminate made of paper/PE/Aluminium/Surlyn. Pack sizes 12 or 20 sachets. A spoon with a 5 ml and 2.5 ml measure is supplied with this pack.






02/09/2009

MHRA PAR – Calpol Suspension (PL 15513/0297-302)

Module 6

Steps taken after procedure

The following table lists some non-safety updates to the Marketing Authorisation for this product that have been approved by the MHRA since the product was first licensed. The table includes updates that are detailed in the annex to this PAR. This is not a complete list of the post-authorisation changes that have been made to this Marketing Authorisation.

Date submitted

Application type

Scope Outcome

28/03/2011 Medical Type IB variation

To update sections 4.2 (Posology and administration) and 4.4 (Special warnings) to include paediatric posology requested by MHRA with regards to paracetamol containing products. Consequently, the PILs and labels has been updated.

Granted 06/06/2011

02/02/2012 Medical Type II variation

To amend product information to reflect the CHM recommendations for the administration device used to measure liquid paediatric paracetamol formulations. The dosing devices have been assessed and this submission supports the introduction of the syringe with a 2.5ml and 5ml measure. Sections 4.2, 4.4, 4.6 and 6.5 of the SPC and the label & leaflet have been updated

Granted 27/03/2012


Please note that this update is only to CALPOL Infant Sugar Free Colour Free 120 mg/5 ml Oral Suspension (PL 15513/0298).

VARIATION ASSESSMENT REPORT

Our Reference: PL 15513/0298 - 0015 Product: Calpol Infant Sugar Free Colour Free 120 mg/ 5 ml Oral

Suspension Marketing Authorisation Holder: MCNEIL PRODUCTS LIMITED Active Ingredient(s): PARACETAMOL. Type of Procedure: National Submission Type: Variation Submission Category: Type II Submission Complexity: Standard EU Procedure Number (if applicable): Reason: To amend product information to reflect the CHM recommendations for the administration device used to measure liquid paediatric paracetamol formulations. The dosing devices have been assessed and this submission supports the introduction of the syringe with a 2.5ml and 5ml measure. Sections 4.2, 4.4, 4.6 and 6.5 of the SPC and the label & leaflet have been updated. Supporting Evidence The following data have been presented in support of the application. This is linked to PL 15513/0123 – 0028 and others in the bulk.

• Stability data are presented on two batches of the lead formulation in the smallest and largest pack sizes as agreed with the MHRA prior to the work being undertaken

• Evidence of continuing child-resistance of the new container closure system • Laboratory and volunteer validation data for the syringe • CE marking and other data demonstrating suitability of the device and closure system

Evaluation The stability data have been generated in real time at ambient and accelerated storage conditions. No results fall outside the limits and the data are compliant with the protocol. The company have expert comment that CR is not affected by the addition of a bung to the container. Certification will be carried out retrospectively on the industrial batches as agreed with the MHRA. Exceptionally it was agreed that the data could be generated post variation and submitted once production batches were available. Given the close fitting of the bung to the bottle lip and assessment of the data from preliminary testing it was deemed that there was no evidence that child-resistance would be impacted. CE certification of the syringe and technical drawings have been provided.


Validation data for the accuracy and precision of the delivery from the syringe have been provided for the lead product. %RSD is well within the 5% limit set. Mean data only are provided but on the basis of the %RSD data there would seem to be no need to seek the raw data at this time Conclusion The data presented provide assurance that the new syringe device is superior to the spoon in both accuracy and precision of delivery of the dose. New labelling and PILs are provided which reflect the new administration device and include diagrams to aid the parent. Decision - Approved 27 March 2012


Summary of Product Characteristics – updated

1 NAME OF THE MEDICINAL PRODUCT

CALPOL Infant Sugar Free Colour Free 120 mg/5 ml Oral Suspension 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

CALPOL Infant Sugar Free Colour Free 120 mg/5 ml Oral Suspension contains 120 mg Paracetamol in each 5 ml. Excipients: maltitol liquid (E965), sorbitol liquid (E420), methyl parahydroxybenzoate (E218), ethyl parahydroxybenzoate (E214) and propyl parahydroxybenzoate (E216). See section 4.4 for further information. For full list of excipients, see section 6.1.


Oral Suspension.

An ‘off-white’ strawberry flavoured suspension. 4 CLINICAL PARTICULARS 4.1 Therapeutic indications

CALPOL Infant Sugar Free Colour Free 120 mg/5 ml Oral Suspension is indicated for the treatment of mild to moderate pain and as an antipyretic. It can be used in many conditions including headache, toothache, earache, teething, sore throat, colds and influenza, aches and pains and post-immunisation fever.


Age : 2 – 3 months Dose

1. Post-vaccination fever 2. Other causes of Pain and Fever - if your baby weighs over 4 kg and was born after 37 weeks

2.5 ml

If necessary, after 4-6 hours, give a second 2.5 ml dose

• Do not give to babies less than 2 months of age. • Do not give more than 2 doses. • Leave at least 4 hours between doses. • If further doses are needed, talk to your doctor or pharmacist.

Children aged 3 months – 6 years:

Child’s Age

How Much How often (in 24 hours)

3 – 6 months

2.5 ml 4 times

6 – 24 months

5 ml 4 times

2 – 4 years

7.5 ml (5 ml + 2.5 ml) 4 times

4 – 6 years

10 ml (5 ml + 5 ml) 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


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

The Elderly:

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

4.3 Contraindications

CALPOL Infant Sugar Free Colour Free 120 mg/5 ml Oral Suspension is contra-indicated in patients with known hypersensitivity to paracetamol, or any of the other components.


Care is advised in the administration of paracetamol to patients with severe renal impairment or severe hepatic impairment. The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease. Concomitant use of other paracetamol-containing products should be avoided. Due to the presence of maltitol liquid (E965) and sorbitol liquid (E420), patients with rare hereditary problems of fructose intolerance should not take this medicine. Ethyl (E214), Propyl (E216) and Methyl (E218) parahydroxybenzoate may cause allergic reactions (possibly delayed). The label contains the following statements:

Contains paracetamol. Do not give this medicine with any other paracetamol containing products. For oral use only. Never give more medicine than shown in the table. Always use the syringe supplied with the pack. Do not give to babies less than 2 months of age. For infants 2-3 months no more than 2 doses should be given. 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 other medicine consult your doctor or pharmacist before using this product. Keep out of the reach and sight of children. Do not store above 25°C. Keep bottle in the outer carton. Shake the bottle for at least 10 seconds before use. Do not exceed the stated dose. If symptoms persist consult your doctor.

Immediate medical advice should be sought in the event of an overdose, even if the child seems well. (label) Immediate medical advice should be sought in the event of an overdose, even if the child seems well, because of the risk of delayed, serious liver damage. (leaflet) Talk to your doctor: If your child has an inherited intolerance to fructose or been diagnosed with an intolerance to some other sugars. (leaflet)

The sorbitol liquid (E420) and maltitol liquid (E965) content of this product means that this product is unsuitable for people with inherited intolerance to fructose (leaflet).

4.5 Interaction with other medicinal products and other forms of interaction

The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by colestyramine.


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. Chronic alcohol intake can increase the hepatotoxicity of paracetamol overdose and may have contributed to the acute pancreatitis reported in one patient who had taken an overdose of paracetamol. Acute alcohol intake may diminish an individual’s ability to metabolise large doses of paracetamol, the plasma half-life of which can be prolonged. The use of drugs that induce hepatic microsomal enzymes, such as anticonvulsants and oral contraceptives, may increase the extent of metabolism of paracetamol, resulting in reduced plasma concentrations of the drug and a faster elimination rate.

4.6 Fertility, pregnancy and lactation

Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage, but patients should follow the advice of their doctor regarding its use.

Paracetamol is excreted in breast milk but not in a clinically significant amount.Available published data do not contraindicate breast feeding.

4.7 Effects on ability to drive and use machines

None known 4.8 Undesirable effects

Adverse effects of paracetamol are rare but hypersensitivity/anaphylactic reactions including skin rash may occur. There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis but these were not necessarily causality related to paracetamol. Most reports of adverse reactions to paracetamol relate to overdose with the drug. 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.

4.9 Overdose

Liver damage is possible in adults who have taken 10 g 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 carbamezipine, 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.


Paracetamol has analgesic and antipyretic effects similar to those of aspirin and is useful in the treatment of mild to moderate pain. It has only weak anti-inflammatory effects. ATC code: NO2BE01, other analgesics and antipyretics.

5.2 Pharmacokinetic properties

Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. Peak plasma concentrations are reached 30-90 minutes post dose and the plasma half-life is in the range of 1 to 3 hours after therapeutic doses. Drug is widely distributed throughout most body fluids. Following therapeutic doses 90-100% of the drug is recovered in the urine within 24 hours almost entirely following hepatic conjugation with glucuronic acid (about 60%), sulphuric acid (about 35%) or cysteine (about 3%). Small amounts of hydroxylated and deacetylated metabolites have also been detected. Children have less capacity for glucuronidation of the drug than do adults. In overdosage there is increased N-hydroxylation followed by glutathione conjugation. When the latter is exhausted, reaction with hepatic proteins is increased leading to necrosis.


The active ingredient of this product is a well known constituent of medicinal products and its safety profile is well documented.


Maltitol liquid (E965) Sorbitol liquid (non crystallising) (E420) Glycerol Dispersible cellulose Xanthan gum Ethyl parahydroxybenzoate (E214) Methyl parahydroxybenzoate (E218) Propyl parahydroxybenzoate (E216) Polysorbate 80 Strawberry Flavour 500286E Purified water

6.2 Incompatibilities

None known 6.3 Shelf life


Do not store above 25°C. Keep bottle in the outer carton.


6.5 Nature and contents of container

Amber glass bottle with an aluminium cap fitted with a polyethylene wad. (1000 ml only). Or Amber glass bottle with a two-piece white plastic child-resistant external cap, fitted with an inner plastic cap, including a tamper evident ring fitted with a polyethylene or polyvinylidene chloride (PVDC) polyethylene laminate faced wad. Or Amber glass bottle with a two-piece white plastic child-resistant external cap, fitted with an inner plastic cap, including a tamper evident ring, in high density polyethylene. The cap contains a plug made of Low Density Polyethylene (LDPE). Pack sizes: 30 ml, 70 ml, 140 ml and 200 ml or 1000 ml. A syringe with a 5 ml and 2.5 ml measure is supplied with this pack.



McNeil Products Limited Foundation Park Roxborough Way Maidenhead Berkshire SL6 3UG UK 8 MARKETING AUTHORISATION NUMBER(S)

PL 15513/0298 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

02/09/2009 10 DATE OF REVISION OF THE TEXT

27/03/2012


Patient Information Leaflet - updated


Labelling - updated

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