calpol sugar free infant suspension sachets, pl … sugar free infant suspension sachets is...

MHRA PAR; CALPOL SUGAR FREE INFANT SUSPENSION SACHETS, PL 15513/0155

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CALPOL SUGAR FREE INFANT

SUSPENSION SACHETS

PL 15513/0155

UKPAR

TABLE OF CONTENTS Lay Summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

Page 9

Summary of Product Characteristics

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Patient Information Leaflet

Page 16

Labelling Page 18


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CALPOL SUGAR FREE INFANT SUSPENSION SACHETS

PL 15513/0155

LAY SUMMARY

The MHRA granted Pfizer Consumer Healthcare a Marketing Authorisation (licence) for the medicinal product Calpol Sugar Free Infant Suspension Sachets (product licence number: 15513/0155) on 26 February 2007. This medicine contains the active ingredient paracetamol and is used to treat mild to moderate pain (including teething pain) and fever (including post immunisation fever). This application is identical to a previously granted application for Calpol Sugar Free Infant Suspension (PL 15513/0006), which was formulated to provide a palatable, sugar free form of paracetamol in a 5 ml dose dispensed from a bottle pack. Calpol Sugar Free Infant Suspension Sachets provide a convenient and portable unit dose in the form of 5 ml sachets. Calpol Sugar Free Infant Suspension Sachets is available to buy without prescription from pharmacies and other outlets. No new or unexpected safety concerns arose from this simple application and it was, therefore, judged that the benefits of taking Calpol Sugar Free Infant Suspension Sachets outweigh the risks; hence a Marketing Authorisation has been granted.


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PL 15513/0155

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS Introduction

Page 4

Pharmaceutical assessment

Page 5

Preclinical assessment

Page 6

Clinical assessment

Page 7

Overall conclusions and risk benefit assessment Page 8


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INTRODUCTION The application for Calpol Sugar Free Infant Suspension Sachets (PL 15513/0155) was submitted as a simple abridged informed consent application according to Article 10c of Directive 2001/83/EC. The applicant cross-refers to Calpol Sugar Free Infant Suspension (PL 15513/0006), licensed to Pfizer Consumer Healthcare on 18 April 1997 following a Change of Ownership from The Wellcome Foundation. The Wellcome Foundation was granted a product licence on 4 July 1988 for Calpol Sugar Free Infant Suspension 120mg/5ml (PL 00003/0244). No new data were submitted nor was it necessary for this simple application, as the data are identical to those of the previously granted cross-reference product. As the cross-reference product was granted prior to the introduction of current legislation, no Public Assessment Report (PAR) was generated for it. The product contains the active ingredient paracetamol, which treats mild to moderate pain and is also an antipyretic. Calpol Sugar Free Infant Suspension Sachets is a General Sales List (GSL) product.

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PHARMACEUTICAL ASSESSMENT

The applicant is the Marketing Authorisation Holder (MAH) for the reference product; therefore it is accepted that the company has access to all of the relevant data and has Module 3 in their possession. A sister company is the finished product manufacturer; therefore it is accepted that it will be prepared to manufacture the finished product. It is also assumed that access to the reference product is given by virtue of the fact that the applicant holds both reference and test products. Active ingredient The paracetamol used in this product comes from the same sources as that used to make the reference product. The active ingredient is subject to European Certificates of Suitability (CEP), this means that it complies with the monograph of the European Pharmacopoeia. Finished product The product formulation, batch release sites, finished product manufacturers and assemblers are in line with the reference product. The product also complies with ICH guidance and the Ph Eur general monograph for suspensions. Overall summaries The quality, clinical and preclinical overall summaries confirm that the application is identical to that of the reference product in all particulars. Satisfactory signed declarations and CVs have been provided for the quality, preclinical and clinical experts. Product literature All product literature (Summary of Product Characteristics, Patient information Leaflet and labelling) is satisfactory. Conclusion A product license may be granted for this product.


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PRECLINICAL ASSESSMENT No new preclinical data has been supplied with this application and none is required for an application of this type.


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CLINICAL ASSESSMENT

No new clinical data has been supplied with this application and none is required for an application of this type.


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OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT QUALITY The data for this application is consistent with that previously assessed for the cross-reference product and as such has been judged to be satisfactory. PRECLINICAL No new preclinical data was submitted and none is required for an application of this type. EFFICACY AND SAFETY Paracetamol has been used in pain relief and as an antipyretic for many years. This application is identical to the previously granted application for Calpol Sugar Free Infant Suspension (PL 15513/0006). No new or unexpected safety concerns arise from this application. The SPC, PIL and labelling are satisfactory and consistent with that for the cross-reference product. RISK BENEFIT ASSESSMENT The quality of the product is acceptable and no new preclinical or clinical safety concerns have been identified. The applicant’s product is identical to the cross-reference product. Extensive clinical experience with calcium carbonate and colecalciferol is considered to have demonstrated the therapeutic value of the compounds. The risk benefit ratio is therefore considered to be positive.


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PL 15513/0155

STEPS TAKEN FOR ASSESMENT

1 The MHRA received the marketing authorisation application on 25 July 2005 2 Following standard checks and communication with the applicant the MHRA

considered the application valid on 5 December 2005 3 Following assessment of the application the MHRA requested further

information on the quality dossier on 3 May 2006. The applicant responded to the MHRA’s requests, providing further information on 19 December 2006

4 The application was determined on 26 February 2007


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SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

CALPOL Sugar Free Infant Suspension Sachets 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Calpol Sugar Free Infant Suspension Sachets contains 120 mg Paracetamol in each 5 ml and the following excipients with a recognised pharmaceutical action: Excipients Quantity Unit Ref Sorbitol Liquid 9.67.50 mg EP Methyl parahydroxybenzoate (E218) 5.000 mg EP Propyl parahyroxybenzoate (E216) 1.000 mg EP Ethyl parahydroxybenzoate (E214) 2.000 mg EP Carmoisine E122 (Azorubin) 0.075 mg FP For a full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Oral Suspension. 4 CLINICAL PARTICULARS 4.1 Therapeutic indications

Calpol Sugar Free Infant Suspension Sachets 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:


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

4.4 Special warnings and precautions for use

Calpol Sugar Free Infant Suspension 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. 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) Do not give with any other paracetamol-containing products.

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.


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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 the 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 including skin rash may occur. There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis 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 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


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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 patient 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: NO2 BE01 – 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.

5.3 Preclinical safety data

Mutagenicity There are no studies relating to the mutagenic potential of Calpol Sugar Free Infant Suspension 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.


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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 Infant Suspension 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 Infant 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 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

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


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6.2 Incompatibilities

None known 6.3 Shelf life

36 months 6.4 Special precautions for storage

Do not store above 25°C. Keep container in 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.

6.6 Special precautions for disposal None applicable.

7 MARKETING AUTHORISATION HOLDER

Pfizer Consumer Healthcare Alternative Trading Style: Warner-Lambert Consumer Healthcare Walton Oaks Dorking Road Walton-on-the-Hill Surrey, KT20 7NS.

8 MARKETING AUTHORISATION NUMBER(S)

PL 15513/0155 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 26/02/2007 10 DATE OF REVISION OF THE TEXT

26/02/2007


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LEAFLET


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LABELLING

Carton:


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Carton with Braille:


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Sachet (front):


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Sachet (back):

calpol sugar free infant suspension sachets, pl … sugar free infant suspension sachets is...

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