Public Assessment Report Decentralised Procedure - … · Belgium (BE), Germany (DE) and the Netherlands (NL) Procedure Number UK/H/2055/001/DC ... Calcium effervescent tablet has

Public Assessment Report

Decentralised Procedure

CALCIUM 500 MG EFFERVESCENT TABLETS

UK/H/2055/001/DC UK Licence No: PL 20075/0134

ACCORD HEALTHCARE LIMITED

PAR Calcium 500 mg Effervescent Tablets UK/H/2055/001/DC

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LAY SUMMARY

On 1st November 2011, the UK granted Accord Healthcare Limited a Marketing Authorisation (licence) for Calcium 500 mg Effervescent Tablets. Calcium 500 mg Effervescent Tablets contain the active ingredient calcium carbonate (which when dispersed in water provide 500mg of elemental calcium as calcium citrate). The tablets provide extra calcium, in addition to the normal diet; they are used to treat conditions in which the body’s calcium levels need to be increased. Calcium is essential for healthy growth of bones and teeth. No new or unexpected safety concerns arose from this application and it was, therefore, judged that the benefits of taking Calcium 500 mg Effervescent Tablets outweigh the risks; hence this Marketing Authorisation has been granted.


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TABLE OF CONTENTS

Module 1: Information about initial procedure Page 4 Module 2: Summary of Product Characteristics Page 5 Module 3: Product Information Leaflets Page 9 Module 4: Labelling Page 11 Module 5: Scientific Discussion Page 13 1 Introduction 2 Quality aspects 3 Non-clinical aspects 4 Clinical aspects 5 Overall conclusions Module 6: Steps taken after initial procedure Not applicable


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Module 1

Product Name

Calcium 500 mg Effervescent Tablets

Type of Application

Generic application, Article 10.1

Active Substance

Calcium carbonate

Form

Effervescent tablets

Strength

500 mg (calcium citrate when 1250 mg of calcium carbonate has been dissolved in water)

MA Holder

Accord Healthcare Limited Sage House, 319, Pinner Road North Harrow Middlesex HA1 4 HF United Kingdom

Reference Member State (RMS)

The United Kingdom (UK)

Concerned Member States (CMS)

Belgium (BE), Germany (DE) and the Netherlands (NL)

Procedure Number

UK/H/2055/001/DC

End of Procedure

Day 210: 5th October 2011


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Module 2 Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Calcium 500 mg Effervescent Tablets 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 1250 mg of Calcium Carbonate which when dissolved in water provides 500mg of calcium as calcium citrate. Excipients: Sodium content approximately 48 mg/tablet. For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Effervescent tablet Light orange coloured, round, flat, bevelled edges tablets plain on both sides.

4 CLINICAL PARTICULARS 4.1 Therapeutic indications

• Treatment of calcium deficiency states including osteomalacia, rickets and malabsorption syndromes affecting the upper gastrointestinal tract.

• As adjunct to specific therapy in the prevention and treatment of osteoporosis. • As a therapeutic supplement during times when intake may be inadequate, particularly those

associated with the increased demand of childhood, old age, pregnancy and lactation. 4.2 Posology and method of administration

The tablets must be dissolved in a glass of water (100 ml or more) and the solution should then be drunk immediately after complete dissolution of the tablets. Adults and the Elderly For calcium deficiency states including malabsorption, the dosage should be tailored to the individual patient's needs. A dose of 0.5g to 1.5g per day is recommended. For the treatment of osteoporosis a dose of up to 1.5g per day is normally required. In patients with adequate dietary calcium intake, 500mg daily may be sufficient. Up to 1.5g of calcium per day is the recommended dosage for therapeutic supplementation. Children For calcium deficiency states including malabsorption and rickets, a dose of 0.5g to 1.0g per day should be followed. For therapeutic supplementation, a dose of up to 1.0g per day is recommended.

4.3 Contraindications

Hypersensitivity to any of the excipients. Hypercalcaemia (eg. due to hyperparathyroidism, hypervitaminosis D, decalcifying tumours, severe renal failure, bone metastases), severe hypercalciuria calci-lithiasis and renal calculi. Long term immobilisation accompanied by hypercalciuria and/or hypercalcaemia.

4.4 Special warnings and precautions for use

In mild hypercalciuria (exceeding 7.5 mmol/24 hours in adults or 0.12-0.15 mmol/kg/24 hours in children) or renal failure, or where there is evidence of stone formation in the urinary tract; adequate checks must be kept on urinary calcium excretion. If necessary the dosage should be reduced or calcium therapy discontinued. Patients with stone formation in the anamnesis should have an adequate fluid intake. It is advised to take an extra glass of water during meals and in the morning and evening. Patients suffering from hyperparathyroidism should be checked on serum calcium and creatinin during the calcium administration. Vitamin D increases calcium absorption. Therefore the combination of high dose vit. D and calcium administration should be avoided. In patients for which such a combination is essential, serum calcium should be monitored and corrected for hypoproteinemia if necessary. For patient on haemodialysis it should be reckoned that in the solution calcium mono and dicitrate are present.


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4.5 Interaction with other medicinal products and other forms of interaction Concomitant administration with vitamin D causes an increase in calcium absorption and plasma levels may continue to rise after stopping vitamin D therapy. The effects of digoxin and other cardiac glycosides may be accentuated by calcium and toxicity may be produced, especially in combination with vitamin D. Calcium salts reduce the absorption of some drugs, in particular tetracyclines. Therefore it is recommended that administration of Calcium effervescent tablets be separated from these products by at least 3 hours. Certain foods (e.g. those containing oxalic acid, phosphate or phytinic acid) may reduce the absorption of calcium. Concomitant intake with levothyroxine may reduce levothyroxine absorption. Thiazide diuretics increase renal absorption of calcium, so the risk of hypercalcaemia should be considered. Bisphosphonate, sodium fluoride: it is advisable to allow a two hour minimum period before taking Calcium effervescent tablets (risk of reduction of the gastrointestinal absorption of bisphosphonate and sodium fluoride). Quinolone antibiotics (ciprofloxacin, norfloxacin, ofloxacin), calcium may reduce the serum concentrations of quinolone antibiotics.

4.6 Fertility, Pregnancy and lactation

The adequate daily intake (including food and supplementation) for normal pregnant and lactating women is 1000-1300 mg calcium. Pregnancy During pregnancy, the daily intake of calcium should not exceed 1500 mg. Calcium 500 mg Effervescent Tablets can be used during pregnancy. Lactation Significant amounts of calcium are secreted in human milk during lactation, but at therapeutic doses of Calcium 500 mg Effervescent Tablets no effects on the breastfed newborns/infants are anticipated. Calcium 500 mg Effervescent Tablets can be used during breast-feeding. Fertility There are no data on the effects of calcium on fertility available.

4.7 Effects on ability to drive and use machines

Calcium effervescent tablet has no influence on the ability to drive and use machines. 4.8 Undesirable effects

Mild gastrointestinal disturbances have occurred rarely (eg. nausea, abdominal pain, diarrhoea, constipation, flatulence and eructation). Hypercalciuria and, in rare cases, hypercalcaemia in cases of long-term treatment with high doses. Skin reactions, such as pruritis, rash, and urticaria (especially urticaria in patients with a past history of allergy) have been reported. The colouring agent E110 can cause allergic type reactions including asthma. Allergy is more common in those people who are allergic to aspirin.

4.9 Overdose

The amount of calcium absorbed will depend on the individual’s calcium status. Deliberate over dosage is unlikely with effervescent preparations and acute over dosage has not been reported. It might cause gastrointestinal disturbance but would not be expected to cause hypercalcaemia, except in patients treated with excessive doses of vitamin D. Symptoms of overdose may include thirst, nausea, vomiting, polydipsia, polyuria, dehydration, hypertension, vasomotor disorders and constipation. Treatment should be aimed at lowering serum calcium levels, e.g. stop any calcium intake and vitamin D, administration of oral phosphates and rehydration according to the severity of intoxication, use alone or in combination, diuretics, corticosteroids, calcitonin, possibly associated with peritoneal dialysis. Chronic overdoses can lead to vascular and organ calcifications as a result of hypercalcaemia.


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5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Pharmacotherapeutic group: mineral supplements, ATC code: A12AA04 Calcium is an essential element of tissues and plasma.

5.2 Pharmacokinetic properties

Absorption When the tablets are added to water, insoluble calcium carbonate is converted into absorbable calcium citrate. About 30% calcium salts are absorbed mainly in jejunum and duodenum. The serum calcium level is kept constant: 40-60% in ionized form, 5-10% bound in complexes and the rest is bound to plasma proteins. Calcium seems so well absorbed on an empty stomach, even in cases of hypochlorhydria. The absorption rate is about 30 to 40% of the dose ingested. Elimination Calcium is excreted through saliva, bile and pancreatic secretions, intestinal and sweat.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Anhydrous citric acid (E 330) Sodium cyclamate (E952) Saccharin sodium (E954) Sunset yellow supra (E110) Simethicone emulsion (30%) Ethanol anhydrous (E1510) Powdarome orange Macrogol 6000 Mono sodium glycine carbonate (E640) Sodium benzoate (E 211) Qualitative composition of Powdarome orange: Flavouring preparation Flavouring substances identical to natural substances Maize maltodextrin Acacia gum (E 414) Alpha-tocopherol (E 307) Butylated hydroxyanisole (BHA) (E 320) TBHQ (E319)

6.2 Incompatibilities

Not applicable. 6.3 Shelf life

30 months 6.4 Special precautions for storage

Keep the polypropylene tube tightly closed. Store in the original container in order to protect from moisture. Keep out of the reach and sight of children.

6.5 Nature and contents of container

White opaque plain polypropylene tube and white opaque tamper evident polyethylene cap with inbuilt desiccant. Contains 17 tablets in a tube. Pack size: 68 (4 x 17) tablets per carton.

6.6 Special precautions for disposal

No special requirements.


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7 MARKETING AUTHORISATION HOLDER Accord Healthcare Limited Sage House, 319, Pinner Road North Harrow Middlesex HA1 4 HF United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 20075/0134 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 01/11/2011 10 DATE OF REVISION OF THE TEXT

01/11/2011


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Module 3 Patient Information Leaflet


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Module 4 Labelling


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Module 5 Scientific discussion during initial procedure

I INTRODUCTION Based on the review of the data on quality, safety and efficacy, Belgium, Germany, the Netherlands and the UK considered that the application for Calcium 500 mg Effervescent Tablets could be approved. This medicine is available from pharmacies only (P) and is indicated for:

• The treatment of calcium deficiency states including osteomalacia, rickets and malabsorption syndromes affecting the upper gastrointestinal tract.

• As adjunct to specific therapy in the prevention and treatment of osteoporosis. • As a therapeutic supplement during times when intake may be inadequate, particularly

those associated with the increased demand of childhood, old age, pregnancy and lactation.

This application for Calcium 500 mg Effervescent Tablets was submitted according to Article 10.1 of Directive 2001/83/EC, claiming to be a generic medicinal product of Cacit Effervescent Tablets 500 mg, first authorised in the UK to Warner Chilcott Pharmaceuticals UK Limited on 9th October 1989 (PL 00364/0045). This licence then underwent a change of ownership to Warner Chilcott UK Limited on 11th May 2010 (PL 10947/0016). Calcium is an essential element of tissues and plasma. No new non-clinical studies were conducted, which is acceptable given that the product contains a widely-used, well-known active substance. The pharmacology of calcium carbonate is well-established. No clinical studies have been performed and none are required for this application as the proposed product is an aqueous solution at the time of administration and contains the same concentration of active substance as the already approved reference product. For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites. For manufacturing sites outside the community, the RMS has accepted copies of current GMP Certificates or satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’ issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-Community sites. The RMS considers that 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. A satisfactory justification has been provided for the absence of a Risk Management Plan.


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II. ABOUT THE PRODUCT Name of the product in the Reference Member State

Calcium 500 mg Effervescent Tablets

Name(s) of the active substance(s) (INN) Calcium carbonate

Pharmacotherapeutic classification (ATC code)

Mineral supplements (A12AA04)

Pharmaceutical form and strength(s) 500 mg Effervescent Tablets

Reference numbers for the Decentralised Procedure UK/H/2055/001/DC

Reference Member State The United Kingdom (UK)

Member States concerned Belgium (BE), Germany (DE) and the Netherlands (NL)

Marketing Authorisation Number(s) PL 20075/0134

Name and address of the authorisation holder Accord Healthcare Limited Sage House, 319, Pinner Road North Harrow Middlesex HA1 4 HF United Kingdom


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III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 QUALITY ASPECTS S. Active substance INN name: Calcium carbonate Chemical name: Calcium carbonate Structural formula:

Molecular formula: CaCO

3

Appearance: White or almost white powder. Molecular weight: 100.1 Solubility: practically insoluble in water, but quite soluble in water containing

dissolved carbon dioxide. Calcium carbonate complies with its European Pharmacopoeia monograph. All aspects of the manufacture of the active substance from its starting materials are controlled by a Certificate of Suitability. An appropriate specification with suitable test methods and limits is provided for the active substance. The methods of testing and limits for residual solvents are in compliance with current guidelines. Batch analysis data are provided and comply with the proposed specification. The container closure system complies with the Certificate of Suitability. Stability studies have been performed with the active substance and no significant changes of the parameters were observed. On the basis of the results, the RMS agreed that a suitable re-test period could be approved. P. Medicinal Product Other Ingredients Other ingredients in the tablets consist of the pharmaceutical excipients anhydrous citric acid (E 330), sodium cyclamate (E952), saccharin sodium (E954), sunset yellow supra (E110), simethicone emulsion (30%), ethanol anhydrous (E1510), Powdarome orange, macrogol 6000, mono sodium glycine carbonate (E640) and sodium benzoate (E 211). The excipients of Powdarome orange are flavouring preparation, flavouring substances identical to natural substances, maize maltodextrin, acacia gum (E 414), alpha-tocopherol (E 307), butylated hydroxyanisole (BHA) (E 320) and TBHQ (E319). With the exception of sunset yellow supra, Powdarome orange, simethicone emulsion (30%) and mono sodium glycine carbonate (E640), all excipients comply with their respective European Pharmacopoeia monographs. Simethicone emulsion (30%) complies with the United States Pharmacopoeia. Mono sodium glycine carbonate (E640) complies with


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in-house specifications. Sunset yellow supra (E110) complies with 95/45/EC Directive concerning colours for use in foodstuffs. Powdarome orange complies with 88/388/EEC Directive relating to flavourings for use in foodstuffs. None of the excipients used contain material of animal or human origin. No genetically modified organisms (GMO) have been used in the preparation of this product. Pharmaceutical Development The objective of the development programme was to produce a safe, efficacious product containing calcium carbonate that could be considered a generic medicinal product of Cacit Effervescent Tablets 500 mg. The applicant has provided suitable product development information. Justifications for the use and amounts of each excipient have been provided and are valid. Manufacturing Process A satisfactory batch formula has been provided for the manufacture of the product, along with an appropriate account of the manufacturing process. The manufacturing process has been validated and has shown satisfactory results. Satisfactory process validation data on batches have been provided. Finished Product Specification The finished product specification is acceptable. Test methods have been described and adequately validated, as appropriate. Batch data have been provided and comply with the release specifications. Container-Closure System This product is packaged in white opaque plain polypropylene tubes and white opaque tamper evident polyethylene caps with inbuilt desiccant. There are 17 effervescent tablets in a tube. The pack size is 68 (4 x 17) effervescent tablets per carton. Satisfactory specifications and Certificates of Analysis have been provided for all packaging components. All primary product packaging complies with EU legislation. Stability of the product Stability studies were performed on batches of the finished products in the packaging proposed for marketing and in accordance with current guidelines. These data support a shelf-life of 30 months with the following storage instructions:

‘Keep the polypropylene tube tightly closed. Store in the original container in order to protect from moisture. Keep out of the reach and sight of children.’

This is satisfactory. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL), Labels The SmPC, PIL and labelling are pharmaceutically acceptable. A representative sample of the UK PIL and label mock-ups are included in modules 3 and 4 of this report. User testing results have been submitted for the PIL for this product. The results indicate that the PIL is in accordance with Article 59 of Council Directive 2001/83/EC, as amended and is


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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. MAA form The MAA form is pharmaceutically satisfactory. Quality Overall Summary The quality overall summary has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical dossier. Conclusion It is recommended that a Marketing Authorisation is granted for this application from a quality point of view.


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III.2 NON-CLINICAL ASPECTS The pharmacodynamics, pharmacokinetics and toxicological properties of calcium carbonate are well-known. As calcium carbonate is a widely used, well-known active substance, the applicant has not provided any new non-clinical data and none are required. An overview based on literature review is, thus, appropriate. The proposed limits for the residual solvents were found to comply with current international conference on harmonisation of technical requirements for registration of pharmaceuticals for human use (ICH) guidelines. The non-clinical overview has been written by an appropriately qualified person and is a suitable summary of the non-clinical aspects of the dossier. A satisfactory justification has been provided for the absence of an Environmental Risk Assessment. It is recommended that a Marketing Authorisation is granted for this application from a non-clinical point of view.


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III.3 CLINICAL ASPECTS This assessment report represents an evaluation of the key elements of the information provided by the company in the dossier. CLINICAL PHARMACOLOGY The applicant’s product is a generic product of the reference product; both products contain the same quantitative and qualitative composition of the active ingredient. As per the Note for Guidance on the Investigation of Bioavailability and Bioequivalence CPMP/EWP/QWP/1401/98 Rev 1, ‘If the test product is an aqueous oral solution at time of administration and contains an active substance in the same concentration as an approved oral solution, bioequivalence studies may be waived.’ No new pharmacokinetic or pharmacodynamic data were submitted with this generic application and none were required. The test and reference products are identical at the point of administration. Therefore, a human bioavailability study is not required for this application. EFFICACY No new efficacy data were submitted with this application and none were required. SAFETY No new safety data were submitted with this application and none were required. SUMMARY OF PRODUCT CHARACTERISTICS (SmPC), PATIENT INFORMATION LEAFLET (PIL) AND LABELLING The SmPC, PIL and labelling are clinically satisfactory and consistent with those for the reference product, where appropriate. CLINICAL OVERVIEW The clinical overview has been written by an appropriately qualified physician and is a suitable summary of the clinical aspects of the dossier. MAA FORM The MAA form is clinically satisfactory. CONCLUSIONS It is recommended that a Marketing Authorisation is granted for this application from a clinical point of view.


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IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY The important quality characteristics of Calcium 500 mg Effervescent Tablets are well defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit-risk balance. NON-CLINICAL No new non-clinical data were submitted and none are required for an application of this type. EFFICACY No bioequivalence studies have been performed and none are required for this application, given the composition of the product and its intended route of administration. No new or unexpected safety concerns arise from this application. The SmPC, PIL and labelling are satisfactory and consistent with that for the reference product. BENEFIT-RISK ASSESSMENT The quality of the product is acceptable and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with calcium carbonate is considered to have demonstrated the therapeutic value of the compound. The benefit-risk is, therefore, considered to be positive.


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Module 6

STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY

Date submitted

Application type

Scope Outcome

Documents

Public Assessment Report Decentralised Procedure - … · Belgium (BE), Germany (DE) and the Netherlands (NL) Procedure Number UK/H/2055/001/DC ... Calcium effervescent tablet has