Public Assessment Report Scientific discussion. Norsed Combi D SE/H/959/01/MR

Transcription

1 Public Assessment Report Scientific discussion Norsed Combi D (risedronate sodium and calcium carbonate/cholecalciferol) SE/H/959/01/MR This module reflects the scientific discussion for the approval of Norsed Combi D. The procedure was finalised at For information on changes after this date please refer to the module Update. Postadress/Postal address: P.O. Box 26, SE Uppsala, SWEDEN Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala Telefon/Phone: +46 (0) Fax: +46 (0) Internet: registrator@mpa.se Template version:

2 I. INTRODUCTION Warner Chilcott (formerly Procter & Gamble Pharmaceuticals) and sanofi-aventis have applied for a marketing authorisation for Norsed Combi D, film-coated tablet, 35 mg (risedronate sodium) and effervescent granules 1000 mg/880 IE (calcium/cholecalciferol). The active substances are risedronate sodium, calcium carbonate, cholecalciferol. For approved indications, see the Summary of Product Characteristics. The procedure was referred to CMD as one member state questioned the combination pack and the use of a market research study to justify the use of the combination pack, and also feared a worse adverse event profile for the combination pack. Following a discussion in CMD, the question about adverse events for combination packs was resolved while the first question was referred to CHMP. Following a written procedure, the remaining question was resolved in CHMP. II. II.1 QUALITY ASPECTS Introduction Norsed Combi D is presented in the form of film-coated tablets and effervescent granules. Each film-coated tablet contains 35 mg risedronate sodium, (equivalent to 32.5 mg risedronic acid) and each sachet of effervescent granules contains 1000 mg calcium (as 2500 mg calcium carbonate) and 22 micrograms (880 IU) cholecalciferol (vitamin D3). The tablet excipients are lactose, microcrystalline cellulose, crospovidone, magnesium stearate, hypromellose, macrogol, hydroxypropylcellulose, silicon dioxide, titanium dioxide (E171), yellow iron oxide (E172) and red iron oxide (E172). The effervescent granules contain citric acid, malic acid, gluconolactone, maltodextrin, sodium cyclamate, saccharin sodium, sorbitol (E420), mannitol (E421), gluconolactone, acacia dextrin, natural lemon oils, natural lime flavour, rice starch, potassium carbonate, all-rac- -tocopherol, hydrogenated soya-bean oil, gelatin, sucrose and maize starch. The product is a combination pack of weekly units including one blister (consisting of PVC/aluminium foil) containing one tablet and six sachets (consisting of laminated aluminium paper foil) containing effervescent granules. II.2 Drug Substance Sodium risedronate has not a monograph in the European Pharmacopoeia whereas cholecalciferol and calcium carbonate have. Sodium risedronate is a white to off-white crystalline powder which solubility in water is ph dependent. Calcium carbonate is a white powder that is practically insoluble in water. Cholecalciferol concentrate consist of white or yellowish white small particles. The structures of the drug substances have been confirmed and their physicochemical properties sufficiently described. The routes of synthesis have been confirmed to yield substances of satisfactory and consistent quality. 2/7

3 The specifications for the drug substances are adequate, including relevant tests, methods and acceptance criteria. The limits for impurities/degradation products have been justified. The analytical methods and procedures applied are suitably described and confirmed to be satisfactory validated. Adequate stability studies have been performed. II.3 Medicinal Product Norsed Combi D is formulated using excipients described in the current European Pharmacopoeia except for silicon dioxide, iron oxide, gluconolactone and lemon and lime flavours. Each of the excipients is controlled according to acceptable specifications. The excipients are either of vegetable origin or have demonstrated compliance with Commission Directive 2003/63/EC and the note for guidance on Minimising the risk of transmitting Animal Spongiform Encephalopathy Agents via human and veterinary medicinal products (EMEA/410/01). The product development has been satisfactory described and taken into consideration the physicochemical properties of the drug substances. The choice of excipients has been justified. The manufacturing process has been adequately described. Critical steps have been identified and validation studies confirmed the ability of the process to consistently yield product of satisfactory quality. The product specifications cover appropriate parameters for the selected dosage forms and for their intended purpose. Satisfactory validations have been presented for the analytical methods and procedures. The conditions used in the stability studies are according to the ICH stability guideline. The studies support the shelf life claimed in the SPC. III. NON-CLINICAL ASPECTS No new data have been submitted. The application is based on the same non-clinical data as in the applications for the risedronate 5 mg tablet and the 35 mg tablet. For assessment of these data, please refer to assessment reports in the MR procedures SE/H/192/01/MR and SE/H/192/03/MR. IV. CLINICAL ASPECTS IV.1 Introduction Osteoporosis treatment with bisphosphonates generally also includes treatment with calcium and vitamin D. The absorption of risedronate is significantly impaired if taken at the same time as calcium, and the current instructions is that they should not be taken at the same time. The aim of the combination pack is to help those patients who are advised to take calcium 1000 mg and vitamin D3 880 IU together with risedronate 35 mg to better understand dosing instructions and possibly improve compliance. The instruction for the new combination pack is 3/7

4 that patients should take the 35 mg risedronate sodium tablet on day 1 and the calcium + vitamin D sachets on days 2-7 of each weekly period. IV.2 Pharmacokinetics There are no new pharmacokinetic data for this application. The application is based on the same pharmacokinetic data as that included in the applications for the risedronate 5 mg tablet and the 35 mg tablet. Since the risedronate sodium tablet and the calcium + vitamin D sachets are administered on different days, an interaction between the two products in the combination pack is not expected. IV.3 Pharmacodynamics No new pharmacodynamic data are submitted for this application. The application is based on the pharmacodynamic data included in the applications for the risedronate 5 mg tablet and the 35 mg tablet. IV.4 Clinical efficacy No new clinical efficacy data are presented in this submission and no additional efficacy claims are requested for Norsed Combi D compared to the Norsed 35 mg tablet (SE/H/194/03/MR). Specific data for the combination pack is not considered necessary, as all efficacy trials with risedronate, were performed with supplementation of calcium and vitamin D3, and this is reflected in the SPCs for the previously approved risedronate-only products. Data for the calcium and vitamin D3 sachets have been previously submitted in marketing applications for Cacit Vitamin D3 = Kalde, via the MR procedure FR/H/103/02. An evaluation of the understanding of the dosing instructions for this particular package, being a combination of Norsed 35 mg and Cacit Vitamine D3, was performed. The proportion of questions a patient answered correctly was dependent on whether or not she had previously used a bisphosphonate; previous bisphosphonate users having significantly (p < ) higher percentage of correct answers. The proportion of questions a participant answered correctly for the combination pack was significantly better than the proportion of questions answered correctly for the separate packs (p < ). Persons who had earlier been taking a bisphosphonate had significantly more correct answers to the questions than persons who had not taken bisphosphonates earlier (p < ). Participant s preferences for combined or separate packs were compared and significantly more participants preferred the combination pack (p < ). In conclusion, clinical efficiency of Norsed Combi D is equal to what has been established for the products Norsed Septimum and Cacit Vitamin D3. IV.5 Clinical safety Spontaneous post-marketing adverse event reporting for risedronate has been consistent. The types of events most frequently reported by health care professionals are gastrointestinal and musculoskeletal signs and symptoms. Skin disorders, headache/neurological signs and symptoms and abnormal liver enzymes are among the most commonly reported events. 4/7

5 After registration, the product information for Cacit Vitamine D3 has been updated with skin reactions, such as pruritus, rash and urticaria. Other adverse reactions listed are hypercalciuria, constipation, flatulence, nausea, abdominal pain and diarrhoea. Altogether 20 non-serious and six serious adverse events were reported for Cacit Vitamine D3 during the latest PSUR period. Among the serious cases, two were assessed as related to treatment. One of these was hypercalcemia, the other one was urticaria. None was fatal. Vitamin D3 should be used with caution in patients with impairment of renal function and the effect on calcium and phosphate levels should be monitored. It should not be used in patients with severe renal insufficiency. The risk of soft tissue calcification should be taken into account. During long-term treatment, serum calcium levels and serum creatinin should be monitored. This is especially important in elderly patients on concomitant treatment with digitalis glycosides or diuretics and in patients with a tendency to calculus formation. Calcium/vitamin D3 sachets should be used with caution in patients with sarcoidosis and in immobilised patients due to the increased risk of hypercalcaemia. In conclusion, risedronate, calcium carbonate and vitamin D3 as cholecalciferol are well known products, with well known safety profiles and the combined use is not expected to cause any new safety problems, provided that dosing is adequate. IV.6 Discussion on the clinical aspects Risedronate 35 mg once a week is an approved therapy. Calcium and vitamin D3 are recommended as additional therapy to patients treated for postmenopausal osteoporosis and the pivotal studies for risedronate in this indication have been performed with the addition of calcium and vitamin D3. Thus, no new efficacy data is considered necessary for the combination pack. No increased risks for the combination pack, compared with use of the individual products, are anticipated. In addition, no risks for interactions between the drugs in this combination pack are foreseen as risedronate and calcium/vitamin D3 are administered on different days. V. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION User consultation A user consultation with target patient groups on the package information leaflet (PIL) has been performed on the basis of a bridging report making reference to SE/H/192/03/MR. The bridging report submitted by the applicant has been found acceptable. The risk/benefit ratio is considered positive and Norsed Combi D, film-coated tablet, 35 mg (risedronate sodium) and effervescent granules 1000 mg/880 IE (calcium/cholecalciferol) is recommended for approval. 5/7

6 VI. APPROVAL The Mutual recognition procedure for Norsed Combi D, film-coated tablet, 35 mg (risedronate sodium) and effervescent granules 1000 mg/880 IE (calcium/cholecalciferol) was successfully finalised on after an article 29 referral. 6/7

7 Public Assessment Report Update Scope Procedure number Product Information affected Date of start of the procedure Date of end of procedure Approval/ non approval Assessment report attached Y/N (version) Postadress/Postal address: P.O. Box 26, SE Uppsala, SWEDEN Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala Telefon/Phone: +46 (0) Fax: +46 (0) Internet: Template version: