The First and Only Osteoporosis Treatment Pack Combining A Weekly Bisphosphonate (Actonel 35 mg) with Calcium & Vitamin D in a Single Pack Tuesday 29 January 2008 PDF Print NEW SOLUTION DESIGNED TO HELP IMPROVE COMPLIANCE IN OSTEOPOROSIS PATIENTS The first and only osteoporosis treatment pack combining a weekly bisphosphonate (Actonel 35 mg) with calcium & vitamin D in a single pack, launched today 29 January 2008 Actonel Combi*, a new convenient option designed to help patients take their osteoporosis supplementation regularly and correctly , is launched today. Actonel Combi combines the dosing of a once weekly bisphosphonate (Actonel 35mg [risedronate]) with vitamin D (880 International Units) and the recommended daily dose of calcium (1000mg) in a single pack for the same Drug Tariff price as Actonel 35mg. In the UK, it is standard practice to co-prescribe calcium and vitamin D with a bisphosphonate for osteoporosis patients. Calcium is known to strengthen the bone framework and vitamin D aids the absorption of calcium from food. However, new research in the leading peer reviewed journal Osteoporosis International, reveals that osteoporosis patients may not be receiving the full benefit of their osteoporosis treatment due to failure to fully comply with their co-prescribed calcium and vitamin D supplementation which can lead to decreased ability of bisphosphonates to reduce fracture risk3. Dr Sally Hope, a GP from Oxfordshire, comments: “We can see from recent market research data conducted in Europe that 43% of patients are not taking any calcium and/ or vitamin D supplementation with their bisphosphonate treatment, despite clear recommendations to do so3. Providing calcium and vitamin D in a package with a bisphosphonate may be a simple solution to the problem, providing patients with an improved chance of fracture protection.” The importance of combination therapy Low dietary intake of calcium and vitamin D together with an existing deficiency can lead to decreased bone mineral density4. In turn, loss of bone density is the most important cause of increased risk of fracture5. Across Europe, almost 30 per cent of postmenopausal women with osteoporosis are vitamin D deficient4,6 and many elderly women fail to achieve a sufficient dietary calcium intake7. Approximately one in two women over the age of 50 in the UK will break a bone, predominantly due to osteoporosis8. Often referred to as a ‘silent disease’, osteoporosis usually does not have any symptoms until a bone is fractured and compliance to treatment is often poor. “As calcium interferes with the absorption of bisphosphonates9, taking calcium supplements incorrectly could result in reduced effectiveness of osteoporosis therapy,” comments Dr Richard Keen, Consultant Rheumatologist, Royal National Orthopaedic Hospital, London. “Any measures that help overcome this issue are very welcome.” Currently 70,000 osteoporotic hip fractures occur every year in England and Wales10, costing the UK an estimated £726 million per annum11. Amongst those patients who suffer a hip fracture, approximately one in five will die within the following year12,13, and around 40 percent will be unable to walk independently one year later14. * Please refer to the ‘About Actonel Combi’ section in the Notes to Editors for details - Ends - For further information please contact: Sebastian Stokes Red Door Communications Tel: 020 8392 8022 firstname.lastname@example.org Georgina McVey Red Door Communications Tel: 020 8392 8065 email@example.com David Keown The Alliance for Better Bone Health Tel: 01483 554447 NOTES TO EDITORS: About Actonel Combi A weekly unit of Actonel Combi consists of one Actonel 35 mg film-coated tablet and six calcium 1000 mg /vitamin D3 880 IU sachets in a box. Actonel Combi is indicated for the treatment of postmenopausal osteoporosis, to reduce the risk of vertebral fractures and for the treatment of established postmenopausal osteoporosis, to reduce the risk of hip fractures. Actonel Combi is only intended for use in assessed patients for whom the amount of calcium and vitamin D3 included is considered to provide adequate supplementation. The recommended dose in adults is one Actonel 35 mg tablet on the first day followed on the next day by one calcium/vitamin D3 sachet, dissolved in water, daily for six days (refer to the Summary of Product Characteristics for full dosing instructions). This seven-day sequence is then repeated each week starting with an Actonel 35 mg tablet. About the Actonel Combi preference study A quantitative patient research study was conducted with 200 women, in three cities in France during October 2006. A combined packaging was developed containing four weekly boxes with each box containing one Actonel 35mg once a week tablet, six sachets of calcium 1000mg and vitamin D 880IU and a patient information leaflet. Participants were 55 years or older and were divided into two groups; osteoporosis patients on bisphosphonates and people not on bisphosphonates (regardless of whether or not they had osteoporosis). (Actonel Combi is only licensed for those with postmenopausal osteoporosis). All participants took part in a face to face interview using a standard questionnaire. The aim of the study was to evaluate patient perception of compliance, convenience and completeness of a new packaging of Actonel 35 mg plus calcium and vitamin D supplementation. About osteoporosis Osteoporosis is a skeletal disease that increases bone fragility and susceptibility to fracture. Fracture is a devastating consequence of osteoporosis and can occur at any site of the body. 30-50% of women will suffer a fracture related to osteoporosis in their lifetime - equivalent to the lifetime risk for cardiovascular disease15. About The Alliance for Better Bone Health The Alliance for Better Bone Health was formed by Procter & Gamble Pharmaceuticals and Aventis part of the sanofi-aventis Group, in May 1997 to promote bone health and disease awareness through numerous activities to support physicians and patients around the globe. About Procter & Gamble [NYSE:PG] Procter & Gamble has a rich heritage in health care that extends back more than 150 years. Then and now, P&G is driven by our mission to improve the lives of people around the world every day. P&G’s health care products include prescription medicines, over-the-counter medications and oral care products. P&G began developing and marketing prescription products in the late-1960s. Three billion times a day, P&G brands touch the lives of people around the world. The company has one of the strongest portfolios of trusted, quality, leadership brands, including Actonel®, Asacol®, Crest®, Fibresure®, Intrinsa®, Metamucil®, Oral-B®, Pepto-bismol®, Thermacare®, Vicks®, Pampers®, Ariel®, Always®, Pantene®, Herbal Essences®, Mach3®, Fairy®, Ace®, Lenor®, M. Propre®, Tampax®, Tempo®, Dash®, Pringles®, Iams®, Eukanuba®, Duracell®, Olay®, Head & Shoulders®, Wella, Gillette®, and Braun. The P&G community consists of 138,000 employees working in over 80 countries worldwide. Please visit http://www.pg.com for the latest news and in-depth information about P&G and its brands. For more information about P&G Pharmaceuticals, please visit www.pgpharma.com About sanofi-aventis Sanofi-aventis, a leading global pharmaceutical company, discovers, develops and distributes therapeutic solutions to improve the lives of everyone. Sanofi-aventis is listed in Paris (EURONEXT: SAN) and in New York (NYSE: SNY). Forward Looking Statements For sanofi-aventis: This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, as amended. Forward-looking statements are statements that are not historical facts. These statements include product development, product potential projections and estimates and their underlying assumptions, statements regarding plans, objectives, intentions and expectations with respect to future events, operations, products and services, and statements regarding future performance. Forward-looking statements are generally identified by the words "expects," "anticipates," "believes," "intends," "estimates," "plans" and similar expressions. Although 'sanofi-aventis' management believes that the expectations reflected in such forward-looking statements are reasonable, investors are cautioned that forward-looking information and statements are subject to various risks and uncertainties, many of which are difficult to predict and generally beyond the control of sanofi-aventis, that could cause actual results and developments to differ materially from those expressed in, or implied or projected by, the forward-looking information and statements. These risks and uncertainties include among other things, the uncertainties inherent in research and development, future clinical data and analysis, including post marketing, decisions by regulatory authorities, such as the FDA or the EMEA, regarding whether and when to approve any drug, device or biological application that may be filed for any such product candidates as well as their decisions regarding labelling and other matters that could affect the availability or commercial potential of such products candidates, the absence of guarantee that the products candidates if approved will be commercially successful, the future approval and commercial success of therapeutic alternatives as well as those discussed or identified in the public filings with the SEC and the AMF made by sanofi-aventis, including those listed under "Risk Factors" and "Cautionary Statement Regarding Forward-Looking Statements" in sanofi-aventis' annual report on Form 20-F for the year ended December 31, 2006. Other than as required by applicable law, sanofi-aventis does not undertake any obligation to update or revise any forward-looking information or statements. For P&G: All statements, other than statements of historical fact included in this release, are forward-looking statements, as that term is defined in the Private Securities Litigation Reform Act of 1995. Such statements are based on financial data, market assumptions and business plans available only as of the time the statements are made, which may become out of date or incomplete. We assume no obligation to update any forward-looking statement as a result of new information, future events or other factors. Forward-looking statements are inherently uncertain, and investors must recognize that events could differ significantly from our expectations. In addition to the risks and uncertainties noted in this release, there are certain factors that could cause actual results to differ materially from those anticipated by some of the statements made. These include: (1) the ability to achieve business plans, including with respect to lower income consumers and growing existing sales and volume profitably despite high levels of competitive activity, especially with respect to the product categories and geographical markets (including developing markets) in which the Company has chosen to focus; (2) the ability to successfully execute, manage and integrate key acquisitions and mergers, including (i) the Domination and Profit Transfer Agreement with Wella, and (ii) the Company’s merger with The Gillette Company, and to achieve the cost and growth synergies in accordance with the stated goals of these transactions; (3) the ability to manage and maintain key customer relationships; (4) the ability to maintain key manufacturing and supply sources (including sole supplier and plant manufacturing sources); (5) the ability to successfully manage regulatory, tax and legal matters (including product liability, patent, and intellectual property matters as well as those related to the integration of Gillette and its subsidiaries), and to resolve pending matters within current estimates; (6) the ability to successfully implement, achieve and sustain cost improvement plans in manufacturing and overhead areas, including the Company's outsourcing projects; (7) the ability to successfully manage currency (including currency issues in volatile countries), debt, interest rate and commodity cost exposures; (8) the ability to manage continued global political and/or economic uncertainty and disruptions, especially in the Company's significant geographical markets, as well as any political and/or economic uncertainty and disruptions due to terrorist activities; (9) the ability to successfully manage competitive factors, including prices, promotional incentives and trade terms for products; (10) the ability to obtain patents and respond to technological advances attained by competitors and patents granted to competitors; (11) the ability to successfully manage increases in the prices of raw materials used to make the Company's products; (12) the ability to stay close to consumers in an era of increased media fragmentation; and (13) the ability to stay on the leading edge of innovation and maintain a positive reputation on our brands. For additional information concerning factors that could cause actual results to materially differ from those projected herein, please refer to our most recent 10-K, 10-Q and 8-K reports. A recommendation is made to consider the Summary of Product Characteristics attached alongside this press release for posology and method of administration, side effects, precautions and contraindications prior to prescribing Actonel Combi. REFERENCES: 1. Fardellone P and Varbanov A. A convenient new approach to simplify osteoporosis treatment regimen for risedronate plus calcium and vitamin D. Osteoporosis Int 2007; 18 Suppl 1:P29-175. 2. Francis RM et al. Calcium and vitamin D in the prevention of osteoporotic fractures. Q J Med 2006; 99(6): 355-363. 3. Quesada JM and Mann B. Low usage of calcium and vitamin D with bisphosphonate therapy in post-menopausal osteoporotic women in France and in Spain. Osteoporosis Int 2007;18 (Suppl 1):P354. 4. Lips P et al. A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of Raloxifene evaluation clinical trial. J Clin Endrocrinol Metab 2001; 86: 1212 – 1221. 5. Rodriguez-Martinez MA & Garcia-Cohen EC. Role of Ca (2+) and vitamin D in the prevention and treatment of osteoporosis. Pharmacol Ther 2002;93(1):37-49. 6. Lips P. Which circulating level of 25-hydroxyvitamin D is appropriate? Journal of Steroid Biochemistry and Molecular Biology 2004; 89-90: 611-614. 7. Mason P. Calcium – An update. The Pharmaceutical Journal 2002; 268: 329-330. 8. National Osteoporosis Society website. http://www.nos.org.uk/about.htm. Accessed November 2007 9. Actonel/Optinate Combi D 35mg + 1000mg / 880 IU film coated tablets and effervescent granules. Summary of Product Characteristics. 10. National Institute for Health and Clinical Excellence. Bisphosphonates (alendronate, etidronate, risedronate), selective oestrogen receptor modulators (raloxifene) and parathyroid hormone (teriparatide) for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. Technology Appraisal No. 87. January 2005 11. University of York. The economic cost of hip fracture in the UK: avoiding slips, trips and broken hips. June 2000 12. Cooper C, Atkinson EJ, Jacobsen SJ, et al. Population-based study of survival after osteoporotic fractures. Am J Epidemiol 1993; 137:1001-1005. 13. Leibson CL, Tosteson AN, Gabriel SE, et al. Mortality, disability, and nursing home use for persons with and without hip fracture: a population-based study. J Am Geriatr Soc 2002; 50: 1644-1650. 14. Magaziner J, Simonsick EM, Kashner TM, et al. Predictors of functional recovery one year following hospital discharge for hip fracture: a prospective study. J Gerontol 1990; 45: M101-M107. 15. International Osteoporosis Foundation. Facts and statistics about osteoporosis and its impact. http://www.osteofound.org/press_centre/fact_sheet.html. Last accessed 7th November 2006. SUMMARY OF PRODUCT CHARACTERISTICS: 1. NAME OF THE MEDICINAL PRODUCT Actonel Combi 35 mg film-coated tablets + 1000 mg / 880 IU effervescent granules 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each filmcoated tablet contains 35 mg risedronate sodium, (equivalent to 32.5 mg risedronic acid). Each sachet of effervescent granules contains 2500 mg calcium carbonate equivalent to 1000 mg calcium and 22 micrograms (880 IU) colecalciferol (vitamin D3). Excipients: Each film-coated tablet contains lactose. Each sachet of effervescent granules contains potassium (163 mg), sucrose, soya-bean oil and sorbitol. For full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet. Oval, light-orange, film-coated tablet with RSN on one side and 35 mg on the other. Effervescent granules White effervescent granules. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Treatment of postmenopausal osteoporosis, to reduce the risk of vertebral fractures. Treatment of established postmenopausal osteoporosis, to reduce the risk of hip fractures (see section 5.1). Actonel Combi is only intended for used in assessed patients for whom the amount of calcium and vitamin D3 included is considered to provide adequate supplementation. 4.2 Posology and method of administration A weekly unit of Actonel Combi consists of 1 Actonel 35 mg film-coated tablet and 6 calcium/vitamin D3 sachets in a box. The recommended dose in adults is 1 Actonel 35 mg tablet on the first day followed on the next day by 1 calcium/vitamin D3 sachet daily for 6 days. This 7-day sequence is then repeated each week starting with Actonel 35 mg tablet. Actonel 35 mg (light-orange tablet): The Actonel 35 mg tablet should be taken orally on the same day each week. The absorption of risedronate sodium is affected by food, thus to ensure adequate absorption, patients should take the tablet with plain water at least 30 minutes before the first food, other medicinal product or drink (other than water) of the day. The tablet must be swallowed whole and not sucked or chewed. To aid delivery of the tablet to the stomach the Actonel 35 mg tablet is to be taken while in an upright position with a glass of plain water (>120 ml). Patients should not lie down for 30 minutes after taking the tablet (see section 4.4). Calcium/vitamin D3 (sachet): Calcium/vitamin D3 sachet should be taken each day for 6 days per week starting on the day after the Actonel 35 mg tablet is taken. The contents of the sachet should be poured into a glass of plain water, stirred and drunk immediately once the fizzing has subsided. In case the Actonel 35 mg tablet dose is missed, patients should be instructed that the Actonel 35 mg tablet should be taken on the next day in the morning according to the dosing instructions. In this particular instance, patients should then take their calcium/vitamin D3 sachet on the following day. Patients should be instructed that they should never take the tablet and the sachet the same day. If the calcium/vitamin D3 sachet dose is missed, the patient should be instructed to continue taking one sachet each day beginning on the day the missed dose is remembered. Patient should be instructed that they should not take two sachets on the same day. Any remaining calcium/vitamin D3 sachet at the end of the weekly cycle should be discarded. Elderly: No dosage adjustment is necessary since bioavailability, distribution and elimination were similar in elderly (>60 years of age) compared to younger subjects. This has also been shown in the very elderly, 75 years old and above in postmenopausal population. Renal Impairment: No dosage adjustment is required for those patients with mild to moderate renal impairment. The use of risedronate sodium and calcium/vitamin D3 is contraindicated in patients with severe renal impairment (creatinine clearance lower than 30ml/min) (see sections 4.3 and 5.2). Children: Safety and efficacy of Actonel Combi has not been established in children and adolescents. 4.3 Contraindications Hypersensitivity to risedronate sodium, calcium carbonate, colecalciferol or to any of the excipients (in particular soya-bean oil). Hypocalcaemia (see section 4.4) Hypercalcaemia. Hypercalciuria Diseases and/or conditions (such as prolonged immobilization) associated with hypercalcaemia and/or hypercalciuria Nephrolithiasis Pregnancy and lactation. Severe renal impairment (creatinine clearance <30ml/min). Hypervitaminosis D 4.4 Special warnings and precautions for use Risedronate sodium: Foods, drinks (other than plain water) and medicinal products containing polyvalent cations (such as calcium, magnesium, iron and aluminium) may interfere with the absorption of risedronate sodium and should not be taken at the same time. Therefore the risedronate sodium tablet (light-orange tablet) should be taken at least 30 minutes before the first food, other medicinal product or drink of the day (see section 4.2). Efficacy of bisphosphonates in the treatment of postmenopausal osteoporosis is related to the presence of low bone mineral density (BMD) [T-score at hip or lumbar spine ≤-2.5 standard deviations (SD)] and/or prevalent fracture. High age or clinical risk factors for fracture alone are not sufficient reasons to initiate treatment of osteoporosis with a bisphosphonate. The evidence to support efficacy of bisphosphonates including risedronate sodium in very elderly women (>80 years) is limited (see section 5.1). Some bisphosphonates have been associated with oesophagitis and oesophageal ulcerations. Therefore patients should pay attention to the dosing instructions (see section 4.2). In patients who have a history of oesophageal disorders which delay oesophageal transit or emptying e.g. stricture or achalasia, or who are unable to stay in the upright position for at least 30 minutes after taking the tablet, risedronate sodium should be used with special caution because of limited clinical experience in these patients. Prescribers should emphasise the importance of the dosing instructions to these patients. Hypocalcaemia should be treated before starting Actonel Combi therapy. Other disturbances of bone and mineral metabolism (i.e. parathyroid dysfunction, hypovitaminosis D) should be treated at the time of starting Actonel Combi therapy. Osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported in patients with cancer receiving treatment regimens including primarily intravenously administered bisphosphonates. Many of these patients were also receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis receiving oral bisphosphonates. A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene). While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment. In patients with mild to moderate renal impairment or a history of absorptive or renal hypercalciuria, nephrocalcinosis, kidney stone formation, or hypophosphataemia, renal function, serum and urinary calcium and phosphate should be monitored regularly. This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. Calcium carbonate/vitamin D3: 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. The risk of soft tissue calcification should be taken into account. In patients with severe renal insufficiency, vitamin D in the form of colecalciferol is not metabolised normally and another form of vitamin D should be used (see section 4.3) During long-term treatment, serum and urinary calcium levels should be followed and renal function should be monitored through measurement of serum creatinine. Monitoring is especially important in elderly patients on concomitant treatment with cardiac glycosides or diuretics (see section 4.5) and in patients with a high tendency to calculus formation. Treatment must be reduced or suspended if urinary calcium exceeds 7.5 mmol/24 hour (300 mg/24 hour). In case of hypercalcaemia or signs of impaired renal function, treatment with calcium/vitamin D3 sachets should be discontinued. The dose of vitamin D3 in the sachets should be considered when prescribing other drugs containing vitamin D. Additional doses of calcium or vitamin D should be taken under close medical supervision. In such cases it is necessary to monitor serum calcium levels and urinary calcium excretion frequently. Calcium/vitamin D3 sachets should be used with caution in patients suffering from sarcoidosis because of the risk of increased metabolism of vitamin D to its active metabolite. In these patients, serum calcium levels and urinary calcium excretion must be monitored. Calcium/vitamin D3 sachets should be used with caution in immobilised patients with osteoporosis due to the increased risk of hypercalcaemia. The calcium/vitamin D3 treatment might be discontinued in prolonged immobilization and should only be resumed once the patient becomes mobile again. This medicinal product contains sorbitol and sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicinal product. 4.5 Interaction with other medicinal products and other forms of interaction Risedronate sodium: No formal interaction studies have been performed with risedronate sodium, however no clinically relevant interactions with other medicinal products were found during clinical trials. In the risedronate sodium Phase III osteoporosis studies with daily dosing, acetyl salicylic acid or non-steroidal anti-inflammatory drug (NSAID) use was reported by 33% and 45% of patients respectively. In the Phase III once a week study, acetyl salicylic acid or NSAID use was reported by 57% and 40% of patients respectively. Among regular acetyl salicylic acid or NSAID users (3 or more days per week) the incidence of upper gastrointestinal adverse events in risedronate sodium treated patients was similar to that in control patients. If considered appropriate risedronate sodium may be used concomitantly with oestrogen supplementation. Concomitant ingestion of medications containing polyvalent cations (e.g. calcium, magnesium, iron and aluminium) will interfere with the absorption of risedronate sodium (see section 4.4). Risedronate sodium is not systemically metabolised, does not induce cytochrome P450 enzymes, and has low protein binding. Calcium carbonate/vitamin D3: Thiazide diuretics reduce the urinary excretion of calcium. Due to increased risk of hypercalcemia serum calcium should be regularly monitored during concomitant use of thiazide diuretics. Systemic corticosteroids reduce calcium absorption. During concomitant use, it may be necessary to increase the dose of calcium. Calcium carbonate may interfere with the absorption of concomitant administered tetracycline preparations. For this reason, tetracycline preparations should be administered at least two hours before or four to six hours after oral intake of calcium carbonate/vitamin D3. Hypercalcaemia may increase the toxicity of digitalis and other cardiac glycosides (risk of dysrhythmia) during treatment with calcium combined with vitamin D3. Such patients should be monitored with regard to electrocardiogram (ECG) and serum calcium levels. If sodium fluoride is used concomitantly, this preparation should be administered at least three hours before intake of calcium carbonate/vitamin D3 since gastrointestinal absorption may be reduced. Oxalic acid (found in spinach and rhubarb) and phytic acid (found in whole cereals) may inhibit calcium absorption through formation of insoluble compounds with calcium ions. The patient should not take calcium products within two hours of eating foods with high concentration of oxalic acid and phytic acid. Simultaneous treatment with ion exchange resins such as cholestyramine or laxatives such as paraffin oil may reduce the gastrointestinal absorption of vitamin D. 4.6 Pregnancy and lactation This medicinal product is contraindicated during pregnancy and lactation (see section 4.3). Risedronate sodium: There are no adequate data from use of risedronate sodium in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk to humans is unknown. Studies in animals indicate that a small amount of risedronate sodium pass into breast milk. Risedronate sodium must not be used during pregnancy or by breast-feeding women. Calcium carbonate/vitamin D3: During pregnancy the daily intake should not exceed 1500 mg calcium and 600 IU colecalciferol (15μg vitamin D3). There are no indications that vitamin D at therapeutic doses is teratogenic in humans. Studies in animals have shown reproductive toxicity with high doses of vitamin D. In pregnant women, overdoses of calcium and vitamin D should be avoided as permanent hypercalcaemia has been related to adverse effects on the developing foetus. Calcium and vitamin D 3 pass into breast milk. Calcium carbonate 2500 mg/vitamin D3 880 IU dose granules must not be used during pregnancy and lactation. 4.7 Effects on ability to drive and use machines No effects on ability to drive and use machines have been observed. 4.8 Undesirable effects Risedronate sodium: Risedronate sodium has been studied in phase III clinical trials involving more than 15,000 patients. The majority of undesirable effects observed in clinical trials were mild to moderate in severity and usually did not require cessation of therapy. Adverse experiences reported in phase III clinical trials in postmenopausal women with osteoporosis treated for up to 36 months with risedronate sodium 5mg/day (n=5020) or placebo (n=5048) and considered possibly or probably related to risedronate sodium are listed below using the following convention (incidences versus placebo are shown in brackets): very common (≥1/10); common (≥1/100; <1/10); uncommon (≥1/1,000; <1/100); rare (≥1/10,000; <1/1,000); very rare (<1/10,000). Nervous system disorders: Common: headache (1.8% vs. 1.4%) Eye disorders: Uncommon: iritis* Gastrointestinal disorders: Common: constipation (5.0% vs. 4.8%), dyspepsia (4.5% vs. 4.1%), nausea (4.3% vs. 4.0%), abdominal pain (3.5% vs. 3.3%), diarrhoea (3.0% vs. 2.7%) Uncommon: gastritis (0.9% vs. 0.7%), oesophagitis (0.9% vs. 0.9%), dysphagia (0.4% vs. 0.2%), duodenitis (0.2% vs. 0.1), oesophageal ulcer (0.2% vs. 0.2%) Rare: glossitis (<0.1% vs. 0.1%), oesophageal stricture (<0.1% vs. 0.0%), Musculoskeletal and connective tissues disorders: Common: musculoskeletal pain (2.1% vs. 1.9%) Investigations (hepatobiliary): Rare: abnormal liver function tests* * No relevant incidences from Phase III osteoporosis studies; frequency based on adverse event/ laboratory/ rechallenge findings in earlier clinical trials. In a one-year, double-blind, multicentre study comparing risedronate 5 mg daily (n= 480) and risedronate sodium 35 mg weekly (n=485) in postmenopausal women with osteoporosis, the overall safety and tolerability profiles were similar. The following additional adverse experiences considered possibly or probably drug related by investigators have been reported (incidence greater in risedronate 35 mg than in risedronate sodium 5 mg group): gastrointestinal disorder (1.6% vs. 1.0%) and pain (1.2% vs. 0.8%). Laboratory findings: Early, transient, asymptomatic and mild decreases in serum calcium and phosphate levels have been observed in some patients. The following additional adverse reactions have been reported during post-marketing use (frequency unknown): Eye disorders: iritis, uveitis Muskuloskeletal and connective tissues disorders: osteonecrosis of the jaw Skin and subcutaneous tissue disorders: hypersensitivity and skin reactions, including angioedema, generalised rash, and bullous skin reactions, some severe. Calcium carbonate/vitamin D3 Adverse reactions are listed below, by system organ class and frequency. Metabolism and nutrition disorders Uncommon (>1/1,000, <1/100): Hypercalcaemia and hypercalciuria. Gastrointestinal disorders Rare (>1/10,000, <1/1,000): Constipation, flatulence, nausea, abdominal pain and diarrhoea. Skin and subcutaneous disorders Rare (>1/10,000, <1/1,000): Pruritus, rash and urticaria. 4.9 Overdose Risedronate sodium: No specific information is available on the treatment of acute overdose with risedronate sodium. Decreases in serum calcium following substantial overdose may be expected. Signs and symptoms of hypocalcaemia may also occur in some of these patients. Milk or antacids containing magnesium, calcium or aluminium should be given to bind risedronate sodium and reduce absorption of risedronate sodium. In cases of substantial overdose, gastric lavage may be considered to remove unabsorbed risedronate sodium. Calcium carbonate/vitamin D3: Overdose can lead to hypervitaminosis, hypercalciura and hypercalcaemia. Symptoms of hypercalcaemia may include anorexia, thirst, nausea, vomiting, constipation, abdominal pain, muscle weakness, fatigue, mental disturbances, polydipsia, polyuria, bone pain, nephrocalcinosis, renal calculi and in severe cases, cardiac arrhythmias. Extreme hypercalcaemia may result in coma and death. Persistently high calcium levels may lead to irreversible renal damage and soft tissue calcification. Treatment of hypercalcaemia: The treatment with calcium must be discontinued. Treatment with thiazide diuretics, lithium, vitamin A, vitamin D3 and cardiac glycosides must also be discontinued. Emptying of the stomach in patients with impaired consciousness. Rehydration, and, according to severity, isolated or combined treatment with loop diuretics, bisphosphonates, calcitonin and corticosteroids. Serum electrolytes, renal function and diuresis must be monitored. In severe cases, ECG and central venous pressure should be followed. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmaco-therapeutic group: Bisphosphonates, combinations, ATC Code: M05BB. Vitamin D and analogues. Colecalciferol: ATC Code: A11CC05 Risedronate sodium: Risedronate sodium is a pyridinyl bisphosphonate that binds to bone hydroxyapatite and inhibits osteoclast-mediated bone resorption. The bone turnover is reduced while the osteoblast activity and bone mineralisation is preserved. In preclinical studies risedronate sodium demonstrated potent antiosteoclast and antiresorptive activity, and dose dependently increased bone mass and biomechanical skeletal strength. The activity of risedronate sodium was confirmed by measuring biochemical markers for bone turnover during pharmacodynamic and clinical studies. Decreases in biochemical markers of bone turnover were observed within 1 month and reached a maximum in 3-6 months. Decreases in biochemical markers of bone turnover were similar with risedronate sodium 35 mg weekly and risedronate sodium 5 mg daily at 12 months. Treatment of Postmenopausal Osteoporosis: A number of risk factors are associated with postmenopausal osteoporosis including low bone mass, low bone mineral density, early menopause, a history of smoking and a family history of osteoporosis. The clinical consequence of osteoporosis is fractures. The risk of fractures is increased with the number of risk factors. Based on effects on mean change in lumbar spine bone mineral density (BMD), risedronate sodium 35 mg weekly (n=485) was shown to be equivalent to risedronate sodium 5 mg daily (n=480) in a one year, double-blind, multicentre study of postmenopausal women with osteoporosis. The clinical programme for risedronate sodium administered once daily studied the effect of risedronate sodium on the risk of hip and vertebral fractures and contained early and late postmenopausal women with and without fracture. Daily doses of 2.5 mg and 5 mg were studied and all groups, including the control groups, received calcium and vitamin D (if baseline levels were low). The absolute and relative risk of new vertebral and hip fractures were estimated by use of a time-to first event analysis. • Two placebo-controlled trials (n=3661) enrolled postmenopausal women under 85 years with vertebral fractures at baseline. Risedronate sodium 5 mg daily given for 3 years reduced the risk of new vertebral fractures relative to the control group. In women with respectively at least 2 or at least 1 vertebral fractures, the relative risk reduction was 49% and 41% respectively (incidence of new vertebral fractures with risedronate sodium 18.1% and 11.3%, with placebo 29.0% and 16.3%, respectively). The effect of treatment was seen as early as the end of the first year of treatment. Benefits were also demonstrated in women with multiple fractures at baseline. Risedronate sodium 5 mg daily also reduced the yearly height loss compared to the control group. • Two further placebo controlled trials enrolled postmenopausal women above 70 years with or without vertebral fractures at baseline. Women 70-79 years were enrolled with femoral neck BMD Tscore <-3 SD (manufacturer’s range, i.e. -2.5 SD using NHANES III) and at least one additional risk factor. Women ≥80 years could be enrolled on the basis of at least one non-skeletal risk factor for hip fracture or low bone mineral density at the femoral neck. Statistical significance of the efficacy of risedronate sodium versus placebo is only reached when the two treatment groups 2.5 mg and 5 mg are pooled. The following results are only based on a-posteriori analysis of subgroups defined by clinical practise and current definitions of osteoporosis: - In the subgroup of patients with femoral neck BMD T-score ≤-2.5SD (NHANES III) and at least one vertebral fracture at baseline, risedronate sodium given for 3 years reduced the risk of hip fractures by 46% relative to the control group (incidence of hip fractures in combined risedronate sodium 2.5 and 5 mg groups 3.8%, placebo 7.4%); - Data suggest that a more limited protection than this may be observed in the very elderly (≥80 years). This may be due to the increasing importance of non-skeletal factors for hip fracture with increasing age. In these trials, data analysed as a secondary endpoint indicated a decrease in the risk of new vertebral fractures in patients with low femoral neck BMD without vertebral fracture and in patients with low femoral neck BMD with or without vertebral fracture. • Risedronate sodium 5 mg daily given for 3 years increased BMD relative to control at the lumbar spine, femoral neck, trochanter and wrist and maintained bone density at the mid-shaft radius. • In a one-year follow-up off therapy after three years treatment with risedronate sodium 5 mg daily there was rapid reversibility of the suppressing effect of risedronate sodium on bone turnover rate. • Bone biopsy samples from postmenopausal women treated with risedronate sodium 5 mg daily for 2 to 3 years, showed an expected moderate decrease in bone turnover. Bone formed during risedronate sodium treatment was of normal lamellar structure and bone mineralisation. These data together with the decreased incidence of osteoporosis related fractures at vertebral sites in women with osteoporosis appear to indicate no detrimental effect on bone quality. • Endoscopic findings from a number of patients with a number of moderate to severe gastrointestinal complaints in both risedronate sodium and control patients indicated no evidence of treatment related gastric, duodenal or oesophageal ulcers in either group, although duodenitis was uncommonly observed in the risedronate sodium group. Calcium carbonate/vitamin D3: In case of calcium deficiency, oral intake of calcium supplementation supports the remineralisation of the skeleton. Vitamin D3 increases the intestinal absorption of calcium. Administration of calcium and vitamin D3 counteracts the increase in parathyroid hormone (PTH) which is caused by calcium deficiency which causes increased bone resorption. A clinical study of institutionalised patients suffering from vitamin D deficiency indicated that a daily intake of effervescent granules of 1000 mg calcium/880 IU colecalciferol for six months normalised the value of the 25-hydoxylated metabolite of vitamin D3 and reduced secondary hyperparathyroidism. 5.2 Pharmacokinetic properties Risedronate sodium: Absorption: risedronate sodium absorption after an oral dose is relatively rapid (tmax ~1 hour) and is independent of dose over the range studied (single dose study, 2.5 to 30 mg; multiple dose studies, 2.5 to 5 mg daily and up to 50 mg dosed weekly). Mean oral bioavailability of the tablet is 0.63% and is decreased when risedronate sodium is administered with food. Bioavailability was similar in men and women. Distribution: The mean steady state volume of distribution of risedronate sodium is 6.3 l/kg in humans. Plasma protein binding is about 24%. Metabolism: There is no evidence of systemic metabolism of risedronate sodium. Elimination: Approximately half of the absorbed risedronate sodium dose is excreted in urine within 24 hours, and 85% of an intravenous dose is recovered in the urine after 28 days. Mean renal clearance is 105 ml/min and mean total clearance is 122 ml/min, with the difference probably attributed to clearance due to adsorption to bone. The renal clearance is not concentration dependent, and there is a linear relationship between renal clearance and creatinine clearance. Unabsorbed risedronate sodium is eliminated unchanged in faeces. After oral administration the concentrationtime profile shows three elimination phases with a terminal half-life of 480 hours. Calcium carbonate: Absorption: During dissolution the calcium salt contained in the effervescent granules is transformed into calcium citrate. Calcium citrate is well absorbed, approximately 30% to 40% of the ingested dose. Distribution and metabolism: 99% of calcium in the body is concentrated in the hard structure of bones and teeth. The remaining 1% is present in the intra- and extracellular fluids. About 50% of the total blood calcium content is physiologically active ionised form with approximately 10% being complexed to citrate, phosphate or other anions, the remaining 40% being bound to proteins, principally albumin. Elimination: Calcium is eliminated through faeces, urine and sweat. Renal excretion depends on glomerular filtration and calcium tubular reabsorption. Vitamin D3: Absorption: Vitamin D is readily absorbed in the small intestine. Distribution and metabolism: Colecalciferol and its metabolites circulate in the blood bound to a specific globulin. Colecalciferol is converted in the liver by hydroxylation to the active form 25- hydroxycolecalciferol. It is then further converted in the kidneys to 1,25 hydroxycolecalciferol. 1,25 hydroxycolecalciferol is the metabolite responsible for increasing calcium absorption. Vitamin D that is not metabolised is stored in adipose and muscle tissues. Elimination: Vitamin D is excreted in faeces and urine. 5.3 Preclinical safety data Risedronate sodium: In toxicological studies in rat and dog dose dependent liver toxic effects of risedronate sodium were seen, primarily as enzyme increases with histological changes in rat. The clinical relevance of these observations is unknown. Testicular toxicity occurred in rat and dog at exposures considered in excess of the human therapeutic exposure. Dose related incidences of upper airway irritation were frequently noted in rodents. Similar effects have been seen with other bisphosphonates. Lower respiratory tract effects were also seen in longer term studies in rodents, but the clinical significance of these findings is unclear. In reproduction toxicity studies at exposures close to clinical exposure ossification changes were seen in sternum and/or skull of foetuses from treated rats and hypocalcemia and mortality in pregnant females allowed to deliver. There was no evidence of teratogenesis at 3.2mg/kg/day in rat and 10mg/kg/day in rabbit, although data are only available on a small number of rabbits. Maternal toxicity prevented testing of higher doses. Preclinical data reveal no special hazard for humans based on conventional studies of genotoxicity and carcinogenesis. Calcium carbonate/vitamin D3: At doses far higher than the human therapeutic range, teratogenicity has been observed in animal studies (see section 4.6). There is no further information of relevance to the safety assessment in addition to what is stated in other parts of the SPC. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Film-coated tablet: Tablet core: Lactose monohydrate Microcrystalline cellulose Crospovidone Magnesium stearate. Film coating: Dri-Klear: (hypromellose, macrogol 400, hydroxypropylcellulose, macrogol 8000 and silicon dioxide) Chroma-Tone White (DDB-7536W) Titanium dioxide (E171) Hypromellose Ferric oxide yellow (E172) Ferric oxide red (E172). Effervescent granules: Citric acid anhydrous Malic acid, Gluconolactone, Maltodextrin, Sodium cyclamate, Saccharin sodium, Flavour Lemon LCA Code 120 (sorbitol (E420), mannitol (E421), gluconolactone, dextrin, acacia, lemon oils and lime flavour) Rice starch, Potassium carbonate, All-rac-α-Tocopherol, Soya-bean oil, hydrogenated Gelatin, Sucrose, Maize starch. 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container Combination pack constituted of an outer carton pack containing weekly unit(s) (carton boxes). Each weekly unit contains: Clear PVC/aluminium foil blister containing one tablet Six sachets (laminated aluminium paper foil) containing effervescent granules Pack sizes: 1 weekly unit: 1x(1 film-coated tablet + effervescent granules in 6 sachets) 2 weekly units; 2x(1 film-coated tablet + effervescent granules in 6 sachets) 4 weekly units: 4x(1 film-coated tablet + effervescent granules in 6 sachets) 3x4 weeklys units; 12x(1 film-coated tablet + effervescent granules in 6 sachets) 4x4 weekly units: 16x(1 film-coated tablet + effervescent granules in 6 sachets) Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements 7. MARKETING AUTHORISATION HOLDER Procter & Gamble Pharmaceuticals UK Ltd. Rusham Park, Whitehall Lane, Egham, Surrey TW20 9NW UK 8. MARKETING AUTHORISATION NUMBER(S) PL 00364/0085 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 2006-10-13 10. DATE OF REVISION OF THE TEXT 2007-05-04 This press release was distributed by ResponseSource Press Release Wire on behalf of Red Door Communications in the following categories: Men's Interest, Health, Women's Interest & Beauty, Medical & Pharmaceutical, for more information visit http://pressreleasewire.responsesource.com/about.