(colecalciferol) PL 40861/0002

Transcription

1 FULTIUM-D IU CAPSULES (colecalciferol) PL 40861/0002 UKPAR TABLE OF CONTENTS Lay Summary Page 2 Scientific Discussion Page 4 Steps Taken for Assessment Page 41 Summary of Product Characteristics Page 42 Patient Information Leaflet Page 43 Labelling Page 44 Steps taken after authorisation - summary Page 47 Annex 1 Page 48 1

2 LAY SUMMARY FULTIUM-D IU CAPSULES (colecalciferol) This is a summary of the Public Assessment Report (PAR) for Fultium-D IU Capsules (PL 40861/0002, formerly PL 17871/0151). It explains how the application for Fultium-D IU Capsules was assessed and its authorisation recommended, as well as the conditions of use. It is not intended to provide practical advice on how to use Fultium-D IU Capsules. For practical information about using Fultium-D IU Capsules, patients should read the package leaflet or contact their doctor or pharmacist. Fultium-D IU Capsules may be referred to as Fultium-D 3 or Fultium-D IU in this report. What is Fultium-D 3 and what is it used for? Fultium-D 3 is a medicine with well-established use. This means that the medicinal use of the active substance of Fultium-D 3 is well established in the European Union for at least ten years, with recognised efficacy and an acceptable level of safety. Fultium-D 3 contains the active ingredient colecalciferol (800 IU colecalciferol is equivalent to 20 micrograms of vitamin D 3 ). Vitamin D is found in the diet and is also produced in the skin after exposure to the sun. Often vitamin D is given in combination with calcium. Fultium-D 3 is recommended for use when the patient has a normal intake of dietary calcium. Fultium-D IU Capsules may be prescribed to treat or prevent vitamin D deficiency. Deficiency of vitamin D may occur when diet or lifestyle does not provide the patient with enough vitamin D or when the body requires more vitamin D (for instance when a woman is pregnant). Fultium-D IU Capsules may also be prescribed for certain bone conditions, such as thinning of the bone (osteoporosis) when it will be given with other medicines. How does Fultium-D 3 work? The active ingredient colecalciferol (equivalent to vitamin D 3 ) acts to maintain normal concentrations of calcium and phosphate in plasma by facilitating their absorption from the small intestine, enhancing their mobilisation from bone and decreasing their excretion by the kidney. How is Fultium-D 3 used? Fultium-D 3 is available as capsules, which are taken by mouth and must be swallowed whole with water. This medicine should always be taken exactly as described in the package leaflet or as instructed by the patient s doctor or pharmacist. The patient should check with the doctor or pharmacist if he/she is not sure. Please read section 3 of the package leaflet (PL) for detailed information on dosing recommendations, the route of administration, and the duration of treatment. Fultium-D 3 can be obtained with a prescription. 2

3 What benefits of Fultium-D 3 have been shown in studies? As colecalciferol is a well-known substance and its use in the treatment and prevention of vitamin D deficiency and as an adjunct to therapy for certain bone conditions, such as thinning of the bone (osteoporosis) is well established, the applicant presented data from the scientific literature at the time of initial assessment. The literature provided confirmed the efficacy and safety of colecalciferol in the treatment and prevention of vitamin D deficiency and as an adjunct to therapy for certain bone conditions, such as thinning of the bone (osteoporosis). What are the possible side effects from Fultium-D 3? Like all medicines, Fultium-D 3 can cause side effects, although not everybody gets them. Uncommon side effects (affecting less than 1 in 100 people) with Fultium-D 3 may include too much calcium in the: blood (hypercalcaemia) The following may be experienced: feeling or being sick, loss of appetite, constipation, stomach ache, feeling very thirsty, muscle weakness, drowsiness or confusion urine (hypercalciuria) For the full list of side effects reported with Fultium-D 3 see section 4 of the package leaflet available on the MHRA website. Also, for the full list of restrictions, see the package leaflet. Why is Fultium-D 3 approved? The MHRA concluded that, in accordance with EU requirements, the benefits of Fultium-D IU Capsules outweigh the identified risks and recommended that the product be approved for use. What measures are being taken to ensure the safe and effective use of Fultium-D 3? A risk management plan has been developed to ensure that Fultium-D 3 is used as safely as possible. Based on this plan safety information has been included in the Summary of Product Characteristics and the package leaflet for Fultium-D IU Capsules, including the appropriate precautions to be followed by healthcare professionals and patients. Known side effects are continuously monitored. Furthermore new safety signals reported by patients/healthcare professionals will be monitored/reviewed continuously as well. Other information about Fultium-D 3. A Marketing Authorisation (Fultium-D IU Capsules, PL 17871/0151) was first granted in the UK to Jenson Pharmaceutical Services Limited on 28 October Subsequent to a Change of Ownership procedure, the Marketing Authorisation (Fultium-D IU Capsules; PL 40861/0002) was granted in the UK to Internis Pharmaceuticals Limited on 24 September The full PAR for Fultium-D IU Capsules follows this summary. For more information about treatment with Fultium-D 3, read the package leaflet, or contact your doctor or pharmacist. This summary was last updated in January

4 FULTIUM-D IU CAPSULES PL 40861/0002 SCIENTIFIC DISCUSSION TABLE OF CONTENTS Introduction Page 5 Pharmaceutical assessment Page 7 Non-clinical assessment Page 9 Clinical assessment Page 9 Overall conclusions and risk benefit assessment Page 40 4

5 INTRODUCTION The UK granted a Marketing Authorisation for the medicinal product Fultium D 3 800IU Capsules (PL 17871/0151) to Jenson Pharmaceutical Services Limited on 28th October This product is a prescription-only medicine. This is an abridged, bibliographic application, submitted under Article 10a of Directive 2001/83/EC, as amended. Fultium D 3 800IU Capsules are used to treat and prevent vitamin D deficiency, as well as vitamin D insufficiency in adolescents, adults and in the elderly. Fultium D 3 800IU Capsules are also used as an adjunct to specific therapy for osteoporosis. Vitamin D is produced naturally when our skin is exposed to ultraviolet B (UVB) radiation from the sun. UVB converts 7-dehydrocholesterol precursors into previtamin D3, which spontaneously changes to vitamin D3. Vitamin D3 is converted via two hydroxylation reactions into 25-hydroxyvitamin D3 (25(OH)D) and its final active form, 1,25-dihydroxyvitamin D3 (1,25(OH)D). The level of 25(OH)D in the blood is the most reliable indicator of vitamin D status. Sun exposure is the most important source of vitamin D. Vitamin D deficiency, with levels of 25(OH)D below 25nmol/L (10ng/ml), could result in the disease rickets (or osteomalacia). The disease resulting as a deficiency is considered to be due to malabsorption of calcium and phosphorus. Vitamin D together with parathyroid hormone (PTH) is a major regulator of plasma calcium concentration. As the efficiency of calcium absorption decreases, PTH secretion increases. PTH stimulates synthesis of calcitriol to improve calcium absorption efficiency but as this tends to be insufficient, it leads to further increases in PTH concentration. Increased PTH lowers the renal threshold for phosphorus which together with the reduced absorption produces hypophosphatemia. Hypophosphotaemia impairs osteoblast and chondroblast cell function and leads to disordered metaphyseal growth plates and the characteristic histological features of rickets and osteomalacia. Vitamin D deficiency in children results in rickets, the signs of rickets include the late closure of the fontanelles, unossified areas in the skull, beading of the ribs (pigeon chest), bowed femurs and separated knees. In adults, vitamin D deficiency results in osteomalacia, a disease characterised by generalised accumulation of undermineralised bone matrix. Severe osteomalacia may be associated with extreme bone pain and tenderness. Muscle weakness, particularly of large proximal muscles, is typical. Gross deformity of bone occurs only in advanced stages of the disease. Circulating 25-OHD concentrations below 8ng/ml are highly predictive of osteomalacia. The necessary intake of vitamin D will depend on the shortfall of exposure to effective UV radiation. Most countries have their own recommendations for vitamin D intake, recognising that there may be insufficient sun exposure in larger or smaller groups of the population. Term infants are born with a store of vitamin D reflecting the mother s vitamin D status. These stores provide the infant with sufficient vitamin D for 4-6 weeks. The vitamin D content of mothers milk from women living in industrialised societies is not considered sufficient to maintain adequate vitamin D status in the child. Thus, many countries recommend 10 μg vitamin D/day to infants from 4 weeks onwards. The same amount is recommended for pregnant and lactating women. The current allowance of vitamin D recommended by most European countries is 5 μg/day (200 IU) for adults and 10 μg vitamin D per day for everyone older than years. The separate European countries often have more detailed recommendations than the general ones mentioned here, and the recommended values vary somewhat. 5

6 No new non-clinical or clinical efficacy studies were necessary for this application, which is acceptable given that this was a bibliographic application for a product containing an active of well-established use. Bioequivalence studies are not necessary to support this bibliographic application. The therapeutic use and safety profile of colecalciferol as a treatment for vitamin D deficiency and as an adjunctive treatment in osteoporosis is well-established. The applicant has presented adequate clinical safety and efficacy data from published papers in support of this application, it should be noted that the non-clinical and clinical data submitted are a summary of those papers. The MHRA has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place for this product type at all sites responsible for the manufacture and assembly of these products. Evidence of compliance with GMP has been provided for the named manufacturing and assembly sites. The MHRA considers that the pharmacovigilance system as described by the Marketing Authorisation Holder (MAH) fulfils the requirements and provides adequate evidence that the MAH has the services of a Qualified person (QP) 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. The MAH has provided adequate justification for not providing a Risk Management Plan (RMP). Vitamin D 3 is a well-established active that is widely used in other licensed pharmaceutical products and is also available in a higher strength as a nutritional supplement. There are no on-going safety concerns relating to vitamin D 3. No new or unexpected safety concerns arose during review of information provided by the Marketing Authorisation Holder and it was, therefore, judged that the benefits of taking Fultium D 3 800IU Capsules (PL 17871/0151) outweigh the risks; hence a Marketing Authorisation was granted. Subsequent to a Change of Ownership procedure, the Marketing Authorisation (Fultium-D IU Capsules; PL 40861/0002) was granted in the UK to Internis Pharmaceuticals Limited on 24 September

7 PHARMACEUTICAL ASSESSMENT DRUG SUBSTANCE INN/ BAN: Colecalciferol Chemical name: (5Z, 7E)-9,10-secocholesta-5,7,10(19)-trien-3β-ol Structure: Chemical name: C 27 H 44 O Molecular weight: General Properties: clear, yellow liquid, practically insoluble in water, slightly soluble in anhydrous ethanol, miscible with solvents of fats. The active substance, colecalciferol, is the subject of a European Pharmacopoeia (Ph Eur) monograph. Manufacture All aspects of the manufacture and control of the active substance colecalciferol are covered by a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability. DRUG PRODUCT Description and Composition The drug product is presented as a soft, blue, transluscent capsule; each capsule contains 800 IU colecalciferol (equivalent to 20 micrograms of vitamin D 3 ). Other ingredients Other ingredients consist of pharmaceutical excipients, arachis oil (peanut oil), butylhydroxytoluene (BHT) make up the capsule content; glycerol (E422), purified water, brilliant blue W.S (E133) and gelatin make up the capsule shell. All ingredients within the capsule and the capsule shell comply with their relevant Ph. Eur monographs; with the exception of Brilliant Blue W.S (E133) which shows compliance to its US monograph. Appropriate justification for the inclusion of each excipient has been provided. Satisfactory Certificates of Analysis have been provided for all the excipients. With the exception of gelatin none of the excipients used contain material derived from animal or human origin. The applicant has provided Certificates of Suitability from each supplier confirming that the gelatin is sourced from healthy animals. Furthermore, no genetically modified organisms are used in the manufacture of any of the excipients. 7

8 Pharmaceutical Development Given that colecalciferol has the potential to degrade, development focus was targeted at validating a robust, accurate process that would minimise any potential for degradation. The objective of the pharmaceutical development programme was to produce a stable drug product with long term stability and therefore ensure the quality of the drug product throughout shelf life. The applicant states that a dissolution test for colecalciferol is not physicochemically possible due to the non aqueous, fatty oil matrix in which the drug substance is dissolved. Although the drug substance itself is insoluble in water, confirmation has been provided that the dosage form complies with the specification of the Ph.Eur disintegration test. The applicant has provided sufficient evidence of the maximum time required for the capsule to disintegrate over a range of ph conditions as well as in water. Manufacture A description and flow-chart of the manufacturing method has been provided. In-process controls are appropriate considering the nature of the product and the method of manufacture. Process validation studies have been conducted and are accepted. The validation data demonstrated consistency of the manufacturing process. Finished Product Specification Finished product specifications are provided for both release and shelf-life, and are satisfactory; they provide an assurance of the quality and consistency of the finished product. Acceptance limits have been justified with respect to conventional pharmaceutical requirements and, where appropriate, safety. Test methods have been described and adequately validated, as appropriate. Satisfactory batch analysis data are provided and accepted. The data demonstrate that the batches are compliant with the proposed specifications. Certificates of Analysis have been provided for any reference standards used. Container Closure System The finished product is licensed for marketing in blister strips composed of white polyvinylchloride (PVC), polyvinylidene chloride (PVdC) and aluminium foil and placed with the Patient Information Leaflet (PIL) into cardboard outer cartons in pack sizes of 28, and 60 capsules. The Applicant states that not all pack sizes may be marketed and in-line with the medicines legislation have committed to provide full colour mock-up for each presentation prior to marketing. Satisfactory specifications and Certificates of Analysis for all packaging components used have been provided. All primary product packaging complies with EU legislation, Directive 2002/72/EC (as amended), and is suitable for contact with foodstuffs. Stability Finished product stability studies have been conducted in accordance with current guidelines and results were within the proposed specification limits. Based on the results, a shelf-life of 24 months has been approved, with the following storage instructions, Store blister foil in original container in order to protect from light. Expert Report A satisfactory quality overview is provided, and has been prepared by an appropriately qualified expert. The CV of the expert has been supplied. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL), Labels The SmPC, PIL and labelling are pharmaceutically acceptable. Colour mock-ups of the labelling and PIL have been provided. The labelling is satisfactory and fulfils the statutory requirements for Braille. 8

9 The applicant has submitted results of PIL user testing. The results indicate that the PIL is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that it contains. MAA Form The MAA form is pharmaceutically satisfactory. Conclusion There are no objections to approval of Fultium D 3 800IU Capsules from a pharmaceutical point of view. NON-CLINICAL ASSESSMENT This is an abridged, bibliographic application for Fultium D 3 800IU Capsules, submitted under Article 10a of Directive 2001/83/EC, as amended. Specific non-clinical studies have not been performed, which is acceptable considering that this was a bibliographic application for a product containing an active ingredient of well-established use. A non-clinical overview report has been written by a suitably qualified person and is satisfactory. The CV of the non-clinical expert has been supplied. The marketing authorisation holder has provided adequate justification for not submitting an Environment Risk Assessment (ERA). Vitamins are exempted from the requirement for an ERA. There are no environmental concerns associated with the method of manufacture or formulation of the product. There are no objections to approval of Fultium D 3 800IU Capsules from a non-clinical point of view. CLINICAL ASSESSMENT 1. CLINICAL PHARMACOLOGY 1.1 Pharmacokinetics Absorption Vitamin D is absorbed through the small intestine in association with lipids and with the aid of bile salts; it is then taken up in the lymph. Vitamin D in the plasma is bound to a protein synthesised in the liver, vitamin-d binding protein, for transport to the liver. A proportion of all vitamin D reaching the liver is 25-hydroxylated and released into the circulation, so circulating levels of 25(OH)D are proportional to the liver stores. In the plasma 25(OH)D circulates bound to another vitamin-d binding protein, alpha-2 globulin. Vitamin D absorption is not affected by the vitamin D status. Vitamin D absorption is impaired in patients with intestinal fat malabsorption syndromes, but there is little evidence of a general decline in fat absorption in healthy aging. Obesity is associated with vitamin D insufficiency and secondary hyperparathyroidism, which, according to a human study is likely due to the decreased bioavailability of vitamin D 3 from cutaneous and dietary sources because of its deposition in body fat compartments Distribution Vitamin D and its hydroxylated metabolites 25(OH)D, 24,25(OH)2D, and 1,25(OH)2D are lipophilic molecules. Because of their low solubility in the aqueous media of plasma, vitamin D compounds are 9

10 transported in the circulation bound to plasma proteins. The most important of these carrier proteins is the vitamin D-binding protein (DBP). DBP is synthesized in the liver and circulates in plasma at concentrations 20 times higher than the total amount of vitamin D metabolites. Since DBP has a single sterol binding site, only 5% of the total DBP of normal human plasma is occupied with vitamin D compounds. Therefore, under normal physiological conditions, nearly all circulating vitamin D compounds are protein bound, which has a great influence on vitamin D pharmacokinetics. DBP-bound vitamin D metabolites have limited access to target cells and are, therefore, less susceptible to hepatic metabolism and subsequent biliary excretion, which prolongs their half-life in circulation. Albumin and lipoproteins are also important plasma carrier proteins with lower affinities for vitamin D metabolites than DBP. Vitamin D administered parenterally binds to both lipoproteins and DBP. However, lipoproteins are more efficient than DBP to deliver the vitamin D 3 synthesized in the skin to the hepatocyte for 25-hydroxylation, whereas lymph chylomicrons mediate the intestinal absorption and hepatic uptake of the vitamin D ingested in the diet Elimination Metabolism The liver and kidney are the main sites for the metabolic activation of vitamin D 3. Vitamin D 3 is first hydroxylated at the 25-carbon atom by a vitamin D 3-25-hydroxylase enzyme. This reaction requires reduced nicotinamide adenine dinucleotide phosphate (NADPH) and molecular oxygen. In mammals the liver is the predominant site. The product of this hydroxylation, 25(OH)D, also known as calcidiol, is the principle circulating metabolite. Following the initial hydroxylation, 25(OH)D is carried from the liver, in plasma bound to an alpha2- globulin and is transported to the kidney, where it undergoes a second hydroxylation before it becomes functional. The second hydroxylation is catalysed by 25(OH)D 3-1- hydroxylase (1OH-ase) and produces 1,25(OH) 2 D 3 (calcitriol). This renal enzyme is found in the mitochondria of the proximal convoluted tubules and is rate limiting. It is this dihydroxy metabolite of vitamin D 3 that is believed to stimulate intestinal calcium transport, intestinal phosphate transport, bone calcium mobilisation and other functions attributed to vitamin D). It prevents rickets, and is at least five times as biologically active as vitamin D 3 or 25(OH)D. It functions at least three times faster than its precursors, in promoting calcium absorption. The rate of conversion to 1,25(OH) 2 D 3 by the kidney is PTH dependent. PTH is secreted in response to low plasma calcium levels. In recent years, many reports have demonstrated that the kidney is not unique in its ability to convert 25(OH)D to 1,25(OH)2D. Numerous cells and tissues express 1-alpha-hydroxylase in vitro; however, in humans, these extrarenal sources of 1,25(OH)2D only contribute significantly to circulating 1,25(OH)2D levels during pregnancy, in chronic renal failure, and in pathological conditions such as sarcoidosis, tuberculosis, granulomatous disorders, and rheumatoid arthritis. Evidence from animal and in vitro studies suggest that human decidua and human and rodent placental tissue have the capacity to metabolise 25(OH)D 3 to 1,25(OH)2D 3. 1-Alphahydroxylation of 25(OH)D 3 has been demonstrated in vitro cell culture systems including neonatal keratinocytes, chick embryonic calvaria, human bone cells, human osteosarcoma cells and macrophages. Kidney mitochondria contain another enzyme, 25(OH)D 3-24-hydroxylase (24OH-ase) which hydroxylates 25(OH)D 3 to form 24,25(OH)2D 3. This metabolite is of limited activity and its biological function is uncertain. It has been suggested that the 24-hydroxylation is the initial step in the degradation process. However, the final degradation product of vitamin D is calcitroic acid, which is excreted in the urine. It appears that there is no direct regulation of 25-hydroxylase activity and that the formation of the hepatic derivative is determined by the vitamin D supply. In contrast, formation of 1,25(OH)2D 3 is under homeostatic control, regulated by the supply of calcium and the prevailing 1,25(OH)2D 3 10

11 concentrations. This is why 1,25(OH)2D 3 has come to be considered as a steroid hormone rather than a vitamin. Excretion Because of their high lipid solubility, colecalciferol and its metabolites are eliminated slowly from the body. Colecalciferol has a plasma half-life of 19 to 25 hours and a terminal half-life of weeks to months. Calcifediol has an experimental elimination half-life of 19 days. Metabolites are eliminated primarily (96%) through the bile and faeces Dose proportionality and time dependency The dose of colecalciferol administered is based on the requirements of the individual patient. No further discussion on this is provided by the applicant and this is satisfactory Intra- and inter-individual variability Not applicable Pharmacokinetics in target population Pharmacokinetics in the target population is unlikely to be different to that in the general population, so no further discussion is required Special populations Impaired renal function Both forms of vitamin D are inactive and must undergo conversion in the liver and kidneys to form biologically active compounds. Ergocalciferol and colecalciferol are hydroxylated by hepatic microsomal enzymes to 25(OH)D, also referred to as calcifediol. Further conversion of this intermediate form in the kidneys produces the physiologically active form, 1,25-dihydroxyvitamin D, or calcitriol. Vitamin D products are primarily eliminated through excretion in the bile. The mean elimination halflife of 1,25-dihydroxyvitamin D is 5 to 8 hours in adults. It is, therefore, likely that in patients with impaired hepatic function a higher dosage of Fultium would be required to maintain plasma vitamin D levels. These patients are therefore at risk of a lack of efficacy from the treatment rather than a safety concern. However, as the SmPC recommends that the product is given under medical supervision and that the legal status of this product is POM, this risk is mitigated. Impaired hepatic function Both forms of vitamin D are inactive and must undergo conversion in the liver and kidneys to form biologically active compounds. Ergocalciferol and colecalciferol are hydroxylated by hepatic microsomal enzymes to 25(OH)D, also referred to as calcifediol. Further conversion of this intermediate form in the kidneys produces the physiologically active form, 1,25-dihydroxyvitamin D, or calcitriol. Vitamin D products are primarily eliminated through excretion in the bile. The mean elimination halflife of 1,25-dihydroxyvitamin D is 5 to 8 hours in adults. It is, therefore, likely that in patients with impaired hepatic function a higher dosage of Fultium would be required to maintain plasma vitamin D levels. These patients are, therefore, at risk of a lack of efficacy from the treatment rather than a safety concern. However, as the SmPC recommends that the product is given under medical supervision and it is now proposed that the legal status of this product is POM, this risk is mitigated. Elderly In a submitted study, an age-related decline in the absorption, transport or liver hydroxylation of orally consumed vitamin D2 was observed. A comparison was made between a group of nine young men (aged 22 to 28 years) and a group of nine older men (aged 65 to 73 years), both groups had self-reported 11

12 vitamin D intakes of less than 200 IU per day. The subjects were randomised to either a treatment group (received 1800 IU per day of ergocalciferol, Vitamin D 2 ) or to a control group. A significant interaction between the age of the subject and the supplement group was noted after three weeks. Another study showed that there was no age-related impairment among men in the absorption or metabolism of 20 μg/day vitamin D 3 taken orally for at least eight weeks. Twenty-five healthy young men (age 18 35) and 25 healthy older men (62-79) were randomly assigned to supplementation with either 20 μg/day (800 IU) of vitamin D 3 or to no intervention and followed for eight weeks. By the end of the eight-week adaptation period, plasma vitamin D 3 of young and old men had increased by 4.3 and 6.2 nmol/l respectively. In the supplemented group, mean 25(OH)D concentrations of both the young and old men increased during the study, and the magnitude of the change after eight weeks was nearly identical in the two age groups (22.5 and 22.1 nmol/l in the young and the old men, respectively). In the control group there was a modest decrease in 25(OH)D of both the young and old men. This finding contrasts with those of the previous study. The vitamin D dose given in the later study was much lower than that given in the earlier study and it may be that a true age-related difference in vitamin D absorption or metabolism becomes apparent only at a moderately high dose. However, there is no obvious physiological reason that this should be the case. Another possible explanation for the different findings is that there is an age difference in the metabolism of vitamin D 2, a synthetic or plant-derived compound not normally present in human circulation, but not vitamin D 3, a physiologic compound in humans. There is evidence in both rats and humans that vitamin D 3 supplementation results in a greater increase in 25(OH)D than does a comparable dose of vitamin D 2, perhaps because of differing rates of enzymatic 25-hydroxylation in the mitochondrial fraction or because some vitamin D 2 but no vitamin D 3 is metabolized to 24(OH)D instead of 25(OH)D. Though speculative, it is possible that the relative importance of these mechanisms changes with age. The results of this study are consistent with the preservation of intestinal fat absorption in aging. Vitamin D absorption is impaired in patients with intestinal fat malabsorption syndromes, but there is little evidence of a general decline in fat absorption in healthy aging. No special warning or precautions have been provided for use in the elderly. Based on the evidence provided, this is not required in this population. Adolescents An adequate vitamin D status is essential during both childhood and adolescence, for its important role in cell growth, skeletal structure and development. Vitamin D deficiency is mostly seen during periods in which rapid growth and physiological alterations occur. Vitamin D deficiency in adolescents is gradually increasing as a result of modern life styles. The HELENA study (Healthy Lifestyle in Europe by Nutrition in Adolescence) examined the vitamin D status in 1006 adolescents in nine European countries and showed that 15% of adolescents had a severe vitamin D deficiency (< 27.5 nmol/l), 27.4% of adolescents were deficient (between nmol/l), 38.8% were insufficient (between nmol/l) and 18.9% had sufficient vitamin D (> 75 nmol/l) (Gonzalez-Gross et al, 2011). Another study has been undertaken to evaluate the prevalence and predictors of vitamin D insufficiency in children in Great Britain. The study confirmed an under-recognised risk of vitamin D insufficiency in adolescents. Plasma vitamin D levels were shown to decrease progressively with age in both sexes, with adolescents (aged years) having an odds ratio more than three times that of younger children (4-8 years) of having vitamin D insufficiency. Non-white children had 37 times the odds ratio compared with white children of being vitamin D insufficient. In the United Kingdom the current posology of licensed products containing colecalciferol indicates that for adolescents the maximum dose of colecalciferol is 800 IU (Sandocal D 1200, Novartis) and for children 400 IU. It should also be noted that the recent EU approval for Detremin recommends that colecalciferol 667 IU be given as a maintenance dose to children over the age of one who are vitamin D deficient. The maximum dose allowed in children under 1 year being 3340 IU colecalciferol and above 12

13 1 year being 6000 IU. The Endocrine Practice Guidelines Committee published a report in 2011 and recommended that in children at risk for vitamin D deficiency the daily requirement was 600 to 1000 IU colecalciferol. The upper limit for tolerability in these cases being 4000 IU colecalciferol. The 2011 report from the Food and Nutrition Board of the Institute of Medicine in the USA selected a Recommended Dietary Allowance of 600 IU vitamin D for adolescents (aged 9-18 years) and a tolerable upper intake level of 4000 IU daily. However, it was noted that consideration may need to be given for a higher recommended dietary allowance for vitamin D in this population. The Health Council of the Netherlands has also produced an advisory report on intake of vitamin D. Their recommendation was that spending fifteen minutes a day outdoors in combination with a healthy diet generates sufficient vitamin D in children and adults with a light skin. All other groups need additional vitamin D from supplements (10 20 μg/day; IU per day). In view of the data, the applicant proposes to keep adolescents as a target treatment group for Fultium. It is noted that for children other dosage forms are available which are more suited. However, in adolescents there is a clinical need for vitamin D supplementation and the studies demonstrate that daily treatment in the range IU is tolerable and will correct vitamin D insufficiency in the majority of adolescents. However, more vitamin D may be required in cases of vitamin D deficiency or where there are other risk factors and the decision on the dosage should be at the discretion of the medical practitioner. The information relating to adolescents in the SmPC for Fultium is satisfactory Interactions Simultaneous treatment with ion exchange resins such as cholestyramine or laxatives such as paraffin oil may reduce the gastrointestinal absorption of vitamin D (CMPM 2003). The cytotoxic agent actinomycin and imidazole antifungal agents interfere with vitamin D activity by inhibiting the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D by the kidney enzyme, 25- hydroxyvitamin D-1-hydroxylase. Glucocorticoids, phenobarbital and phenytoin antagonise the effect of vitamin D on intestinal calcium absorption. These drugs also protect rats against high doses of vitamin D. The applicant has adequately discussed the drug interactions, including the most common reactions with ion exchange resins, laxatives, cytotoxic agents, anti-fungals and some other inhibitors of absorption Exposure relevant for safety evaluation Not applicable Overall conclusions on pharmacokinetics The information on pharmacokinetics has been adequately addressed and described in the SmPC. 1.2 Pharmacodynamics Primary pharmacology Vitamin D receptor (VDR) is a high-affinity receptor for 1,25-dihydroxyvitamin D [1,25(OH) 2 D]. This 50- to 70-kDa protein facilitated association with nuclear chromatin, displayed saturable binding of 1,25(OH) 2 D 3, and had a specificity for other vitamin D metabolites that precisely matched their in vivo biopotency. The VDR was found originally in the classic vitamin D target organs involved in mineral homeostasis: the intestine, bone, kidney, and the parathyroid glands. More recently, the VDR has been detected in many other tissues and cells types as well. These non-classic vitamin D target organs respond to 1,25(OH) 2 D 3 with a diverse range of biological actions including immunomodulation, the control of other hormonal systems, inhibition of cell growth, and induction of cell differentiation (Brown et al,1999, DeLuca, 2004). The cellular response to 1,25(OH)D is mainly regulated by changing the cellular amount of VDR. Treatment with 1,25(OH)D increases the receptor level presumably due to stabilisation of the receptor. 13

14 The most critical role of 1,25(OH) 2 D 3 in mineral homeostasis is to enhance the efficiency of the small intestine to absorb dietary calcium and phosphate as demonstrated conclusively in the VDR null mice. In the absence of VDR, normalization of circulating levels of calcium and phosphorus through dietary supplementation corrected most of the phenotypic features of vitamin D resistance including parathyroid gland growth, bone mineralization, and growth plate histology. These findings concur with prior clinical observations in patients with vitamin D-resistant rickets, whose bone abnormalities were resolved by calcium infusions. 1,25(OH) 2 D 3 increases the entry of calcium through the plasma membrane into the enterocyte, the movement of calcium through the cytoplasm, and the transfer of calcium across the basolateral membrane into the circulation. 1,25(OH) 2 D 3 is the only hormone known to stimulate intestinal calcium transport directly. Other vitamin D metabolites can stimulate calcium transport, but only at higher doses, consistent with their lower affinity for the VDR. The mechanism for stimulation of transcellular calcium transport is not entirely clear, but induction of a cytosolic calcium-binding protein (calbindin D) and the basolateral calcium pump undoubtedly are important components. The VDR-mediated effects of 1,25(OH) 2 D 3 may not be the only mode of action by which the hormone stimulates calcium absorption by the enterocyte. Rapid effects of 1,25(OH) 2 D 3 appear to mediate an increase in both the vesicular and paracellular pathways for intestinal calcium absorption. In addition to its effects on calcium absorption, 1,25(OH) 2 D 3 increases active phosphate transport. However, significant phosphate absorption also occurs in 1,25(OH) 2 D 3 -deficient states. The sterol directly stimulates the expression of the Na-Pi cotransporter and affects the composition of the enterocyte plasma membrane, increasing fluidity and phosphate uptake. Sodium independent entry of phosphate occurs independently of vitamin D status. Vitamin D induces bone mineralization by increasing serum levels of calcium and phosphate. The higher potency of 1,25(OH) 2 D 3 in regulating mineral homeostasis makes it the most likely vitamin D metabolite involved in bone mineralization. 1,25(OH) 2 D 3 also maintains normal serum calcium and phosphate by inducing bone resorption through enhancement of osteoclastogenesis and osteoclastic activity. Osteoblasts and osteoblast-derived substances are required for 1,25(OH) 2 D 3 induction of osteoclastic bone resorption. PTH (parathyroid hormone) and 1,25(OH) 2 D 3 directly affect calcium homeostasis, and each exerts important regulatory effects on the other. Whereas PTH is the principal hormone involved in the minuteto-minute regulation of ionized calcium levels in the extracellular fluid, 1,25(OH) 2 D 3 plays a key role in the day-to-day maintenance of calcium balance. PTH stimulates the production of 1,25(OH) 2 D 3 by activating the renal 1-alphahydroxylase, and 1,25(OH) 2 D 3 in turn suppresses the synthesis and secretion of PTH and controls parathyroid cell growth. Vitamin D deficiency, therefore, causes parathyroid hyperplasia and secondary hyperparathyroidism. 1,25(OH) 2 D 3 suppression of PTH synthesis occurs through negative regulation of the rate of PTH gene transcription by the 1,25(OH) 2 D 3 VDR/RXR complex. The most important effects of 1,25(OH) 2 D 3 in the kidney are the suppression of 1-alphahydroxylase activity and the stimulation of 24-hydroxylase activity. Both effects of the sterol are VDR mediated. The role of vitamin D in the renal handling of calcium and phosphate is controversial due to the simultaneous effects of the sterol on intestinal calcium and phosphate, which affects renal filtered load, and on serum PTH levels. 1,25(OH) 2 D 3 increases renal calcium reabsorption. 1,25(OH) 2 D 3 enhances calcium reabsorption and calbindin expression, and it accelerates PTH-dependent calcium transport in the distal tubule, the site with the highest VDR content and where active calcium transport is known to occur. The effect of 1,25(OH) 2 D 3 enhancing renal absorption of phosphate only in the presence of PTH suggests that this may not be a direct action of the sterol on the kidney but rather the result of 1,25(OH) 2 D 3 suppression of PTH. 14

15 1.2.2 Secondary pharmacology Effects of vitamin D extend beyond calcium homeostasis. Receptors for calcitriol are distributed widely through the body. Vitamin D may improve muscle strength through a highly specific nuclear receptor in muscle tissue. In a study it was investigated whether there is an association between 25(OH)D concentrations and lower extremity function in ambulatory older persons, whether that association differs by activity level, and, if so, whether there is an identifiable threshold in the association. The study was a population-based survey of the ambulatory US population aged 60 to 90 years (n = 4100). Lower-extremity function according to serum 25(OH)D concentrations was assessed by linear regression analyses and regression plots after control for activity level (inactive or active) and several other potential confounders. Separate analyses were performed for the timed 8-foot (ie, 2.4 m) walk test and a repeated sit-to-stand test. The 8-foot walk test compared subjects in the lowest and highest quintiles of 25(OH)D; the latter group had an average decrease of 0.27 s [95% CI: , s (or 5.6%); P for trend < 0.001]. The sit-to-stand test compared subjects in the lowest and highest quintiles of 25(OH)D; the latter group had an average decrease of 0.67 s [95% CI: , s (or 3.9%); p for trend = 0.017]. In the 25(OH)D reference range of nmol/l, most of the improvement occurred in subjects with 25(OH)D concentrations between 22.5 and about 40 nmol/l, and further improvement was seen in the range of nmol/l. Stratification by activity level showed no significant effect modification. In both active and inactive ambulatory persons aged 60 years, 25(OH)D concentrations between 40 and 94 nmol/l are associated with better musculoskeletal function in the lower extremities than are concentrations < 40 nmol/l. A community based study found that vitamin D given once every four months decreased the overall risk of fracture by 39%, and in another study 800 IU of vitamin D 15

16 given to elderly people (mean age 85) over a 12 week period increased muscle strength and decreased the number of falls by almost a half. The prevalence of multiple sclerosis is highest where environmental supplies of vitamin D are lowest. It is well recognized that the active hormonal form of vitamin D, 1,25(OH) 2 D, is a natural immunoregulator. The mechanism by which vitamin D nutrition is thought to influence multiple sclerosis involves paracrine or autocrine metabolism of 25(OH)D by cells expressing the enzyme 1a- OHase in peripheral tissues involved in immune and neural function. Vitamin D deficiency is caused by insufficient sunlight exposure or low dietary vitamin D 3 intake. Subtle defects in vitamin D metabolism, including genetic polymorphisms related to vitamin D, might possibly be involved as well. Optimal 25(OH)D serum concentrations, throughout the year, may be beneficial for patients with multiple sclerosis, both to obtain immune-mediated suppression of disease activity, and also to decrease disease related complications, including increased bone resorption, fractures, and muscle weakness. According to a population-based survey, in older age (above 50 years) low serum 25(OH) 2 D 3 concentrations may be associated with periodontal disease independently of bone mineral density. A study has been undertaken in healthy men and women, aged years, to examine the influence of calcium and vitamin D intake on serum parathyroid hormone and bone turnover markers. Patients were randomly allocated to four groups: 1) double placebo, 2) calcium (1200 mg daily) plus placebo, 3) vitamin D 3 (100 μg) plus placebo, and 4) vitamin D 3 and calcium. Fasting serum and urine as well as serum and urine 2 hours after a calcium load (600 mg of calcium carbonate) were obtained at baseline and 3 months. Ninety-nine participants were randomized; 78 completed the study. Baseline demographics, protein intake and laboratory studies did not differ among the four groups. Study medication compliance was 90%. Fasting bone turnover markers declined after 3 months only in the two groups given calcium supplements and increased in the vitamin D 3 plus placebo calcium group. The calcium load resulted in a decrease in PTH and in bone turnover markers that did not differ among groups. Urinary calcium excretion increased in the combined group. Mean serum 25-hydroxyvitamin D increased from a baseline of 67 (18 SD) nmol/litre to 111 (30 SD) nmol/litre after vitamin D supplementation. It was concluded that increased habitual calcium intake lowered markers of bone turnover. Acute ingestion of a calcium load lowered PTH and bone turnover markers. Additional intake of 100 μg/d vitamin D 3 did not lower PTH or markers of bone turnover. Known pharmacodynamic effects of colecalciferol have been reflected in the product information and are satisfactory Relationship between plasma concentration and effect See pharmacokinetics/pharmacodynamics section on control of vitamin D Pharmacodynamic interactions with other medicinal products or substances The applicant has discussed pharmacodynamic interactions in the SmPC and this is satisfactory Genetic differences in pharmacodynamic response The relationship between vitamin D receptor gene polymorphisms and bone density, osteocalcin and growth has been investigated (Ozaydin et al, 2010). No significant relationship was found between VDR genotypes and areal bone mineral density, osteocalcin level or growth in either sex. But there was a strong tendency for a higher bone mineral density at the lumbar spine of TT and AA genotypes compared to tt and Aa genotypes. The children with TT genotype were taller and heavier than the children with tt genotype. This study would suggest that the VDR gene TaqI polymorphism may be associated with body weight and bone mass. 16

17 A review of the literature has not provided any other evidence to suggest there are any genetic differences in pharmacodynamic response Assessor s overall conclusions on pharmacodynamics Pharmacodynamics has been adequately addressed. 2. CLINICAL EFFICACY 2.1 Dose-Response and Main Clinical Studies Vitamin D 3 (colecalciferol) is currently available in the UK as a nutritional supplement at high doses. Products available include Vitamin D IU and 5000 IU microtablets, Solgar Vitamin D IU Soft Gelatin Capsules and products containing 1000 IU vitamin D 3 are available in the UK High Street shops. Whilst no medicinal claims can be made for such products they are used to maintain healthy vitamin D levels. The safety and efficacy of vitamin D 3 has been well established in the EU being available without medical prescription for many years. However, medical supervision of patients receiving the proposed doses of vitamin D 3 (up to 1600 IU) is required to prevent hypercalcaemia. On the basis of this, the legal status of the product will be Prescription Only Medicine (POM), which will ensure that the patient receives medical supervision as part of a tailored individualised medical care programme whilst taking this product. A recent review in the British Medical Journal outlines the requirements for treatment of vitamin D deficiency within the UK. The British National Formulary (2011) also contains information on the treatment of vitamin D deficiency noting that colecalciferol in a dose of 800 IU may be given to treat vitamin D deficiency whilst higher doses may be necessary for severe deficiency. It should be noted that colecalciferol is included in the General Sales List as an active which can be included in licensed medicinal products. In line with the General Sales List (GSL), a product with a maximum daily dosage of 400 IU colecalciferol can be available without medical prescription and be purchased without the presence of the pharmacist. Fultium contains 800 IU and would, therefore, be outside of the scope of the GSL. The NHS in the UK has produced guidance on the treatment of vitamin D deficiency in the UK (East Lancashire Health Economy Guideline, the St George s Hospital Guidelines, the Imperial Centre for Endocrinology guidelines and the 2010 paper from the NHS East and South East of England Pharmacy Services). These well-established and peer-reviewed guidelines state that more than 50% of the adult population of England has vitamin D deficiency and advocates use of supplements to treat this deficiency. Within the UK, a number of products containing calcium and colecalciferol have been authorised. The combination product of calcium and vitamin D is widely used in both adults up to a maximum dose of 800 IU, which is equivalent to one Fultium capsule. The current range of UK-licensed products containing colecalciferol all contain calcium, there is no licensed product available to treat vitamin D deficiency which does not include calcium. The use of 800 IU colecalciferol is well-established in adults and the elderly, and Fultium is for use in those patients who have adequate calcium intake and, therefore, are only suffering from vitamin D deficiency. A recent meta-analysis identified 18 independent randomized controlled trials (15 of which were based in the EU) and included 57,311 participants. A total of 4777 deaths from any cause occurred during a trial size adjusted mean of 5.7 years. Daily doses of vitamin D supplements varied from 300 to 2000 IU. The trial size adjusted mean daily vitamin D dose was 528 IU. In nine trials, there was a 1.4- to 5.2-fold difference in serum 25-hydroxyvitamin D (25(OH)D) between the intervention and control groups. The summary relative risk for mortality from any cause was 0.93 (95%confidence interval, ). There 17

18 was neither indication for heterogeneity nor indication for publication biases. The summary relative risk did not change according to the addition of calcium supplements in the intervention. Intake of ordinary doses of vitamin D supplements seems to be associated with decreases in total mortality rates. In a study in the Netherlands undertaken over 3.5 years, 400 IU colecalciferol daily was administered to 2578 community patients. Despite the results not showing that vitamin D supplementation decreased the incidence of hip fractures, there was a positive effect on bone mineral density of the femoral neck in a sample of the study. The authors concluded that vitamin D supplementation should be considered primarily for frail elderly persons who do not go outside in the sunshine. In the US, a study in ten healthy postmenopausal black women who were given 800 IU vitamin D for three months demonstrated an increase in the levels of 25(OH)D and a decrease in the levels of serum intact PTH. The results of the study suggested that 800 IU vitamin D daily was effective in raising serum 25(OH)D levels. In a study undertaken in Italy sixty women aged 65 or older were given either colecalciferol 300,000 IU once every three months or colecalciferol 1000 IU daily for six months. All patients entering the study had documented vitamin D deficiency. After 3 and 6 months of treatment both groups had a significant increase in 25(OH)D and a reduction in PTH. Mean absolute increase at six months was higher in the group given 300,000 IU colecalciferol intermittently. The percentage decrease of PTH was the same in both groups. The authors concluded that higher doses may be required for adequate vitamin D repletion. Several papers have evaluated the safety of high doses of colecalciferol. One paper evaluates the safety of ergocalciferol (vitamin D 2 ) and colecalciferol, both administered either 1600 IU daily or 50,000 IU monthly in older adults for 1 year. The results showed that overall, colecalciferol was slightly, but significantly, more effective than ergocalciferol in increasing serum 25(OH)D. One year of either ergocalciferol or colecalciferol dosing (1,600 IU daily or 50,000 IU monthly) did not produce toxicity, and 25(OH)D levels of less than 30 ng/ml persisted in approximately 20% of individuals despite good compliance. Substantial between-individual response to administered ergocalciferol and colecalciferol was observed. In another study veterans (aged 70 and over) were given colecalciferol 2000 IU daily for 6 months. The results of this randomised, double-blind, placebo-controlled trial indicated that supplementation with 2000 IU daily for six months was safe and generally corrected vitamin D deficiency in most, but not all, individuals. As well as published papers of clinical trials, as stated above, there are guidelines within the UK which provide information for clinicians on the treatment of vitamin D deficiency. One of these guidelines is the East Lancashire Health Economy Guideline the Guideline on the Diagnosis and Management of Vitamin D Deficiency. These guidelines advocate a higher initial dose in severe deficiency followed by a lower maintenance dose of IU colecalciferol daily. In moderate deficiency (insufficiency) a daily dose of IU is recommended. The Clinical Guidelines from Imperial College also advocate a loading dose in severe deficiency of vitamin D and a long term maintenance therapy. Their recommendations are: Loading dose over 3 months: Prescribe colecalciferol (Dekristol) 20,000 IU capsules, one capsule weekly for 12 weeks, then go on to maintenance dose. Consider giving IM ergocalciferol 300,000 IU two injections spaced by 3 months if there are concerns regarding absorption (e.g. in malabsorption). Maintenance dose: 18

19 Usually between IU colecalciferol per day depending on weight, e.g. Holland and Barrett Vitamin D 3 25 microgram tablets, 1-2 tablets a day, or colecalciferol (Dekristol) 20,000 IU capsules, one capsule every 2 weeks. Higher doses may be required e.g. if the patient is taking drugs that accelerate Vitamin D metabolism or if there are concerns regarding absorption The guideline from St George s Hospital in London which were prepared in 2010 also advocate a loading dose for severe vitamin D deficiency with a maintenance dose once vitamin D levels are corrected. It is also noted that in some patients this maintenance therapy may be lifelong. It can, therefore, be seen that the data and recommendations for monotherapy with vitamin D within the UK (and within the EU) is extensive. The doses used in the published studies range from IU daily, and a recent publication by Giusti suggests that a higher daily dose than 1000 IU may be required. The many clinical guidelines in place within the UK recommend that treatment should, in cases of severe deficiency be initiated with a loading dose and a maintenance dose in long term treatment or with moderate vitamin D deficiency. It should also be noted that the recently licensed product, Detremin, allows a maximum daily dose of 4000 IU colecalciferol for the treatment of vitamin D deficiency. 2.2 Conclusion on Dose-Response Studies The applicant has provided evidence in support of the proposed dose and the indication sought. Most patients likely to be treated with this product present with aches, pains and proximal muscle weakness related to the deficiency and less with fractures related to vitamin D deficiency. Limited data has been provided in support of resolution of symptoms relating to vitamin D deficiency. The evidence provided states that administration for unlimited time should be performed with caution. Time limit has been given for the treatment of severe vitamin D deficiency. The applicant has included additional warnings for medical supervision of patients whilst on treatment. The use of colecalciferol in combination, particularly with calcium, is well-established in the management of patients with osteoporosis. The use of colecalciferol in the prevention and correction of vitamin D deficiency is well-established. Considering all the evidence which is now available, this indication is approvable. The applicant has categorised patients as those with severe and those with moderate deficiency. In most of the evidence provided, patients categorised as having severe vitamin D deficiency are defined as deficient and those considered by the applicant as moderate deficiency are considered to have vitamin D insufficiency; this wording is satisfactory. As part of patient management, an assessment of calcium supplement should be made for individual subjects. Although some subjects are considered to have sufficient dietary calcium intake, additional calcium may still be required in the management of their symptoms. The indication For the prevention and treatment of Vitamin D deficiency with an additional statement in the SmPC that the need for supplemental calcium should be considered for individual patients and this should be under close medical supervision; is satisfactory. Limited data has been provided to support the proposed dose of four capsules (3200 IU) for patients with severe deficiency. However, there is some evidence to suggest that in the short-term treatment of vitamin D deficiency, this dose can be used safely in some patients under medical supervision. Considering that this is the case, the dosage recommendation and duration of treatment proposed by the applicant is satisfactory and is in-line with clinical practice within the UK- and EU-approved products: 19

20 The applicant has demonstrated (with NHS clinical guidelines, published literature and the approval of other colecalciferol products within the EU), that the use of colecalciferol to treat and prevent vitamin D deficiency is well-established. The posology schedule proposed by the applicant is satisfactory. 2.3 Efficacy Studies The applicant has presented studies in the literature supporting the indications sought for in this application. Not all the studies presented have been conducted in the European Community. Vitamin D deficiency - Prevention Prevention of vitamin D deficiency by vitamin D supplementation would appear to be a self-serving solution. However, the core question here is whether oral colecalciferol supplementation is appropriate for prevention. There is a growing consensus that serum 25(OH)D concentrations of at least nmol/l are needed for optimal bone health, on the basis of studies of older white subjects living in Europe and the United States. The studies show that increasing serum 25(OH)D concentrations to this level decreases parathyroid hormone (PTH) concentrations, decreases rates of bone loss, and reduces rates of fractures. Among US blacks, low 25(OH)D concentrations are associated with higher concentrations of PTH, which are associated with lower bone mineral density. Vitamin D supplements decrease PTH and bone turnover marker concentrations among blacks (Dawson-Hughes, 2004). Chapuy et al 1992 This study investigated the effect of calcium and vitamin D supplements in reducing the risk of hip fractures among elderly people. They studied 3270 women between the ages of 69 to 106 years living in 180 nursing homes or apartment houses for elderly people. They were required to be ambulatory and have no serious medical conditions with a life expectancy of at least 18 months. The study looked at women treated with tricalcium phosphate (containing 1.2g of elemental calcium) and 20µg (800 IU) of Vitamin D 3 compared with women who received a double placebo. The end points examined were the numbers of hip fractures and the total number of nonvertebral fractures after treatment with vitamin D 3 and calcium compared with those who received the placebo. It concluded that supplementation with vitamin D 3 and calcium reduces the risk of hip fractures and other non-vertebral fractures among elderly women. Conclusions on this study The patients in the study were not considered to be Vitamin D deficient, but with levels within the range classified as insufficient. However the study looked at the effect of a combination treatment with calcium which has to be taken into consideration when assessing the evidence available on treating patients with colecalciferol alone. Dawson-Hughes et al 1997 (United States) A randomised double-blind, placebo-controlled trial in healthy ambulatory men and women aged 65 years and over; received either placebo or calcium and vitamin D supplement and investigated the effects over 3 years. The end points examined were bone mineral density, biochemical measures of bone metabolism and the incidence of non-vertebral fractures. A difference in bone mineral density and the number of fractures was observed between the two groups. The authors concluded that in this age group living in the community, dietary supplementation with calcium and vitamin D moderately reduced bone loss and incidence of non-vertebral fractures. Conclusion on this study This study represents a group of patients not diagnosed as vitamin D deficient and with their calcium levels within the normal range. It applies to a combination treatment with calcium and therefore of limited value in supporting single treatment with colecalciferol in reduction of bone loss and nonvertebral fractures. 20