(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

21 Trivedi et al 2003 A randomised double-blind controlled trial comparing the effect of treatment of men and women aged 65 years and over living in the community with IU oral vitamin D 3 or matching placebo every four months over 5 years on the rate of fractures in the UK subjects were randomised (2037 men and 649 women). The study was conducted by post and subjects sent their study medication by post every four months for the 5 year study period. Mean calcium intake at 4 years was 742mg/day and was not found to be different by treatment allocation. After 5 years, 268 men and women had incident fractures, of which 147 had fractures in common osteoporotic sites (hip, wrist or forearm, or vertebrae). Relative risks in the vitamin D group compared with the placebo group were 0.78 (95% confidence interval 0.61 to 0.99, P=0.04) for any first fracture and 0.67 (0.48 to 0.93, P=0.02) for first hip, wrist or forearm, or vertebral fracture. 471 participants died. The relative risk for total mortality in the vitamin D group compared with the placebo group was 0.88 (0.74 to 1.06, P=0.18). Findings were consistent in men and women and in doctors and the general practice population. This study looks at single treatment with vitamin D and shows there is a potential benefit in this population of patients. The dose used is however IU every 4 months which is more convenient for subjects than the proposed 800 IU daily in this application. Other studies have suggested that receiving 800IU daily may be more efficacious in increasing 25(OH)D 3 levels than higher doses received infrequently. Although this supports single treatment with vitamin D, the applicant has not discussed how their proposed posology equates to a single treatment with 100,000 IU every 4 months. Lips et al 1996 This was a prospective randomised double-blind trial, to determine whether vitamin D supplementation decreases the incidence of hip fractures and other peripheral bone fractures. This study was conducted in the Netherlands. Subjects were randomised to receive either active treatment with 400 IU vitamin D 3 or placebo. Study participants received study drug daily for 3 to 3.5 years. Compliance was checked by way of a questionnaire and by measurement of the serum 25(OH)D concentration. No important difference in baseline characteristics was found between the two groups subjects were enrolled (1916 women, 662 men). These subjects were 70 years of age and over and living independently, in apartments for elderly persons, or in homes for elderly persons. Dietary calcium intake and 25 (OH)D were estimated in a subset of participants and found to be 868 mg/day. Mean serum 25(OH)D concentration in the third year was 23 nmol/l in the placebo group and 60 nmol/l in the vitamin D group. Hip fractures occurred in 48 people in the placebo group and 58 people in the vitamin D group (p = 0.39 ITT). Other peripheral fractures occurred in 74 people in the placebo group and 77 people in the vitamin D group (p=0.86). The authors concluded that their study did not show a decrease in the incidence of hip fractures and other peripheral fractures in the population studied. There was a significant difference between the two groups in mean serum 25(OH)D after 1 year in residents of apartments and homes for the elderly (270 sampled) and during the third year in a random sample of 96 subjects. The significant information gained from this study is the increase in serum 25(OH)D in subjects receiving vitamin D compared to placebo over the three year study period, hence maintaining levels in these groups. However, the dose used in the study was only 400IU. This appears to be sufficient to prevent vitamin D deficiency in some subjects, although not been shown to reduce the risk of fractures in susceptible population. The applicant states in the that serum 25(OH)D concentrations of at least nmol/l are needed for optimal bone health. In the Trivedi study, the men had a mean serum 25(OH)D which was just within this range at 75.6 nmol/l at the end of the study. The average for all was 74.3 nmol/l. In the study by Chapuy and the study by Dawson-Hughes, subjects achieved 25(OH)D values above this range. This range was however not achieved in the study by Lips using a dose of 400 IU (probably why no difference in fracture rates was seen between the two groups). 21

22 Vitamin D supplementation Black women have lower levels of serum 25-hydroxyvitamin D (25(OH)D) with higher serum PTH levels than white women. Correction of these alterations in the vitamin D-endocrine system could lead to less bone loss in postmenopausal women and, consequently, preservation of bone mass. A study investigating vitamin D supplementation in postmenopausal black women aged years is discussed. They were given 20 μg (800 IU) vitamin D 3 daily for 3 months. The mean daily dietary calcium intake was 400mg/day ( mg/day).it was concluded that Vitamin D 3 supplementation raises serum 25(OH)D levels in postmenopausal black women, decreases secondary hyperparathyroidism, and reduces bone turnover. This was a small exploratory study and apart from showing an increase in these patients in 25 (OH) D levels, it only provides limited information in supporting well-established use of vitamin D 3 for this indication. Adolescents A study was designed to assess the impact of a single loading dose of 200,000 IU of vitamin D3 on the winter vitamin D status of healthy adolescents. Vitamin D status was assessed by 25-OH-D levels before, 3 weeks, and 3 months after this single dose, and safety was assessed by serum calcium and PTH and urinary calcium excretion in random samples from 27, 23, and 17 healthy adolescents derived from the same institution. The 25-OH-D peak value 2 weeks after the vitamin D supplement of nmol/l (mean, 96 nmol/l), and a residual level at 3 months of nmol/l (mean, 57 nmol/l) serum calcium and urinary calcium excretion expressed by the calcium/creatinine ratio were normal and stable at 2 weeks and 3 months, remaining less than 0.5 for the calcium/creatinine ratio. This simple measure, ensuring good compliance during adolescence, ensured optimal winter vitamin D status with no signs of overload. This formulation is different to the one proposed and although it shows sustenance of levels. The use of Vitamin D supplement in adolescents is further discussed under Special Populations. Vitamin D deficiency - Treatment Vitamin D deficiency leads to secondary hyperparathyroidism, increased bone turnover and bone loss, predisposing to osteoporosis and osteoporotic fractures. Overt rickets and osteomalacia are now uncommon in Western populations, but subclinical vitamin D deficiency is widespread amongst older individuals, especially those in nursing homes or who are housebound. It is also common in healthy older individuals living independently. Correction of vitamin D deficiency is associated with rapid improvement in bone density, and may reduce fracture risk. Hence, treating vitamin D deficiency is important in the prevention and treatment of osteoporosis. However, the past few decades have seen a resurgence of vitamin D deficiency rickets in developed countries, particularly in dark skinned infants who are exclusively breast fed for prolonged periods without additional vitamin supplements. Rickets remains a problem in the UK especially in at risk ethnic minority groups. According to a recent UK study symptomatic hypocalcaemia is an important, but under-recognised presenting feature. Growth rate is likely to be an important factor in determining the mode of presentation. Unexplained hypocalcaemia should be attributed to vitamin D deficiency in at risk ethnic minority groups until proved otherwise. It is thought that 1000 IU of vitamin D daily is required to meet vitamin D needs in the absence of any sun exposure. It has been estimated that 90% to 95% of a person s vitamin D requirements comes from 22

23 their casual exposure to sunlight. CHMP approved Calcichew-D 3 (a daily 800 IU Vitamin D 3 ) for use for elderly in case of calcium and vitamin D deficiency. In the literature treatment of vitamin D deficiency is usually straightforward and consists of oral supplementation with vitamin D. An alternative, equally effective, treatment strategy is to use stosstherapy, a single large dose of vitamin D (300,000 to 600,000 IU) as a single dose, given either orally or parenterally. This is particularly useful if there are concerns about compliance with treatment. In a New Zealand study high-dose oral regimen for rapid correction of vitamin D deficiency was performed, which made use of the calciferol IU tablets available in that country. Thirty two women (67 84 years) with serum 25-hydroxyvitamin D concentrations less than 10 μg/l were treated with oral calciferol 50,000 IU daily for 10 days. It was concluded that this regimen provided a simple, safe and effective way of managing vitamin D deficiency. Its short-term nature may result in higher compliance than daily dosing regimens. The applicant s expert states that it is evident that daily 800 IU in vitamin D deficiency, approved by CHMP can be sufficient only in mild, occult vitamin D deficiencies. Kuwabara et al, 2009 (Japan) This was an intervention study to assess an improvement of vitamin D status in Japanese institutionalised elderly by supplementation with 800 IU of vitamin D 3 per day. Sixty-two institutionalised elderly were randomly assigned to two groups; receiving either supplements of 200 mg calcium plus 800 IU vitamin D 3 /day (Ca+VD group), or supplements of 200 mg calcium/day (Ca group) for 30 days. The end points examined were: serum concentrations of 25-hydroxyvitamin D (25(OH)D), parathyroid hormone (PTH), and bone turnover markers were measured before and after intervention. Mean serum 25(OH)D concentration significantly increased to 19.3 ng/ml in the Ca+VD group and to 11.1 ng/ml in the Ca group. Post intervention serum 25OH-D level was significantly higher in the Ca+VD group than in the Ca group (p<0.001).85.5% of subjects who took more than 80% of their supplements for 30 days, serum PTH level in the Ca+VD group was significantly lower than in the Ca groups. Bone turnover markers were not significantly changed after intervention in either group. Daily supplementation of 800 IU vitamin D 3 was considered effective in the institutionalized elderly with minimal chance of sun exposure, but further studies with longer duration are necessary. Comments on the study This study demonstrates that supplement with Vitamin D and calcium increases 25(OH)D levels more significantly than calcium alone if considering just the fact that levels of 25 (OH)D is increased by the addition of Vitamin D, and the combined effect in reducing PTH. However, the dose used might not be sufficient in treating patients with Vitamin D deficiency as the increase to 19.3 ng/ml (<50nmol/l) is still considered insufficient. Sahota et al, 2001 A population-based, prospective cohort study on 150 elderly subjects recruited from an orthogeriatric rehabilitation ward within 7 days of surgery for hip fractures. The study investigated the effects of hypovitaminosis D on the calcium-parathyroid hormone endocrine axis, bone mineral density and fracture type, and the optimal role of combination calcium and vitamin D therapy after hip fracture in elderly patients. It was concluded that there was a high prevalence of hypovitaminosis D in active, elderly people living at home who present with a hip fracture. However, secondary hyperparathyroidism occurs in only half of these patients. This subgroup attempts to maintain calcium homeostasis but does so at the expense of increased bone turnover, leading to amplified hip bone loss and an excess of extracapsular over intracapsular fractures. 23

24 This study does not assess the effect of treatment with the proposed product either alone or in combination with calcium. Torrenté de la Jara et al, 2006, Switzerland This observational study looked at female asylum seekers suffering from hypovitaminosis D and the effects of treatment with a combination calcium and colecalciferol daily either alone or with a higher dose of vitamin D given on a monthly basis. Twenty-two patients (66.7%) responded completely to treatment; the remaining patients were considered to be non-responders. After treatment was initiated, the responders' symptoms disappeared completely after 2.84 months. The mean number of emergency medical visits fell, and analgesic drugs that were prescribed also decreased. Comments on the study Only 10 patients received calcium and colecalciferol daily. The analysis did not compare the outcome of the two groups but symptom resolution, consultation of healthcare professional or analgesic use in the whole group of patients. Therefore, no data specifically to support the dose proposed in this population. Giusti et al, 2010 This was a randomised-controlled study with a 6 month follow-up conducted in two osteoporosis centres in Italy. The objective of the study was to compare the effects on parathyroid hormone (PTH) and 25- hydroxy-vitamin D (25(OH)D) of two dosing regimens of colecalciferol in women with secondary hyperparathyroidism (shpth) and hypovitaminosis D and to investigate variables affecting 25(OH)D response to colecalciferol have been compared. Sixty community-dwelling women aged 65 and older with shpth and hypovitaminosis D, creatinine clearance greater than 65 ml/min and without diseases or drugs known to influence bone and vitamin D metabolism were recruited into the study. Colecalciferol 300,000 IU was administered every 3 months, once at baseline and once at 3 months (intermittent D 3 group) or oral colecalciferol 1,000 IU/day (daily D 3 group). All subjects received daily calcium supplements, depending on their dietary intake, to maintain a daily input of 1500mg. Serum PTH, 25(OH)D, calcium, bone-specific alkaline phosphatase, beta-c-terminal telopeptide of type I collagen, phosphate, 24-hour urinary calcium excretion were measured. All participants had vitamin D deficiency. After 3 and 6 months, both groups had a significant increase in 25(OH)D and a reduction in PTH. 25(OH)D response to colecalciferol showed a wide variability. In a logistic regression analysis, body mass index and type of treatment appeared to be significantly associated with normalization of 25(OH)D values. Colecalciferol 300,000 IU every 3 months was more effective than 1,000 IU daily in correcting vitamin D deficiency, although the two groups achieved similar effects on PTH at 6 months. Only 55% of the higher-dose intermittent group reached desirable concentrations of 25(OH)D, suggesting that yet-higher doses were required for adequate vitamin D repletion. This study has investigated the role of two different vitamin D 3 preparations in raising 25(OH)D levels in patients found to be deficient. Although the results show that both groups demonstrated a response to treatment, this was more in the subjects receiving intermittent colecalciferol and the effect was observed in 55% of patients. In addition, all subjects are reported to have received supplemental calcium. This study adds to the body of evidence of treating patients with vitamin deficiency with colecalciferol especially if dosed up to 1600 IU as proposed in the product SmPC. However, this was in combination with calcium and the role of treating patients with colecalciferol alone and if similar response is expected with regards to PTH has not been discussed. There is also likely to be a compliance issue with daily intake of colecalciferol as opposed to intermittent, which probably accounts for the difference seen between the two groups. Hackman et al 2010, Australia 24

25 The aim of this study was to compare the efficacy and safety of a 10-day, high-dose versus a 3-month, continuous low-dose oral colecalciferol course in a vitamin D deficient population. The primary end points were the change in serum 25-hydroxyvitamin D (25(OH)D) concentrations at 3 months and the development of hypercalcaemia and hypercalciuria. Both the 10-day, high-dose and the 3-month, lowdose colecalciferol regimens effectively increased serum 25(OH)D to within the normal range. The highdose regimen may be an effective and cheap alternative for patients with vitamin D deficiency. As expected, vitamin D levels were corrected at the doses given which are again different to the regimen proposed by the applicant. In addition, all subjects received calcium supplementation in this study. Von Hurst et al 2010, New Zealand The objective of this study was to measure the effect of vitamin D supplementation, in vitamin D deficient women. In women who were under 49 years and premenopausal there was no significant response to supplementation in either C-telopeptide or osteocalcin. It was concluded that correcting vitamin D deficiency in older women suppressed the age-induced increase in bone turnover and reduced the bone resorption which would normally be exacerbated in conditions of low serum 25(OH)D. This study was conducted in New Zealand in South Asian women. They were given a higher dose daily of colecalciferol than proposed with this product. It can be seen that there is a benefit in supplementing patients known to be vitamin D deficient, to correct this hypovitaminosis, in this population. In addition, in older women, treatment suppresses bone turnover and resorption. McCullough et al 2009, US Vitamin D supplementation may be required for certain subgroups in the United States in whom status and intake are inadequate, but the impact of various doses, and whether calcium administration jointly or independently influences vitamin D metabolite levels, is unclear. In a pilot chemoprevention trial of biomarkers of risk for colorectal adenoma, the impact of vitamin D supplementation and/or calcium supplementation on plasma vitamin D metabolite concentrations were measured. Ninety-two adult men and women living in the south-eastern United States were randomized to 800 IU vitamin D 3, 2000 mg elemental calcium, both, or placebo daily for 6 months. The vitamin D status at baseline and postintervention were measured and compared to the change in plasma 25-hydroxyvitamin D (25(OH)D) and 1,25(OH)2D levels by intervention group using general linear models. Eighty-two percent of the study population had insufficient plasma 25(OH)D concentrations (<75 nmol/l) at baseline, with the lowest levels observed among African American participants. Vitamin D supplements, with or without calcium supplementation, raised plasma 25(OH)D concentrations, on average, by 25 to 26 nmol/l. Half of the study participants were classified as having sufficient 25(OH)D status after 6 months of 800 IU of vitamin D 3 daily. Calcium alone did not influence 25(OH)D concentrations. In this south-eastern U.S. population, half of the study participants receiving 800 IU vitamin D 3 daily had blood 25(OH)D concentrations of <=75 nmol/l after a 6-month intervention period, supporting higher vitamin D dose requirements estimated by some groups. Supplementation with vitamin D 3 at a dose of 800IU is shown to increase 25(OH)D to levels classified as sufficient in 50% of patients known to be either deficient or have insufficient vitamin D levels at baseline. No difference was seen between the Vitamin D only group versus calcium plus vitamin D group in 25 (OH)D levels post-intervention. Although the study was not conducted in the EU, it supports the proposed dose and indication for this product. Osteoporosis Treatment Lips et al,

26 A prospective randomized, double-blind, placebo-controlled clinical trial to determine whether vitamin D supplementation decreases the incidence of hip fractures and other peripheral bone fractures. It was concluded that these results do not show a decrease in the incidence of hip fractures and other peripheral fractures in elderly persons after vitamin D supplementation. The data suggest that other risk factors are more important in this study population. Assessor s Comment Based on the result of this study, it does not support single treatment of treatment or prevention of osteoporotic fractures with colecalciferol. Komulainen et al, 1999 This study assessed the long term effects of hormone replacement therapy (HRT) and vitamin D 3 (VitaminD) on bone mineral density (BMD). 464 non-osteoporotic early postmenopausal women from the Kuopio Osteoporosis Study (in Finland) (n = 13,100) were randomized to four groups: 1. HRT (115, age 52.9 ( ), sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate, 2. Vitamin D 3 (112, age 52.9 ( ), 300 IU plus 93 mg calcium/day, no intake during June, August, the Vitamin D 3 dosage was lowered to 100 IU /day after 4yr of treatment because of adverse lipid changes noticed during the first years of the trial 3. HRT and Vitamin D combined (116, age 52.5 ( ), 4. placebo (115, age 52.6 ( ), plus 500 mg/day calcium lactate equivalent to 93 mg calcium/day) The average Ca-intake was similar in the four groups. Lumbar (L2 L4) and femoral neck BMD were determined by dual x-ray absorptiometry (DXA) at baseline and after 2.5 and 5 years of treatment. Intention to treat analysis (n = 464) showed that after 5 years, lumbar BMD remained unchanged in the HRT and HRT plus Vitamin D groups [10.2% (p = 0.658) and 10.9% (p = 0.117), respectively], whereas lumbar BMD decreased by 4.6% in the Vitamin D group and by 4.5% in the placebo group (p < in both). The loss of femoral neck BMD was less in the HRT (21.4%; p = 0.005) and HRT plus Vitamin D (21.3%; P = 0.003) groups than in the Vitamin D and placebo groups (24.3%; p < in both). Among those 370 women who complied with the 5-year treatment, the effect was more pronounced: lumbar BMD had increased by 1.5% in the HRT (p = 0.009) and by 1.8% in the HRT plus Vitamin D group (p = 0.005), with a plateau after 2.5 yr, whereas lumbar BMD had decreased in both the Vitamin D and placebo groups (4.6% and 4.7%; p < 0.001, respectively). Femoral neck BMD decreased again less in the HRT (20.4%) and HRT plus Vitamin D (20.6%) groups than in the Vitamin D and placebo groups (24.4% in both). This study confirms the positive long term effect of HRT on BMD also seen in intention to treat analysis. The data suggest that low dose vitamin D 3 supplementation does not prevent bone loss in healthy, non-osteoporotic, early postmenopausal women, and it confers no benefit additional to that of HRT alone. Comments on study The applicant has not proposed an indication in non-osteoporotic patients. The study conclusion is therefore consistent with the proposed indication in the SmPC even at the lower dose used in this study. Trivedi et al, 2003 A randomised double-blind placebo-controlled study, to determine the effect of four monthly vitamin D supplementation on the rate of fractures in men and women aged 65 years and over living in the community. Participants in the vitamin D treatment group had a 22% lower rate for first fracture at any site and a 33% lower rate for a fracture occurring in the hip, wrist or forearm, or vertebrae. Findings were consistent in men and women and in doctors and the general practice population. 26

27 Assessor s Comment The dose used in this study is different to that proposed by the applicant. Although the dose is reported to be equivalent to 800 IU daily, there is no evidence to show that both products are bioequivalent. In addition, other studies have suggested a difference between the effect of infrequent high dose dosing and daily dosing with 800 IU as proposed by the applicant. Therefore this study has limited value in supporting this application. Meyer et al, 2002 The authors studied if an intervention with 10 μg (400 IU) of vitamin D 3 per day could prevent hip fracture and other osteoporotic fractures in a double-blinded randomised controlled trial There was no difference in the incidence of hip fracture,or in the incidence of all non-vertebral fractures in the vitamin D group compared with the control group. Compared with the control group, persons in the vitamin D group increased their serum 25-hydroxyvitamin D concentration with 22 nmol/liter (p = 0.001). In conclusion, it was found that an intervention with 10 μg (400 IU) of vitamin D 3 alone produced no fracture-preventing effect in a nursing home population of frail elderly people. This is consistent with the study reported by Lipps et al, 1996 conducted in a different population in Amsterdam. Treatment with colecalciferol at 400 IU has not been shown to have a fracture-preventing effect. Papadimitropoulos et al, 2002 The objective of this meta-analysis was to review the effect of standard or hydroxylated vitamin D, with or without calcium on bone density and fractures in postmenopausal women. Vitamin D reduced the incidence of vertebral fractures and showed a trend toward reduced incidence of non-vertebral fractures. Most patients in the trials that evaluated vertebral fractures received hydroxylated vitamin D, and most patients in the trials that evaluated non-vertebral fractures received standard vitamin D. Hydroxylated vitamin D had a consistently larger impact on bone density than did standard vitamin D. The authors concluded that Vitamin D decreases vertebral fractures and may decrease non-vertebral fractures. The available data are uninformative regarding the relative effects of standard and hydroxylated vitamin D. With the range of studies included in this meta-analysis which include studies where calcium supplementation is used and different doses of vitamin D, the applicability of this to the proposed product is unclear and hence the expected effect of this product on vertebral and non-vertebral fractures. Avenell et al, 2005 Vitamin D and related compounds have been used to prevent fractures. The aim of this Cochrane Review was to determine the effects of vitamin D or analogues, with or without calcium, in the prevention of fractures in older people. The authors searched the Cochrane Bone, Joint and Muscle Trauma Group trials register, the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2005), MEDLINE, EMBASE, CINAHL, and reference lists of articles. Randomised or quasirandomised trials comparing vitamin D or an analogue, alone or with calcium, against placebo, no intervention, or calcium, reporting fracture outcomes, in older people. Two authors independently assessed trial quality, and extracted data. Data were pooled, where admissible, using the fixed-effect model, or random-effects model if the relative risks were heterogeneous. Vitamin D alone showed no statistically significant effect on hip fracture (seven trials, 18,668 participants, RR 1.17, 95% CI 0.98 to 1.41), vertebral fracture (four trials, 5698 participants, RR (random effects) 1.13, 95% CI 0.50 to 2.55) or any new fracture (eight trials, 18,935 participants, RR 1.02, 95% CI 0.93 to 1.11). Vitamin D with calcium was found to marginally reduce hip fractures (seven trials, 10,376 participants, RR 0.81, 95% CI 0.68 to 0.96), non-vertebral fractures (seven trials, 10,376 27

28 participants, RR 0.87, 95% CI 0.78 to 0.97), but there was no evidence of effect of vitamin D with calcium on vertebral fractures. The effect appeared to be restricted to those living in institutional care. Hypercalcaemia was more common when vitamin D or its analogues was given compared with placebo or calcium (14 trials, 8035 participants, RR 2.38, 95% CI 1.52 to 3.71). The risk was particularly high with calcitriol (three trials, 742 participants, RR 14.94, 95% CI 2.95 to 75.61). There was no evidence that vitamin D increased gastro-intestinal symptoms (seven trials, 10,188 participants, RR (random effects) 1.03, 95% CI 0.79 to 1.36) or renal disease (nine trials, 10,107 participants, RR 0.80, 95% CI 0.34 to 1.87). The authors concluded that frail older people confined to institutions may sustain fewer hip and other non-vertebral fractures if given vitamin D with calcium supplements. Effectiveness of vitamin D alone in fracture prevention is unclear. There is no evidence of advantage of analogues of vitamin D compared with vitamin D. Calcitriol may be associated with an increased incidence of adverse effects. Vitamin D with calcium supplements reduces the risk of fracture in some older people. Vitamin D is necessary for building bone. Older people often have low vitamin D levels. Therefore, it has been suggested that taking additional vitamin D may help to reduce the risk of hip and other fractures. It is still not clear whether vitamin D alone can reduce the risk of fracture. Vitamin D taken with additional calcium supplements does appear to reduce fracture risk in people living in institutional care. In line with proposed indications, vitamin D has not been shown to be effective in the prevention of fractures or in the management of osteoporosis alone. Sanders et al, 2010, Australia This was a double-blind, placebo-controlled trial of 2256 community-dwelling women, aged 70 years or older, considered at high risk of fracture. They were randomly assigned to receive 500,000 IU of colecalciferol or placebo each autumn to winter for 3 to 5 years. The main outcome measures were numbers of falls and fractures. Among older community-dwelling women, annual oral administration of high-dose colecalciferol resulted in an increased risk of falls and fractures. Limited information provided here to support the dosage recommendation and the indications sought. Salovaara et al 2010 To determine whether daily 800 IU of vitamin D and 1000 mg of calcium supplementation prevents fractures. It was concluded that this study did not produce statistically significant evidence that vitamin D and calcium supplementation prevents fractures in a 65- to 71-year-old general population of postmenopausal women. No additional information provided on efficacy of vitamin D 3 therapy for the indications sought. Applicant s expert s opinion: In conclusion, results of trials assessing fracture reduction with oral vitamin D alone in individuals NOT diagnosed with osteoporosis have been equivocal. In the randomized, double-blind, placebo-controlled trial in ref. Trivedi et al, 2003 vitamin D 100,000 IU every 4 months reduced the risk of first hip, wrist or forearm, or vertebral fractures by 33%. However, in the randomized, placebo-controlled trial in ref. Lips et al, 1996 did not show a decrease in the incidence of hip fractures and other peripheral fractures in Dutch elderly persons after vitamin D supplementation and in the randomized, placebo and active-controlled trial in ref Komulainen et al, 1999 low dose vitamin D 3 supplementation did not prevent bone loss in healthy, non-osteoporotic, early postmenopausal women. 28

29 The first of the two meta-analyses above concluded that vitamin D decreases vertebral fractures and may decrease non-vertebral fractures. However, this meta-analysis has not separated trials using vitamin D alone from those using vitamin D with calcium. This represents a bias in the evaluation of the efficacy of vitamin D monotherapy in the prevention of osteoporosis. The Cochrane meta-analysis concluded that vitamin D alone, without calcium, showed no significant effect on the prevention of fractures. To date, there have been no major placebo-controlled studies proving unanimously the efficacy of small daily doses of vitamin D (daily IU) alone in prevention of osteoporosis or head-to-head studies of calcium and vitamin D vs. vitamin D alone to demonstrate the incremental benefit provided by vitamin D alone over calcium and vitamin D. In addition there is no prospective, randomised, controlled study in MEDLINE on colecalciferol monotherapy in diagnosed osteoporotic patients. Insufficient evidence has been provided to demonstrate the well-established use of colecalciferol monotherapy in the management of osteoporosis. Vitamin D 3 as an adjunct to specific osteoporosis treatment Vitamin D 3 has been extensively studied regarding its impact on fracture risk reduction. In fact, vitamin D 3 deficiency has been associated with greater incidence of hip fracture in many populations, including postmenopausal women. In a detailed review by LeBoff and colleagues (1999) of women with osteoporosis who were hospitalized due to hip fractures, 50% were found to have signs of vitamin D deficiency. A meta-analysis of randomized, controlled fracture prevention trials with vitamin D reported that oral vitamin D supplementation between 700 to 800 IU per day appeared to reduce the risk of hip and any non-vertebral fractures in ambulatory or institutionalized elderly persons. An oral vitamin D dose of 400 IU/d was not sufficient for fracture prevention. A vitamin D 3 dose of 700 to 800 IU per day reduced the relative risk of hip fracture by 26% and any non-vertebral fracture by 23%. In both NICE guidances (Technology Appraisal Guidances 160 and 161) which reviews the treatment of osteoporosis it states that, This guidance assumes that women who receive treatment have an adequate calcium intake and are vitamin D replete. Unless clinicians are confident that women who receive treatment meet these criteria, calcium and/or vitamin D supplementation should be considered. This is further supported by the British National Formulary where it states, Those at risk of osteoporosis should maintain an adequate intake of calcium and vitamin D and any deficiency should be corrected by increasing dietary intake or taking supplements. A recent paper provides information on the use of adjunctive colecalciferol treatment in Canada. In this prospective, single-cohort, open-label, multi-centre study community-dwelling men and postmenopausal women with osteoporosis received vitamin D IU/day supplementation co-administered with alendronate 70 mg/wk for 16 weeks. The primary outcome was the distribution of serum 25(OH)D at baseline. Secondary outcome measures included changes from baseline in serum 25(OH)D levels, adherence to study treatments, and incidence of treatment-related adverse events. Of the 681 patients included in the analysis, 485 (71.2%) completed the study. Patients were predominantly female (83.1%) with a mean (SD) age of 67.6 (10.7) years. At baseline, mean (SD) serum 25(OH)D concentration was 25.4 (9.9) ng/ml and 68.0% of the patients had inadequate (less than 30 ng/ml) vitamin D status. At week 16, concentrations increased by 35.1% to 31.2 (9.2) ng/ml (p < 0.001) and the proportion of patients with inadequate 25(OH)D levels was reduced to 47.0%. Adherence to the treatment regimen was high (greater than 95%). Gastrointestinal disorders were the most frequently reported (6.9%) treatment-related adverse events. The authors concluded that this treatment regimen consisting of alendronate 70 mg/wk administered with daily vitamin D IU supplementation significantly increased patients' serum 25(OH)D levels, but 47% did not achieve optimal levels. These results, it was noted, supported both the National Osteoporosis Foundation and Osteoporosis Canada recommendations for higher vitamin D 3 supplement doses (of at least 800 IU daily) in osteoporotic patients receiving pharmacologic therapy for osteoporosis and for monitoring their serum 25(OH)D response. 29

30 Another recent review has confirmed that a number of studies suggest that the combination of calcium and vitamin D 3 is effective in osteoporosis prevention and treatment when administered at the respective dosages of at least 1200_mg and 800_IU per day. Overall, combined treatment with calcium and vitamin D 3 appeared to be effective in reducing the incidence of non-vertebral and hip fractures. Also, in all drug studies (of antiresorptive and anabolic agents and strontium ranelate) that demonstrated a reduction in risk of osteoporotic fractures, patients also took calcium and vitamin D supplements. Another review from the Netherlands discusses the optimal use of colecalciferol in treating osteoporosis. The conclusions were that poor vitamin D status and low calcium intake are important determinants for osteoporosis and fracture risk. Based on evidence from the literature, adequate supplementation, with at least 700 IU of vitamin D, preferably colecalciferol is required for improving physical function and prevention of falls and fractures. The German product, Dektrisol, is authorised within the EU as an adjunctive treatment for osteoporosis at a maximum daily dose of 800 IU colecalciferol. The Swedish product Detremin is given at a maximum dose of 667 IU for this indication and it is noted in the SmPC that doses above 800 IU have not been systematically investigated. In the Public Assessment Report for Detremin the Clinical Assessor for the Medicines Product Agency in Sweden states: Supportive treatment with calcium and vitamin D in a wide variety of doses and combinations has been used as additive treatment in most clinical trials in osteoporosis. This is a widely accepted indication for vitamin D. For these reasons the applicant intends to keep the indication as stated in the application but agrees that, for this indication, the maximum daily dose of Fultium in osteoporosis should be 1 capsule (800 IU) daily. The SmPC and PIL reflect this information. Comments on the use of Vitamin D 3 as an adjunct to specific therapy for osteoporosis in patients with vitamin D deficiency or at risk of vitamin D insufficiency The applicant supports the role and dose recommended with two review articles. The combination with calcium is well-established and some products, like alendronate and risedronate now have formulations which include vitamin D and raloxifene recommends supplemental calcium and vitamin D in patients in whom dietary intake is insufficient, which are discussed below. In addition, when the studies with these products are reviewed, patients are noted to have received supplemental calcium and vitamin D in both control and intervention groups. Based on this evidence, this indication is approvable. Colecalciferol/calcium and alendronate or clodronate Black, 1996, USA The aim of this study was to investigate the effect of alendronate on the risk of fractures in postmenopausal women with low bone mass. Women aged with low femoral-neck BMD were enrolled in two study groups based on the presence or absence of an existing vertebral fracture. Each group received a daily dose of alendronate or placebo; both groups received a daily maintenance dose of calcium and 250IU vitamin D for the duration of the test period of 36 months. The primary end-point, were defined by new vertebral fractures. Results showed that the risk of fractures was lower in the alendronate than the placebo group. The authors concluded that among women with low bone mass and existing vertebral fractures, alendronate was well tolerated and substantially reduced the frequency of morphometric and clinical vertebral fractures, as well as other clinical fractures. The aim of this study was to study the role of alendronate on the risk of fractures and not the colecalciferol. Even considering the dose used of colecalciferol in the study, it does not provide any evidence to support this application. 30

31 McComsey et al, 2007, USA Bisphosphonates are currently the mainstay of treatment for postmenopausal and male osteoporosis in HIV-uninfected individuals; however, their efficacy and safety in HIV-infected patients remained unclear. This was a prospective, randomised, placebo-controlled multicentre study to evaluate the safety and effectiveness of calcium carbonate (500 mg elemental calcium daily) and vitamin D (200 IU daily) supplementation with or without once weekly alendronate (70mg) in improving bone mineral density (BMD) in HIV-infected individuals receiving stable antiretroviral therapy. Results showed that compared with calcium/vitamin D alone, alendronate plus calcium/vitamin D resulted in significant improvements in BMD at the lumbar spine, total hip, and trochanter, but not at the femoral neck, compared with baseline. There were trends towards significant increases in BMD values in the calcium/vitamin D group at the lumbar spine, total hip and femoral neck. It was concluded that onceweekly alendronate with daily calcium and vitamin D supplement is safe and effective in the treatment of decreased BMD in HIV-infected patients. This does not provide additional information on the role of this product for this indication, especially the dose used which is different from that proposed. Bonnick et al, 2007, USA This 2-year, randomized, double-blind, multicenter trial enrolled healthy, postmenopausal women with low bone mineral density (BMD). Patients with a dietary calcium intake 800 mg/day received daily vitamin D 400 IU and alendronate 10 mg/calcium-placebo, alendronate 10 mg/elemental calcium 1000 mg, or alendronate placebo/ calcium 1000 mg (2:2:1). Endpoints included BMD, bone turnover markers (BTMs), and adverse events. It was concluded, that in postmenopausal women with a daily intake of 800 mg calcium and 400 IU vitamin D, 24-month treatment with alendronate 10 mg daily with or without calcium 1000 mg resulted in significantly greater increases in BMD and reduction of bone turnover than supplemental calcium alone. Addition of supplemental calcium to alendronate treatment, although had no effect on BMD, resulted in a statistically significant additional reduction in BTMs. This study does not specifically investigate the role of colecalciferol for this indication but with the presence or absence of calcium in the treatment. The dose of colecalciferol used is not as proposed for this product. Fioreani et al, 2007 This was a prospective study in post-menopausal women with newly diagnosed primary biliary cirrhosis with an objective to optimise the rationale for the medical treatment of bone loss. Patients with either osteopenia or osteoporosis received the following treatment: oral calcium carbonate (1000 mg/day) plus vitamin D 3 (880 IU/day) plus i.m. disodium clodronate 100mg every 10 days for 4 years. No significant differences in biochemical parameters of bone metabolism were observed between the three groups. The authors concluded that a 4-year treatment with clodronate plus calcium/vitamin D 3 supplements does not significantly improve osteoporosis or osteopenia in primary biliary cirrhosis women in menopause, but prevents the natural bone loss in these group of patients. Only study presented which was conducted in EU. The focus of this is on the combination with calcium and not the effect of the addition of colecalciferol. Colecalciferol/calcium and risendronate Reginster et al, 2000, EU and Australia A randomised, double-masked, placebo-controlled study performed at 80 European and Australian centres to determine the efficacy and safety of risedronate in the prevention of vertebral fractures in postmenopausal women with established osteoporosis. Postmenopausal women with two or more 31

32 prevalent vertebral fractures received risedronate 2.5 or 5 mg/day or placebo; all subjects also received elemental calcium 1000 mg/day, and up to 500 IU/day vitamin D if baseline levels were low. The study duration was 3 years. Risedronate 5 mg provides effective and well-tolerated therapy for severe postmenopausal osteoporosis, reducing the incidence of vertebral fractures and improving bone density in women with established disease. Comment s on this study The focus of this study is not on the role of colecalciferol in combination with risedronate and again, it has been used here in combination with calcium. When products are available which provide a combination of this, the additional role of colecalciferol alone has not been discussed. McClung et al, 2001 The authors studied women aged between 70 to 79 years old who had osteoporosis and women at least 80 years old who had at least one non-skeletal risk factor for hip fracture or low bone mineral density at the femoral neck The women were randomly assigned to receive treatment with oral risedronate (2.5 or 5.0 mg daily) or placebo for three years. The participants also received daily 1000 mg calcium and 500 IU vitamin D if the serum 25OHD concentration was below 16ng/ml. The primary end point was the occurrence of hip fracture. Risedronate significantly reduces the risk of hip fracture among elderly women with confirmed osteoporosis but not among elderly women selected primarily on the basis of risk factors other than low bone mineral density. This study investigated the use of risedronate in combination with calcium and vitamin D. Again it is a study looking at vitamin D in combination with calcium and at a different dose to that proposed. Harris et al, 1999a, USA This was a randomised, double-blind, placebo-controlled study to test the efficacy and safety of daily treatment with risedronate to reduce the risk of vertebral and other fractures in postmenopausal women with established osteoporosis. Ambulatory postmenopausal women younger than 85 years with at least 1 vertebral fracture at baseline were enrolled. Subjects were randomly assigned to receive oral treatment for 3 years with risedronate (2.5 or 5 mg/d) or placebo. All subjects received calcium, 1000 mg/day. Vitamin D (colecalciferol, up to 500 IU/day) was provided if baseline levels of 25-hydroxyvitamin D were low. Main outcome measures included incidence of new vertebral fractures.; incidence of nonvertebral fractures and change from baseline in bone mineral density. The data suggest that risedronate therapy is effective and well tolerated in the treatment of women with established postmenopausal osteoporosis. In combination with calcium and at a different dose to that proposed. The focus is not on the role of vitamin D. Colecalciferol/calcium and raloxifene Cummings et al, 1999 The objective of this study was to determine whether women taking raloxifene have a lower risk of invasive breast cancer. A randomized, double-blind trial, in which postmenopausal women with osteoporosis taking raloxifene or placebo were followed for a median of 40 months Administration of raloxifene, or 1 placebo tablet were compared;; all participants received daily supplements containing 500 mg of calcium and 400 to 600 IU of colecalciferol. The authors concluded that among postmenopausal women with osteoporosis, the risk of invasive breast cancer was decreased by 76% during 3 years of treatment with raloxifene. 32

33 Vitamin D was administered in combination with calcium and at a different dose to that proposed. The focus is not on the role of vitamin D. Meunier et al, 1999 The objective of this study was to examine the effects of raloxifene on bone mass density, biochemical markers of bone metabolism and serum lipids in postmenopausal women with low bone density or osteoporosis. This 24-month, double-masked study assessed the efficacy and safety of raloxifene in 129 postmenopausal women with osteoporosis or low bone density Women were randomly assigned to a treatment group of either placebo or raloxifene and concomitantly all received 1000 mg/day calcium and 300 IU/day vitamin D 3. The authors concluded that raloxifene increased bone density, decreased bone turnover, and improved the serum lipid profile with minimal adverse events, and may be a safe and effective treatment for postmenopausal women with osteoporosis or low bone density. Vitamin D was administered in combination with calcium and at a different dose to that proposed. The focus is not on the role of vitamin D. Ettinger et al, 1999 The objective of this study was to determine the effect of raloxifene therapy on risk of vertebral and nonvertebral fractures. A randomized, blinded, placebo-controlled trial enrolling 7705 women aged 31 to 80 years in 25 countries who had been postmenopausal for at least 2 years and for having osteoporosis. Participants were randomized to 60 mg/day or 120 mg/day of raloxifene or to identically appearing placebo pills; in addition, all women received supplemental 500 mg calcium and 600 IU colecalciferol for 36 months. The conclusions drawn from the study were that in postmenopausal women with osteoporosis, raloxifene increases bone mineral density in the spine and femoral neck and reduces risk of vertebral fracture. Vitamin D was administered in combination with calcium and at a different dose to that proposed. Also, the focus is not on the role of vitamin D. Boivin et al, 2003 This was a prospective longitudinal study to evaluate the mineralization of bone (MDMB) in a group of patients. Patients were randomly assigned to a treatment groups: placebo All patients received daily calcium (500 mg) and vitamin D(3) ( IU) supplementation for the duration of the study. Raloxifene treatment was found to shift the distribution of total bone mineral to higher values of MDMB. Vitamin D was administered in combination with calcium and at a different dose to that proposed. The focus is not on the role of vitamin D. Colecalciferol/calcium and calcitonin Chesnut et al 2000 This was a 5-year, double-blind, randomised, placebo-controlled study to determine whether salmon calcitonin nasal spray reduced the risk of new vertebral fractures in postmenopausal women with osteoporosis. Postmenopausal women with established osteoporosis were randomly assigned to receive salmon calcitonin nasal spray or placebo daily. All participants received elemental calcium (1,000 mg) and vitamin D (400 IU) daily; vertebral fractures were assessed as primary end-points in all active treatment groups. Salmon calcitonin nasal spray at a dose of 200 IU daily significantly reduces the risk of new vertebral fractures in postmenopausal women with osteoporosis. 33

34 Vitamin D was administered in combination with calcium and at a different dose to that proposed. Also, the focus is not on the role of vitamin D. Colecalciferol/calcium and Human Parathyroid hormone Greenspan et al, 2007 This study aimed to determine the safety of parathyroid hormone (PTH) and its effect on the incidence of vertebral fractures in postmenopausal women with osteoporosis in a 18-month, randomized, doubleblind, placebo-controlled trial. Women received 100 µg of recombinant human PTH or placebo daily by subcutaneous injection. All received calcium, 700 mg/day, and vitamin D 3, 400 IU/day. New or worsened vertebral fractures (primary outcome) and changes in bone mineral density and safety (secondary outcomes) were measured. The authors concluded that parathyroid hormone together with calcium and vitamin D supplements reduced the overall risk for new or worsened vertebral fracture in postmenopausal women with osteoporosis. The focus of this study was on the role of recombinant PTH and not to demonstrate the role of vitamin D at the dose proposed by the applicant for this indication. 2.4 Clinical studies in special populations 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). 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. Having determined that vitamin D insufficiency is an issue amongst the adolescent population, consideration has to be given to the appropriate preventative and treatment strategy. In a study in Denmark in adolescent white girls it was shown that the vitamin D intakes required to maintain wintertime serum 25(OH)D concentrations above the thresholds 25 nmol/l and 50 nmol/l in more than 97.5% of adolescent girls were 8.3 μg/d ( 344 IU) and 18.6 μg/d (744 IU) respectively. Another study in adolescents (boys and girls) in Iran assigned 105 boys and 105 girls, aged between 14 and 20 years) into three groups (Ghazi et al, 2010). Group A received 50,000 IU vitamin D 3 monthly (which is equivalent to 1600 IU daily), Group B received 50,000 IU bimonthly (equal to 800 IU per day) and Group C received placebo. At baseline girls had significantly lower concentrations of 25(OH)D than boys. Mean 25(OH)D increased in both Groups A and B, and increased more in Group A. In both treatment groups vitamin D 3 was well tolerated. The authors concluded that monthly or bimonthly administration of vitamin D 3 (equivalent to IU daily) improved the status of body vitamin D, although it was not able to ensure optimum 25(OH)D levels (> 75 nmol/l). The authors postulated that higher doses or longer periods of supplementation may be required. A study in obese adolescents with severe vitamin D deficiency treated with 50,000 IU vitamin D weekly for 6-8 weeks and those adolescents with moderate deficiency with 800 IU daily for three months. There were no concerns over the safety of the medicines. 34

35 There was an increase in plasma 25(OH)D levels that only normalised in 28% of patients. The authors suggested that possibly higher vitamin D doses are warranted for obese adolescents whose total 25(OH)D levels do not normalize after the initial course of treatment. 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 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). Comments on the studies provided to support treatment in this special population 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 is satisfactory. 2.5 ANALYSIS PERFORMED ACROSS TRIALS (POOLED ANALYSES AND META- ANALYSIS) Papadimitropoulos et al, 2002 The objective of this meta-analysis was to review the effect of vitamin on bone density and fractures in postmenopausal women. The authors searched MEDLINE and EMBASE from 1966 to 1999 and examined citations of relevant articles and proceedings of international meetings. They contacted osteoporosis investigators and primary authors to identify additional studies and to obtain unpublished data. 25 trials were included that randomized women to standard or hydroxylated vitamin D with or without calcium supplementation or a control and measured bone density or fracture incidence for at least 1 year. For each trial, three independent reviewers assessed the methodological quality and abstracted data. Vitamin D reduced the incidence of vertebral fractures [relative risk (RR) 0.63, 95% confidence interval (CI) , p < 0.01) and showed a trend toward reduced incidence of nonvertebral fractures (RR 0.77, 95% CI , p < 0.09). Most patients in the trials that evaluated vertebral fractures received hydroxylated vitamin D, and most patients in the trials that evaluated nonvertebral fractures received standard vitamin D. Hydroxylated vitamin D had a consistently larger impact on bone density than did standard vitamin D. Total body differences in percentage change between hydroxylated vitamin D and control were 2.06 (0.72, 3.40) and 0.40 (- 0.25, 1.06) for standard vitamin D. At the lumbar spine and forearm sites, hydroxylated vitamin D doses above 50 μg yielded larger effects than lower doses. Vitamin D resulted in an increased risk of discontinuing medication in comparison to control as a result of either symptomatic adverse effects or abnormal laboratory results (RR 1.37, 95% CI ), an effect that was similar in trials of standard and hydroxylated vitamin 35

36 D. The authors concluded that Vitamin D decreases vertebral fractures and may decrease non-vertebral fractures. The available data are uninformative regarding the relative effects of standard and hydroxylated vitamin D Avenell et al, 2005 Vitamin D and related compounds have been used to prevent fractures. The aim of this Cochrane Review was to determine the effects of vitamin D or analogues, with or without calcium, in the prevention of fractures in older people. The authors searched the Cochrane Bone, Joint and Muscle Trauma Group trials register, the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2005), MEDLINE, EMBASE, CINAHL, and reference lists of articles. Randomised or quasirandomised trials comparing vitamin D or an analogue, alone or with calcium, against placebo, no intervention, or calcium, reporting fracture outcomes, in older people. Two authors independently assessed trial quality, and extracted data. Data were pooled, where admissible, using the fixed-effect model, or random-effects model if the relative risks were heterogeneous. Vitamin D alone showed no statistically significant effect on hip fracture (seven trials, 18,668 participants, RR 1.17, 95% CI 0.98 to 1.41), vertebral fracture (four trials, 5698 participants, RR (random effects) 1.13, 95% CI 0.50 to 2.55) or any new fracture (eight trials, 18,935 participants, RR 1.02, 95% CI 0.93 to 1.11). Vitamin D with calcium was found to marginally reduce hip fractures (seven trials, 10,376 participants, RR 0.81, 95% CI 0.68 to 0.96), non-vertebral fractures (seven trials, 10,376 participants, RR 0.87, 95% CI 0.78 to 0.97), but there was no evidence of effect of vitamin D with calcium on vertebral fractures. The effect appeared to be restricted to those living in institutional care. Hypercalcaemia was more common when vitamin D or its analogues was given compared with placebo or calcium (14 trials, 8035 participants, RR 2.38, 95% CI 1.52 to 3.71). The risk was particularly high with calcitriol (three trials, 742 participants, RR 14.94, 95% CI 2.95 to 75.61). There was no evidence that vitamin D increased gastro-intestinal symptoms (seven trials, 10,188 participants, RR (random effects) 1.03, 95% CI 0.79 to 1.36) or renal disease (nine trials, 10,107 participants, RR 0.80, 95% CI 0.34 to 1.87). The authors concluded that frail older people confined to institutions may sustain fewer hip and other non-vertebral fractures if given vitamin D with calcium supplements. Effectiveness of vitamin D alone in fracture prevention is unclear. There is no evidence of advantage of analogues of vitamin D compared with vitamin D. Calcitriol may be associated with an increased incidence of adverse effects. Vitamin D with calcium supplements reduces the risk of fracture in some older people. Vitamin D is necessary for building bone. Older people often have low vitamin D levels. Therefore, it has been suggested that taking additional vitamin D may help to reduce the risk of hip and other fractures. It is still not clear whether vitamin D alone can reduce the risk of fracture. Vitamin D taken with additional calcium supplements does appear to reduce fracture risk in people living in institutional care. 2.6 ASSESSOR S OVERALL CONCLUSIONS ON CLINICAL EFFICACY Adequate literature data has been provided to support the indications requested in this application. The efficacy of vitamin D 3 supplementation is well-established. 3. CLINICAL SAFETY 3.1 Introduction The applicant has stated that the safety data discussed pertains to the use of the colecalciferol and in particular how these relate to the information in the SmPC. 3.2 Patient exposure As this product is currently not marketed and there have been no clinical studies submitted, no patients have been exposed to Fultium 800 IU Soft Gelatin Capsules. 3.3 Adverse events In a meta-analysis the pooled estimate of the relative risk (RR) of discontinuing vitamin D treatment as a result of either symptomatic adverse effects or abnormal laboratory results was 1.37 (95% CI , 36

37 p value 0.05, heterogeneity p value = 0.99). The RR of withdrawal was similar in the trials of standard vitamin D (RR 1.40, 95% CI, 0.94 to 2.06, p values = 0.10) and hydroxylated vitamin D (RR 1.34, 95% CI , p value = 0.27), respectively (p value on the difference between the two estimates of RR = 0.90). Excess vitamin D may lead to hypercalcaemia and hypercalciuria. Hypercalcaemia results in the deposition of calcium in soft tissues, diffuse demineralisation of bones and irreversible renal and cardiovascular toxicity. Moderate levels of vitamin D intake may enhance renal stone formation in predisposed individuals. It has been suggested that excess vitamin D may be linked to heart disease, but there is limited evidence for this. Data are available from a range of human supplementation studies, but the levels of vitamin D intake at which hypercalcaemia or hypercalciuria occurs vary between studies. Likely reasons for this include differences in populations studied; for example, several of the studies are in older people, a group vulnerable to vitamin D deficiency, while other studies are in younger adults, who are not likely to be vitamin D deficient. Individuals and groups are also likely to differ in their exposure to vitamin D sources other than supplementation, such as consumption of vitamin D-fortified foods and through exposure to the sun. A safe upper level suitable for long-term intake by the whole population cannot be established based on the available data from studies in humans or animals. The human data are adequate to provide guidance. The highest level of vitamin D supplementation at which no effect on calcium was observed was 0.10 mg (4000 IU)/day. This was from a 5 month supplementation study of vitamin D 3 in 63 adults aged years. In contrast, the lowest level of vitamin D at which effects have been observed was 0.05 mg (2000 IU)/day from a 6 month study of supplementation with vitamin D (of unspecified form) in females above the age of 60 and males above the age of 65. Two out of the 63 subjects developed hypercalcaemia (serum calcium > 2.75 mmol/l). The reason for the difference is not known but may be due to difference in other sources of vitamin D exposure or in the study populations. Taking the evidence as a whole, long-term exposures of up to mg (1000 IU)/day vitamin D appear to be well-tolerated and may be necessary to prevent deficiency in some groups. Higher levels (for example, mg (1800 IU)/day) may be tolerated without adverse effects over the short-term under medical supervision and may be necessary to correct a deficiency. The use of an uncertainty factor is not appropriate because the value is derived from an overview of a number of human studies which measured sensitive biochemical markers of calcium homeostasis. For guidance purposes only, a level of mg (1000 IU)/day supplementary vitamin D would not be expected to cause adverse effects in the general population. This is equivalent to mg/kg bw/day for a 60 kg adult. Due to the difficulties in assessing total vitamin D exposure, an estimate for total intake has not been provided. Such an intake, or more, might well be required under medical supervision in managing overt or occult deficiency states. It should be noted that scaling on a body weight basis to children and infants may not be appropriate for vitamin D as it may lead to the recommended intake for an infant not being met. Considering all the evidence available, the legal status for this product should be POM. 3.4 Serious adverse events and deaths The most serious consequence of acute or chronic overdose would be hypercalcaemia due to vitamin D toxicity. Symptoms may include nausea, vomiting, polyuria, anorexia, weakness, apathy, thirst and constipation. Chronic overdoses can lead to vascular and organ calcification as a result of hypercalcaemia. Treatment should consist of stopping all intake of vitamin D and rehydration. A case is reported of a 16 month-old previously healthy boy with refractory hypercalcaemia due to an overdose of an over-the-counter vitamin supplement containing vitamin D. The patient presented to the emergency department with a few weeks' history of irritability, constipation and intermittent vomiting. His serum calcium was found to be 18 mg/dl. He was first treated with intravenous fluids, furosemide and glucocorticoids without significant improvement, but became eucalcaemic within 24 hours after 37

38 receiving a single dose of pamidronate. This case highlights the potential danger of high dose vitamin supplements in children, and the beneficial effects of treatment with a bisphosphonate. In another case a previously healthy, 2-year-old boy with resistant hypercalcaemia and hypertension resulting from an unintentional overdose with an imported vitamin D supplement presented to an emergency department. The patient presented initially with colic and constipation and was discharged after a benign physical examination. The symptoms persisted and, on the second visit, the patient was found to have a serum calcium level of 14.4 mg/dl. Despite therapy with intravenously administered 5% dextrose solution at one-half normal strength, furosemide, calcitonin, and hydrocortisone, the calcium concentration increased to 15.0 mg/dl on the second hospital day and did not decrease until the fourth hospital day, when it fell to 13.9 mg/dl. The vitamin D concentration peaked at 470ng/mL on hospital day 3. With additional questioning, the mother revealed that she had been giving her son a daily dose of 1 ampoule of Raquiferol, an imported vitamin D supplement, instead of the recommended 2 drops per day. Each ampoule contained 600,000 IU of vitamin D; therefore, the boy received a total of 2,400,000 IU over 4 days. The patient's hypercalcaemia persisted for 14 days and was complicated by persistent hypertension. No renal, cardiac, or neurologic complications were noted. At discharge, the vitamin D concentration was still elevated at 389ng/ml and the total calcium level had decreased to 11 mg/dl. The boy made a complete clinical recovery. Comment on serious adverse events and deaths due to vitamin D 3. The reported cases are unlikely to happen with this product given the high dose of colecalciferol compared to that proposed with this product and also as the product is not recommended for use in this population. 3.5 Safety in special populations Use in Pregnancy and Lactation Pregnancy and lactation do not constitute contraindications of use of Vitamin D. A recent study in 147 pregnant Iranian women has shown that 95.8% of the women were vitamin D deficient. The consequences of severe clinical vitamin D deficiency in pregnancy can be life threatening to the newborn, while lesser degrees of hypovitaminosis D may have important long-term implications for offspring health (Hyppönen & Boucher, 2010). Adequate vitamin D intake is essential for maternal and fetal health during pregnancy, and epidemiological data indicate that many pregnant women have sub-optimal vitamin D levels (Shin et al, 2010). Notably, vitamin D deficiency correlates with preeclampsia, gestational diabetes mellitus, and bacterial vaginosis, and an increased risk for C-section delivery. Recent work emphasizes the importance of non-classical roles of vitamin D in pregnancy and the placenta. The placenta produces and responds to vitamin D where vitamin D functions as a modulator of implantation, cytokine production and the immune response to infection. Past experiences with routine provision of 10 μg/d (400 IU/day) to all pregnant mothers suggest that this dose is sufficient to prevent overt neonatal complications of vitamin D deficiency. Recent data suggest that supplementation with dosages above 10 μg/d may be required for optimal health in the mother and child; however, further research is required for the assessment of the benefits and safety of supplementation with higher dosages. Lack of unified advice on vitamin D supplementation of pregnant mothers in the UK hinders the implementation of primary prevention strategies and is likely to leave some deficient mothers without supplementation. The proposed wording for section 4.6 of the SmPC states that the recommended daily intake in pregnant women is 400IU, however in women who are considered to be vitamin D deficient a higher dose may be required. During pregnancy women should follow the advice of their medical practitioner as their requirements may vary depending on the severity of their disease and their response to treatment. With respect to the information on lactation, the applicant proposes to use the wording adopted by the recent EU approved product Detremin. This section will state; Vitamin D and its metabolites are excreted in breast milk. Overdose in infants induced by nursing mothers has not been observed, however, when 38

39 prescribing additional vitamin D to a breast-fed child the practitioner should consider the dose of any additional vitamin D given to the mother. This wording is satisfactory Renal Impairment Vitamin D administration is not contraindicated in patients with mild to moderate renal impairment, as long as adequate precautions are followed. However, severe kidney insufficiency, simultaneous administration of any other vitamin D derivate, vitamin D overdosing or hyperactivity of the parathyroid gland make colecalciferol treatment contraindicated. Comments Statements have been provided in the SmPC to address Pregnancy and lactation and renal impairment. 3.6 Immunological events As the product contains arachis oil, warning on peanut allergy has been included in product information. 3.7 Safety related to drug-drug interactions and other interactions Simultaneous administration of any other vitamin D derivative, vitamin D overdosing or hyperactivity of the parathyroid gland make colecalciferol treatment contraindicated. 3.8 Discontinuation due to AES N/A 3.9 Post marketing experience/risk management No post marketing data are available Proposals for post authorisation follow up (post marketing surveillance) No proposals for post-authorisation follow up were included, save for routine pharmacovigilance Assessor s overall conclusions on clinical safety The summary of safety is generally adequate and this information has been adequately reflected in the SmPC to be in line with other similar products containing colecalciferol. 39

40 OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT QUALITY The important quality characteristics of Fultium D 3 800IU Capsules are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. NON-CLINICAL No new non-clinical data were submitted and none are required for an application of this type. EFFICACY No new clinical data are submitted and none are required for this type of application. The published literature supports the efficacy of this product in the proposed indications. The safety and efficacy of vitamin D 3 is well-known. The presented evidence for well-established use of the product is sufficient. The literature review identifies no new safety issues or concerns. PRODUCT LITERATURE The approved SmPC is satisfactory. The approved labelling artwork complies with statutory requirements. In line with current legislation, the name of the product appears in Braille on the outer packaging and sufficient space has been included for a standard UK pharmacy dispensing label. RISK BENEFIT ASSESSMENT The quality of the product is acceptable and no new non-clinical or clinical safety concerns have been identified. Vitamin D 3 is an active substance of well-known safety and efficacy. Extensive clinical experience with vitamin D 3 is considered to have demonstrated the therapeutic value of the compound. The risk benefit is, therefore, considered to be positive. 40

41 FULTIUM-D IU CAPSULES PL 17871/0151 STEPS TAKEN FOR ASSESMENT 1 The MHRA received the Marketing Authorisation application (PL 17871/0151) on 28 th February Following standard checks and communication with the applicant the MHRA considered the application valid on 1st March Following assessment of the applications the MHRA requested further information relating to the quality dossiers on 7 th June 2011, 13 th September 2011 and 13 th October 2011 and information relating to the clinical dossiers on 7 th June 2011, and 13 th September The applicant responded to the MHRA s requests, providing further information on the quality dossier on 22 nd August 2011, 29 th September 2011 and 25 th October 2011 further information on the clinical dossier on 20 th July 2011 and 29 th September The application (PL 17871/0151) was determined on 28 th October

42 SUMMARY OF PRODUCT CHARACTERISTICS In accordance with Directive 2010/84/EU, the Summaries of Product Characteristics (SmPCs) for products granted Marketing Authorisations at a national level are available on the MHRA website. 42

43 PATIENT INFORMATION LEAFLET In accordance with Directive 2010/84/EU, the Patient Information Leaflets (PILs) for products granted Marketing Authorisations at a national level are available on the MHRA website. 43

44 FULTIUM-D IU CAPSULES PL 40861/0002 CARTON: LABELLING 44

45 45

46 BLISTER FOIL 46

47 FULTIUM-D IU CAPSULES PL 40861/0002 STEPS TAKEN AFTER AUTHORISATION - SUMMARY Date submitted Application Scope type 14 October 2014 Type II To update section 4.2 (Posology and administration) of the Summary of Product Characteristics (SmPC) to specify the posology for the prevention of vitamin D deficiency during pregnancy and breast-feeding. Consequentially the Patient Information Leaflet (PIL) has been updated. Outcome Approved 12 December

48 ANNEX 1 Our Reference: PL 40861/0002, Case 0006 Product: Fultium-D IU Capsules Marketing Authorisation Holder: Internis Pharmaceuticals Limited Active Ingredient(s): Colecalciferol Type of Procedure: Submission Type: Submission Category: Submission Complexity: EU Procedure Number (if applicable): National Variation Type II Standard Not applicable Reason: To update section 4.2 (Posology and administration) of the Summary of Product Characteristics (SmPC) to specify the posology for the prevention of vitamin D deficiency during pregnancy and breast-feeding. Consequentially the Patient Information Leaflet (PIL) has been updated. Supporting Evidence The MAH has included the updated SmPC and PIL fragments as well as a clinical overview justifying the changes. Evaluation The following was presented in the overview to support the application: A randomized controlled trial compared the effectiveness and safety of prenatal 2000 IU and 4000 IU per day compared with 400 IU per day vitamin D 3 supplementation in a population in which vitamin D deficiency is endemic. Arab women (United Arab Emirates) were randomized at weeks of gestation to 400, 2000, or 4000 IU per day vitamin D 3 ; treatment was continued to delivery. Serum 25(OH)D concentrations were measured during pregnancy and at delivery. Of 192 enrolled, 162 (84%) continued to delivery. Serum 25(OH)D at enrollment was low with a mean of 20.5 nmol/l. Mean serum 25(OH)D concentrations at delivery and in cord blood were significantly higher in the 2000 and 4000 IU than the 400 IU per day group (P < 0.001) and was highest in the 4000 IU per day group. The percent who achieved 25(OH)D greater than 80 nmol/l and greater than 50 nmol/l concentrations in mothers and infants was highest in 4000 IU per day group (65.1% and 90.7%, respectively). Discussion Whilst the population in the study is not comparable to that in the UK, it does show that the treatment of deficient subjects with a IU/day is effective in treatment. As such the study is considered supportive in the treatment of deficiency. In a similar study, a total of 257 pregnant women at weeks' gestation were randomised to 2000 IU per day vs 4000 IU per day following a 1-month run-in at 2000 IU per day. Participants were monitored for hypercalciuria, hypercalcemia, and 25(OH)D status. In this group, based in South Carolina, maternal 25(OH)D (n = 161) at baseline was somewhat higher than that seen in the previous study at 56.7 nmol/l, and increased to 90.4 ± 37.4 nmol/l and 94.6 ± 33.7 nmol/l in the 2000 IU and 4000 IU groups, respectively. Although maternal 25(OH)D change from baseline did not differ between groups, 25(OH)D levels increased more rapidly for the higher dose group (P <0.01). Neonatal vitamin D status was good; mean cord blood 25(OH)D was 55.2 ± 25.7 nmol/l in the 2000 IU group and 67.4 ± 33.2 nmol/l in the 4000 IU group (P = 0.024). After controlling for race and study site, preterm birth and 48

49 labour were inversely associated with pre-delivery and mean 25(OH)D, but not baseline 25(OH)D. While outcome data were suggestive of risk reduction in infection, pre-term labour, and pre-term birth, the study was not powered for these endpoints, and did not include a control group (400 IU). Discussion This study is in patients with normal vitamin D levels. It demonstrates that such patients do not need such large supplementation and is as such is not supportive of this application. A randomised controlled trial reported in 494 women with a singleton pregnancy at 12 to 16 weeks gestation that received 400, 2,000 or 4,000 IU vitamin D 3 day until delivery. The primary outcome was maternal/neonatal circulating 25(OH)D at delivery, with secondary outcomes 25(OH)D 80 nmol/l achieved and 25(OH)D concentration required to achieve maximal 1,25(OH)2D production. The results for the 350 completed subjects showed mean 25(OH)D by group at delivery and 1-month before delivery as being significantly different (p<0.0001), and percent who achieved sufficiency was significantly different by group, greatest in 4,000 IU group (p<0.0001). The relative risk (RR) for achieving 80 nmol/l within one month of delivery was significantly different between 2,000 vs. 400 IU, RR 1.52 [CI ]); 4,000 vs. 400 IU, (RR 1.60 [CI ]), but not between 4,000 vs. 2,000 IU, (RR 1.06 [CI ]). Circulating 25(OH)D had a direct influence on circulating 1,25(OH)2D concentrations throughout pregnancy (p<0.0001) with maximal production of 1,25(OH)2D in all strata in the 4,000 IU group. The publication concludes that vitamin D supplementation of 4,000 IU per day for pregnant women was safe and most effective in achieving sufficiency in all women and their neonates regardless of race. Discussion The MAH has not discussed the patients base vitamin D status in the summary, however the paper shows that again, the subjects were not deficient and that treatment with 400 IU maintained such levels. The paper is therefore seen to support 400 IU as the standard maintenance dose as per UK national guidelines. The paper is not supportive in giving such patients higher doses or in deficiency. In the review of the prevention of rickets and vitamin D deficiency in infants, children and adolescents, Wagner et al (2008) referred to studies in which supplements of 1000 IU per day of vitamin D to pregnant women resulted in a 12.5 to 15.0 nmol/l increase in circulating 25(OH)D concentrations in both maternal and cord serum compared with non-supplemented controls. Maternal 25(OH)D concentrations ranged from a mean of approximately 25 nmol/l at baseline to 65 ± 17.5 nmol/l at 230 days of gestation in the group of women who received 1000 IU of vitamin D per day during the last trimester. In comparison, 25(OH)D concentrations were 32.5 ± 20.0 nmol/l in the unsupplemented control group. These data suggest that doses exceeding 1000 IU of vitamin D per day are necessary to achieve 25(OH)D concentrations of >50 nmol/l in pregnant women. Wagner concluded that the significance of these findings for those who care for the paediatric population is that when a woman who has vitamin D deficiency gives birth, her neonate also will be deficient. Discussion With no comparison to 400 IU, it is difficult to know how 1000 IU dosing is different to the recommended maintenance dose in this population. Of note, the population is considered insufficient but not deficient and the levels reached were at the end of treatment still insufficient but nearly replete. This can be seen as supportive of the treatment with IU in those whom need maintenance after treatment, where levels may be low but not insufficient any more. 49

50 Grant et al (2014) investigated dose / 25(OH)D levels from 27 weeks gestation to birth and then in their infants from birth to age 6 months. The 276 women were randomised to one of three treatment groups; placebo / placebo, 1,000 IU per day during pregnancy followed by 400 IU per day for the infant or 2,000 IU per day during pregnancy followed by 800 IU per day for the infant. Serum 25(OH)D and calcium concentrations were measured at enrolment, 36 weeks gestation, in cord blood and in the infants at 2, 4 and 6 months of age. At enrolment, the proportions with serum 25(OH)D 20 ng/ml for placebo, lower-dose, and higher-dose groups were 54%, 64%, and 55%, respectively. The proportion with 25(OH)D 20 ng/ml was larger in both intervention groups at 36 weeks' gestation (50%, 91%, 89%, P <0.001). In comparison with placebo, the proportion of infants with 25(OH)D 20 ng/ml was larger in both intervention groups to age 4 months: cord blood (22%, 72%, 71%, P <0.001), 2 months (50%, 82%, 92%, P <0.001), and 4 months (66%, 87%, 87%, P = 0.004), but only in the higher-dose group at age 6 months (74%, 82%, 89%, P = 0.07; higher dose versus placebo P = 0.03, lower dose versus placebo P = 0.21). It was concluded that daily vitamin D supplementation during pregnancy and then infancy with 1000/400 IU or 2000/800 IU increases the proportion of infants with 25(OH)D 20 ng/ml, with the higher dose sustaining this increase for longer. Discussion The data from the above study concerning the women shows that the dosing in non replete individuals at the IU range is acceptable. As such it supports the treatment of deficiency and the maintenance in those treated. It does not support the use in normal maintenance. Safety: Discussion No issues with regard to safety in the proposed dose ranges are seen. Conclusion The application supports the efficacy and safety of the posology in the treatment of deficiency in pregnancy. It also supports the higher dose maintenance in patients who have been treated for deficiency. However, the data gives no convincing evidence that in a normal population with satisfactory vitamin D levels a dose higher than 400 IU (as per UK national guidelines) for maintainance of vitamin D status is required. The amendments to the SmPC and PIL are acceptable. In accordance with Directive 2010/84/EU, the Summaries of Product Characteristics (SmPCs) and Patient Information Leaflets (PILs) for products granted Marketing Authorisations at a national level are available on the MHRA website. 50

51 Decision: Approved 12 December