Public Assessment Report

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1 Public Assessment Report Fultium-D 3 20,000 IU Capsules (Colecalciferol) UK Licence No: PL 17871/0210 Jenson Pharmaceutical Services Ltd

2 LAY SUMMARY Fultium-D 3 20,000 IU Capsules (colecalciferol) This is a summary of the Public Assessment Report (PAR) for Fultium-D 3 20,000 IU Capsules (PL 17871/0210). It explains how Fultium-D 3 20,000 IU Capsules were assessed and their authorisation recommended, as well as their conditions of use. It is not intended to provide practical advice on how to use Fultium-D 3 20,000 IU Capsules. For practical information about using Fultium-D 3 20,000 IU Capsules, patients should read the package leaflet or contact their doctor or pharmacist. What are Fultium-D 3 20,000 IU Capsules and what are they used for? Fultium-D 3 20,000 IU Capsules is a medicine with well-established use. This means that the medicinal use of the active substance of Fultium-D 3 20,000 IU Capsules has been in well-established use in the European Union (EU) for at least ten years, with recognised efficacy and an acceptable level of safety. Fultium-D 3 20,000 IU Capsules are used to treat or prevent vitamin D deficiency. Deficiency of vitamin D may occur when a diet or lifestyle does not provide a patient enough vitamin D or when the body requires more vitamin D (for instance during pregnancy). Fultium-D 3 may also be prescribed for certain bone conditions, such as thinning of the bone (osteoporosis) when it will be given to a patient with other medicines. How do Fultium-D 3 20,000 IU Capsules work? Fultium-D 3 20,000 IU Capsules is a vitamin product containing colecalciferol (equivalent to 500 micrograms vitamin D 3 ). 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 are Fultium-D 3 20,000 IU Capsules used? Fultium-D 3 20,000 IU Capsules are taken by mouth. A single capsule should be swallowed whole with water, preferably with the main meal of the day. The recommended dose in adults for prevention of vitamin D deficiency is 1 capsule (20,000 IU) per month, higher doses may be required in certain situations. The recommended dose in adults for treatment of vitamin D deficiency is 2 capsules (40,000 IU) per week for 7 weeks, followed by maintenance therapy, (equivalent to 1,400-2,000 IU/day, such as 2-3 capsules per month), based on the doctor s advice. The recommended dose in adolescents (12-18 years) is 1 capsule (20,000 IU) every 6 weeks for prevention of vitamin D deficiency and once every 2 weeks for 6 weeks for the treatment of vitamin D deficiency. Fultium-D 3 20,000 IU Capsules should not be used in children under 12 years. This medicinal product is not recommended for use during pregnancy and breast feeding. Fultium-D 3 20,000 IU Capsules can only be obtained on prescription from a doctor. For further information on how Fultium-D 3 20,000 IU Capsules are used, please refer to the Summary of Product Characteristics and the Patient Information Leaflet available on the MHRA website. 2

3 What benefits of Fultium-D 3 20,000 IU Capsules have been shown in studies? As colecalciferol is a well-known substance, and its use in the treatment and prevention of vitamin D deficiency is well-established, the applicant presented data from the scientific literature. The literature provided confirmed the efficacy and safety of colecalciferol in the treatment and prevention of vitamin D deficiency. What are the possible side effects of Fultium-D 3 20,000 IU Capsules? Like all medicines, this medicine can cause side effects, although not everybody gets them. For information about side effects that may occur with taking Fultium-D 3 20,000 IU Capsules, please refer to the package leaflet or the Summary of Product Characteristics available on the MHRA website. Why are Fultium-D 3 20,000 IU Capsules approved? The use of Fultium-D 3 20,000 IU Capsules in the treatment and prevention of vitamin D deficiency is well-established in medical practice and documented in the scientific literature. No new or unexpected safety concerns arose from this application. It was, therefore, considered that the benefits of Fultium-D 3 20,000 IU Capsules outweigh the risks and the grant of a Marketing Authorisation was recommended. What measures are being taken to ensure the safe and effective use of Fultium-D 3 20,000 IU Capsules? A Risk Management Plan has been developed to ensure that Fultium-D 3 20,000 IU Capsules are 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 3 20,000 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. Other information about Fultium-D 3 20,000 IU Capsules A Marketing Authorisation was granted in the UK on 23 rd January The full PAR for Fultium-D 3 20,000 IU Capsules follows this summary. For more information about treatment with Fultium-D 3 20,000 IU Capsules, read the Patient Information Leaflet (PIL), or contact your doctor or pharmacist. This summary was last updated in March

4 TABLE OF CONTENTS I Introduction Page 5 II Quality aspects Page 6 III Non-clinical aspects Page 7 IV Clinical aspects Page 13 V User consultation Page 26 VI Overall conclusion, benefit/risk assessment and Page 27 recommendation Table of content of the PAR update Page 31 4

5 I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the Medicines and Healthcare products Regulatory Agency (MHRA) granted Jenson Pharmaceutical Services Ltd a Marketing Authorisation for the medicinal product Fultium-D 3 20,000 IU Capsules (PL 17871/0210) on 23 rd January The product is a prescription-only medicine (POM) indicated for the treatment and prevention of vitamin D deficiency and as an adjunct to specific therapy for osteoporosis in patients with vitamin D deficiency, in adults, the elderly and adolescents. This is a line extension application submitted under Article 10a, well-established use, of Directive 2001/83/EC, as amended, and concerns a new strength of the currently licensed products, Fultium-D IU Capsules (PL 17871/0151) and Fultium-D 3 3,200 IU Capsules (PL 17871/0208). In its biologically active form vitamin D 3 stimulates intestinal calcium absorption, incorporation of calcium into the osteoid, and release of calcium from bone tissue. In the small intestine it promotes rapid and delayed calcium uptake. The passive and active transport of phosphate is also stimulated. In the kidney, it inhibits the excretion of calcium and phosphate by promoting tubular resorption. The production of parathyroid hormone (PTH) in the parathyroids is inhibited directly by the biologically active form of vitamin D 3. PTH secretion is inhibited additionally by the increased calcium uptake in the small intestine under the influence of biologically active vitamin D 3. No new non-clinical or clinical studies were necessary for this application, which is acceptable given that this is a bibliographic application for a product containing an active of well-established use. Bioequivalence studies are not necessary to support this application. 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 manufacturing and assembly of this product. Evidence of compliance with GMP has been provided for the named manufacturing and assembly sites. A summary of the pharmacovigilance system and a detailed risk management plan have been provided with this application and these are satisfactory. 5

6 II QUALITY ASPECTS II.1 Introduction Each Fultium-D 3 20,000 IU Capsule contains 20,000 IU colecalciferol (equivalent to 500 micrograms vitamin D 3 ) as active ingredient. The excipients present in this product are maize oil, refined, butylated hydroxytoluene (BHT) (E321) making up the capsule, the capsule shell is composed of glycerol (E422), purified water, red carmine (E120) and gelatin (E441). All excipients comply with their respective European Pharmacopoeia monographs with the exception of red carmine (E120) which complies with the United States Pharmacopeia monograph. Satisfactory Certificates of Analysis have been provided for these excipients. The only excipient used that contains material of animal or human origin is gelatin. Satisfactory documentation has been provided by the gelatin suppliers stating that the gelatin they provide complies with the criteria described in the current version of the monograph Products with risk of transmitting agents of animal spongiform encephalopathies. The finished product is packaged in opaque, white polyvinylchloride (PVC)/polyvinylidenechloride (PVdC)/aluminium foil blisters. Pack sizes of 7, 10, 14, 15, 20, 28 and 30 capsules have been authorised, although not all pack sizes may be marketed. Satisfactory specifications and Certificates of Analysis have been provided for all packaging components. All primary packaging complies with the current European regulations concerning materials in contact with food. II.2 Drug Substance INN: Colecalciferol Chemical name(s): (5Z,7E)-9,10-Secocholesta-5,7,10(19)-trien-3β-ol Structure: Molecular formula: Molecular weight: Appearance: Solubility: C 27 H 44 O g/mol White or almost white crystalline powder. Practically insoluble in water, freely soluble in ethanol (96 per cent) and soluble in fatty oils. Colecalciferol is the subject of a European Pharmacopoeia monograph. All aspects of the manufacture and control of the active substance colecalciferol are covered by a European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificate of Suitability. 6

7 II.3 Medicinal Product Pharmaceutical Development The objective of the development programme was to formulate a safe, efficacious, stable line extension presentation containing 20,000 IU of colecalciferol. Manufacture of the product A satisfactory batch formula has been provided for the manufacture of the product, along with an appropriate account of the manufacturing process. The manufacturing process has been validated and has shown satisfactory results. Process validation data on commercial batches have been provided. The results are satisfactory. Finished Product Specification The finished product specification is satisfactory. The test methods have been described and have been adequately validated. Batch data have been provided that comply with the release specifications. Certificates of Analysis have been provided for any working standards used. Stability of the product Finished product stability studies have been conducted in accordance with current guidelines and in the packaging proposed for marketing. Based on the results, a shelf-life of 24 months with storage conditions Do not store above 30 C and Store blister foil in original container in order to protect from light have been set. These are satisfactory. II.4 Discussion on chemical, pharmaceutical and biological aspects The grant of a Marketing Authorisation is recommended. III NON-CLINICAL ASPECTS III.1 Introduction Colecalciferol is a widely used, well-known active substance. The applicant has not provided additional studies and further studies are not required for this type of application. An overview based on literature review is, thus, appropriate. The non-clinical overview has been written by an appropriately qualified person. The pharmacology, pharmacokinetics and toxicology aspects of this report were considered adequate. III.2 Pharmacodynamics Vitamin D plays a central role in calcium and phosphate homeostasis and is essential for the proper development and maintenance of bone. Colecalciferol is converted to 25(OH)D mainly in the liver, which in turn is converted to the active form, 1,25(OH) 2 D, mainly in the kidney. Its effects on the classic vitamin D-responsive tissues (intestine, skeleton, parathyroid gland and kidney) are described below, as discussed in the applicant s non-clinical overview. Intestine 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. 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. 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 are important components. The vitamin D receptor (VDR)-mediated effects of 1,25(OH) 2 D 3 may not be the only mode of action by 7

8 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, although significant phosphate absorption also occurs in 1,25(OH) 2 D 3 -deficient states. Skeleton Vitamin D is essential for the development and maintenance of a mineralised skeleton. Vitamin D deficiency results in rickets in young growing animals and osteomalacia in adults. 1,25(OH) 2 D 3 induces bone formation by inducing the synthesis of bone matrix proteins and mineral apposition. Parathyroid glands Parathyroid hormone (PTH) 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 ionised 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-alpha hydroxylase, 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. Kidney The most important effects of 1,25(OH) 2 D 3 in the kidney are the suppression of 1-alpha hydroxylase activity and the stimulation of 24-hydroxylase activity. Both effects of the sterol are VDR mediated. 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. Secondary pharmacodynamics The effects of vitamin D on a range of non-classic vitamin D-responsive tissues was also described. Hematopoietic tissues Anaemia, decreased bone cellularity, extramedullary erythropoiesis and a time-dependent reduction in spleen colony-forming units have been reported in vitamin D deficiency and vitamin D-deficient rickets. The immune system A role for vitamin D was suggested in immunology prior to the finding of the VDR in cells of the immune system. Recurrent infections are commonly associated with vitamin D-deficient rickets, and an impaired defence mechanism often accompanies chronic renal failure, a state of prolonged 1,25(OH) 2 D 3 deficiency. In both conditions, the impaired immunity can be improved with 1,25(OH) 2 D 3 therapy. 1,25(OH) 2 D 3 interacts with mature monocytes and macrophages, enhancing their immune function and improving host defence against both bacterial infection and tumour cell growth. In addition, 1,25(OH) 2 D 3 promotes macrophage survival and function at the increased temperatures associated with tissue inflammation by inducing heat shock protein synthesis. In contrast to the stimulatory effects of the hormone on monocytes and macrophages, the main action of 1,25(OH) 2 D 3 in lymphocytes is to act as an immunosuppressive agent. It does so by decreasing both the rate of proliferation and the activity of T cells and B cells, and by inducing the availability of suppressor T cells, which further contributes to limiting lymphocyte activity. Skin 1,25(OH) 2 D 3 has antiproliferative and prodifferentiating effects of in keratinocytes, melanocytes, and fibroblasts and immunosuppressive properties on Langerhan s cells, the antigen presenting cells of the skin and skin development. It has been shown that UVB-induced production of vitamin D 3 in human 8

9 skin results in formation of substantial amounts of calcitriol in keratinocytes which suppress the growth and initiate differentiation of these cells. Muscle Experimental studies showed that muscle tissue is a direct target site for vitamin D metabolites and offer biochemical evidence for the association between vitamin D deficiency and muscle weakness. Although 1,25(OH) 2 D 3 is considered to be the active metabolite affecting target sites, including muscle, clinical studies reported a relation between serum 25(OH)D 3 and muscle strength and functional ability. Two mechanisms might explain these findings. First, the serum 25(OH)D 3 concentration is 1000 times that of serum 1,25(OH) 2 D 3, which might result in competitive binding of the two vitamin D metabolites on the VDR. Another possible explanation is that peripheral tissues, previously recognised as target sites for vitamin D metabolites, were found to express the mitochondrial enzyme calcidiol 1-monooxygenase, or 1-alpha-hydroxylase. Activation of 25(OH)D 3 locally in target tissues may be involved in regionally controlled cell function. Pancreas Vitamin D deficiency results in impaired glucose-mediated insulin secretion that can be reversed by vitamin D repletion. In uremic patients, 1,25(OH) 2 D 3 therapy significantly increases serum insulin concentrations. It has been postulated that 1,25(OH) 2 D 3, through a VDR-mediated modulation of calbindin expression, controls intracellular calcium flux in the islet cells, which in turn affects insulin release. Lung 1,25(OH) 2 D 3 has been suggested as a local paracrine/autocrine effector of fetal lung maturation and is known to affect fibroblast apoptosis. In addition to the vitamin D-responsive tissues discussed above, non-classic target tissues are also affected by vitamin D. 1,25(OH) 2 D 3 exerts a diverse range of biological actions including the control of growth and differentiation of numerous normal and cancerous cell types, modulation of hormone secretion by several endocrine glands, regulation of reproductive function and protection of specific neurons from degenerative processes. Prostate cancer incidence and mortality are inversely associated with solar UV radiation and with serum 25(OH)D concentrations, and it has been estimated that about 20% of the breast cancer burden of Europe is a manifestation of vitamin D deficiency. The antiproliferative and prodifferentiating properties of 1,25(OH) 2 D 3 suggested an important role for the sterol during embryonic development. However, the lack of a functional VDR both in patients and in the VDR null mice produces significant phenotype, only after weaning, suggesting that the VDR is not essential in the development of major organ systems during embryogenesis. An exception is the essential role of the VDR in skin and hair development. A role for vitamin D in reproduction was suggested by the demonstration of reduced female fertility in vitamin D deficient rats and the uterine hypoplasia of the VDR null mice. Female fertility could be corrected by 1,25(OH) 2 D 3, but not by simply raising serum calcium. In contrast, the reduced fertility of vitamin D-deficient males can be restored by raising serum calcium, suggesting that the VDR may not be essential for spermatogenesis and male reproduction. In vivo, 1,25(OH) 2 D 3 administration to rat or mice prevents or halts the progression of encephalomyelitis, which suggests that the nervous system is a target for the immunosuppressive actions of the sterol. Cultures of newborn brain microglia and cells of the monocyte-macrophage lineage, synthesise 1,25(OH) 2 D 3. The sterol, in turn, promotes phagocytic activity of adult retinal glia. Ex vivo studies in isolated avian nerves suggest a role for vitamin D in conductance velocity in motor neurons. The potential of 1,25(OH) 2 D 3 to prevent the loss of injured neurons was suggested by the antiproliferative and prodifferentiating effects of the sterol in a neuroblastoma cell line. 9

10 The essential role of vitamin D on the maintenance of calcium and phosphorus homeostasis has been adequately reviewed in the non-clinical overview. This is satisfactory. III.3 Pharmacokinetics Vitamin D 3 is the product of ultraviolet irradiation of 7-dehydrocholesterol (a cholesterol-like precursor) found in abundant quantities in the skin of animals or can be provided in the diet. Absorption Vitamin D is absorbed in the small intestine, a process that requires the presence of fat, bile and pancreatic enzymes and is transported via lymph to the liver. Distribution Vitamin D and its hydroxylated metabolites 25(OH)D, 24,25(OH) 2 D, and 1,25(OH) 2 D are lipophilic molecules and are transported in the circulation bound to plasma proteins, the most important of which is the vitamin D-binding protein (DBP). Vitamin D administered parenterally binds to both lipoproteins and DBP. Lipoproteins are more efficient than DBP to deliver vitamin D synthesised 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. Metabolism The first step in the metabolic activation of vitamin D 3 is hydroxylation of carbon 25 to form 25(OH)D. This occurs primarily in the liver, although other tissues including skin, intestine and kidney have been reported to catalyse 25-hydroxylation of vitamin D. The hepatic 25-hydroxylation involves cytochrome P450 monooxygenase(s). At least two enzymes have been reported: one mitochondrial, the other microsomal, although the identity of the cytochrome P450s remains to be determined. Plasma 25(OH)D levels are commonly used as an indicator of vitamin D status. 25(OH)D is further hydroxylated to form 1,25(OH) 2 D, the active form of vitamin D3. This occurs mainly in the kidney, catalysed by 25(OH)D-1-alpha-hydroxylase. Vitamin D compounds are catabolised primarily by oxidation of the side chain. The major catabolic enzyme is vitamin D-24-hydroxylase, another mitochondrial cytochrome P450 requiring molecular oxygen and reduced ferredoxin. The oxidation of the side chain of 25(OH)D 3 and 1,25(OH) 2 D 3 is initiated at carbon C-24. This is followed by further oxidation of carbon C-24 to a ketone, oxidation of carbon C-23, and subsequent oxidative cleavage of the side chain. Each oxidation step leads to progressive loss of biological activity. The final cleavage product of 1,25(OH) 2 D 3, calcitroic acid, is biologically inert. The control of serum 1,25(OH) 2 D 3 levels is dictated by the calcium and phosphorus needs of the animal, and exerted through the coordinated action of classic mineral-regulating target organs, the kidney, intestine, bone, and the parathyroid glands. The major regulators of 1,25(OH) 2 D 3 levels are parathyroid hormone (PTH), calcium, phosphate and 1,25(OH) 2 D 3 itself. 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. 25(OH)D has an experimental elimination half-life of 19 days. Metabolites are eliminated primarily (96%) through the bile and faeces. The pharmacokinetic properties of vitamin D have been adequately reviewed in the non-clinical overview. 10

11 III.4 Toxicology Single dose toxicity and repeated-dose toxicity Hypercalcaemia associated with hypervitaminosis D gives rise to numerous debilitating effects that would include loss of tubular concentration function of the kidney with polyuria and hypercalciuria, which would predispose to nephrolithiasis and reduced glomerular filtration rate. Prolonged hypercalcaemia can cause calcification of soft tissues, including kidney, blood vessels, the heart and the lungs. Single dose toxicity and LD 50 values have been published following oral administration of colecalciferol to a number of species including mice, rats and dogs. Immediate effects in dogs are bloody diarrhoea, anorexia, thirst, polyuria and prostration. Repeated dose studies have reported in a number of species including rats, cats, pigs, horses and monkeys. In rats given daily doses of 0, 5000, 10,000 or 20,000 IU vitamin D 3 /kg body weight from 10 weeks of age, serum calcium and phosphorus levels and calcium excretion into urine were markedly increased. At the low and mid-doses, the rats showed occasional foci of kidney tubular calcification while this was more prevalent at the highest dose of 20,000 IU vitamin D 3 /kg. At 26 weeks all kidneys from the highest dose showed mild to moderate nephrocalcinosis, while those in the low and mid-dose groups showed mild and nearly no calcinosis, respectively. Groups of two month-old swine were fed dietary vitamin D 3 at doses of 2.5, 7.5, 50 and 100 μg/kg feed (equivalent to 0.12, 0.45, 3 and 6 μg vitamin D 3 /kg body weight, respectively) for four months. Particularly the highest dose group had thickening of the intima of the coronary vessels. Increased levels of lipid containing- and degenerative cells were also seen. Colecalciferol was more toxic in Rhesus monkeys than ergocalciferol. Daily doses of 50,000 IU, 100,000 IU and 200,000 IU of colecalciferol or ergocalciferol were given, and all receiving colecalciferol developed hypercalcaemia, died within 16 to 160 hours of the start of the study and had extensive soft tissue mineralisation and nephrocalcinosis. As with other animals, high doses of vitamin D given to horses results in soft tissue calcification. A number of cases of calcinosis were seen in cats during and pathological examination of 5 out of 21 animals was performed. Elevated levels of phosphorus, blood urea nitrogen and serum creatinine were determined. Increased density of systemic bones was revealed by X-ray analysis and marked calcification was observed in most organs. In the lungs, kidneys and the stomach, the calcification was associated with deposition of oxalate crystals. The cats had been fed commercial pet food containing 6,370 IU vitamin D/100 g diet (approximately 1600 μg/kg). The length of feeding varied since the cats were aged 1-9 years and had been fed the food from an early age. Genotoxicity and carcinogenicity A negative bacterial reverse mutation (Ames) test has been reported, using Salmonella typhimurium strains TA1535, TA1537, TA97, TA98 and TA100. Carcinogenicity studies have not been conducted but vitamin D is an endogenous substance produced naturally by contact of the skin by UV light, therefore any cancer potential risk from this replacement therapy is not expected to exceed that of a population with normal vitamin D level. Furthermore, vitamin D 3 appears to have antiproliferative properties. 11

12 Reproductive and Developmental toxicity Teratogenicity is reported to have been observed in animal studies at higher doses of vitamin D than the human therapeutic range. Offspring from pregnant rabbits treated with high doses of vitamin D have lesions anatomically similar to those of supravalvular aortic stenosis and offspring not showing such changes show vascular toxicity similar to that seen in adult humans following acute vitamin D toxicity. Ultrastructural studies were conducted on the coronary arteries of six week old piglets. Offspring of sows that had been fed high levels of vitamin D during pregnancy (55 μg/kg), had more degenerated smooth muscle cells in their coronary arteries, than those from sows fed low doses (8 μg/kg) of vitamin D, suggesting that excess dietary intake of vitamin D by pregnant animals may have potential angiotoxic effects on the coronary arteries of their offspring. In pregnant rats administered high doses, 320,000 or 480,000 IU vitamin D daily by oral gavage (8,000 or 12,000 μg/day) for 1, 2 or 4 days during gestation, a significant decline in maternal weight, as well as a high rate of morbidity and mortality was observed. In dams killed on day 22 of pregnancy, fetal and placental growths were significantly retarded. Fetal bone lesions associated with a generalised loss of ossification, placental oedema or calcification, accompanied by a loss of structure of the placenta and degenerative manifestations were observed. A striking alteration in the fetal face was noted in 33-39% of the fetuses, termed by the authors carnival fetuses, consisting of the appearance of white nacreous plaques around the eyes and ears. Similar observations were made in pregnant mice. The recommended daily allowance (RDA) of vitamin D for pregnant or lactating women of 18 years or younger is 5 μg (200 IU)/day and for pregnant or lactating women of years is also 5 μg (200 IU)/day. The upper level (UL) which is the maximum level of a daily nutrient intake that is likely to pose no risk of adverse effects is 50 μg (2000 IU)/day for all age groups. The published literature on the toxicology of colecalciferol has generally been reviewed adequately in the applicant s non-clinical overview. Although vitamin D and its active metabolite are essential for the normal functioning of physiological systems in animals and man, excess levels of colecalciferol are toxic and lead to the development of hypercalcaemia and associated symptoms such as hypercalciuria, ectopic calcification and renal and cardiovascular damage. Similarly, although vitamin D is required for reproduction and lactation and normal growth and development, excess intake during pregnancy is teratogenic in the rabbit. The impurities and residual solvents in the active substance are controlled within appropriate limits and raise no toxicological concerns. III.5 Ecotoxicity/environmental risk assessment (ERA) The Marketing Authorisation holder has provided adequate justification for not submitting an Environmental Risk Assessment (ERA). This is acceptable as vitamins are unlikely to result in significant risk to the environment. III.6 Discussion on the non-clinical aspects This application for high dose vitamin D is based on well-established use and as such the dossier comprises a review of published literature. The essential nature of vitamin D and its active metabolite for the normal functioning of physiological systems and growth and development in animals and man has been described, as well as the adverse effects of excessive intake. There are no objections to the approval of this product from a non-clinical point of view. 12

13 IV CLINICAL ASPECTS IV.1 Introduction Colecalciferol is a well-established active substance and has been licensed in the UK and EU for many years. This is a line extension application for a new strength of the currently licensed products, Fultium- D IU Capsules (PL 17871/0151) and Fultium-D 3 3,200 IU Capsules (PL 17871/0208). No new clinical studies have been supplied, however, the applicant has submitted sufficient bibliographic data in support of this application. In addition, a new clinical overview has been provided to cover this new formulation. IV.2 Pharmacokinetics The pharmacokinetics of vitamin D are well-established. 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 absorption is not affected by the vitamin D status. 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. 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. 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 (the time needed for the amount of a compound present in all body stores to decrease by half) of weeks to months. Calcifediol has an experimental elimination half-life of 19 days. Metabolites are eliminated primarily (96%) through the bile and faeces. The applicant s summary of the pharmacokinetics of vitamin D is considered acceptable. IV.3 Pharmacodynamics UV-B irradiation of the skin triggers photolysis of 7- hydroxycholesterol (provitamin D 3 ) to previtamin D 3 in the plasma membrane of human skin keratinocytes. Previtamin D 3 is then rapidly converted to vitamin D 3 by the body s temperature. Vitamin D 3 from the skin and dietary vitamin D undergo sequential hydroxylations to 25(OH)D (in the liver) and to the biologically active form 1,25 dihydroxyvitamin D (in the kidneys). Excessive solar UV-B irradiation does not cause vitamin D 13

14 intoxication as excess pre- and vitamin D 3 are photolysed to biologically inactive products. The principal physiological function of vitamin D in all vertebrates, including humans, is to maintain serum calcium and phosphorus concentrations in a range that supports cellular processes, neuromuscular function and bone ossification. Vitamin D 3 and vitamin D 2, together with the provitamins they are made from, are all derivatives of sterols and their chemical structure resembles cholesterol, bile acids and the sex hormones. Traditionally, vitamin D has been assigned a passive role in calcium metabolism in that its presence in adequate concentrations was thought to permit efficient absorption of dietary calcium, and to allow full expression of the actions of parathyroid hormone (PTH). It is however also known that vitamin D has a much more active role in calcium homeostasis. Even though it is termed vitamin D, it is the expert s assertion that vitamin D is a hormone that, together with PTH, is major regulator of the concentration of calcium in plasma. The following characteristics of vitamin D are consistent with its hormonal nature: it is synthesised in the skin and under ideal conditions is probably not required in the diet; it is transported in blood to distant sites in the body, where it is activated by a tightly regulated enzyme; its active form binds to specific receptors in target tissues, resulting ultimately in an increased concentration of plasma calcium. Simultaneous treatment with ion exchange resins such as cholestyramine or laxatives such as paraffin oil may reduce the gastrointestinal absorption of vitamin D. 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. Ketoconazole may inhibit both synthetic and catabolic enzymes of vitamin D. Reductions in serum endogenous vitamin D concentrations have been observed following the administration of 300 mg/day to 1200 mg/day ketoconazole for a week to healthy men. However, in vivo drug interaction studies of ketoconazole with vitamin D have not been investigated. The applicant s summary of the pharmacodynamics of vitamin D is considered acceptable. IV.4 Clinical efficacy The efficacy of colecalciferol is well-established. High Dose: The use of the loading dose for the treatment of vitamin D deficient adults is recommended in literature references and guidelines so this additional commentary will concentrate on the justification to support the use of 2 x Fultium-D 3 20,000 IU Capsules being dosed weekly for 7 weeks. This dose is equivalent to the total administration of a 280,000 IU loading dose (or 5714 IU per day). The justification for this loading dose is supported by the following publications: One of the three new papers described a randomised, double blind, parallel study which evaluated the dose response of monthly supplementation of 25,000, 50,000 and 100,000 IU doses in deficient adult male (n = 65) and female (n = 85) patients over 18 years of age and with body mass index values between 18 and 30 kg/m 2. Each patient group started with mean baseline 25(OH)D levels of between 13 and 14 ng/ml. The results following the 12 week supplementation of either 100,000 IU, 200,000 or 300,000 IU showed a linear dose: response relationship. The rate of recovery of plasma 25(OH)D levels 14

15 for each of the dosing regimens after 4, 8 and 12 week dosing is illustrated by the profiles represented below: While this study was continued through to 12 weeks, the data generated across the first 8 weeks is most relevant to the proposed 7 week loading dose posology for Fultium-D 3 20,000 IU Capsules. Furthermore, the subset of patients receiving 100,000 IU per month is closest to the 40,000 IU per week (160,000 IU per month) proposed for Fultium. By the 8 week data point, this patient group (n = 50) had shown a mean 25(OH)D of 20 ng/ml. This is consistent with the set criteria which requires the loading dose to provide a 25(OH)D of greater than 10 ng/ml. It should be noted that baseline 25(OH)D levels in these patients were above that normally regarded to be deficient, that is, above 10 ng/ml but the dose response and recovery of 25(OH)D is in line with that expected following treatment of patients with Fultium-D 3 20,000 IU Capsules. Achieving greater than 10 ng/ml with this loading dose is of prime importance for highly deficient individuals so the demonstration of a mean 25(OH)D of 20 ng/ml is highly supportive. Otherwise with this study, the investigators concluded that starting with loading dose treatment in vitamin D deficient patients allowed faster correction of the condition. There were no safety concerns found with any of the treatment administered during this study. The second new study was a similar study involving multiple doses of 25,000 IU but in this study the investigators considered the treatment of patients suffering with different degrees of vitamin D deficiency. In each patient cohort the investigated dose was compared to placebo in a 4 : 1 ratio randomised in the group. While they struggled to recruit a full cohort of patients with 25(OH)D levels of greater than 30 ng/ml, the other three groups of patients study included 40 patients receiving the active preparation and 10 patients receiving the placebo formulation. The dose given to the most highly deficient patient group (less than 10 ng / ml) receiving the active preparation was 3 x 25,000 IU at the start of the study and at week 2 followed by doses of 2 x 25,000 IU at week 4 and week 8 (total dose of 250,000 IU). The dose given to the patient group with 25(OH)D levels of between 10 and 20 ng/ml that were receiving the active preparation was 2 x 25,000 IU at the start of the study and at week 2 followed by doses of 1 x 25,000 IU at week 4 and week 8 (total dose of 175,000 IU). The dose given to the patient group with 25(OH)D levels of between 20 and 30 ng/ml that were receiving the active preparation was 2 x 25,000 IU at the start of the study followed by 1 x 25,000 IU at weeks 2, 4 and 8 (total dose of 15

16 125,000 IU). The active received by the patient group with 25(OH)D levels greater than 30 ng/ml was 1 x 25,000 IU on each occasion (total dose of 100,000 IU). At the end of the study more than half of the patients treated with the active preparation had achieved 25(OH)D plasma levels in excess of 30 ng/ml and 94% had 25(OH)D plasma levels in excess of 20 ng/ml. The doses administered were found to be safe but it was the higher total loading dose that achieved repletion most readily. The results obtained with the first group described above have greatest relevance when making specific reference to the proposed posology of 40,000 IU per week for 7 weeks for Fultium-D 3 20,000 IU Capsules (total of 280,000 IU) in deficient patients (< 10 ng/ml). In one of the studies, the total 250,000 IU dose over 8 weeks clearly demonstrated efficacy over the placebo group. This active drug substance receiving group had mean 25(OH)D levels of 9 ng/ml at the beginning of the study and by 8 weeks the mean 25(OH)D level had recovered to 28 ng/ml, a 25(OH)D of 19 ng/ml. Again, the results align well with the posology proposed for adult treatment using Fultium-D 3 20,000 IU Capsules. Furthermore, the recommendation of the 7 week loading dose period is shown to be appropriate by both this study and the study reported above. In both studies the administration of product was continued to 12 weeks but the results at 12 weeks were similar to those seen after the initial 8 weeks of loading dose. The third additional publication investigated the monthly dosing of 50,000 IU to healthy young adults for 6 months. This was a double blind, randomised, placebo controlled study in 150 Belgian adults aged between 18 and 30. The direct comparison of 50,000 IU per month (a total of 300,000 IU) with placebo showed clear efficacy for the active treatment arm of the study. The mean plasma 25(OH)D levels rose from 21.2 ng/ml to 30.6 ng/ml ( 25(OH)D of 9.4 ng/ml) after 3 months of treatment and to 36.0 ng/ml ( 25(OH)D of 14.8 ng/ml) after 6 months of treatment. This study did not report 25(OH)D results prior to 3 months into the study so the earlier 25(OH)D values cannot be provided but this slower rate of loading dose administration shows a slower recovery in 25(OH)D levels. No differences in serum calcium levels between the two groups were seen through this study and no other safety issues were identified. The clinical overview originally provided with the application for Fultium-D 3 20,000 IU Capsules also referred to other publications which have relevance to the revised posology now proposed for the product. Investigations of loading dose regimens were investigated in van Groningen (2010a and 2010b). While these were the studies which reported the link between dose requirements and body mass, they still provide useful support of clinical efficacy associated with the 2 x Fultium-D 3 20,000 IU Capsules since they used comparable loading doses. The highest dose administered to patients in van Groningen (2010a) was 25,000 IU every week and cohorts in two of the groups received this dose for either 6 weeks or 8 weeks; total loading doses of either 150,000 IU or 200,000 IU. Again, these are a little lower than that proposed for Fultium-D 3 20,000 IU Capsules in terms of both weekly dose and total loading dose but the results are still supportive of the efficacy claim for the proposed product. The cohort receiving the 6 week loading dose treatment showed a mean Δ25(OH)D level of 43 nmol/l (17 ng/ml) and the cohort receiving the 8 week loading dose treatment showed a mean Δ25(OH)D level of 69 nmol/l (28 ng/ml). The subsequent study published by van Groningen et al (2010b) investigated the treatment of fifty vitamin D deficient subjects (aged 24 to 74) with 50,000 IU colecalciferol three times a week until the calculated cumulative dose was reached. The calculated cumulative dose ranged from 75,000 to 300,000 IU. This dosing rate was higher than that now proposed for Fultium-D 3 20,000 IU Capsules but the total loading dose range bridges the proposed 280,000 IU loading dose. The mean serum 25(OH)D in this study increased from 26 nmol/l to 77 nmol/l, a Δ25(OH)D of 51 nmol/l (20 ng/ml). A one year study, double blind placebo-controlled intervention trial with 421 subjects were included, and 312 completed the study. The subjects were randomized to vitamin D 3 40,000 IU per week (DD group), vitamin D 3 20,000 IU per week (DP group), or placebo (PP group). All subjects were given 500 mg calcium daily. The DD group in this study is obviously the most relevant group since this is the same dose level as that now proposed for Fultium-D 3 20,000 IU Capsules but the extensive duration of 16

17 dosing makes the findings of this study less significant than those described above. At baseline the mean serum 25(OH)D levels were 58 nmol/l (all subjects) and increased to 141 nmol/l in the DD group (a 25(OH)D of 83 nmol/l or 33.2 ng/ml). A study of 75 subjects with osteopaenia / osteoporosis revealed that weekly 50,000 IU doses of vitamin D3 was more effective in normalising 25(OH)D concentrations and suppressing PTH concentrations to normality in the majority than daily 1,000 IU doses. The justifications for adolescent part of the proposed posology is combined for treatment and prevention since two of the previously cited publications bridge the proposed posologies. A study examined the effects of supplementation with vitamin D3 in 102 Iranian girls aged 12 to 15 years who received 50,000 or 100,000 IU vitamin D3 as two doses three months apart (equivalent to 16,667 IU or 33,333 IU per month). For Fultium-D3 20,000 IU Capsules we are proposing 40,000 IU per month for treatment and 20,000 IU per month for prevention so the equivalent monthly doses are similar. Following treatment, mean 25(OH)D concentrations were 38 nmol/l and 57 nmol/l in the 50,000 and 100,000 IU vitamin D groups respectively. These data suggest that, in a population with a high prevalence of severe deficiency, vitamin D3 administered at a dose of 100,000 IU every three months (equal to IU per month) can raise 25(OH)D levels above 30 nmol/l. It was concluded that in order to achieve optimal levels, a higher dose or shorter dosing interval would be required and this would be achieved using the posology being proposed for the Fultium dose. 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, Group B received 50,000 IU bimonthly and Group C received placebo. As mentioned above, Fultium-D 3 20,000 IU Capsules are proposed for dosing at 40,000 IU per month for treatment and 20,000 IU every 6 weeks for prevention so the equivalent monthly doses are similar. 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 improved the status of body vitamin D. A study investigated the quantitative relation between steady state colecalciferol input and the resulting serum 25(OH)D concentration to estimate the proportion of the daily requirement during winter that is met by colecalciferol reserves in body tissue stores. Colecalciferol was administered to 67 males daily in controlled oral doses labelled at 0, 25 (1,000 IU), 125 (5,000 IU), and 250 (10,000 IU) μg colecalciferol for approximately 20 weeks during winter months in a northern latitude. The time course of serum 25(OH)D concentration was measured at intervals over the course of treatment. From a mean baseline value of 70.3 nmol/l, equilibrium concentrations of serum 25(OH)D changed during the winter months in direct proportion to the dose, with a slope of approximately 0.70 nmol/l for each additional 1 μg colecalciferol input. The different study durations may be a factor in these differences but there is insufficient detail in the two publications to allow any direct comparison to be made. The calculated oral input required to sustain the serum 25(OH)D concentration present before the study (ie, in the autumn) was 12.5 μg (500 IU)/d, whereas the total amount from all sources (supplement, food, tissue stores) needed to sustain the starting 25(OH)D concentration was estimated at approximately 96 μg (3,840 IU)/d. By difference, the tissue stores provided approximately 78 to 82 μg per day. The study also showed that the healthy males seemed to use between 3,000 and 5,000 IU colecalciferol per day and that they apparently met > 80% of their winter colecalciferol need with cutaneously synthesized accumulations from solar sources during the preceding summer months. A study of 75 subjects with osteopaenia / osteoporosis revealed that weekly 50,000 IU doses of vitamin D 3 was more effective in normalising 25(OH)D concentrations and suppressing PTH concentrations to normality in the majority than daily 1,000 IU doses. 17

18 In a recently published paper reviewing oral vitamin D supplementation in adult populations, it was suggested that daily dosing is often inadequate due to poor patient compliance. The authors therefore concluded that larger doses given at timed intervals may be a better alternative strategy. In this review, the authors identified 2243 articles in PUBMED using the terms "high dose vitamin D," "single dose vitamin D," "bolus vitamin D," or "annual dose vitamin D." Two independent reviewers identified eligible manuscripts, and a third reviewer evaluated disagreements. Thirty manuscripts were selected according to the selected criteria and the results showed that large, single doses of vitamin D consistently increased serum 25(OH)D concentrations in several vitamin D sufficient and deficient populations. Vitamin D 3 doses of 300,000 IU or greater provided optimal changes in serum 25(OH)D and parathyroid hormone (PTH) concentrations. Vitamin D supplementation also impacted bone health and extra-skeletal endpoints. The authors concluded that this review recommends vitamin D3 be used for supplementation over vitamin D 2, and that single vitamin D 3 doses of 300,000 IU and greater are most effective at improving vitamin D status and suppressing PTH concentrations for up to 3 months. Two further conclusions from the study were that lower doses may be sufficient in certain populations and that vitamin D doses >500,000 IU should be used judiciously in order to minimise adverse events. The aim of a study was to assess the efficacy of therapeutic loading doses of vitamin D supplementation on serum 25(OH)D levels in vitamin D deficient adolescents by taking a total of 482 subjects recruited and dividing them into three groups. Each group receiving 60,000 IU of vitamin D 3 weekly for either 4, 6 or 8 weeks followed by 600 IU daily for 12 weeks. Clinical evaluation was followed by estimation of biochemical markers and serum 25(OH)D levels. Deficiency was observed in 94.8% of adolescents at the start of the study. All three vitamin D loading doses were equally efficacious in achieving vitamin D sufficiency >75 nmol/l (>30 ng/ml) in more than 90% subjects in the three groups. Mean 25(OH)D levels in groups 2 and 3 following maintenance therapy were 67.5±16.5 nmol/l (27.0±6.6 ng/ml) and 70.0±21.8 nmol/l (28.0±8.7 ng/ml), respectively. The authors concluded that supplementing 60,000 IU of vitamin D 3 per week for 4 to 8 weeks, followed by 600 IU daily was an effective strategy for achieving vitamin D sufficiency in Indian adolescents. With respect to variations in dosing regimens, similar significant increases were seen in serum 25(OH)D levels (30-37 μg/l) for daily (1,500 IU vitamin D 3 ), weekly (10,500 IU vitamin D 3 ) or monthly (45,000 IU vitamin D 3 ) dosing in 48 subjects with hip fracture treated for 8 weeks. A study of 59 subjects with vitamin D deficiency treated with either 50,000 IU daily for 10 days or 3 months treatment with 3,000 IU daily, followed by 1,000 IU maintenance therapy was carried out. The authors found that both regimes were equally effective in restoring 25(OH)D concentrations to target (75 nmol/l) and increased concentrations by similar amounts (50 nmol/l). They did not encounter any subjects with toxicity (25(OH)D >220nmol/l) or hypercalcaemia. These authors concluded that high and intermittent dosing was safe, convenient and potentially less costly than daily dosing in terms of restoration of vitamin D concentrations. A study tested two different monthly doses of colecalciferol (30,000 IU and 60,000 IU vitamin D 3 ) in a placebo controlled randomised clinical trial. At the start of the study, 75% of the population were vitamin D insufficient and 10% deficient. Although the lower dose showed a substantial increase in mean serum 25(OH)D, (22 nmol/l) only 24% of participants had a post-supplementation level of over 75 nmol/l, the level proposed by many to be optimal for human health. In comparison, approximately half of those randomised to the higher dose (60,000 IU) achieved this level following a mean increase of 36 nmol/l. Importantly, only 18% in the 30,000 IU group had levels less than the NOS guideline recommended treatment target of 50 nmol/l while the 60,000 IU group achieved this target of replacement. 18

19 A study undertaken to compare the efficacy, tolerability and safety of high doses of intramuscular vitamin D 2 with oral vitamin D 3 supplementation in women with low vitamin-d levels is reported. 107 patients (25(OH)D 50 nmol/l), aged 21 to 89 years were recruited and separated in two groups according to serum vitamin D levels. The first included individuals with serum vitamin D levels between 30 and 50 nmol/l and the second group had more severe depletion (<30 nmol/l). All of the higher baseline group patients (n=65) were treated with either oral monthly colecalciferol 40,000 IU (n=33) or ergocalciferol 300,000 IU bolus injection regimen (n=32). The lower baseline group (n=42) received 300,000 IU oral colecalciferol (n=21) or 300,000 IU intramuscular ergocalciferol (n=21). The primary end points were the serum levels in 25(OH)D at 3 and 6 months for the higher baseline group and at 6 weeks, 3 months and 6 months for the other group. The oral colecalciferol regimen showed significantly greater levels of 25(OH)D from the injectable ergocalciferol treatment at 6 weeks, 3 and 6 months in both groups. The mean difference of 25(OH)D concentrations from baseline was significantly greater for oral colecalciferol treatment at 6 weeks and 3 months in both groups. Less than 5% of patients on injectable ergocalciferol treatment achieved levels >50 nmol/l at 6 weeks, 3 and 6 months, whereas in oral treatment, 100 and 75% of individuals obtained >50 nmol/l at 6 weeks and 3 months, respectively. All patients in the oral colecalciferol regimen with secondary hyperparathyroidism at baseline (45%, n=23) normalized their PTH levels at 3 months, whereas only 49% (41%, n=22) was corrected at 3 months, in the injection ergocalciferol regimen. No case of hypercalcemia, vitamin D toxicity, hypercalciuria or nephrolithiasis were observed. A study compared 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. Fifty-nine vitamin D deficient inpatients (serum 25(OH)D < or = 50 nmol/l) were enrolled in a prospective, randomised, open-label trial. Participants were randomly assigned to a high-dose regimen of colecalciferol IU daily for 10 days or a 3- month, continuous low-dose colecalciferol regimen of 3000 IU daily for 30 days, followed by 1000 IU daily for 60 days. Both groups received calcium citrate 500 mg daily. Twenty-six patients completed the study within 3 - or + 1 months. The mean increases in serum 25(OH)D were similar in both the high- and low-dose groups (to 55 v 51 nmol/l, respectively; P = 0.9). There was no significant difference in the proportion of subjects who attained serum 25(OH)D concentrations > 50 nmol/l between the high- and low-dose groups (9/10 v 13/14, respectively; P = 1.0). Hypercalciuria (urine calcium > 7.5 mmol/day) occurred in three patients (two low-dose, one high-dose), while renal impairment worsened in one patient. No patient developed hypercalcaemia (corrected calcium > 2.6 mmol/l), vitamin D toxicity (25(OH)D > 200 nmol/l) or nephrolithiasis during the study. Both the 10- day, high-dose and the 3-month, low-dose colecalciferol regimens effectively increased serum 25(OH)D to within the normal range. A study in patients with baseline levels of 25(OH)D < 75 nmol/l and treated them with 40,000 IU of oral colecalciferol once-monthly for 3 successive months was undertaken. Every 4 months, the 25(OH)D levels were reassessed. According to measured 25(OH)D levels, the need for therapy continuation was re-evaluated and those patients with 25(OH)D levels < 75 nmol/l were treated for another 3 month cycle. Six cycles were completed in the 24 month study period. Patients with sufficient 25(OH)D stores did not receive further colecalciferol therapy during the following cycle, although therapy was reintroduced if insufficient stores were found in the next cycle. Treatment with phosphate binders, calcimimetics, vitamin D analogues or calcitriol was not discontinued. Of 101 haemodialysis patients at baseline, only three (3.0%) had sufficient 25(OH)D levels (> 75 nmol/l); the majority (52 [51.5%]) were mildly deficient (12 37nmol/l), 17 (16.8%) were severely deficient (< 12 nmol/l), and 29 (28.7%) had insufficient 25(OH)D levels (40 75 nmol/l). During the course of treatment, severe deficiency disappeared as patient 25(OH)D levels gradually improved, they moved into the group of patients who had insufficient 25(OH)D levels. At the end of the study, the majority of patients (50 [76.9%]) had insufficient 25(OH)D levels, nine(13.8%) were mildly deficient and six (9.2%) had sufficient 25(OH)D levels. 19

20 In a New Zealand study high-dose oral regimen for rapid correction of vitamin D deficiency was performed, which made use of the calciferol 50,000 IU tablets available in that country. Thirty two women (mean age 76 ± 4 years; range years) with serum 25-hydroxyvitamin D concentrations less than 10 μg/l were treated with oral calciferol 50,000 IU daily for 10 days. At an average time after treatment of four months, serum 25-hydroxyvitamin D increased from 8 ± 1 μg/l to 21 ± 5 μg/l, bringing all but one patient within the reference range (14 76 μg/l). Serum parathyroid hormone level decreased after treatment by 0.7 ± 1.7 pmol/l (p <0.05), and alkaline phosphatase activity decreased by 5 ± 11 ug/l (p < 0.05). Serum calcium increased by 0.06 ± 0.08 mmol/l (p <0.001), but all values were within the reference range. Data collected from a separate cohort of elderly inpatients showed that similar increases could be achieved with a single 300,000 IU dose, and suggested that serum 25-hydroxyvitamin D levels decline with a half-life of 90 days. A study was designed to assess the impact of a single loading dose of 200,000 IU of vitamin D 3 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 71 to 129 nmol/l (mean, 96 nmol/l), and a residual level at 3 months of 29 to 83 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. A study investigated 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. The study was a randomized-controlled trial with 6-month follow-up. Sixty communitydwelling 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. Colecalciferol 300,000 IU was administered every 3 months, once at baseline and once at 3 months (intermittent D; 3; group) or colecalciferol 1,000 IU/day (daily D; 3; group). 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. The two groups had similar baseline characteristics. All participants had vitamin D deficiency 25(OH)D <20 ng/ml), and 36 subjects (60%) had severe deficiency (<10 ng/ml), with no difference between the groups (severe deficiency: intermittent D; 3; group, n=18; daily D; 3; group, n=18). After 3 and 6 months, both groups had a significant increase in 25(OH)D and a reduction in PTH. Mean absolute increase±standard deviation of 25(OH)D at 6 months was higher in the intermittent D; 3; group (22.7±11.8 ng/ml) than in the daily D; 3; group (13.7±6.7 ng/ml, P<.001), with a higher proportion of participants in the intermittent D; 3; group reaching desirable serum concentration of 25(OH)D 30 ng/ml (55% in the intermittent D; 3; group vs 20% in the daily D; 3; group, P<.001). Mean percentage decrease of PTH in the two groups was comparable, and at 6 months, a similar proportion of participants reached normal PTH values. 25(OH)D response to colecalciferol showed a wide variability. In a study, the objective was to compare the effects on parathyroid hormone and 25(OH)D when dosing either 300,000 IU every three months or 1,000 IU daily (equivalent to 90,000 IU every three months). 60 women aged 65 and older were included in the study. They had creatine clearance rates greater than 65 ml/min and were without diseases or drugs known to influence bone and vitamin D metabolism. The two groups had similar baseline characteristics and all had vitamin D deficiency with serum 25(OH)D levels below 20 ng/ml. 36 of the subjects were actually severely deficient with levels < 10 ng/ml. These 36 subjects were equally divided between the two groups. After 3 and 6 months both groups had a significant increase in 25(OH)D and a reduction in PTH. Mean absolute increase in 25(OH)D at 6 months was higher for the intermittently dosed group than the daily dosed group; intermittent D 3 group 20

21 = 22.7 ± 11.8 ng/ml, daily D 3 group = 13.7 ± 6.7 ng/ml but as mentioned above, the total colecalciferol dose given to each group across each three month period differed. Both groups achieved similar reductions on PTH at 6 months. No subjects developed hypercalcaemia or vitamin D toxicity with either approach. The effect of vitamin D 3 supplementation (daily 800 IU or 100,000 IU every 3 months) compared with sunlight exposure on serum 25(OH)D levels was studied. Baseline serum 25(OH)D for the 211 people included in the study was 22.5 ± 11.1 nmol/l. After six months, mean serum levels increased to 53 nmol/l with 800 IU daily, to 50.5 nmol/l with 100,000 IU every 3 months and to 29.1 nmol/l with sunlight exposure. This study clearly showed equivalent recoveries of serum 25(OH)D levels when comparing equal total doses administered either daily or once every three months. No toxicity or hypercalcaemia was noted in either group. Low dose In 2013, the Journal of Adolescent Health published a position statement from The Society for Adolescent Health and Medicine. This position statement included a recommendation to provide vitamin D supplementation of about 600 IU daily (equivalent to 18,000 IU per month) to healthy adolescents and at least 1,000 IU daily (equivalent to 30,000 IU per month) for adolescents who are at risk for vitamin D deficiency or insufficiency. These dose recommendations are similar to those now proposed for the 20,000 IU dose of Fultium-D 3. Additionally, it should be noted that the approved posology for Fultium-D IU Capsules is: Vitamin D deficiency or insufficiency in children over 12 years 1 capsule daily depending on the severity of the disease and the patient s response to treatment. Should only be given under medical supervision. An author studied the intake of vitamin D 3 needed to raise serum 25(OH)D to > 75 nmol/l. The design of their clinical study was a 6 month, prospective, randomized, double-blinded, double dummy, placebocontrolled study of vitamin D 3 supplementation. Serum 25(OH)D was measured by radioimmunoassay and the Vitamin D 3 intake was adjusted every 2 months by use of an algorithm based on serum 25(OH)D concentration. A total of 138 subjects entered the study. The population included healthy male and female subjects (white and African Americans). The dose administered was based on prestudy 25(OH)D concentrations. Those subjects with a baseline level of between 50 and 80 nmol/l were started on 50 μg (2,000 IU) per day, while those with baseline levels of <50 nmol/l were started on 100 μg (4,000 IU) per day. Doses were adjusted after an 8 week serum 25(OH)D check so that patients were maintained within a 80 to 140 nmol/l range. After two dose adjustments, almost all active subjects attained concentrations of 25(OH)D that were at least 75 nmol/l, and no subjects exceeded serum concentrations of 220 nmol/l. The mean slope at 9 weeks [defined as 25(OH)D change / baseline dose] was 0.66 ±0.35 (nmol/l) / (μg/d) and did not differ statistically between black and white subjects. The mean daily dose was 86 μg (3,440 IU). The results obtained predicted an optimal daily dose of 115 μg/d (4,600IU). No hypercalcemia or hypercalciuria was observed during the study. It concluded that the intake of vitamin D 3 required to attain serum 25(OH)D concentrations >75 nmol/l must consider the wide variability in the dose-response curve and basal 25(OH)D concentrations. It also concluded that a daily dose of 95 μg colecalciferol per day was required for subjects with serum 25(OH)D levels of at least 55 nmol/l and that a daily dose of 125 μg (5,000) colecalciferol per day (equivalent to 45,000 IU per week) was required for subjects with serum 25(OH)D levels below the 55 nmol/l threshold. A study investigated the administration of the same annual dose of 292,000 IU of vitamin D 3 administered on either daily (800 IU) or single doses given four monthly (97,333 IU) to elderly women. This was a one year comparative study of the serum 25(OH)D concentrations and renal function. 40 women aged between 69.3 and 78.8 years took part in the study. In terms of serum 25(OH)D concentrations, dosing of 800 IU daily was more efficient than a 97,333 IU dose every four months and this finding also supports the findings of other groups that investigated the benefits of using mega 21

22 annual doses to treat deficient patients. In this study reported the target level of 75 nmol/l was reached by 47% of subjects in the 800 IU daily group and only 28% in the 4 monthly dosed group. Renal function did not worsen in either group. A study investigated the bioequivalence of the different forms of vitamin D, ergocalciferol (vitamin D 2 ) and colecalciferol (vitamin D 3 ) in a parallel group, double-blind, randomized study comparing supplementation with 50 μg/d (2000 IU per day) doses of vitamin D 2 or D 3 with a placebo over a period of 8 weeks. 25(OH)D concentrations were the primary measure of the study. The study was conducted during the winter of 2012 at a latitude of N when UVB irradiation is virtually absent. Blood samples for the determinations of vitamin D status and PTH were collected at baseline and after 4 and 8 weeks of supplementation. In the placebo group (n = 19), 25(OH)D decreased from 39.4 ± 14.2 to 31.1 ± 12.4 nmol/l after 8 weeks (P <.01). In the vitamin D 3 group (n = 42), the concentrations of 25(OH)D increased from 41.5 ± 22.8 nmol/l at baseline to 88.0 ± 22.1 nmol/l after 8 weeks (P <.01). In the group receiving vitamin D 2 (n = 46), the 25(OH)D concentrations also increased significantly. The total 25(OH)D was not different between the groups at baseline but differed significantly between the groups after 4 and 8 weeks (P <.001). The study concluded that vitamin D 3 increases the total 25(OH)D concentration more than vitamin D 2. A study set out to investigate the influence of a 6 month vitamin D supplementation in patients with non-insulin-requiring type 2 diabetes mellitus. They included 86 patients in a placebo controlled, randomised, double-blind study. During the 6 month period patients received Vigantol oil once a week corresponding to a daily dose of 1904 IU or placebo oil, followed by 6 months of follow-up. At start and at 3 month intervals 25(OH)D, PTH, body mass index, HbA1c, insulin, C-peptide, and homeostasis model assessment-index were measured. The primary outcome was a change in fasting blood glucose and insulin levels. After 6 months of therapy, the verum group's 25(OH)D had increased to a median of 35 ng/ml in comparison to the placebo group (median 20 ng/ml, p<10-6). PTH tended to decrease in the verum group (25.5 pg/ml vs pg/ml, p=0.08). After 6 months of therapy, 31 patients (78%) achieved a 25(OH)D concentration of >20 ng/ml. Their HbA1c was significantly lower at baseline (p=0.008) and after therapy (p=0.009) than in patients with 25(OH)D below 20 ng/ml. CPeptide, insulin, and HOMAindex did not change significantly in the verum group but fasting insulin was positively correlated with 25(OH)D concentrations after 6 months of therapy in both groups. There were no significant effects of vitamin D with a daily dose of 1904 IU on metabolic parameters in type 2 diabetes. The applicant has supplied a comprehensive summary of data on the efficacy of vitamin D for a wide range of doses, both high and low. The applicant s SmPC, as requested, is supported by the bibliographic data. The data presented supports the current best practice guidance from the National Osteoporosis Society and the use of this formulation. IV.5 Clinical safety The safety of colecalciferol is well established. The safety review is considered adequate. The safety of a wide number of doses and posologies has been presented, including those giving much higher doses than in the requested posology. The safety review is considered adequate. The safety profile of colecalciferol is therefore considered well characterised. IV.6 Risk Management Plan (RMP) The Marketing Authorisation Holder has submitted a risk management plan, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to Fultium-D 3 20,000 IU Capsules. 22

23 Summary of the safety concerns 23

24 Summary Table of Risk Minimisation Measures 24

25 25

26 IV.7 Discussion on the clinical aspects The grant of a Marketing Authorisation is recommended. V USER CONSULTATION For Fultium-D 3 20,000 IU Capsules a user consultation with target patient groups on the package information leaflet (PIL) has been performed on the basis of a bridging report making reference to Fultium-D IU Capsules (PL 17871/0151). The bridging report submitted by the applicant is acceptable. 26

27 VI OVERALL CONCLUSION, BENEFIT-RISK ASSESSMENT AND RECOMMENDATION QUALITY The important quality characteristics of Fultium-D 3 20,000 IU 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. As the pharmacokinetics, pharmacodynamics and toxicology of colecalciferol are well-known, no additional data were required. CLINICAL No new clinical data were submitted and none were required for applications of this type. The published literature supports the efficacy of this product in the proposed indications. The efficacy of colecalciferol is well-known. The presented evidence for well-established use of the active substance is sufficient. The safety profile of colecalciferol is well-known. The literature review identified no new or unexpected safety issues or concerns. PRODUCT LITERATURE The SmPC, PIL and labelling are satisfactory and in line with current guidance. BENEFIT-RISK ASSESSMENT The quality of the product is acceptable, and no new non-clinical or clinical concerns have been identified. Extensive clinical experience with colecalciferol is considered to have demonstrated the therapeutic value of the compound. The benefit risk is, therefore, considered to be positive. 27

28 Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and labelling In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPCs) and Patient Information Leaflets (PILs) for products that are granted Marketing Authorisations at a national level are available on the MHRA website. Labelling 28

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