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

Public Assessment Report

Fultium-D3 20,000 IU Capsules

(Colecalciferol)

UK Licence No: PL 17871/0210

Jenson Pharmaceutical Services Ltd

PAR Fultium-D3 20,000 IU Capsules

PL 17871/0210

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LAY SUMMARY Fultium-D3 20,000 IU Capsules

(colecalciferol)

This is a summary of the Public Assessment Report (PAR) for Fultium-D3 20,000 IU Capsules (PL

17871/0210). It explains how Fultium-D3 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-D3 20,000 IU Capsules.

For practical information about using Fultium-D3 20,000 IU Capsules, patients should read the package

leaflet or contact their doctor or pharmacist.

What are Fultium-D3 20,000 IU Capsules and what are they used for?

Fultium-D3 20,000 IU Capsules is a medicine with ‘well-established use’. This means that the medicinal

use of the active substance of Fultium-D3 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-D3 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-D3 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-D3 20,000 IU Capsules work?

Fultium-D3 20,000 IU Capsules is a vitamin product containing colecalciferol (equivalent to 500

micrograms vitamin D3). Vitamin D3 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-D3 20,000 IU Capsules used?

Fultium-D3 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-D3 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-D3 20,000 IU Capsules can only be obtained on prescription from a doctor.

For further information on how Fultium-D3 20,000 IU Capsules are used, please refer to the Summary of

Product Characteristics and the Patient Information Leaflet available on the MHRA website.


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What benefits of Fultium-D3 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-D3 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-D3 20,000 IU Capsules, please

refer to the package leaflet or the Summary of Product Characteristics available on the MHRA website.

Why are Fultium-D3 20,000 IU Capsules approved?

The use of Fultium-D3 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-D3

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-D3 20,000 IU

Capsules?

A Risk Management Plan has been developed to ensure that Fultium-D3 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-D3 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-D3 20,000 IU Capsules

A Marketing Authorisation was granted in the UK on 23rd

January 2015.

The full PAR for Fultium-D3 20,000 IU Capsules follows this summary.

For more information about treatment with Fultium-D3 20,000 IU Capsules, read the Patient Information

Leaflet (PIL), or contact your doctor or pharmacist.

This summary was last updated in March 2015.


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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


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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-D3 20,000 IU Capsules (PL 17871/0210) on 23rd

January 2015. 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-D3

800 IU Capsules (PL 17871/0151) and Fultium-D3 3,200 IU Capsules (PL 17871/0208).

In its biologically active form vitamin D3 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 D3. PTH secretion is inhibited additionally by the increased calcium uptake in the

small intestine under the influence of biologically active vitamin D3.

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.


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II QUALITY ASPECTS

II.1 Introduction

Each Fultium-D3 20,000 IU Capsule contains 20,000 IU colecalciferol (equivalent to 500 micrograms

vitamin D3) 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: C27H44O

Molecular weight: 384.7 g/mol

Appearance: White or almost white crystalline powder.

Solubility: 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.


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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)2D, 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)2D3 in mineral homeostasis is to enhance the efficiency of the small

intestine to absorb dietary calcium and phosphate. 1,25(OH)2D3 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)2D3 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)2D3 may not be the only mode of action by


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which the hormone stimulates calcium absorption by the enterocyte. Rapid effects of 1,25(OH)2D3

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)2D3 increases active phosphate

transport, although significant phosphate absorption also occurs in 1,25(OH)2D3-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)2D3 induces

bone formation by inducing the synthesis of bone matrix proteins and mineral apposition.

Parathyroid glands

Parathyroid hormone (PTH) and 1,25(OH)2D3 directly affect calcium homeostasis, and each exerts

important regulatory effects on the other. Whereas PTH is the principal hormone involved in the minute-

to-minute regulation of ionised calcium levels in the extracellular fluid, 1,25(OH)2D3 plays a key role in

the day-to-day maintenance of calcium balance. PTH stimulates the production of 1,25(OH)2D3 by

activating the renal 1-alpha hydroxylase, and 1,25(OH)2D3 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)2D3 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)2D3 increases renal calcium reabsorption. 1,25(OH)2D3 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)2D3

deficiency. In both conditions, the impaired immunity can be improved with 1,25(OH)2D3 therapy.

1,25(OH)2D3 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)2D3 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)2D3 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)2D3 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 D3 in human


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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)2D3 is considered to be the active metabolite affecting target sites, including muscle, clinical

studies reported a relation between serum 25(OH)D3 and muscle strength and functional ability. Two

mechanisms might explain these findings. First, the serum 25(OH)D3 concentration is 1000 times that of

serum 1,25(OH)2D3, 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)D3 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)2D3 therapy significantly increases serum insulin

concentrations. It has been postulated that 1,25(OH)2D3, 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)2D3 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)2D3 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)2D3 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)2D3, 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)2D3 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)2D3. 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)2D3 to prevent the loss of injured neurons was suggested by the

antiproliferative and prodifferentiating effects of the sterol in a neuroblastoma cell line.


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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 D3 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)2D, and 1,25(OH)2D 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 D3 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)2D, 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)D3 and 1,25(OH)2D3 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)2D3, calcitroic acid, is

biologically inert.

The control of serum 1,25(OH)2D3 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)2D3 levels are parathyroid

hormone (PTH), calcium, phosphate and 1,25(OH)2D3 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.


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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 LD50 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 D3/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 D3/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 D3 at doses of 2.5, 7.5, 50 and 100 μg/kg feed

(equivalent to 0.12, 0.45, 3 and 6 μg vitamin D3/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 1989-1990 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

D3 appears to have antiproliferative properties.


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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 19-50 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.


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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-

D3 800 IU Capsules (PL 17871/0151) and Fultium-D3 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 D3. Vitamin D3 is first

hydroxylated at the 25-carbon atom by a vitamin D3-25-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)D3-1- hydroxylase (1OH-ase) and produces

1,25(OH)2D3 (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 D3 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 D3 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)2D3 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 D3) to previtamin

D3 in the plasma membrane of human skin keratinocytes. Previtamin D3 is then rapidly converted to

vitamin D3 by the body’s temperature. Vitamin D3 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


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intoxication as excess pre- and vitamin D3 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 D3 and vitamin D2, 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-D3 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/m2. 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


PL 17871/0210

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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-D3 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-D3 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


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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-D3 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-D3 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-D3 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-D3 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-D3 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-D3 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 D3 40,000 IU per week (DD

group), vitamin D3 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-D3 20,000 IU Capsules but the extensive duration of


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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 33.333 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 D3 monthly,

Group B received 50,000 IU bimonthly and Group C received placebo. As mentioned above, Fultium-D3

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 D3 was well

tolerated. The authors concluded that monthly or bimonthly administration of vitamin D3 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

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.


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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 D3 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 D2, and that single vitamin D3 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 D3 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 D3 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 D3), weekly (10,500 IU vitamin D3) or monthly (45,000

IU vitamin D3) 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 D3) 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.


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A study undertaken to compare the efficacy, tolerability and safety of high doses of intramuscular

vitamin D2 with oral vitamin D3 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 50 000 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.


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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 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. 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 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 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 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.

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 D3 group


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= 22.7 ± 11.8 ng/ml, daily D3 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 D3 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-D3.

Additionally, it should be noted that the approved posology for Fultium-D3 800 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 D3 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, placebo-

controlled study of vitamin D3 supplementation. Serum 25(OH)D was measured by radioimmunoassay

and the Vitamin D3 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 D3 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 D3

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


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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 D2)

and colecalciferol (vitamin D3) in a parallel group, double-blind, randomized study comparing

supplementation with 50 μg/d (2000 IU per day) doses of vitamin D2 or D3 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 51°47’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 D3 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 D2 (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 D3 increases the total 25(OH)D

concentration more than vitamin D2.

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. 35.0 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 HOMA-

index 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-D3 20,000

IU Capsules.


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Summary of the safety concerns


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Summary Table of Risk Minimisation Measures


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IV.7 Discussion on the clinical aspects

The grant of a Marketing Authorisation is recommended.

V USER CONSULTATION For Fultium-D3 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-D3 800 IU Capsules (PL 17871/0151). The bridging report submitted by the applicant is

acceptable.


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VI OVERALL CONCLUSION, BENEFIT-RISK ASSESSMENT AND

RECOMMENDATION

QUALITY

The important quality characteristics of Fultium-D3 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.


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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


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Table of content of the PAR update

Steps taken after the initial procedure with an influence on the Public Assessment Report (Type II

variations, PSURs, commitments)

Scope Procedure

number

Product

information

affected

Date of

start of the

procedure

Date of end

of

procedure

Approval/

non

approval

Assessment

report

attached

Y/N

(version)

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

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