invita d3 2,400 iu/ml oral drops, solution (colecalciferol ... · invita d3 2,400 iu/ml oral drops,...

Public Assessment Report

InVita D3 2,400 IU/ml oral drops, solution

(colecalciferol)

UK Licence No: PL 24837/0046

Consilient Health Limited

PAR InVita D3 2,400 IU/ml oral drops, solution PL 24837/0046

2

LAY SUMMARY InVita D3 2,400 IU/ml oral drops, solution

(colecalciferol)

This is a summary of the Public Assessment Report (PAR) for InVita D3 2,400 IU/ml oral drops,

solution (PL 24837/0046). It explains how InVita D3 2,400 IU/ml oral drops, solution was assessed and

its authorisation recommended, as well as its conditions of use. It is not intended to provide practical

advice on how to use InVita D3 2,400 IU/ml oral drops, solution.

For practical information about using InVita D3 2,400 IU/ml oral drops, solution, patients should read

the package leaflet or contact their doctor or pharmacist.

What is InVita D3 2,400 IU/ml oral drops, solution and what is it used for?

InVita D3 2,400 IU/ml oral drops, solution is a medicine with ‘well-established use’. This means that

the medicinal use of the active substance of InVita D3 2,400 IU/ml oral drops, solution 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.

InVita D3 2,400 IU/ml oral drops, solution are used:

• to prevent vitamin D deficiency when there is a significant risk of deficiency or an

increased demand for vitamin D

How does InVita D3 2,400 IU/ml oral drops, solution work?

InVita D3 2,400 IU/ml oral drops, solution contains colecalciferol (equivalent to vitamin D3). Vitamin

D3 helps the kidneys and intestine absorb calcium and also helps to build bones.

How is InVita D3 2,400 IU/ml oral drops, solution used?

InVita D3 2,400 IU/ml oral drops, solution is taken by mouth. The prescribed number of drops of this

medicine can be taken on its own or mixed with a spoonful or a small amount of cold or lukewarm food

immediately before use. This medicine is best absorbed when taken with a large meal.

The recommended dose in children and adolescents for prevention of vitamin D deficiency is 400

IU/day (6 drops) for 0-1 years and 600 IU/day (9 drops) for 1-18 years.

This medicine can be mixed with a small amount of children’s foods, yogurt, milk, cheese or other dairy

products. InVita D3 2,400 IU/ml oral drops, solution should not be added into a bottle of milk or

container of soft food, in case the child does not consume the whole portion, and does not receive the

full dose.

The recommended dose in pregnant and breast feeding women for prevention of vitamin D deficiency is

400 IU/day (6 drops).

InVita D3 2,400 IU/ml oral drops, solution can only be obtained on prescription from a doctor.

For further information on how InVita D3 2,400 IU/ml oral drops, solution is used, please refer to the

Summary of Product Characteristics and the Patient Information Leaflet available on the MHRA

website.

What benefits of InVita D3 2,400 IU/ml oral drops, solution have been shown in studies?

As colecalciferol is a well-known substance, and its use in the prevention of vitamin D deficiency is

well-established, the applicant presented data from the scientific literature. The literature provided


3

confirmed the efficacy and safety of colecalciferol in the prevention of vitamin D deficiency in infants,

children, pregnant women, and in breast-feeding women.

What are the possible side effects of InVita D3 2,400 IU/ml oral drops, solution?

Like all medicines, this medicine can cause side effects, although not everybody gets them.

For information about side effects that may occur with taking InVita D3 2,400 IU/ml oral drops,

solution, please refer to the package leaflet or the Summary of Product Characteristics available on the

MHRA website.

Why is InVita D3 2,400 IU/ml oral drops, solution approved?

The use of InVita D3 2,400 IU/ml oral drops, solution for the approved indications is well-established.

Literature data have been submitted to support this application. No new or unexpected safety concerns

arose from this application. It was, therefore, considered that the benefits of InVita D3 2,400 IU/ml oral

drops, solution 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 InVita D3 2,400 IU/ml oral

drops, solution?

A Risk Management Plan has been developed to ensure that InVita D3 2,400 IU/ml oral drops, solution

is used as safely as possible. Based on this plan, safety information has been included in the Summary of

Product Characteristics and the package leaflet for InVita D3 2,400 IU/ml oral drops, solution, 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 InVita D3 2,400 IU/ml oral drops, solution

A Marketing Authorisation was granted in the UK on 28th

January 2015.

The full PAR for InVita D3 2,400 IU/ml oral drops, solution follows this summary.

For more information about treatment with InVita D3 2,400 IU/ml oral drops, solution, read the Patient

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

This summary was last updated in September 2015.


4

TABLE OF CONTENTS

I Introduction Page 5

II Quality aspects Page 6

III Non-clinical aspects Page 7

IV Clinical aspects Page 7

V User consultation Page 13

VI Overall conclusion, benefit/risk assessment and Page 13

Recommendation

Table of content of the PAR update Page 16


5

I INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the Medicines and Healthcare products

Regulatory Agency (MHRA) granted Consilient Health Limited a Marketing Authorisation for the

medicinal product InVita D3 2,400 IU/ml oral drops, solution (PL 24837/0046) on 28th

January 2015.

The product is a prescription-only medicine (POM) indicated for the prevention of vitamin D deficiency

in infants, children, pregnant and breast feeding women.

The application was submitted under Article 10a of Directive 2001/83/EC, as amended, claiming to be

an application for a product containing an active substance of well-established use.

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

small intestine under the influence of biologically active vitamin D.

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.


6

II QUALITY ASPECTS

II.1 Introduction

This product is an oral drops, solution and 1 ml solution (36 drops) contains 0.06 mg colecalciferol

(equivalent to 2,400 IU vitamin D3) or 1 drop contains 1.67 micrograms colecalciferol (equivalent to 67

IU vitamin D3), as an active ingredient. The excipients present in this product are all-rac-α-tocopherol

acetate, sweet orange peel oil, polyglyceryl oleate (E475) and olive oil, refined.

All excipients comply with their respective European Pharmacopoeia monographs with the exception of

sweet orange peel oil and polyglyceryl oleate (E475) which comply with an in-house specification.

Satisfactory Certificates of Analysis have been provided for these excipients.

The finished product is packaged in a type III dropper glass bottle with the central dropper made of

polyethylene and screw cap made of polypropylene. The pack sizes are 1, 2, 3 or 4 dropper container(s)

with 10 ml solution. 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

PhEur name: Cholecalciferol

Chemical name(s): (5Z,7E)-9,10-Secocholesta-5,7,10(19)-trien-3β-ol

Structure:

Molecular formula: C27H44O

Molecular weight: 384.6 g/mol

Appearance: White or almost white crystalline powder

Solubility: Practically insoluble in water, freely soluble in ethanol (96 per cent) and soluble

in trimethylpentane and in fatty oils.

Colecalciferol is the subject of the European Pharmacopoeia monograph (Cholecalciferol).

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.

II.3 Medicinal Product

Pharmaceutical Development

The objective of the development programme was to formulate a safe, efficacious and stable oral drops,

solution containing 2,400 IU of colecalciferol.

http://www.pharmacopoeia.co.uk/bp2012/ixbin/bp.cgi?a=imagezoom&file=bp2012_v1_07_medicinal_and_pharmaceutical_substances_5/large/cholecalciferol_1_2012_70_cs.png


7

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 using

the minimum commercial scale batch sizes and has shown satisfactory results. The applicant has

committed to perform further process validation on three full scale commercial batches.

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 3 years with a storage condition “Store in the original package, in

order to protect from light” has been set. After first opening the bottle the product may be stored for a

maximum of 3 months. 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 As colecalciferol is a widely used, well-known active substance, the applicant has not provided any

additional studies and none are required. An overview based on a literature review is appropriate.

The non-clinical overview has been written by an appropriately qualified person and is a suitable

summary of the non-clinical aspects of the dossier.

III.2 Pharmacology

No new data have been submitted and none are required for applications of this type.

III.3 Pharmacokinetics


III.4 Toxicology


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

There are no objections to the approval of this product from a non-clinical point of view.

IV CLINICAL ASPECTS

IV.1 Introduction

This application is submitted under article 10a of Directive 2001/83/EC, as amended. As colecalciferol

is a widely used, well known active substance, the applicant has not provided any additional studies and

none are required. An overview based on a literature review is appropriate.


8

The scientific evidence found on the published literature was sufficient to discuss all the

pharmacological, pharmacokinetic, efficacy and safety profiles of the product. Bioequivalence studies

are not necessary to support this bibliographic application.

IV.2 Pharmacokinetics

The pharmacokinetics of vitamin D are well established. It is both an endogenous substance and

absorbed in the gastrointestinal (GI) tract from food.

Vitamin D is absorbed in the small intestine, in the duodenum and in the distal ileum. The need for bile

salts in the absorption of vitamin D has been demonstrated.

Once vitamin D is absorbed, presumably through the lacteal system in association with chylomicrons, it

becomes associated with a vitamin D-binding protein that migrates with the -globulin. Although some

vitamin D is associated with the lipoproteins, most is bound to the transport protein that migrates with

-globulins.

In a study on the absorption of vitamin D3-3H in healthy volunteers, subjects were given oral doses of

0.1 to 1 mg of vitamin D3-3H, containing 1.5 to 15μC of tritium, in arachis oil, and their plasma and

fecal radioactivity was assayed during the subsequent 6 days. Radioactivity was present in the plasma 3

hours after a dose and at this stage was largely located in the chylomicrons. It reached a peak at 6 to 12

hours and thereafter declined exponentially, with a mean half-life of 54 hours. The net absorption of 0.5

to 1 mg doses, calculated from the fecal excretion of radioactivity, ranged from 62.4 to 91.3%.

A study looked at the role of the duodenum in vitamin D3 absorption in man. Two different radioisotope

forms of vitamin D3 were infused separately and simultaneously into the duodenum and jejunum of

healthy adult male volunteers. Mean apparent absorption of the vitamin D3 isotope infused into the

duodenum was 77% as compared with 65% for the vitamin D3 isotope infused into the jejunum.

The maximal absorption of tritium labelled vitamin D3 takes place in the mid-jejunum and its transfer

into the blood is mainly via the lymph.

Vitamin D from nutritional origin is transported via chylomicrons from the intestine via lymph veins to

the liver, whereas skin produced vitamin D is probably transported mainly via vitamin D binding protein

(DPB), on albumin-like plasma carrier protein. The liver but also some other tissues metabolize vitamin

D3 into 25-OHD, probably by the enzyme CYP27. This steral –27–hydroxylase is an enzyme

responsible for 25 – or 24 hydroxylation of vitamin D3 or D2, respectively. The enzyme is, however,

found in many tissues outside the liver.

Following the administration of vitamin D3 to animals, either by intravenous or oral means, some 60-

80% accumulates in the liver. Predominantly in the liver but not exclusively, vitamin D3 is hydroxylated

on carbon 25 to produce the obligatory intermediate 25-OH- D3. Some 25 – hydroxylation can take

place in intestine and kidney. A specific vitamin D 25-hydroxylose is located in the endoplasmic

reticulum of liver.

This hydroxylase likely operates under conditions of high vitamin D dosage an intake and probably does

not function at low and physiologic concentrations. Thus, when large doses of vitamin D are given, it is

likely that the mitochondrial 25–hydroxylase produces large amounts of 25-OH- D3 contributing to large

concentrations found in the plasma following high dosages of vitamin D.

25-OH- D3 must be metabolized further before it carries out the functions of vitamin D in the intestine,

kidney and bone. This reaction takes place exclusively in the kidney. Thus, 25-OH- D3 is further

hydroxylated in the 1 -position to produce 1, 25-dihydroxy vitamin D3 (1,25(OH)2 D3).


9

From the physiologic point of view, it must be recognised that the 1-hydroxylase reaction is the most

significant in the metabolism of vitamin D. It is this hydroxylase that is regulated by the need for

calcium or the need for phosphorus, and therefore must be regarded as the major regulated step in the

metabolism of the vitamins.

1,25-(OH)2 D3 is very rapidly metabolised in man and animals. In man, it has a half-life of

approximately 2 – 4 hours in plasma and perhaps somewhat longer in target tissues.

In a study, Vitamin D3-3H has been administered intravenously to seven normal subjects, three patients

with biliary fistulas and four patients with cirrhosis. Plasma D3-3H half times normally ranged from 20

to 30 hours.

Urinary radioactivity averaged 2.4% of the administered dose for the 48-hour period after infusion, and

all excreted radioactivity represented chemically altered metabolites of vitamin D. The metabolites in

urine were mainly water-soluble, with 26% in conjugated form.

From 3 to 6% of the injected radioactivity was excreted in the bile of subjects with T-tube drainage and

5% in the faeces of patients having no T-tube.

The pattern of fecal and biliary radioactivity suggested that the passage of vitamin D and its metabolites

from bile into the intestine represent an essential stage for the fecal excretion of vitamin D metabolites

in man.

Hepatic Failure:

A study compared the absorption of colecalciferol and 25- hydroxycolecalciferol in normal patients and

in patients with mild and severe cholestatic liver disease. 3H-colecalciferol and

3H-25-

hydroxycolecalciferol were given orally and serial blood samples were drawn for measurement of the

serum level of radiolabeled vitamin. Absorption of 25-hydroxycolecalciferol peaked earlier and was

greater than absorption of colecalciferol in all times in all three groups. Patients with mild cholestasis

(normal bilirubin and fecal fat excretion) absorbed both forms of the vitamin normally. Those with

severe cholestasis (jaundice and steatorrhea) had minimal absorption of colecalciferol but relatively

preserved absorption of 25-hydroxycolecalciferol. Absorption of colecalciferol and 25-

hydroxycolecalciferol was inversely related to fecal fat excretion.

The overall regulation of vitamin D metabolism in chronic liver disease and the formation of dihydroxy

metabolites therefore appear to be similar to those in-patients with normal liver function.

Renal Failure:

A study was performed looking at the handling of vitamin D in subjects with chronic renal failure. The

results from the study suggest the presence of an extrarenal 25OH D3-24-hydroxylase and 25OH D3-26-

hydroxylase and confirm the presence of 25 OH D3-lactone in human plasma.

The data also indicate that analogous to 1,25(OH)2 D3, the kidney may be the sole site of production of

25OH D3-lactone. The significantly reduced or non-detectable plasma levels of vitamin D3 in the

chronic renal failure and anephric patients may reflect abnormalities in the hepatobiliary-intestinal

and/or cutaneous metabolism of vitamin D.

Finally, 25,26(OH)2 D3 levels, significantly decreased in the chronic renal failure patients, were

normalised in the anephric patients on long-term haemodialysis. These changes noted in 25,26(OH)2 D3

may reflect alterations in the uremic state occurring with haemodialysis in these chronic renal disease

patients.

The applicant has adequately characterised the pharmacokinetics of vitamin D.


10

IV.3 Pharmacodynamics

Colecalciferol is an endogenous compound present as a precursor in the skin of both man and animals. It

has a variety of essential physiological roles. Vitamin D is required to maintain normal blood levels of

calcium and phosphate, which are in turn needed for the normal mineralisation of bone, muscle

contraction, nerve conduction, and general cellular function in all cells of the body. Vitamin D achieves

this after its conversion to the active form 1,25-dihydroxyvitamin D [1,25-(OH)2D], or calcitriol. This

active form regulates the transcription of a number of vitamin D-dependent genes which code for

calcium-transporting proteins and bone matrix proteins.

Vitamin D also modulates the transcription of cell cycle proteins, which decrease cell proliferation and

increase cell differentiation of a number of specialised cells of the body (e.g. osteoclastic precursors,

enterocytes, and keratinocytes). Vitamin D also possesses immunomodulatory properties that may alter

responses to infections in vivo. These cell differentiating and immunomodulatory properties underlie the

reason why vitamin D derivatives are now also used successfully in the treatment of psoriasis and other

skin disorders.

Colecalciferol (vitamin D3) is formed in the skin on exposure to UV light and converted into its

biologically active form, 1,25-dihydroxycolecalciferol, in two hydroxylation steps, first in the liver

(position 25) and then in the renal tissue (position 1). Along with parathormone and calcitonin, 1,25-

dihydroxycolecalciferol has a considerable impact on the regulation of calcium and phosphate

metabolism. In vitamin D deficiency the skeleton does not calcify (resulting in rickets) or decalcification

of bones occurs (resulting in osteomalacia).

According to production, physiological regulation and mechanism of action, vitamin D3 is to be

considered as precursor of a steroid hormone. In addition to physiological production in the skin,

colecalciferol can be supplied via the diet or in the form of a drug. Since in the latter case the product

inhibition of cutaneous vitamin D synthesis is circumvented, overdose and intoxications may occur.

Human beings activate it metabolically in the same way as colecalciferol. It has the same qualitative and

quantitative effects.

Adults require 5 μg daily, equivalent to 200 IU. Healthy adults can cover their requirement by producing

vitamin D on their own through sufficient exposure to the sun. Alimentary vitamin D supply plays a

subordinate role, but can be important under critical conditions (climate, lifestyle). Fish liver oil and fish

are particularly rich in vitamin D; small amounts are found in meat, egg yolk, milk, dairy products and

avocado.

Deficiency diseases can occur, among others, in immature pre-term new-born infants, infants

exclusively breast-fed for more than six months without calcium-containing foods and children fed a

strictly vegetarian diet. The causes of rarely occurring vitamin D deficiency in adults may be inadequate

alimentary intake, insufficient exposure to UV light, malabsorption and maldigestion, liver cirrhosis as

well as renal insufficiency.

Vitamin D, a steroid hormone produced in the skin, has specific regulatory or functional effects on other

parts of the body. Vitamin D is hydroxylated in the liver to 25- hydroxyvitamin D (25[OH]D) and

further hydroxylated in the kidney to 1,25- dihydroxyvitamin D. Hydroxylation in the kidney is

regulated closely by parathyroid hormone (PTH), hypocalcemia, and hypophosphatemia and is inhibited

by 1,25- dihydroxyvitamin D. As well, 1,25-dihydroxyvitamin D (produced locally within cells)

regulates gene transcription through nuclear high-affinity VTD receptors. These receptors are found in

the classic target organs: gut, bone, kidney, and parathyroid and many other tissues as well, such as

brain, breast, colon, heart, pancreas, prostate, skin, and immune system. Vitamin D regulates cell growth

and maturation, inhibits renin production, stimulates insulin secretion, and modulates the function of

activated T- and B-lymphocytes and macrophages.


11

A host of proteins and enzymes such as vitamin D-binding protein, the putative liver 25- hydroxylase,

CYP27B1 and 25-hydroxyvitamin D-24-hydroxylase (24-OHase or CYP24), along with others such as

megalin (an endocytic receptor responsible for the resorption of vitamin D-binding protein in the

kidney) and FGF23 (known to inhibit CYP27B1), weave themselves into a complicated network to

maintain a balance among the vitamin D, 25(OH)D and 1,25(OH)2D levels. In addition, contributing to

the complexity of the VDR signalling system is the presence of numerous membrane proteins, cytosolic

factors and transcription co-activators/co-repressors that are often associated with the regulation of

nuclear receptors.

Atherosclerosis is a process that involves a complex interplay among different factors such as

inflammation, thrombosis and various cell types including smooth muscle and endothelial cells. As

mentioned above, Vitamin D receptor (VDR) seems involved in regulating thrombogenic activity, and

VDR activation may reduce thrombosis and sustain plaque stability in atherosclerosis. Also,

inflammation is linked to plaque vulnerability; VDR activation, through its immunomodulating effects,

may inhibit macrophage activation and prevent plaque instability.

Beside inflammation and thrombosis, phenotypic change in smooth muscle cells is an important

contributing factor in atherosclerosis. In a study employing DNA microarray technology to assess the

gene expression profile in primary culture of human coronary artery smooth muscle cells treated with

VDRAs, we found that VDRAs regulated the expression of many genes involved in cell differentiation

and proliferation and also down-regulated the expression of natriuretic peptide precursor B, plasminogen

activator inhibitor-1 and thrombospondin-1.

The non-clinical and clinical data suggest that VDR is involved in regulating cardiovascular functions

and vitamin D and its analogs are potentially useful for treating cardiovascular disease (CVD). Many of

the clinical studies considered a level of 25(OH)D at ≤15 ng/mL deficient, while a level between 15 and

30 ng/mL is borderline and a level more than 30 ng/mL is perhaps necessary in order to reduce CVD

risk.

The applicant has adequately characterised the pharmacodynamics of vitamin D.

IV.4 Clinical efficacy

The efficacy of colecalciferol is well-established.

The applicant has presented data which supports the dosage levels requested in the posology for both

children and pregnant women. The well-established use of vitamin D at the doses needed in the

indications requested is therefore acceptable.

IV.5 Clinical safety

The safety of colecalciferol is well-established.

The safety review is considered adequate. Safety data is presented in a wide variety of doses, including

those giving much higher doses than in the requested posology. This supports the safe use of vitamin D

at these doses in the appropriate populations. The safety profile is therefore considered well

characterised.

IV.6 Risk Management Plan (RMP)

The Marketing Authorisation Holder (MAH) 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 InVita D3 2,400

IU/ml oral drops, solution.


12

A summary of safety concerns and planned risk minimisation activities, as approved in the RMP,

is listed below:


13

IV.7 Discussion on the clinical aspects

The grant of a Marketing Authorisation is recommended.

V USER CONSULTATION The package leaflet has been evaluated via a user consultation study in accordance with the

requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC, as amended. The language used for

the purpose of user testing the PIL was English.

The results show that the package leaflet meets the criteria for readability as set out in the guideline on

the readability of the label and package leaflet of medicinal products for human use.

VI OVERALL CONCLUSION, BENEFIT-RISK ASSESSMENT AND

RECOMMENDATION

QUALITY

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.


14

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


15


16

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)

invita d3 2,400 iu/ml oral drops, solution (colecalciferol ... · invita d3 2,400 iu/ml oral drops,...

Documents