Public Assessment Report - BE/H/0230/001/DC D-CURE CALCIUM 1000 mg/1000 I.E Chewable tablets
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Public Assessment Report
D-CURE CALCIUM 1000 mg/1000 I.E
Chewable tablets
(Calcium carbonate/Cholecalciferol)
BE/H/0230/001/DC
Applicant: Laboratoires SMB S.A.
BE licence no: BE476951
Date: 13/08/2015
1.This assessment report is published by the Federal Agency for Medicines and Health Products
following Article 21 (3) and (4) of Directive 2001/83/EC, amended by Directive 2004/27/EC and
Article 25 paragraph 4 of Directive 2001/82/EC as amended by 2004/28/EC. The report comments on
the registration dossier that was submitted to the Federal Agency for Medicines and Health Products
and its fellow organisations in all concerned EU member states.
It reflects the scientific conclusion reached by the Federal Agency for Medicines and Health Products
and all concerned member states at the end of the evaluation process and provides a summary of the
grounds for approval of a marketing authorisation.
This report is intended for all those involved with the safe and proper use of the medicinal product,
i.e. healthcare professionals, patients and their family and carers. Some knowledge of medicines and
diseases is expected of the latter category as the language in this report may be difficult for laymen
to understand.
This assessment report shall be updated by a following addendum whenever new information
becomes available.
To the best of the Federal Agency for Medicines and Health Products’ knowledge, this report does
not contain any information that should not have been made available to the public. The Marketing
Autorisation Holder has checked this report for the absence of any confidential information.
2.PAR D-CURE CALCIUM 1000 mg/1000 I.E Chewable tablets BE/H/0230/001/DC
I.1.1 TABLE OF CONTENTS
Chapter 1: Administrative Information Page 4
Chapter 2: Scientific Discussion Page 5
1. Introduction
2. Quality aspects
3. Non-clinical aspects
4. Clinical aspects
5. Overall conclusion, benefit/risk assessment and recommendation
Chapter 3: Steps taken after the initial procedure – update Page 13
Annex: Summary Public Assessment Report Non generics Page 16
3.PAR D-CURE CALCIUM 1000 mg/1000 I.E Chewable tablets BE/H/0230/001/DC
ADMINISTRATIVE INFORMATION
Name of the medicinal product D-Cure Calcium
INN (or common name) of the active Calcium carbonate/Cholecalciferol
substance(s)
Pharmaco-therapeutic Group Calcium, combinations with other drugs
and ATC Code A12AX
Pharmaceuticals form(s) Chewable tablet
Strength(s) 1000 mg/1000 I.E.
Target Species NA
Indications D-Cure Calcium is indicated for the correction of
calcium and Vitamin D deficiency in the elderly.
D-Cure Calcium may be used as an adjunct to
specific therapy for osteoporosis, in patients with
either established vitamin D and calcium combined
deficiencies or in those patients at high risk of
needing such therapeutic supplements.
Type of application DCP
Know Active substances
Legal Basis WEU 10a
Type of active substance chemical substance
Prescription status For RMS: non prescription (including OTC)
Reference number for the procedure BE/H/0230/001/DC
Reference Member State Belgium (BE)
Concerned Member State Luxembourg (LU), the Netherlands (NL), the United
Kingdom (UK)
Marketing Authorisation Holder Laboratoires SMB S.A.
rue de la pastorale 26-28
B-1080 Brussels
4.PAR D-CURE CALCIUM 1000 mg/1000 I.E Chewable tablets BE/H/0230/001/DC
Public Assessment Report
Scientific discussion
D-CURE CALCIUM 1000 mg/1000 I.E
Chewable tablets
(Calcium carbonate/Cholecalciferol)
BE/H/0230/001/DC
Date: 06/11/2015
5PAR D-CURE CALCIUM 1000 mg/1000 I.E Chewable tablets BE/H/0230/001/DC
This module reflects the scientific discussion for the approval of D-CURE CALCIUM 1000
mg/1000 I.E Chewable tablets. The procedure was finalised at 09/07/2015. For information on
changes after this date please refer to the module ‘Update’.
6PAR D-CURE CALCIUM 1000 mg/1000 I.E Chewable tablets BE/H/0230/001/DC
II. INTRODUCTION
This application concerns a stand - alone application, submitted according to Article 10 (a) of Directive
2001/83/EC as amended, related to medicinal products containing constituent(s) with a well-established
medicinal use, with recognized efficacy and an acceptable level of safety, by means of a detailed
scientific bibliography.
Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing
authorisation for D-CURE CALCIUM 1000 mg/1000 I.E Chewable tablets from Laboratoires SMB
S.A.
The product is indicated for the correction of calcium and Vitamin D deficiency in the elderly.
D-Cure Calcium may be used as an adjunct to specific therapy for osteoporosis, in patients with either
established vitamin D and calcium combined deficiencies or in those patients at high risk of needing
such therapeutic supplements.
A comprehensive description of the indications and posology is given in the SmPC.
III. QUALITY ASPECTS
III.1 Introduction
D-CURE CALCIUM 1000 mg/1000 IU are chewable tablets containing 1000 IU of cholecalciferol and
2.5 g of calcium carbonate (equivalent to 1000 mg of calcium) and are breakable into halves.
The chewable tablet has a round shape and is white to almost white with a break mark.
The tablet can be divided into equal doses.
The chewable tablets are packed in a polypropylene tablet container with polyethylene desiccant cap.
Each Polypropylene tablet container contains 14 tablets.
The excipients are DL-alpha tocopherol (E307), Medium chain triglycerides, Modified food starch
(E1450), Sucrose,Sodium ascorbate (E301), Silicon dioxide (E551), Povidone K29/32, Isomalt (E953),
Sucralose, Magnesium stearate, Crospovidone, Orange aroma.
III.2 Drug Substance
Calcium carbonate
Calcium carbonate is covered by a Certificate of suitability delivered by EDQM and complies with Ph.
Eur. Monograph 0014 for calcium carbonate with additional tests for residuals solvents. Acceptable
batch and stability results have been supplied. A retest period of 60 months is agreed when the product
is stored at room temperature in unopened containers.
Cholecalciferol
Cholecalciferol is manufactured as a stabilized concentrate powder form. Pure cholecalciferol is covered
by a Certificate of suitability delivered by EDQM and complies to the Ph. Eur. monograph for
Cholecalciferol 0072 with additional tests for residuals solvents.
Cholecalciferol concentrate (powder form) complies with the Ph. Eur. monograph 0574. The stabilized
mixture include cholecalciferol, DL-alpha tocopherol, medium chain triglycerides, modified food
7PAR D-CURE CALCIUM 1000 mg/1000 I.E Chewable tablets BE/H/0230/001/DC
starch, sucrose, sodium ascorbate and silicon dioxide. Manufacturing of the stabilized form has been
described with sufficient details. Impurities have been discussed based on the description of the process
and ad hoc specifications have been proposed by the manufacturer of the concentrate form and by the
finished product manufacturer. Batches results, validation data and stability results have been supplied.
III.3 Medicinal Product
D-CURE CALCIUM 1000 mg/1000 IU are chewable tablets containing 1000 IU of cholecalciferol and
2.5 g of calcium carbonate (equivalent to 1000 mg of calcium) and are breakable into halves. The choice
and function of all excipients has been sufficiently justified. The development is acceptable.
The excipients of the tablets, povidone, isomalt, sucralose, magnesium stearate and crospovidone are
described in the Ph Eur and comply with their respective monograph. There is one non-compendial
excipient, the orange aroma, which is controlled according to ad hoc house specifications.
Calcium carbonate/cholecalciferol chewable tablets is regarded as a conventional pharmaceutical
dosage form using conventional manufacturing processes including blending, wet granulation, drying
and sifting, blending and tableting steps. A satisfactory process validation has been performed including
granulation, mixing and tableting steps.
The specifications proposed for the tablets are acceptable, the absence of testing for calcium and
cholecalciferol related products has been sufficiently justified. Cholecalciferol related substances are
not retested anymore on the final tablets since they are in very low quantities in the final tablets and
sufficiently tested on the pure cholecalciferol and on the stabilized concentrated powder. Identification
of calcium and cholecalciferol are performed respectively via a colorimetric method and by HPLC.
Assay of cholecalciferol is performed by HPLC whereas calcium is assayed by a titration method.
Routine and shelf-life limits are proposed for hardness and friability, which are critical parameters for
chewable tablets. Dissolution testing is performed for calcium and not for cholecalciferol, which is
common for fat soluble vitamin containing formulations. Skip testing is applied for microbiological
control. Acceptable breakability has been demonstrated. The analytical methods have been adequately
described and validated. Certificates of analysis are included for 3 industrial scale batches.
The immediate packaging consists in a white PP tube and a white PP desiccant cap including a capsule
of silica gel; the documentation/data supplied for the packaging is sufficient.
Stability results have been supplied for 3 pilot scale batches and 3 full-scale batches up to 24 and 18
months in ICH long term conditions, 6 months accelerated results are also provided. A shelf-life of 24
months if stored below 25°C in the original packaging has been accepted. An in-use stability study has
been performed, which support a shelf-life of at least 14 days after first opening of the PP tube.
Some outstanding points of clarification will be solved via PACs (post-approval commitments).
III.4 Discussion on chemical, pharmaceutical and biological aspects
All outstanding points of clarification will be solved via PACs (post-approval commitments).
IV. NON-CLINICAL ASPECTS
8PAR D-CURE CALCIUM 1000 mg/1000 I.E Chewable tablets BE/H/0230/001/DC
IV.1 Introduction
The non-clinical section is based on a review and discussion on the extensive amount of literature
pertaining to pharmacodynamics, pharmacokinetics and toxicology of cholecalciferol/calcium.
Additional non-clinical studies to assess the pharmacological properties of cholecalciferol/calcium were
not performed.
IV.2 Pharmacology – Pharmacokinetics – Toxicology
The non-clinical overview in Module 2 is of poor quality. However, adequate non-clinical summaries
(pharmacology, PK and toxicology) were provided, allowing for a critical non-clinical evaluation. In
addition, 82 supportive references up to the year 2010 were included in Module 4.
The non-clinical summaries justify that there is no need to generate new non-clinical data. The
pharmacology, pharmacokinetics and toxicology of calcium/cholecalciferol are well-known in view of
the long clinical experience with these active substances.
In animal studies high doses of vitamin D caused teratogenicity and fetotoxicity this is reflected in the
SmPC section 5.
IV.3 Ecotoxicity/environmental risk assessment (ERA)
The applicant has provided a justification for absence of environmental risk assessment in line with the
Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use
(EMEA/CHMP/SWP/4447/00).
V. CLINICAL ASPECTS
V.1 Pharmacokinetics
The applicant has demonstrated the similarity of its product with marketed preparations in an appropriate
way. We agree that D-CURE CALCIUM Chewable Tablets presents the same pharmaceutical form, the
same active compound and sufficiently similar ingredients that the different drug products of calcium
with vitamin D already registered.
The applicant has provided the list of calcium with vitamin D3 drug products in form of chewable tablets
available on the Belgium market. These chewable tablets constitute half of the drug products containing
the association calcium-vitamin D3 marketed in Belgium.
We agree that according to the study from Heaney et al. (Heaney et al. 2001) it could be acceptable to
conclude that the bioavailability of calcium tablets is solely dependent on the properties of the drug
substance.
In Belgium most drug products containing calcium alone or with cholecalciferol are manufactured using
the carbonate salts. Similarly, on the European market, calcium carbonate (Ph.Eur) and cholecalciferol
concentrate, powder form (Ph. Eur) are used in the different medical products as demonstrated in the
different EPARs as well as in SmPCs and PILs.
Moreover, D-CURE CALCIUM Chewable Tablets contains classical excipients.
Therefore, it can be considered that data on the pharmacokinetics of calcium and vitamin D obtained
with the different formulations can be bridged to the current formulation, i.e. the D-CURE CALCIUM
Chewable Tablets. This is consistent with the conclusions of the different EPARs where the
9PAR D-CURE CALCIUM 1000 mg/1000 I.E Chewable tablets BE/H/0230/001/DC
bioavailability of calcium and vitamin D from the news products should not be compared to that from
existing products on the market.
V.2 Pharmacodynamics
Not applicable
V.3 Clinical efficacy
In order to demonstrate the efficacy of dose of 1000 IU of vitamin D in the indication “Correction of
calcium and vitamin D deficiency in the elderly”, the applicant has provided numerous publications.
From the results of these studies, the efficacy of 1000 IU of vitamin D has been demonstrated in this
proposed indication.
Concerning the proposed indication “adjunct to specific therapy for osteoporosis” the applicant has also
submitted a review of the literature. We agree that the results of these studies show that vitamin D is
efficacious at the proposed dose.
As in the specific case of vitamin D, efficacy and safety are clearly correlated to the levels of 25-
hydroxyvitamin D [25(OH)D], the applicant has also provided numerous studies investigating the effect
of vitamin D in raising serum 25(OH)D levels. Many of them support the proposed dose of 1000 IU
vitamin D in raising serum 25(OH)D levels.
The additional review of the current literature should be considered sufficient to justify the proposed
dose of 1000 mg calcium/1000 IU of vitamin D.
According to the Guideline on Clinical Development of Fixed Combination Medicinal Products
(CHMP/EWP/240/95 Rev. 1), the dosage of each substance within the fixed combination must be such
that the combination is safe and effective for a significant target population and the benefit/risk
assessment of the fixed combination is equal or exceeds that of each substance taken alone.
Since the clinical trials submitted by the applicant have demonstrated that 1000 mg calcium and 1000
IU vitamin D are safe and efficacious for the proposed indications, this proposed dosage regimen should
be considered justified in accordance with the European Guideline.
In addition, as the difference between the proposed 1000 mg/1000 IU dosing and the approved 1200
mg/800I U dosing can be considered “small”, a study to compare them will require a big sample size
and it is not realistic to perform that.
V.4 Clinical safety
Based on the clinical studies provided by the applicant, the safety of the tablet containing 1000 mg of
calcium combined with 1000 IU of cholecalciferol is considered as well-established.
In addition from the safety data discussed above, vitamin D has been found to be safe at higher doses
than the proposed dose (1000 IU).
Therefore, no issue concerning safety with D-CURE CALCIUM Chewable Tablets is expected.
Pharmacovigilance system
The Applicant has submitted a summary of Laboratoires SMB’s Pharmacovigilance System
(Pharmacovigilance System Master File code MFL2735), signed by the EU QPPV Dr. Lucas Fotsing
and the local representative of the MAH and dated the 12th of December 2012, consisting of following
elements:
- proof that the applicant has at his disposal a qualified person responsible for pharmacovigilance;
10PAR D-CURE CALCIUM 1000 mg/1000 I.E Chewable tablets BE/H/0230/001/DC
- the Member States in which the qualified person resides and carries out his/her tasks;
- the contact details of the qualified person;
- a statement signed by the applicant to the effect that the applicant has the necessary means to
fulfil the tasks and responsibilities listed in Title IX;
- a reference to the location where the pharmacovigilance system master file for the medicinal
product is kept.
Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements
as set out in the Commission Implementing Regulation and as detailed in the respective GVP module,
the RMS considers the Summary acceptable.
V.5 Risk Management Plan
The Applicant has introduced an updated RMP (version 0.2) which is approvable.
The following table includes the proposed safety concerns:
For all safety concerns, the Applicant will perform routine pharmacovigilance activities. No additional
pharmacovigilance activities are planned.
The Applicant considers that routine risk minimisation and proposed SmPC and PL statements regarding
the safety concerns are adequate and sufficient to monitor the benefit-risk profile of the product. No
additional risk minimisation activities are proposed.
VI. 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. 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.
VII. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND
RECOMMENDATION
Benefit/risk assessment
11PAR D-CURE CALCIUM 1000 mg/1000 I.E Chewable tablets BE/H/0230/001/DC
Vitamin D is actually available at doses ranging from 200 IU to 880 IU in combination with calcium at
doses from 500 mg to 1000 mg in different medicinal products for the following indications :
- Correction of calcium and Vitamin D deficiency in the elderly.
- As an adjunct to specific therapy for osteoporosis, in patients with either established vitamin D
and calcium combined deficiencies or in those patients at high risk of needing such therapeutic
supplements.
D-CURE CALCIUM Chewable Tablets containing 1000 mg of calcium combined with 1000 IU of
cholecalciferol was developed for the same indications.
The review of the current literature should be considered as adequate to justify the proposed dose of
1000 mg calcium/1000 IU of vitamin D.
The clinical studies provided by the applicant have demonstrated that vitamin D and calcium at these
doses are efficacious and safe for the proposed indications.
In addition, bridging the literature data to D-CURE CALCIUM Chewable Tablets should be also
considered as sufficient.
In conclusion, the benefit risk of D-CURE CALCIUM Chewable Tablets is positive.
Periodic Safety Update Report (PSUR)
For submission of the next PSUR, the MAH should follow the EURD list. It is noted that currently no
PSURs are required for Cholecalciferol/Calcium carbonate containing products authorized under
Articles 10(1), 10(a), 14, 16a of Directive 2001/83/EC as amended.
Common renewal date
The common renewal date will be set exactly five years after conclusion of the DCP (ie. 9 July 2020).
Final list of recommendations not falling under Article 21a/22 of Directive 2001/83/EC
Follow-up measures:
Some points of consideration relating to the quality part of the dossier will be addressed through post-
approval commitments by the applicant and the ASMF holder of the cholecalciferol concentrate
powder form.
Proposed list of conditions pursuant to Article 21a or specific obligations pursuant to article 22
of Directive 2001/83/EC
Risk Management Plan (RMP)
The MAH shall perform the required pharmacovigilance activities and interventions detailed in
the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed
subsequent updates of the RMP.
An updated RMP should be submitted:
- At the request of the RMS;
- Whenever the risk management system is modified, especially as the result of new
information being received that may lead to a significant change to the benefit/risk profile or
as the result of an important (pharmacovigilance or risk minimisation) milestone being
reached.
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the
same time.
Additional risk minimisation measures
None.
12PAR D-CURE CALCIUM 1000 mg/1000 I.E Chewable tablets BE/H/0230/001/DC
Public Assessment Report
Update
D-CURE CALCIUM 1000 mg/1000 I.E
Chewable tablets
(Calcium carbonate/Cholecalciferol)
13PAR D-CURE CALCIUM 1000 mg/1000 I.E Chewable tablets BE/H/0230/001/DC
This module reflects the procedural steps and scientific information after the finalisation of the
initial procedure.
14Scope Procedure number Product infomation Date of start of the Date of end of App
affected procedure procedure non
< Type II analytical or clinical procedure; renewal; < sections of SmPC and
line extention > PL modified >
< Title of variation or line extention>
15PAR D-CURE CALCIUM 1000 mg/1000 I.E Chewable tablets BE/H/0230/001/DC
CMDh/233/2011
June 2014
Summary Public Assessment Report
non-generics
D-CURE CALCIUM 1000 mg/1000 I.E
Chewable tablets
(Calcium carbonate/Cholecalciferol)
BE/H/0230/001/DC
Date: 14/01/2016
16PAR D-CURE CALCIUM 1000 mg/1000 I.E Chewable tablets BE/H/0230/001/DC
Summary Public Assessment Report
non-generics
D-Cure Calcium 1000 mg/1000 I.E Chewable tablet
Calcium carbonate/Cholecalciferol / D-Cure Calcium 1000 mg/1000 I.E Chewable tablet
This is a summary of the public assessment report (PAR) for D-CURE CALCIUM. It explains
how D-CURE CALCIUM 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 D-CURE
CALCIUM.
For practical information about using D-CURE CALCIUM, patients should read the package
leaflet or contact their doctor or pharmacist.
What is D-CURE CALCIUM and what is it used for?
D-CURE CALCIUM chewable tablets is a medicine with ‘well-established use’. This means
that the medicinal use of the active substance of D-Cure Calcium is well established in the
European Union for at least ten years, with recognised efficacy and an acceptable level of safety.
D-CURE CALCIUM is used :
- in the correction of calcium and vitamin D deficiencies in the elderly,
- in combination with osteoporosis treatments where calcium and vitamin D levels are
too low or where there is a high risk of them being too low.
How does D-CURE CALCIUM work?
D-CURE CALCIUM chewable tablets contain two active substances, calcium carbonate and
cholecalciferol (vitamin D3). Both calcium and vitamin D3 are found in the diet and vitamin
D is also produced in the skin after exposure to the sun.
Vitamin D3 regulates calcium and phosphate metabolism, guaranteeing calcium absorption by
the intestinal mucosa.
How is D-CURE CALCIUM used?
The pharmaceutical form of D-CURE CALCIUM is a chewable tablet and the route of
administration is oral use.
The recommended dose:
Take 1 tablet of D-CURE CALCIUM once a day, preferably during the evening meal.
Do not take a double dose to make up for a forgotten tablet.
The tablets may be chewed or sucked, they must not be swallowed whole.
The tablet can be divided into equal doses.
The medicine can be obtained without a prescription.
17PAR D-CURE CALCIUM 1000 mg/1000 I.E Chewable tablets BE/H/0230/001/DC
What benefits of D-CURE CALCIUM have been shown in studies?
As Calcium carbonate/Cholecalciferol is a well-known substance, and its use in the correction
of calcium and vitamin D deficiencies in the elderly or in combination with osteoporosis
treatments where calcium and vitamin D levels are too low or where there is a high risk of them
being too low, is well established, the applicant presented data from the scientific literature.
The literature provided confirmed the efficacy and safety of Calcium carbonate/Cholecalciferol
in the treatment of the correction of calcium and vitamin D deficiencies in the elderly or in
combination with osteoporosis treatments where calcium and vitamin D levels are too low or
where there is a high risk of them being too low.
What are the possible side effects from D-CURE CALCIUM?
The most common side effects with D-CURE CALCIUM (which may affect more than 1 in
100 people) are:
- hypercalcaemia (too much calcium in your blood) - the symptoms include nausea,
vomiting, lack of appetite, constipation, stomach ache, bone pain, extreme thirst, needing to
pass urine more often, muscle weakness, drowsiness and confusion;
- hypercalciuria (too much calcium in your urine).
For the full list of all side effects reported with D-CURE CALCIUM, see section 4 of the
package leaflet.
Do not take D-CURE CALCIUM :
- if you are allergic to calcium carbonate or cholecalciferol (vitamin D3) or any of the
other ingredients of this medicine (listed in section 6);
- if you are inactive and have high levels of calcium in your blood (hypercalcaemia) or
urine (hypercalciuria);
- if you have calcium deposits in the tissues of your body;
- if you have serious kidney problems;
- if you have kidney stones or calcium stones in general;
- if you have abnormally high levels of vitamin D;
- if you are less than 18 year of age.
Why is D-CURE CALCIUM approved?
The FAMHP decided that D-CURE CALCIUM ’s benefits are greater than its risks and
recommended that it be approved for use.
What measures are being taken to ensure the safe and effective use of D-CURE CALCIUM?
A risk management plan has been developed to ensure that D-CURE CALCIUM 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 D-CURE CALCIUM, including the
appropriate precautions to be followed by healthcare professionals and patients.
Known side effects are continuously monitored. Furthermore new safety signals reported by
patients/healthcare professionals will be monitored/reviewed continuously as well.
18PAR D-CURE CALCIUM 1000 mg/1000 I.E Chewable tablets BE/H/0230/001/DC
Other information about D-CURE CALCIUM.
The marketing authorisation for D-CURE CALCIUM was granted on 13/08/2015.
The full PAR for D-CURE CALCIUM can be found on the website
http://mri.medagencies.org/Human/Product/Details/44765. For more information about
treatment with D-CURE CALCIUM, read the package leaflet
http://mri.medagencies.org/download/BE_H_0230_001_FinalPL.pdf or contact your doctor or
pharmacist.
This summary was last updated in 01-2016.
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