Variations
(Version 1.2, 10 February 2026)
After obtaining a marketing authorisation, the marketing authorisation holder (MAH) is required to follow the latest scientific and technical progress and to monitor information on the safety and efficacy of the medicinal product that may affect the benefit-risk balance. Throughout the life cycle of the medicinal product, the MAH must update the conditions/obligations/restrictions granted with marketing authorisation, as well as the approved product information/medicinal product dossier on which the authorisation was based on. Any change/amendment of the information approved shall be submitted as a variation.
1. Definition of variation
Variation to the terms of a marketing authorisation are set out in Article 50 of the Medicinal Products Act (Official Gazette No. 76/13, 90/14, 100/18, 136/25, hereinafter: the Act) and amended Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use (hereinafter: the Variations Regulation). The Variations Regulation is in force in all EU Member States and applies to all marketing authorisations granted via national (NP), MRP/DCP and CP (details on marketing authorisation procedures are available at Marketing authorisation procedures).
The latest revised Variations Regulation applies for variations implemented and submitted from 1 January 2025.
2. Application for variation
The application for variation should be submitted by the MAH to HALMED. When submitting a variation, the MAH should classify it in accordance with the current Guidelines on the details of the various categories of variation, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use, and on the documentation to be submitted pursuant to those procedures C/2025/5045 (hereinafter: the Classification Guideline), drawn up in accordance with Article 4 of the Variations Regulation.
New Classification Guideline (C/2025/5045) applies for variation implemented and submitted from 15 January 2026. More details are available at CMDh/procedural-guidance/variation/revised-variations-framework.
2.1. Elements to be submitted for variation
The following should be submitted:
1. Cover letter for variation
2. Variation Application Form (eAF) available at eSubmission/EU Electronic Application Forms
The annexes listed in the eAF shall be enclosed, as applicable to the submitted variation.
3. Proof of payment of relevant fee for submitted variation according to HALMEDˈs Fees
4. Documentation for the variation specified in the Classification Guideline, depending on type and classification of variation.
For a type II variation and an unforeseen variation (not classified by the Classification Guideline, nor in the classification recommended under Article 5 of the Variations Regulation), for which documentation is not specified in the Classification Guideline, it is necessary to submit relevant scientific data/documentation supporting the requested variation.
When applying for a variation to a marketing authorisation in MRP/DCP, the MAH should follow the "Best Practice Guides (BPGs) for the Submission and Processing of Variations in the Mutual Recognition Procedure” of the Coordination Group for MRP and DCP (hereinafter: CMD(h)), as well as other guides/instructions published on the CMD (h) website at "Procedural Guidance/Variations". HALMED also follows these guides/instructions when processing applications for variations for the national marketing authorisations and recommends that MAHs use them when applying for purely national variations.
2.2. Grouping of variations
The conditions for acceptable grouping of variations are laid down in Article 7 and Annex III and Article 7.a (super-grouping of IA variations) of the Variations Regulations.
HALMED recommends that MAHs use the CMD(h) guide "Examples for acceptable and not acceptable groupings for MRP/DCP products" as well as "Chapter 6: CMDh BPG for the Processing of (Super-)Grouped Applications in the Mutual Recognition Procedure" published at CMDh/procedural-guidance/variation as well as Q/A documents published on EMA’s website Grouping of variations: questions and answers.
If MAH plans to submit the super-grouped variation application with Croatia acting as Reference Authority they should fill out the "Letter of intent for the submission of a type IA super-grouped procedure" available on the link CMDh/templates/variation and send it to DCP.MRP@halmed.hr.
2.3. Worksharing variations
In accordance with Article 20 of the Variations Regulation, MAH is required to submit the same variation (type IB or type II) or the same group of variations (type IA/IB/II) affecting more than one authorisation from the same holder, in a single application via work-sharing procedure. It is recommended to use the guidance "Chapter 7: CMDh BPG on Variation Worksharing” published at CMDh/procedural-guidance/variation.
If MAH plans to submit the worksharing variation application with Croatia acting as Reference Authority they should fill out the "Letter of intent for the submission of worksharing procedure" available on the link CMDh/templates/variation and send it to DCP.MRP@halmed.hr.
2.4. Questions and answers
HALMED recommends that MAHs follow the questions and answers that the CMD(h) continuously updates and publishes in the document CMDh/Questions & Answers/ Variations, which provides additional clarifications useful for submitting a variation application.
2.5. Variations following referrals, PSUSA procedure and PRAC recommendations on safety signals
For variations resulting from the outcome of a referral procedure, an application should be submitted in accordance with Instructions for variation application after Referral.
For variations resulting from a PSUSA procedure, an application should be submitted in accordance with Instructions for variation application following the outcome of the PSUSA procedure and for variations based on a PRAC recommendation following a safety signal, application should be submitted in accordance with Instructions for variation application following PRAC recommendations on safety signals. These instructions are continuously updated with the latest adopted procedure outcomes and recommendations.
3. Recommendation for classification of unforeseen variations
For an unforeseen variation that is not specified in the Classification Guideline and for which no recommendation for classification has been given under Article 5 of the Variations Regulation, the MAH may submit a request for a recommendation on classification to the relevant authority prior to submission of variation. For detailed instructions on how to submit a request for a recommendation on classification of a variation, MAHs should follow the instructions in "Chapter 8: Best practice guide on CMD(h) recommendations on unforeseen variations" published on CMDh/procedural-guidance/variation and used the templates for variations under Article 5. of Variation Regulation published on CMDh/templates/variation.
The recommendation on classification of variations given via procedure under Article 5 is consistent with the Classification Guideline and harmonised among all EU Member States. The recommendations published on CMDh/procedural-guidance/variation/art-5-recommendations, in the document "Recommendation for classification of unforeseen variations according to Article 5", should be taken into consideration for the classification of variations prior to submission, in addition to the Classification Guideline.
4. Change in prescription and dispensing status of a medicinal product
A change in the prescription status ("subject to medical prescription” to "not subject to medical prescription") under Article 33 of the Ordinance, and a change of dispensing status of medicinal products ("pharmacy” to "pharmacy and specialised retail stores”) under Article 34 of the Ordinance, are not covered by the Variations Regulation and the Classification Guideline. Hence, these changes are regulated nationally. When submitting an application for these changes, it is necessary to follow HALMED's recommendations on classification, which are published at Over-the-counter (OTC) Medicines. The variation application must include all elements mandatory for variation application, along with the documentation supporting the change in accordance with Article 33 or Article 34 of the Ordinance and above mentioned HALMED’s recommendations on classification.
These changes may refer to NP and MRP/DCP marketing authorisations. In the case of the MRP/DCP authorisations, the variations applications should be submitted to the competent authority of the Member State where the changes are applicable and these variations are processed nationally.
5. Change under Article 36 of the Ordinance
Changes under Article 36 of the Ordinance (corresponding to Article 61(3) of Directive 2001/83/EC) are not covered by the Variations Regulation/Classification Guideline and relate to changes of the package leaflet and/or labelling and/or mock-up of the outer/inner packaging of the medicinal product, which is not connected with the change of the summary of product characteristics.
An application for a change under Article 36 of the Ordinance (Article 61 (3) of Directive 2001/83/EC) should be submitted by the MAH to HALMED and/or the Member State’s competent authority where the change is applicable.
5.1. Elements to be submitted for notification
The following should be submitted:
1. Cover letter for notification
2. Notification Form published on CmDH website at CMDh/procedural-guidance/art-61.3 which is used for variation application in accordance with Article 36 of the Ordinance. The same form is used for NP and MRP/DCP marketing authorisations.
3. Proof of payment of fee for change under Article 36 according to HALMEDˈs Fees
4. Documentation supporting the requested change.
