In accordance with paragraph 8 of Section IV of the Procedure for Expert Evaluation, the applicant must amend the instructions for medical use of the medicinal product upon receipt of new data, including bringing the instructions for medical use into line with the approved instructions for medical use of the original (reference) medicinal product, and ensure that the information on the medicinal product corresponds to current scientific knowledge.
- In May 2022, the registration certificate holder (RCH) submitted Type II variations, including an updated European Union (EU) RMP version 6.0, following completion of the post-authorization safety and efficacy study (PASS) A1501103 included in the pharmacovigilance plan. In addition, following the outcome of the evaluation of the periodic safety update report (PSUR) by the Pharmacovigilance Risk Assessment Committee (PRAC) (procedure EMEA/H/C/PSUSA/00003127/202102) of October 2021, the RMP was updated to remove the important identified risk “Peripheral neuropathy” and the missing information on “Resistance” from the list of safety concerns.
- The RCH received the first request for supplementary information (RSI) of 01 September 2022 within the procedure EMEA/H/C/WS2270, according to which the European Medicines Agency (EMA) recommended that the RCH continue to distribute the Patient Alert Card to minimize the identified risks of phototoxicity and squamous cell carcinoma. The updated version of the RMP 6.1 was submitted in November 2022 as part of providing this response.
- In March 2023, the registration certificate holder submitted an updated version of RMP 6.2 in response to the 2th request of 12 January 2023 under procedure EMEA/H/C/WS2270, according to which the EMA stated:
- remove the following important risks and missing information from the summary of safety concerns: “Hepatotoxicity”, “QT interval prolongation”, “Visual disturbances”, “Skin cancer (except squamous cell carcinoma)”, “Suicide-related events”, “Effects on pregnancy”, “Effects in pediatrics”, and “Use not as intended”;
- delete the wording in part III.2. Additional pharmacovigilance activities;
- add the key elements of the Patient Alert Card to Annex 6.
- The registration certificate holder updated RMP version 6.3 in response to the 3th RSI of May 12, 2023, within procedure EMEA/H/C/WS2270, in which the EMA recommended updating it by including additional text, the key elements of the Patient Alert Card in Annex 6.
Annex 6. Detailed information on the proposed additional risk minimization measures (if necessary)
The following risk minimization materials were distributed:
- Checklist for healthcare professionals regarding phototoxicity, squamous cell carcinoma (SCC) and hepatotoxicity.
- Question-and-answer brochure for healthcare professionals on phototoxicity, SCC, and hepatotoxicity.
- Patient alert card on phototoxicity and SCC.
Specifications for additional risk minimization measures
The three components of the risk minimization measures are the Checklist for healthcare professionals, the Questions and Answers brochure for healthcare professionals, and the Patient Alert Card.
The content and layout of the risk minimization materials are not promotional in nature. Testing of the risk minimization materials was conducted in October 2013 on a sample of general practitioners in the United Kingdom and France, before the work on the risk minimization materials was completed and before their further distribution in April 2014. In particular, prototypes of each material (for example, the Checklist for health care professionals, the Questions and Answers Brochure for health care professionals, and the Patient Alert Card) were reviewed during individual moderator-led interviews to ensure clarity and understanding of the content and purpose of each. The findings from this testing made it possible to improve the content and format of the materials in order to improve understanding of the risks of using the medicinal product and ways to manage them.
Development of a Control Checklist for healthcare professionals and other risk minimization measures
The risk minimization materials were designed to be available primarily to healthcare professionals through a paper-based distribution system. In addition, some health authorities [the EMA, the Medicines and Healthcare products Regulatory Agency of the UK (MHRA), and the French National Agency for the Safety of Medicines and Health Products (ANSM)] have posted PDF copies of the materials on their websites for download.
The risk minimization materials were designed to be useful and easy to use and to promote a high level of use of voluntary participation programs. The checklist for health care professionals was used as the main measure performing an educational function and reminding physicians of the screening and prescribing process for medicinal products.
Refinement and adaptation of risk minimization measures and other materials to national conditions
Prototypes of materials for minimizing risks with the use of voriconazole (voriconazole) were submitted for review to representatives of public health authorities and adapted to national norms and rules. The materials were available in the local languages of the countries in which they were distributed.
Implementation of additional risk minimization measures
To ensure appropriate management of the risks of phototoxicity, hepatotoxicity, and cutaneous squamous cell carcinoma, further risk minimization measures were implemented starting in April 2014. These activities included additional risk minimization measures consisting of the following components: a Control checklist for healthcare professionals, a Q&A brochure for healthcare professionals, and a Patient alert card. However, no clear conclusion was reached regarding the effectiveness of these additional risk minimization measures.
The available data from PASS A1501102, which assessed the effectiveness of additional risk minimization measures aimed at reducing the risks of phototoxicity, cutaneous squamous cell carcinoma (SCC) and hepatotoxicity in patients taking voriconazole, indicate that the source of knowledge for healthcare professionals about the risks associated with the use of voriconazole is not sufficiently clearly linked to the additional risk minimization measures. In addition, study A1501103, a non-interventional, retrospective PASS designed to monitor selected safety risks in patients taking voriconazole in real-world conditions, especially with long-term use (i.e., ≥180 days), did not reveal an increased risk of liver disease, phototoxicity, cutaneous SCC, visual disorders and periostitis with the use of voriconazole, or other information that would require continued implementation of the educational materials.
Moreover, after an extensive literature review of relevant publications, clinical guidelines and other sources, there is evidence that the most important recommendations included in both routine and additional risk minimization measures for voriconazole regarding hepatotoxicity, SCC and phototoxicity have been implemented in everyday clinical practice, in particular in the European Region. Since the instructions for medical use of the medicinal product remain the most important routine risk minimization measure, they currently clearly inform physicians of all the necessary safety information, so additional risk minimization measures aimed at healthcare professionals are not expected to provide any further significant awareness among physicians of these well-known risks.
Therefore, the MAH proposed to remove the training materials for healthcare professionals from the RMP and to keep the Patient Alert Card, as proposed by the EMA in the RSI received in September 2022 (procedure EMEA/H/C/WS2270). This proposal was accepted by the EMA in the Updated Assessment Report of 05 January 2023 within the same procedure.
Current additional risk minimization measures
Patient alert card on phototoxicity and SCC
- Reminds patients about the risk of phototoxicity and squamous cell carcinoma of the skin during treatment with voriconazole.
- Reminds patients when and how to report relevant signs and symptoms of phototoxicity and skin cancer.
- Reminds patients of the need to take measures to minimize the risk of skin reactions and squamous cell carcinoma (SCC) of the skin (by avoiding direct sunlight, using sunscreen and protective clothing) during treatment with voriconazole and to inform healthcare professionals if they develop relevant skin changes.
List of medicinal products containing voriconazole (voriconazole) and authorized for medical use in Ukraine (according to the State Register of Medicinal Products as of 22.11.2023).
To analyze the published information, the applicant must use the original text available at the following links:
