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Italian Medicines Agency Agenzia Italiana del Farmaco

Risk management measures

Risk management measures

The risk management system was introduced in European legislation in 2004, even though the Risk Management Plan (RMP) has been mandatory since 2012 with the entry into force of the new legislation  which provided for mandatory submission of the RMP for each new marketing authorisation. Module V of the Guideline on good pharmacovigilance practices (GVP) is the reference guideline.

The objectives of the RMP according to the Commission Implementing Regulation (EU) n. 520/2012 are:

  • Identify the safety profile of the medicinal product concerned;
  • Indicate how to characterise further the safety profile of the medicinal product concerned;
  • Describe measures to prevent or minimise the risks associated with the medicinal product including an assessment of the effectiveness of those interventions
  • Document post-authorisation obligations that have been imposed as a condition of the marketing
  • authorisation (PASS, SEAP).

When should the RMP be submitted?

  • Upon each new Marketing Authorization (MA) in the context of the dossier of a new MA to AIFA’s MA Office
  • As a new introduction for a medicinal product already authorized in the context of a type II variation (C.I.11) and in other cases as identified by regulation (EC) no. 1234/2008, as amended, by using the front end system

An updated RMP shall be sent:

  • upon AIFA’s request
  • when the risk management system changes, especially if the changes arise from new information which can lead to major changes in the benefit/risk ratio

AIFA’s Risk Management Office (MGR) is responsible for evaluating the Educational Material (EM), if provided for by the Risk Management Plan (RMP). The assessment procedure ends with an approval letter.

How to submit the application for evaluation:

The draft educational material shall be submitted to AIFA’s Risk Management Office by certified email (PEC) at the following address: protocollo@pec.aifa.gov.it.

In order to correctly sort and direct the application, the e-mail subject line must start with the acronym “MGR”.

Furthermore, a copy of the application must be submitted  to the e-mail address: mgr@aifa.gov.it, as well.

Paper filing is still possible, though not recommended. In this case, a copy of the documentation to be approved must also be sent on digital support (USB pendrive) or via e-mail to the address mgr@aifa.gov.it (please note that files sent via e-mail cannot exceed 30Mb).

The documents sent by e-mail should not exceed 30Mb. When the files size exceed  this limit, the submission could be performed by Eudralink. The application for authorisation of the Educational materials shall be prepared in compliance with the "Guideline on good pharmacovigilance practices” (GVP) Module XVI and Module XVI Addendum I. For new MAs, the application must be submitted at least 60 days before the expected marketing date of the medicinal product. In the case of already marketed medicinal products, the application for insertion or updating of the Educational Material shall take place at the end of the regulatory procedure implementing the aforementioned measure.

Exclusively for new MAs of medicines authorised with centralised procedure, the application for approval of the Educational Material, if required by the RMP, must be filed with the MGR Office as part of the national phase.

The documentation shall include the following *:

  • Cover letter
  • Distribution plan (which shall include a proposal for the target to be achieved as well as the methods and timing for its distribution)
  • Proposal of the Educational material in an editable format in Italian, in order to allow for revisions by the Risk Management Office
  • Copy of the last RMP approved
  • Any common texts, specifying whether they are approved by the EMA or by the MAH
  • MA resolution for the products approved through national, mutual recognition and decentralised procedures
  • Outcome of the regulatory procedure whereby it was decided to implement/update the Educational Material

* For the list of necessary documents, please refer to GVP Form XVI and Form XVI Addendum I.

Please note that before the medicinal product is marketed on the national territory, the marketing authorisation holder is required to distribute the educational material or other risk minimisation measure if provided for by the RMP.

References:

The AIFA Pharmacovigilance Office (FV) is responsible for evaluating and authorizing Direct healthcare professional communications (DHPC), agreed with EMA, AIFA or proposed by the Marketing Authorization Holder (MAH). DHPCs are a tool for communicating important safety information about medicines to healthcare professionals.

How and when to submit the application for evaluation:

The documentation should be presented to the Pharmacovigilance Office exclusively by certified electronic mail (PEC), at the following address: protocol@pec.aifa.gov.it.

The application should be submitted within the deadlines set by the Communication Plan defined by the competent authority in the case of DHPCs deriving from a regulatory procedure; for DHPCs proposed on the initiative of the MAH, the application must be submitted at least 60 days before the date scheduled for sending the safety communication, unless it is of an urgent nature.

Documentation to be submitted:

The documentation to be submitted should include:

  • EMA communication or cover letter from the marketing authorization holder explaining the reasons for the communication.
  • Proposed text in Italian language for DHPC and in an editable format (word).
  • Text in English of the DHPC, if approved by EMA.
  • Distribution plan (which should include a target proposal to send the DHPC to, as well as the defined distribution methods and timing, according to the EMA recommendations in the case of DHPC approved by EMA). In addition, the company should communicate the provider used for the distribution, the sending means (eg by e-mail and / or paper) and provide the related ISO certifications.

Once the Italian version, and the target and timing of distribution have been agreed, the Company will receive official approval through a formal approval letter.

The paper version of the DHPC should be distributed on yellow paper, double-sided, possibly reducing the print font if necessary, without company logos / headers.

The Company should confirm the distribution, including the numbers of the target reached, with communication to AIFA, attaching a copy of the distributed DHPC.

On the same day agreed for the start of distribution, the DHPC will be published on the AIFA web Portal.

References:

With an aim to improve awareness of the risks associated with the use of valproate in pregnancy, AIFA has agreed with the companies holders of valproate-based medicines the distribution of new educational materials for healthcare professionals and patients and the inclusion of a specific warning on the outer packaging of valproate-based medicinal products.

Upon the first prescription and throughout the duration of treatment, healthcare professionals and patients or carers can use such new educational materials to jointly discuss and evaluate the benefits and risks of using valproate in childbearing age and in relation to a possible pregnancy.

Please note that valproate should not be prescribed to girls, adolescents, women of childbearing age or pregnant women, unless strictly necessary, when other treatments have proven to be ineffective or have not been tolerated.

The new educational material consists of:

The HCP's Guide, the Patient Information Booklet, the Risk Acceptance Form and the Patient Reminder are tools designed to help HCPs manage and minimize the risks associated with the use of valproate in girls and in women of childbearing age or during pregnancy and to make sure that patients or their caregivers understand and accept the risks associated with such therapy.

You are reminded to provide the Patient Information Booklet and the Patient Reminder every time you prescribe (doctors) or distribute (pharmacists) a medicinal product containing valproate to a girl or woman of childbearing age or pregnant, unless the patient states that she already owns one.

It should also be noted that medicinal products containing valproate and related substances are marked with the ▼ symbol which identifies them as medicinal products subject to additional monitoring in order to allow the rapid identification of new safety information.

Further information and useful links:

Retinoids (acitretin, adapalene, alitretinoin, bexarotene, isotretinoin, tazarotene and tretinoin) - update on teratogenicity and neuropsychiatric disorders

Medicines containing retinoids are available in oral and topical forms and are widely used to treat various forms of acne, severe chronic hand eczema unresponsive to corticosteroids, severe forms of psoriasis and keratinization disorders.

Tretinoin can also be used for the treatment of promyelocytic leukemia, and bexarotene is used in the treatment of the cutaneous manifestations of the advanced stage of cutaneous T-cell lymphoma.

Following a recent in-depth review of all relevant data, the European Pharmacovigilance Risk Assessment Committee (PRAC) has strengthened the warnings on teratogenicity and neuropsychiatric disorders reported with these medicines intended for patients and healthcare professionals (through information on the medicine and educational materials).

On this page you can find and download the Latest Approved Educational materials and the DHPC:

* INN (International NonProprietary Name): to be replaced with the name of the active ingredient

Educational material approved on 07/08/2018

Lenalidomide is approved as monotherapy or in combination in several therapeutic indications. For a complete list of the approved indications for each lenalidomide-based medicinal product, posology and method of administration, please refer to the Summary of Product Characteristics (SmPC) of the corresponding medicinal product and/or the cover letter published below.

In particular, due to the potential risk of embryo-fetal toxicity, the use of lenalidomide-based medicinal products is contraindicated during pregnancy. It is also contraindicated in women of childbearing potential unless all conditions are met of the Pregnancy Prevention Program (PPP) developed for lenalidomide.

If lenalidomide is taken during pregnancy, a teratogenic effect is expected.

The PPP is an integral part of the risk minimisation plan, which also includes educational materials for healthcare professionals, patient educational brochures and a patient sheet. Its goal is to reduce and prevent the risks associated with the use of lenalidomide.

As required by the PPP, all Healthcare professionals involved must have read and understood the Educational Material before prescribing or dispensing lenalidomide to any patient.

Lenalidomide must be prescribed and dispensed through the AIFA Multi-Drug Monitoring Registry for drugs under the pregnancy prevention program (PPP).

On this page you can download the Latest Approved Educational materials.

  1. Cover letters with indications and dosage
  2. Handbook for Healthcare Professionals
  3. Checklist for the Pregnancy Prevention Program (PPP)
  4. Patient Handbook
  5. Patient sheet
  6. Adverse Event Reporting Form
  7. Pregnancy Reporting Form

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