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Prac recommendations on signals adopted at the prac meeting of 8-11 september 201425 September 2014 EMA/PRAC/490498/2014 Pharmacovigilance Risk Assessment Committee PRAC recommendations on signals Adopted at the PRAC meeting of 8-11 September 2014 This document provides an overview of the recommendations adopted by the Pharmacovigilance Risk Assessment Committee (PRAC) on the signals discussed during the meeting of 8-11 September 2014 (including the signal European Pharmacovigilance Issues Tracking Tool [EPITT]reference numbers). PRAC recommendations to provide supplementary information are directly actionable by the concerned marketing authorisation holders (MAHs). PRAC recommendations for regulatory action (e.g. amendment of the product information) are submitted to the Committee for Medicinal Products for Human Use (CHMP) for endorsement when the signal concerns Centrally Authorised Products (CAPs), and to the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) for information in the case of Nationally Authorised Products (NAPs). Thereafter, MAHs are expected to take action according to the PRAC recommendations. When appropriate, the PRAC may also recommend the conduct of additional analyses by the Agency or Member States. MAHs are reminded that in line with Article 16(3) of Regulation No (EU) 726/2004 and Article 23(3) of Directive 2001/83/EC, they shall ensure that their product information is kept up to date with the current scientific knowledge including the conclusions of the assessment and recommendations published on the European Medicines Agency (EMA) website (currently acting as the EU medicines webportal). For CAPs, at the time of publication, PRAC recommendations for update of product information have been agreed by the CHMP at their plenary meeting (22-25 September 2014) and corresponding variations will be assessed by the CHMP. For nationally authorised medicinal products, it is the responsibility of the National Competent Authorities (NCAs) of the Member States to oversee that PRAC recommendations on signals are adhered to. Variations for CAPs are handled according to established EMA procedures. MAHs are referred to the available Variations for NAPs (including via mutual recognition and decentralised procedures) are handled at national level in accordance with the provisions of the Member States. 1 The relevant EPITT reference number should be used in any communication related to a signal.
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An agency of the European Union European Medicines Agency, 2014. Reproduction is authorised provided the source is acknowledged. The established procedures and timelines for submission of variation applications pertaining to generic medicinal products are to be followed. For procedural aspects related to the handling of PRAC recommendations on signals (e.g. submission requirements, contact points, etc.) please refer to the PRAC recommendations on signals EMA/PRAC/490498/2014 1. Recommendations for update of the product information
1.1. Androgen deprivation therapy – QT interval prolongation due to long-
Substance (invented name) Abiraterone (Zytiga, EMEA/H/C/002321), Degarelix (Firmagon,
EMEA/H/C/000986), other androgen deprivation therapy Authorisation procedure
Centralised and Non-centralised PRAC rapporteur(s)
Martin Huber (DE) Date of adoption
11 September 2014 Having considered the available evidence, including the case reports from EudraVigilance and the literature papers, suggesting a potential association between the use of medicinal products used for androgen deprivation therapy and QT interval prolongation, as a consequence of low testosterone levels, the PRAC agreed that the MAHs of androgen deprivation therapy (see list below) should submit a variation within 2 months to the EMA and NCA(s) to amend the Product Information (PI) as described below (new text underlined). Summary of Product Characteristics
Androgen deprivation therapy may prolong the QT interval. In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval (see section 4.5) physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating [PRODUCT NAME]. Section 4.5:
Since androgen deprivation treatment may prolong the QT interval, the concomitant use of [PRODUCT NAME] with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated (see section 4.4). Section 4.8:
Frequency unknown/rare/uncommon*: QT prolongation (see sections 4.4 and 4.5) *frequency as derived from clinical trials/safety studies, if no data is available frequency should be label ed as "unknown". PRAC recommendations on signals EMA/PRAC/490498/2014 Package leaflet
Section 2. What you need to know before you use [PRODUCT NAME]
Warnings and precautions
Please tell your doctor if you have any of the following:
Any heart or blood vessel conditions, including heart rhythm problems (arrhythmia), or are being
treated with medicines for these conditions. The risk of heart rhythm problems may be increased when
using [PRODUCT NAME].
Other medicines and [PRODUCT NAME]
[PRODUCT NAME] might interfere with some medicines used to treat heart rhythm problems (e.g.
quinidine, procainamide, amiodarone and sotalol) or might increase the risk of heart rhythm problems
when used with some other drugs(e.g. methadone (used for pain relief and part of drug addiction
detoxification), moxifloxacin (an antibiotic), antipsychotics used for serious mental illnesses).
Section 4. Possible side effects
Uncommon/rare/not known*: changes in ECG (QT prolongation)
List of Androgen Deprivation Therapy products
Products with the ATC codes L02AE Gonadotropin releasing hormone analogues, L02BX Other hormone antagonists and related agents and L02BB Anti-androgens, namely: Products which are not yet listed in the WHO ATC DDD codes: PRAC recommendations on signals EMA/PRAC/490498/2014 1.2. Chlorhexidine cutaneous solutions – Chemical injury including burns
when used in skin disinfection in premature infants
Substance (invented name) Chlorhexidine gluconate containing products - cutaneous solutions
Julie Williams (UK) Date of adoption
11 September 2014 The PRAC reviewed the data submitted by the MAHs (Ecolab Ltd, Mölnlycke Health Care and CareFusion UK), and the advice provided by the Paediatric Committee (PDCO). Having considered the evidence from spontaneous reporting, published literature, as well as the
potential seriousness of the chemical injuries associated with the use of chlorhexidine solutions for skin
disinfection in premature infants, the PRAC recommended that the MAHs for all chlorhexidine
containing cutaneous solutions should submit to the NCAs a variation within 2 months to amend the
Summary of Product Characteristics (SmPC), Package Leaflet (PL) and the product labelling as
described below (new text underlined):
1. Changes to the SmPC:
4.4 Special warnings and precautions for use
The use of chlorhexidine solutions, both alcohol based and aqueous, for skin antisepsis prior to invasive procedures has been associated with chemical burns in neonates. Based on available case reports and the published literature, this risk appears to be higher in preterm infants, especially those born before 32 weeks of gestation and within the first 2 weeks of life. Remove any soaked materials, drapes or gowns before proceeding with the intervention. Do not use excessive quantities and do not allow the solution to pool in skin folds or under the patient or drip on sheets or other material in direct contact with the patient. Where occlusive dressings are to be applied to areas previously exposed to [insert product name], care must be taken to ensure no excess product is present prior to application of the dressing. Section 4.8 (undesirable effects):
Chemical burns in neonates (frequency unknown)
2. Changes to the PL (to be included in the section providing information necessary before using the chlorhexidine product): Use with care in newborn babies, especially those born prematurely. <Product name> may cause chemical skin burns. Where tear-off portion exist in leaflets, this information should include the following wording: Use with care in neonates, especially those born before 32 weeks of gestation and within the first 2 weeks of life. <Product name> may cause chemical skin burns. PRAC recommendations on signals EMA/PRAC/490498/2014 Do not use excessive quantities and do not allow the solution to pool in skin folds or under the patient or drip on sheets or other material in direct contact with the patient. 3. Wording proposed for product labelling of all chlorhexidine products, including those not regulated as medicines: Use with care in newborn babies, especially those born prematurely. <Product name> may cause chemical skin burns. The PRAC considered that communication of this important safety issue to relevant hospital physicians, nursing staff and pharmacists responsible for neonatal/ paediatric intensive care units would be important and may be best delivered by means of a communication issued by NCAs . The following key elements were agreed, which could be highlighted in such communications: • Risk of severe chemical injuries when using alcohol-based or water-based chlorhexidine solutions on preterm infants The risk appears to be higher in preterm infants, especially those born before 32 weeks of gestation and within the first 2 weeks of life The minimum amount of chlorhexidine solution required should be used and the solution should not be allowed to pool in skin folds or under the patients. Any excess solution and any soaked materials, drapes, or gowns from the skin should be removed Patients should be observed closely to detect and manage cutaneous side effects at an early Finally, the PRAC agreed that MAHs of chlorhexidine cutaneous solutions should strengthen their pharmacovigilance activities in terms of closely monitoring cutaneous adverse events in neonates through signal detection and literature monitoring. 1.3. Imatinib – Decreased estimated glomerular filtration rate
Substance (invented name) Imatinib (Glivec), EMEA/H/C/000406
Dolores Montero Corominas (ES) Date of adoption
11 September 2014 Having assessed the data provided by the MAH, the PRAC considered the safety review performed by the MAH does not allow ruling out a role of imatinib in declining renal function. The PRAC recommended that MAH for Glivec (innovator of imatinib) should submit a variation within 2 months to the EMA, to amend the PI as described below (new text underlined). PRAC recommendations on signals EMA/PRAC/490498/2014 Following the update of the reference product, the MAH(s) of generic/hybrid products containing imatinib should update their product information in line with that of the reference product. Summary of Product Characteristics:
Long-term treatment with imatinib may result in a clinically significant decline in renal function. It is important that renal function (including glomerular filtration rate) is tested prior to treatment initiation and monthly during therapy with imatinib, with particular attention to those patients exhibiting internal and external risk factors for renal dysfunction, including concomitant use of GFR affecting medicinal products such as diuretics, ACE inhibitors, angiotensin receptor blockers and non-steroidal anti-inflammatory drugs (NSAIDs) Frequency ‘not known' [unless the MAH can provide a more precise estimate]: Renal failure chronic Package leaflet
Section 4. Possible side effects. Not known [unless the MAH can provide a more precise estimate]. Renal failure chronic Additionally, the MAH should submit in the next PSUR (DLP 10 May 2015) a response to a request for supplementary information list of questions.
1.4. Leuprorelin – Medication error - wrong technique in drug usage
Substance (invented name) Leuprorelin (Eligard)
Carmela Macchiarulo (IT) Date of adoption
17 September 2014 Having considered EudraVigilance data, post-marketing reports and studies by Astellas, the MAH of Eligard, as well as literature, the PRAC has agreed that the MAH of Eligard (leuprorelin) should submit a variation within 1 month to the NCA to amend the product label as described below (new text underlined). The new SmPC should be disseminated together with the direct healthcare professional communication (DHPC). PRAC recommendations on signals EMA/PRAC/490498/2014 Summary of Product Characteristics: Section 4.4 - Special warnings and precautions for use Lack of clinical efficacy may occur due to incorrect reconstitution of the product (see section 4.2). The MAH should also submit to the NCA, within 1 month, a room temperature storage variation to allow storage of the product at room temperature for up to 1 month. Additionally, they should submit within 6 months, a variation to modify the device so that it will be impossible to remove the blue plunger rod without removing the grey stopper. Finally, the PRAC recommended the following actions to be submitted within 1 month: The MAH should submit the proposed poster in English language with the following revisions: The poster should be simplified, showing only the critical steps during reconstitution, leaving out the other parts of the product information. The MAH should clarify why in the proposed DHPC it is stated "PRODUCT AT ROOM TEMPERATURE: Timely removal from the fridge (approximately 30 minutes prior to reconstitution)", considering that the French SmPC as well as the authorized Italian SmPC don't indicate the time of removal from the fridge. A proper justification of this statement should be submitted with the DHPC proposal. The MAH should submit a proposal for the dissemination of the DHPC and the poster, based on the health care professionals involved in the administration of Eligard (with accurate ratios of different HCPs per country) and submit a respective communication plan. After adoption by the PRAC the correct set of the HCPs to be reached by these additional RMMs should be agreed at national level. The MAH should submit the final results of the pilot survey to evaluate the effectiveness of the The contents of the effectiveness study protocol are partially endorsed. Timelines for the conduct of the study should be submitted. In addition, the MAH should assess the effectiveness of the risk minimisation by means of a comparison of the reporting rate of medication error cases and lack of efficacy cases before and after the DHPC. An accordingly updated study protocol should be submitted. The MAH's response does not address the PRAC request to make a proposal for a new presentation of Eligard with fewer and easier handling steps nor does the MAH provide a justification against it. The MAH should submit a timetable for the reformulation of the product. In the absence of a proposal from the MAH for a new presentation, the marketing authorisation of the current presentations may be reconsidered. PRAC recommendations on signals EMA/PRAC/490498/2014 2. Recommendations for submission of supplementary
The presence of a safety signal does not mean that a medicine has caused the reported adverse event.
The adverse event could be a symptom of another illness or caused by another medicine taken by the
patient. The evaluation of safety signals is required to establish whether or not there is a causal
relationship between the medicine and the reported adverse event.
Signal (EPITT No)
Action for MAH
Increased number of eye disorders after information requested change of formulation (UK) Solid renal tumours Martin Huber Supplementary information requested citrate, sulfate, Assess in the next PSUR Stanislawski 16/10/2014) (thrombocytopenia /anaemia) (18067) Accidental exposure of Qun-Ying children to oral information requested formulation (18069) Aggression (18089) information requested (submission by 08/11/2014) Dehydration leading Martin Huber Assess in the next PSUR to renal failure calciphylaxis (18056) information requested (submission by 08/11/2014) Pulmonary arterial hypertension (18046) (FR) information requested (submission by 08/11/2014) PRAC recommendations on signals EMA/PRAC/490498/2014 3. Other recommendations
Signal (EPITT No) PRAC
Action for MAH
pharmacovigilance Pulmonary arterial Qun-Ying Yue No action at this stage interferon beta-1a, interferon beta-1b, Peginterferon alfa-2a, Peginterferon alfa-2b Sodium Julie Williams No action at this stage effervescent, dispersible and soluble medicines PRAC recommendations on signals EMA/PRAC/490498/2014
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