Variation Applications for Updates of Product Information Following PRAC Recommendations on Safety Signals
Instructions for marketing authorisation holders regarding variation applications for updates of product information following PRAC recommendations on safety signals
European Medicines Agency (EMA) publishes Pharmacovigilance Risk Assessment Committee (PRAC) recommendations on safety signals on monthly basis. The list of abovementioned recommendations is available at EMA website and HALMED website (please see the table below).
Starting from the January 2015 PRAC meeting, EMA publishes recommendations for updates of product information translated to all official European Union (EU) languages. The recommended texts need to be included in product information for medicinal products authorised via national and centralized procedures.
Starting from May 2015, EMA started publishing PRAC recommendations in English at the same time as publishing the translations to all official European Union (EU) languages. EMA publishes the recommendations and the translations approximately 3 weeks following the PRAC meeting.
The Croatian translation of PRAC recommendations, starting from May 2015 PRAC meeting, will be published at HALMED website at the same time as the PRAC recommendations in English, on which occasion a Newsletter will be sent. The obligation to submit the variation to HALMED relates to medicinal products, authorised in Croatia via national procedure, which contain active substances and/or excipients for which the PRAC recommendation is adopted. When submitting the variation, marketing authorisation holders are requested to use the adopted Croatian translation whenever available, and to classify the variation as IAIN C.I.z.
Only when Croatian translations are not available at EMA website (signals prior to January 2015 PRAC meeting), marketing authorisation holders are requested to translate the texts from English.
Pursuant to the recommendations from the Co-ordination Group for Mutual Recognition and Decentralised Procedure (CMDh) Recommendation for classification of unforeseen variations according to Article 5 of Commission Regulation (EC) No 1234/2008, the variation should be classified as:
- IAIN C.I.z - when the variation implements the agreed Croatian translation of the PRAC recommendation,
- IB C.I.z - when the variation implements the agreed wording of published PRAC recommendation (only when Croatian translations are not available - signals prior to January 2015 PRAC meeting)
- II C.I.z - when additional data is submitted within the variation, besides the implementation of the agreed wording.
The deadline for submission of variation application for updates of product information is defined in the PRAC recommendation. Marketing authorisation holder is required to quote the relevant EPITT reference number (listed in the table below for the relevant active substance) as the procedure code in the variation application.
Additional information for the marketing authorisation holders
EMA publishes the PRAC recommendation approximately 3 weeks after the end of the PRAC meeting. At that time, HALMED publishes the link to the PRAC recommendation and the Croatian translation of the recommendation and sends the Newsletter containing the summary of the most important information.
In line with article 16(3) of Regulation (EC) No 726/2004 and article 23(3) of Directive 2001/83/EC, marketing authorisation holders have a legal obligation to ensure that their product information is kept up to date with the current scientific knowledge. When the PRAC recommendation relates to regulatory procedure, such as the variation for updates of Summary of Product Characteristics (SmPC) and Package Leaflet (PL), the marketing authorisation holder is requested to submit the variation in the product information. The obligation to submit the variation in the product information to HALMED relates to medicinal products that are authorised in Croatia via national procedure and which contain the active substance for which the endorsed PRAC recommendation includes the change in the product information.
HALMED is reminding the marketing authorisation holders about the importance of keeping track of PRAC recommendations regularly in order to ensure that they are informed of PRAC recommendations relating to their respective medicinal products in a timely manner and that they act in accordance to these recommendations.
In order to update the product information based on PRAC recommendations on safety signals endorsed after July 1st 2013 it is required to submit the variation application for all medicines which are authorised in Croatia via national procedure and are containing the active substance that is subject to PRAC recommendation, regardless of other regulatory procedures that are pending or foreseen (such as renewal, documentation upgrading or variation).
Updating the product information with PRAC recommendations endorsed prior to July 1st 2013 is possible within the procedure of documentation upgrading.
The list of translations of PRAC recommendations is available at EMA website and HALMED website (please see the table below).
The list of all signals discussed at PRAC meetings since September 2012 is available here (updated 25/09/2017).
More information about the assessment procedure, scientific conclusions and the summary of PRAC recommendations for each safety signal is available at EMA website, in PRAC Minutes section.
More information about signal management is available here.
PRAC recommendations, translations and active substances that are subject to recommendations
4 - 8 July 2016PRAC recommendation (02/08/2016)PRAC recommendation (02/08/2016)ferrous sulfate (mouth ulceration - 18623), proton pump inhibitors: dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole (elevated circulating levels of Chromogranin A - 18614)
|PRAC meeting dates||Recommendation in English language (first published /
|Recommendation in Croatian language (first published /
|Active substance subject to signal (EPITT number)|
|29 August - 1 September 2017||PRAC recommendation (25/09/2017)||PRAC recommendation (25/09/2017)||mesalazine (risk of photosensitivity reactions- 18869), pramipexole (dystonia - 18866)|
|3 - 6 July 2017||PRAC recommendation (7/8/2017)||PRAC recommendation (7/8/2017)||amoxicillin, amoxicillin/clavulanic acid (drug reaction with eosinophilia and systemic symptoms (DRESS) - 18802), ciprofloxacin, meropenem (incompatibility leading to possible precipitation when co-administered intravenously - 18790), darbepoetin alfa, epoetin alfa, epoetin beta, epoetin theta, epoetin zeta, methoxy polyethylene glycol-epoetin beta (severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) - 18846), fulvestrant (anaphylactic reaction - 18832), intravenous (IV) fluids containing electrolytes and/or carbohydrates
(hyponatraemia - 18631), prednisolone, prednisone (induced scleroderma renal crisis - 18888)
|6 - 9 June 2017||PRAC recommendation (3/7/2017)||PRAC recommendation (3/7/2017)||gabapentin (respiratory depression without concomitant opioid use - 18814)|
|2 - 5 May 2017||PRAC recommendation (29/05/2017)||Risk minimisation strategy for high-strength and fixed combination insulin products, EMA/686009/2014 (23/10/2015)||brentuximab vedotin (cytomegalovirus (CMV) reactivation - 18799), insulin (pre-filled pens and cartridges - 18893)|
|3 - 6 April 2017||PRAC recommendation (02/05/2017)||PRAC recommendation (02/05/2017)||albiglutide (acute kidney injury - 18778), leflunomide, teriflunomide (falsely decreased ionised calcium levels - 18787), temozolomide (meningoencephalitis herpetic - 18785)|
|6 - 9 March 2017||PRAC recommendation (4/4/2017)||PRAC recommendation (4/4/2017)||loperamide (serious cardiac events with high doses of loperamide from abuse and misuse - 18339), nivolumab, pembrolizumab (transplant rejection - 18781)|
|6 - 9 February 2017||PRAC recommendation (6/3/2017)||PRAC recommendation (6/3/2017)||fluconazole (spontaneous abortion and stillbirth - 18666), nivolumab (pemphigoid - 18759)|
|9 - 12 January 2017||PRAC recommendation (06/02/2017)||PRAC recommendation (06/02/2017)||azacitidine (pericarditis and pericardial effusion - 18733), propofol, valproate (pharmacokinetic drug interaction leading to an increased propofol exposure - 18696)|
|28 November - 1 December 2016||PRAC recommendation (03/01/2017)||PRAC recommendation (03/01/2017)||acenocoumarol, phenprocoumon, fluindione, phenindione (calciphylaxis - 18710), methylphenidate (priapism - 18719), proton pump inhibitors: dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole (gastric polyps - 18725), vildagliptin, vildagliptin/metformin (pemphigoid - 18692)|
|24 - 27 October 2016||PRAC recommendation (21/11/2016)||PRAC recommendation (21/11/2016)||cobicistat containing products: cobicistat, cobicistat/atazanavir sulfate, cobicistat/darunavir, cobicistat/elvitegravir/emtricitabine/tenofovir alafenamide, cobicistat/elvitegravir/emtricitabine/tenofovir disoproxil fumarate (drug interaction with corticosteroids leading to
adrenal suppression - 18647), flucloxacillin (acute generalized exanthematous pustulosis (AGEP) - 18773), olanzapine (restless legs syndrome - 18659)
|26 - 29 September 2016||PRAC recommendation (25/10/2016)||PRAC recommendation (25/10/2016)||levetiracetam, oral solution (medication errors associated with accidental overdose - 10519), metronidazole (severe hepatic and neurologic toxicity in patients with Cockayne syndrome - 18663)|
|30 August - 02 September 2016||PRAC recommendation (26/09/2016)||PRAC recommendation (26/09/2016)||agomelatine (urinary retention - 18637), boceprevir, daclatasvir, dasabuvir, elbasvir/grazoprevir, ledipasvir/sofosbuvir, ombitasvir/paritaprevir/ritonavir, simeprevir, sofosbuvir, sofosbuvir/velpatasvir (drug interaction between direct-acting antivirals (DAAV) and vitamin K antagonists leading to a reduced international normalised ratio (INR) - 18654), cobicistat containing products: cobicistat, cobicistat/atazanavir sulfate, cobicistat/darunavir, cobicistat/elvitegravir/emtricitabine/tenofovir alafenamide, cobicistat/elvitegravir/emtricitabine/tenofovir disoproxil fumarate (drug interaction with corticosteroids leading to adrenal suppression - 18647), iomeprol (haemolysis - 18625)|
|4 - 8 July 2016||PRAC recommendation (02/08/2016)||PRAC recommendation (02/08/2016)||ferrous sulfate (mouth ulceration - 18623), proton pump inhibitors: dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole (elevated circulating levels of Chromogranin A - 18614)|
|06 - 09 June 2015||PRAC recommendation (04/07/2016)||PRAC recommendation (04/07/2016)||riociguat (increased mortality and serious adverse events (SAEs) in patients with pulmonary hypertension (PH) associated with idiopathic interstitial pneumonias (IIP) in a single clinical trial - 18681)|
|10 - 13 May 2016||PRAC recommendation (06/06/2016)||PRAC recommendation (06/06/2016)||natalizumab (Necrotising retinitis - 18605), warfarin (calciphylaxis - 18545)|
|11 - 14 April 2016||PRAC recommendation (10/05/2016)||olanzapine (drug reaction with eosinophilia and systemic symptoms (DRESS) - 18534)|
|14 - 17 March 2016||PRAC recommendation (11/04/2016)||PRAC recommendation (11/04/2016)||axitinib (nephrotic syndrome - 18484), mercaptopurine; azathioprine (lymphoproliferative disorders - 18503), tigecycline (hypofibrinogenaemia - 18479)|
|08 - 11 February 2016||PRAC recommendation (07/03/2016)||PRAC recommendation (07/03/2016)||Bcr-abl tyrosine kinase inhibitors: imatinib, dasatinib, nilotinib, bosutinib, ponatinib (Hepatitis B virus (HBV) reactivation - 18405), levodopa/carbidopa (intestinal gel, intussusception - 18424), mitotane (sex hormone disturbances and development of ovarian macrocysts - 18301)|
11 - 14 January 2016
|PRAC recommendation (08/02/2016)||PRAC recommendation (08/02/2016)||**|
|30 November - 03 December 2015||PRAC recommendation (06/01/2016)||PRAC recommendation (06/01/2016)||Hormone replacement therapy (HRT) medicinal products, which are not pharmaceutical forms for vaginal use, containing oestrogens or combined oestrogens-progestagens (18258)|
|03 - 06 November 2015||PRAC recommendation (30/11/2015)||*||**|
05 - 08 October 2015
|PRAC recommendation (03/11/2015)||PRAC recommendation (03/11/2015)||**|
|07 - 10 September 2015||PRAC recommendation (06/10/2015)||PRAC recommendation (06/10/2015)||alendronic acid (18256), colecalciferol (18256), clodronic acid (18256), etidronic acid (18256), ibandronic (18256), neridronic acid (18256), pamidronic acid (18256), risedronic acid (18256), tiludronic acid (18256), zoledronic acid (18256), leflunomide (18221), thioctic acid (18406), trabectedin (18115)|
|06 - 09 July 2015||PRAC recommendation (07/08/2015)||PRAC recommendation (07/08/2015)||dexlansoprazole (18119), esomeprazole (18119), lansoprazole (18119), omeprazole (18119),
pantoprazole (18119), rabeprazole (18119), donepezil (18261)
|08 - 11 June 2015||PRAC recommendation (30/06/2015)||*||**|
|04 - 07 May 2015||PRAC recommendation (01/06/2015)||PRAC recommendation (01/06/2015)||fingolimod (18241), latanoprost - Xalatan (18068), leflunomide (18189), natalizumab (18137)|
|07 - 10 April 2015||PRAC recommendation (28/04/2015)||PRAC recommendation (13/05/2015)||daclatasvir (18177), sofosbuvir (18177), sofosbuvir, ledipasvir (18177), interferon alfa-2a (18059), interferon alfa-2b (18059), interferon beta-1a (18059), interferon beta-1b (18059), peginterferon alfa-2a (18059), peginterferon alfa-2b (18059), peginterferon beta-1a (18059), trabectedin (18115)|
|09 - 12 March 2015||PRAC recommendation
|PRAC recommendation (22/04/2015)||aripiprazole (18127)|
|09 - 12 February 2015||PRAC recommendation
|PRAC recommendation (23/03/2015)||amiodarone (18091), aripiprazole (18086)|
|06 - 09 January
|PRAC recommendation (27/01/2015 /
|PRAC recommendation (18/02/2015)||atorvastatin (18140), fluvastatin (18140), simvastatin (18140), gadodiamide (408), gadopentetic acid (408), lithium (18090), paroxetine (18089), valproate and related substances (17956)|
|01 - 04 December 2014||PRAC recommendation (22/12/2014)||*||**|
|03 - 06 November 2014||PRAC recommendation
|06 - 09 October 2014||PRAC recommendation
|08 - 11 September 2014||PRAC recommendation
|*||androgen deprivation therapy (13886), imatinib (17946), leuprorelin (17753)|
|07 - 10
|10 - 13 June 2014||PRAC recommendation
|*||fluoroquinolones for systemic use (15914), mycophenolate mofetil (17760), mycophenolic acid (17760)|
|05 - 08 May 2014||PRAC recommendation
|07 - 10 April 2014||PRAC recommendation
|*||clindamycin (17700), fentanyl patches (17778), levonorgestrel-releasing intrauterine device (IUD) (2706), simvastatin (13849)|
|03 - 06 March 2014||PRAC recommendation
|03 - 06 February
|*||amiodarone (17699), interferon beta (17653), paracetamol (17744)|
|06 - 09 January 2014||PRAC recommendation
|*||triamcinolone acetonide, suspension for injection (17616)|
|02 - 05 December 2013||PRAC recommendation
|04 - 07 November 2013||PRAC recommendation
|*||leflunomide (17693), lenograstim (17586), levetiracetam (17450)|
|07 - 10
|02 - 05 September 2013||PRAC recommendation
|PRAC meetings held from 3-5 September 2012 until 8-11 July 2013||PRAC recommendation
|*||clopidogrel (acquired haemophilia A - 17447), clopidogrel (cross-reactivity between clopidogrel and ticlopidine - 13830), clopidogrel (eosinophilic pneumonia - 16235), docetaxel (15433), filgrastim (16899), pegfilgrastim (16899), mirtazapine (16715), tamsulozin (17622), temozolomide (16857), tiotropium bromide (17305), tramadol (17404)|
* Croatian translation is not available
** No recommendations were made at the meeting relating to the active substances authorized in Croatia via national procedure / No recommendations were made at the meeting regarding variation applications for updates of product information