Annex C. (variation to nationally authorised medicinal products)

Transcription

1 Annex C (variation to nationally authorised medicinal products)

2 Annex I Scientific conclusions and grounds for variation to the terms of the marketing authorisations

3 Scientific conclusions Taking into account the PRAC Assessment Report on the PSURs for the products containing fentanyl as a single active substance in transmucosal formulations, including nasal spray, buccal tablet, sublingual tablets, buccal soluble film and lozenges, the scientific conclusions of the CHMP are as follows: There is no new information that would have an impact on benefit of transmucosal fentanyl in the approved indication. In addition, for the time being, no new risks with transmucosal formulations of fentanyl containing medicinal products have been identified. However, some known risks remain of particular concern. Therefore, whilst the benefit-risk balance of fentanyl remains favourable in the management of breakthrough pain in adults who are already receiving maintenance opioid therapy for chronic cancer pain, some changes were recommended to be made to the product information for all transmucosal formulations as detailed below. The PRAC is of the view that the systemic effects of the transmusocal formulations are expected to be the same, regardless of the formulation. So the PRAC considered that the product information of the transmucosal fentanyl should share a similar safety profile. Therefore, in view of the available data regarding fentanyl, and the results of signal evaluation, the following changes were recommended to be made to the section 4.3, 4.4, 4.5, 4.6, 4.8 and 5.3 for all of the transmucosal formulations of fentanyl containing medicinal products based on the evidence of the data summarised below: - Some known risks remain of particular concern, such as the risk of respiratory depression and the risk of abuse and dependence. Therefore an update of section 4.3 was recommended for all fentanyl containing transmucosal formulations to contraindicate the use in patients without maintenance opioid therapy, and to contraindicate the use for the treatment of acute pain other than breakthrough pain. Respiratory depressant effect should also be reflected in section 4.8 for all the fentanyl containing products. - Having reviewed the available data on bradycardia and bradyarrhythmia, an update of section 4.4 was requested to reinforce this warning for all the fentanyl containing transmucosal formulations. - Since there is a world-wide co-prescription of serotoninergic drugs with fentanyl and considering the potential interaction between opioids such as fentanyl and Selective serotonin re-uptake inhibitors or Serotonin norepinephrine reuptake inhibitors as well as case reports and literature data (Ailawadhi et al 2007), it was considered that the risk of serotonin syndrome warranted an update of sections 4.4 and 4.5 for all the fentanyl containing transmucosal formulations. - For the time being, no study provides results regarding quantities of fentanyl in breast milk 48 hours after the last administration of fentanyl. However, given that the terminal half-life elimination after administration of transmucosal fentanyl is approximately 20 hours, the PRAC considered safer to wait 48 hour after the last administration of fentanyl before breastfeeding and requested that the section 4.6 is updated accordingly for all the fentanyl containing transmucosal formulations. - Further to the detection of new signals, the PRAC recommended the addition of following adverse effects: fall, flushing and hot flush, diarrhoea, fatigue, malaise, peripheral oedema, convulsion, hallucination to the section 4.8 for all the fentanyl containing transmucosal formulations. - Further to the evaluation of data from a carcinogenicity study in rats showing evidence of brain lesions, an update of section 5.3 was requested for all the fentanyl containing transmucosal formulations. Grounds recommending the variation to the terms of the Marketing Authorisation(s) On the basis of the scientific conclusions for the transmucosal fentanyl products, the CHMP is of the opinion that the benefit-risk balance of the medicinal products containing the active substance fentanyl (single substance- transmucosal formulations) is favourable subject to the proposed changes to the product information. The CHMP recommends that the terms of the Marketing Authorisation(s) should be varied.

4 Annex II Amendments to the product information of the nationally authorised medicinal product(s)

5 Amendments to be included in the relevant sections of the Summary of Product Characteristics For all transmucosal formulations of medicinal products containing the active substance fentanyl, the product information shall be amended (insertion or replacement of the text as appropriate) to reflect the agreed wording as provided below: Summary of product characteristics Section 4.3 Contraindications [the wording below should be added or replaced as appropriate] Patients without maintenance opioid therapy as there is an increased risk of respiratory depression Treatment of acute pain other than breakthrough pain. Section 4.4 Special warnings and precautions for use [the wording below should be added or replaced as appropriate] Cardiac disease Fentanyl may produce bradycardia. Fentanyl should be used with caution in patients with previous or pre-existing bradyarrythmias. [the wording below should be added] Serotonin Syndrome Caution is advised when <TRADENAME> is coadministered with drugs that affect the serotoninergic neurotransmitter systems. The development of a potentially life-threatening serotonin syndrome may occur with the concomitant use of serotonergic drugs such as Selective Serotonin Re-uptake Inhibitors (SSRIs) and Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs), and with drugs which impair metabolism of serotonin (including Monoamine Oxidase Inhibitors [MAOIs]). This may occur within the recommended dose. Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea). If serotonin syndrome is suspected, treatment with <TRADENAME> should be discontinued.

6 Section 4.5 Interaction with other medicinal products and other forms of interaction [The wording below should be inserted in this section] Serotoninergic Drugs Coadministration of fentanyl with a serotoninergic agent, such as a Selective Serotonin Re-uptake Inhibitor (SSRI) or a Serotonin Norepinephrine Re-uptake Inhibitor (SNRI) or a Monoamine Oxidase Inhibitor (MAOI), may increase the risk of serotonin syndrome, a potentially life-threatening condition. Section 4.6 Fertility, pregnancy and lactation [This section should be amended to reflect the following wording] Breast-feeding Fentanyl passes into breast milk and may cause sedation and respiratory depression in the breastfedchild. Fentanyl should not be used by breastfeeding women and breastfeeding should not be restarted until at least 48 hours after the last administration of fentanyl. Section 4.8 Undesirable effects [The wording below should be inserted in this section] The following adverse reactions have been reported with <TRADENAME> and/or other fentanylcontaining compounds during clinical studies and post marketing experience. fall, flushing and hot flush, diarrhoea, fatigue, respiratory depression, malaise, peripheral oedema, convulsion, hallucination. with the frequency unknown Section 5.3 Preclinical safety data [This section should be amended to reflect the following wording] Carcinogenicity studies (26-week dermal alternative bioassay in Tg.AC transgenic mice; two-year subcutaneous carcinogenicity study in rats) with fentanyl did not reveal any findings indicative of oncogenic potential. Evaluation of brain slides from the carcinogenicity study in rats revealed brain lesions in animals administered high doses of fentanyl citrate. The relevance of these findings to humans is unknown. Package leaflet For all transmucosal formulations of medicinal products containing the active substance fentanyl, the package leaflet shall be amended (insertion or replacement of the text as appropriate) to reflect the agreed wording as provided below: Section 2. what you need to know before you use [TRADENAME]: Do not use [TRADENAME] : If you are not regularly using a prescribed opioid medicine (e.g codeine, fentanyl, hydromorphone, morphine, oxycodone, pethidine), every day on a regular schedule, for at least a week, to control your persistent pain. If you have not been using these medicines you must not use [TRADENAME], because it may increase the risk that breathing could become dangerously slow and/or shallow, or even stop If you suffer from short-term pain other than breakthrough pain.

7 Warnings and precautions: if you have problems with your heart especially slow heart rate if you take antidepressants or antipsychotics, please refer to the section other medicines and [TRADENAME]. Other medicines and [TRADENAME]: The risk of side effects increases if you are taking medicines such as certain antidepressants or antipsychotics. [TRADENAME] may interact with these medicines and you may experience mental status changes (e.g. agitation, hallucinations, coma), and other effects such as body temperature above 38 C, increase in heart rate, unstable blood pressure, and exaggeration of reflexes, muscular rigidity, lack of coordination and/or gastrointestinal symptoms (e.g nausea, vomiting, diarrhoea). Your doctor will tell you whether [TRADENAME] is suitable for you. Pregnancy and breast-feeding: Fentanyl can get into breast milk and may cause side effects in the breast-fed infant. Do not use [TRADENAME] if you are breast-feeding. You should not start breast-feeding within 48 hours after the last dose of [TRADENAME]. Section 4. Possible side effects: Frequency not known: Severe breathing problems, fall, flushing, feeling very warm, diarrhoea, convulsion (fits), swelling of arms or legs, Seeing or hearing things that are not really there (hallucinations), fatigue, malaise