Post Authorization Safety Study of HCV patients treated with Eltrombopag: Multicentre, Prospective Observational Cohort Study of Thrombocytopenic HCV Patients Receiving Eltrombopag Pharmacoepidemiology Category 3 Ongoing safety events among HCV patients who receive Eltrombopag in the post approval, real world setting analysis, December 2016 12 months interim analysis, June 2017 18 months interim analysis, October 2018 Final report, November 2019 HCV-TARGET: Proposed Post Authorization Safety Study of HCV patients treated with Eltrombopag: Hepatitis C Therapeutic Registry and Research Network Pharmacoepidemiology Category 3 Ongoing TEE and Hepatic decompensation Assess occurrence of safety events among HCV patients who receive Eltrombopag in the post approval, real world setting interim, October 2016 Final report, October 2019 HCV Research UK: Proposed Post Authorization Safety Study of HCV patients treated with Eltrombopag Pharmacoepidemiology Category 3 Ongoing TEE and Hepatic decompensation Assess occurrence of safety events among HCV patients who receive Eltrombopag in the post approval, real world setting First interim, October 2016 Final report, October 2019 Effectiveness of Eltrombopag Educational Materials for Hepatitis C associated thrombocytopenia Category 3 Ongoing Key elements within the educational materials including Hepatic decompensation, TEEs and fatal adverse events Measurement of the effectiveness of the Eltrombopag Risk Minimisation education materials Interim report, April 2015 Final report, September 2015 ELT116826 Clinical Safety in SAA patients Safety of eltrombopag in SAA patients April 2016
Category 3 unresponsive to IST unresponsive to IST ELT116643 Clinical Category 3 Ongoing Safety in SAA patients receiving treatment with IST Safety in SAA patients receiving treatment with IST May 2016 RAD201583 Clinical Category 3 Planned Drug-drug interaction (DDI) –cyclosporin and eltrombopag Determine effect of cyclosporin on PK of eltrombopag September 2015 RAD200936 Clinical Category 3 Planned Paediatrics Safety of eltrombopag in paediatric SAA December 2020 Risk minimisation activities The sponsor is proposing routine risk minimisation activities. In the EU-RMP, the sponsor is proposing health care professional and patient education as additional risk minimisation activities. However, in the ASA, the sponsor states the following: No additional risk minimisation measures are planned following the extension of indication to SAA patients. The risk communication in the product labelling associated with cytogenetic abnormalities is considered to be the primary risk minimisation tool and is sufficient to inform prescriber and patient. Reconciliation of issues outlined in the RMP report Table 7 summarises the first round evaluation of the RMP, the sponsor’s responses to issues raised by the evaluator and an evaluation of the sponsor’s responses. Table 7: Reconciliation of issues outlined in the RMP Evaluation Report (Round 1) Recommendation in RMP evaluation report Sponsor’s response (or summary of the response) RMP evaluator’s comment 1. Safety considerations may be raised by the nonclinical and clinical evaluators through the consolidated request for further information and/or the Clinical Evaluation Report. It is important to ensure that the information provided in response to includes a consideration of the relevance Pharmacodynamic, pharmacokinetic, and toxicological evaluations with eltrombopag were completed as part of the nonclinical program in support of the initial registration for Revolade and the subsequent application to register the HCV Indication. There are no new nonclinical The sponsor’s response has been noted.
A complication of SAA is the appearance of cytogenetic abnormalities in bone marrow cells. Cytogenetic abnormalities have been reported in 15 to 20 % of patients with SAA. The clinical consequences are variable, depending upon the specific abnormality and the presence or absence of clinical sequelae such as dysplasia or worsening cytopenias.6 Novartis does not propose to include any specific information about cytogenetic abnormalities in the educational materials. Information communicated to physicians through the Australian PI document is considered the primary tool to educate physicians about this risk. No other regulatory body including the US Food and Drug Administration (US FDA) and the European Medicines Agency (EMA) have requested the addition of such information in the currently implemented educational materials. for the treatment of SAA patients and should be included. This can be brief. It is recommended the existing additional risk minimisation activities be updated to include specific risks associated with the SAA indication (in particular cytogenetic abnormalities and the need for long-term follow-up). The sponsor should provide the updated materials to the TGA. 7. The sponsor should provide the TGA with the following details for agreement: -All draft education materials; -A clear distribution plan; and -A clear plan to measure the effectiveness of the education programme as an additional risk minimisation activity. The educational materials for cITP have been finalised by Novartis and are provided in the attachment of Australian Specific Annex v2.1 [Module 1.8.2]. The educational materials for HCV are currently being amended by Novartis, and it is estimated that these will be available by 18 September 2015. For further details regarding the different educational materials and their availability please refer to [Table 7b]. Both sets of educational materials will be amended to align with the Australian PI and mailed out to the prescribers of Revolade for all indications, within 90 days following availability of the Given the new information provided, this is considered acceptable in the context of this application. The amended materials are herewith requested.
10. Platelet values should be reported in the unit x109/L which is more commonly used in Australia. This has been addressed in the revised PI. This is considered acceptable in the context of this application pending approval by the Delegate. 11. In the ‘Precautions’ section, the PI should contain similar information on hepatic decompensation, as found in the SmPC. This has been addressed in the revised PI. This is considered acceptable in the context of this application pending approval by the Delegate. 12. In the ‘Adverse Events’ Section, the PI should align with the proposed EU SmPC that contains many additional adverse events not proposed to be included in the Australian PI. This applies to all indications. Uncommon events may be grouped separately. This has been addressed in the revised PI. This is considered acceptable in the context of this application pending approval by the Delegate. 13. In the ‘Overdosage’ section, the PI should include the poison information telephone number. The sponsor confirms that the current Revolade CMI contains the Poisons Information Centre contact number, and that the proposed PI has been revised to also include this data in the OVERDOSAGE section. The revised, draft Product Information and Consumer Medicine Information are provided. In addition, please see the responses to 9, 10, 11, 12, 13 and 14. Furthermore, the sponsor provides an update on the international regulatory status of similar applications overseas and the currently approved Product Information in the USA, Canada, and Europe. This is considered acceptable in the context of this application pending approval by the Delegate. 14. It is recommended to the Delegate that the consumer medicines information document be revised to accommodate the changes made to the product information document. The sponsor have revised the current CMI document to include Severe Aplastic Anemia (What Revolade is used for), How much to take it, and possible side effects. The revised document is included with this response. This is considered acceptable in the context of this application pending approval by the Delegate.