Risk minimisation activities The sponsor concludes that routine risk minimisation activities for all the specified safety concerns and missing information are sufficient, except for the important potential risk: ‘Neuropathy’ and the missing information: ‘Patients with severe cardiac impairment’, ‘Long-term safety’ and ‘Concomitant use of ceritinib and gastric acid agents such as PPIs’ for which no risk minimisation activities are proposed. Reconciliation of issues outlined in the RMP report Table 8 summarises the first round evaluation of the RMP, the sponsor’s responses to issues raised by the evaluator and the evaluation of the sponsor’s responses. 8: Reconciliation of issues outlined in the RMP Evaluation Report Recommendation in RMP evaluation report Sponsor’s response RMP evaluator’s comment Safety considerations may be raised by the nonclinical and clinical evaluators through the consolidated section request and/or the Nonclinical and Clinical Evaluation Reports respectively. It is important to ensure that the information provided in response to includes a consideration of the relevance for the Risk Management Plan and any specific information needed to address this issue in the RMP. For any safety considerations so raised, the sponsor should provide information that is relevant and necessary to address the issue in the RMP. The sponsor states: ‘At this time no specific issues have been raised by the Clinical Evaluator regarding the EU RMP submitted and the Nonclinical Evaluation Report first round is not available at this time’. The nonclinical report have now become available and the sponsor should now adequately address any outstanding issues (see Section 2: ‘Comments on the safety specification of the RMP’), preferably before this application is approved. Consistent with the US FDA ‘Postmarketing Requirements’, the important potential risk: ‘Toxicity from drug when taken with food’ should be included as a new safety concern. Consideration must be given as to what pharmacovigilance and risk minimisation activities will be proposed for this new safety concern and only the ASA need be revised accordingly. The sponsor has provided justification and concluded: ‘modeling demonstrates that even if a patient took ceritinib at 750 mg daily with food, the expected increased exposure would not result in a QT prolongation beyond 21.6 ms, indicating a low risk of increased toxicity driven by This is acceptable. trial
increased systemic exposure caused by food intake. Therefore, the applicant does not consider that that ‘Toxicity from drug over‐exposure when taken with food’ should be included as a new safety concern’. As previously stated consideration must be given as to what pharmacovigilance activities will be proposed for the new important potential risk: ‘Toxicity from drug when taken with food’. To that end the sponsor should at least include the US FDA required clinical trial to evaluate the systemic exposure and safety of 450 mg Zykadia (ceritinib) taken with a meal and 600 mg Zykadia (ceritinib) taken with a light meal as compared with that of 750 mg Zykadia (ceritinib) taken in the fasted state in metastatic ALK-positive NSCLC patients as an additional pharmacovigilance activity for this new safety concern. Only the ASA need be revised accordingly and it is expected that at least a draft protocol for this study will be attached to the revised ASA. The sponsor states: ‘As indicated in response to Recommendation 2, the Applicant does not consider that ‘Toxicity from drug over‐exposure when taken with food’ should be included as a new safety concern, therefore no pharmacovigilance activities are proposed. Although Novartis does not propose to add ‘Toxicity from drug over‐exposure when taken with food’ to the summary of ongoing safety concerns at this time, effects on drug exposure due to food interactions will be evaluated in Study A2112 as previously discussed. The sponsor has documented this undertaking in the updated ASA and this is acceptable. When the US FDA approved the ALK-positive NSCLC indication this approval stated: ‘This indication is approved under accelerated approval based on tumor response rate and duration of The sponsor has objected to this recommendation and provided justification for their position. This recommendation remains outstanding for the Delegate’s consideration.
response. An improvement in survival or symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials’. If applicable, it is recommended to the Delegate that similar statements alluding to an absence of efficacy data be included in the Indications section of the Australian PI. Any such change should be adequately reflected in the draft consumer medicine information document. As previously stated consideration must be given as to what risk minimisation activities will be proposed for the new important potential risk: ‘Toxicity from drug over-exposure when taken with food’. It is acknowledged that the following routine risk minimisation is already included under the interactions’ subheading and in the Dosage and Administration section of the draft Australian PI respectively: The bioavailability of ceritinib is increased in the presence of food depending on the fat content in the meal (see Pharmacokinetics; Absorption). Ceritinib should be on an empty stomach. No food should be eaten for at least two hours before and two hours after the dose of ZYKADIA is taken. ZYKADIA should be administered orally once daily at the same time every day. ZYKADIA capsules should be swallowed whole with water. The capsules The sponsor has objected to this wording and proposed alternative wording as follows: ‘No food should be eaten for at least two hours before and two hours after the dose of ZYKADIA is taken in order to avoid systemic exposure exceeding that of a 750 mg ZYKADIA dose taken in the fasted state, which may increase adverse drug reactions’. The sponsor’s overall proposed approach to this matter is generally acceptable, although it is recommended to the Delegate that the following text from the corresponding US FDA monograph be included in the Pharmacokinetics; Absorption section of the Australian PI: ‘A 600 mg or higher ZYKADIA dose taken with a meal is expected to result in systemic exposure exceeding that of a 750 mg ZYKADIA dose taken in the fasted state, and may increase adverse drug reactions’. The ASA should be amended accordingly, preferably before this application is approved. trial
should not be chewed or crushed. ZYKADIA capsules must be taken on an empty stomach. No food should be eaten for at least two hours before and two hours after the dose of ZYKADIA is taken (see Pharmacokinetics; Absorption). However, it is recommended to the Delegate that the last identical sentence be strengthened as follows and all these sections of the Australian PI be to each other: ‘No food should be eaten for at least two hours before and two hours after the dose of ZYKADIA is taken in order to avoid the serious risk of toxicity from drug Any such change should be adequately reflected in the draft consumer medicine information document. In regard to the proposed routine risk minimisation activities, it is recommended to the Delegate that the draft product information document be revised as follows: For the important identified risk: ‘Hepatotoxicity’, the sentence in the PRECAUTIONS section of the Australian PI: ‘Monitor with liver laboratory tests (including ALT, AST, and total bilirubin) prior to the start of treatment and monthly thereafter’ should be amended to: ‘Monitor with liver laboratory tests (including ALT, AST, and total bilirubin) prior to the start of treatment, every 2 weeks for the first month of treatment and monthly thereafter’. This would align with the approved EU SmPC and enhance the safe use of this medicine. The sponsor has objected to this recommendation and provided justification for their position. The sponsor has concluded: ‘Therefore, monthly evaluation of liver laboratory tests is acceptable to follow patients for hepatotoxicity. The AU PI recommendation is based on the US PI, the Canadian Product Monograph, and the Swiss label’. The sponsor states: ‘Novartis acknowledges that the clinical and exposure data in patients with This is acceptable. This is acceptable. This is acceptable. This is acceptable. referenced