Interactions with drugs modulating CYP3A4 and P-gp activities Important potential risks Gastrointestinal perforation Haemodynamic changes potentially leading to serious cardiovascular events (including effects on pressure and syncope) Off-label use Interference with opioid-mediated analgesia Missing information Efficacy/safety in methadone treated population Efficacy safety in cancer pain population Efficacy/safety in high risk cardiovascular patients Efficacy/safety beyond 1 year Efficacy/safety in patients >75 of age Efficacy/safety in patients with severe renal impairment (creatinine clearance <30mL/min) Efficacy/safety in patients with hepatic impairment Efficacy/safety in non-Caucasian and non-African-Americans/Black patients Efficacy/safety in Paediatric populations Efficacy/safety in Pregnancy/lactation RMP reviewer comment ‘Efficacy/safety in short term opioid treatment’ should be added as an item of missing information. ‘Efficacy/safety in patients receiving opioids for opioid dependence’ should be as an item of missing information. Appropriate pharmacovigilance and risk minimisation should be applied to the recommended additional items of missing information. Otherwise, subject to the evaluation of the nonclinical and clinical aspects of the Safety Specification, the summary of safety concerns is considered acceptable. Pharmacovigilance plan Routine pharmacovigilance is proposed for a number of safety concerns. Routine pharmacovigilance includes the use of a targeted follow-up questionnaire for adverse event reports relating to the important potential risk ‘Gastrointestinal perforation’. The following additional pharmacovigilance activities are also proposed in the EU RMP (note that no Australian subjects are to be included in these studies) (Table 15). Table 15: Ongoing safety concerns. Additional activity Assigned safety concern Actions/outcome proposed Estimated planned submission of final data Study D3820C00016 Multiple Dose paediatric pharmacokinetic and safety study. Missing information: Safety in paediatric populations An open label, sequential, multiple oral dose study to assess the pharmacokinetics and safety of naloxegol in paediatric patients aged ≥ 6months to < 18 years with opioid-induced constipation Estimated 4Q2016 trial
following multiple oral dosing. The study will assess single-dose PK as well as multiple dose PK, safety and tolerability for up to 6 months. Study D2288R00081 Post-market observational drug utilisation study All identified and potential risks and missing information. To describe demographic, clinical, and treatment characteristics in the baseline of patients treated with naloxegol. To describe treatment pattern characteristics of naloxegol utilisation at initiation and follow-up. First annual report delivered end of 4Q2016 and every year thereafter until completion. Study D2288R00082 Post-market observational safety study in patients taking opioids for cancer pain All identified and potential and missing information. To estimate rates for Health outcomes of interest naloxegol treated patients with active cancer pain. First annual report delivered end of 4Q2016 and every year thereafter until completion. Study D2288R00084 Post-market observational safety in patients taking opioids for non-cancer pain. Identified and potential risks and missing information To estimate event rates for Health outcomes of interest naloxegol treated patients with pain. annual report delivered by the end of 4Q2016 and every year thereafter until completion. Cardiovascular Study A US post-marketing, comparative, observational study to evaluate the cardiovascular safety of naloxegol in patients with non-cancer pain in comparison to other treatments for constipation. Cardiovascular risk (missing information: efficacy/safety in high risk cardiovascular patients) This observational study will characterize the CV risk and major adverse event cardiac events such as myocardial infarction, cerebrovascular accident and cardiac death. Final report estimated December 2023. Annual reports starting in 2016 until study completion.
Sponsor response AstraZeneca agrees to notify the TGA of the results of all pharmacovigilance activities via appropriate mechanisms, including reporting in PSURs and/or applications to amend the product registration details, as available. Evaluator’s comment The sponsor’s response is acceptable in the context of this evaluation. Recommendation #8 in RMP evaluation report Given naloxegol is now registered in several countries it is expected that the medication error and off-label use sections of the EU-RMP will be updated with post marketing data as it becomes available. Sponsor response AstraZeneca agrees to update all relevant sections of the EU RMP will be updated with post marketing data as it becomes available. Evaluator’s comment The sponsor’s response is acceptable in the context of this evaluation. Recommendation #9 in RMP evaluation report The following EU SmPC contraindication which does not appear in the proposed PI is considered clinically relevant and should be included unless the sponsor can provide a compelling justification for its omission: Conditions in patients with cancer pain Patients with underlying cancer who are at heightened risk of GI perforation, such as those with: underlying malignancies of gastrointestinal or peritoneum recurrent or advanced ovarian cancer vascular endothelial growth factor (VEGF) inhibitor treatment. Sponsor response AstraZeneca acknowledges the evaluator’s comment and proposes adoption of this language in the proposed PI. CONTRAINDICATIONS (new text underlined, deleted text in strikethrough): Conditions in patients with cancer pain Patients with underlying cancer who are at heightened risk of GI perforation, such as with: underlying malignancies of gastrointestinal or peritoneum recurrent or advanced ovarian cancer vascular endothelial growth factor (VEGF) inhibitor treatment. Evaluator’s comment The sponsor’s response is acceptable from an RMP perspective. PI amendments are subject to approval by the Delegate. Recommendation #10 in RMP evaluation report The CYP3A4 contraindication should also contraindicate the concomitant consumption of grapefruit juice as it does in the EU SmPC. trial