The important potential risk: ‘Cardiac Disorders’ is a broad term, although the EU-RMP states that only the MedDRA term Cardiac arrhythmia SMQ is used to monitor this ongoing safety concern. Consequently it is suggested that it be replaced by the important potential risks: ‘Cardiac arrhythmias’ (MedDRA term Cardiac arrhythmias SMQ); ‘Myocardial infarction’ (MedDRA term Myocardial infarction SMQ – narrow); and ‘Cardiac failure’ (MedDRA term Cardiac failure SMQ – narrow). The following MedDRA terms have been included to assess the potential risk of cardio- and cerebrovascular disorders in the UMEC/VI EU RMP: ‘Cardiac arrhythmias’ (MedDRA term Cardiac arrhythmias SMQ), ‘Cardiac failure’ (MedDRA term Cardiac Failure SMQ), Cardiac Ischaemia (MedDRA terms Myocardial Infarction SMQ, Other Ischaemic Heart Disease SMQ), ‘Stroke’ (MedDRA terms CNS haemorrhages and cerebrovascular conditions SMQ). This is acceptable. The PI states: “Consistent with its antimuscarinic activity, Anoro Ellipta should be used with caution in patients with narrow-angle glaucoma or urinary retention.” In addition the safety specifications (SS) of the EU-RMP refers to effects’ as an important pharmacological class effect for LAMA. Consequently it is suggested that glaucoma’ and ‘Urinary retention/bladder obstruction’ should be included as important potential risks. ‘Narrow-angle glaucoma’ and ‘Urinary retention/bladder outflow obstruction’ have been included as important potential risks in the UMEC/VI EU-RMP. This is acceptable. The draft PI states: “As with other inhalation therapies, administration of Anoro Ellipta may produce paradoxical bronchospasm that may be life threatening. Treatment with Anoro Ellipta should be discontinued if paradoxical ‘Paradoxical bronchospasm (which may be life threatening)’ has been included as an important potential risk in the UMEC/VI EU-RMP. This is acceptable. angle
bronchospasm occurs and alternative therapy instituted if necessary.” Consequently it is suggested that ‘Paradoxical bronchospasm’ should be included as an important potential risk. The SS of the EU-RMP refers to ‘Hypokalaemia’, ‘Hyperglycaemia’ & ‘Tremor’ as important pharmacological class effects for LABA and routine pharmacovigilance activities will monitor these effects. Consequently it is suggested that ‘Hypokalaemia’, ‘Hyperglycaemia’ & ‘Tremor’ should be included as important potential risks. The sponsor has provided a justification based on clinical data to support the omission of ‘Hypokalaemia’, ‘Hyperglycaemia’ or ‘Tremor’ as important potential risks in the EU-RMP. This is acceptable and it is noted that this appears to have been accepted by the EMA. The SS of the EU-RMP refers to ‘Gastrointestinal obstruction’ as an important pharmacological class effect for LAMA and routine pharmacovigilance activities will monitor this effect. Consequently it is suggested that ‘Gastrointestinal obstruction’ should be included as important potential risk. The sponsor has provided a justification based on clinical data to support the omission of ‘Gastrointestinal obstruction’ as an important potential risk in the EU-RMP. This is acceptable and it is noted that this appears to have been accepted by the EMA. The draft PI states: “Anoro Ellipta has not been studied in patients with severe hepatic impairment (see PKs – Special Patient Populations).” Consequently it is suggested that ‘Use in patients with severe hepatic impairment’ should be included as important missing information. ‘Safety in subjects with severe hepatic impairment’ has been included as missing information in the updated UMEC/VI This is acceptable.
the PBRER reporting period. GSK proposes to provide additional information regarding these studies to the TGA upon request, following review of the PBRER/RMP. Any impact of these studies on the Australian Product Information (PI) will be provided to the TGA through the submission of an appropriate application. The submitted short study summaries do not lend themselves to detailed assessment. Nevertheless they will be considered by the ACSOM, as to whether the study design is adequate and if not, how could they be strengthened. In addition the committee will consider if Australian patient involvement is required. The sponsor should also provide an assurance that it will submit a draft protocol for these planned studies to the TGA for review once they become available. The sponsor confirms that the protocols for the proposed post authorisation safety studies (PASS) will be submitted to the TGA upon endorsement by the EMA Pharmacovigilance Risk Assessment Committee. Once approved, the final PASS protocols will be provided in the updated UMEC/VI EU RMP. This is acceptable. However, in the light of the ACSOM advice the sponsor should consider amending the draft protocol / synopsis of the drug utilisation study to include Australian patients and an updated version should be provided to the TGA for review once it is available (see above). It is agreed the specified ongoing safety concerns would not appear to warrant additional risk minimisation activities. This is noted. n/a Key changes to the updated RMP In their response to the TGA request for information the sponsor provided an updated (Version: 3.0, dated 14 October 2013) with an updated ASA (Version: 2.0, undated). Key changes from the version evaluated at Round 1 are summarised below: Table 10. Key changes to the updated RMP RMP Section Changes introduced RMP
UMEC 125 µg 407 1.405 0.129 VI 25 µg 404 1.379 0.093 Placebo 275 1.245 -0.031 0.160 (0.122, 0.198) <0.001 0.124 (0.086, 0.162) <0.001 3373 UMEC/VI 62.5 µg /25 µg 413 1.406 0.171 0.052 (0.017, 0.087) 0.002 0.095 (0.060, 0.130) <0.001 UMEC 62.5 µg 418 1.354 0.119 VI 25 µg 421 1.311 0.076 Placebo 280 1.239 0.004 0.115 (0.076, 0.155) <0.001 0.072 (0.032, 0.112) <0.001 Table 14. Active controlled trials (3360, 3374), trough FEV1, Day 169, ITT population. Treatment n LS mean (L) LS mean change (L) Difference from UMEC (95% CI) p Difference from VI (95% CI) p Study 3361 UMEC/VI 125 µg /25 µg 207 1.521 0.211 0.088 (0.037, 0.139) <0.001 UMEC/VI 62.5 µg /25 µg 208 1.519 0.209 0.093 (0.041, 0.144) <0.001 VI 25 µg 205 1.431 0.121 Tiotropium 18µg 203 1.431 0.121 Study 3374 UMEC/VI 125 µg /25 µg 217 1.355 0.208 0.022 (-0.027, 0.072) 0.377 UMEC/VI 62.5 µg /25 µg 215 1.369 0.223 0.037 (-0.012, 0.087) 0.142 UMEC 125 µg 222 1.332 0.186 Tiotropium 18µg 215 1.295 0.149