adapting of the dose to the patient’s needs D.) Inclusion of the Therapeutic Monitoring information within the Precautions section of the Australian PI. All these activities are considered routine risk minimisation activities and therefore, should be removed from the pharmacovigilance section and included in the risk minimisation plan section of the ASA. Furthermore, the sponsor should provide further clarification as to how the awareness of physicians will be raised, as mentioned in point A.), above. 9. The statement Table 16 in the EU-RMP should be amended to describe that ‘Effects of pregnancy and foetal outcomes’ is the only ongoing safety concerns, for which additional pharmacovigilance activities are carried out, in form of a surveillance protocol. The sponsor refers to Section 5.1 Risk minimization measures by safety concern has been updated, where Table 5.1.1 Risk minimization measures: pregnancy and breast-feeding has included the US surveillance protocol which included exposure during pregnancy and assessment of foetal outcomes as a means to assess the effectiveness risk minimization measure. A surveillance protocol constitutes an additional pharmacovigilance activity, not an additional risk minimisation activity. Consequently, Table 5.1.1, and any other table as required, should be amended to describe that no additional risk minimisation activity is carried out for the risk of ‘pregnancy and but that an additional pharmacovigilance activity is carried out. This recommendation remains. 10. It is recommended that the sponsor amends the EU-RMP to include information regarding the potential for medication errors. In response to the recommendation above, the sponsor refers to Section 2.6.4 potential for medical errors within the updated EU-RMP which addresses This is considered acceptable.
this additional EU requirement. 11. The sponsor should provide a table summarising the safety specification, pharmacovigilance plan and planned risk minimization measures in Australian context in the ASA. Wording pertaining to important safety concerns in the proposed Australian PI and CMI should be included in the table. In response to the TGA’s requested changes, please refer to the updated ASA provided in this response. The response has been noted. However, this table should be amended to include the potential risk of ‘lack of efficacy’. 12. The sponsor should amend the ASA to describe ‘bradycardia’ and ‘pyrexia related effects’ as identified risk. Furthermore, to align the classification of the ongoing safety concerns with the EURMP, the ASA should be amended to classify ‘unknown food and drug interactions’ and effects on pregnancy and foetal outcome’ as missing information. As discussed in the Question 4.1, bradycardia and pyrexia are not considered as identified risk on the review by OE. Further, the risks of ‘unknown and food and drug interactions’ and ‘effects on pregnancy and foetal outcome’ have been included within the RMP (Section 2.4.4) and also within the updated ASA. These documents have been provided in the response. This is considered acceptable. 13. The sponsor describes ‘routine pharmacovigilance activities’ in section 3.1.1 and ‘review of the safety information derived through the Carbaglu surveillance protocol’ in section 3.1.2 of the ASA as planned actions in the risk minimization plan. These activities constitute pharmacovigilance activities and therefore, are not considered part of the risk minimisation plan. The sponsor confirms that ‘routine pharmacovigilance activities’ and ‘review of the safety information derived through the Carbaglu surveillance protocol’ have been included within the pharmacovigilance plan section of the ASA rather than the risk minimization section. This is considered acceptable. 14. Recommendations for amendments of the PI/CMI. The sponsor can confirm amendments recommended within the TGA’s evaluation report have been made to the proposed Australian PI and CMI. Copies of the Regarding the potential risk of Rash, the sponsor states in the EU-RMP ‘Rash will be added in the Summary of Product Characteristics (SmPC): frequency uncommon’.