Post-marketing experience No descriptions of post marketing experience are yet available. A plan for acquisition of such data is described in the form of Clinical Protocol B2410. Safety issues with the potential for major regulatory impact Liver toxicity Clinically significant liver toxicity appears unlikely except for an unquantified possibility of this being a risk for patients with pre-existing hepatic impairment. Haematological toxicity No evidence of concern. Serious skin reactions No safety signals evident. Cardiovascular safety On currently available evidence and given the cautionary notes included in the PI regarding patients with existing risk factors, QT prolongation does not appear to be a major issue for pasireotide. Unwanted immunological events No safety signals evident. Other safety issues Safety in special populations Gender, age and race A subgroup evaluation of AE by CTC to look for any effect of gender, age or race was carried out for the dataset in pivotal Study B2305. The percentage of AE was similar between male and female patients. The numbers in the other subcategories were small, and it was difficult to draw any conclusions, particularly with regard to an effect of race as most of the subjects were in any case, Caucasian. Hepatically impaired patients In all of the summary documents, discussion regarding liver toxicity is completely focused on the possibility of hepatic adverse effects occurring in the general target population. There is no data or accompanying discussion on the possibility of this occurring in subjects with mild-to-moderate hepatic dysfunction, although the draft PI proposes that use be allowed in such individuals. Increased pasireotide exposure is seen in the presence of impaired hepatic function, and the sponsor has drawn a distinction between the level to which this occurs in moderately as opposed to severely impaired function based on a statistical test which obscures the observation that a functionally significant level of increased exposure was seen in both these groups, in contrast to those with mildly impaired function (Table 26 below). Furthermore, this distinction is made on the basis of a study which used single doses only, not allowing for the factor of accumulation, and in small numbers of subjects. It is noted that in the draft PI, the sponsor recommends that for patients with moderately impaired hepatic function, a starting dose of 300 µg bd be used and that the maximum dose be limited to 600 µg bd. While the concept of this dose limitation is correct, the quantum chosen appears to be empirical and no
Post-marketing experience No descriptions of post marketing experience are yet available. A plan for acquisition of such data is described in the form of Clinical Protocol B2410. Safety issues with the potential for major regulatory impact Liver toxicity Clinically significant liver toxicity appears unlikely except for an unquantified possibility of this being a risk for patients with pre-existing hepatic impairment. Haematological toxicity No evidence of concern. Serious skin reactions No safety signals evident. Cardiovascular safety On currently available evidence and given the cautionary notes included in the PI regarding patients with existing risk factors, QT prolongation does not appear to be a major issue for pasireotide. Unwanted immunological events No safety signals evident. Other safety issues Safety in special populations Gender, age and race A subgroup evaluation of AE by CTC to look for any effect of gender, age or race was carried out for the dataset in pivotal Study B2305. The percentage of AE was similar between male and female patients. The numbers in the other subcategories were small, and it was difficult to draw any conclusions, particularly with regard to an effect of race as most of the subjects were in any case, Caucasian. Hepatically impaired patients In all of the summary documents, discussion regarding liver toxicity is completely focused on the possibility of hepatic adverse effects occurring in the general target population. There is no data or accompanying discussion on the possibility of this occurring in subjects with mild-to-moderate hepatic dysfunction, although the draft PI proposes that use be allowed in such individuals. Increased pasireotide exposure is seen in the presence of impaired hepatic function, and the sponsor has drawn a distinction between the level to which this occurs in moderately as opposed to severely impaired function based on a statistical test which obscures the observation that a functionally significant level of increased exposure was seen in both these groups, in contrast to those with mildly impaired function (Table 26 below). Furthermore, this distinction is made on the basis of a study which used single doses only, not allowing for the factor of accumulation, and in small numbers of subjects. It is noted that in the draft PI, the sponsor recommends that for patients with moderately impaired hepatic function, a starting dose of 300 µg bd be used and that the maximum dose be limited to 600 µg bd. While the concept of this dose limitation is correct, the quantum chosen appears to be empirical and no
auspar-pasireotide-diaspartate-140327-cer.docx