Regulatory Decision Summary for Norditropin NordiFlex

Turner syndrome (TS) is a genetic disorder of girls and women; the most common finding is short stature.

The medicinal ingredient of Norditropin is somatropin (recombinant human growth hormone).

Assessment of the efficacy and safety of Norditropin for the treatment of children with short stature associated with TS was based primarily on three clinical studies conducted in the Netherlands and the United Kingdom between 1987 and 2004, in 147 girls with short stature due to TS. The assessment of safety was further supported by safety data from the marketed use of Norditropin since 1988 and use specifically in TS patients since the first international approval of this indication in 1990.

The Norditropin studies were randomized and open-label, meaning they were designed to randomly assign TS patients to different treatment groups and that patients knew which treatment they received. There was no placebo or control group, meaning that all patients received Norditropin treatment. Patient height was measured at study entry and at regular intervals until final height was achieved or until the patient withdrew from the study.

In the primary efficacy study, 68 patients were treated for an average of 8.4 years at 0.045 mg/kg/day for the entire study (Dose A); 0.045 mg/kg/day for the first year and 0.067 mg/kg/day thereafter (Dose B); or 0.045 mg/kg/day for the first year, 0.067 mg/kg/day for the second year, and 0.090 mg/kg/day thereafter (Dose C). The results showed that, in the 46 patients who reached final height, all three Norditropin treatment regimens increased growth and 32 patients achieved heights within the normal population range. Height gain was greatest in the dose escalation groups (Dose B and C), but no additional benefit was achieved at the highest dose (Dose C).

In the supportive efficacy study, 19 subjects received 0.067 mg/kg/day of Norditropin, either as a single subcutaneous dose in the evening, or divided into two doses (1/3 in the morning and 2/3 in the evening) for an average of 3.6 years. Increased growth was observed but there was no difference between the two treatment groups.

Long-term Norditropin treatment was generally well-tolerated by patients in the TS studies. The safety profile of Norditropin across the three TS studies was consistent with the known manifestations of Turner syndrome and with the well-known safety profile of Norditropin, as based on extensive post-marketing experience.

No new safety concerns were identified. The TS studies did not include enough patients to detect rare events such as neoplasia (cancer), intracranial hemorrhage or intracranial aneurysm and these remain important potential risks of Norditropin treatment, based on the known properties of human growth hormone.

The benefit-risk balance of Norditropin for the treatment of short stature in patients with Turner syndrome was considered favorable. To ensure that the benefit continues to outweigh any risk after authorization, Health Canada has required several post-approval activities to monitor long-term safety.