Regulatory Decision Summary for Amitiza

Amitiza was associated with a greater proportion of patient responders compared to placebo that experienced a clinically relevant increase in stool frequency. A pooled analysis of three pivotal clinical studies resulted in a 17.1% difference in responders in favour of Amitiza. Additionally, Amitiza was associated with a greater proportion of patient responders compared to placebo that experienced a clinically relevant softening of stool and reduction in degree of straining. A pooled analysis of the pivotal studies resulted in a 21.3% and 14.3% difference in responders in favour of Amitiza with respect to stool consistency and degree of straining, respectively. Additional efficacy outcomes including weekly stool frequency, time to first stool, and event of rescue medication use, were all favourable towards Amitiza compared to placebo. These data, however, are limited to 4-weeks duration. The efficacy of Amitiza beyond 4 weeks has not been established in well-designed, placebo-controlled clinical studies.

Amitiza was generally well-tolerated, with a majority of reported adverse drug reactions (ADRs) being mild to moderate in intensity. The most commonly observed ADRs in Amitiza-treated CIC patients from placebo-controlled studies were consistent with the pharmacodynamics of the drug. These events included nausea (23.6 %), diarrhea (8.3%), abdominal pain (6.3%), headache (8.0%), and dizziness (4.7%). Additional less frequent AEs of interest included chest discomfort/pain, dyspnea, and palpitations. There was no marked evidence of a drug-drug interaction in the context of treatment of patients with CIC. There is no anticipated risk of abuse or misuse with Amitiza. Amitiza has been marketed in the United States since 2006 for the indication of CIC with nearly 10 million prescriptions worldwide and 1,000,000 subject years of exposure. Post-market data give reassurance of a favourable benefit/risk profile of Amitiza in clinical practice. The potential cardiovascular risks of prolonged Amitiza treatment may be considered uncertain.

With respect to the OIC indication, the submission included three multicentre, randomized, double-blind, and placebo-controlled studies (OBD-0631, OBD-0632, and OBD-1033). The pivotal study (OBD-1033) was designed to show a difference between Amitiza and placebo of 16% in overall spontaneous bowel movement (SBM) response rate (primary endpoint). The results showed only a difference of 8.3%. This difference, although statistically significant was not clinically meaningful.

Supportive studies (OBD-0631 and OBD-0632) were designed to show a difference between Amitiza and placebo of 1.5 in mean change from baseline in frequency of SBMs (primary efficacy endpoint). These studies showed a difference of 0.8 for OBD-0631 and 0.2 for OBD-0632.

One of the supportive studies (OBD-0631) showed a statistically significant difference between Amitiza and placebo at Week 8 but the difference was not clinically meaningful. In addition, when results were analysed at the end of the study (Week 12), the results were not statistically or clinically significant. The other supportive study showed no statistically or clinically relevant difference between Amitiza and placebo at Week 8 or Week 12 (end of study). In terms of safety, Amitiza was associated with a higher number of drug-related AEs than placebo. No serious AEs or deaths assessed as drug-related were reported in these studies.

In conclusion, the efficacy of Amitiza has not been established for the treatment of OIC as evidence from the submitted studies did not show a clinically meaningful difference between Amitiza and placebo in this indication. Based on the data submitted, the anticipated benefits of Amitiza are considered to outweigh the potential harms and uncertainties in patients with CIC only.

For more information on Health Canadas decision, please view the Summary Basis of Decision.