Qnexa briefing documents for advisory committee (update 3)

"Lastly, the safety profile associated with long term use of Qnexa is not known. It is notable that phentermine was approved only for short term use (“a few weeks”) for patients with obesity. Topiramate was approved for long term use, but in a population (epilepsy or migraine prophylaxis) that may have important clinical differences than patients who seek treatment for obesity."


Questions to the Advisory Committee
1) Taking into account the results of the assessments made with the PHQ-9 and the Columbia Suicidality Severity Rating Scale (C-SSRS), please comment on the significance of the increased adverse event reports of depression, anxiety, and sleep disorders in subjects treated with Phentermine/Topiramate (PHEN/TPM).
- If approved, please discuss need for monitoring, possible monitoring strategies, and contraindications for use.

2) Please comment on the potential significance of the increased adverse event reports of disorders of attention, memory, language, and other cognitive disorders in subjects treated with PHEN/TPM.
- If approved, please discuss need for monitoring and possible monitoring strategies.

3) Please comment on the potential clinical significance of the metabolic acidosis determined by decreases in serum bicarbonate levels with PHEN/TPM treatment.
- If approved, please discuss need for monitoring, possible monitoring strategies, and contraindications for use.

4) Please comment on the potential clinical significance of the increase in heart rate observed in PHEN/TPM treated individuals.
- If approved, please discuss need for monitoring, possible monitoring strategies, and contraindications for use.

5) Given the doses of topiramate in PHEN/TPM, please comment on whether you believe PHEN/TPM poses a teratogenic risk to the target population for weight loss.
- If you believe it does pose a risk, please comment on how this risk should be managed in women of child-bearing potential if PHEN/TPM is approved.

6) Based on the current available data, do you believe the overall benefit-risk assessment of PHEN/TPM (QNEXA) is favorable to support its approval for the treatment of obesity in individuals with a BMI ≥30 kg/m2 or ≥27 kg/m2 with weight-related co-morbidities?
- Vote: Yes/No/Abstain

"The incidence of TEAEs [treatment-emergent adverse events] in the cardiac arrhythmia subclass was higher in the QNEXA Top-dose group (4.7%) and Mid-dose group (4.2%) than in the placebo group (1.8%). Palpitations, increased heart rate, and tachycardia represented 36 of the 41 cardiac arrhythmia TEAEs in the Serious cardiac adverse events were examined in all subjects included in the Integrated Safety Analysis of the NDA. Overall, there were eight cardiac SAEs in the QNEXA groups (N=2559) and nine in the placebo group (N=1719). The relative risk was 0.60 (95% CI: 0.23-1.54), QNEXA vs. placebo. The incidence of TEAEs in the is 1-year cohort. Palpitations and increased heart rate are expected and dose-related side effects of phentermine and phentermine-containing products. The cardiac arrhythmia TEAEs were primarily mild or moderate in severity and were serious for 4 (0.3%) subjects in the placebo group, 2 (0.4%) subjects in the Mid-dose group, and 2 (0.1%) subjects in the Top-dose group ischemic heart disease subclass was low (0.4% overall) and similar for the treatment groups."

Safety
Although not a requirement for approval of a fixed-dose combination product, the Division looks more favorably on combination products that exhibit a potentially meaningful improvement in the safety profile compared to the individual components. In addition, the applicant has theorized that some of the expected side effects of the two drugs alone may be “mitigated by oppositional pharmacodynamic effects associated with the other component.” In particular, the cognitive slowing observed with topiramate treatment may be lessened with co-administration of phentermine.

Disclosure: no position in VVUS.