Regulatory Decision Summary for Utrogestan

The Sponsors pharmacology package demonstrated that vaginal progesterone between 100 mg to 200 mg three times daily induced adequate endometrial changes required for implantation at least as efficiently as intramuscular progesterone and far more efficiently than oral progesterone.

Utrogestan clinical efficacy and safety was investigated in the pivotal phase III open-label, randomised, multicentric, parallel group study that enrolled 430 women undergoing in vitro fertilisation and compared their gestational status after 12 weeks of treatment with Utrogestan (200 mg three times daily) or an active control approved in Canada for the same indication. 76.3% (328) discontinued prematurely from the trial, mostly due to pregnancy failure (90.5%, 303 patients). Two patients (1.2%) and 5 patients (3.3%) discontinued from the trial due to an adverse event or local intolerance in the Utrogestan and the comparator groups. The trial established that Utrogestan (200 mg three times daily) was associated with an ongoing pregnancy rate of 25.2% (N = 218), compared to 22.2% (N = 212) for the comparator and therefore demonstrated that Utrogestan was non-inferior to the comparator. The patient population was limited to patients of 35 years or less, which limits the data that can be extrapolated to the general population which may include patients over 35.

Utrogestan was associated with few common adverse events (9.6% of patients). The most frequent included Ovarian Hyperstimulation Syndrome (OHSS), vaginal spotting and nausea/vomiting. Severe OHSS has been reported in the pivotal phase III trial, but is unlikely caused by Utrogestan and more likely caused by the ovarian stimulation protocol. Utrogestan was associated with local reactions in 6.9% of patients. Adverse events and local reactions were always reported in similar frequencies in Utrogestan or comparator-treated women.

Utrogestan presents a positive benefit-harm-uncertainty profile at the proposed dosage for the indication of luteal phase support during IVF.