Regulatory Decision Summary for Absorica LD

This New Drug Submission (NDS) was filed to obtain market authorization for Absorica LD (isotretinoin capsules, micronized formulation) for the treatment of severe nodular and/or inflammatory acne, acne conglobata and recalcitrant acne in patients 12 years and older. Because of significant side effects associated with its use, Absorica LD is to be reserved for patients unresponsive to conventional first line therapies.

The recommended dosage is 0.4 to 0.8 mg/kg/day given as a single or two divided doses with or without meals for 15 to 20 weeks. The dosage may be adjusted according to response and/or adverse reactions.

In this NDS, support for the approval of Absorica LD (isotretinoin capsules, micronized formulation) for the treatment of severe nodular and/or inflammatory acne, acne conglobata, and recalcitrant acne was based foremost on pivotal comparative bioavailability studies and secondly on a Phase 3 clinical safety and efficacy trial.

The pivotal comparative bioavailability studies appropriately bridged the proposed Absorica LD micronized formulation to a different, currently marketed, non-micronized isotretinoin capsule formulation (marketed as Absorica, with no suffix, in the United States (US) and as Epuris in Canada. Given that the US comparator was used, it is referred to as “Absorica” henceforth). Absorica LD 32 mg had comparative bioavailability of isotretinoin as Absorica 40 mg, under fasted and high-fat, high-calorie fed conditions. The linearity of the pharmacokinetics of isotretinoin, and the dose proportionality of the 8 mg, 16 mg, 24 mg, and 32 mg strengths of Absorica LD was also demonstrated. Finally, Absorica LD 32 mg had comparable isotretinoin bioavailability under fasted and high-fat, high-calorie fed conditions. Therefore, Absorica LD can be administered with or without food.

To further support the approval of Absorica LD, the sponsor provided a large (N = 925), well-controlled, double-blind, randomized (1:1), Phase 3 study. This study was the same as that referenced in the Epuris Canadian Product Monograph to support the same indications. Although patients in this study received a different isotretinoin formulation, the results of this study were considered applicable to Absorica LD. This is because the aforementioned comparative bioavailability trial appropriately bridged Absorica LD to Absorica formulations. In the Phase 3 study, the efficacy of the test isotretinoin product was found to be non-inferior to a previously marketed reference isotretinoin formulation. The safety profile was also comparable. The most common adverse events associated with isotretinoin were musculoskeletal-related, elevated blood creatine kinase, and visual acuity worsening. Serious adverse reactions included abdominal pain and migraine. In addition to this study, the safety of Absorica LD was supported by scientific literature and post-marketing experience acquired outside of Canada (mainly the US).

For appropriate and safe use, Absorica LD is reserved for patients who are unresponsive to conventional first line therapies for the indicated conditions. Furthermore, Absorica LD is contraindicated in pregnancy, breast-feeding women, patients with hypervitaminosis A, patients with excessively elevated blood lipid values, patients taking tetracyclines, and patients with hepatic and/or renal insufficiency. Serious Warnings include pregnancy prevention, psychiatric and neurological warnings. Tests, such as for liver function, renal function and serum blood lipids are recommended prior to treatment, then as clinically indicated. In addition to these, a new warning for potentially irreversible sexual function-related side effects was added.

A Risk Management Plan (RMP), reviewed by the Marketed Health Products Directorate, was found to be acceptable. As isotretinoin is a known teratogen, physicians prescribing Absorica LD and patients prescribed Absorica LD will be required to follow the Absorica LD Clinical Awareness Resource and Education (C-A-R-E) Program, as described in the RMP. The Program also includes provisions for all patients regarding the risk of psychiatric symptoms during treatment and necessary steps to follow before and during therapy.

The evidence provided in this submission was adequate to demonstrate that the overall benefit-harm-uncertainty profile of Absorica LD is acceptable when used as directed in the Canadian Product Monograph.

For further details about Absorica LD, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.