Regulatory Decision Summary for HEMANGIOL

Hemangiol is an oral solution of propranolol developed for the treatment of patients with proliferating infantile hemangioma (IH) requiring systemic therapy: life- or function threatening IH, ulcerated IH with pain/or lack of response to simple wound care measures, or IH with a risk of permanent scarring or disfigurement. The proposed indication represents a serious condition with limited treatment options and no authorized systemic therapy in Canada.

The efficacy of Hemangiol in patients with IHs requiring systemic therapy was primarily demonstrated in a randomized, double-blind, placebo-controlled adaptive phase II/III clinical trial (study 201), aiming to compare four regimens of Hemangiol [1 or 3 milligram (mg)/kilogram (kg)/day for 12 or 24 weeks] to placebo. The primary efficacy endpoint was binary treatment success (protocol-defined as complete/nearly complete resolution) or failure, determined by blinded, centralized independent assessment of Week 24 photographs of target IH compared to baseline. Per the primary analysis recommended by the Independent Data Monitoring Committee, the number of patients achieving complete/nearly complete resolution was statistically higher in the Hemangiol 3 mg/kg/day arm 24-week treatment arm compared to the placebo arm (60.4% versus 3.6%, p<0.0001). The majority of responders in the Hemangiol 3 mg/kg/day 24-week treatment arm maintained their response status up to Week 96 (the end of study follow up). This level of response is considered clinically significant. Additional evidence was presented in the submission from the small single Hemangiol trial 102, French Hemangiol Compassionate Use Program (CUP) and the literature review of off-label propranolol in IHs, collectively supporting Hemangiol therapy as an effective treatment for IHs requiring systemic therapy, including subtypes of IHs not adequately represented in the pivotal study.

The Hemangiol safety dataset included safety findings from Hemangiol clinical trials, Compassionate Use Program (CUP) in France, and propranolol post-market data from past decades. In clinical trials, common Hemangiol adverse reactions (ARs) were generally mild to moderate in severity and reversible, including neurologic and psychiatric disorders, aggravated respiratory tract infections, diarrhea, vomiting and rash. No death was reported and treatment discontinuation due to an adverse event occurred in 2.5% of patients, including bronchospasm and bronchiolitis. Decreased heart rate, blood pressure or blood sugar were reported, mostly asymptomatic and not considered ARs by the investigator. Severe or serious ARs of Hemangiol were those known to propranolol, including hypoglycemia, bronchospasm, bradycardia, hypotension and heart block, which were mostly reported in the Hemangiol CUP. In addition, rare cases of agranulocytosis and Raynauds phenomenon had been reported in patients treated with propranolol and were considered identified serious risks of Hemangiol. In healthy volunteers, short-term propranolol treatment resulted in reversible impairment of psychomotor function for example (e.g.), short-term memory issues. Long-term neurologic and psychiatric effect of Hemangiol therapy is unclear; properly designed studies are needed to characterize the relationship, if present.

To facilitate safe use of Hemangiol, key safety and uncertainty findings were included in the Product Monograph (PM), as well as recommendations regarding patient selection (e.g., contraindications), dose titration, clinical monitoring during treatment and dose modification in the event of serious ARs. The Hemangiol PM recommends that Hemangiol therapy should be initiated and monitored by experienced health care professionals, and parent/caregiver education should be given for identification and management of warnings signs of Hemangiol ARs. Package inner and outer labels have been assessed and are now compliant with the Plain Language Labeling (PLL) requirements (although the submission was initially filed prior to PLL coming into effect).

The Hemangiol Risk Management Plan was assessed and considered acceptable by the Marketed Health Products Directorate. In addition to routine pharmacovigilance and risk minimization measures, Pierre Fabre Dermo-Cosmétique Canada Inc. (Pierre Fabre) proposed to further explore the safety of Hemangiol with a Drug Utilization Study in France and Germany to assess Hemangiol off-label use and administration errors and to measure effectiveness of risk minimization measures.

In summary, Hemangiol demonstrated clinically significant activity against proliferating IHs requiring systemic therapy with a generally manageable safety profile. Hemangiol also has the potential to cause serious, life-threatening reactions and there is an uncertainty about its long-term neurologic and psychiatric effect. However, in the context of an indication for a serious condition with no authorized systemic therapy in Canada, the clinical benefit of Hemangiol is considered to outweigh the associated risks and uncertainty. Risk mitigation through PLL-compliant package inner and outer labels as well as detailed information in the Product Monograph to guide prescribers and parents in the safe administration of Hemangiol is considered acceptable in the context of the serious condition of the infants included in the authorized indication.