Regulatory Decision Summary for Sibboran

This New Drug Submission (NDS) New Active Substance (NAS) was filed to obtain market authorisation for the use of Sibboran (landiolol) for the short-term reduction of ventricular rate in patients with supraventricular tachycardia including atrial fibrillation and atrial flutter. Following the review, the approved indication was for the short-term reduction of ventricular rate in patients with supraventricular tachycardia including atrial fibrillation and atrial flutter in perioperative, postoperative, or other acute circumstances where short-term control of the ventricular rate is desirable. This NDS was reviewed in accordance with the Health Canada Guidance document Drug Submissions Relying on Third-Party Data (Literature and Market Experience).

A Notice Of Non-compliance (NON) was issued on December 21, 2022, based on the quality review. Potential nitrosamine formation was identified in the active pharmaceutical ingredient manufacturing process and review determined that the level of nitrosamine formation exceeded acceptable limits. Consequently, confirmatory testing for the proposed drug product was necessary, leading to the issuance of the NON. The response to the NON was received on June 23, 2023 and was found to be acceptable.

The efficacy assessment of Sibboran relied primarily on 4 pivotal published studies (Yoshiya 1997, Yoshiya 2002, Taenaka & Kikawa 2013b and Nagai 2013), as well as 15 non-pivotal supportive Onoact clinical studies and the Summary of Clinical Efficacy. A total of 1,992 patients with supraventricular tachycardia (SVT) were treated with landiolol, 348 patients of those in the pivotal studies.

The Yoshiya 1997 study was a phase 3 placebo-controlled study in the peri-operative setting. Patients were classified as high- (pre-existing ischemic heart disease or hypertension) or low-risk patients. Moderate improvement (or better) of heart rate (HR) was observed in 94 of 117 patients (80.3%) in the landiolol group vs 12 of 127 patients (9.4%) in the placebo group. Substantial improvement was observed in 41 patients (35.0%) in the landiolol group vs 4 patients (3.1%) in the placebo group. The mean reduction in HR at 11 minutes post-dose administration was 26.8% in the landiolol group and 11.5% in the placebo group. Similar results were seen for the high-risk and the low-risk group for all efficacy endpoints.

The Yoshiya 2002 study was a phase 3 placebo-controlled study conducted with patients with a history of ischemic heart disease (angina or myocardial infarction [MI]) and/or hypertension or ischemic electrocardiogram (ECG) changes in a peri-operative setting. Moderate improvement (or better) of HR was seen in 18 of 21 patients (85.7%) in the landiolol group vs 2 of 20 patients (10.0%) in the placebo group. Substantial improvement was seen in 14 patients (66.7%) in the landiolol group vs no patient in the placebo group. The HR decreased by 28.3% vs 3.5% at 5 minutes, and by 34.9% vs 16.4% at 11 minutes post-dose administration in the landiolol group vs the placebo group, respectively.

The Taenaka & Kikawa 2013b study was phase 3 placebo-controlled study in patients with risk factors for myocardial ischemia (hypertension, prior MI, angina, ischemic changes on the ECG) who developed SVT within 7 days after surgery. Patients were randomized 1:1:1 to one of two landiolol dose groups or placebo. The landiolol LM group received dose L (1-min loading dose at a rate of 0.03 milligrams per kilogram per minute [mg/kg/min], followed by a 10-min infusion at 0.01 mg/kg/min) followed by dose M (1-min loading at a rate of 0.06 mg/kg/min, followed by a 10-min infusion at 0.02 mg/kg/min). The landiolol MH group received dose M followed by dose H (1-min loading dose at a rate of 0.125 mg/kg/min, followed by a 10-min infusion at 0.04 mg/kg/min). Improvement of HR after the final dose of study drug was seen in 29 of 48 patients (60.4%) and 21 of 50 patients (42.0%) in the landiolol LM and MH groups, respectively, vs none of the 48 patients in the placebo group. There were two primary endpoints: the improvement rate of HR after the initial dose of study drug was 8.3% and 22.0% in the landiolol LM and MH groups, respectively, vs 0.0% in the placebo group; the change in HR after the initial dose of study drug decreased by 15.0%, 13.7% and 1.6% in the LM, MH and placebo groups, respectively. After completion of administration (or at discontinuation), the HR decreased by 23.3%, 18.9% and 2.4% in the LM, MH and placebo groups, respectively.

The Nagai 2013 study was a phase 3, active-controlled study in patients with left ventricular dysfunction in a non-surgical setting. Patients were randomized 1:1 to landiolol or digoxin group. HR control was seen in 40 of 82 patients (48.0%) in the landiolol group vs 13 of 98 patients (13.9%) in the digoxin group. The reduction in HR from baseline to 2 hours was 19.6% in the landiolol group and 11.6% in the digoxin group.

Statistical superiority was seen in the pivotal studies in all settings (peri- and post-operative, and non-surgical) for moderate and substantial improvement of HR, and bradycardic effect (endpoint of change of HR from baseline). This was supported by the 15 non-pivotal published clinical studies. No clinical difference was seen between settings and/or types of SVT.

The safety was based on 38 published clinical studies provided by the sponsor, 4 AOP Orphan Pharmaceuticals-sponsored clinical studies and post-market data (Periodic Safety Update Reports ) from February 2017 to 2020, and post-marketing data for Onoact from the Drug Interview Form [2013a]). The most common adverse events (AEs) in the clinical studies (2,101 patients) were hypotension (6.4%) and bradycardia (1.5%).

In post-marketing Drug Interview Form (2013a), the most common AEs were low blood pressure/hypotension (18.2%), hepatic laboratory abnormalities (2.5%) and bradycardia (0.6%). Severe hypotension, severe bradycardia, cardiogenic shock, cardiac arrest, sinus arrest and complete atrioventricular block were reported. Related Warnings and Precautions were added to the Product Monograph (PM).

There is limited data regarding the use of landiolol for greater than 24 hours and limited information in the published studies regarding the results of the laboratory monitoring, use of landiolol in patients with acute or recent MI (within 1 month) and in patient with severe hepatic impairment. This information was included in the PM.

A Notice of Noncompliance (NON) was issued based on the quality review, due to concerns regarding nitrosamine formation levels. The review of the Response to the NON was acceptable from a quality perspective.

A Risk Management Plan for Sibboran was submitted and reviewed by the Marketed Health Products Directorate and was considered acceptable.

Overall, the benefit-harm-uncertainty profile is favourable for Sibboran for the recommended indications, therefore a Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations was recommended.

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