Summary Basis of Decision for Sibboran

In line with Health Canada’s Guidance Document: Drug Submissions Relying on Third-Party Data (Literature and Market Experience), third‑party published clinical studies were submitted to support the intended use of Sibboran. The clinical package submitted by the sponsor was based primarily on four published pivotal studies (Yoshiya et al., [1997]; Yoshiya et al., [2002]; Taenaka and Kikawa, [2013b]; and Nagai et al., [2013]). Additional supportive data from four bridging studies sponsored by AOP Orphan Pharmaceuticals that investigated the pharmacokinetics and pharmacodynamics of landiolol (the medicinal ingredient in Sibboran) were also provided.

Clinical Pharmacology

Landiolol is a selective beta‑1‑adrenoreceptor antagonist that inhibits the positive chronotropic effects of the catecholamines adrenaline and noradrenaline on the heart, where beta‑1‑receptors are predominantly located. Landiolol reduces the sympathetic drive, resulting in the reduction of heart rate, decreasing the spontaneous firing of ectopic pacemakers, while slowing the conduction and increasing the refractory period of the atrioventricular node. Landiolol does not exhibit any membrane‑stabilizing activity or intrinsic sympathomimetic activity in vitro. In non‑clinical studies, landiolol controlled tachycardia in an ultra‑short‑acting manner with fast onset and offset of action, while further demonstrating anti‑ischemic and cardioprotective effects.

Landiolol Half-Life, Accumulation, Dose Proportionality, and Metabolite Profile

A double‑blind, randomized, two‑period, crossover study tested landiolol lyophilizate in fourteen healthy Caucasian subjects. Landiolol was administered as an intravenous infusion, at a dose of 10 mcg/kg/min for 2 hours, followed by 20 mcg/kg/min for 2 hours, and 40 mcg/kg/min for 20 hours. The peak serum concentration for landiolol with the low, medium, and high dose was 232, 516, and 975 ng/mL, respectively. The time to peak drug concentration was 90, 60 and 30 minutes, respectively. The elimination half‑life of landiolol was 4.52 minutes suggesting that landiolol does not accumulate after repeated dosing.

A post‑hoc analysis showed dose proportionality for landiolol across all dose ranges. The mean concentrations of both landiolol metabolites, M1 and M2, reached a peak at more than 20 hours after the start of the infusion, indicating much slower elimination than the parent drug. The area under the blood concentration curve from time zero hours extrapolated to infinity (AUC_0-inf) was 12 times higher for M1 than for M2. The M1 metabolite showed no beta‑blocking activity even at doses 200 times higher than the parent drug, landiolol.

Bridging Studies

The clinical pharmacology package and the supportive safety and efficacy package submitted by the sponsor are based on published studies with the reference product Onoact and were conducted predominantly in Japanese subjects. Extrapolation to the Caucasian population was shown in four bridging studies which investigated the pharmacokinetics and pharmacodynamics of landiolol in healthy Caucasian volunteers. The results were considered adequate to show comparability of pharmacokinetic and pharmacodynamic parameters of landiolol in Caucasian and Asian subjects at a therapeutically relevant dose range.

Special Patient Populations

Landiolol was administered intravenously at a dose of 60 mcg/kg/min for one minute and thereafter continuously administered at a dose of 20 mcg/kg/min for 60 minutes to 6 patients with mild to moderate hepatic impairment (5 patients with Child‑Pugh class A liver function, one patient with Child‑Pugh class B liver function; patients with Child‑Pugh class C liver function were excluded from the study) and 6 healthy volunteers. Patients with hepatic impairment showed a reduction in the volume of distribution of landiolol and an increase of landiolol plasma levels by 40%. The elimination half‑life of the drug was not different from that observed in healthy adults.

The pharmacokinetics in patients with renal impairment has not been evaluated. Metabolite M1 is excreted through the kidneys and is likely to accumulate in patients with renal impairment. However, this metabolite has no beta‑blocking activity even at doses 200 times higher than the parent drug. No significant renal reabsorption is anticipated based on the low molecular weight of approximately 0.5 kDa which is below the molecular weight cut‑off for glomerular filtration capacity.

Drug-Drug Interactions

Concomitant use of landiolol with calcium channel blockers, inhalation anesthetics, ganglion blockers, tricyclic antidepressants, barbiturates or phenothiazines may increase the risk of hypotension. Verapamil, diltiazem, Class I or III antiarrhythmic agents and digitalis preparations may cause excessive suppression of cardiac function and/or atrioventricular conduction abnormalities. Anesthetics with bradycardic effect, esterase substrates, cholinesterase inhibitors, catecholamine‑depleting drugs and antisympathetic agents may have an additive bradycardic effect. Effects of landiolol may be counteracted by sympathomimetic agents. Concomitant use of clonidine may increase the risk of “rebound” hypertension.

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

Clinical Efficacy

Sibboran has been shown to be efficacious in patients in perioperative, postoperative, and non-surgical settings who are at risk of increased heart rate due to activation of the sympathetic system. The market authorization of Sibboran was based primarily on literature sources and post-market data filed in accordance with the conditions and requirements set out in Health Canada’s Guidance Document: Drug Submissions Relying on Third-Party Data (Literature and Market Experience). The evidence submitted for this NDS was primarily based on a comprehensive examination of four published pivotal studies (Yoshiya et al., [1997]; Yoshiya et al., [2002]; Taenaka and Kikawa, [2013b]; and Nagai et al., [2013]). Additional 15 non‑pivotal supportive studies (some sponsored by AOP Orphan Pharmaceuticals) were also included based on the reference product Onoact. A summary of clinical efficacy was also provided.

Of the four pivotal studies, three were conducted in an operative setting (perioperative or postoperative) and were placebo‑controlled. The remaining study was conducted in a non‑surgical setting and was digoxin‑controlled.

Clinical Studies in a Perioperative Setting

Yoshiya et al., (1997)

This study was a prospective, multicentre, randomized, double‑blind, placebo‑controlled, Phase III study conducted in a perioperative setting. The study involved multiple study sites in Japan and was conducted between June 1995 and June 1996. The study population consisted of adult patients (20 years of age and older), undergoing various types of surgery (head/neck, abdomen, chest, bone/joints) who developed perioperative tachycardia or tachyarrhythmia (defined as a heart rate ≥100 beats per minute [bpm] during anesthesia). Patients were excluded if they had acute or recent myocardial infarction (within one month of onset), severe heart failure, atrioventricular block (a second degree or higher degree block) or sick sinus syndrome, severe liver, kidney, or blood disorder, and if they used tricyclic or tetracyclic antidepressants.

In total, 284 patients were randomized in a 1:1 ratio to receive either landiolol (number of patients [n] = 140) or a placebo (n = 144). Of these, 133 patients (landiolol group: n = 63; placebo group: n = 70) were classified as “high‑risk” patients (who had pre‑existing ischemic heart disease and/or hypertension with a risk of cardiac function worsening due to sustained tachycardia), or “low‑risk” patients, 151 patients (landiolol group: n = 77; placebo group: n = 74), (with tachyarrhythmia due to endocrine diseases or sustained tachycardia triggered by the surgical or the anesthetic procedure). The majority of patients in the “high‑risk” subset had hypertension as a risk factor. Mean age was 60.8 years old in the landiolol group and 61.5 years in the placebo group, with pre‑dose systolic blood pressure values of 139.9 mmHg and 137.0 mmHg, respectively. Mean age in the “low‑risk” subset was 47.1 years in the landiolol group and 45.4 years in the placebo group, with pre‑dose systolic blood pressure values of 122.0 mmHg and 120.2 mmHg, respectively. Pre‑dose mean heart rate was 112 bpm in the landiolol group (while no data were available for the placebo group). For the vast majority of patients (>95%), the type of tachyarrhythmia was sinus tachycardia.

Study treatment was initiated if a perioperative sinus tachycardia (defined as heart rate ≥100 bpm and persisting for 3 minutes or more) or supraventricular tachycardia (defined as a heart rate ≥100 bpm persisting for 1 minute or more) occurred, or in case tachycardia persisted despite correction of precipitating causes (such a light anesthesia or hypovolemia). Landiolol was administered as bolus/infusion, initiated at loading doses of 125 mcg/kg/min for 1 minute, followed by continuous infusion at 40 mcg/kg/min for 10 minutes. A placebo (saline solution) was administered using the same regimen for the placebo group.

The assessment of efficacy supporting the indication included two endpoints: improvement of tachyarrhythmia and change in heart rate. The heart rate was monitored before anesthesia induction until 60 minutes after discontinuation of study drug administration. Patients who had a heart rate reduction of ≥20% were categorized as showing moderate improvement (or better). Patients who had a heart rate reduction of ≥30% were categorized as showing substantial improvement (or better). The second endpoint was the mean change in heart rate at 11 minutes post dose compared to baseline.

Of the 284 patients who were randomized, 244 patients (landiolol group: n = 117; placebo group: n = 127) were included in the evaluation of improvement of tachycardia. The results from the study showed that 94 of 117 patients (80.3%) in the landiolol group experienced a moderate improvement (or better) in heart rate compared to 12 of 127 patients (9.4%) in the placebo group. In addition, a substantial improvement in heart rate was seen in 41 patients (35.0%) in the landiolol group compared to 4 patients (3.1%) in the placebo group. The overall mean reduction in heart rate at 11 minutes post dose was 26.8% in the landiolol group and 11.5% in the placebo group.

Overall, the efficacy of landiolol in improving tachycardia/tachyarrhythmia was demonstrated, with benefits in both the “high‑risk” and “low‑risk” patient groups.

Yoshiya et al., (2002)

This study was a prospective, multicentre, randomized, double‑blind, placebo‑controlled, Phase III study conducted to evaluate the efficacy in the treatment of supraventricular tachycardia in a perioperative setting. This study involved 19 sites in Japan and was conducted between November 1998 and March 2000. The study population consisted of adult patients (20 years of age and older, and weighing 90 kg or less) with a history of ischemic heart disease (angina or myocardial infarction) and/or hypertension or ischemic electrocardiogram changes, undergoing various types of surgery (head/neck, abdomen, chest, bone/joints) who developed perioperative tachyarrhythmia. Patients were excluded if they experienced an acute or recent myocardial infarction (within one month of onset), severe heart failure (New York Heart Association stage III or IV), atrioventricular block (second degree or higher degree block) or sick sinus syndrome, liver, kidney, or blood disorder, and if they used tricyclic or tetracyclic antidepressants or oral beta‑blockers within one week prior to surgery.

In total, 58 patients were randomized in a 1:1 ratio and classified as either “high‑risk” patient (who had pre‑existing ischemic heart disease and/or hypertension with a risk of cardiac function worsening due to sustained tachycardia), or “low‑risk” patient (who had tachyarrhythmia due to endocrine diseases or sustained tachycardia triggered by the surgical or the anesthetic procedure). Of the 58 patients, 54 were treated with landiolol or a placebo (landiolol: n = 27; placebo: n = 27). Of the 54 treated patients, 41 were evaluated for efficacy in the per-protocol analysis (landiolol: n = 21; placebo: n = 20).

The average age of the patients in the study was 58 years old in the landiolol group and 59 years old in the placebo group. Mean pre‑dose heart rate was 112 and 109 bpm in the landiolol and placebo groups, respectively. In the majority of patients, the main risk factors were hypertension or preoperative ischemic changes. For 93% of patients, the type of tachyarrhythmia was sinus tachycardia, whereas the remaining patients had paroxysmal atrial fibrillation.

Study treatment was initiated if a perioperative sinus tachycardia (defined as a heart rate ≥120 bpm or heart rate ≥100 bpm and rate-pressure product ≥15,000 bpm*mmHg for 3 minutes or more) or supraventricular tachyarrhythmia (defined as a heart rate ≥100 bpm persisting for 1 minute or more) occurred, or in case tachycardia persisted despite correction of precipitating causes (such as light anesthesia or hypovolemia). Landiolol was administered as bolus/infusion, initiated at loading doses of 125 mcg/kg/min for 1 minute, followed by continuous infusion at 40 mcg/kg/min for 10 minutes. A placebo (saline solution) was administered using the same regimen. If no bradycardic effect was achieved within 5 minutes of administration (defined as a heart rate decrease <10% compared to pre‑dose value), the administration of study drug was discontinued immediately.

The assessment of efficacy supporting the indication included two endpoints: improvement of tachyarrhythmia and change in heart rate. The heart rate was monitored before anesthesia induction until 60 minutes after discontinuation of study drug administration. Patients who had a heart rate reduction of ≥20% were categorized as showing moderate improvement (or better). Patients who had a heart rate reduction of ≥30% were categorized as showing substantial improvement (or better). The second endpoint was the mean change in heart rate at 5 minutes and 11 minutes post dose compared to baseline.

The results from the study showed that 18 of 21 patients (85.7%) patients in the landiolol group experienced a moderate improvement (or better) in heart rate compared to 2 of 20 patients (10.0%)in the placebo group. In addition, a substantial improvement in heart rate reduction was seen in 14 patients (66.7%) in the landiolol group compared to no patient (0.0%) in the placebo group. The overall mean reduction in heart rate was 28.3% (landiolol group) versus 3.5% (placebo group) at 5 minutes post dose, and 34.9% (landiolol group) versus 16.4% (placebo group) at 11 minutes post dose.

Overall, the efficacy of landiolol in improving tachycardia/tachyarrhythmia was demonstrated, with benefits in both the “high‑risk” and “low‑risk” patient groups.

Clinical Study in a Postoperative Setting

Taenaka and Kikawa (2013b)

This was a prospective, multicentre, randomized, double‑blind, placebo‑controlled, Phase III study in patients with risk factors for myocardial ischemia (hypertension, prior myocardial infarction, angina, ischemic changes on the electrocardiogram) who developed supraventricular tachycardia within 7 days after surgery (i.e., postoperative supraventricular tachyarrhythmias). The study was conducted at 60 study centres in Japan between December 1996 to December 1997.

The study population comprised of patients who developed postoperative supraventricular tachyarrhythmias (including atrial fibrillation, atrial flutter, paroxysmal supraventricular tachyarrhythmia, and sinus tachycardia) that persisted despite the elimination of possible causes for the supraventricular tachyarrhythmia. The majority of patients enrolled were male and the age of patients ranged between 20 to 80 years. The most common type of supraventricular tachyarrhythmia was sinus tachycardia, followed by paroxysmal supraventricular tachyarrhythmia.

Study treatment was initiated in patients who developed postoperative supraventricular tachyarrhythmia, if sinus tachycardia (defined as a heart rate >120 bpm persisting for 3 minutes or more) or supraventricular tachyarrhythmia (defined as a heart rate >100 bpm persisting for 1 minute or more) occurred.

In total, 165 patients were enrolled in the study and randomized in a 1:1:1 ratio to one of two landiolol dose groups (LM or MH) or to a placebo group (PP). Of the 165 patients enrolled, 54 patients were treated with landiolol LM, 55 patients were treated with landiolol MH, and 54 patients were treated with a placebo. The landiolol LM group first received low dose “L” (1‑minute loading dose at a rate of 0.03 mg/kg/min, followed by a 10-minute infusion at 0.01 mg/kg/min). If the targeted heart-rate reduction was not obtained at the end of the first 10‑minute infusion, the same LM group then received medium dose “M” (1-minute loading at a rate of 0.06 mg/kg/min, followed by a 10-minute infusion at 0.02 mg/kg/min). The landiolol MH group first received dose “M”. If the targeted heart-rate reduction was not obtained at the end of the first 10‑minute infusion, the same MH group then received high dose “H” (1‑minute loading dose at a rate of 0.125 mg/kg/min, followed by a 10-minute infusion at 0.04 mg/kg/min). The placebo PP group first received dose “P” (1‑minute loading dose at a rate of 0 mg/kg/min, followed by a 10‑minute infusion at 0 mg/kg/min) followed by another round of dose “P”.

The assessment of efficacy included two key evaluation endpoints. The first endpoint was the percentage of patients who met improvement of heart-rate criteria (heart rate <100 bpm and heart-rate reduction of ≥20% from baseline at two hours after administration). The second endpoint was the mean change in heart rate post dose compared to baseline.

The results of the patients that remained in the study after discontinuation and completion of infusion in this study showed that improvement of heart rate 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. In comparison, no improvement in heart rate was seen in the 48 placebo-treated patients. In terms of the first key endpoint, improvement rate of heart rate after the initial dose of study drug was 8.3% and 22.0% in the landiolol LM and MH groups, respectively, versus 0.0% in the placebo group. As for the second key endpoint, the change in heart rate 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 heart rate decreased by 23.3%, 18.9% and 2.4% in the LM, MH and placebo groups, respectively.

Clinical Study in a Non‑Surgical Setting

Nagai et al., (2013)

This was a prospective, multicentre, randomized, single‑blind, active‑controlled Phase III study conducted in a non‑surgical setting in patients with left ventricular dysfunction. The study was conducted in 95 study centres in Japan between March 2011 and August 2012.

The main inclusion criteria were adult patients with atrial fibrillation or atrial flutter and left ventricular ejection fraction (25% to 50%) experiencing tachycardia (defined as a heart rate ≥120 bpm) in a non‑surgical setting. Patients were excluded if they had the necessity for electrical cardioversion, severe valve stenosis, suspected or confirmed hyperthyroidism, implantable cardiac pacemaker and/or implantable defibrillator, the necessity for mechanical ventilation, or cardiogenic shock (defined as a systolic blood pressure <90 mmHg).

The use of antiarrhythmic drugs, sympathomimetic drugs, sympatholytic drugs, defibrillator use, catheter ablation, and pacemaker therapy were prohibited from administration until completing all observations at 2 hours after starting treatment. However, patients treated with oral beta‑blockers (carvedilol or bisoprolol) or oral digitalis preparations for chronic heart failure, chronic atrial fibrillation, and/or chronic atrial flutter could participate in the study under continued treatment without changes in their doses.

The study included 200 patients randomized in a 1:1 ratio to receive either landiolol (n = 93) or digoxin (n = 107) treatment. The treatment was administered as continuous intravenous infusion, initiated at a dose of 1 mcg/kg/min, and titrated to a maximum dose of 10 mcg/kg/min according to the patient’s condition. Landiolol was administered for at least 2 hours and up to 72 hours. Digoxin was administered as continuous intravenous infusion, initiated at a dose of 0.25 mg and could be up titrated within 72 hours according to the patient’s condition. For patients treated with oral digitalis, the parenteral digoxin dose could be reduced to 0.125 mg according to the patient’s condition to prevent digitalis intoxication. The mean dose of landiolol was 6.7 mcg/kg/min at 2 hours, and 6.3 mcg/kg/min throughout the treatment. The mean duration of landiolol treatment was 20.4 hours.

Demographics and baseline characteristics were very similar between the two treatment groups. In the landiolol treatment group, 77.2% of patients were categorized in the New York Heart Association (NYHA) class III and 22.8% of patients were in NYHA class IV versus 86.0% and 14.0 %, respectively, in digoxin-treated patients. The mean left ventricular ejection fraction was 36.4% in the landiolol treatment group versus 36.7% in the digoxin treatment group. The most common cardiovascular disease at baseline was hypertension (68% in the landiolol group and 65% in the digoxin group), followed by ischemic heart disease (13% in the landiolol group and 17% in the digoxin group). The most common type of arrhythmia was atrial fibrillation, occurring in 86% of landiolol-treated patients and 88% in digoxin-treated patients. The mean pre-dose heart rate was 138 bpm in both groups.

Successful improvement of heart rate was defined as ≥20% reduction in heart rate together with heart rate <110 bpm at 2 hours after starting intravenous administration of landiolol or digoxin.

The results from the study showed that improvement of heart rate was seen in 40 of 82 patients (48.0%) in the landiolol treatment group compared to 13 of 98 patients (13.9%) in digoxin treatment group. The mean reduction in heart rate from baseline to two hours was 19.6% in the landiolol group and 11.6% in the digoxin group.

Indication

The New Drug Submission for Sibboran was filed by the sponsor with the following proposed indication:

Sibboran (landiolol hydrochloride) is indicated for the short-term reduction of ventricular rate in patients with supraventricular tachycardia including atrial fibrillation and atrial flutter.

Health Canada approved the following indication:

Sibboran (landiolol hydrochloride) is indicated 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 with a short-acting agent is desirable.

For more information, refer to the Sibboran Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety profile of Sibboran was based on 38 published clinical studies submitted (including the four pivotal studies), four AOP Orphan Pharmaceuticals-sponsored clinical studies, post-market experience (periodic safety update reports [from February 2017 to 2020] based in the reference product Rapibloc, and post-market data from the Drug Interview Form [2013a] based on the reference product Onoact).

In the four pivotal studies, the most frequently reported adverse reactions was hypotension. In the perioperative setting, 33 patients in the landiolol group had decreased blood pressure compared to 11 patients in the placebo group. In the postoperative setting, 11 landiolol‑treated patients reported decreased blood pressure compared to one placebo‑treated patient.

In the study by Nagai et al., (2013), which was conducted in a non‑surgical setting, the most common adverse event in the landiolol‑treatment group compared to the digoxin‑treatment group was hypotension (7 patients versus [vs] 4 patients, respectively), vomiting (4 patients [4.3%] vs 1 patient [0.9%], respectively), nausea, increased blood creatinine and blood increased urea (3 patients [3.2%] vs no patients in the digoxin group, 3 patients [2.8%] and 1 patient [0.9%] respectively in the digoxin group), and asthma (1 patient [1.1%] vs no patients in the digoxin group). Two serious adverse events were reported in the landiolol treatment group (congestive heart failure and embolic stroke in one patient each). The event of heart failure was fatal, however, the relationship with landiolol was not determined in the study.

Similarly in the postoperative setting, the most common adverse events reported before and after the drug approval were low blood pressure/hypotension (before approval: 38 patients [15.9%] and after approval: 37 patients [6.1%]), and hepatic impairment (hepatobiliary disorders: 0 and 3 [0.5%] and hepatic laboratory abnormalities: 28 [11.7%] and 5 [0.8%] before and after approval respectively).

The post‑marketing data from the Drug Interview Form (2013a) for the reference product Onoact had a similar adverse event profile compared to the four pivotal clinical studies. The most common adverse events reported were low blood pressure/hypotension (29 patients [4.5%]) and bradycardia (5 patients [0.8%]), and hepatic impairment (disorder of hepatic function in 3 patients [0.5%], elevated aspartate transaminase level in 4 patients [0.6%], and elevated blood bilirubin level in 2 patients [0.3%]). One patient had bronchospasm post‑approval. In the pre‑approval data from this interview form, similar common adverse events were seen (low blood pressure/hypotension in 60 patients [11.7%], bradycardia in 3 patients (0.6%), and hepatic laboratory abnormalities. One patient experience asthma complication. Serious adverse events reported in the Onoact Drug Interview Form (2013a) were shock (1 patient), cardiac arrest (2 patients), complete atrioventricular block (incidence unknown), sinus arrest (1 patient), heart failure (incidence unknown), and severe bradycardia (2 patients). The outcomes were not specified.

Three of the four completed AOP Orphan Pharmaceuticals‑sponsored clinical studies included only healthy subjects. The most commonly reported adverse events was headache. There was no hypotension, bradycardia, serious adverse events, or deaths.

In the periodic safety update reports from February 2017 to 2020, it was reported that five patients experienced decreased blood pressure/hypotension (4 cases were severe and 1 non-serious), two patients had serious bradycardia, two patients required resuscitation. Syncope, angina pectoris, cardiac arrest, circulatory collapse were serious adverse events reported in one patient each.

Overall, the most common adverse events observed with use of landiolol in the 38 clinical studies (2,101 patients) was hypotension (6.4%) followed by bradycardia (1.5%). Both adverse events are known and expected adverse drug reactions due to the mechanism of action of landiolol. In the placebo‑controlled studies, higher proportion of landiolol-treated patients had hypotension (5.4%) compared to placebo‑treated patients (1.1%). In post‑marketing Drug Interview Form (2013a) the most common adverse events were decreased blood pressure/hypotension (18.2%), hepatic laboratory abnormalities (2.5%) and bradycardia (0.6%).

In addition to hypotension and bradycardia, other important potential risks were observed. Rare cases of shock (0.05%), embolic stroke (0.05%) and cardiac failure (0.05%) have been observed in clinical studies. In controlled studies, one patient had a sinus arrest and in uncontrolled studies one patient experienced a cardiac arrest. In post‑market reports, two patients had cardiac arrest and three had sinus arrests. Additionally, in the 2020 periodic safety update report, serious adverse events of shock, cardiac arrest, sinus arrest and complete atrioventricular block were reported with unknown frequency. One event of cardiac arrest was fatal. Therefore, a Serious Warnings and Precautions box was added to the Sibboran Product Monograph to highlight the need for continuous monitoring of heart rate and blood pressure.

Hepatotoxicity is also a potential risk associated with the use of Sibboran. In the placebo‑controlled studies, there was also a higher incidence of abnormal laboratory tests associated with hepatobiliary disorders in landiolol‑treated patients (11%) compared to placebo‑treated patients (1.4%). Furthermore, cases of disorder of hepatic function (0.4%), elevated aspartate transaminase (0.4%), elevated bilirubin (0.4%), elevated lactate dehydrogenase (0.2%), and elevated alanine transaminase (0.2%) were reported in the post‑market setting. Since data regarding the treatment in patients with hepatic impairment is limited, a cautionary statement has been included in the Sibboran Product Monograph. Appropriate warnings and precautions are in place in the approved Sibboran Product Monograph to address other missing information, such as, limited data on long-term use (>24 hours), limited information in published studies on results from laboratory assessment, and on the use in patients with acute or recent myocardial infarct (within 1 month).

In line with Health Canada’s Guidance Document: Drug Submission Relying on Third‑party Data (Literature and Market Experience), third party non‑clinical information on Sibboran was provided from a comprehensive examination of the literature based on the marketed Japanese reference product Onoact, as well as the non-clinical studies conducted by AOP Orphan Pharmaceuticals.

Non-clinical pharmacology studies submitted confirmed the specificity and selectivity of landiolol (the medicinal ingredient in Sibboran) for the beta 1‑adrenoreceptor when tested in rat, guinea pig, and dog receptor specimens. Furthermore, in an in vitro study using guinea pig right atria and tracheal strips, cardioselectivity was shown to be approximately 8‑fold greater than that of esmolol and 375‑fold greater than that of propranolol (ratios of 255 versus 33 versus 0.68).

Pharmacokinetic parameters of landiolol were evaluated in a series of in vitro and in vivo studies demonstrating that rats and dogs were acceptable species for the safety evaluation of landiolol and its major metabolites. Distribution of radioactivity was seen in the placenta of pregnant rats with low radioactivity levels transferred to the fetus. Although gastrointestinal absorption of landiolol is unknown, landiolol migrates to the milk in lactating rats indicating a potential transmission of landiolol via milk to nursing pups. Landiolol is eliminated mainly by metabolic clearance and the biotransformation profiles are qualitatively similar across the selected species.

The non-clinical toxicology program showed that a single intravenous infusion of landiolol resulted in no drug‑related adverse effects up to an infusion rate of 0.11 mg/kg/min (approximately three times above the safety factor). Repeat dosing with landiolol via bolus intravenous administration (over a period of 28 days) was lethal in rats (at a dose of 100 mg/kg/day) and caused acute adverse events in dogs (at a dose of 25 and 50 mg/kg/day). However, the lethality in rats was observed at 400 times the maximum human infusion rate (16.2 mg/kg/min). Repeat dosing with landiolol through continuous intravenous administration (the clinical intended route) resulted in no significant adverse events at a 14‑fold safety margin (0.6 mg/kg/min).

Landiolol and associated impurities were not genotoxic in a battery of in vitro and in vivo genotoxicity studies. Repeat dosing of pregnant rats and rabbits with landiolol via bolus intravenous administration (16.1 mg/kg/min), caused a reduction in pup survival as well as bone ossification delay in rats, but with no notable differences in the development and behavior of rat and rabbit offspring. Safety margin was around 200 times (the no-observed-adverse-effect level was 8.1 mg/kg/min) of the human maximum infusion rate (0.04 mg/kg/min) in the submitted reproduction and development studies. Landiolol was not hemolytic, did not cause any related local irritation in rabbits, and was deemed to have a very low risk of phototoxicity.

Overall, the non‑clinical pharmacology, and toxicology program for Sibboran are adequate and considered acceptable.

For more information, refer to the Sibboran Product Monograph, approved by Health Canada and available through the Drug Product Database.

The chemistry and manufacturing information submitted for Sibboran has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life is acceptable when the drug product is stored at room temperature (15 ºC to 25 ºC).

Proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use limits and/or qualified from toxicological studies).

The design, operations, and controls of the facilities and equipment that are involved in the production are considered suitable for the activities and products manufactured.

None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations.