Summary Basis of Decision for Lancora

Clinical Pharmacology

The active ingredient of Lancora is ivabradine, as ivabradine hydrochloride. Ivabradine is a heart rate lowering agent which blocks the hyperpolarisation-activated cyclic nucleotide-gated (HCN) channel responsible for the cardiac pacemaker I_f current, which regulates heart rate.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies.

Pharmacodynamics

Ivabradine causes a dose-dependent reduction in heart rate. The size of the reduction is related to the baseline heart rate; i.e., the higher the baseline heart rate, the greater the heart rate reduction. The heart rate lowering effect of ivabradine also dose-dependently increases the uncorrected QT interval. Analysis of heart rate reduction vs. dose indicates a plateau effect at doses >20 mg twice daily.

In patients with conduction disorders, ivabradine not only slows down the heart rate, but also prolongs the mean duration of the atrial-His (AH) interval (by 27 ms) and PR interval (by 29 ms).

Regular monitoring of the QT/QTc and PR intervals is recommended during treatment with Lancora.

Pharmacokinetics

The absolute oral bioavailability of ivabradine is approximately 40%, due to first-pass elimination in the gut and liver. Following administration of ivabradine with a high-fat, high-calorie meal, the absorption of ivabradine was delayed by approximately 0.5 hour, and the rate and extent of absorption of ivabradine was increased by approximately 45% and 42%, respectively, when compared to administration under fasting conditions. Lancora should therefore be taken with food.

Ivabradine is exclusively metabolized by the cytochrome P450 (CYP) enzyme, CYP3A4. Because the metabolism of ivabradine is dependent on CYP3A4, exposure to ivabradine is significantly increased by moderate or strong CYP3A4 inhibitors. Also concomitant use with CYP3A4 inducers may decrease ivabradine exposure. Appropriate warnings are stated in the Lancora Product Monograph. Strong CYP3A4 inhibitors and moderate CYP3A4 inhibitors with heart rate reducing properties (i.e., diltiazem and verapamil) are contraindicated.

Instructions on how to concomitantly use ivabradine with drugs known to moderately inhibit (without heart rate lowering effect) or induce CYP3A4 is also provided in the Drug Interactions and Dosage and Administration sections of the Lancora Product Monograph.

Ivabradine was not studied in patients with severe hepatic impairment. Because ivabradine is extensively metabolized in the liver, a large increase in systemic exposure is expected in this population. Lancora is therefore contraindicated in patients with severe hepatic impairment.

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

Clinical Efficacy

The clinical efficacy of Lancora was primarily evaluated in a single pivotal study, SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial). This study was a Phase III, randomized, double-blind, multicentre, placebo-controlled, parallel-group, event-driven, morbidity-mortality study conducted in 6,505 patients with stable chronic heart failure New York Heart Association (NYHA) Class II to IV, left ventricular ejection fraction ≤35% and in sinus rhythm, with a baseline resting heart rate of ≥70 beats per minute (bpm). The patients were treated with standard chronic heart failure therapies. Treatment with Lancora or placebo was started at a dose of 5 mg twice daily (bid) followed by titration based on the patient's resting heart rate to a maximum dose of 7.5 mg bid. The heart rate range to achieve was between 50 bpm and 60 bpm. Dosing could also be reduced to 2.5 mg bid or be interrupted if the patient had a heart rate lower than 50 bpm or experienced symptoms of bradycardia.

The primary endpoint was a composite of time to first occurrence of hospitalisation for worsening heart failure or cardiovascular (CV) death. The study showed that in the randomized set (intention-to-treat population), Lancora was superior to placebo in reducing the incidence of the primary endpoint (hazard ratio [95% confidence interval (CI)]: 0.82 [0.75; 0.90], p<0.0001), yielding a relative risk reduction (RRR) of 18% and an absolute risk reduction (ARR) of 4.2%. The effect observed was mainly driven by the reduced rate of hospitalisation for worsening heart failure (p<0.0001), as no significant CV death benefit was observed (p = 0.128). The maximal Lancora effect on heart rate was reported after 28 days of treatment (i.e., -15 bpm with Lancora vs. -5 bpm with placebo). Improvement from baseline to last post-randomization visit in heart failure NYHA classification was reported in 27.6% of Lancora patients vs. 24.0% of placebo patients. The treatment effect of Lancora generally appeared consistent among the different patient subgroups analyzed, although the benefit tended to be less marked in some particular subgroups; namely patients aged ≥65 years, and patients receiving beta-blockers approaching the guideline-recommended target doses. It is noteworthy that the treatment effect observed in patients with baseline resting heart rate ≥77 bpm (number of patients [n] = 3,357) was statistically significantly greater than in patients with baseline resting heart rate <77 bpm (n = 3,144) (p value 0.0288; 77 bpm being considered as the median baseline resting heart rate [pre-specified subgroup analysis]).

In patients treated with Lancora with a baseline resting heart rate <77 bpm, the RRR for the primary endpoint was 7% (hazard ratio [95% CI]: 0.93 [0.80; 1.08]) compared to patients on placebo, which did not reach statistical significance. The hazard ratio (Lancora vs. placebo) for the components of the primary endpoint also did not show statistical significance: cardiovascular death (1.07 [0.87; 1.31]) and hospitalization for worsening heart failure (0.83 [0.69; 1.00]). Moreover, the incidence of deaths from any cause, cardiovascular deaths and deaths from heart failure in this patient subgroup was numerically higher with Lancora than with placebo, which resulted in hazard ratios above 1.0. The between-group difference was however not statistically significant.

In patients with a baseline resting heart rate ≥77 bpm, Lancora was shown to be superior to placebo in reducing the incidence of the primary endpoint (hazard ratio [95% CI]: 0.75 [0.67; 0.85], p<0.0001), yielding a RRR of 25% and an ARR of 6.8%. Both components of the primary endpoint [i.e., CV death (p = 0.0137) and hospitalisation for worsening heart failure (p<0.0001)] were shown to contribute to the treatment effect observed in this patient subgroup. The Kaplan-Meier Plots for the primary endpoint showed that the treatment curves started to separate after 1 month of treatment and continued to diverge up to 30 months of treatment. Hence, given the efficacy results in patients with baseline heart rate ≥77 bpm and the uncertainty in terms of treatment benefit observed for the complementary patient subgroup (i.e., patients with baseline heart rate <77 bpm), ivabradine treatment benefit is considered clearer in the former subgroup of patients (i.e., heart rate ≥77 bpm). It is also noteworthy that the safety profile of Lancora in patients with heart rate ≥77 bpm was consistent with the safety profile observed in the overall study population. Overall, this indicates a favorable benefit-risk profile in the subgroup of patients with a baseline heart rate ≥77 bpm.

Several issues were raised during the review of this drug submission which resulted in a Notice of Deficiency (NOD) and then, a NOD Withdrawal. Along with the fact that only a single pivotal study was submitted, there were difficulties in identifying the appropriate patient population that would benefit from Lancora treatment. Indeed, the efficacy analyses based on the patient baseline heart rate and background beta-blocker regimen generated several key questions. For instance, using a single measurement of the resting heart rate to choose a patient to be treated with Lancora was considered as an issue. Furthermore, it was thought that there would be confusion on how Lancora should be used with background beta-blocker treatment. There was also a risk that Lancora may be used as an alternative to beta-blockers. Several additional safety concerns were also identified during the review.

The sponsor filed a Request for Reconsideration. Canadian medical and biostatistical experts external to Health Canada reviewed the data and concluded that there was sufficient evidence to support the sponsor's proposed indication for heart failure; one trial was sufficient, and they made some recommendations in terms of product labelling and these recommendations were taken into account in the Lancora Product Monograph. The submission was returned to the review division for re-evaluation. Subsequently, the review division concluded that the data presented were sufficient to support the efficacy for Lancora for the indication recommended below.

Indication

The New Drug Submission for Lancora was filed with the following indication:

• Lancora is indicated for the treatment of symptomatic chronic heart failure of NYHA Classes II to IV and with left ventricular ejection fraction (LVEF) ≤35% in adult patients in sinus rhythm and with heart rate ≥77 bpm, in combination with optimal standard chronic heart failure treatment.
  
  
• Lancora has been demonstrated to significantly reduce the risk for cardiovascular mortality and hospitalisations for worsening heart failure.

Health Canada removed patients with heart failure Class IV from the indication because the SHIFT data were deemed insufficient (limited subset of patients, 1.7% of the overall study population) to assess the benefit/risk of ivabradine treatment in this patient population.

To ensure safe and effective use of the product, Health Canada approved the following indication:

Lancora is indicated for the treatment of stable chronic heart failure with reduced left ventricular ejection fraction (≤35%) in adult patients with NYHA Classes II or III who are in sinus rhythm with a resting heart rate ≥77 bpm, to reduce the incidence of cardiovascular mortality and hospitalisations for worsening heart failure. Lancora should be administered in combination with standard chronic heart failure therapies.


• Lancora should be initiated and up-titrated under the supervision of a physician who is experienced with the treatment of patients with heart failure.

Overall analysis of efficacy

In the randomized set of the pivotal study; i.e., patients with baseline heart rate ≥70 bpm, Lancora was statistically significantly superior to placebo for the incidence of the primary composite endpoint; first event of CV death or hospitalization for worsening heart failure. The treatment effect reflected a reduction in the risk of hospitalization for worsening heart failure; there was no statistically significant benefit on the CV death component of the primary endpoint. There are limited data on the efficacy and safety of Lancora beyond 30 months of treatment.

More convincing efficacy results were observed in the subpopulation of patients with a baseline resting heart rate ≥77 bpm. Lancora was shown to statistically significantly reduce the incidence of the primary endpoint compared to placebo and both components (i.e., CV death and hospitalisation for worsening heart failure) contributed to the beneficial treatment effect seen in this subgroup of patients. Therefore, the indication was recommended for patients with a baseline resting heart rate at or above 77 bpm. As Lancora treatment decisions are based on specific heart rate thresholds, serial heart rate measurements, conducted on at least three separate visits, are required to obtain an accurate measure of heart rate prior to initiating or modifying treatment with Lancora. Clear directions are provided in the Lancora Product Monograph. The Lancora Product Monograph also includes several contraindications which limit the patient population suitable for treatment with Lancora.

Lancora is not meant to replace treatment with beta-blockers, well known to be effective in the treatment of heart failure patients. Every effort should be made by the treating physician to achieve the guideline-recommended target doses of the beta-blockers prior to considering initiating treatment with Lancora.

It is also noteworthy that some studies (i.e., BEAUTIFUL and SIGNIFY trials) have shown lack of benefit in patients with stable coronary artery disease treated with ivabradine and therefore, a cautionary statement was included in the Lancora Product Monograph to emphasize that Lancora is not indicated in this patient population.

Additional information may be found in the Lancora Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety profile of Lancora in patients with chronic stable heart failure was evaluated in the pivotal Phase III study (SHIFT) described in the Clinical Efficacy section.

Among the patients treated with Lancora, 2,548 patients (79%) were exposed to treatment for at least 12 months, 1,141 patients (35%) for at least 24 months, and 15 patients (0.5%) for at least 36 months. Patients were followed to study termination, irrespective of whether the study drug had been discontinued (mean follow-up: 22.1 months).

The most common treatment-emergent adverse events reported at a higher incidence with Lancora vs. placebo included atrial fibrillation, inadequately controlled blood pressure, bradycardia (symptomatic or asymptomatic), ventricular extrasystoles, myocardial infarction, and phosphenes. Although less frequent, events of heart conduction disorders (i.e., second and third degree atrioventricular [AV] block), torsade de pointes, ventricular fibrillation and sinus node dysfunction were also more frequently reported with Lancora than with placebo.

The following adverse events were carefully evaluated during the review process:

Bradycardia

Lancora is a heart rate lowering drug. Patients treated with Lancora are therefore exposed to risk of bradycardia (symptomatic or asymptomatic). Symptomatic bradycardia was reported in 4.6% of Lancora patients vs. 0.9% of placebo patients, and a higher incidence of asymptomatic bradycardia was also reported with Lancora vs. placebo (5.6% vs. 1.4%, respectively). Several approaches were adopted in the Lancora Product Monograph to manage the risk of bradycardia in patients treated with Lancora. These include a dose adjustment based on the patient's heart rate, serial measurements of heart rate prior to making treatment decisions, use of 7.5 mg bid as the maximal recommended dose, use of a lower starting dose of 2.5 mg bid for patients at risk (e.g., patients aged ≥75 years), and a contraindication in patients with a heart rate <70 bpm. The Lancora Product Monograph also states that caution should be exercised and heart rate be monitored if Lancora is used concomitantly with other heart rate lowering drugs, or used in patients with hypokalemia because the combination of hypokalemia and bradycardia is a predisposing factor to the onset of severe arrhythmias.

Atrial fibrillation

Atrial fibrillation was more frequently reported in the Lancora group than in the placebo group (8.3% Lancora vs. 6.7% placebo).

Serious cases of atrial fibrillation were more frequent in the Lancora group than in the placebo group (3.9% vs. 3.3%, respectively) and one fatal case was reported in the Lancora group. The higher incidence of atrial fibrillation however did not appear to be associated with an increased incidence of stroke. Several meta-analyses or pooled analyses published in the literature confirmed that Lancora treatment exposes patients to a greater risk of developing atrial fibrillation. Patients should be regularly monitored for the occurrence of atrial fibrillation during treatment with Lancora and treatment should be discontinued if atrial fibrillation occurs. Concomitant treatment with amiodarone was identified as a risk factor and should therefore be avoided.

Blood pressure inadequately controlled

Blood pressure (BP) inadequately controlled was reported in 228 patients (7.1%) on Lancora, vs. 198 patients (6.1%) on placebo, all patients having a known history of hypertension. No differences were observed between both treatment arms in terms of severity or seriousness of the BP inadequately controlled events and no cases were reported as fatal. Eighty-six percent of the cases required new treatment or a dose increased of on-going therapy. Performance of regular BP monitoring and reassessment of anti-hypertensive treatments in hypertensive patients requiring Lancora treatment is recommended.

Visual effects

Data from the pivotal study indicated that "Vision Disorders" (MedDRA High Level Group Term) were reported in 122 patients (3.8%) in the Lancora group compared to 31 patients (1.0%) in the placebo group. Most events were mild to moderate in intensity; 14 led to treatment discontinuation (9 Lancora vs. 5 placebo); and none were fatal. Phosphenes accounted for most of the visual effects reported. In the Lancora group, 67% of the events were reported within the first month, 83% within the first 3 months, and 93% within the first 6 months of treatment. Visual effects reported with Lancora are described as luminous phenomena such as a transiently enhanced brightness in a limited area of the visual field, halos, image decomposition (stroboscopic or kaleidoscopic effects), colored bright lights, or multiple images (retinal persistency). These events are usually intermittent events triggered by sudden variations in light intensity and result from an effect of Lancora on retinal photoreceptors. In most cases, the events resolved spontaneously during treatment or were reversible after treatment discontinuation. Cessation of treatment should be considered if any unexpected deterioration in visual function occurs. Caution should be exercised in patients with retinitis pigmentosa. The possible occurrence of such luminous phenomena should be taken into account when driving or using machines in situations where sudden variations in light intensity may occur, especially when driving at night.

Heart conduction disorders

Lancora has been shown to slow conduction through the AV node. The incidence of third degree AV block was 0.57% with Lancora vs. 0.18% with placebo. No cases were fatal. In the Lancora group, 83% of the cases recovered, half of them after treatment discontinuation. Medical history of intraventricular block was identified as a risk factor. Hence, patients with intraventricular conduction defects (bundle branch block left, bundle branch block right) and ventricular dyssynchrony should be closely monitored. A lower starting dose of Lancora is recommended in patients with history of conduction defects and Lancora treatment should be discontinued if third-degree AV block occurs. It is noteworthy that patients with second- and third-degree AV block were excluded from the SHIFT study. Lancora use in patients with third-degree AV block is contraindicated and use in patients with second-degree AV block should be avoided.

Disorder of sinus node function

Disorders of the sinus node function (including sick sinus syndrome and sino-atrial block) were reported at incidences of 0.4% (13 cases) for Lancora vs. 0.03% (1 case) for placebo. Most of the cases reported were serious, but none were fatal. Among the 13 cases reported in the Lancora group, 8 led to treatment discontinuation, 6 had a cardiac pacemaker implanted, and 4 required the addition of a new medical treatment or the increase of an on-going treatment. Six cases of sick sinus syndrome were reported during the study; all in the Lancora group. Patients with sick sinus syndrome or sinoatrial block were excluded from the study. Lancora treatment should be discontinued if sinus node dysfunction occurs. Lancora use is contraindicated in patients with sick sinus syndrome or sinoatrial block.

Severe cardiac arrhythmias

In the pivotal study, there were 24 cases (0.74%) of ventricular fibrillation reported in the Lancora group vs. 12 cases (0.37%) in the placebo group. There were no between group differences in terms of seriousness or treatment discontinuation, but more fatal cases were reported with Lancora than with placebo (11 cases vs. 3 cases, respectively). Two cases of torsade de pointes were also reported exclusively in the Lancora group; both being serious, but nonfatal.

The heart rate lowering effect of Lancora may exacerbate existing QT interval prolongation and give rise to severe arrhythmias, including torsade de pointes and ventricular fibrillation. Combination of hypokalemia and bradycardia is also a predisposing factor to the onset of severe arrhythmias.

Several measures have been included in the Lancora Product Monograph to manage the risk of severe cardiac arrhythmias, namely, regular monitoring of patient's QT/QTc and PR intervals during treatment with Lancora is recommended; use in patients with existing long QT interval is contraindicated (e.g., patients with congenital long QT syndrome); use in patient at risk of QT prolongation should be avoided (e.g., familial history of QT prolongation or concomitant treatment with QT prolonging therapies) and if concomitant use with QT prolonging therapies is deemed necessary, close cardiac monitoring is required; and caution should also be exercised when Lancora is used in hypokalemic patients and close cardiac monitoring is recommended. Lancora treatment should be discontinued if severe cardiac arrhythmia occurs.

Overall analysis of safety

Several safety issues were raised during the review of this drug submission. The following adverse events were considered as requiring particular attention not only because of their higher incidence in patients treated with Lancora compared to patients treated with placebo, but also because of the seriousness, causal relationship, required medical interventions and/or outcome: atrial fibrillation, blood pressure inadequately controlled, bradycardia (symptomatic or asymptomatic), phosphenes, sick sinus syndrome, ventricular fibrillation, torsade de pointes and cardiac conduction disorders (i.e. second and third degree AV block).

Lancora is considered as a drug having significant benefits accompanied by significant potential for harms, but these harms are manageable with appropriate labelling. Risk mitigation strategies were incorporated into the Lancora Product Monograph to communicate the key safety issues that were observed, provide guidance with regard to monitoring, and provide comprehensive guidance with regard to dose modifications associated with adverse events. Information is therefore available to health care professionals to help them limit and appropriately manage those risks.

Overall, despite the identified safety concerns associated with Lancora, the safety profile of Lancora is acceptable and manageable for the treatment of stable chronic heart failure with reduced left ventricular ejection fraction (≤35%) in adult patients with NYHA Classes II or III who are in sinus rhythm with a resting heart rate ≥77 bpm, to reduce the incidence of cardiovascular mortality and hospitalisations for worsening heart failure. Appropriate warnings and precautions are in place in the approved Lancora Product Monograph to address the identified safety concerns.

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