Summary Basis of Decision for Bystolic

Clinical Pharmacology

Bystolic is a cardioselective competitive β1-adrenergic receptor antagonist (beta-blocker). The exact mechanism of action of its antihypertensive response has not been definitively established. The effect of beta-adrenergic receptor antagonists to decrease blood pressure appears to be related to decreased heart rate, decreased myocardial contractility, decreased sympathetic activity, and suppression of renin activity. Bystolic also has vasodilating properties, likely due to its ability to increase nitric oxide release from human endothelial cells, but the relative contribution of this release to the overall blood pressure lowering effect of Bystolic has not been demonstrated.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. The clinical pharmacological data support the use of Bystolic for the recommended indication.

The interaction potential of Bystolic [nebivolol hydrochloride (HCl)] with representative compounds from several classes of drugs expected to be administered concomitantly was examined. Nebivolol exposure increases significantly with inhibition of cytochrome P450 (CYP)2D6. If Bystolic is co-administered with an inhibitor of this enzyme (e.g., fluoxetine, quinidine, paroxetine, propafenone, and cimetidine) or a substrate (e.g., thioridazine, venlafaxine), caution should be exercised and the dose of Bystolic may need to be reduced.

Inducers of CYP2D6 (e.g., dexamethasone, rifampin) may decrease the exposure of nebivolol. Therefore, the dose of Bystolic may need to be adjusted when co-administrated with a CYP2D6 inducer.

The added beta-blocking action of Bystolic may produce excessive reduction of sympathetic activity, exacerbate the effects of myocardial depressants or inhibitors of atrioventricular conduction. Patients should be monitored closely when Bystolic is co-administered with drugs including, but not limited to:

• α2-adrenergic receptor agonists (e.g., clonidine, guanethidine);
• Anesthetic agents (e.g., ether, cyclopropane and trichloroethylene);
• Antiarrhythmics (e.g., amiodarone, disopyramide, flecainide);
• Calcium channel blockers (CCBs) (particularly non-dihydropyridine CCBs: verapamil, diltiazem, et cetera);
• Cholinesterase inhibitors;
• Digoxin;
• Sphingosine-1 phosphate receptor modulators (e.g., fingolimod);
• Some of HIV protease inhibitors.

Caution should be exercised when Bystolic is co-administered with the following drugs:

• Antidiabetic agents (e.g., insulin and oral hypoglycemic agents);
• Diuretics (e.g., hydrochlorothiazide, furosemide, and spironolactone);
• Histamine-2 Receptor Antagonists;
• Sildenafil;
• Valsartan

No pharmacokinetic interaction has been observed when nebivolol is concomitantly administered with activated charcoal, alcohol, digoxin, losartan, ramipril and warfarin in healthy adult volunteers. Moreover, nebivolol has no significant effects on the anticoagulant activity of warfarin [prothrombin time (PT) and international normalized ratio (INR)].

Therefore, based on the Phase I healthy subject pharmacokinetic and pharmacodynamic studies, the dose of Bystolic may need to be adjusted when co-administrated with a CYP2D6 inhibitor, substrate or inducer. Many other drugs may affect the clinical use of Bystolic, or vice versa.

In order to support the dosing recommendations for Bystolic, a single-dose, relative bioavailability and food effect study was conducted in 18 healthy volunteers characterized according to their metabolizing status. In poor metabolizers (PMs), the bioavailabilities of d,l-nebivolol and l-nebivolol are comparable when administered under fasting and fed conditions; however, the bioavailability of d-nebivolol is not comparable when administered under fasting and fed conditions. In extensive metabolizers (EMs), the bioavailability of d,l-nebivolol is comparable when administered under fasting and fed conditions; however, the bioavailabilities of d-nebivolol and l-nebivolol, analysed separately, are not comparable when administered under fasting or fed conditions.

Notwithstanding the data for d-nebivolol and l-nebivolol, nebivolol HCl is administered as a racemic mixture; therefore, given that the bioavailability of d,l-nebivolol is comparable when administered under fasting and fed conditions, the data support the dosing recommendations that Bystolic can be administered with or without food.

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

Clinical Efficacy

Efficacy of Bystolic as a Monotherapy

The clinical efficacy of Bystolic as a monotherapy was evaluated in three 12-week, randomized, double-blind, multicentre, placebo-controlled, pivotal Phase III studies (Studies NEB-302, NEB-305, and NEB-202, herein referred to as Studies 1, 2, and 3, respectively). Studies 1 and 2 included 1,716 patients in the general hypertensive population with a mean age of 54 years. Of the enrolled patients 55% were male, 26% were non-Caucasian, 7% were diabetic and 6% were genotyped as poor metabolizers (PMs). Study 3 included 300 Black hypertensive patients with a mean age of 51 years. Of these patients 45% were male, 14% were diabetic, and 2.3% were PMs.

In total, 2,016 patients with mild to moderate hypertension who had baseline diastolic blood pressure (DBP) of 95 to 109 mmHg were randomized to be treated with Bystolic doses ranging from 1.25 mg to 40 mg (1,811 patients) or with placebo (205 patients). Health Canada assessed the 40-mg dose for safety purposes only. Patients received treatment once-daily for 12 weeks. Overall, the studies reported good compliance to treatment (from 84% to 98.7%) and the mean duration of treatment was 78.0 days for Bystolic and 75.7 days for placebo.

The primary endpoint for the three monotherapy studies was the change from baseline in trough sitting DBP at Week 12. Change from baseline in trough sitting systolic blood pressure (SBP) was assessed as a secondary endpoint.

The least square (LS) mean reduction in trough sitting DBP was statistically significantly greater with Bystolic doses ≥5 mg than with placebo in all studies (placebo: -2.8 to -4.6 mmHg; 5 mg: -7.7 to -8.4 mmHg; 10 mg: -8.5 to -9.2 mmHg; 20 mg: -8.9 to -9.8 mmHg; p ≤0.004). Bystolic reduced trough sitting DBP in patients regardless of race (Black vs. Non-Black patients), age (≥65 years vs. <65 years of age) or gender. These Bystolic doses also decreased sitting SBP, although the effect seen was less pronounced than for DBP. The LS mean reduction in trough sitting SBP was statistically significantly greater with Bystolic than with placebo for all doses in Study 1, the 20 mg dose in Study 2, and the 10 mg and 20 mg doses in Study 3.

The blood pressure lowering effect of Bystolic was seen within two weeks of treatment and was maintained over the 24-hour dosing interval with trough-to-peak ratios for diastolic response ranging from 60-90% in all studies for Bystolic doses of 2.5-20.0 mg.

The blood pressure lowering effect of Bystolic was maintained over long-term therapy. Twenty-eight days after cessation of Bystolic treatment, blood pressure returned toward baseline, without however reaching that level. At the end of the 28 day follow-up phase post-discontinuation, the response rate (defined as trough sitting DBP <90 mmHg) was still at 72.2%. There was no evidence of rebound hypertension after abrupt cessation of Bystolic therapy; however, some patients experienced increases in heart rate above baseline levels following withdrawal of Bystolic.

After 12 weeks of treatment, the response rate in Study 1 was 50.0% for Bystolic 2.5 mg, 50.3% for 5 mg, 53.6% for 10 mg, and 59.6% for 20 mg, versus 24.7% for placebo (all p ≤0.001). The response rates in Study 2 were 66.0%, 66.8% and 68.9% in the Bystolic 5 mg, 10 mg, and 20 mg groups, respectively, versus 49.3%, for the placebo group (all p ≤0.009). In Study 3, the percentages of responders were 36.7%, 58.0%, 58.8% and 64.0% in the Bystolic 2.5 mg, 5 mg, 10 mg, and 20 mg groups compared with a placebo response rate of 26.5% (p ≤0.002 for Bystolic doses of 5 mg and above).

The efficacy of the 2.5 mg dose was not consistently shown in all of the studies and therefore, this dose is not recommended as the starting dose for the general population. The 2.5 mg dose should only be used in specific populations such as patients with moderate hepatic impairment or severe renal impairment. A lower Bystolic dose may also need to be used in patients co-administered a CYP2D6 inhibitor.

Efficacy of Bystolic Monotherapy in Subpopulations

Subgroup analyses showed that the efficacy of Bystolic did not appear to be affected by race (Black vs. Non-Black patients), gender, or age (≥65 years of age vs. <65 years of age). Clinical pharmacology studies showed that the metabolic disposition of nebivolol was highly influenced by CYP2D6 phenotype resulting in significantly higher nebivolol exposure in poor metabolizers (PMs) compared to extensive metabolizers (EMs). Despite these differences in the pharmacokinetics of nebivolol, EMs and PMs displayed similar blood pressure responses, since CYP2D6 products (metabolites) of nebivolol in EMs appear to be pharmacologically active at β1-adrenergic receptors.

Combination Therapy

In addition to the pivotal monotherapy studies, one randomized, double-blind, placebo-controlled, parallel-group, 12-week, Phase III study (Study CAN-3) evaluated the efficacy of Bystolic (1 mg, 5 mg and 10 mg) in combination with hydrochlorothiazide (HCTZ) (12.5 mg and 25 mg). This study included 240 patients with mild to moderate essential hypertension.

The primary efficacy endpoint was the change from baseline in trough sitting DBP at Week 12. The concomitant use of Bystolic/hydrochlorothiazide (HCTZ) was shown to provide greater anti-hypertensive effects over monotherapy components and placebo. After 12 weeks of treatment, the comparison versus the respective monocomponents was statistically significant for the changes in SBP (secondary efficacy endpoint) for the 5 mg/12.5 mg; 5 mg/25 mg; 10 mg/12.5 mg; and 10 mg/25 mg Bystolic/HCTZ combinations (p <0.05), but not for the changes in DBP (primary efficacy endpoint). The anti-hypertensive effects of all the Bystolic/HCTZ combination doses were better than with placebo (p ≤0.0002).

Significant increases in the percentage of patients who responded to treatment were obtained with Bystolic/HCTZ combination, as compared to placebo (p <0.02). The response rates were 15%, 60%, 85%, 80% and 85% with placebo, Bystolic/HCTZ 5 mg/12.5 mg, 5 mg/25 mg, 10 mg/12.5 mg and 10 mg/25 mg combinations, respectively.

The co-administration of HCTZ was not shown to have a significant impact on nebivolol plasma concentrations.

Overall, this study was considered appropriate to support the indication for concomitant use with thiazide diuretics.

Overall Analysis of Efficacy

The pivotal monotherapy studies demonstrated that Bystolic is statistically significantly better than placebo in reducing mean trough sitting DBP (primary efficacy endpoint) at doses ≥5 mg. The effects of this decrease were considered clinically significant. The 5 mg dose is recommended as the starting dose for up-titration in the general population of patients with mild to moderate essential hypertension. The effect of Bystolic increases numerically with increasing doses, but not in a proportional manner. For instance, in Study 1, doubling the dose of Bystolic led only to a 9.5% to 14.5% greater effect (that is a difference of -0.5 to -0.8 mmHg for sitting DBP at trough). In the step-up trend test for the pooled analysis of Study 1 and 2, no statistically significant incremental increases in efficacy were detected for doses of Bystolic ≥10 mg, although there were numerical improvements in efficacy with increasing dose. The blood pressure reducing effect of Bystolic was more pronounced on DBP than its effect on SBP.

The original indication proposed with the New Drug Submission was as follows:

Bystolic (nebivolol) is indicated for the treatment of mild to moderate hypertension. Bystolic may be used alone or in combination with diuretics. Bystolic may be used as an add-on therapy to further reduce blood pressure in patients whose hypertension is not adequately controlled with angiotensin converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), or diuretic antihypertensive therapy.

Following review of the submission Health Canada revised the indication to:

Bystolic (nebivolol tablets) is indicated for the treatment of mild to moderate essential hypertension. Bystolic may be used alone or concomitantly with thiazide diuretics. Bystolic is not recommended for the emergency treatment of hypertensive crises.

The indication for concomitant use with ACE inhibitors and ARBs was not granted as the studies provided were not appropriately designed to support this indication and/or did not have the statistical power to show that these combinations were better than the monotherapies. At the time of authorization, evidence was available demonstrating concomitant use of Bystolic with HCTZ provides further benefit over these respective monotherapies and is considered safe. It remains unknown if a similar benefit/risk profile would also be observed for the concomitant use of Bystolic with other anti-hypertensive agents.

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

Clinical Safety

In total, the safety profile of Bystolic was evaluated in numerous studies that included more than 3,700 patients. The Phase II/III safety profile was primarily evaluated in six studies, namely Studies 1, 2, and 3 (described in the Clinical Efficacy section) as well as Studies NEB-203, NEB-321 and NEB-306 (herein referred to as Studies 4, 5, and 6, respectively). These six studies combined provided safety data from 2,464 Bystolic-treated hypertensive patients. In addition, safety data from the CAN-3 study (also described in the Clinical Efficacy section) provided data from an additional 180 Bystolic-treated patients. Among these studies, three were pivotal placebo-controlled monotherapy studies (Studies 1, 2, and 3), two studies evaluated the safety of the concomitant use of Bystolic with other anti-hypertensive therapies (CAN-3 and Study 5) and one study evaluated long-term safety (Study 6). Across these studies, Bystolic-treated patients averaged 53 years of age, with 436 patients (18%) aged ≥65 years. There were 652 Black patients (27%) and 144 poor metabolizers (5.9%) treated with Bystolic.

The overall safety profile of Bystolic at doses of 2.5 mg to 20.0 mg was consistent with known beta-blocker class effects. The most common adverse events (AEs) observed with Bystolic in the pivotal studies were headache (7.1%), fatigue (3.6%), nasopharyngitis (3.1%), dizziness (2.9%), diarrhea (2.5%), and upper respiratory tract infections (2.1%). The AEs bradycardia, dizziness, dyspnea, diarrhea and nausea were more likely at higher doses of Bystolic and shortly after initiating treatment. The long-term safety data were consistent with those of the short-term trials.

In the Phase II/III studies, orthostatic hypotension was reported at an incidence of 13% during treatment with Bystolic as compared to 5% at baseline; however, measurements were taken more frequently during Bystolic treatment than at baseline.

Bystolic was shown to decrease trough seated heart rate in a dose-dependent fashion with LS mean decreases of -2.8 bpm for the 2.5 mg strength, -5.3 bpm for 5 mg, -6.0 bpm for 10 mg, and -7.5 bpm for 20 mg as compared to +1.1 bpm for placebo (from a pooled analysis of 2 pivotal studies).

The most frequently reported AEs leading to discontinuation in the Phase II/III and Phase III/IV studies were bradycardia/sinus bradycardia, myocardial infarction, nausea, headache, dizziness, sexual dysfunction, and hypertension. No deaths were reported in the pivotal studies or in a 9-month extension study. In total, there were thirteen deaths reported during the Phase II/III and Phase III/IV programs withfour fatal events occurring after the last Bystolic dose had been taken. All other cases were considered by the investigators as either remotely or definitely not related to the study drug.

Drug-Drug Interactions

In addition to the drug interactions that apply to other beta-blockers, Bystolic was shown to interact with CYP2D6 inhibitors; therefore a dose reduction may be required. Furthermore, potential interactions with CYP2D6 substrates, CYP2D6 inducers, and sildenafil have also been identified.

PR Interval Prolongation

The review of the thorough QT study and pivotal study ECG data showed that Bystolic decreases heart rate and prolongs the PR interval. Bystolic should be used with caution in patients with conduction disorders, arrhythmia and ischemic heart disease. Furthermore, concomitant medications that result in a decrease in heart rate and/or PR interval prolongation should be carefully considered to determine whether the therapeutic benefit outweighs the potential risk.

These effects of Bystolic as well as risk management strategies have been included in the Product Monograph.

Safety of Bystolic Monotherapy in Subpopulations

Subgroup analyses by gender, age, and race of individual or pooled studies showed AE profiles similar to that of the general study population, the only exception being that bradycardia/sinus bradycardia and dyspnea seemed to occur at a higher frequency in patients ≥65 years of age than in younger patients. Despite the fact that considerable differences in nebivolol pharmacokinetics were observed between PMs and EMs, the AE incidence was similar in both subgroups and these AEs were not found to be of greater severity or seriousness in PMs. It is noteworthy, however, that only 116 PMs participated in the pivotal placebo-controlled monotherapy trials, which limits interpretation of the safety data in this patient population.

Significant increases in nebivolol exposure were observed in patients with moderate liver impairment or severe renal impairment. As a result, the initial recommended dose of Bystolic for these patients is 2.5 mg/day.

Combination Therapy

The safety profile of the Bystolic/HCTZ combinations was similar to the monotherapy components and was not associated with a substantially greater number of side effects as compared to monotherapies. The most commonly reported AEs with the combinations were fatigue, hypoaesthesia, headache and dizziness. Some of the AEs, such as polyuria, vertigo and vision abnormal were only reported in patients on the combinations with no such events reported with the monotherapies.

Overall Safety Analysis

Based on the overall safety data reviewed, Bystolic is well-tolerated with the expected safety profile for a beta-blocker.

Bystolic is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container; patients with severe bradycardia (generally <50 bpm prior to start of therapy); patients with cardiogenic shock; patients with decompensated heart failure; patients with second or third degree atrioventricular (AV) block; patients with sick sinus syndrome or sinoatrial block; patients with severe hepatic impairment (Child-Pugh Score >B); and patients with severe peripheral arterial circulatory disorders. Appropriate warnings and precautions are in place in the approved Bystolic Product Monograph to address the identified safety concerns.

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