Bystolic
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Bystolic - Scientific Information

Manufacture: Actavis
Country: Canada
Condition: High Blood Pressure (Hypertension)
Class: Cardioselective beta blockers
Form: Tablets
Ingredients: nebivolol (as nebivolol hydrochloride), colloidal silicon dioxide, croscarmellose sodium, D&C Red #27 Lake (10 and 20 mg only), FD&C Blue #2 Lake, FD&C Yellow #6 Lake, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, polysorbate 80, and sodium lauryl sulfate

Pharmaceutical information

Drug Substance

Proper name: Nebivolol hydrochloride
Chemical name: (1RS,1’RS)-1,1’-[(2RS,2’SR)-bis(6-fluoro-3,4-dihydro-2H-1- benzopyran-2-yl)]- 2,2’-iminodiethanol hydrochloride.
Molecular formula and molecular mass: C22H25F2NO4•HCl with a MW: 441.90 g/mol
Structural formula: Nebivolol is a racemic mixture of d-Nebivolol and l-Nebivolol with the stereochemical designations of [SRRR]-nebivolol and [RSSS]-nebivolol, respectively.
Physicochemical properties: Nebivolol hydrochloride is a white to almost white powder that is soluble in methanol, dimethylsulfoxide, and N,N-dimethylformamide, sparingly soluble in ethanol, propylene glycol, and polyethylene glycol, and very slightly soluble in hexane, dichloromethane, methylbenzene and water. The pKa of nebivolol hydrochloride is 8.4 for the amino group.

Clinical trials

The antihypertensive efficacy of BYSTOLIC (nebivolol tablets) as monotherapy has been investigated in three randomized, double-blind, multi-centre, placebo-controlled trials at doses ranging from 1.25 to 40 mg for 12 weeks (Studies 1, 2 and 3). In two separate combination studies, additional antihypertensive effect was demonstrated when BYSTOLIC was administered concomitantly with either thiazide diuretics or ACE inhibitors. Sustained efficacy over 24 hours has been shown for BYSTOLIC once-daily dosing schedule.

Monotherapy Studies

Study demographics and trial design

Table 1: Summary of Patient Demographics for Clinical Trials in Treatment of Mild to Moderate Essential Hypertension
Study# Trial
design
Dosage, route of
administration and
duration
Study subjects
(ITT/completed
study)
Median
age
(Range)
Sex
(M - Male,
F-Female)
Study 1 Double-
blind,
placebo-
controlled
Oral
Placebo, BYSTOLIC 1.25
mg, 2.5 mg, 5 mg, 10 mg, 20
mg, 30/40 mg
28 to 42-day, single-blind
placebo run-in,
12 weeks double-blind
treatment
Placebo 81/67
BYSTOLIC
1.25 mg 83/68,
2.5 mg 82/68,
5 mg 165/148,
10 mg 166/133,
20 mg 166/144,
30/40 mg 166/149

Total 909/777
54 years
(22-84)
M: 518(57%)
F: 391(43%)
Study 2 Double-
blind,
placebo-
controlled
Oral
Placebo, BYSTOLIC
5 mg, 10 mg, 20 mg.
28 to 42-day single-blind
placebo run-in,
12 weeks double-blind
treatment
Placebo 75/61
BYSTOLIC
5 mg 244/218,
10 mg 244/206,
20 mg 244/217

Total 807/702
53 years
(22-82)
M: 432(53.5%)
F: 375(46.5%)
Study 3
Double-
blind,
placebo-
controlled
Oral
Placebo, BYSTOLIC 2.5 mg,
5 mg, 10 mg, 20 mg, 40 mg
14 to 42-day, single-blind,
placebo run-in,
12 weeks double-blind
treatment
Placebo 49/41
BYSTOLIC
2.5 mg 49/42,
5 mg 50/41,
10 mg 51/47,
20 mg 50/45,
40 mg 51/43

Total 300/259
50 years
(26-79)
M: 136(45.3%)
F: 164(54.7%)

The three monotherapy trials included a total of 2,016 patients (1,811 BYSTOLIC, 205 placebo) with mild to moderate hypertension who had baseline diastolic blood pressures (DBP) of 95 to 109 mmHg. Patients received either BYSTOLIC or placebo once daily for 12 weeks. Two of these monotherapy trials (Studies 1 and 2) studied 1,716 patients in the general hypertensive population with a mean age of 54 years, 55% males, 26% non-Caucasians, 7% diabetics and 6% genotyped as poor metabolizers (PMs). The third monotherapy trial (Study 3) studied 300 Black hypertensive patients with a mean age of 51 years, 45% males, 14% diabetics, and 2.3% as PMs.

Study Results

The primary endpoint in the three monotherapy trials was the change from baseline in trough sitting DBP as Week 12. Change from baseline in trough sitting systolic blood pressure (SBP) was used as a secondary endpoint. Blood pressure reductions by dose for each study are presented in Table 2. The least square (LS) mean reduction in trough sitting DBP was significantly greater with BYSTOLIC doses ≥5 mg than with placebo in all studies. BYSTOLIC reduced trough sitting DBP in patients regardless of race, age or sex.

The LS mean reduction in trough sitting SBP was 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.

Table 2: Analysis of Sitting Diastolic and Systolic Blood Pressure (mmHg) at Trough at Week 12
Study Treatment group Placebo BYSTOLIC
2.5 mg 5 mg 10 mg 20 mg
Study 1

Mean Baseline
SBP/DBP:

153.1/99.5 mmHg
Trough Sitting Diastolic BP (mmHg)
LS Mean Changea -2.9 -8.5 -8.4 -9.2 -9.8
p-valuea,b <0.001 <0.001 <0.001 <0.001
Trough Sitting Systolic BP (mmHg)
LS Mean Changea +2.2 -6.3 -5.9 -7.0 -6.5
p-valuea,b <0.001 <0.001 <0.001 <0.001
Study 2

Mean Baseline
SBP/DBP:

151.3/99.0 mmHg
Trough Sitting Diastolic BP (mmHg)
LS Mean Changea -4.6 -- -7.8 -8.5 -9.1
p-valuea,b -- 0.002 <0.001 <0.001
Trough Sitting Systolic BP (mmHg)
LS Mean Changea -0.4 -- -4.2 -3.5 -6.7
p-valuea,b -- 0.035NS 0.086NS <0.001
Study 3

SBP/DBP:
Mean Baseline
SBP/DBP:

151.3/99.0 mmHg
Trough Sitting Diastolic BP (mmHg)
LS Mean Changea -2.8 -5.7 -7.7 -8.9 -8.9
p-valuea,b 0.084NS 0.004 <0.001 <0.001
Trough Sitting Systolic BP (mmHg)
LS Mean Changea -0.4 -1.9 -3.0 -6.4 -7.6
p-valuea,b 0.611NS 0.383NS 0.044 0.005

a From an ANCOVA with factor treatment and covariates (baseline blood pressure, metabolism rate, diabetes status, gender, race, and age group).
bBased on pairwise comparison of treatment vs. placebo
LS=least-squares, NS=not significant

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 mg.

Twenty-eight days after cessation of BYSTOLIC treatment, blood pressure returned toward baseline, without however reaching that level. There was no evidence of rebound hypertension after abrupt cessation of therapy.

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 vs. 24.7% for placebo (all p≤0.001). The response rates in Study 2 were 49.3%, 66.0%, 66.8% and 68.9% in the placebo, BYSTOLIC 5 mg, 10 mg, and 20 mg groups, respectively (all p≤0.009). In Study 3, the percentage 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).

Heart rate was assessed in all studies. In Study 1, mean seated trough heart rate changes were +0.2, -4.3, -6.5, -6.5 and -9.7 bpm for placebo, BYSTOLIC 2.5 mg, 5 mg, 10 mg and 20 mg, respectively. The reductions observed with BYSTOLIC were significant as compared to placebo (p<0.001 for doses 2.5 to 20 mg). Heart rate was also significantly lowered for all doses in Study 2. Mean placebo-subtracted reductions ranged from -5.1 bpm to -7.2 bpm (p<0.001 vs. placebo). In Study 3, reductions in sitting heart rate at peak plasma drug level for BYSTOLIC 5 mg, 10 mg, and 20 mg were statistically significant (p<0.015).

Concomitant Therapy Studies

Diuretics

BYSTOLIC 1 mg, 5 mg and 10 mg and hydrochlorothiazide (HCTZ) 12.5 mg, and 25 mg were studied alone and in combination in a 12-week, randomized, double-blind, placebo-controlled, parallel-group, 12-arm factorial study including 240 patients with mild to moderate essential hypertension (mean baseline sitting SBP/DBP of 157.7/100.8 mmHg). The average age was 52 and 66% of the patients were male. The primary efficacy endpoint was the change from baseline in trough sitting DBP at Week 12. Blood pressure reductions by dose are presented in Table 3. The mean reductions in trough sitting DBP (primary efficacy endpoint) from baseline were statistically significant for all treatment arms (p<0.05 vs. baseline). All active treatment (monotherapy and combination) were also found to be more effective than placebo (p<0.05). No statistical analysis for comparison vs. placebo was performed for the secondary endpoint, trough sitting SBP.

Table 3: Summary of Mean Changes from Baseline in Trough Sitting Blood Pressure (SBP/DBP) (mmHg) for Patients Receiving BYSTOLIC, HCTZ, or BYSTOLIC/HCTZ in Combination
BYSTOLIC HCTZ
0 mg 12.5 mg 25 mg
0 mg -0.2 / -1.4 -11.2 / -4.6 -15.0 / -5.8
1 mg -6.5 / -5.5 -14.1 / -9.4 -19.4 / -10.3
5 mg -16.7 / -8.5 -16.0 / -9.9 -17.9 / -12.4
10 mg -17.6 / -13.8 -21.9 / -12.6 -29.0 / -15.3

N=20 patients/arm; within treatment comparisons to baseline were statistically significant for all treatment groups with p-value ≤0.003.
DBP: all pairwise comparisons vs. placebo were statistically significant with p-value <0.05
SBP: comparisons vs. placebo not assessed

Significant reductions in trough sitting DBP from baseline were observed as early as week two. Significant increases in the percentage of patients who responded to treatment were obtained with BYSTOLIC in combination with HCTZ, as compared to placebo (p<0.02). The response rates were 60%, 85%, 80% and 85% for the 5 mg/12.5 mg, 5 mg/25 mg, 10 mg/12.5 mg and 10 mg/25 mg BYSTOLIC/HCTZ combinations, respectively, and 15% for placebo. BYSTOLIC 5 mg and 10 mg in combination with HCTZ, 12.5 mg and 25 mg, provided heart rate reductions of -3 bpm to -10 bpm (p<0.05 vs. placebo) for all combination groups excluding BYSTOLIC 5 mg/HCTZ 25 mg.

Angiotensin Converting Enzyme (ACE) Inhibitors

BYSTOLIC 5 mg to 20 mg and lisinopril 10 mg to 40 mg were studied alone and in combination in a 12-week, multi-centre, randomized, double-blind, placebo- and active-controlled, parallel- group, 4-arm study including 656 patients with stage 2 diastolic hypertension (DBP ≥ 100 mm Hg). The mean baseline sitting SBP/DBP was 163.8/104.4 mmHg. The mean age of patients was 49.3 years, 57.8% were males, 14.9% were diabetic and 38.0% were non-Caucasian. The primary efficacy endpoint was the change from baseline in trough sitting DBP at Week 6 and the secondary efficacy endpoint was the change from baseline in trough sitting SBP at Week 6.

Blood pressure reductions by treatment group are presented in Table 4. The combination of BYSTOLIC and lisinopril was significantly more effective in lowering DBP than BYSTOLIC or lisinopril alone (p≤0.001). All active treatments (combination and monotherapy) were more effective than placebo (p≤0.0013). The combination treatment group showed a statistically significant greater reduction in DBP compared with the average effect of BYSTOLIC and lisinopril (p<0.0001). Significant reductions in trough sitting DBP from baseline were observed as early as two weeks of treatment.

Table 4: Analysis of Sitting Diastolic and Systolic Blood Pressure (mmHg) at Trough at Week 6
Placebo
(N=93)
BYSTOLIC
+ Lisinopril
(N=189)
BYSTOLIC
(N=189)
Lisinopril
(N=189)
Trough Sitting Diastolic BP (mmHg)
Mean Baseline
DBP:
104.4 mmHg
Mean Change -8.0 -17.2 -13.3 -12.0
LSMD*a 9.0 -- 3.3 5.1
p-value 1a <0.0001 -- 0.0010 <0.0001
p-value 2b -- <0.0001 -- --
Trough Sitting Systolic BP (mmHg)
Mean Baseline
SBP:

163.8 mmHg
Mean Change -9.9 -19.2 -14.4 -16.1
LSMD*a 10.0 -- 3.5 3.2
p-value 1a <0.0001 -- 0.0470 0.0704
p-value 2b -- 0.0278 -- --

ANCOVA, analysis of covariance; LSMD, least squares mean difference
* Analysis was based on ANCOVA model with treatment group and study center as factors and baseline value as a covariate
a [*] comparing the combination group vs. placebo, the combination group vs. BYSTOLIC, and the combination group vs. lisinopril.
b [*] comparing the combination group vs. the average of BYSTOLIC and lisinopril.

The combination of BYSTOLIC and lisinopril was significantly more effective in lowering SBP than BYSTOLIC alone (p=0.0470). The combination showed a numerically greater reduction in SBP than lisinopril alone (p=0.0704). All active treatments (combination and monotherapy) were found to be more effective than placebo (p≤0.0033). The combination treatment group showed a statistically significant greater reduction in SBP compared with the average effect of BYSTOLIC and lisinopril (p=0.0278).

After 6 weeks of treatment, the response rate (BP < 140/90 mmHg or < 130/80 mmHg for diabetic patients) was significantly greater for patients treated with the combination of BYSTOLIC and lisinopril at 33.9%, compared to 21.6%, 21.7% and 7.5% for patients treated with BYSTOLIC monotherapy, lisinopril monotherapy or placebo respectively (all p≤0.0031).

Geriatrics (≥ 65 years of age)

Of the 2,016 patients in the placebo-controlled monotherapy studies, 375 patients were 65 years of age or older. No overall differences in efficacy or in the incidence of adverse events were observed between older and younger patients.

Detailed pharmacology

Nebivolol is a racemic mixture containing equal amounts of two enantiomers, d-nebivolol and l-nebivolol. It is a selective β1-adrenergic antagonist with vasodilating properties. The d- enantiomer provides selective β1-adrenergic receptor blockade, whereas l-nebivolol possesses vasodilating properties thought to be attributable to nitric oxide modulation via the L-arginine- nitric oxide pathway.

Preclinical pharmacology studies show that nebivolol binds to human cardiac β1-adrenergic receptors with high affinity (Ki = 0.7 nM). Nebivolol antagonizes β1-adrenergic receptor mediated responses in isolated tissues from guinea pigs and dogs and in rat heart cell cultures in vitro. Nebivolol also effectively inhibits various β1-adrenergic receptors responses in vivo in rodent, cat and dog models. Nebivolol retains β1-adrenergic receptor selectivity in a wide variety of these test systems. Nebivolol does not have relevant effects in other test systems, such as α-adrenergic and muscarinic receptor systems.

Nebivolol, dose-dependently, reduces blood pressure in spontaneously hypertensive rats following acute and repeated administration and does not produce an increase in peripheral vascular resistance or decrease in cardiac output in anesthetized dogs, but at peak after 10 mg/kg orally, a 38% decrease of cardiac output was observed as compared to baseline in awake dogs.

Mechanistic studies in isolated coronary arteries showed that nebivolol and, more potently, l- nebivolol induce the release of nitric oxide from vascular endothelium in vitro. In both pre- clinical and clinical studies, nebivolol-induced vasodilation can be blocked by inhibitors of nitric oxide synthase. This property appears to contribute to the pharmacological profile of nebivolol.

In addition, nebivolol protected myocardial cells from calcium overload and preserved cardiac function in ischemic myocardium. Nebivolol demonstrated antiarrhythmic activity in vivo, suppressing experimentally induced arrhythmias produced by ischemia and reperfusion (rat and dog) as well as those induced by aconitine (rat) and by ouabain (guinea pig), but it also increased atrial conduction time thus leading to increased PQ and PR intervals and significantly decreased HR. Moreover, nebivolol increased the ventricular fibrillation threshold in anesthetized open- chest guinea pigs and dogs, but it increased AV blocks and branch bundle block occurence.

Nebivolol seems to have low affinity for α-adrenoreceptors in in vitro receptor binding assays (Ki ≥ 295 nM) at target therapeutic concentrations, and had apparently little activity at α1- adrenergic receptors in in vivo and ex vivo functional assays (IC50 ≥ 1.4 μM). Nebivolol was found to lack appreciable activity or to be inactive on responses mediated by serotonin, histamine, dopamine, acetylcholine (muscarinic and nicotinic), angiotensin II and bradykinin receptor activation, but bound at higher concentrations to β2-adrenergic, serotonin (5HT1A) and dopamine receptors (D4.4) (Ki = 4.5 nM, 15.1 nM, 56.2 nM respectively). In addition, receptor binding or transactivation assays also demonstrated that nebivolol did not bind to opioid, GABAergic and various hormone receptors, such as the estrogen receptor. Therefore at therapeutic plasma concentrations, nebivolol has little activity at other receptors that would produce vasodilation except for β2-adrenergic, serotonin (5HT1A) and dopamine receptors (D4.4).

Nebivolol is predominantly metabolized in humans and in animals by CYP2D6 (75%) and to a lesser extent by CYP3A4 (16-20%) [see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics]. In vitro studies have demonstrated that nebivolol has an inhibitory effect on cytochrome P450 isozymes including CYP3A4/5 (Ki: 13 μM), CYP2A6 (Ki: 49 μM), CYP2C8 (Ki: 55 μM), CYP2B6 (Ki: 92 μM), CYP1A2 (Ki: 92 μM), CYP2C9 (Ki: 110 μM), CYP2C19 (Ki: 130 μM) and CYP4A9/11 (Ki: 180 μM). In addition, nebivolol was also found to significantly increase (by 50%) the activity of CYP2E1. Given the Cmax/Ki ratios, it is unlikely that these inhibitory effects in vitro would translate into clinically meaningful inhibitory effects.

Toxicology

Acute Toxicity

Single-dose study findings revealed that nebivolol has a low order of acute toxicity by the oral route. The highest non-lethal dose levels tested were approximately 80 and >260 times the maximum recommended human dose (MRHD) for the rat and dog, respectively, based on body surface area. Single-dose studies at high doses of nebivolol showed that female rats were more sensitive than male rats, while there were no sex differences with mice or dogs.

Long Term Toxicity

Repeated dose oral toxicology studies of nebivolol were conducted in mice for 3 months and in rats and dogs for 3, 6 and 12 months duration. Target organs for repeat dose studies in rodents were spleen, adrenals, gonads, lungs, and lymph nodes, with decreases in hemoglobin, hematocrit, red blood cells, cholesterol, triglycerides, and phospholipids and an increase in potassium. The no-observed-adverse-effect level (NOAEL) for these effects in the one-year rat study was 5 mg/kg/day. The AUC values for 5 mg/kg/day were 5.6- and 7.2- (extensive metabolizers) and 0.17- and 0.23- (poor metabolizers) times the maximum anticipated human exposure for a 20 mg clinical dose for male and female rats, respectively. The target organs for nebivolol in dogs were spleen and heart. The changes in ECG reported in dog studies included the prolongation of QTc and QRS intervals at ≥20 and 40 mg/kg in the 6- and 12-month studies, respectively. A lengthening of the PQ interval was evident at ≥20 and ≥10 mg/kg, respectively. These doses were at least ≥17 times the MRHD. The NOAEL for the ECG changes in the 12-month study was 2.5 mg/kg, which corresponds to ∼2 times the MRHD based on body surface area.

Carcinogenesis

In a two-year study of nebivolol in mice, a statistically significant increase in the incidence of testicular Leydig cell hyperplasia and adenomas was observed in male mice at 40 mg/kg/day (10 times the MRHD based on body surface area), but not at 10 mg/kg/day. This finding was unique to mice (i.e., not seen in rats or dogs). Relative exposures for male and female mice, respectively, at 40 mg/kg/day were 343- and 310- (extensive metabolizers) and 11- and 10- (poor metabolizers) times the maximum anticipated human exposure for a 20 mg clinical dose. At the 10 mg/kg/day dose, which did not show an increase in Leydig cell tumors, relative exposures were 37- (extensive metabolizers) and 1- (poor metabolizers) times the maximum anticipated human exposure for a 20 mg clinical dose. Development of testicular Leydig cell hyperplasia and adenomas were associated with an increase in serum LH level secondary to nebivolol-related decrease in serum testosterone. No evidence of a tumorigenic effect was observed in a 24-month study in Wistar rats receiving doses of nebivolol up to 40 mg/kg/day; relative exposures for males and females, respectively, at 40 mg/kg/day were 271- and 150- (extensive metabolizers) and 8- and 4- (poor metabolizers) times the maximum anticipated human exposure for a 20 mg clinical dose.

Mutagenesis

Nebivolol was not genotoxic when tested in a battery of assays (Ames, in vitro mouse lymphoma TK+/-, in vitro human peripheral lymphocyte chromosome aberration, in vivo Drosophila melanogaster sex-linked recessive lethal, and in vivo mouse bone marrow micronucleus tests).

Reproduction and Development

Effects on spermatogenesis were seen in male rats and mice at ≥40 mg/kg/day (20 and 10 times the MRHD, respectively, based on body surface area). For rats the effects on spermatogenesis were not reversed and may have worsened during a four-week recovery period. The effects of nebivolol on sperm in mice, however, were partially reversible.

Decreased pup body weights occurred at 1.25 and 2.5 mg/kg in rats, when exposed during the perinatal period (late gestation, parturition and lactation). At 5 mg/kg and higher doses (2.5 times the MRHD based on body surface area), prolonged gestation, dystocia and reduced maternal care were produced with corresponding increases in late fetal deaths and stillbirths and decreased birth weight, live litter size and pup survival. Insufficient numbers of pups survived at 5 mg/kg to evaluate the offspring for reproductive performance.

In studies in which pregnant rats were given nebivolol during organogenesis, reduced fetal body weights were observed at maternally toxic doses of 20 and 40 mg/kg/day (10 and 20 times the MRHD based on body surface area), and small reversible delays in sternal and thoracic ossification associated with the reduced fetal body weights and a small increase in resorption occurred at 40 mg/kg/day (20 times the MRHD based on body surface area). No adverse effects on embryo-fetal viability, sex, weight or morphology were observed in studies in which nebivolol was given to pregnant rabbits at doses as high as 20 mg/kg/day (20 times the MRHD based on body surface area).