Bystolic: Indications, Dosage, Precautions, Adverse Effects
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Bystolic - Product 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

Summary product information

Route of Administration Dosage Form /Strength Nonmedicinal Ingredients
Oral Tablet
2.5 mg,
5 mg,
10 mg,
20 mg
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

Indications and clinical use

BYSTOLIC (nebivolol tablets) is indicated for the treatment of mild to moderate essential hypertension.

BYSTOLIC may be used alone or concomitantly with thiazide diuretics or angiotensin converting enzyme (ACE) inhibitors [see DRUG INTERACTIONS, DOSAGE AND ADMINISTRATION and CLINICAL TRIALS].

BYSTOLIC is not recommended for the emergency treatment of hypertensive crises.

Geriatrics (≥ 65 years of age):

No dosage adjustment is required in geriatric patients. Of the total number of patients receiving BYSTOLIC in clinical studies, 436 (18%) were 65 years of age or older. No differences in efficacy or safety of BYSTOLIC were observed between older and younger patients [see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions].

Pediatrics (< 18 years of age):

The safety and efficacy of BYSTOLIC in pediatric patients have not been established and therefore use in children is not recommended.

Contraindications

  • Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.
  • Severe bradycardia (generally <50 bpm prior to start of therapy)
  • Patients with cardiogenic shock
  • Decompensated heart failure
  • Second or third degree atrioventricular (AV) block
  • Sick sinus syndrome or sinoatrial block
  • Patients with severe hepatic impairment (Child-Pugh Score >B)
  • Severe peripheral arterial circulatory disorders

Warnings and precautions

General

Effects on ability to drive and use machines

No studies on the effects of BYSTOLIC (nebivolol tablets) on the ability to drive and use machines have been performed. Some adverse effects of a reduction in blood pressure, such as lightheadedness, dizziness or syncope may impair the patient’s ability to concentrate and react and, therefore, constitute a risk in situations where these abilities are of particular importance.

Use with CYP2D6 Inhibitor

Nebivolol exposure increases significantly with inhibition of CYP2D6 [see DRUG INTERACTIONS]. The dose of BYSTOLIC may need to be reduced.

Cardiovascular

Abrupt Cessation of Therapy

Do not abruptly discontinue BYSTOLIC therapy in patients with coronary artery disease. Severe exacerbation of angina, myocardial infarction and ventricular arrhythmias have been reported in patients with coronary artery disease following the abrupt discontinuation of therapy with β-blockers. Myocardial infarction and ventricular arrhythmias may occur with or without preceding exacerbation of angina pectoris. Caution patients without overt coronary artery disease against interruption or abrupt discontinuation of therapy. As with other β-blockers, when discontinuation of BYSTOLIC is planned, the dosage should be gradually reduced over a period of about two weeks and the patient should be carefully observed and advised to limit physical activity to a minimum. The same frequency of administration should be maintained. In situations of greater urgency, BYSTOLIC should be discontinued stepwise over a shorter time and under closer observation.

If the angina worsens or acute coronary insufficiency develops, re-start BYSTOLIC promptly, at least temporarily.

Decreased Heart Rate and PR Interval Prolongation

Like other β1-blocking agents, BYSTOLIC causes a decrease in heart rate and PR interval prolongation [see ACTION AND CLINICAL PHARMACOLOGY, Electrocardiography]. Bradycardia and atrioventricular block have been reported with the use of BYSTOLIC [see ADVERSE REACTIONS]. Caution should be observed in patients with first degree atrioventricular block, conduction disorders, a history of syncope or arrhythmia, angina, or ischemic heart disease. 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 outweights the potential risk [see DRUG INTERACTIONS].

Sinus Bradycardia

Severe sinus bradycardia may occur with the use of BYSTOLIC from unopposed vagal activity remaining after blockade of β1-adrenergic receptors; in such cases, dosage should be reduced.

Peripheral Artery Disorders

β-blockers may aggravate the symptoms of peripheral arterial circulatory disorders, mainly due to their blood pressure lowering effect. Caution should be exercised in individuals with such disorders.

Non-dihydropyridine Calcium Channel Blockers

The combination of non-dihydropyridine calcium channel blockers of the verapamil and diltiazem type and β-blockers warrants caution since additive effects on myocardial contractility, heart rate and AV conduction have been observed. Close medical supervision is recommended [see DRUG INTERACTIONS].

Endocrine and Metabolism

Diabetes and Hypoglycemia

BYSTOLIC should be used with caution in patients subject to hypoglycemic episodes since β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia.

Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. BYSTOLIC is β1-selective; however, it is not known whether BYSTOLIC has these effects. Patients subject to spontaneous hypoglycemia and diabetic patients receiving insulin or oral hypoglycemic agents should be advised about these possibilities.

Thyrotoxicosis

In patients with thyrotoxicosis, possible deleterious effects from long-term use of BYSTOLIC have not been adequately appraised. β-blockers may mask clinical signs of hyperthyroidism, such as tachycardia and give a false impression of improvement. Therefore, these patients should be carefully monitored for thyroid function. Abrupt withdrawal of β-blockers may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm.

Pheochromocytoma

BYSTOLIC should be used with caution and only after pretreatment with α-receptor blockers in patients with known or suspected pheochromocytoma.

Hepatic/Biliary/Pancreatic

Impaired Hepatic Function

Metabolism of nebivolol is decreased in patients with moderate hepatic impairment. BYSTOLIC has not been studied in patients with severe hepatic impairment [see CONTRAINDICATIONS, DOSAGE AND ADMINISTRATION, and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions].

Immune

Risk of Anaphylactic Reactions

While taking β-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenge.There may be increased difficulty in treating an allergic-type reaction in patients on β-blockers since these patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. While larger doses of epinephrine may be needed to overcome the bronchospasm,these doses can be associated with excessive α-adrenergic stimulation with consequent hypertension, reflex bradycardia and heart block and possible potentiation of bronchospasm.

Peri-Operative Considerations

Anesthesia and Major Surgery

It is not advisable to withdraw β-adrenoceptor blocking drugs prior to surgery in the majority of patients. However, care should be taken when using BYSTOLIC with anesthetic agents that depress the myocardial function, such as ether, cyclopropane, and trichloroethylene [see DRUG INTERACTIONS]. Some patients receiving β-adrenoceptor blocking drugs have been subject to protracted severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has been reported.

In emergency surgery, the β-blocking effects of BYSTOLIC can be reversed by β-agonists, e.g., dobutamine or isoproterenol.

If β-blocking therapy is withdrawn prior to major surgery, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

Renal

Impaired Renal Function

Renal clearance of nebivolol is decreased in patients with severe renal impairment. BYSTOLIC has not been studied in patients receiving dialysis and is therefore not recommended for use in this patient population [see DOSAGE AND ADMINISTRATION, and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions].

Respiratory

Bronchospastic Disease

In general, patients with bronchospastic pulmonary disease should not receive β-blockers. However, because of its relative β1-selectivity, BYSTOLIC may be used cautiously in patients with bronchospastic disease who do not respond to, or who cannot tolerate other antihypertensive treatment. Since β1-selectivity is not absolute, the lowest possible dose of BYSTOLIC should be employed, a β2-agonist (bronchodilator) should be made available, and the patient should be monitored closely. In patients already on bronchodilator therapy the dose may have to be increased.

Skin

Oculomucocutaneous Syndrome

Various skin rashes and conjunctival xerosis have been reported with β-blockers, including BYSTOLIC. A severe syndrome (oculomucocutaneous syndrome) whose signs include conjunctivitis sicca and psoriasiform rashes, otitis, and sclerosing serositis has occurred with the

chronic use of one β-adrenergic blocking agent (practolol). This syndrome has not been observed with BYSTOLIC. However, physicians should be alert to the possibility of such reactions and should discontinue treatment in the event that they occur.

Special Populations

Pregnant Women

No studies of nebivolol were conducted in pregnant women. Use BYSTOLIC during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus, taking into account that toxicity was seen in animals.

Animal Data: In rats, maternal toxicity included mortality, ptosis and decreased body weights at ≥10 mg/kg (∼5 times the maximum recommended human dose (MRHD) on body surface area basis). Reprotoxicity included low prolonged gestation with dystocia, increased duration of

gestation and decreased nursing behaviour at doses ≥5 mg/kg (∼2.5 times the MRHD on body surface area basis). These effects were associated with increased fetal deaths and stillborn pups, and decreased birth weight, live litter size and pup survival rate.

Nebivolol or its metabolites crossed the placental barrier in pregnant rats. When nebivolol was administered to pregnant rats, developmental abnormalities including split thoracic vertebrae changes in sternebrae and ureter dilatation occurred at 40 mg/kg (∼20 times the MRHD on body surface area basis).

Nursing Women

It is not known whether this drug is excreted in human milk, but nebivolol and its metabolites have been found in the milk of lactating rats. Because of the potential for β- blockers to produce serious adverse reactions in nursing infants, especially bradycardia, BYSTOLIC is not recommended in nursing women.

Pediatrics (< 18 years of age)

Safety and efficacy in pediatric patients have not been established and therefore use in children is not recommended.

Adverse reactions

Adverse Drug Reaction Overview

BYSTOLIC (nebivolol tablets) has been evaluated for safety in more than 7,100 patients with hypertension with a clinical trial exposure to BYSTOLIC in approximately 5,400 patients. Patients received BYSTOLIC for up to 36 months, with over 1,000 patients treated for at least 6 months, and approximately 500 patients for more than one year.

In placebo-controlled monotherapy trials, the most common adverse events (≥ 2% of patients) observed with BYSTOLIC were headache (7.1%), fatigue (3.6%), nasopharyngitis (3.1%), dizziness (2.9%), diarrhea (2.5%), and upper respiratory tract infections (2.1%). BYSTOLIC was well tolerated and adverse events have generally been mild to moderate in intensity.

In placebo-controlled monotherapy trials, discontinuation of therapy due to adverse events was reported in 2.6% of patients treated with BYSTOLIC (47/1811), and in 2.0% of patients given placebo (4/205). The most common events leading to discontinuation are headache (0.2%), nausea (0.2%), bradycardia (0.2%), myocardial infarction (0.2%), orthostatic hypotension (0.1%), dyspnea (0.1%), and chest pain (0.1%) for patients who received BYSTOLIC.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

In three multi-center, randomized, parallel-group, double-blind, placebo-controlled monotherapy trials, 1,811 hypertensive patients were treated over 12 weeks with a BYSTOLIC dose ranging from 1.25 mg to 40 mg, and 205 patients were given placebo. The median exposure to treatment in these three trials was 85-days.

Table 1: Number (%) of Patients with Adverse Events (Incidence ≥1% in any BYSTOLIC group) by Preferred Term - Placebo-Controlled, 12-Week Monotherapy Studies (Pooled Safety Population)
System Organ Class/
Preferred Term
Placebo
(n=205)
BYSTOLIC
2.5 mg
(n=131)
BYSTOLIC
5 mg
(n=459)
BYSTOLIC
10 mg
(n=461)
BYSTOLIC
20 mg
(n=460)
Cardiac Disorders
Bradycardia/Sinus
Bradycardia
1 (0.5%)03 (0.7%)3 (0.7%)10 (2.2%)
Palpitations02 (1.5%)2 (0.4%)4 (0.9%)1 (0.2%)
Eye Disorders
Vision blurred02 (1.5%)2 (0.4%)3 (0.7%)3 (0.7%)
Gastrointestinal Disorders
Diarrhea4 (2.0%)2 (1.5%)11 (2.4%)9 (2.0%)15 (3.3%)
Nausea1 (0.5%)3 (2.3%)3 (0.7%)13 (2.8%)10 (2.2%)
Constipation5 (2.4%)1 (0.8%)2 (0.4%)5 (1.1%)3 (0.7%)
Dry mouth02 (1.5%)3 (0.7%)3 (0.7%)1 (0.2%)
Dyspepsia3 (1.5%)1 (0.8%)5 (1.1%)5 (1.1%)4 (0.9%)
General Disorders and Administration Site Conditions
Fatigue3 (1.5%)6 (4.6%)10 (2.2%)11 (2.4%)27 (5.9%)
Chest Pain02 (1.5%)2 (0.4%)5 (1.1%)8 (1.7%)
Edema02 (1.5%)001 (0.2%)
Edema Peripheral1 (0.5%)1 (0.8%)4 (0.9%)6 (1.3%)2 (0.4%)
Pain001 (0.2%)1 (0.2%)5 (1.1%)
Infections and Infestation
Nasopharyngitis9 (4.4%)5 (3.8%)17 (3.7%)10 (2.2%)17 (3.7%)
Upper Respiratory Tract
Infection
5 (2.4%)2 (1.5%)11 (2.4%)6 (1.3%)12 (2.6%)
Urinary Tract Infection2 (1.0%)2 (1.5%)9 (2.0%)2 (0.4%)7 (1.5%)
Sinusitis2 (1.0%)06 (1.3%)7 (1.5%)5 (1.1%)
Influenza1 (0.5%)06 (1.3%)2 (0.4%)6 (1.3%)
Bronchitis1 (0.5%)04 (0.9%)4 (0.9%)5 (1.1%)
Investigations
C-Reactive Protein
Increased
1 (0.5%)5 (3.8%)3 (0.7%)4 (0.9%)5 (1.1%)
Blood Triglycerides
Increased
3 (1.5%)1 (0.8%)1 (0.2%)9 (2.0%)3 (0.7%)
Low Density Lipoprotein
Increased
1 (0.5%)2 (1.5%)2 (0.4%)1 (0.2%)1 (0.2%)
Musculoskeletal and Connective Tissue Disorders
Arthralgia3 (1.5%)3 (2.3%)6 (1.3%)7 (1.5%)4 (0.9%)
Back Pain2 (1.0%)1 (0.8%)2 (0.4%)7 (1.5%)9 (2.0%)
Pain In Limb1 (0.5%)1 (0.8%)5 (1.1%)2 (0.4%)3 (0.7%)
Nervous System Disorders
Headache12 (5.9%)8 (6.1%)41 (8.9%)28 (6.1%)28 (6.1%)
Dizziness4 (2.0%)4 (3.1%)7 (1.5%)12 (2.6%)19 (4.1%)
Carpal Tunnel Syndrome02 (1.5%)000
Psychiatric Disorders
Insomnia1 (0.5%)3 (2.3%)3 (0.7%)4 (0.9%)9 (2.0%)
Respiratory, Thoracic and Mediastinal Disorders
Cough2 (1.0%)3 (2.3%)5 (1.1%)7 (1.5%)3 (0.7%)
Sinus Congestion03 (2.3%)4 (0.9%)4 (0.9%)1 (0.2%)
Dyspnea1 (0.5%)01 (0.2%)5 (1.1%)7 (1.5%)
Pharyngolaryngeal Pain01 (0.8%)1 (0.2%)3 (0.7%)5 (1.1%)
Skin and Subcutaneous Tissue Disorders
Rash03 (2.3%)05 (1.1%)4 (0.9%)

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Adverse events reported in the placebo-controlled studies with incidence rates of less than <1% and at a higher frequency than placebo-treated patients are listed below.

Blood and Lymphatic System Disorders: anemia; leukopenia; lymphadenopathy

Cardiac Disorders: myocardial infarction: myocardial ischemia; angina pectoris; atrioventricular block first degree; cardiac failure congestive; extrasystoles; tachycardia; withdrawal arrhythmia

Ear And Labyrinth Disorders: deafness; ear pain; hearing impaired; vertigo

Eye Disorders: conjunctival haemorrhage; conjunctivitis; eye pain; glaucoma; vision disturbances

Gastrointestinal Disorders: abdominal pain; flatulence; gastro-oesophageal reflux disease; oral mucosal lesions; toothache; vomiting

General Disorders and Administration Site Conditions: influenza-like illness; pyrexia; weakness Immune System Disorders: hypersensitivity

Infections and Infestations: fungal infection; gastroenteritis; hepatitis; localized infection; lower respiratory tract infection

Investigations: alanine aminotransferase increased; aspartate aminotransferase increased; blood alkaline phosphatase increased; blood glucose increased; blood uric acid increased; cardiac murmur; haematocrit/hemoglobin decreased; high density lipoprotein decreased; weight increased

Metabolism and Nutrition Disorders: diabetes mellitus; gout; hypercholesterolaemia; hyperkalaemia; hyperlipidaemia

Musculoskeletal and Connective Tissue Disorders: arthritis; muscle cramps; muscle weakness; myalgia

Nervous System Disorders: burning sensation; cerebral haemorrhage; hypoaesthesia; memory impairment; migraines; paraesthesia; transient ischemic attack

Psychiatric Disorders: anxiety; decreased libido; depression; nightmare

Renal and Urinary Disorders: haematuria; proteinuria; urinary frequency increased

Reproductive System and Breast Disorders: dysmenorrhoea; erectile dysfunction; galactorrhoea

Respiratory, Thoracic and Mediastinal Disorders: epistaxis; nasal congestion

Skin and Subcutaneous Tissue Disorders: angioneurotic oedema; contusion; pruritus; sweating

Vascular Disorders: deep vein thrombosis; flushing; hypotension; intermittent claudication; orthostatic hypotension; phlebitis

Abnormal Hematologic and Clinical Chemistry Findings

In placebo-controlled monotherapy studies, patients were reported to have laboratory abnormalities of clinical significance for the clinical laboratory parameters shown in Table 2.

Table 2: Number of Patients with Abnormal Laboratory Results of Clinical Significance Occurring After First Dose of Treatment in Placebo-Controlled, 12-Week Monotherapy Studies (Pooled Safety Population)
Parameters (values of clinical significance)Placebo
(n=205)
Nebivolol
2.5 mg
(n=131)
5 mg
(n=459)
10 mg
(n=461)
20 mg
(n=460)
Chemistry
AST (≥3 X ULN)003 (0.7%)2 (0.4%)4 (0.9%)
Blood urea nitrogen (BUN) (≥10.7 mmol/L)01 (0.8%)2 (0.4%)3 (0.7%)2 (0.4%)
Uric acid (Male ≥625 μmol/L; Female ≥506 μmol/L)002 (0.4%)01 (0.2%)
Hematology
Eosinophils (≥10%)2 (1.0%)1 (0.8%)8 (1.7%)3 (0.7%)5 (1.1%)
Hematocrit (Male ≤37%; Female ≤32%)3 (1.5%)2 (1.5%)4 (0.9%)5 (1.1%)9 (2.0%)
Hemoglobin (Male ≤7.1 mmol/L; Female ≤5.9 mmol/L)1 (0.5%)1 (0.8%)2 (0.4%)1 (0.2%)4 (0.9%)
Urinalysis
Protein (increase ≥2units)2 (1.0%)04 (0.9%)1 (0.2%)5 (1.1%)

AST, aspartate aminotransferase; Normal ranges: AST: 0-42 U/L; BUN: 2.5-8.9 mmol/L; uric acid: 149-446 μmol/L; hematocrit: 35-46%; hemoglobin: 7.4-9.7 mmol/L.

The clinical laboratory parameters for which patients were reported to experience shifts from normal at baseline to the out-of-normal range during nebivolol treatment phase with a higher frequency than in placebo-treated patients are listed below.

Triglycerides: Shifts from normal to values above the upper limit of normal (2.2 mmol/L) were reported in 11.5%, 14.3%, 17.0% and 16.3% of patients treated with nebivolol 2.5 mg, 5 mg, 10 mg and 20 mg, respectively, as compared to 10.5% with placebo.

HDL cholesterol: Shifts from normal to values below the lower limit of normal (0.9 mmol/L) were reported in 1.1%, 3.0%, 4.4% and 4.1% of patients treated with nebivolol 2.5 mg, 5 mg, 10 mg and 20 mg, respectively, as compared to 1.3% with placebo.

Post-Market Adverse Drug Reactions

Other adverse events reported in post-marketing use include: abnormal hepatic function (including increased AST, ALT and bilirubin), acute pulmonary edema, acute renal failure, angioedema, atrioventricular block (both second and third degree), bronchospasm, hepatitis, hypersensitivity (including urticaria and allergic vasculitis), peripheral ischemia/claudication, pruritus, psoriasis, Raynaud’s phenomenon, somnolence, suicidal ideation, syncope, thrombocytopenia and various rash and skin disorders. Few cases, some fatal, of cardiac arrest have been reported shortly after initiation of nebivolol therapy; causality has not been established.

Drug interactions

Overview

Nebivolol is a substrate for CYP2D6. Inhibitors, inducers or substrates of CYP2D6 alter the exposure of nebivolol. When BYSTOLIC (nebivolol tablets) is co-administered with an inhibitor, inducer, or substrate of this enzyme, the dose of BYSTOLIC may need to be adjusted.

Based on in vitro results, the potential of nebivolol to have a clinically meaningful inhibitory effect on other cytochrome P450 isozymes is unlikely (i.e. CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, CYP3A4/5 and CYP4A9/11) [see DETAILED PHARMACOLOGY].

Like other β1-blocking agents, BYSTOLIC causes a decrease in heart rate and PR interval prolongation [see WARNINGS AND PRECAUTIONS, Cardiovascular and ACTION AND CLINICAL PHARMACOLOGY, Electrocardiography]. The concomitant use of BYSTOLIC with other drugs that lower heart rate and/or prolong the PR interval, including, but not limited to, antiarrhythmics, non-dihydropyridine calcium channel blockers, digitalis glycosides,α2-adrenoceptor agonists, cholinesterase inhibitors, sphingosine-1 phosphate receptor modulators (e.g. fingolimod), and some of the HIV protease inhibitors, should be carefully considered to determine whether the therapeutic benefit outweighs the potential risk.

Drug-Drug Interactions

Table 3: Established or Potential Drug-Drug Interactions
Common NameReferenceEffectClinical Comments
α2-adrenergic receptor
agonists (e.g.,
clonidine, guanethidine)
TThe added β-blocking action of BYSTOLIC may produce excessive reduction of sympathetic activity.Closely monitor patients concomitantly treated with an α2-agonist. In patients who are receiving BYSTOLIC and clonidine, discontinue BYSTOLIC for several days before the gradual tapering of clonidine.
Angiotensin
converting enzyme
(ACE) inhibitors
CTNo pharmacokinetic interaction was seen when nebivolol was co-administered with ramipril.
The risk of bradycardia/sinus bradycardia was slightly increased when nebivolol was given concomitantly with lisinopril compared to administration of nebivolol alone.
More patients showed a shift in total cholesterol and low density lipoprotein cholesterol (LDL-C) from normal to high range when treated concomitantly with nebivolol and lisinopril compared to patients treated with each of these drugs alone.
Use caution when BYSTOLIC is co-administered with ACE inhibitors.
Anesthetic agents
(e.g., ether,
cyclopropane and
trichloroethylene)
TConcomitant use with anesthetic agents which depress myocardial function can exacerbate myocardial depression.Monitor patients ECG and blood pressure closely when BYSTOLIC is co-administered with anesthetic agents.
Antiarrhythmics
(e.g.,amiodarone,
disopyramide,flecainide)
C, TBYSTOLIC can exacerbate the effects of myocardial depressants or inhibitors of atrioventricular conduction.Monitor patients closely when BYSTOLIC is co- administered with antiarrhythmics. Dose adjustment may be needed.
Antidiabetic agents
(e.g., insulin and
oral hypoglycemic agents)
C, Tβ-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia.Use caution when BYSTOLIC is co- administered in patients subject to hypoglycemic episodes.
Calcium channel
blockers (particularly
verapamil and
diltiazem, etc.)
C*, TBYSTOLIC can exacerbate the effects of myocardial depressants or inhibitors of atrioventricular conduction.
Cases of serious effects (e.g. bradycardia, syncope, requiring hospitalization) in patients treated with nebivolol and verapamil, diltiazem were reported.
Monitor patients closely when BYSTOLIC is co-administered with non-dihydropyridine calcium channel blockers.
CYP2D6 inducers
(e.g.,
dexamethasone,
rifampin)
TInhibitors or substrates of CYP2D6 increase the exposure of nebivolol.
Fluoxetine, a CYP2D6 inhibitor, administered at 20 mg per day for 21 days prior to a single 10 mg dose of BYSTOLIC to 10 healthy adults, led to an 8-fold increase in the AUC and 3-fold increase in Cmax for d-nebivolol.
Use caution when BYSTOLIC is co-administered with CYP2D6 inhibitors/substrates.
The dose of BYSTOLIC may need to be reduced.
CYP2D6 inhibitors
(e.g., fluoxetine,
quinidine, paroxetine,
propafenone and
cimetidine) and substrates (e.g., thioridazine, venlafaxine)
CT, CInhibitors or substrates of CYP2D6 increas the exposure of nebivolol.
Fluoxetine, a CYP2D6 inhibitor,administered at 20 mg per day for 21 days prior to a single 10 mg dose of BYSTOLIC to 10 healthy adults, led to an 8-fold increase in the AUC and 3-fold increase in Cmax for d-nebivolol.
Use caution when BYSTOLIC is co-administered with CYP2D6 inhibitors/substrates. The dose of BYSTOLIC may need to be reduced.
DigoxinT, C*Concomitant administration of BYSTOLIC and digoxin can exacerbate slowing atrioventricular conduction and heart rate.
Cases of bradycardia were reported with concomitant use.
Monitor patients closely when BYSTOLIC is co-administered with digoxin.
Diuretics:
hydrochlorothiazide,
furosemide,
spironolactone
CT, C*No pharmacokinetic interactions were observed in healthy adults between BYSTOLIC (10 mg daily for 10 days) and furosemide (40 mg single dose), hydrochlorothiazide (25 mg once daily for 10 days), or spironolactone (25 mg once daily for 10 days).
Cases of bradycardia, hypotension and loss of consciousness were reported with concomitant use.
Use caution when BYSTOLIC is co-administered with diuretics.
Histamine-2 Receptor AntagonistsCTThe pharmacokinetics of BYSTOLIC (5 mg single dose) were not affected by the co-administration of ranitidine (150 mg twice daily). Cimetidine (400 mg twice daily) causes a 23% increase in the plasma levels of d-nebivolol.No specific action required.
SildenafilCTThe co-administration of nebivolol and sildenafil decreased AUC and Cmax of sildenafil by 21 and 23% respectively. The effect on the Cmax and AUC for d-nebivolol was also small (<20%). Given that both agents modulate the nitric oxide pathway, vital signs were measured.Use caution when BYSTOLIC is co-administered with sildenafil.
When co-administered, the effects on pulse and blood pressure were approximately the sum of the effects of sildenafil and nebivolol.
ValsartanCTConcomitant administration of BYSTOLIC (20 mg once daily) and valsartan (320 mg once daily) in 30 healthy adult volunteers resulted in a 47% and 19% reduction in d-nebivolol Cmax and AUC, respectively.

C=Case Study, CT=Clinical Trial, I=In vitro, T=Theoretical, C* = Case Report from PSUR data

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

Drug-Food Interactions

Food does not significantly alter the pharmacokinetics of nebivolol. BYSTOLIC may be taken with or without food.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory testing have not been established.

Dosage and administration

Recommended Dose and Dosage Adjustment

In the treatment of mild to moderate essential hypertension, the dose of BYSTOLIC (nebivolol tablets) should be individualized to the needs of the patient.

For most patients, the recommended starting dose is 5 mg once daily, with or without food. For patients requiring further reduction in blood pressure, the dose can be increased at two-week intervals up to 20 mg once daily.

Once-daily dosing has shown to sustain efficacy over 24 hours. A more frequent dosing regimen is unlikely to be beneficial.

Concomitant use of ACE inhibitors

When BYSTOLIC is to be co-administered with an ACE inhibitor, the lowest dose of the added agent should be employed initially and if needed, can be then increased at two-week intervals up to the maximum recommended dose [see DRUG INTERACTIONS].

Renal Impairment

In patients with severe renal impairment (ClCr less than 30 mL/min) the recommended initial dose is 2.5 mg once daily; titrate up slowly if needed. BYSTOLIC has not been studied in patients receiving dialysis and is therefore not recommended for use in this patient population [see WARNINGS AND PRECAUTIONS and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions].

Hepatic Impairment

In patients with moderate hepatic impairment, the recommended initial dose is 2.5 mg once daily; titrate up slowly if needed. BYSTOLIC has not been studied in patients with severe hepatic impairment and therefore is contraindicated in that population [see CONTRAINDICATIONS, and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions].

Geriatric Patients

No dose adjustments are usually necessary for elderly patients.

CYP2D6 Polymorphism

No dose adjustments are necessary for patients who are CYP2D6 poor metabolizers. The clinical effect and safety profile observed in poor metabolizers were similar to those of extensive metabolizers [see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions].

Missed Dose

If patients miss a dose, they should wait until their next scheduled dose. Patients should not double their dose. BYSTOLIC should be taken once approximately every 24 hours.

Overdosage

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Symptoms:

In clinical trials and worldwide post-marketing experience there were reports of BYSTOLIC (nebivolol tablets) overdose. The most common signs and symptoms associated with BYSTOLIC overdosage are bradycardia and hypotension. Other important adverse reactions reported with BYSTOLIC overdose include heart failure, dizziness, hypoglycemia, fatigue and vomiting. Other adverse reactions associated with β-blocker overdose include bronchospasm and heart block.

The largest known ingestion of BYSTOLIC worldwide involved a patient who ingested up to 500 mg of BYSTOLIC along with several 100 mg tablets of acetylsalicylic acid in a suicide attempt. The patient experienced hyperhydrosis, pallor, depressed level of consciousness, hypokinesia, hypotension, sinus bradycardia, hypoglycemia, hypokalemia, respiratory failure and vomiting. The patient recovered.

Treatment:

Because of extensive drug binding to plasma proteins, hemodialysis is not expected to enhance nebivolol clearance. Administration of activated charcoal is not recommended as it has no effect on the pharmacokinetics of BYSTOLIC.

If overdose occurs, provide general supportive and specific symptomatic treatment. Based on

expected pharmacologic actions and recommendations for other β-blockers, consider the following general measures, including stopping BYSTOLIC, when clinically warranted:

Bradycardia: Administer IV atropine. If the response is inadequate, isoproterenol or another agent with positive chronotropic properties may be given cautiously. Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary.

Hypotension: Administer IV fluids and vasopressors. Intravenous glucagon may be useful.

Heart Block (second or third degree): Monitor and treat with isoproterenol infusion. Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary.

Congestive Heart Failure: Initiate therapy with digitalis glycoside and diuretics. In certain cases, consider the use of inotropic and vasodilating agents.

Bronchospasm: Administer bronchodilator therapy such as a short-acting inhaled β2-agonist and/or aminophylline.

Hypoglycemia: Administer IV glucose. Repeated doses of IV glucose or possibly glucagon may be required.

Supportive measures should continue until clinical stability is achieved.

Action and clinical pharmacology

Mechanism of Action

BYSTOLIC (nebivolol tablets) is a cardioselective β-adrenergic receptor antagonist with vasodilating activity. The exact mechanism of action of its antihypertensive response has not been definitively established. The ability of β-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. Nebivolol also has vasodilating properties, likely due to its ability to increase nitric oxide release from human endothelial cells, which may decrease peripheral vascular resistance, but their relative contribution to the overall blood pressure lowering effect of nebivolol has not been demonstrated.

Nebivolol lacks appreciable affinity for α-adrenergic receptors. Nebivolol does not appear to have intrinsic sympathomimetic activity at β1-adrenergic receptors.

Pharmacodynamics

Nebivolol is preferentially β1-selective with a 320-fold higher affinity for human cardiac β1- vs. β2-adrenergic receptors. In extensive metabolizers (most of the population) and at doses less than or equal to 20 mg, nebivolol is preferentially β1-selective. At clinically relevant doses in extensive metabolizers, nebivolol is not expected to significantly block α1-adrenergic receptors as determined in a clinical study with the 5 mg dose and inferred from nebivolol Cmax (32 nM at 20 mg dose) in relation to its binding affinity for α1-adrenergic receptors (Ki of 330 nM). In poor metabolizers and at higher doses, nebivolol inhibits both β1- and β2-adrenergic receptors. Several metabolites of nebivolol that demonstrate binding affinity at the β1-adrenergic receptor have been identified following oral administration of nebivolol. The Ki for the active metabolites range from 0.7 nM to 19.8 nM, compared to Ki = 0.7 nM for nebivolol, suggesting that these metabolites may contribute to the β-blocking activity.

Nebivolol is a racemic mixture of d-nebivolol and l-nebivolol. Exposure to l-nebivolol is higher than to d-nebivolol but l-nebivolol contributes little to the drug’s β1-blocking activity as d- nebivolol’s β-receptor affinity is > 1000-fold higher than l-nebivolol [see DETAILED PHARMACOLOGY].

Electrocardiography

A randomized, open-label, placebo- and active-controlled (atenolol and moxifloxacin), parallel group study was performed to assess the effect of BYSTOLIC on electrocardiographic intervals in healthy subjects (N=67-71/group). BYSTOLIC was administered at a therapeutic dose of 20 mg QD on days 1-3 and a supratherapeutic dose of 40 mg QD on days 4-7. ECG assessments were performed on days 1, 4, and 7. BYSTOLIC reduced heart rate and increased the PR interval as presented in Table 4.

Table 4: Maximum Placebo-Adjusted Mean Changes from Baseline During Treatment with BYSTOLIC on Days 1, 4, and 7
Heart Rate (bpm)PR Interval (msec)
Mean (90% CI)Time (h)Mean (90% CI)Time (h)
Day 1-14.2 ( -18.0, -10.3)613.0( 9.0, 17.0)2.5
Day 4-19.4 ( -23.1, -15.7)413.8( 9.3, 18.3)2.5
Day 7-20.8 ( -24.2, -17.4)23.511.4( 7.2, 15.5)4.0

Similar effects on heart rate and the PR interval were seen with the active comparator atenolol, administered as 100 mg QD on days 1-3 and as 200 mg QD on days 4-7.

BYSTOLIC was not demonstrated to have a treatment-related effect on the Fridericia-corrected QT interval (QTcF=QT/RR0.33) in this study.

Pharmacokinetics

Table 5: Summary of d,l-Nebivolol Pharmacokinetic Parameters after Repeated Oral Administration of 10 mg Dose for 14 Days
ParameterExtensive Metabolizers (EM)Poor Metabolizers (PM)
AUC (ng.hr/ml)19.7663
Cmax (ng/ml)3.532
Tmax (hr)1.23.7
T1/2 (hr)12.756
CL/F (L/hr)65716

Absorption

BYSTOLIC is an immediate release tablet. The absolute bioavailability has not been determined. Pharmacokinetic steady state is reached in 3 and 5 days in CYP2D6 extensive and poor metabolizers, respectively.

Food does not significantly alter the pharmacokinetics of nebivolol. Under fed conditions, nebivolol glucuronides are slightly reduced. BYSTOLIC may be administered with or without food.

Distribution

In human plasma, approximately 98% of nebivolol is bound to protein (mostly to albumin), regardless of nebivolol concentration, and the drug is widely distributed into tissues, including the brain.

Metabolism

Nebivolol is predominantly (75%) metabolized by cytochrome P450 2D6 via direct glucuronidation and to a lesser extent, via N-dealkylation and oxidation of the parent compound. Its stereospecific metabolites contribute to the pharmacologic activity. Nebivolol is also metabolized to a lesser extent by CYP3A4/5 (16-20%). d-Nebivolol, has an effective half- life of about 13 hours in CYP2D6 extensive metabolizers (EM, most people), and 22 hours in poor metabolizers (PM) and exposure to d-nebivolol is substantially increased in poor metabolizers. This may have less importance than usual, however, because the metabolites, including the hydroxyl metabolite and glucuronides (the predominant circulating metabolites),partially contribute to β-blocking activity of nebivolol.

Excretion

After a single oral administration of 14C-nebivolol, 37% of the dose was recovered in urine and 42% in feces for EMs and 57% in urine and 8% in feces for PMs. Essentially all nebivolol was excreted as multiple oxidative metabolites or their corresponding glucuronide conjugates.

Special Populations and Conditions

Pediatrics

The pharmacokinetics of nebivolol in patients <18 years of age has not been studied.

Geriatrics

Based on the results of a population pharmacokinetic analysis, no differences were seen in the pharmacokinetics of nebivolol in elderly (≥ 65 years) patients as compared to younger patients.

Gender

Based on the results of a population pharmacokinetic analysis, no differences in the pharmacokinetics of nebivolol were seen between males and females.

Race

Based on the results of a population pharmacokinetic analysis, no differences were observed in the pharmacokinetics of nebivolol and its glucuronide metabolites among different races.

Hepatic Insufficiency

d-Nebivolol peak plasma concentration and exposure (AUC) increased 3.5-fold, and the apparent clearance decreased by 90% in patients with moderate hepatic impairment (Child-Pugh Class B). No studies have been performed in patients with severe hepatic impairment and nebivolol is contraindicated in these patients.

Renal Insufficiency

The exposure (AUC) of d-nebivolol increased approximately 2- and 5-fold in patients with moderate and severe renal impairment, respectively. The apparent clearance of d-nebivolol was unchanged following a single 5 mg dose of BYSTOLIC in patients with mild renal impairment (ClCr 50 to 80 mL/min, n=7), while it was reduced by 48% in patients with moderate (ClCr 30 to 50 mL/min, n=9), and by 66% in patients with severe renal impairment (ClCr <30 mL/min, n=5). No studies have been conducted in patients on dialysis.

Genetic Polymorphism

A small percentage of the general population (about 7% of Caucasians, 2% of African Americans, and about 2% of Asians) is deficient in CYP2D6 enzyme activity, and is considered poor metabolizers of CYP2D6 metabolized drugs. Nebivolol undergoes hepatic metabolism mainly (up to 77% in animals and 75% in humans) by CYP2D6, and is subject to this genetic polymorphism.

Poor CYP2D6 metabolizers have been shown to have markedly higher plasma concentrations of nebivolol and less oxidative related metabolites compared with people with normal CYP2D6 activity, while maintaining their ability to glucuronidate nebivolol.

Storage and stability

Store at controlled room temperature (15 - 30oC). Protect from light.

Special handling instructions

No special handling is required.

Dosage forms, composition and packaging

BYSTOLIC (nebivolol tablets) is available as tablets for oral administration containing nebivolol hydrochloride equivalent to 2.5, 5, 10, and 20 mg of nebivolol, and will be supplied in bottles of 30 tablets.

BYSTOLIC contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, D&C Red #27 Lake (10 mg 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.

BYSTOLIC tablets are triangular-shaped, biconvex, unscored, differentiated by colour and are engraved with “FL” on one side and the number of mg (2.5, 5, 10, or 20) on the other side. The 2.5 mg tablet is light blue, the 5 mg tablet is beige, the 10 mg tablet is pinkish-purple, and the 20 mg tablet is light blue.