Included as part of the PRECAUTIONS section.
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 the 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, carefully observe and advise patients to minimize
physical activity. Taper BYSTOLIC over 1 to 2 weeks when possible. If the
angina worsens or acute coronary insufficiency develops, re-start BYSTOLIC
promptly, at least temporarily.
Angina And Acute Myocardial Infarction
BYSTOLIC was not studied in patients with angina pectoris
or who had a recent MI.
In general, patients with bronchospastic diseases should
not receive β-blockers.
Anesthesia And Major Surgery
Because beta-blocker withdrawal has been associated with
an increased risk of MI and chest pain, patients already on beta-blockers
should generally continue treatment throughout the perioperative period. If
BYSTOLIC is to be continued perioperatively, monitor patients closely when
anesthetic agents which depress myocardial function, such as ether,
cyclopropane, and trichloroethylene, are used. 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withdrawn prior to major surgery, the impaired ability of the heart to respond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
The β-blocking effects of BYSTOLIC can be reversed
by β-agonists, e.g., dobutamine or isoproterenol. However, such patients
may be subject to protracted severe hypotension. Additionally, difficulty in
restarting and maintaining the heartbeat has been reported with
Diabetes And Hypoglycemia
β-blockers may mask some of the manifestations of
hypoglycemia, particularly tachycardia. Nonselective βblockers may
potentiate insulin-induced hypoglycemia and delay recovery of serum glucose
levels. It is not known whether nebivolol has these effects. Advise patients
subject to spontaneous hypoglycemia and diabetic patients receiving insulin or
oral hypoglycemic agents about these possibilities.
β-blockers may mask clinical signs of
hyperthyroidism, such as tachycardia. Abrupt withdrawal of β-blockers may
be followed by an exacerbation of the symptoms of hyperthyroidism or may
precipitate a thyroid storm.
Peripheral Vascular Disease
β-blockers can precipitate or aggravate symptoms of
arterial insufficiency in patients with peripheral vascular disease.
Non-dihydropyridine Calcium Channel Blockers
Because of significant negative inotropic and
chronotropic effects in patients treated with β-blockers and calcium
channel blockers of the verapamil and diltiazem type, monitor the ECG and blood
pressure in patients treated concomitantly with these agents.
Use With CYP2D6 Inhibitors
Nebivolol exposure increases with inhibition of CYP2D6 [see
DRUG INTERACTIONS]. The dose of BYSTOLIC may need to be reduced.
Impaired Renal Function
Renal clearance of nebivolol is decreased in patients
with severe renal impairment. BYSTOLIC has not been studied in patients
receiving dialysis [see CLINICAL PHARMACOLOGY and DOSAGE AND
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 CLINICAL PHARMACOLOGY and DOSAGE AND
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. Such patients may be
unresponsive to the usual doses of epinephrine used to treat allergic
In patients with known or suspected pheochromocytoma,
initiate an α-blocker prior to the use of any βblocker.
Patient Counseling Information
See FDA-approved patient
labeling (PATIENT INFORMATION).
Advise patients to take
BYSTOLIC regularly and continuously, as directed. BYSTOLIC can be taken with or
without food. If a dose is missed, take the next scheduled dose only (without
doubling it). Do not interrupt or discontinue BYSTOLIC without consulting the
Patients should know how they
react to this medicine before they operate automobiles, use machinery, or
engage in other tasks requiring alertness.
Advise patients to consult a
physician if any difficulty in breathing occurs, or if they develop signs or
symptoms of worsening congestive heart failure such as weight gain or
increasing shortness of breath, or excessive bradycardia.
Caution patients subject to
spontaneous hypoglycemia, or diabetic patients receiving insulin or oral
hypoglycemic agents, that β-blockers may mask some of the manifestations
of hypoglycemia, particularly tachycardia.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
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 at 40 mg/kg/day (5 times the maximally recommended human
dose of 40 mg on a mg/m² basis). Similar findings were not reported in mice
administered doses equal to approximately 0.3 or 1.2 times the maximum
recommended human dose. No evidence of a tumorigenic effect was observed in a
24-month study in Wistar rats receiving doses of nebivolol 2.5, 10 and 40
mg/kg/day (equivalent to 0.6, 2.4, and 10 times the maximally recommended human
dose). Co-administration of dihydrotestosterone reduced blood LH levels and
prevented the Leydig cell hyperplasia, consistent with an indirect LH-mediated effect
of nebivolol in mice and not thought to be clinically relevant in man.
A randomized, double-blind, placebo-and
active-controlled, parallel-group study in healthy male volunteers was
conducted to determine the effects of nebivolol on adrenal function,
luteinizing hormone, and testosterone levels. This study demonstrated that 6
weeks of daily dosing with 10 mg of nebivolol had no significant effect on
ACTH-stimulated mean serum cortisol AUC0-120 min, serum LH, or serum total
Effects on spermatogenesis were seen in male rats and
mice at ≥ 40 mg/kg/day (10 and 5 times the MRHD, respectively). 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.
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).
Use In Specific Populations
Available data regarding use of BYSTOLIC in pregnant
women are insufficient to determine whether there are drug-associated risks of
adverse developmental outcomes. There are risks to the mother and fetus
associated with poorly controlled hypertension in pregnancy. The use of beta
blockers during the third trimester of pregnancy may increase the risk of
hypotension, bradycardia, hypoglycemia, and respiratory depression in the
neonate [see Clinical Considerations]. Oral administration of nebivolol
to pregnant rats during organogenesis resulted in embryofetal and perinatal
lethality at doses approximately equivalent to the maximum recommended human
The estimated background risk of major birth defects and
miscarriage for the indicated population is unknown. In the U.S. general
population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2-4% and 15-20%,
Disease-Associated Maternal And/Or Embryo/Fetal Risk
Hypertension in pregnancy increases the maternal risk for
pre-eclampsia, gestational diabetes, premature delivery, and delivery
complications (e.g., need for cesarean section, and post-partum hemorrhage).
Hypertension increases the fetal risk for intrauterine growth restriction and
intrauterine death. Pregnant women with hypertension should be carefully
monitored and managed accordingly.
Fetal/Neonatal Adverse Reactions
Neonates of women with hypertension, who are treated with
beta-blockers during the third trimester of pregnancy, may be at increased risk
for hypotension, bradycardia, hypoglycemia, and respiratory depression. Observe
newborns for symptoms of hypotension, bradycardia, hypoglycemia and respiratory
depression and manage accordingly.
Nebivolol was shown to increase embryo-fetal and
perinatal lethality in rats at approximately 1.2 times the MRHD or 40 mg/day on
a mg/m² basis. 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 (1.2 times the MRHD), 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. These events occurred only when nebivolol was
given during the perinatal period (late gestation, parturition and lactation).
Insufficient numbers of pups survived at 5 mg/kg to evaluate the offspring for
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 (5 and 10 times the MRHD), 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 (10 times the MRHD).
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 (10 times the MRHD).
There is no information regarding the presence of
nebivolol in human milk, the effects on the breastfed infant, or the effects on
milk production. Nebivolol is present in rat milk [see Data]. Because of
the potential for βblockers to produce serious adverse reactions in
nursing infants, especially bradycardia, BYSTOLIC is not recommended during
In lactating rats, maximum milk levels of unchanged
nebivolol were observed at 4 hours after single and repeat doses of 2.5
mg/kg/day. The daily dose (mg/kg body weight) ingested by a rat pup is 0.3% of
the dam dose for unchanged nebivolol.
Safety and effectiveness in pediatric patients have not
been established. Pediatric studies in ages newborn to 18 years old have not
been conducted because of incomplete characterization of developmental toxicity
and possible adverse effects on long-term fertility [see Nonclinical
Juvenile Animal Toxicity Data
Daily oral doses of nebivolol to juvenile rats from
post-natal day 14 to post-natal day 27 showed sudden unexplained death at
exposures equal to those in human poor metabolizers given a single dose of 10
mg. No mortality was seen at half the adult human exposure.
In surviving rats, cardiomyopathy was seen at exposures
greater than or equal to the human exposure. Male rat pups exposed to twice the
human exposure showed decreases in total sperm count as well as decreases in
the total and percentage of motile sperm.
Of the 2800 patients in the U.S. sponsored
placebo-controlled clinical hypertension studies, 478 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.
In a placebo-controlled trial of 2128 patients (1067
BYSTOLIC, 1061 placebo) over 70 years of age with chronic heart failure
receiving a maximum dose of 10 mg per day for a median of 20 months, no
worsening of heart failure was reported with nebivolol compared to placebo. However,
if heart failure worsens consider discontinuation of BYSTOLIC.