Included as part of the PRECAUTIONS section.
Use of drugs that act on the renin-angiotensin system
during the second and third trimesters of pregnancy reduces fetal renal
function and increases fetal and neonatal morbidity and death. Resulting
oligohydramnios can be associated with fetal lung hypoplasia and skeletal
deformations. Potential neonatal adverse effects include skull hypoplasia,
anuria, hypotension, renal failure, and death. When pregnancy is detected,
discontinue BYVALSON as soon as possible [see Use in Specific Populations].
In patients with an activated
renin-angiotensin-aldosterone system, such as volume-and/or salt-depleted
patients (e.g., those receiving high doses of diuretics), symptomatic
hypotension may occur in patients receiving BYVALSON. Correct these conditions
prior to administration of BYVALSON, or start the treatment under close medical
If excessive hypotension occurs, the patient should be
placed in the supine position and, if necessary, given an intravenous infusion
of normal saline. A transient hypotensive response is not a contraindication to
further treatment, which usually can be continued without difficulty once the
blood pressure has stabilized.
Abrupt Cessation Of Therapy
Do not abruptly discontinue BYVALSON 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. As with other β-blocker
therapies, when discontinuation of BYVALSON is planned, carefully observe and
advise patients to minimize physical activity. Taper nebivolol using
monotherapy over 1 to 2 weeks when possible. If the angina worsens re-start
nebivolol promptly, at least temporarily.
Worsening heart failure or fluid retention may occur
during nebivolol therapy because of its Ã-blocking effects. Consider diuretic
therapy and treat heart failure appropriately, according to current guidelines.
In general, patients with bronchospastic diseases should
not receive β-blockers.
Anesthesia And Major Surgery
Chronically administered beta-blocking therapy should not
be routinely withdrawn prior to major surgery, however the impaired ability of
the heart to respond to reflex adrenergic stimuli may augment the risks of
general anesthesia and surgical procedures. Monitor patients closely when
anesthetic agents which depress myocardial function, such as ether,
cyclopropane, and trichloroethylene, are used.
Diabetes And Hypoglycemia
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. 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 βblockers 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 heart rate and
blood pressure in patients treated concomitantly with these agents.
Impaired Renal Function
Changes in renal function including acute renal failure
can be caused by drugs that inhibit the reninangiotensin system and by
diuretics. Patients whose renal function may depend in part on the activity of
the renin-angiotensin system (e.g. patients with renal artery stenosis, chronic
kidney disease, severe congestive heart failure, or volume depletion) may be at
particular risk of developing acute renal failure on valsartan. Monitor renal
function periodically in these patients. Consider withholding or discontinuing
therapy in patients who develop a clinically significant decrease in renal
function on valsartan [see DRUG INTERACTIONS].
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 a α-blocker prior to the use of any βblocker.
In hypertensive patients, greater than 20% increases in
serum potassium were observed in 4.4% of valsartan-treated patients compared to
2.9% of placebo-treated patients. Discontinuation of BYVALSON may be required.
Patient Counseling Information
Advise the patient to read the
FDA-approved patient labeling (PATIENT INFORMATION).
Advise pregnant women and
females of reproductive potential of the potential risk to a fetus. Advise
females of reproductive potential to notify their healthcare provider with a
known or suspected pregnancy [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
Advise women not to breastfeed
during treatment with BYVALSON [see Use in Specific Populations].
Advise patients that
lightheadedness can occur, especially during the first days of therapy, and
that it should be reported to the prescribing physician. Tell patients that if
syncope occurs to discontinue BYVALSON until the physician has been consulted.
Caution all patients that
inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead
to an excessive fall in blood pressure, with the same consequences of
lightheadedness and possible syncope.
Advise patents not to use salt
substitutes containing potassium without consulting their physician.
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 mg/kg/day, 10
mg/kg/day 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.
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
There was no evidence of carcinogenicity when valsartan
was administered in the diet to mice and rats for up to 2 years at doses up to
160 and 200 mg/kg/day, respectively. These doses in mice and rats are about 2.6
and 6 times, respectively, the maximum recommended human dose on a mg/m² basis.
(Calculations assume an oral dose of 320 mg/day and a 60-kg patient.)
Mutagenicity assays did not reveal any valsartan-related
effects at either the gene or chromosome level. These assays included bacterial
mutagenicity tests with Salmonella (Ames) and E coli; a gene mutation test with
Chinese hamster V79 cells; a cytogenetic test with Chinese hamster ovary cells;
and a rat micronucleus test.
Valsartan had no adverse effects on the reproductive
performance of male or female rats at oral doses up to 200 mg/kg/day. This dose
is 6 times the maximum recommended human dose on a mg/m² basis.
(Calculations assume an oral dose of 320 mg/day and a 60-kg patient.)
Use In Specific Populations
BYVALSON can cause fetal harm when administered to a
pregnant woman. Use of drugs that act on the renin-angiotensin system during
second and third trimesters of pregnancy reduces fetal renal function and
increases fetal and neonatal morbidity and death. Most epidemiologic studies
examining fetal abnormalities after exposure to angiotensin receptor blockers
use in the first trimester have not distinguished drugs affecting the
renin-angiotensin system from other antihypertensive agents. Studies in rats
and rabbits with valsartan showed fetotoxicity only at maternally toxic doses [see
Data]. Embryo-fetal and perinatal lethality have been observed when
nebivolol was given to pregnant rats during organogenesis at doses
approximately equivalent to the MRHD. Published reports include cases of
anhydramnios and oligohydramnios in pregnant women treated with valsartan. When
pregnancy is detected, discontinue BYVALSON as soon as possible.
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 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.
Oligohydramnios in pregnant women who use drugs affecting
the renin-angiotensin system in the second and third trimesters of pregnancy
can result in the following: reduced fetal renal function leading to anuria and
renal failure, fetal lung hypoplasia and skeletal deformations, including skull
hypoplasia, hypotension, and death. In the unusual case that there is no
appropriate alternative to therapy with drugs affecting the renin-angiotensin
system for a particular patient, apprise the mother of the potential risk to
In patients taking BYVALSON during pregnancy, perform
serial ultrasound examinations to assess the intra-amniotic environment. Fetal
testing may be appropriate, based on the week of gestation. Patients and
physicians should be aware, however, that oligohydramnios may not appear until
after the fetus has sustained irreversible injury. Closely observe infants with
histories of in utero exposure to BYVALSON for hypotension, oliguria, and
hyperkalemia. If oliguria or hypotension occur in neonates with a history of in
utero exposure to BYVALSON, support blood pressure and renal perfusion.
Exchange transfusions or dialysis may be required as a means of reversing
hypotension and substituting for disordered renal function.
No reproductive animal toxicity studies have been
conducted with the combination of nebivolol and valsartan. Reproductive animal
toxicity studies have been conducted for nebivolol and valsartan alone.
Nebivolol was shown to increase embryo-fetal and
perinatal lethality in rats at approximately 1.2 times the maximum recommended
human dose (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 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 (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).
No teratogenic effects were observed when valsartan was
administered to pregnant mice and rats at oral doses up to 600 mg/kg/day and to
pregnant rabbits at oral doses up to 10 mg/kg/day. However, significant
decreases in fetal weight, pup birth weight, pup survival rate, and slight
delays in developmental milestones were observed in studies in which parental
rats were treated with valsartan at oral, maternally toxic (reduction in body
weight gain and food consumption) doses of 600 mg/kg/day during organogenesis
or late gestation and lactation. In rabbits, fetotoxicity (i.e., resorptions,
litter loss, abortions, and low body weight) associated with maternal toxicity
(mortality) was observed at doses of 5 and 10 mg/kg/day. The no observed
adverse effect doses of 600, 200 and 2 mg/kg/day in mice, rats and rabbits
represent 9, 6, and 0.1 times, respectively, the maximum recommended human dose
on a mg/m² basis. Calculations assume an oral dose of 320 mg/day and
a 60-kg patient.
There is no information regarding the presence of
BYVALSON or its individual components in human milk, the effects on the
breastfed infant, or the effects on milk production. Nebivolol and valsartan
are present in rat milk [see Data]. Because of the potential for
β-blockers to produce serious adverse reactions in nursing infants,
especially bradycardia, and the potential for valsartan to affect postnatal
renal development in nursing infants, advise a nursing woman not to breastfeed
during treatment with BYVALSON.
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. For valsartan, drug was detected in the
milk of lactating rats 15 minutes after administration of a 3 mg/kg dose.
Safety and effectiveness in pediatric patients have not
In clinical trials of BYVALSON, 204 (8.3%) patients who
were treated with BYVALSON were ≥ 65 years and 16 (0.6%) were ≥ 75
No overall differences in safety or effectiveness were
observed between elderly patients and younger patients, and other reported
clinical experience have not identified differences in responses between the
elderly and younger patients, but greater sensitivity of some older individuals
cannot be ruled out.
Safety and effectiveness of BYVALSON in patients with
moderate and severe renal impairment (creatinine clearance [CrCl] ≤ 60
mL/min) have not been studied. No dosage adjustment is required for patients
with mild or moderate renal impairment.
BYVALSON is not recommended as initial treatment in
patients with severe renal impairment, because the recommended starting dose of
nebivolol in this population, 2.5 mg once daily, is lower than the dose of
nebivolol contained in BYVALSON.
There are no studies of BYVALSON in patients with hepatic
insufficiency. No initial dosage adjustment is required for patients with mild
BYVALSON is not recommended as initial treatment in
patients with moderate hepatic impairment, because the recommended starting
dose of nebivolol, 2.5 mg once daily, is not available.
BYVALSON is not recommended for use in patients with
severe hepatic impairment [see CONTRAINDICATIONS].