WARNINGS
Hepatic Injury: Mild hepatocellular
injury, confirmed by rechallenge, has occurred rarely
with Coreg therapy. In controlled studies of hypertensive
patients, the incidence of liver function abnormalities
reported as adverse experiences was 1.1% (13 of 1,142
patients) in patients receiving Coreg and 0.9% (4 of 462
patients) in those receiving placebo. One patient receiving
carvedilol in a placebo-controlled trial withdrew for
abnormal hepatic function.
In controlled studies of congestive heart failure, the
incidence of liver function abnormalities reported as
adverse experiences was 5.0% (38 of 765 patients) in patients
receiving Coreg and 4.6% (20 of 437 patients) in those
receiving placebo. Three patients receiving carvedilol
(0.4%) and two patients receiving placebo (0.5%) in placebo-controlled
trials withdrew for abnormal hepatic function.
Hepatic injury has been reversible and has occurred after
short- and/or long-term therapy with minimal clinical
symptomatology. No deaths due to liver function abnormalities
have been reported.
At the first symptom/sign of liver dysfunction (e.g.,
pruritus, dark urine, persistent anorexia jaundice, right
upper quadrant tenderness or unexplained “flu-like”
symptoms), laboratory testing should be performed. If
the patient has laboratory evidence of liver injury or
jaundice, carvedilol should be stopped and not restarted.
Peripheral Vascular Disease: b-blockers
can precipitate or aggravate symptoms of arterial insufficiency
in patients with peripheral vascular disease. Caution
should be exercised in such individuals.
Anesthesia and Major Surgery: If Coreg
treatment is to be continued perioperatively, particular
care should be taken when anesthetic agents which depress
myocardial function, such as ether, cyclopropane and trichloroethylene,
are used. See OVERDOSAGE for information on treatment
of bradycardia and hypertension.
Diabetes and Hypoglycemia: b-blockers
may mask some of the manifestations of hypoglycemia, particularly
tachycardia. Nonselective b-blockers may potentiate insulin-induced
hypoglycemia and delay recovery of serum glucose levels.
Patients subject to spontaneous hypoglycemia, or diabetic
patients receiving insulin or oral hypoglycemic agents,
should be cautioned about these possibilities and carvedilol
should be used with caution. In congestive heart failure
patients, there is a risk of worsening hyperglycemia (see
PRECAUTIONS
).
Thyrotoxicosis: b-adrenergic blockade may
mask clinical signs of hyperthyroidism, such as tachycardia.
Abrupt withdrawal of b-blockade may be followed by an exacerbation
of the symptoms of hyperthyroidism or may precipitate thyroid
storm.
PRECAUTIONS
General
Since Coreg (carvedilol) has b-blocking activity, it
should not be discontinued abruptly, particularly in patients
with ischemic heart disease. Instead, it should be discontinued
over 1 to 2 weeks.
In clinical trials, Coreg caused bradycardia in about
2% of hypertensive patients and 9% of congestive heart
failure patients. If pulse rate drops below 55 beats/min.,
the dosage should be reduced.
Hypotension and postural hypotension occurred in 9.7%
and syncope in 3.4% of congestive heart failure patients
receiving carvedilol compared to 3.6% and 2.5% of placebo
patients, respectively. The risk for these events was
highest during the first 30 days of dosing, corresponding
to the up-titration period and was a cause for discontinuation
of therapy in 0.7% of carvedilol patients, compared to
0.4% of placebo patients.
Postural hypotension occurred in 1.8% and syncope in
0.1% of hypertensive patients, primarily following the
initial dose or at the time of dose increase and was a
cause for discontinuation of therapy in 1% of patients.
To decrease the likelihood of syncope or excessive hypotension,
treatment should be initiated with 3.125 mg b.i.d. for
congestive heart failure patients and 8.25 mg b.i.d. for
hypertensive patients. Dosage should then be increased
slowly, according to recommendations in the DOSAGE AND
ADMINISTRATION section, and the drug should be taken with
food. During initiation of therapy, the patient should
be cautioned to avoid situations such as driving or hazardous
tasks, where injury could result should syncope occur.
Rarely, use of carvedilol in patients with congestive
heart failure has resulted in deterioration of renal function.
Patients at risk appear to be those with low blood pressure
(systolic BP<100 mm Hg), ischemic heart disease and
diffuse vascular disease, and/or underlying renal insufficiency.
Renal function has returned to baseline when carvedilol
was stopped. In patients with these risk factors it is
recommended that renal function be monitored during up-titration
of carvedilol and the drug discontinued or dosage reduced
if worsening of renal function occurs.
Worsening cardiac failure or fluid retention may occur
during up-titration of carvedilol. If such symptoms occur,
diuretics should be increased and the carvedilol dose
should not be advanced until clinical stability resumes
(see DOSAGE AND ADMINISTRATION). Occasionally it is necessary
to lower the carvedilol dose or temporarily discontinue
it.Such episodes do not preclude subsequent successful
titration of carvedilol.
In patients with pheochromocytoma, an a-blocking agent
should be initiated prior to the use of any b-blocking
agent. Although carvedilol has both a- and b-blocking
pharmacologic activities, there has been no experience
with its use in this condition. Therefore, caution should
be taken in the administration of carvedilol to patients
suspected of having pheochromocytoma.
Agents with non-selective b-blocking activity may provoke
chest pain in patients with Prinzmetal’s variant
angina. There has been no clinical experience with carvedilol
in these patients although the a-blocking activity may
prevent such symptoms. However, caution should be taken
in the administration of carvedilol to patients suspected
of having Prinzmetal’s variant angina.
Risk of Anaphylactic Reaction
While taking b-blockers, patients with a history of severe
anaphylactic reaction to a variety of allergens may be
more reactive to repeated challenge, either accidental,
diagnostic or therapeutic. Such patients may be unresponsive
to the usual doses of epinephrine used to treat allergic
reaction.
Nonallergic Bronchospasm (e.g., chronic bronchitis
and emphysema)
Patients with bronchoapastic disease should, in general,
not receive b-blockers. Coreg may be used with caution,
however, in patients who do not respond to, or cannot
tolerate, other antihypertensive agents. It is prudent,
if Coreg (carvedilol) is used, to use the smallest effective
dose, so that inhibition of endogenous or exogenous b-blocking
agents minimized.
In clinical trials of patients with congestive heart
failure, patients with bronchospastic disease were enrolled
if they did not require oral or inhaled medication to
treat their bronchospastic disease. In such patients,
it is recommended that carvedilol be used with caution.The
dosing recommendations should be followed closely and
the dose should be lowered if any evidence of bronchospasm
is observed during up-titration.
Hypertensive Patients with Left Ventricular
Failure: In hypertensive patients who have
congestive heart failure controlled with digitalis, diuretics
and/or an angiotensin converting enzyme inhibitor, Coreg
(carvedilol) may be used. However, since it is likely
that such patients are dependent, in part, on sympathetic
stimulation for circulatory support, it is recommended
that dosing follow the instructions for patients with
congeative heart failure.
In congestive heart failure patients with diabetes,carvedilol
therapy may lead to worsening hyperglycemia, which responds
to intensification of hypoglycemic therapy. It is recommended
that blood glucose be monitored when carvedilol dosing
is initiated, adjusted, or discontinued.
Information for Patients
See PATIENT INFORMATION section.
Drug Interactions
See DRUG INTERACTIONS section.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In 2-year studies conducted in rats given carvedilol
at doses up to 75 mg/kg/day (12 times the maximum recommended
human dose[ MRHD] when compared on a mg/m2 basis) or in
mice given up to 200 mg/kg/day (16 times the MRHD on a
mg/m2 basis), carvedilol had no carcinogenic effect.
Cervedilol was negative when nested in a battery of genotoxicity
assays, including the Ames and the CHO/HGPRT assays for
mutagenicity and the in vitro hamster micro-nucleus and
in vivo human lymphocyte cell tests for clastogenicity.
At doses ³200 mg/kg/day (³32 times the MRHD
as mg/m2) carvedilol was toxic to adult rats (sedation,
reduced weight gain) and was associated with a reduced
number of successful matings, prolonged mating time, significantly
fewer corpora lutea and implants per dam and complete
resorption of 18% of the litters. The no observed-effect
dose level for overt toxicity and impairment of fertility
was 60 mg/kg/day (10 times the MRHD as mg/m2 ).
Pregnancy: Teratogenic Effects. Pregnancy Category
C.
Studies performed in pregnant rats and rabbits given
carvedilol revealed increased post-implantation loss in
rats at doses of 300 mg/kg/day (50 times the MRHD as mg/m2)
and in rabbits at doses of 75mg/kg/day (25 times the MRHD
as mg/m2). In the rats, there was also a decrease in fetal
body weight at the maternally toxic dose of 300 mg/kg/day
(50 times the MRHD as mg/m²), which was accompanied
by an elevation in the frequency of fetuses with delayed
skeletal development (missing or stunted 13th rib). In
rats the no-observed-effect level for developmental toxicity
was 60 mg/kg/day (10 times the MRHD as mg/m2 ); in rabbits
it was 15 mg/kg/day (5 times the MRHD as mg/m2). There
are no adequate and well-controlled studies in pregnant
women. Coreg should be used during pregnancy only if the
potential benefit justifies the potential risk to the
fetus.
Nursing Mothers
It is not known whether this drug is excreted in human
milk. Studies in rats have shown that carvedilol and/or
its metabolites (as well as other b-blockers) cross the
placental barrier and are excreted in breast milk. There
was increased mortality at one week post-partum in neonates
from rats treated with 60 mg/kg/day (10 times the MRHD
as mg/m2) and above during the last trimester through
day 22 of lactation. Because many drugs are excreted in
human milk and because of the potential for serious adverse
reactions in nursing infants from b-blockers, especially
bradycardia, a decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account
the importance of the drug to the mother. The effects
of other a- and b-blocking agents have included perinatal
and neonatal distress.
Pediatric Use
Safety and efficacy in patients younger than 18 years
of age have not been established.
Geriatric Use
Of the 765 patients with congestive heart failure randomized
to Coreg in U.S. clinical trials, 31% (235) were 65 years
of age or older. Of 1,869 patients receiving Coreg in
congestive heart failure trials worldwide, 39% were 65
years of age or older. There were no notable differences
in efficacy or the incidence of adverse events between
older and younger patients.
Of the 2,065 hypertensive patients in U.S. clinical trials
of efficacy or safety who were treated with Coreg (carvedilol),
21% (436) were 65 years of age or older. Of 3,722 patients
receiving Coreg in hypertension clinical trials conducted
worldwide, 24% were 65 years of age or older. There were
no notable differences in efficacy or the incidence of
adverse events between older and younger patients. With
the exception of dizziness (incidence 8.8% in the elderly
vs. 6% in younger patients), there were no events for
which the incidence in the elderly exceeded that in the
younger population by greater than 2.0%.
Similar results were observed in a postmarketing surveillance
study of 3,328 Coreg patients, of whom approximately 20%
were 65 years of age or older
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