CARVEDILOL
DESCRIPTION:
Carvedilol is a nonselective beta-adrenergic blocking agent with alpha1-blocking
activity. It is (+/-)-1-(Carbazol-4-yloxy)-3-((2-(o-
methoxyphenoxy)ethyl)amino)-2-propanol. It is a race-mic mixture.
TABLETS FOR ORAL ADMINISTRATION:
CARCA (carvedilol) is a white, oval, film-coated tablet containing 3.125 mg,
6.25 mg, 12.5 mg, tablets of carvedilol. The 6.25 mg, 12.5 mg tablets are Tiltab(R) tablets. Inactive ingredients consist of colloidal silicon
dioxide, crospovidone, hydroxypropyl methylcellulose, lactose, magnesium
stearate, polyethylene glycol, polysorbate 80, povidone, sucrose and titanium
dioxide.
Carvedilol is a white to off-white powder with a molecular weight of 406.5 and a
molecular formula of C24H26N2O4. It is freely soluble in dimethylsulfoxide;
soluble in methylene chloride and methanol; sparingly soluble in 95% ethanol and
isopropanol; slightly soluble in ethyl ether; and practically insoluble in
water, gastric fluid (simulated, TS, pH 1.1) and intestinal fluid (simulated, TS
without pancreatin, pH 7.5).
ACTIONS/CLINICAL PHARMACOLOGY:
CARCA is a racemic mixture in which nonselective beta-adrenoreceptor blocking
activity is present in the S(-) enantiomer and alpha-adrenergic blocking
activity is present in both R(+) and S(-) enantiomers at equal potency. CARCA
has no intrinsic sympathomimetic activity.
PHARMACOKINETICS
CARCA is rapidly and extensively absorbed following oral administration, with
absolute bioavailability of approximately 25% to 35% due to a significant degree
of first-pass metabolism. Following oral administration, the apparent mean
terminal elimination half-life of carvedilol generally ranges from 7 to 10
hours. Plasma concentrations achieved are proportional to the oral dose
administered. When administered with food, the rate of absorption is slowed, as
evidenced by a delay in the time to reach peak plasma levels, with no
significant difference in extent of bioavailability. Taking CARCA with food
should minimize the risk of orthostatic hypotension.
Carvedilol is extensively metabolized. Following oral administration of
radiolabelled carvedilol to healthy volunteers, carvedilol accounted for only
about 7% of the total radioactivity in plasma as measured by area under the
curve (AUC). Less than 2% of the dose was excreted unchanged in the urine.
Carvedilol is metabolized primarily by aromatic ring oxidation and
glucuronidation. The oxidative metabolites are further metabolized by
conjugation via glucuronidation and sulfation. The metabolites of carvedilol are
excreted primarily via the bile into the feces. Demethylation and hydroxylation
at the phenol ring produce three active metabolites with beta- receptor blocking
activity. Based on preclinical studies, the 4'-hydroxyphenyl metabolite is
approximately 13 times more potent than carvedilol for beta-blockade.
Compared to carvedilol, the three active metabolites exhibit weak vasodilating
activity. Plasma concentrations of the active metabolites are about one-tenth of
those observed for carvedilol and have pharmacokinetics similar to the parent.
Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of
R(+)-carvedilol approximately 2 to 3 times higher than S(-)-carvedilol following
oral administration in healthy subjects. The mean apparent terminal elimination
half-lives for R(+)-carvedilol range from 5 to 9 hours compared with 7 to 11
hours for the S(-)-enantiomer.
The primary P450 enzymes responsible for the metabolism of both R(+) and S(-)-
carvedilol in human liver microsomes were CYP2D6 and CYP2C9 and to a lesser
extent CYP3A4, 2C19, 1A2, and 2E1. CYP2D6 is thought to be the major enzyme in
the 4'- and 5'-hydroxylation of carvedilol, with a potential contribution from
3A4. CYP2C9 is thought to be of primary importance in the O- methylation pathway
of S(-)carvedilol.
Carvedilol is subject to the effects of genetic polymorphism with poor
metabolizers of debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2-to
3-fold higher plasma concentrations of R(+)-carvedilol compared to extensive
metabolizers. In contrast, plasma levels of S(-)-carvedilol are increased only
about 20% to 25% in poor metabolizers, indicating this enantiomer is metabolized
to a lesser extent by cytochrome p450 2D6 than R(+)-carvedilol. The
pharmacokinetics of carvedilol do not appear to be different in poor
metabolizers of S- mephenytoin (patients deficient in cytochrome P450 2C19).
Carvedilol is more than 98% bound to plasma proteins, primarily with albumin.
The plasma- protein binding is independent of concentration over the therapeutic
range. Carvedilol is a basic, lipophilic compound with a steady-state volume of
distribution of approximately 115 L, indicating substantial distribution into
extravascular tissues. Plasma clearance ranges from 500 to 700 mL/min.
CONGESTIVE HEART FAILURE: Steady-state plasma concentrations of carvedilol and
its enantiomers increased proportionally over the 6.25 to 50 mg dose range in
patients with congestive heart failure. Compared to healthy subjects, congestive
heart failure patients had increased mean AUC and Cmax values for carvedilol and
its enantiomers, with up to 50% to 100% higher values observed in 6 patients
with NYHA class IV heart failure. The mean apparent terminal elimination half-
life for carvedilol was similar to that observed in healthy subjects.
PHARMACOKINETIC DRUG-DRUG INTERACTIONS: Since carvedilol undergoes substantial
oxidative metabolism, the metabolism and pharmacokinetics of carvedilol may be
affected by induction or inhibition of cytochrome P450 enzymes.
Rifampin: In a pharmacokinetic study conducted in 8 healthy male subjects,
rifampin (600 mg daily for 12 days) decreased the AUC and Cmax of carvedilol by
about 70%.
Cimetidine: In a pharmacokinetic study conducted in 10 healthy male subjects,
cimetidine (1000 mg/day) increased the steady-state AUC of carvedilol by 30%
with no change in Cmax.
Glyburide: In 12 healthy subjects, combined administration of carvedilol (25 mg
once daily) and a single dose of glyburide did not result in a clinically
relevant pharmacokinetic interaction for either compound.
Hydrochlorothiazide: A single oral dose of carvedilol 25 mg did not alter the
pharmacokinetics of a single oral dose of hydrochlorothiazide 25 mg in 12
patients with hypertension. Likewise, hydrochlorothiazide has no effect on the
pharmacokinetics of carvedilol.
Digoxin: Following concomitant administration of carvedilol (25 mg once daily)
and digoxin (0.25 mg once daily) for 14 days, steady-state AUC and trough
concentrations of digoxin were increased by 14% and 16%, respectively, in 12
hypertensive patients.
Torsemide: In a study of 12 healthy subjects, combined oral administration of
carvedilol 25 mg once daily and torsemide 5 mg once daily for 5 days did not
result in any significant differences in their pharmacokinetics compared with
administration of the drug alone.
Warfarin: Carvedilol (12.5 mg twice daily) did not have an effect on the steady-
state prothrombin time ratios and did not alter the pharmacokinetics of R(+)-
and S(-)-warfarin following concomitant administration with warfarin in 9
healthy volunteers.
SPECIAL POPULATIONS
Elderly: Plasma levels of carvedilol average about 50% higher in the elderly
compared to young subjects.
Hepatic Impairment: Compared to healthy subjects, patients with cirrhotic liver
disease exhibit significantly higher concentrations of carvedilol (approximately
4- to 7-fold) following single- dose therapy (see WARNINGS, Hepatic Injury).
Renal Insufficiency: Although carvedilol is metabolized primarily by the liver,
plasma concentrations of carvedilol have been reported to be increased in
patients with renal impairment. Based on mean AUC data, approximately 40% to 50%
higher plasma concentrations of carvedilol were observed in hypertensive
patients with moderate to severe renal impairment compared to a control group of
hypertensive patients with normal renal function. However, the ranges of AUC
values were similar for both groups. Changes in mean peak plasma levels were
less pronounced, approximately 12% to 26% higher in patients with impaired renal
function.
Consistent with its high degree of plasma protein-binding, carvedilol does not
appear to be cleared significantly by hemodialysis.
PHARMACODYNAMICS AND CLINICAL TRIALS
CONGESTIVE HEART FAILURE
PHARMACODYNAMICS
The basis for the beneficial effects of CARCA (carvedilol) in congestive heart
failure is not established.
Two placebo-controlled studies compared the acute hemodynamic effects of CARCA
to baseline measurements in 59 and 49 patients with NYHA class II-IV heart
failure receiving diuretics, ACE inhibitors, and digitalis. There were
significant reductions in systemic blood pressure, pulmonary artery pressure,
pulmonary capillary wedge pressure, and heart rate. Initial effects on cardiac
output, stroke volume index, and systemic vascular resistance were small and
variable.
These studies measured hemodynamic effects again at 12 to 14 weeks. CARCA
significantly reduced systemic blood pressure, pulmonary artery pressure, right
atrial pressure, systemic vascular resistance, and heart rate, while stroke
volume index was increased.
Among 839 patients with NYHA class II-III heart failure treated for 26 to 52
weeks in 4 U.S. placebo-controlled trials, average left ventricular ejection
fraction (EF) measured by radionuclide ventriculography increased by 8 EF units
(%) in CARCA patients and by 2 EF units in placebo patients (between-group
difference of 6 units). This treatment effect was nominally statistically
significant in each trial.
HYPERTENSION
PHARMACODYNAMICS
The mechanism by which beta-blockade produces an antihypertensive effect has not
been established.
Beta-adrenoreceptor blocking activity has been demonstrated in animal and human
studies, showing that carvedilol (1) reduces cardiac output in normal subjects;
(2) reduces exercise- and/or isoproterenol-induced tachycardia and (3) reduces
reflex orthostatic tachycardia. Significant beta- adrenoreceptor blocking effect
is usually seen within 1 hour of drug administration.
Alpha1-adrenoreceptor blocking activity has been demonstrated in human and
animal studies, showing that carvedilol (1) attenuates the pressor effects of
phenylephrine; (2) causes vasodilation and (3) reduces peripheral vascular
resistance. These effects contribute to the reduction of blood pressure and
usually are seen within 30 minutes of drug administration.
Due to the alpha1-receptor blocking activity of carvedilol, blood pressure is
lowered more in the standing than in the supine position, and symptoms of
postural hypotension (1.8%), including rare instances of syncope, can occur.
Following oral administration, when postural hypotension has occurred, it has
been transient and is uncommon when CARCA (carvedilol) is administered with food
at the recommended starting dose and titration increments are closely followed
(see DOSAGE AND ADMINISTRATION).
In hypertensive patients with normal renal function, therapeutic doses of CARCA
decreased renal vascular resistance with no change in glomerular filtration rate
or renal plasma flow. Changes in excretion of sodium, potassium, uric acid and
phosphorous in hypertensive patients with normal renal function were similar
after CARCA and placebo.
CARCA has little effect on plasma catecholamines, plasma aldosterone or
electrolyte levels, but it does significantly reduce plasma renin activity when
given for at least 4 weeks. It also increases levels of atrial natriuretic
peptide.
CLINICAL STUDIES:
CLINICAL TRIALS
CONGESTIVE HEART FAILURE
Four U.S. multicenter, double-blind, placebo- controlled studies enrolled 1094
patients (696 randomized to car-vedilol) with NYHA class II-III heart failure
and ejection fraction <0.35. The vast majority were on digitalis, diuretics, and
an ACE inhibitor at study entry. Patients were assigned to the studies based
upon exercise ability. An Australia-New Zealand double-blind, placebo-controlled
study enrolled 415 patients (half randomized to carvedilol) with less severe
heart failure. All protocols excluded patients expected to undergo cardiac
surgery during the 6 to 12 months of double-blind follow-up. All randomized
patients had tolerated a 2-week course on carvedilol 6.25 mg b.i.d.
In each study, there was a primary end-point, either progression of heart
failure (one U.S. study) or exercise tolerance (2 U.S. studies meeting
enrollment goals and the Australia-New Zealand study). There were many secondary
end- points specified in these studies, including NYHA classification, patient
and physician global assessments, and cardiovascular hospitalization. Death was
not a specified end-point in any study, but it was analyzed in all studies.
Other analyses not prospectively planned included the sum of deaths and total or
cardiovascular hospitalizations. In situations where the primary end-points of a
trial do not show a significant benefit of treatment, assignment of significance
values to the other results is complex, and such values need to be interpreted
cautiously.
The results of the U.S. and Australia-New Zealand trials were as follows:
Slowing Progression Of Heart Failure: One U.S. multicenter study (366 subjects)
had as its primary end-point the sum of cardiovascular mortality, cardiovascular
hospitalization, and sustained increase in heart failure medications. Heart
failure progression was reduced, during an average follow-up of 7 months, by 48%
(p=0.008).
In the Australia-New Zealand study, death and total hospitalizations were
reduced by about 25% over 18 to 24 months. In the three largest U.S. studies,
death and total hospitalizations were reduced by 19%, 39% and 49%, nominally
statistically significant in the last two studies. The Australia-New Zealand
results were statistically borderline.
Functional Measures: None of the multicenter studies had NYHA classification as
a primary end- point, but all such studies had it as a secondary end-point.
There was at least a trend toward improvement in NYHA class in all studies.
Exercise tolerance was the primary end-point in 3 studies; in none was a
statistically significant effect found.
Subjective Measures: Quality of life, as measured with a standard questionnaire
(a primary end- point in one study), was unaffected by carvedilol. However,
patients' and investigators' global assessments showed significant improvement
in most studies.
Mortality: Mortality was not a planned end-point in any study. Overall, in the
U.S. trials, mortality was reduced, nominally significantly so in 2 studies, but
the actual effect size and statistical significance of this observation are
difficult to define.
HYPERTENSION
CARCA was studied in two placebo-controlled trials that utilized twice-daily
dosing, at total daily doses of 12.5 to 50 mg. In these and other studies, the
starting dose did not exceed 12.5 mg. At 50 mg per day, CARCA reduced sitting
trough (12-hour) blood pressure by about 9/5.5 mm Hg; at 25 mg/day the effect
was about 7.5/3.5 mm Hg. Comparisons of trough to peak blood pressure showed a
trough to peak ratio for blood pressure response of about 65%. Heart rate fell
by about 7.5 beats per minute at 50 mg/day. In general, as is true for other
beta-blockers, responses were smaller in black than non-black patients. There
were no age- or gender-related differences in response.
The peak antihypertensive effect occurred 1 to 2 hours after a dose. The dose-
related blood pressure response was accompanied by a dose- related increase in
adverse effects (see ADVERSE REACTIONS).
INDICATIONS AND USAGE:
CONGESTIVE HEART FAILURE
CARCA is indicated for the treatment of mild or moderate (NYHA class II or III)
heart failure of ischemic or cardiomyopathic origin, in conjunction with
digitalis, diuretics, and ACE inhibitor, to reduce the progression of disease as
evidenced by cardiovascular death, cardiovascular hospitalization, or the need
to adjust other heart failure medications.
CARCA may be used in patients unable to tolerate an ACE inhibitor. CARCA may be
used in patients who are or are not receiving digitalis, hydralazine or nitrate
therapy.
HYPERTENSION
CARCA (carvedilol) is also indicated for the management of essential
hypertension. It can be used alone or in combination with other antihypertensive
agents, especially thiazide-type diuretics (see PRECAUTIONS, Drug Interactions).
CONTRAINDICATIONS:
CARCA is contraindicated in patients with NYHA class IV decompensated cardiac
failure requiring intravenous inotropic therapy, bronchial asthma (two cases of
death from status asthmaticus have been reported in patients receiving single
doses of CARCA) or related bronchospastic conditions, second- or third-degree AV
block, sick sinus syndrome (unless a permanent pacemaker is in place),
cardiogenic shock or severe bradycardia.
Use of CARCA in patients with clinically manifest hepatic impairment is not
recommended.
CARCA is contraindicated in patients with hypersensitivity to the drug.
WARNINGS:
HEPATIC INJURY: Mild hepatocellular injury, confirmed by rechallenge, has
occurred rarely with CARCA 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 CARCA 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 CARCA 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: Beta-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 CARCA 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: Beta-blockers may mask some of the manifestations of
hypoglycemia, particularly tachycardia. Nonselective beta- 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: Beta-adrenergic blockade may mask clinical signs of
hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta-blockade may be
followed by an exacerbation of the symptoms of hyperthyroidism or may
precipitate thyroid storm.
PRECAUTIONS:
GENERAL
Since CARCA (carvedilol) has beta-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, CARCA 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 6.25
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
titration of carvedilol.
In patients with pheochromocytoma, an alpha- blocking agent should be initiated
prior to the use of any beta-blocking agent. Although carvedilol has both
alpha- and beta-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 beta-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 alpha-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 Beta-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 bronchospastic disease should, in general, not receive Beta-
blockers. CARCA may be used with caution, however, in patients who do not
respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if
CARCA (carvedilol) is used, to use the smallest effective dose, so that
inhibition of endogenous or exogenous Beta-agonists is 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, CARCA (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 congestive 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
Patients taking CARCA should be advised of the following:
- they should not interrupt or discontinue using CARCA without a physician's
advice.
- congestive heart failure patients should consult their physician if they
experience signs or symptoms of worsening heart failure such as weight gain or
increasing shortness of breath.
- they may experience a drop in blood pressure when standing, resulting in
dizziness and, rarely, fainting. Patients should sit or lie down when these
symptoms of lowered blood pressure occur.
- if patients experience dizziness or fatigue, they should avoid driving or
hazardous tasks.
- they should consult a physician if they experience dizziness or faintness, in
case the dosage should be adjusted.
- they should take CARCA with food.
- diabetic patients should report any changes in blood sugar levels to their
physicians.
- contact lens wearers may experience decreased lacrimation.
DRUG INTERACTIONS
(Also see ACTIONS/CLINICAL PHARMACOLOGY, Pharmacokinetic Drug-Drug
Interactions.)
Inhibitors Of CYP2D6; Poor Metabolizers Of Debrisoquine: Interactions of
carvedilol with strong inhibitors of CYP2D6 (such as quinidine, fluoxetine,
paroxetine, and propafenone) have not been studied, but these drugs would be
expected to increase blood levels of the R(+) enantiomer of carvedilol (see
ACTIONS/CLINICAL PHARMACOLOGY). Retrospective analysis of side effects in
clinical trials showed that poor 2D6 metabolizers had a higher rate of dizziness
during up-titration, presumably resulting from vasodilating effects of the
higher concentrations of the alpha-blocking R(+) enantiomer.
Catecholamine-Depleting Agents: Patients taking both agents with Beta-blocking
properties and a drug that can deplete catecholamines (e.g., reserpine and
monoamine oxidase inhibitors) should be observed closely for signs of
hypotension and/or severe bradycardia.
Clonidine: Concomitant administration of clonidine with agents with Beta-
blocking properties may potentiate blood pressure- and heart-rate-lowering
effects. When concomitant treatment with agents with Beta-blocking properties
and clonidine is to be terminated, the Beta-blocking agent should be
discontinued first. Clonidine therapy can then be discontinued several days
later by gradually decreasing the dosage.
Digoxin: Digoxin concentrations are increased by about 15% when digoxin and
carvedilol are administered concomitantly. Both digoxin and CARCA slow AV
conduction. Therefore, increased monitoring of digoxin is recommended when
initiating, adjusting or discontinuing CARCA.
Inducers And Inhibitors Of Hepatic Metabolism: Rifampin reduced plasma
concentrations of carvedilol by about 70%. Cimetidine increased AUC by about 30%
but caused no change in Cmax.
Calcium Channel Blockers: Isolated cases of conduction disturbance (rarely with
hemodynamic compromise) have been observed when CARCA is co- administered with
diltiazem. As observed with other agents with Beta-blocking properties, if CARCA
(carvedilol) is to be administered orally with calcium channel blockers of the
verapamil or diltiazem type, it is recommended that ECG and blood pressure be
monitored.
Insulin Or Oral Hypoglycemics: Agents with Beta- blocking properties may enhance
the blood-sugar- reducing effect of insulin and oral hypoglycemics. Therefore,
in patients taking insulin or oral hypoglycemics, regular monitoring of blood
glucose is recommended.
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/M(squared) basis) or in mice given up to 200 mg/kg/day (16 times the MRHD on
amg/M(squared) basis), carvedilol had no carcinogenic effect.
Carvedilol was negative when tested in a battery of genotoxicity assays,
including the Ames and the CHO/HGPRT assays for mutagenicity and the In Vitro
hamster micronucleus and In Vivo human lymphocyte cell tests for clastogenicity.
At doses >/=200 mg/kg/day (>/=32 times the MRHD as mg/M(squared)) 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/M(squared)).
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 (500 times
the MRHD as mg/M(squared)) and in rabbits at doses of 75 mg/kg/day (25 times the
MRHD as mg/M(squared)). 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/M(squared)), 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/M(squared)); in rabbits it was 15 mg/kg/day (5 times the
MRHD as mg/M(squared)). There are no adequate and well-controlled studies in
pregnant women. CARCA 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 Beta-
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/M(squared)) and above during the last
trimester through day 22 of lactation. Because may drugs are excreted in human
milk and because of the potential for serious adverse reactions in nursing
infants from Beta-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 alpha-and Beta-
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 CARCA in U.S.
clinical trials, 31% (235) were 65 years of age or older. Of 1,869 patients
receiving CARCA in congestive heart failure trials worldwide, 39% were 65 years
of age or older. There was 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 CARCA (carvedilol), 21% (436) were 65 years of age or
older. Of 3,722 patients receiving CARCA 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
CARCA patients, of whom approximately 20% were 65 years of age or older.
DRUG INTERACTIONS:
(Also see ACTIONS/CLINICAL PHARMACOLOGY, Pharmacokinetic Drug-Drug
Interactions.)
Inhibitors Of CYP2D6; Poor Metabolizers Of Debrisoquine: Interactions of
carvedilol with strong inhibitors of CYP2D6 (such as quinidine, fluoxetine,
paroxetine, and propafenone) have not been studied, but these drugs would be
expected to increase blood levels of the R(+) enantiomer of carvedilol (see
ACTIONS/CLINICAL PHARMACOLOGY). Retrospective analysis of side effects in
clinical trials showed that poor 2D6 metabolizers had a higher rate of dizziness
during up-titration, presumably resulting from vasodilating effects of the
higher concentrations of the alpha-blocking R(+) enantiomer.
Catecholamine-Depleting Agents: Patients taking both agents with Beta-blocking
properties and a drug that can deplete catecholamines (e.g., reserpine and
monoamine oxidase inhibitors) should be observed closely for signs of
hypotension and/or severe bradycardia.
Clonidine: Concomitant administration of clonidine with agents with Beta-
blocking properties may potentiate blood pressure- and heart-rate-lowering
effects. When concomitant treatment with agents with Beta-blocking properties
and clonidine is to be terminated, the Beta-blocking agent should be
discontinued first. Clonidine therapy can then be discontinued several days
later by gradually decreasing the dosage.
Digoxin: Digoxin concentrations are increased by about 15% when digoxin and
carvedilol are administered concomitantly. Both digoxin and CARCA slow AV
conduction. Therefore, increased monitoring of digoxin is recommended when
initiating, adjusting or discontinuing CARCA.
Inducers And Inhibitors Of Hepatic Metabolism: Rifampin reduced plasma
concentrations of carvedilol by about 70%. Cimetidine increased AUC by about 30%
but caused no change in Cmax.
Calcium Channel Blockers: Isolated cases of conduction disturbance (rarely with
hemodynamic compromise) have been observed when CARCA is co- administered with
diltiazem. As observed with other agents with Beta-blocking properties, if CARCA
(carvedilol) is to be administered orally with calcium channel blockers of the
verapamil or diltiazem type, it is recommended that ECG and blood pressure be
monitored.
Insulin Or Oral Hypoglycemics: Agents with Beta- blocking properties may enhance
the blood-sugar- reducing effect of insulin and oral hypoglycemics. Therefore,
in patients taking insulin or oral hypoglycemics, regular monitoring of blood
glucose is recommended.
(See Also PRECAUTIONS section.)
ADVERSE REACTIONS:
CONGESTIVE HEART FAILURE
CARCA has been evaluated for safety in congestive heart failure in more than
1,900 patients worldwide of whom 1,300 participated in U.S. clinical trials.
Approximately 54% of the total treated population received CARCA for at least 6
months and 20% received CARCA for at least 12 months. The adverse experience
profile of CARCA in congestive heart failure patients was consistent with the
pharmacology of the drug and the health status of the patients. In the U.S.
clinical trials comparing CARCA in daily doses up to 100 mg (n=765) to placebo
(n=437), 5.4% of CARCA patients discontinued for adverse experiences vs. 8.0% of
placebo patients.
Table 1 shows adverse events in U.S. placebo- controlled clinical trials of
congestive heart failure patients that occurred with an incidence of greater
than 2% regardless of causality and were more frequent in drug-treated patients
than placebo-treated patients. Median study medication exposure was 6.33 months
for both CARCA (carvedilol) and placebo patients.
TABLE 1
ADVERSE EVENTS IN THE U.S. PLACEBO-CONTROLLED
CONGESTIVE HEART FAILURE TRIALS
INCIDENCE >2%, REGARDLESS OF CAUSALITY;
WITHDRAWAL RATES DUE TO ADVERSE EVENTS
---------------------------------------------------------------------------------------------------------------------------------------------
ADVERSE REACTIONS WITHDRAWALS
---------------------------------------------------------------------------------------------------------------------------------------------
CARCA PLACEBO CARCA PLACEBO
(N=765) (N=437) (N=765) (N=437)
% occurrence % occurrence % withdrawals % withdrawals
AUTONOMIC NERVOUS
SYSTEM
Sweating increased 2.9 2.1 --- ---
BODY AS A WHOLE
Fatigue 23.9 22.4 0.7 0.7
Chest pain 14.4 14.2 0.1 ---
Pain 8.6 7.6 --- 0.2
Injury 5.9 5.5 --- ---
Drug level increased 5.1 3.7 --- 0.2
Edema generalized 5.1 2.5 --- ---
Edema dependent 3.7 1.8 --- ---
Fever 3.1 2.3 --- ---
Edema legs 2.2 0.2 0.1 0.2
CARDIOVASCULAR
Bradycardia 8.8 0.9 0.8 ---
Hypotension 8.5 3.4 0.4 0.2
Syncope 3.4 2.5 0.3 0.2
Hypertension 2.9 2.5 0.1 ---
AV block 2.9 0.5 --- ---
Angina pectoris 2.0 1.1 --- ---
aggravated
CENTRAL NERVOUS SYSTEM
Dizziness 32.4 19.2 0.4 ---
Headache 8.1 7.1 0.3 ---
Paresthesia 2.0 1.8 0.1 ---
GASTROINTESTINAL
Diarrhea 11.8 5.9 0.3 ---
Nausea 8.5 4.8 --- ---
Abdominal pain 7.2 7.1 0.3 ---
Vomiting 6.3 4.3 0.1 ---
HEMATOLOGIC
Thrombocytopenia 2.0 0.5 0.1 ---
METABOLIC
Hyperglycemia 12.2 7.8 0.1 ---
Weight increase 9.7 6.9 0.1 0.5
Gout 6.3 6.2 --- ---
BUN increased 6.0 4.6 0.3 0.2
NPN increased 5.8 4.6 0.3 0.2
Hypercholesterolemia 4.1 2.5 --- ---
Dehydration 2.1 1.6 --- ---
Hypervolemia 2.0 0.9 --- ---
MUSCULOSKELETAL
Back Pain 6.9 6.6 --- ---
Arthralgia 6.4 4.8 0.1 0.2
Myalgia 3.4 2.7 --- ---
RESISTANCE MECHANISM
Upper respiratory
tract infection 18.3 17.6 --- ---
Infection 2.2 0.9 --- ---
RESPIRATORY
Sinusitis 5.4 4.3 --- ---
Bronchitis 5.4 3.4 --- 0.2
Pharyngitis 3.1 2.7 --- ---
URINARY/RENAL
Urinary tract infection 3.1 2.7 --- ---
Hematuria 2.9 2.1 --- ---
VISION
Vision abnormal 5.0 1.8 0.1 ---
------------------------------------------------------------------------------------------------------------------------------------------------------------
INCIDENCE >2%, REGARDLESS OF CAUSALITY; WITHDRAWAL RATES DUE TO ADVERSE EVENTS
In addition to the events in Table 1, asthenia, cardiac failure, flatulence,
anorexia, dyspepsia, palpitation, extrasystoles, hyperkalemia, arthritis, angina
pectoris, insomnia, depression, anemia, viral infection, dyspnea, coughing,
respiratory disorder, rhinitis, rash, and leg cramps were also reported, but
rates were equal to, or more common in, placebo-treated patients.
The following adverse events were reported more frequently with CARCA in U.S.
placebo-controlled trials in patients with congestive heart failure:
INCIDENCE >1% TO <2%
BODY AS A WHOLE: Peripheral edema, allergy, sudden death, malaise, hypovolemia.
CARDIOVASCULAR: Fluid overload, postural hypotension.
CENTRAL AND PERIPHERAL NERVOUS SYSTEM: Hypesthesia, vertigo.
GASTROINTESTINAL: Melena, periodontitis.
LIVER AND BILIARY SYSTEM: SGPT increased, SGOT increased.
METABOLIC AND NUTRITIONAL: Hyperuricemia, hypoglycemia, hyponatremia, increased
alkaline phosphatase, glycosuria.
PLATELET, BLEEDING AND CLOTTING: Prothrombin decreased, purpura.
PSYCHIATRIC: Somnolence.
REPRODUCTIVE, MALE: Impotence.
URINARY SYSTEM: Abnormal renal function, albuminuria.
HYPERTENSION
CARCA (carvedilol) has been evaluated for safety in hypertension in more than
2,193 patients in U.S. clinical trials and in 2,976 patients in international
clinical trials. Approximately 36% of the total treated population received
CARCA for at least 6 months. In general, CARCA was well tolerated at doses up to
50 mg daily. Most adverse events reported during CARCA therapy were of mild to
moderate severity. In U.S. controlled clinical trials directly comparing CARCA
monotherapy in doses up to 50 mg (n=1,142) to placebo (n=462), 4.9% of CARCA
patients discontinued for adverse events vs. 5.2% of placebo patients. Although
there was no overall difference in discontinuation rates, discontinuations were
more common in the carvedilol group for postural hypotension (1% vs. 0). The
overall incidence of adverse events in U.S. placebo-controlled trials was found
to increase with increasing dose of CARCA. For individual adverse events this
could only be distinguished for dizziness, which increased in frequency from 2%
to 5% as total daily dose increased from 6.25 mg to 50 mg.
Table 2 shows adverse events in U.S. placebo- controlled clinical trials for
hypertension that occurred with an incidence of greater than 1% regardless of
causality, and that were more frequent in drug-treated patients than placebo-
treated patients.
TABLE 2
ADVERSE EVENTS IN U.S. PLACEBO-CONTROLLED
HYPERTENSION TRIALS
INCIDENCE >/=1%, REGARDLESS OF CAUSALITY;
WITHDRAWAL RATES DUE TO ADVERSE EVENTS
-------------------------------------------------------------------------------------------------------------------------------------------
ADVERSE REACTIONS WITHDRAWALS
-------------------------------------------------------------------------------------------------------------------------------------------
CARCA PLACEBO CARCA PLACEBO
(N=1,142) (N=462) (N=1,142) (N=462)
% occurrence % occurrence % withdrawals % withdrawals
BODY AS A WHOLE
Fatigue 4.3 3.9 0.3 0.2
Injury 2.9 2.6 0.1 ---
CARDIOVASCULAR
Bradycardia 2.1 0.2 0.4 ---
Postural
hypotension 1.8 --- 1.0 ---
Dependent edema 1.7 1.5 0.1 0.4
Peripheral edema 1.4 0.4 0.2 ---
CENTRAL NERVOUS SYSTEM
Dizziness 6.2 5.4 0.4 1.3
Insomnia 1.6 0.6 --- 0.2
Somnolence 1.8 1.5 --- ---
GASTROINTESTINAL
Abdominal pain 1.4 1.3 0.1 ---
Diarrhea 2.2 1.3 0.1 ---
HEMATOLOGIC
Thrombocytopenia 1.1 0.2 --- ---
METABOLIC
Hypertri-
glyceridemia 1.2 0.2 --- ---
MUSCULOSKELETAL
Back pain 2.3 1.5 0.1 ---
RESISTANCE MECHANISM
Viral Infection 1.8 1.3 --- ---
RESPIRATORY
Rhinitis 2.1 1.9 --- ---
Pharyngitis 1.5 0.6 --- ---
Dyspnea 1.4 0.9 0.4 0.2
URINARY/RENAL
Urinary tract
infection 1.8 0.6 --- ---
--------------------------------------------------------------------------------------------------------------------------------------------------------
In addition to the events in Table 2, chest pain, dyspepsia, headache, nausea,
pain, sinusitis, and upper respiratory tract infection were also reported, but
rates were at least as great in placebo-treated patients.
The following adverse events were reported as possibly or probably related in
worldwide open or controlled trials with CARCA (carvedilol) in patients with
hypertension or congestive heart failure.
INCIDENCE >0.1% TO =1%
CARDIOVASCULAR: Peripheral ischemia, tachycardia.
CENTRAL AND PERIPHERAL NERVOUS SYSTEM: Hypokinesia.
GASTROINTESTINAL: Bilirubinemia, increased hepatic enzymes (0.2% of hypertension
patients and 0.4% of congestive heart failure patients were discontinued from
therapy because of increases in hepatic enzymes; see WARNINGS, Hepatic Injury).
GENERAL: Substernal chest pain, edema.
PSYCHIATRIC: Nervousness, sleep disorder, aggravated depression, impaired
concentration, abnormal thinking, paroniria, emotional lability.
RESPIRATORY SYSTEM: Asthma (see CONTRAINDICATIONS).
REPRODUCTIVE: Male: decreased libido.
SKIN AND APPENDAGES: Pruritus, rash erythematous, rash maculopapular, rash
psoriaform, photosensitivity reaction.
SPECIAL SENSES: Tinnitus.
URINARY SYSTEM: Micturition frequency.
AUTONOMIC NERVOUS SYSTEM: Dry mouth, sweating increased.
METABOLIC AND NUTRITIONAL: Hypokalemia, diabetes mellitus, hypertriglyceridemia.
HEMATOLOGIC: Anemia, leukopenia.
The following events were reported in >/=0.1% of the patients and are
potentially important: complete AV block, bundle branch block, myocardial
ischemia, cerebrovascular, disorder, convulsions, migraine, neuralgia, paresis,
anaphylactoid reaction, alopecia, exfoliative dermatitis, amnesia, GI
hemorrhage, bronchospasm, pulmonary edema, decreased hearing, respiratory
alkalosis, increased BUN, decreased HDL, pancytopenia and atypical lymphocytes.
Other adverse events occurred sporadically in single patients and cannot be
distinguished from concurrent disease states or medications.
CARCA therapy has not been associated with clinically significant changes in
routine laboratory tests in hypertensive patients. No clinically relevant
changes were noted in serum potassium, fasting serum glucose, total
triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea
nitrogen or creatinine.
OVERDOSAGE:
The acute oral LD50 doses in male and female mice and male and female rats are
over 8000 mg/kg.
Overdosage may cause severe hypotension, bradycardia, cardiac insufficiency,
cardiogenic shock and cardiac arrest. Respiratory problems, bronchospasms,
vomiting, lapses of consciousness and generalized seizures may also occur.
The patient should be placed in a supine position and, where necessary, kept
under observation and treated under intensive-care conditions. Gastric lavage or
pharmacologically induced emesis may be used shortly after ingestion. The
following agents may be administered:
For Excessive Bradycardia: atropine, 2 mg IV.
To Support Cardiovascular Function: glucagon, 5 to 10 mg IV rapidly over 30
seconds, followed by a continuous infusion of 5 mg/hour, sympathomimetics
(dobutamine, isoprenaline, adrenaline) at doses according to body weight and
effect.
If peripheral vasodilation dominates, it may be necessary to administer
adrenaline or noradrenaline with continuous monitoring of circulatory
conditions. For therapy-resistant bradycardia, pacemaker therapy should be
performed. For bronchospasm, Beta- sympathomimetics (as aerosol or IV) or
aminophylline IV should be given. In the event of seizures, slow IV injection
of diazepam or clonazepam is recommended.
NOTE: In the event of severe intoxication where there are symptoms of shock,
treatment with antidotes must be continued for a sufficiently long period of
time consistent with the 7- to 10-hour half-life of carvedilol.
Cases of overdosage with CARCA alone or in combination with other drugs have
been reported. Quantities ingested in some cases exceeded 1000 milligrams.
Symptoms experienced included low blood pressure and heart rate. Standard
supportive treatment was provided and individuals recovered.
DOSAGE AND ADMINISTRATION:
CONGESTIVE HEART FAILURE
DOSAGE MUST BE INDIVIDUALIZED AND CLOSELY MONITORED BY A PHYSICIAN DURING UP-
TITRATION. Prior to initiation of CARCA, the dosing of digitalis, diuretics and
ACE inhibitors (if used) should be stabilized. The recommended starting dose of
CARCA is 3.125 mg twice daily for two weeks. If this dose is tolerated, it can
be increased to 6.25 mg twice daily. Dosing should then be doubled every 2 weeks
to the highest level tolerated by the patient. At initiation of each new dose,
patients should be observed for signs of dizziness or light-headedness for one
hour. The maximum recommended dose is 25 mg twice daily in patients weighing
less than 85 kg (187 lbs) and 50 mg twice daily in patients weighing more than
85 kg. CARCA (carvedilol) should be taken with food to slow the rate of
absorption and reduce the incidence of orthostatic effects.
Before each dose increase the patient should be seen in the office and evaluated
for symptoms of worsening heart failure, vasodilation (dizziness, light-
headedness, symptomatic hypotension) or bradycardia, in order to determine
tolerability of CARCA. Transient worsening of heart failure may be treated with
increased doses of diuretics although occasionally it is necessary to lower the
dose of CARCA or temporarily discontinue it. Symptoms of vasodilation often
respond to a reduction in the dose of diuretics or ACE inhibitor. If these
changes do not relieve symptoms, the dose of CARCA may be decreased. The dose of
CARCA should not be increased until symptoms of worsening heart failure or
vasodilation have been stabilized. Initial difficulty with titration should not
preclude later attempts to introduce CARCA. If congestive heart failure patients
experience bradycardia (pulse rate below 55 beats/min.), the dose of CARCA
should be reduced.
HYPERTENSION
DOSAGE MUST BE INDIVIDUALIZED. The recommended starting dose of CARCA is 6.25 mg
twice daily. If this dose is tolerated, using standing systolic pressure
measured about 1 hour after dosing as a guide, the dose should be maintained for
7 to 14 days, and then increased to 12.5 mg twice daily if needed, based on
trough blood pressure, again using standing systolic pressure one hour after
dosing as a guide for tolerance. This dose should also be maintained for 7 to 14
days and can then be adjusted upward to 25 mg twice daily if tolerated and
needed. The full antihypertensive effect of CARCA is seen within 7 to 14 days.
Total daily dose should not exceed 50 mg. CARCA should be taken with food to
slow the rate of absorption and reduce the incidence of orthostatic effects.
Addition of a diuretic to CARCA, or CARCA to a diuretic can be expected to
produce additive effects and exaggerate the orthostatic component of CARCA
action.
CARCA (carvedilol) should not be given to patients with severe hepatic
impairment (see CONTRAINDICATIONS).
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