carvedilol 12.5 MG Oral Tablet
Generic Name: CARVEDILOL
Brand Name: Carvedilol
- Substance Name(s):
CYP P450 2D6 enzyme inhibitors may increase and rifampin may decrease carvedilol levels.
( 7.1 , 7.5 ) Hypotensive agents (e.g., reserpine, MAO inhibitors, clonidine) may increase the risk of hypotension and/or severe bradycardia.
( 7.2 ) Cyclosporine or digoxin levels may increase.
( 7.3 , 7.4 ) Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate.
Concomitant use can increase the risk of bradycardia.
( 7.4 ) Amiodarone may increase carvedilol levels resulting in further slowing of the heart rate or cardiac conduction.
( 7.6 ) Verapamil- or diltiazem-type calcium channel blockers may affect ECG and/or blood pressure.
7) Insulin and oral hypoglycemics action may be enhanced.
8) 7.1 CYP2D6 Inhibitors and Poor Metabolizers Interactions of carvedilol with potent inhibitors of CYP2D6 isoenzyme (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 Clinical Pharmacology (12.3) ].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 α-blocking R(+) enantiomer.
7.2 Hypotensive Agents Patients taking A β-blocker 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.
Concomitant administration of clonidine with β-blocker may cause hypertension and bradycardia.
When concomitant treatment with β-blocker and clonidine is to be terminated, the β-blocker agent should be discontinued first.
Clonidine therapy can then be discontinued several days later by gradually decreasing the dosage.
7.3 Cyclosporine Modest increases in mean trough cyclosporine concentrations were observed following initiation of carvedilol treatment in 21 renal transplant subjects suffering from chronic vascular rejection.
In about 30% of subjects, the dose of cyclosporine had to be reduced in order to maintain cyclosporine concentrations within the therapeutic range, while in the remainder no adjustment was needed.
On the average for the group, the dose of cyclosporine was reduced about 20% in these subjects.
Due to wide interindividual variability in the dose adjustment required, it is recommended that cyclosporine concentrations be monitored closely after initiation of carvedilol therapy and that the dose of cyclosporine be adjusted as appropriate.
7.4 Digitalis Glycosides Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate.
Concomitant use can increase the risk of bradycardia.
Digoxin concentrations are increased by about 15% when digoxin and carvedilol are administered concomitantly.
Therefore, increased monitoring of digoxin is recommended when initiating, adjusting, or discontinuing Carvedilol tablets [see Clinical Pharmacology (12.5) ].
7.5 Inducers/Inhibitors of Hepatic Metabolism Rifampin reduced plasma concentrations of carvedilol by about 70% [see Clinical Pharmacology (12.5) ].
Cimetidine increased AUC by about 30% but caused no change in C max [see Clinical Pharmacology (12.5) ].
7.6 Amiodarone Amiodarone, and its metabolite desethyl amiodarone, inhibitors of CYP2C9, and P-glycoprotein increased concentrations of the S(-)-enantiomer of carvedilol by at least 2 fold [ see Clinical Pharmacology (12.5) ].
The concomitant administration of amiodarone or other CYP2C9 inhibitors such as fluconazole with carvedilol may enhance the β-blocking properties of carvedilol resulting in further slowing of the heart rate or cardiac conduction.
Patients should be observed for signs of bradycardia or heart block, particularly when one agent is added to pre-existing treatment with the other.
7.7 Calcium Channel Blockers Conduction disturbance (rarely with hemodynamic compromise) has been observed when carvedilol tablet is co-administered with diltiazem.
As with β-blockers, if carvedilol tablet is administered with calcium channel blockers of the verapamil or diltiazem type, it is recommended that ECG and blood pressure be monitored.
7.8 Insulin or Oral Hypoglycemics β-blockers 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 Warning and Precautions (5.6) ].
7.9 Anesthesia If treatment with carvedilol is to be continued perioperatively, particular care should be taken when anesthetic agents that depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used [ see Overdosage (10) ].
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.
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 per 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, β-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 carvedilol tablets alone or in combination with other drugs have been reported.
Quantities ingested in some cases exceeded 1,000 milligrams.
Symptoms experienced included low blood pressure and heart rate.
Standard supportive treatment was provided and individuals recovered.
Carvedilol is a nonselective β-adrenergic blocking agent with α 1 -blocking activity.
It is (±)-1-(Carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol.
Carvedilol is a racemic mixture with the following structure: Carvedilol is a white to almost white crystalline powder with a molecular weight of 406.5 and a molecular formula of C 24 H 26 N 2 O 4 .
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).
Each carvedilol tablet intended for oral administration contains 3.125 mg or 6.25 mg or 12.5 mg or 25 mg of carvedilol.
In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, povidone, talc, and titanium dioxide.
structured formula for carvedilol
14.1 Heart Failure A total of 6,975 subjects with mild to severe heart failure were evaluated in placebo-controlled trials of carvedilol.
Mild-to-Moderate Heart Failure Carvedilol was studied in 5 multicenter, placebo-controlled trials, and in 1 active-controlled trial (COMET trial) involving subjects with mild-to-moderate heart failure.
Four US multicenter, doubleblind, placebo-controlled trials enrolled 1,094 subjects (696 randomized to carvedilol) with NYHA class II-III heart failure and ejection fraction less than or equal to 0.35.
The vast majority were on digitalis, diuretics, and an ACE inhibitor at trial entry.
Patients were assigned to the trials based upon exercise ability.
An Australia-New Zealand double-blind, placebo-controlled trial enrolled 415 subjects (half randomized to carvedilol) with less severe heart failure.
All protocols excluded subjects expected to undergo cardiac transplantation during the 7.5 to 15 months of double-blind follow-up.
All randomized subjects had tolerated a 2-week course on carvedilol 6.25 mg twice daily.
In each trial, there was a primary end point, either progression of heart failure (1 US trial) or exercise tolerance (2 US trials meeting enrollment goals and the Australia-New Zealand trial).
There were many secondary end points specified in these trials, including NYHA classification, patient and physician global assessments, and cardiovascular hospitalization.
Other analyses not prospectively planned included the sum of deaths and total 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 US and Australia-New Zealand trials were as follows: Slowing Progression of Heart Failure One US multicenter trial (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 trial, death and total hospitalizations were reduced by about 25% over 18 to 24 months.
In the 3 largest US trials, death and total hospitalizations were reduced by 19%, 39%, and 49%, nominally statistically significant in the last 2 trials.
The Australia-New Zealand results were statistically borderline.
Functional Measures None of the multicenter trials had NYHA classification as a primary end point, but all such trials had it as a secondary end point.
There was at least a trend toward improvement in NYHA class in all trials.
Exercise tolerance was the primary end point in 3 trials; in none was a statistically significant effect found.
Subjective Measures Health-related quality of life, as measured with a standard questionnaire (a primary end point in 1 trial), was unaffected by carvedilol.
However, patients’ and investigators’ global assessments showed significant improvement in most trials.
Mortality Death was not a pre-specified end point in any trial, but was analyzed in all trials.
Overall, in these 4 US trials, mortality was reduced, nominally significantly so in 2 trials.
The COMET Trial In this double-blind trial, 3,029 subjects with NYHA class II-IV heart failure (left ventricular ejection fraction less than or equal to 35%) were randomized to receive either carvedilol (target dose: 25 mg twice daily) or immediate-release metoprolol tartrate (target dose: 50 mg twice daily).
The mean age of the subjects was approximately 62 years, 80% were males, and the mean left ventricular ejection fraction at baseline was 26%.
Approximately 96% of the subjects had NYHA class II or III heart failure.
Concomitant treatment included diuretics (99%), ACE inhibitors (91%), digitalis (59%), aldosterone antagonists (11%), and “statin” lipid-lowering agents (21%).
The mean duration of follow-up was 4.8 years.
The mean dose of carvedilol was 42 mg per day.
The trial had 2 primary end points: all-cause mortality and the composite of death plus hospitalization for any reason.
The results of COMET are presented in Table 3 below.
All-cause mortality carried most of the statistical weight and was the primary determinant of the trial size.
All-cause mortality was 34% in the subjects treated with carvedilol and was 40% in the immediate-release metoprolol group (P = 0.0017; hazard ratio = 0.83, 95% CI: 0.74 to 0.93).
The effect on mortality was primarily due to a reduction in cardiovascular death.
The difference between the 2 groups with respect to the composite end point was not significant (P = 0.122).
The estimated mean survival was 8.0 years with carvedilol and 6.6 years with immediate-release metoprolol.
Tablet 3 Results of COMET It is not known whether this formulation of metoprolol at any dose or this low dose of metoprolol in any formulation has any effect on survival or hospitalization in patients with heart failure.
Thus, this trial extends the time over which carvedilol manifests benefits on survival in heart failure, but it is not evidence that carvedilol improves outcome over the formulation of metoprolol (TOPROL-XL) with benefits in heart failure.
Severe Heart Failure (COPERNICUS) In a double-blind trial (COPERNICUS), 2,289 subjects with heart failure at rest or with minimal exertion and left ventricular ejection fraction less than 25% (mean 20%), despite digitalis (66%), diuretics (99%), and ACE inhibitors (89%) were randomized to placebo or carvedilol.
Carvedilol was titrated from a starting dose of 3.125 mg twice daily to the maximum tolerated dose or up to 25 mg twice daily over a minimum of 6 weeks.
Most subjects achieved the target dose of 25 mg.
The trial was conducted in Eastern and Western Europe, the United States, Israel, and Canada.
Similar numbers of subjects per group (about 100) withdrew during the titration period.
The primary end point of the trial was all-cause mortality, but cause-specific mortality and the risk of death or hospitalization (total, cardiovascular [CV], or heart failure [HF]) were also examined.
The developing trial data were followed by a data monitoring committee, and mortality analyses were adjusted for these multiple looks.
The trial was stopped after a median follow-up of 10 months because of an observed 35% reduction in mortality (from 19.7% per patient-year on placebo to 12.8% on carvedilol, hazard ratio 0.65, 95% CI: 0.52 to 0.81, P = 0.0014, adjusted) (see Figure 1).
The results of COPERNICUS are shown in Table 4.
Table 4 Results of COPERNICUS Trial in Subjects with Severe Hearth Failure Cardiovascular = CV: Hearth failure = HF Figure 1.
Survival Analysis for COPERNICUS (Intent-to-Treat) The effect on mortality was principally the result of a reduction in the rate of sudden death among subjects without worsening heart failure.
Patients’ global assessments, in which carvedilol-treated subjects were compared with placebo, were based on pre-specified, periodic patient self-assessments regarding whether clinical status post-treatment showed improvement, worsening, or no change compared with baseline.
Subjects treated with carvedilol showed significant improvements in global assessments compared with those treated with placebo in COPERNICUS.
The protocol also specified that hospitalizations would be assessed.
Fewer subjects on carvedilol than on placebo were hospitalized for any reason (372 versus 432, P = 0.0029), for cardiovascular reasons (246 versus 314, P = 0.0003), or for worsening heart failure (198 versus 268, P = 0.0001).
Carvedilol tablets had a consistent and beneficial effect on all-cause mortality as well as the combined end points of all-cause mortality plus hospitalization (total, CV, or for heart failure) in the overall trial population and in all subgroups examined, including men and women, elderly and non-elderly, blacks and non-blacks, and diabetics and non-diabetics (see Figure 2).
Effects on Mortality for Subgroups in COPERNICUS Table 3 Rev.
09/2017 Table 4 Rev.
09/2017 Figure 1 Figure 2 14.2 Left Ventricular Dysfunction following Myocardial Infarction CAPRICORN was a double-blind trial comparing carvedilol and placebo in 1,959 subjects with a recent myocardial infarction (within 21 days) and left ventricular ejection fraction of less than or equal to 40%, with (47%) or without symptoms of heart failure.
Subjects given carvedilol received 6.25 mg twice daily, titrated as tolerated to 25 mg twice daily.
Subjects had to have a systolic blood pressure greater than 90 mm Hg, a sitting heart rate greater than 60 beats per minute, and no contraindication to β-blocker use.
Treatment of the index infarction included aspirin (85%), IV or oral β-blockers (37%), nitrates (73%), heparin (64%), thrombolytics (40%), and acute angioplasty (12%).
Background treatment included ACE inhibitors or angiotensin receptor blockers (97%), anticoagulants (20%), lipid-lowering agents (23%), and diuretics (34%).
Baseline population characteristics included an average age of 63 years, 74% male, 95% Caucasian, mean blood pressure 121/74 mm Hg, 22% with diabetes, and 54% with a history of hypertension.
Mean dosage achieved of carvedilol was 20 mg twice daily; mean duration of follow-up was 15 months.
All-cause mortality was 15% in the placebo group and 12% in the carvedilol group, indicating a 23% risk reduction in subjects treated with carvedilol (95% CI 2% to 40%, P = 0.03), as shown in Figure 3.
The effects on mortality in various subgroups are shown in Figure 4.
Nearly all deaths were cardiovascular (which were reduced by 25% by carvedilol), and most of these deaths were sudden or related to pump failure (both types of death were reduced by carvedilol).
Another trial end point, total mortality and all-cause hospitalization, did not show a significant improvement.
There was also a significant 40% reduction in fatal or non-fatal myocardial infarction observed in the group treated with carvedilol (95% CI: 11% to 60%, P = 0.01).
A similar reduction in the risk of myocardial infarction was also observed in a meta-analysis of placebo-controlled trials of carvedilol in heart failure.
Survival Analysis for CAPRICORN (Intent-to-Treat) Figure 4.
Effects on Mortality for Subgroups in CAPRICORN Mortality Rate Carvedilol vs Placebo Effects on Mortality for Subgroups in CAPRICORN 14.3 Hypertension Carvedilol tablets were studied in 2 placebo-controlled trials that utilized twice-daily dosing, at total daily doses of 12.5 to 50 mg.
In these and other trials, the starting dose did not exceed 12.5 mg.
At 50 mg per day, carvedilol tablets reduced sitting trough (12-hour) blood pressure by about 9/5.5 mm Hg; at 25 mg per 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 per day.
In general, as is true for other β-blockers, responses were smaller in black than non-black subjects.
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 (6) ].
14.4 Hypertension with Type 2 Diabetes Mellitus In a double-blind trial (GEMINI), carvedilol, added to an ACE inhibitor or angiotensin-receptor blocker, was evaluated in a population with mild-to-moderate hypertension and well-controlled type 2 diabetes mellitus.
The mean HbA1c at baseline was 7.2%.
Carvedilol was titrated to a mean dose of 17.5 mg twice daily and maintained for 5 months.
Carvedilol had no adverse effect on glycemic control, based on HbA1c measurements (mean change from baseline of 0.02%, 95% CI: -0.06 to 0.10, P = NS) [ see Warnings and Precautions (5.6) ].
/STORAGE AND HANDLING Carvedilol Tablets, 6.25 mg are white to off-white, round, biconvex, beveled edge, film-coated tablets debossed with ‘ZC40’ on one side and plain on other side and are supplied as follows: NDC-68382-350-59 Unit of Use Bottles of 60 Carvedilol Tablets, 12.5 mg are white to off-white, round, biconvex, beveled edge, film-coated tablets debossed with ‘ZC41’ on one side and plain on other side and are supplied as follows: NDC-68382-351-59 Unit of Use Bottles of 60 Carvedilol Tablets USP, 25 mg are white to off-white, round, biconvex, beveled edge, film-coated tablets debossed with ‘ZC42’ on one side and plain on other side and are supplied as follows: NDC-68645-496-59 Unit of Use Bottles of 60 Storage: WARNING: KEEP OUT OF THE REACH OF CHILDREN Tamper Evident: Do Not Use this product if bottle seal is not intact CHILD-RESISTANT: Tighten cap on bottle after use.
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Protect from moisture, freezing and excessive heat.
Dispense contents in a tight, light-resistant container.
RECENT MAJOR CHANGES
Drug Interactions ( 7 ) December 2008 Contraindications ( 4 ) April 2008
8.5 Geriatric Use Of the 765 subjects with heart failure randomized to carvedilol in US clinical trials, 31% (235) were aged 65 years or older, and 7.3% (56) were aged 75 years or older.
Of the 1,156 subjects randomized to carvedilol in a long-term, placebo-controlled trial in severe heart failure, 47% (547) were aged 65 years or older, and 15% (174) were aged 75 years or older.
Of 3,025 subjects receiving carvedilol in heart failure trials worldwide, 42% were aged 65 years or older.
Of the 975 myocardial infarction subjects randomized to carvedilol tablets in the CAPRICORN trial, 48% (468) were aged 65 years or older, and 11% (111) were aged 75 years or older.
Of the 2,065 hypertensive subjects in US clinical trials of efficacy or safety who were treated with carvedilol tablets, 21% (436) were aged 65 years or older.
Of 3,722 subjects receiving carvedilol tablets in hypertension clinical trials conducted worldwide, 24% were aged 65 years or older.
With the exception of dizziness in hypertensive subjects (incidence 8.8% in the elderly versus 6% in younger subjects), no overall differences in the safety or effectiveness (see Figure 2 and 4 ) were observed between the older subjects and younger subjects in each of these populations.
Similarly, other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.
DOSAGE FORMS AND STRENGTHS
Tablets: 3.125 mg, 6.25 mg, 12.5 mg, 25 mg (3) The white to off-white, round, film-coated tablets are available in the following strengths: 3.125 mg– debossed with Z and 1, 6.25 mg–debossed with ZC40, 12.5 mg–debossed with ZC41 and 25 mg–debossed with ZC42.
MECHANISM OF ACTION
12.1 Mechanism of Action Carvedilol is a racemic mixture in which nonselective β-adrenoreceptor blocking activity is present in the S(-) enantiomer and α 1 -adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency.
carvedilol has no intrinsic sympathomimetic activity.
INDICATIONS AND USAGE
Carvedilol tablets are an alpha/beta-adrenergic blocking agent indicated for the treatment of: mild to severe chronic heart failure (1.1) left ventricular dysfunction following myocardial infarction in clinically stable patients( 1.
2) Hypertension( 1.
3) 1.1 Heart Failure Carvedilol tablets are indicated for the treatment of mild-to-severe chronic heart failure of ischemic or cardiomyopathic origin, usually in addition to diuretics, ACE inhibitors, and digitalis, to increase survival and, also, to reduce the risk of hospitalization [ see Drug Interactions (7.4) and Clinical Studies (14.1) ].
1.2 Left Ventricular Dysfunction following Myocardial Infarction: Carvedilol tablets are indicated to reduce cardiovascular mortality in clinically stable patients who have survived the acute phase of a myocardial infarction and have a left ventricular ejection fraction of less than or equal to 40% (with or without symptomatic heart failure) [ see Clinical Studies (14.2) ] 1.3 Hypertension: Carvedilol tablets are indicated for the management of essential hypertension [see Clinical Studies (14.3, 14.4)].
It can be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics [see Drug Interactions (7.2)].
8.4 Pediatric Use Effectiveness of carvedilol tablets in patients younger than 18 years has not been established.
In a double-blind trial, 161 children (mean age: 6 years, range: 2 months to 17 years; 45% younger than 2 years) with chronic heart failure [NYHA class II-IV, left ventricular ejection fraction less than 40% for children with a systemic left ventricle (LV), and moderate-severe ventricular dysfunction qualitatively by echo for those with a systemic ventricle that was not an LV] who were receiving standard background treatment were randomized to placebo or to 2 dose levels of carvedilol.
These dose levels produced placebo-corrected heart rate reduction of 4 to 6 heart beats per minute, indicative of β-blockade activity.
Exposure appeared to be lower in pediatric subjects than adults.
After 8 months of follow-up, there was no significant effect of treatment on clinical outcomes.
Adverse reactions in this trial that occurred in greater than 10% of subjects treated with carvedilol and at twice the rate of placebo-treated subjects included chest pain (17% versus 6%), dizziness (13% versus 2%), and dyspnea (11% versus 0%).
8.1 Pregnancy Risk Summary Available data regarding use of carvedilol 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] .
In animal reproduction studies, there was no evidence of adverse developmental outcomes at clinically relevant doses [see Data] .
Oral administration of carvedilol to pregnant rats during organogenesis resulted in post-implantation loss, decreased fetal body weight, and an increased frequency of delayed fetal skeletal development at maternally toxic doses that were 50 times the maximum recommended human dose (MRHD).
In addition, oral administration of carvedilol to pregnant rabbits during organogenesis resulted in increased post-implantation loss at doses 25 times the MRHD [see Data] .
The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the U.S.
general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations 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 postpartum 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.
Data Animal Data: Studies performed in rats and rabbits given carvedilol during fetal organogenesis revealed increased post-implantation loss in rats at a maternally toxic dose of 300 mg per kg per day (50 times the MRHD as mg per m2) and in rabbits (in the absence of maternal toxicity) at doses of 75 mg per kg per day (25 times the MRHD as mg per m2).
In the rats, there was also a decrease in fetal body weight at 300 mg per kg per day (50 times the MRHD as mg per m2) accompanied by an increased incidence of fetuses with delayed skeletal development.
In rats, the no-effect level for embryo-fetal toxicity was 60 mg per kg per day (10 times the MRHD as mg per m2); in rabbits, it was 15 mg per kg per day (5 times the MRHD as mg per m2).
In a pre-and post-natal development study in rats administered carvedilol from late gestation through lactation, increased embryo-lethality was observed at a maternally toxic dose of 200 mg per kg per day (approximately 32 times the MRHD as mg per m2), and pup mortality and delays in physical growth development were observed at 60 mg per kg per day (10 times the MRHD as mg per m2) in the absence of maternal toxicity.
The no-effect level was 12 mg per kg per day (2 times the MRHD as mg per m2).
Carvedilol was present in fetal rat tissue.
WARNING AND CAUTIONS
WARNINGS AND PRECAUTIONS Acute exacerbation of coronary artery disease upon cessation of therapy: Do not abruptly discontinue.
( 5.1 ) Bradycardia, hypotension, worsening heart failure/fluid retention may occur.
Reduce the dose as needed.
( 5.2 , 5.3 , 5.4 ) Non-allergic bronchospasm (e.g., chronic bronchitis and emphysema): Avoid β-blockers.
( 4 ) However, if deemed necessary, use with caution and at lowest effective dose.
( 5.5 ) Diabetes: Monitor glucose as β-blockers may mask symptoms of hypoglycemia or worsen hyperglycemia.
( 5.6 ) 5.1 Cessation of Therapy Patients with coronary artery disease, who are being treated with carvedilol tablets, should be advised against abrupt discontinuation of therapy.
Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in angina patients following the abrupt discontinuation of therapy with β-blockers.
The last 2 complications may occur with or without preceding exacerbation of the angina pectoris.
As with other β-blockers, when discontinuation of carvedilol tablets is planned, the patients should be carefully observed and advised to limit physical activity to a minimum.
Carvedilol tablets should be discontinued over 1 to 2 weeks whenever possible.
If the angina worsens or acute coronary insufficiency develops, it is recommended that carvedilol tablets be promptly reinstituted, at least temporarily.
Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue therapy with carvedilol abruptly even in patients treated only for hypertension or heart failure.
5.2 Bradycardia In clinical trials, carvedilol tablets caused bradycardia in about 2% of hypertensive subjects, 9% of subjects with heart failure, and 6.5% of subjects with myocardial infarction and left ventricular dysfunction.
If pulse rate drops below 55 beats per minute, the dosage should be reduced.
5.3 Hypotension In clinical trials of primarily mild-to-moderate heart failure, hypotension and postural hypotension occurred in 9.7% and syncope in 3.4% of subjects receiving carvedilol tablets compared with 3.6% and 2.5% of placebo subjects, 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 subjects receiving carvedilol tablets, compared with 0.4% of placebo subjects.
In a long-term, placebo-controlled trial in severe heart failure (COPERNICUS), hypotension and postural hypotension occurred in 15.1% and syncope in 2.9% of heart failure subjects receiving carvedilol tablets compared with 8.7% and 2.3% of placebo subjects, respectively.
These events were a cause for discontinuation of therapy in 1.1% of subjects receiving carvedilol tablets, compared with 0.8% of placebo subjects.
Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive subjects, primarily following the initial dose or at the time of dose increase and was a cause for discontinuation of therapy in 1% of subjects.
In the CAPRICORN study of survivors of an acute myocardial infarction, hypotension or postural hypotension occurred in 20.2% of subjects receiving carvedilol tablets compared with 12.6% of placebo subjects.
Syncope was reported in 3.9% and 1.9% of subjects, respectively.
These events were a cause for discontinuation of therapy in 2.5% of subjects receiving carvedilol tablets, compared with 0.2% of placebo subjects.
Starting with a low dose, administration with food, and gradual up-titration should decrease the likelihood of syncope or excessive hypotension [see Dosage and Administration(2.1, 2.2) ] .
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.
5.4 Heart Failure/Fluid Retention Worsening heart 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 (2) ].
Occasionally it is necessary to lower the carvedilol dose or temporarily discontinue it.
Such episodes do not preclude subsequent successful titration of, or a favorable response to, carvedilol.
In a placebo-controlled trial of subjects with severe heart failure, worsening heart failure during the first 3 months was reported to a similar degree with carvedilol and with placebo.
When treatment was maintained beyond 3 months, worsening heart failure was reported less frequently in subjects treated with carvedilol than with placebo.
Worsening heart failure observed during long-term therapy is more likely to be related to the patients’ underlying disease than to treatment with carvedilol.
5.5 Non-allergic Bronchospasm Patients with bronchospastic disease (e.g., chronic bronchitis, emphysema) should, in general, not receive β-blockers.
Carvedilol tablets may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents.
It is prudent, if carvedilol tablets are used, to use the smallest effective dose, so that inhibition of endogenous or exogenous β-agonists is minimized.
In trials of subjects with heart failure, subjects 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.
5.6 Glycemic Control in Type 2 Diabetes In general, 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.
Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these possibilities.
In patients with heart failure and 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.
Trials designed to examine the effects of carvedilol on glycemic control in patients with diabetes and heart failure have not been conducted.
In a trial designed to examine the effects of carvedilol on glycemic control in a population with mild-to-moderate hypertension and well-controlled type 2 diabetes mellitus, carvedilol had no adverse effect on glycemic control, based on HbA1c measurements [ see Clinical Studies (14.4) ].
5.7 Peripheral Vascular Disease β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease.
Caution should be exercised in such individuals.
5.8 Deterioration of Renal Function Rarely, use of carvedilol in patients with heart failure has resulted in deterioration of renal function.
Patients at risk appear to be those with low blood pressure (systolic blood pressure less than 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.
5.9 Major Surgery Chronically administered β-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.
5.10 Thyrotoxicosis β-adrenergic blockade may mask clinical signs of hyperthyroidism, such as tachycardia.
Abrupt withdrawal of β-blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate thyroid storm.
5.11 Pheochromocytoma In patients with pheochromocytoma, an α-blocking agent should be initiated prior to the use of any β-blocking agent.
Although carvedilol has both α- and β-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.
5.12 Prinzmetal’s Variant Angina Agents with non-selective β-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 α-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.
5.13 Risk of Anaphylactic Reaction While taking β-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.
5.14 Intraoperative Floppy Iris Syndrome Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients treated with alpha-1 blockers (carvedilol is an alpha/beta blocker).
This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions.
The patient’s ophthalmologist should be prepared for possible modifications to the surgical technique, such as utilization of iris hooks, iris dilator rings, or viscoelastic substances.
There does not appear to be a benefit of stopping alpha-1 blocker therapy prior to cataract surgery.
INFORMATION FOR PATIENTS
PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).
Patients taking carvedilol tablets should be advised of the following: • Patients taking carvedilol tablets should be advised of the following: • Patients should take carvedilol tablets with food.
• Patients should not interrupt or discontinue using carvedilol tablets without a physician’s advice.
•Patients with heart failure should consult their physician if they experience signs or symptoms of worsening heart failure such as weight gain or increasing shortness of breath.
•Patients 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 experiencing dizziness or fatigue, patients should avoid driving or hazardous tasks.
•Patients should consult a physician if they experience dizziness or faintness, in case the dosage should be adjusted.
•Diabetic patients should report any changes in blood sugar levels to their physician.
•Contact lens wearers may experience decreased lacrimation.
The brands listed are registered trademark of their respective owner.
Manufactured by: Cadila Healthcare Ltd.
India Distributed by: Zydus Pharmaceuticals (USA) Inc.
Pennington, NJ 08534 Distributed by: The Kroger Co.
Cincinnati, OH 45202 Packaged by: Legacy Pharmaceutical Packaging, LLC Earth City, MO 63045 Rev.: 09/17 20265-2
DOSAGE AND ADMINISTRATION
Take with food.
Individualize dosage and monitor during up-titration.
( 2 ) Heart failure: Start at 3.125 mg twice daily and increase to 6.25, 12.5, and then 25 mg twice daily over intervals of at least 2 weeks.
Maintain lower doses if higher doses are not tolerated.
(2.1) Left ventricular dysfunction following myocardial infarction: Start at 6.25 mg twice daily and increase to 12.5 mg then 25 mg twice daily after intervals of 3 to 10 days.
A lower starting dose or slower titration may be used.
(2.2) Hypertension: Start at 6.25 mg twice daily and increase if needed for blood pressure control to 12.5 mg then 25 mg twice daily over intervals of 1 to 2 weeks.
(2.3) Carvedilol should be taken with food to slow the rate of absorption and reduce the incidence of orthostatic effects.
2.1 Heart Failure DOSAGE MUST BE INDIVIDUALIZED AND CLOSELY MONITORED BY A PHYSICIAN DURING UP-TITRATION.
Prior to initiation of Carvedilol tablets, it is recommended that fluid retention be minimized.
The recommended starting dose of Carvedilol tablets is 3.125 mg twice daily for 2 weeks.
If tolerated, patients may have their dose increased to 6.25, 12.5, and 25 mg twice daily over successive intervals of at least 2 weeks.
Patients should be maintained on lower doses if higher doses are not tolerated.
A maximum dose of 50 mg twice daily has been administered to patients with mild-to-moderate heart failure weighing over 85 kg (187 lbs).
Patients should be advised that initiation of treatment and (to a lesser extent) dosage increases may be associated with transient symptoms of dizziness or lightheadedness (and rarely syncope) within the first hour after dosing.
During these periods, patients should avoid situations such as driving or hazardous tasks, where symptoms could result in injury.
Vasodilatory symptoms often do not require treatment, but it may be useful to separate the time of dosing of Carvedilol tablets from that of the ACE inhibitor or to reduce temporarily the dose of the ACE inhibitor.
The dose of Carvedilol tablets should not be increased until symptoms of worsening heart failure or vasodilation have been stabilized.
Fluid retention (with or without transient worsening heart failure symptoms) should be treated by an increase in the dose of diuretics.
The dose of Carvedilol tablets should be reduced if patients experience bradycardia (heart rate less than 55 beats per minute).
Episodes of dizziness or fluid retention during initiation of Carvedilol tablets can generally be managed without discontinuation of treatment and do not preclude subsequent successful titration of, or a favorable response to, carvedilol.
2.2 Left Ventricular Dysfunction following Myocardial Infarction DOSAGE MUST BE INDIVIDUALIZED AND MONITORED DURING UP-TITRATION.
Treatment with carvedilol tablets may be started as an inpatient or outpatient and should be started after the patient is hemodynamically stable and fluid retention has been minimized.
It is recommended that carvedilol tablets be started at 6.25 mg twice daily and increased after 3 to 10 days, based on tolerability, to 12.5 mg twice daily, then again to the target dose of 25 mg twice daily.
A lower starting dose may be used (3.125 mg twice daily) and/or the rate of up-titration may be slowed if clinically indicated (e.g., due to low blood pressure or heart rate, or fluid retention).
Patients should be maintained on lower doses if higher doses are not tolerated.
The recommended dosing regimen need not be altered in patients who received treatment with an IV or oral β-blocker during the acute phase of the myocardial infarction.
2.3 Hypertension DOSAGE MUST BE INDIVIDUALIZED.
The recommended starting dose of carvedilol tablets 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 1 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 carvedilol tablet is seen within 7 to 14 days.
Total daily dose should not exceed 50 mg.
Concomitant administration with a diuretic can be expected to produce additive effects and exaggerate the orthostatic component of carvedilol action.
2.4 Hepatic Impairment Carvedilol tablets should not be given to patients with severe hepatic impairment [see CONTRAINDICATIONS (4)].