1. INDICATIONS AND USAGE
Left Ventricular Dysfunction Following Myocardial Infarction
Carvedilol tablets, USP 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 ≤40% (with or without symptomatic
heart failure)
Hypertension
Carvedilol tablets, USP are indicated for the management of essential hypertension. It can be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics
2. DOSAGE AND ADMINISTRATION
Carvedilol should be taken with food to slow the rate of absorption and reduce the incidence of orthostatic effects.
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.
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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 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
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.Hepatic Impairment
Carvedilol tablets should not be given to patients with severe hepatic impairment
3. DOSAGE FORMS AND STRENGTHS
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.
4. CONTRAINDICATIONS
Carvedilol tablets are contraindicated in the following conditions:
- Bronchial asthma or related bronchospastic conditions. Deaths from status asthmaticus have been reported following single doses of Carvedilol tablets.
- Second- or third-degree AV block
- Sick sinus syndrome
- Severe bradycardia (unless a permanent pacemaker is in place)
- Patients with cardiogenic shock or who have decompensated heart failure requiring the use of intravenous inotropic therapy. Such patients should first be weaned from intravenous therapy before initiating Carvedilol tablets
- Patients with severe hepatic impairment
- Patients with a history of a serious hypersensitivity reaction (e.g., Stevens-Johnson syndrome, anaphylactic reaction, angioedema) to Carvedilol, any of the components of Carvedilol tablets.
5. WARNINGS AND PRECAUTIONS
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.
Bradycardia
In clinical trials, Carvedilol
tablets caused bradycardia in about 2% of hypertensive patients, and
6.5% of myocardial infarction patients with left ventricular
dysfunction. If pulse rate drops below 55 beats/minute, the dosage
should be reduced.
Hypotension
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.
In the CAPRICORN study of survivors of an acute myocardial
infarction, hypotension or postural hypotension occurred in 20.2% of
patients receiving Carvedilol tablets compared to 12.6% of placebo
patients. Syncope was reported in 3.9% and 1.9% of patients,
respectively. These events were a cause for discontinuation of therapy
in 2.5% of patients receiving Carvedilol tablets, compared to 0.2% of
placebo patients.Starting with a low dose, administration with food, and gradual up-titration should decrease the likelihood of syncope or excessive hypotension. 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.
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.
Non-allergic Bronchospasm
Patients with bronchospastic disease
(e.g., chronic bronchitis and 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 clinical trials, 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.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.
Studies designed to examine the effects of Carvedilol on glycemic control in patients with diabetes and heart failure have not been conducted.
In a study 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)].
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.
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 <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.
Major Surgery
Chronically
administered beta-blocking therapy should not be routinely withdrawn
prior to major surgery; however, the impaired ability of the heart to
respond to reflex adrenergic stimuli may augment the risks of general
anesthesia and surgical procedures.
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.
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.
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.
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.
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.
6. ADVERSE REACTIONS
Clinical Studies Experience
Carvedilol tablets have been
evaluated for safety in patients with left ventricular dysfunction
following myocardial infarction and in hypertensive patients. The
observed adverse event profile was consistent with the pharmacology of
the drug and the health status of the patients in the clinical trials.
Adverse events reported for each of these patient populations are
provided below. Excluded are adverse events considered too general to be
informative, and those not reasonably associated with the use of the
drug because they were associated with the condition being treated or
are very common in the treated population. Rates of adverse events were
generally similar across demographic subsets (men and women, elderly and
non-elderly, blacks and non-blacks).
Left Ventricular Dysfunction Following Myocardial Infarction:Carvedilol tablets have been evaluated for safety in survivors of an acute myocardial infarction with left ventricular dysfunction in the CAPRICORN trial which involved 969 patients who received Carvedilol tablets and 980 who received placebo. Approximately 75% of the patients received Carvedilol tablets for at least 6 months and 53% received Carvedilol tablets for at least 12 months. Patients were treated for an average of 12.9 months and 12.8 months with Carvedilol tablets and placebo, respectively.
The following adverse events were reported with a frequency of >1% but ≤3% and more frequently with Carvedilol tablets: flu syndrome, cerebrovascular accident, peripheral vascular disorder, hypotonia, depression, gastrointestinal pain, arthritis, and gout. The overall rates of discontinuations due to adverse events were similar in both groups of patients. In this database, the only cause of discontinuation >1%, and occurring more often on Carvedilol was hypotension (1.5% on Carvedilol, 0.2% on placebo).
Hypertension:
Carvedilol tablets have been evaluated for safety in hypertension in more than 2,193 patients in US clinical trials and in 2,976 patients in international clinical trials. Approximately 36% of the total treated population received Carvedilol tablets for at least 6 months. Most adverse events reported during therapy with Carvedilol tablets were of mild to moderate severity. In US controlled clinical trials directly comparing Carvedilol tablets in doses up to 50 mg (n = 1,142) to placebo (n = 462), 4.9% of patients receiving Carvedilol tablets discontinued for adverse events versus 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% versus 0). The overall incidence of adverse events in US placebo-controlled trials increased with increasing dose of Carvedilol tablets. 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 1 shows adverse events in US placebo-controlled clinical trials for hypertension that occurred with an incidence of >1% regardless of causality, and that were more frequent in drug-treated patients than placebo-treated patients.
| Carvedilol Tablets |
Placebo |
|
| (n = 1,142) |
(n = 462) |
|
|
||
| Cardiovascular |
||
| Bradycardia | 2 | - |
| Postural hypotension | 2 | - |
| Peripheral edema | 1 | - |
| Central Nervous System |
||
| Dizziness | 6 | 5 |
| Insomnia | 2 | 1 |
| Gastrointestinal |
||
| Diarrhea | 2 | 1 |
| Hematologic |
||
| Thrombocytopenia | 1 | - |
| Metabolic |
||
| Hypertriglyceridemia | 1 | - |
The following adverse events not described above were reported as possibly or probably related to Carvedilol tablets in worldwide open or controlled trials with Carvedilol tablets in patients with hypertension.
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 were discontinued from therapy because of increases in hepatic enzymes)
Psychiatric:
Nervousness, sleep disorder, aggravated depression, impaired concentration, abnormal thinking, paroniria, emotional lability.
Respiratory System:
Asthma
Reproductive, male:
Decreased libido.
Skin and Appendages:
Pruritus, rash erythematous, rash maculopapular, rash psoriaform, photosensitivity reaction.
Special Senses:
Tinnitus.
Urinary System:
Micturition frequency increased.
Autonomic Nervous System:
Dry mouth, sweating increased.
Metabolic and Nutritional:
Hypokalemia, hypertriglyceridemia.
Hematologic:
Anemia, leukopenia.
The following events were reported in ≤0.1% of 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.
Laboratory Abnormalities
Reversible elevations in serum
transaminases (ALT or AST) have been observed during treatment with
Carvedilol tablets. Rates of transaminase elevations (2- to 3-times the
upper limit of normal) observed during controlled clinical trials have
generally been similar between patients treated with Carvedilol tablets
and those treated with placebo. However, transaminase elevations,
confirmed by rechallenge, have been observed with Carvedilol tablets. In
a long-term, placebo-controlled trial in severe heart failure, patients
treated with Carvedilol tablets had lower values for hepatic
transaminases than patients treated with placebo, possibly because
improvements in cardiac function induced by Carvedilol led to less
hepatic congestion and/or improved hepatic blood flow.
Carvedilol tablets have not been associated with clinically
significant changes in serum potassium, total triglycerides, total
cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or
creatinine. No clinically relevant changes were noted in fasting serum
glucose in hypertensive patients.Postmarketing Experience
The following adverse reactions have
been identified during post-approval use of Carvedilol tablets. Because
these reactions are reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate their frequency or
establish a causal relationship to drug exposure.
Blood and Lymphatic System DisordersAplastic anemia.
Immune System Disorders
Hypersensitivity (e.g., anaphylactic reactions, angioedema, urticaria).
Renal and Urinary Disorders
Urinary incontinence.
Respiratory, Thoracic and Mediastinal Disorders
Interstitial pneumonitis.
Skin and Subcutaneous Tissue Disorders
Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.
7. DRUG INTERACTIONS
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.
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.
Hypotensive Agents
Patients taking both agents with
β-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. Concomitant
administration of clonidine with agents with β-blocking properties may
potentiate blood-pressure and heart-rate-lowering effects. When
concomitant treatment with agents with β-blocking properties and
clonidine is to be terminated, the β-blocking agent should be
discontinued first. Clonidine therapy can then be discontinued several
days later by gradually decreasing the dosage.
Cyclosporine
Modest increases in mean trough
cyclosporine concentrations were observed following initiation of
Carvedilol treatment in 21 renal transplant patients suffering from
chronic vascular rejection. In about 30% of patients, 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 patients. 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.
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
Inducers/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.
Amiodarone
Amiodarone, and its metabolite
desethyl amiodarone, inhibitors of CYP2C9 and P385 glycoprotein,
increased concentrations of the S(-) enantiomer of Carvedilol by at
least 2-fold
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.
Calcium Channel Blockers
Conduction disturbance (rarely with
hemodynamic compromise) has been observed when Carvedilol tablet is
co-administered with diltiazem. As with other agents with β-blocking
properties, if Carvedilol tablet is to be administered 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 β-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
Anesthesia
If treatment with Carvedilol
extended-release capsules 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 (10)].
8. USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C. Studies
performed in pregnant rats and rabbits given Carvedilol revealed
increased post-implantation loss in rats at doses of 300 mg/kg/day (50
times the maximum recommended human dose [MRHD] as mg/m2) and in rabbits at doses of 75 mg/kg/day (25 times the MRHD as mg/m2).
In the rats, there was also a decrease in fetal body weight at the
maternally toxic dose of 300 mg/kg/day (50 times the MRHD as mg/m2),
which was accompanied by an elevation in the frequency of fetuses with
delayed skeletal development (missing or stunted 13th rib). In rats the
no-observed-effect level for developmental toxicity was 60 mg/kg/day (10
times the MRHD as mg/m2); in rabbits it was 15 mg/kg/day (5 times the MRHD as mg/m2).
There are no adequate and well-controlled studies in pregnant women.
Carvedilol tablets 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 β-blockers) cross the placental
barrier and are excreted in breast milk. There was increased mortality
at one week post-partum in neonates from rats treated with 60 mg/kg/day
(10 times the MRHD as mg/m2) and above during
the last trimester through day 22 of lactation. Because many drugs are
excreted in human milk and because of the potential for serious adverse
reactions in nursing infants from β-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 α- and β-blocking agents have included perinatal
and neonatal distress.
Pediatric Use
Effectiveness of Carvedilol tablets in patients younger than 18 years of age has not been established.
In a double-blind trial, 161 children (mean age 6 years, range 2
months to 17 years; 45% less than 2 years old) with chronic heart
failure [NYHA class II-IV, left ventricular ejection fraction <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 4-6
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 patients treated with Carvedilol and at twice the rate of
placebo-treated patients included chest pain (17% versus 6%), dizziness
(13% versus 2%), and dyspnea (11% versus 0%).Geriatric Use
Of the 975 myocardial infarction
patients randomized to Carvedilol tablets in the CAPRICORN trial, 48%
(468) were 65 years of age or older, and 11% (111) were 75 years of age
or older.
Of the 2,065 hypertensive patients in US clinical trials of efficacy
or safety who were treated with Carvedilol tablets, 21% (436) were 65
years of age or older. Of 3,722 patients receiving Carvedilol tablets in
hypertension clinical trials conducted worldwide, 24% were 65 years of
age or older.With the exception of dizziness in hypertensive patients (incidence 8.8% in the elderly versus 6% in younger patients), no overall differences in the safety or effectiveness (see Figure 2) 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.
10. OVERDOSAGE
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, 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.
11. DESCRIPTION
Carvedilol is a nonselective β-adrenergic blocking agent with α1-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:
Each Carvedilol tablet, USP 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.
The product meets USP Dissolution Test 3.
12. CLINICAL PHARMACOLOGY
Mechanism of Action
Carvedilol is a racemic mixture in which nonselective β-adrenoreceptor blocking activity is present in the S(-) enantiomer and α1-adrenergic
blocking activity is present in both R(+) and S(-) enantiomers at equal
potency. Carvedilol has no intrinsic sympathomimetic activity.
Pharmacodynamics
Left Ventricular Dysfunction Following Myocardial Infarction:
The basis for the beneficial effects of Carvedilol tablets in
patients with left ventricular dysfunction following an acute myocardial
infarction is not established.Hypertension:
The mechanism by which β-blockade produces an antihypertensive effect has not been established.
β-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 β-adrenoreceptor blocking effect is usually seen within 1 hour of drug administration.
α1-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 α1-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 Carvedilol tablets is administered with food at the recommended starting dose and titration increments are closely followed
In hypertensive patients with normal renal function, therapeutic doses of Carvedilol tablets decreased renal vascular resistance with no change in glomerular filtration rate or renal plasma flow. Changes in excretion of sodium, potassium, uric acid, and phosphorus in hypertensive patients with normal renal function were similar after Carvedilol tablets and placebo.
Carvedilol tablets have 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.
Pharmacokinetics
Carvedilol 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
Carvedilol tablets 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 3
active metabolites with β-receptor blocking activity. Based on
preclinical studies, the 4'-hydroxyphenyl metabolite is approximately 13
times more potent than Carvedilol for β-blockade.Compared to Carvedilol, the 3 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.
Specific Populations
Geriatric:
Plasma levels of Carvedilol average about 50% higher in the elderly compared to young subjects.Hepatic Impairment:
Compared to healthy subjects, patients with severe liver impairment (cirrhosis) exhibit a 4- to 7-fold increase in Carvedilol levels. Carvedilol is contraindicated in patients with severe liver impairment.
Renal Impairment:
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.
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.
Amiodarone:In a pharmacokinetic study conducted in 106 Japanese patients with heart failure, coadministration of small loading and maintenance doses of amiodarone with Carvedilol resulted in at least a 2-fold increase in the steady-state trough concentrations of S(-) Carvedilol
Cimetidine:
In a pharmacokinetic study conducted in 10 healthy male subjects, cimetidine (1,000 mg/day) increased the steady-state AUC of Carvedilol by 30% with no change in Cmax
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
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 had no effect on the pharmacokinetics of Carvedilol.
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%
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 drugs 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.
13. NONCLINICAL TOXICOLOGY
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 MRHD when compared on a mg/m2 basis) or in mice given up to 200 mg/kg/day (16 times the MRHD on a mg/m2 basis), Carvedilol had no carcinogenic effect.
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/m2) Carvedilol was toxic to adult rats (sedation, reduced weight gain) and was associated with a reduced number of successful matings, prolonged mating time, significantly fewer corpora lutea and implants per dam, and complete resorption of 18% of the litters. The no-observed-effect dose level for overt toxicity and impairment of fertility was 60 mg/kg/day (10 times the MRHD as mg/m2).
14. CLINICAL STUDIES
Left Ventricular Dysfunction Following Myocardial Infarction
CAPRICORN was a double-blind study
comparing Carvedilol and placebo in 1,959 patients with a recent
myocardial infarction (within 21 days) and left ventricular ejection
fraction of ≤40%, with (47%) or without symptoms of heart failure.
Patients given Carvedilol received 6.25 mg twice daily, titrated as
tolerated to 25 mg twice daily. Patients had to have a systolic blood
pressure >90 mm Hg, a sitting heart rate >60 beats/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 patients treated
with Carvedilol (95% CI 2-40%, p = 0.03), as shown in Figure 1. The
effects on mortality in various subgroups are shown in Figure 2. 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 study
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.
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 studies, the starting
dose did not exceed 12.5 mg. At 50 mg/day, Carvedilol tablets 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/minute at 50
mg/day. In general, as is true for other β-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 (6)].Hypertension With Type 2 Diabetes Mellitus
In a double-blind study (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)].
16. HOW SUPPLIED/STORAGE AND HANDLING
Carvedilol Tablets USP, 3.125 mg are
white to off-white, round, biconvex, film-coated tablets debossed with
'Z' on one side and '1' on other side and are supplied as follows:
NDC-68382-092-17 in bottles of 28 tabletsNDC-68382-092-01 in bottles of 100 tablets
NDC-68382-092-05 in bottles of 500 tablets
Carvedilol Tablets USP, 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-68382-093-17 in bottles of 28 tablets
NDC-68382-093-01 in bottles of 100 tablets
NDC-68382-093-05 in bottles of 500 tablets
Carvedilol Tablets USP, 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-68382-094-17 in bottles of 28 tablets
NDC-68382-094-01 in bottles of 100 tablets
NDC-68382-094-05 in bottles of 500 tablets
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-68382-095-17 in bottles of 28 tablets
NDC-68382-095-01 in bottles of 100 tablets
NDC-68382-095-05 in bottles of 500 tablets
Storage:
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Protect from moisture. Dispense in a tight, light-resistant container.
17. PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling [17.2]
Patient Advice
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 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.
FDA-Approved Patient Labeling
Patient labeling is provided separately.
Manufactured by:
Cadila Healthcare Ltd.India
Distributed by:
Zydus Pharmaceuticals USA Inc.
Pennington, NJ 08534
Rev.: 04/14
Revision Date: 2014/04/17
PHARMACIST-DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT
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- - - - - - - - - - - - - - - - - - - - - - - -
- - - - - - - - - - - - - - - - - - - - - - - -
- - - - - - - - - - - - - - - - - - - - - - - -
- - - - - - - - - - - - - PATIENT INFORMATION
Carvedilol TABLETS, USP
Read the Patient Information that comes with Carvedilol tablets before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about Carvedilol tablets, ask your doctor or pharmacist.
WHAT IS Carvedilol?
Carvedilol is a prescription medicine that belongs to a group of medicines called "beta-blockers". Carvedilol tablets are used, often with other medicines, for the following conditions:
- To treat patients with high blood pressure (hypertension)
- To treat patients who had a heart attack that worsened how well the heart pumps
WHO SHOULD NOT TAKE Carvedilol TABLETS?
Do not take Carvedilol tablet if you:
- Have severe heart failure and are hospitalized in the intensive care unit or require certain intravenous medications that help support circulation (inotropic medications)
- Are prone to asthma or other breathing problems
- Have a slow heartbeat or a heart that skips a beat (irregular heartbeat)
- Have liver problems
- Are allergic to any of the ingredients in Carvedilol tablets. The active ingredient is Carvedilol. See the end of this leaflet for a list of all the ingredients in Carvedilol tablets.
Tell your doctor about all of your medical conditions, including if you:
- Have asthma or other lung problems (such as bronchitis or emphysema)
- Have problems with blood flow in your feet and legs (peripheral vascular disease) Carvedilol tablets can make some of your symptoms worse.
- Have diabetes
- Have thyroid problems
- Have a condition called pheochromocytoma
- Have had severe allergic reactions
- Are pregnant or trying to become pregnant. It is not known if Carvedilol tablets are safe for your unborn baby. You and your doctor should talk about the best way to control your high blood pressure during pregnancy.
- Are breastfeeding. It is not known if Carvedilol passes into your breast milk. You should not breastfeed while using Carvedilol tablets.
- Are scheduled for surgery and will be given anesthetic agents
- Are taking prescription or non-prescription medicines, vitamins, and herbal supplements. Carvedilol tablets and certain other medicines can affect each other and cause serious side effects. Carvedilol tablets may affect the way other medicines work. Also, other medicines may affect how well Carvedilol tablets works
HOW SHOULD I TAKE Carvedilol TABLETS?
It is important for you to take your medicine every day as directed by your doctor. If you stop taking Carvedilol tablets suddenly, you could have chest pain and/or a heart attack. If your doctor decides that you should stop taking Carvedilol tablets, your doctor may slowly lower your dose over a period of time before stopping it completely.
- Take Carvedilol tablets exactly as prescribed. Your doctor will tell you how many tablets to take and how often. In order to minimize possible side effects, your doctor might begin with a low dose and then slowly increase the dose.
- Do not stop taking Carvedilol tablets and do not change the amount of Carvedilol tablets you take without talking to your doctor.
- Tell your doctor if you gain weight or have trouble breathing while taking Carvedilol tablets.
- Take Carvedilol tablets with food.
- If you miss a dose of Carvedilol tablets, take your dose as soon as you remember, unless it is time to take your next dose. Take your next dose at the usual time. Do not take 2 doses at the same time.
- If you take too much Carvedilol tablets, call your doctor or poison control center right away.
Carvedilol tablets can cause you to feel dizzy, tired, or faint. Do not drive a car, use machinery, or do anything that needs you to be alert if you have these symptoms.
WHAT ARE POSSIBLE SIDE EFFECTS OF Carvedilol TABLETS?
- Low blood pressure (which may cause dizziness or fainting when you stand up). If these happen, sit or lie down right away and tell your doctor.
- Tiredness. If you feel tired or dizzy you should not drive, use machinery, or do anything that needs you to be alert.
- Slow heartbeat
- Changes in your blood sugar. If you have diabetes, tell your doctor if you have any changes in your blood sugar levels.
- Carvedilol tablets may hide some of the symptoms of low blood sugar, especially a fast heartbeat.
- Carvedilol tablets may mask the symptoms of hyperthyroidism (overactive thyroid).
- Worsening of severe allergic reactions.
- Rare but serious allergic reactions (including hives or swelling of the face, lips, tongue, and/or throat that may cause difficulty in breathing or swallowing) have happened in patients who were on Carvedilol. These reactions can be life-threatening.
Call your doctor if you have any side effects that bother you or don't go away.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store Carvedilol tablets?
- Store Carvedilol tablets at 20º to 25 º C (68 º to 77 ºF). Keep the tablets dry.
- Safely, throw away Carvedilol tablets that are out of date or no longer needed.
- Keep Carvedilol tablets and all medicines out of the reach of children.
Medicines are sometimes prescribed for conditions other than those described in patient information leaflets. Do not use Carvedilol tablets for a condition for which it was not prescribed. Do not give Carvedilol tablets to other people, even if they have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about Carvedilol tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Carvedilol tablets that is written for healthcare professionals. Please address medical inquiries to, (MedicalAffairs@zydususa.com) Tel.: 1-877-993-8779.
WHAT ARE THE INGREDIENTS IN Carvedilol TABLETS, USP?
Active Ingredient: Carvedilol, USP
Inactive Ingredients: Colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, povidone, talc, and titanium dioxide.
Carvedilol tablets come in the following strengths: 3.125 mg, 6.25 mg, 12.5 mg and 25 mg
What is high blood pressure (hypertension)?
Blood pressure is the force of blood in your blood vessels when your heart beats and when your heart rests. You have high blood pressure when the force is too much. High blood pressure makes the heart work harder to pump blood through the body and causes damage to blood vessels. Carvedilol can help your blood vessels relax so your blood pressure is lower. Medicines that lower blood pressure may lower your chance of having a stroke or heart attack.
Manufactured by:
Cadila Healthcare Ltd.India
Distributed by:
Zydus Pharmaceuticals USA Inc.
Pennington, NJ 08534
Rev.: 06/13
Revision Date: 2013/06/08
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
NDC 68382-092-01 in bottle of 100 Tablets
Carvedilol Tablets USP, 3.125 mgRx only
100 Tablets
ZYDUS
Carvedilol Tablets USP, 6.25 mg
Rx only
100 Tablets
ZYDUS
Carvedilol Tablets USP, 12.5 mg
Rx only
100 Tablets
ZYDUS
Carvedilol Tablets USP, 25 mg
Rx only
100 Tablets
ZYDUS
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| Labeler - Zydus Pharmaceuticals (USA) Inc. (156861945) |
| Registrant - Zydus Pharmaceuticals (USA) Inc. (156861945) |
| Establishment | |||
| Name | Address | ID/FEI | Operations |
| Cadila Healthcare Limited | 918596198 | Analysis(68382-095), Manufacture(68382-095) | |
| Establishment | |||
| Name | Address | ID/FEI | Operations |
| CADILA HEALTHCARE LIMITED | 677605858 | Manufacture(68382-095) | |
