Download Carvedilol: Uses, Warnings, Side Effects, and Interactions for Hypertension and more Study notes Art in PDF only on Docsity!
Pharmacist: Dispense With Information For Patients. Rx Only
Pharmacist Information: Dispense in a tight, light-resistant container as described in the USP.
Keep out of the reach of children.
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from moisture.
Each Tablet Contains: Carvedilol.........................12.5 mg
C.S. No. 5413L
USUAL DOSAGE:
See package outsert
for complete product
information.
NDC 57664-245-
Carvedilol Tablets
12.5 mg
100 TABLETS
N 3
57664 24588
Pharmacist: Dispense With Information For Patients.
Rx Only
NDC 57664-245-
Carvedilol Tablets
12.5 mg
500 TABLETS
USUAL DOSAGE:
See package outsert
for complete product
information.
Pharmacist Information:
Dispense in a tight, light-resistant
container as described in the USP.
Keep out of the reach of children.
Store at 20° to 25°C (68° to 77°F)
[See USP Controlled Room
Temperature].
Protect from moisture.
Each Tablet Contains:
Carvedilol.........................12.5 mg
C.S. No. 5414L
N 3
57664 24513
Pharmacist: Dispense With Information For Patients. Rx Only
Pharmacist Information: Dispense in a tight, light-resistant container as described in the USP.
Keep out of the reach of children.
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from moisture.
Each Tablet Contains: Carvedilol.........................25 mg
C.S. No. 5416L
USUAL DOSAGE:
See package outsert
for complete product
information.
NDC 57664-247-
Carvedilol Tablets
25 mg
100 TABLETS
N 3
57664 24788
Pharmacist: Dispense With Information For Patients.
Rx Only
NDC 57664-247-
Carvedilol Tablets
25 mg
500 TABLETS
USUAL DOSAGE:
See package outsert
for complete product
information.
Pharmacist Information:
Dispense in a tight, light-resistant
container as described in the USP.
Keep out of the reach of children.
Store at 20° to 25°C (68° to 77°F)
[See USP Controlled Room
Temperature].
Protect from moisture.
Each Tablet Contains:
Carvedilol.........................25 mg
C.S. No. 5417L
N 3
57664 24713
Pharmacist: Dispense With Information For Patients. Rx Only
Pharmacist Information: Dispense in a tight, light-resistant container as described in the USP.
Keep out of the reach of children.
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from moisture.
Each Tablet Contains: Carvedilol.........................6.25 mg
C.S. No. 5410L
USUAL DOSAGE:
See package outsert
for complete product
information.
NDC 57664-244-
Carvedilol Tablets
6.25 mg
100 TABLETS
N 3
57664 24488
Pharmacist Information: Dispense in a tight, light-resistant container as described in the USP.
Keep out of the reach of children.
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from moisture.
Each Tablet Contains: Carvedilol.........................6.25 mg
C.S. No. 5411L
USUAL DOSAGE:
See package outsert
for complete product
information.
NDC 57664-244-
Carvedilol Tablets
6.25 mg
500 TABLETS
N 3
57664 24413 Pharmacist: Dispense With Information For Patients. Rx Only
INFORMATION FOR PATIENTS TAKING CARVEDILOL TABLETS
Rx only
Read the patient information that comes with CARVEDILOL 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, ask
your doctor or pharmacist.
WHAT IS CARVEDILOL?
CARVEDILOL is a prescription medicine that belongs to a group of medicines called “beta-blockers”.
CARVEDILOL is 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
CARVEDILOL is not approved for use in children under 18 years of age.
WHO SHOULD NOT TAKE CARVEDILOL?
Do not take CARVEDILOL 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 tablet. The active ingredient is carvedilol. See the
end of this leaflet for a list of all the ingredients in carvedilol tablets.
WHAT SHOULD I TELL MY DOCTOR BEFORE TAKING CARVEDILOL?
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 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 is safe for your unborn
baby. You and your doctor should talk about the best way to control your high blood pressure dur-
ing pregnancy.
- Are breastfeeding. It is not known if CARVEDILOL passes into your breast milk. You should not
breastfeed while using CARVEDILOL.
- Are scheduled for surgery and will be given anesthetic agents
- Are taking prescription or non-prescription medicines, vitamins, and herbal supplements.
CARVEDILOL and certain other medicines can affect each other and cause serious side effects.
CARVEDILOL may affect the way other medicines work. Also, other medicines may affect how well
CARVEDILOL works.
Keep a list of all the medicines you take. Show this list to your doctor and pharmacist before you start a
new medicine.
HOW SHOULD I TAKE CARVEDILOL?
It is important for you to take your medicine every day as directed by your doctor. If you stop taking
CARVEDILOL suddenly, you could have chest pain and/or a heart attack. If your doctor decides that you
should stop taking CARVEDILOL, your doctor may slowly lower your dose over a period of time before
stopping it completely.
- Take CARVEDILOL 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 and do not change the amount of CARVEDILOL you take without
talking to your doctor.
- Tell your doctor if you gain weight or have trouble breathing while taking CARVEDILOL.
- Take CARVEDILOL with food.
- If you miss a dose of CARVEDILOL, 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, call your doctor or poison control center right away.
WHAT SHOULD I AVOID WHILE TAKING CARVEDILOL?
CARVEDILOL 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?
- 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 heart beat
- Changes in your blood sugar. If you have diabetes, tell your doctor if you have any changes in
your blood sugar levels.
- CARVEDILOL may hide some of the symptoms of low blood sugar, especially a fast heartbeat.
- CARVEDILOL may mask the symptoms of hyperthyroidism (overactive thyroid).
- Worsening of severe allergic reactions.
Other side effects of CARVEDILOL include shortness of breath, weight gain, diarrhea, and fewer tears or
dry eyes that become bothersome if you wear contact lenses.
Call your doctor if you have any side effects that bother you or don’t go away.
How should I store CARVEDILOL?
- Store carvedilol tablet at 20˚ to 25˚C (68˚ to 77˚ F). [See USP Controlled Room Temperature]. Keep the
tablets dry.
- Safely, throw away CARVEDILOL that is out of date or no longer needed.
- Keep CARVEDILOL and all medicines out of the reach of children.
GENERAL INFORMATION ABOUT CARVEDILOL
Medicines are sometimes prescribed for conditions other than those described in patient information leaflets.
Do not use CARVEDILOL for a condition for which it was not prescribed. Do not give CARVEDILOL 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. If you would like more information,
talk with your doctor. You can ask your doctor or pharmacist for information about CARVEDILOL that is written
for healthcare professionals. You can also find out more about CARVEDILOL by visiting the website www.cara-
co.com or calling 1-800-818-4555. This call is free.
WHAT ARE THE INGREDIENTS IN CARVEDILOL TABLET?
Active Ingredient: Carvedilol
Inactive Ingredients: mannitol, povidone, colloidal silicon dioxide, sucrose, crospovidone, talc, magnesium
stearate, and opadry white
Carvedilol tablets come in the following strengths: 6.25 mg, 12.5 mg, 25 mg
C.S. No.: 5765T
PHARMACEUTICAL
LABORATORIES, LTD.
DETROIT, MI 48202
when carvedilol is co-administered with diltiazem. As with other agents with ß-blocking proper- ties, if carvedilol is to be administered with calcium channel blockers of the verapamil or dilti- azem type, it is recommended that ECG and blood pressure be monitored.
7.7 Insulin or Oral Hypoglycemics Agents with ß-blocking properties may enhance the blood-sugar-reducing effect of insulin and oral hypoglycemics. Therefore, in patients taking insulin or oral hypoglycemics, regular monitoring of blood glucose is recommended [see Warnings and Precautions (5.6)].
8 USE IN SPECIFIC POPULATIONS 8.1 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 MRHD as mg/m^2 ) and in rabbits at doses of 75 mg/kg/day (25 times the MRHD as mg/m^2 ). In the rats, there was also a decrease in fetal body weight at the maternally toxic dose of 300 mg/kg/day (50 times the MRHD as mg/m^2 ), which was accompanied by an elevation in the fre- quency of fetuses with delayed skeletal development (missing or stunted 13th rib). In rats the no-observed-effect level for developmental toxicity was 60 mg/kg/day (10 times the MRHD as mg/m^2 ); in rabbits it was 15 mg/kg/day (5 times the MRHD as mg/m^2 ). There are no adequate and well-controlled studies in pregnant women. Carvedilol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
8.3 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 ß-blockers) cross the placental barrier and are excreted in breast milk. There was increased mortality at one week post-partum in neonates from rats treated with 60 mg/kg/day (10 times the MRHD as mg/m^2 ) and above dur- ing 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 ß-block- ers, especially bradycardia, a decision should be made whether to discontinue nursing or to dis- continue the drug, taking into account the importance of the drug to the mother. The effects of other α- and ß-blocking agents have included perinatal and neonatal distress.
8.4 Pediatric Use Pediatrics: Effectiveness of CARVEDILOL 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 dysfunc- tion 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 two dose levels of carvedilol. These dose levels produced placebo-corrected heart rate reduction of 4-6 heart beats per minute, indicative of beta-blockade activity. Exposure appeared to be lower in pediatric sub- jects 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% vs. 6%), dizziness (13% vs. 2%), and dyspnea (11% vs. 0%).
8.5 Geriatric Use Of the 975 myocardial infarction patients randomized to carvedilol 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 treat- ed with carvedilol, 21% (436) were 65 years of age or older. Of 3,722 patients receiving carvedilol 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 ver- sus 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, cardio- genic 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 obser- vation 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, fol- lowed 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, ß-sympathomimet- ics (as aerosol or IV) or aminophylline IV should be given. In the event of seizures, slow IV injec- tion 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 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 ß-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, oval, film-coated tablet containing 6.25 mg, 12.5 mg, and 25 mg of carvedilol. Inactive Ingredients in the tablet are mannitol, povidone, colloidal silicon dioxide, sucrose, crospovidone, talc, magnesium stearate, and opadry white.
Carvedilol is a white to off-white powder with a molecular weight of 406.5 and a molecular for- mula 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 (simulat- ed, TS without pancreatin, pH 7.5). 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Carvedilol is a racemic mixture in which nonselective ß-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.
12.2 Pharmacodynamics Left Ventricular Dysfunction Following Myocardial Infarction The basis for the beneficial effects of carvedilol in patients with left ventricular dysfunc- tion following an acute myocardial infarction is not established.
Hypertension The mechanism by which ß-blockade produces an antihypertensive effect has not been established. ß-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 ß-adrenoreceptor blocking effect is usually seen within 1 hour of drug administration. α 1 -adrenoreceptor blocking activity has been demonstrated in human and animal studies, showing that carvedilol (1) attenuates the pressor effects of phenylephrine; (2) causes vasodi- lation; 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 α 1 -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%), includ- ing rare instances of syncope, can occur. Following oral administration, when postural hypoten- sion has occurred, it has been transient and is uncommon when carvedilol is administered with food at the recommended starting dose and titration increments are closely followed (see DOSAGE AND ADMINISTRATION [2]). In hypertensive patients with normal renal function, therapeutic doses of carvedilol 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 and placebo. Carvedilol has little effect on plasma catecholamines, plasma aldosterone, or electrolyte levels, but it does significantly reduce plasma renin activity when given for at least 4 weeks. It also increases levels of atrial natriuretic peptide.
12.3 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 gen- erally 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 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 radioactiv- ity in plasma as measured by area under the curve (AUC). Less than 2% of the dose was excret- ed unchanged in the urine. Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation. The oxidative metabolites are further metabolized by conjugation via glu- curonidation and sulfation. The metabolites of carvedilol are excreted primarily via the bile into the feces. Demethylation and hydroxylation at the phenol ring produce three active metabolites with ß-receptor blocking activity. Based on preclinical studies, the 4’-hydroxyphenyl metabolite is approximately 13 times more potent than carvedilol for ß-blockade. Compared to carvedilol, the three active metabolites exhibit weak vasodilating activity. Plasma concentrations of the active metabolites are about one-tenth of those observed for carvedilol and have pharmacokinetics similar to the parent.
Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of R(+)-
carvedilol approximately 2 to 3 times higher than S(-)-carvedilol following oral administration in healthy subjects. The mean apparent terminal elimination half-lives for R(+)-carvedilol range from 5 to 9 hours compared with 7 to 11 hours for the S(-)-enantiomer. The primary P450 enzymes responsible for the metabolism of both R(+) and S(-)- carvedilol in human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent CYP3A4, 2C19, 1A2, and 2E1. CYP2D6 is thought to be the major enzyme in the 4’- and 5’- hydroxylation of carvedilol, with a potential contribution from 3A4. CYP2C9 is thought to be of primary importance in the O-methylation pathway of S(-)-carvedilol. Carvedilol is subject to the effects of genetic polymorphism with poor metabolizers of debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2- to 3-fold higher plasma concen- trations 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 pharmaco- kinetics 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, indicat- ing substantial distribution into extravascular tissues. Plasma clearance ranges from 500 to 700 mL/min. 12.4 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 hyper- tensive 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 sim- ilar for both groups. Changes in mean peak plasma levels were less pronounced, approximate- ly 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. 12.5 Drug-Drug Interactions Since carvedilol undergoes substantial oxidative metabolism, the metabolism and pharma- cokinetics of carvedilol may be affected by induction or inhibition of cytochrome P450 enzymes. Rifampin In a pharmacokinetic study conducted in 8 healthy male subjects, rifampin (600 mg daily for 12 days) decreased the AUC and Cmax of carvedilol by about 70% [see Drug Interactions (7.5)]. Cimetidine In a pharmacokinetic study conducted in 10 healthy male subjects, cimetidine (1000 mg/day) increased the steady-state AUC of carvedilol by 30% with no change in C (^) max [see Drug Interactions (7.5)]. 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. Digoxin Following concomitant administration of carvedilol (25 mg once daily) and digoxin (0.25 mg once daily) for 14 days, steady-state AUC and trough concentrations of digoxin were increased by 14% and 16%, respectively, in 12 hypertensive patients. Torsemide In a study of 12 healthy subjects, combined oral administration of carvedilol 25 mg once daily and torsemide 5 mg once daily for 5 days did not result in any significant differences in their pharmacokinetics compared with administration of the 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 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In 2-year studies conducted in rats given carvedilol at doses up to 75 mg/kg/day (12 times the maximum recommended human dose [MRHD] when compared on a mg/m^2 basis) or in mice given up to 200 mg/kg/day (16 times the MRHD on a mg/m^2 basis), carvedilol had no carcino- genic effect. Carvedilol was negative when tested in a battery of genotoxicity assays, including the Ames and the CHO/HGPRT assays for mutagenicity and the in vitro hamster micronucleus and in vivo human lymphocyte cell tests for clastogenicity. At doses >200 mg/kg/day (>32 times the MRHD as mg/m^2 ) carvedilol was toxic to adult rats (sedation, reduced weight gain) and was associated with a reduced number of successful matings, prolonged mating time, significantly fewer corpora lutea and implants per dam, and complete resorption of 18% of the litters. The no-observed-effect dose level for overt toxicity and impairment of fertility was 60 mg/kg/day (10 times the MRHD as mg/m^2 ). 14 CLINICAL STUDIES 14.1 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. 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 ß-block- er use. Treatment of the index infarction included aspirin (85%), IV or oral ß-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/ 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, indicat- ing 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 reduci- ton in the risk of myocardial infarction was also observed in a meta-analysis of placebo-con- trolled trials of carvedilol in heart failure. Figure 1. Survival Analysis for CAPRICORN (intent-to-treat)
Figure 2. Effects on Mortality for Subgroups in CAPRICORN
14.2 Hypertension Carvedilol was 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 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 ß-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)]. 16 HOW SUPPLIED/STORAGE AND HANDLING Carvedilol Tablets, 6.25 mg are available in the following form: White colored, film coated, oval, biconvex tablets, debossed with “244” on one side and plain on the other side. Bottle of 100 NDC 57664-244- Bottle of 500 NDC 57664-244- Bottle of 1000 NDC 57664-244- Carvedilol Tablets, 12.5 mg are available in the following form: White colored, film coated, oval, biconvex tablets, debossed with “245” on one side and plain on the other side. Bottle of 100 NDC 57664-245- Bottle of 500 NDC 57664-245- Bottle of 1000 NDC 57664-245- Carvedilol Tablets, 25 mg are available in the following form: White colored, film coated, oval, biconvex tablets, debossed with “247” on one side and plain on the other side. Bottle of 100 NDC 57664-247- Bottle of 500 NDC 57664-247- Bottle of 1000 NDC 57664-247- 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 17.1 Patient Advice Patients taking CARVEDILOL should be advised of the following:
- Patients should take CARVEDILOL with food.
- Patients should not interrupt or discontinue using CARVEDILOL 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. 17.2 FDA-Approved Patient Labeling PATIENT INFORMATION-Rx Only CARVEDILOL TABLETS Read the Patient Information that comes with CARVEDILOL 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 ques- tions about CARVEDILOL, ask your doctor or pharmacist. WHAT IS CARVEDILOL? Carvedilol is a prescription medicine that belongs to a group of medicines called “beta-block- ers”. CARVEDILOL is 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 CARVEDILOL is not approved for use in children under 18 years of age. WHO SHOULD NOT TAKE CARVEDILOL? Do not take CARVEDILOL 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 tablet. The active ingredient is carvedilol. See the end of this leaflet for a list of all the ingredients in carvedilol tablets. WHAT SHOULD I TELL MY DOCTOR BEFORE TAKING CARVEDILOL? 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 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 is 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.
- Are scheduled for surgery and will be given anesthetic agents
- Are taking prescription or non-prescription medicines, vitamins, and herbal supplements. CARVEDILOL and certain other medicines can affect each other and cause serious side effects. CARVEDILOL may affect the way other medicines work. Also, other medicines may affect how well CARVEDILOL works Keep a list of all the medicines you take. Show this list to your doctor and pharmacist before you start a new medicine. HOW SHOULD I TAKE CARVEDILOL? It is important for you to take your medicine every day as directed by your doctor. If you stop taking CARVEDILOL suddenly, you could have chest pain and/or a heart attack. If your doc- tor decides that you should stop taking CARVEDILOL, your doctor may slowly lower your dose over a period of time before stopping it completely.
- Take CARVEDILOL 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 and do not change the amount of CARVEDILOL you take without talking to your doctor.
- Tell your doctor if you gain weight or have trouble breathing while taking CARVEDILOL.
- Take CARVEDILOL with food.
- If you miss a dose of CARVEDILOL, 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, call your doctor or poison control center right away. WHAT SHOULD I AVOID WHILE TAKING CARVEDILOL? CARVEDILOL 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?
- 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 heart beat
- Changes in your blood sugar. If you have diabetes, tell your doctor if you have any changes in your blood sugar levels.
- CARVEDILOL may hide some of the symptoms of low blood sugar, especially a fast heart- beat.
- CARVEDILOL may mask the symptoms of hyperthyroidism (overactive thyroid).
- Worsening of severe allergic reactions. Other side effects of CARVEDILOL include shortness of breath, weight gain, diarrhea, and fewer tears or dry eyes that become bothersome if you wear contact lenses. Call your doctor if you have any side effects that bother you or don’t go away. How should I store CARVEDILOL?
- Store carvedilol tablet at 20˚ to 25˚C (68˚ to 77˚ F). [See USP Controlled Room Temperature]. Keep the tablets dry.
- Safely, throw away CARVEDILOL that is out of date or no longer needed.
- Keep CARVEDILOL and all medicines out of the reach of children. GENERAL INFORMATION ABOUT CARVEDILOL Medicines are sometimes prescribed for conditions other than those described in patient informa- tion leaflets. Do not use CARVEDILOL for a condition for which it was not prescribed. Do not give CARVEDILOL 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. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about CARVEDILOL that is written for healthcare professionals. You can also find out more about CARVEDILOL by visiting the website www.caraco.com or calling 1-800-818-4555. This call is free. WHAT ARE THE INGREDIENTS IN CARVEDILOL TABLET? Active Ingredient: Carvedilol Inactive Ingredients: mannitol, povidone, colloidal silicon dioxide, sucrose, crospovidone, talc, magnesium stearate, and opadry white Carvedilol tablets come in the following strengths: 6.25 mg, 12.5 mg, 25 mg
C.S. No.: 5419T Iss. 8/
PHARMACEUTICAL
LABORATORIES, LTD.
DETROIT, MI 48202
to your doctor.
- Tell your doctor if you gain weight or have trouble breathing while taking CARVEDILOL.
- Take CARVEDILOL with food.
- If you miss a dose of CARVEDILOL, 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, call your doctor or poison control center right away.
WHAT SHOULD I AVOID WHILE TAKING CARVEDILOL?
CARVEDILOL 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?
- 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 heart beat
- Changes in your blood sugar. If you have diabetes, tell your doctor if you have any changes in your blood sugar levels.
- CARVEDILOL may hide some of the symptoms of low blood sugar, espe- cially a fast heartbeat.
- CARVEDILOL may mask the symptoms of hyperthyroidism (overactive thy- roid).
- Worsening of severe allergic reac- tions.
Other side effects of CARVEDILOL include shortness of breath, weight gain, diarrhea, and fewer tears or dry eyes that become bothersome if you wear contact lenses.
Call your doctor if you have any side effects that bother you or don’t go away.
How should I store CARVEDILOL?
- Store carvedilol tablet at 20˚ to 25˚C (68˚ to 77˚ F). [See USP Controlled Room Temperature]. Keep the tablets dry.
- Safely, throw away CARVEDILOL that is out of date or no longer needed.
- Keep CARVEDILOL and all medicines out of the reach of children.
GENERAL INFORMATION ABOUT CARVEDILOL
Medicines are sometimes prescribed for con- ditions other than those described in patient information leaflets. Do not use CARVEDILOL for a condition for which it was not prescribed. Do not give CARVEDILOL 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. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about CARVEDILOL that is written for healthcare professionals. You can also find out more about CARVEDILOL by visiting the website www.caraco.com or call- ing 1-800-818-4555. This call is free.
WHAT ARE THE INGREDIENTS IN CARVEDILOL TABLET?
Active Ingredient: Carvedilol
Inactive Ingredients: mannitol, povidone, colloidal silicon dioxide, sucrose, crospovi- done, talc, magnesium stearate, and opadry white
Carvedilol tablets come in the following strengths: 6.25 mg, 12.5 mg, 25 mg
PHARMACEUTICAL
LABORATORIES, LTD.
DETROIT, MI 48202
