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Cardiac products (Carloc)
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Cardiac products (Carloc)
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Carloc
Carvedilol Tablets
COMPOSITION
CARLOC-12.5 Tablets
Each uncoated tablet contains:
Carvedilol 12.5 mg
DOSAGE FORM
Tablet
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PHARMACOLOGY
Pharmacodynamics
Carvedilol is a non-selective beta-blocker with alpha 1 -blocking activity, without intrinsic sympathomimetic activity. Carvedilol is a racemic mixture in which non-selective beta-adrenoreceptor blocking activity is present in the S(-) enantiomer and alpha-adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency.
Heart Failure: The basis for the beneficial effects of carvedilol in heart failure is not established. In patients with New York Heart Association (NYHA) class II-IV heart failure receiving diuretics, angiotensin converting enzyme (ACE) inhibitors, and digitalis, carvedilol causes significant reductions in systemic blood pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, and heart rate. Initial effects on cardiac output, stroke volume index, and systemic vascular resistance were small and variable.
Left Ventricular Dysfunction Following Myocardial Infarction: The basis for the beneficial effects of carvedilol in patients with left ventricular dysfunction following an acute myocardial infarction is not established.
Hypertension : The mechanism by which beta-blockade produces an antihypertensive effect has not been established. Beta-adrenoreceptor blocking activity has been demonstrated in animal and human studies showing that carvedilol reduces: (1) cardiac output in normal subjects; (2) exercise- and/or isoproterenol-induced tachycardia; and (3) reflex orthostatic tachycardia. Significant beta-adrenoreceptor blocking effect is usually seen within 1 hour of drug administration.
Alpha 1 -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 alpha 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%), including rare instances of syncope, can occur. Following oral administration, when postural hypotension 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.
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.
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 with food should minimize the risk of orthostatic hypotension.
Carvedilol is extensively metabolized. Following oral administration of radiolabeled carvedilol to healthy volunteers, carvedilol accounted for only about 7% of the total radioactivity in plasma as measured by area under the curve (AUC). Less than 2% of the dose was excreted unchanged in the urine. Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation. The oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation. The metabolites of carvedilol are excreted primarily via the bile into the feces. Demethylation and hydroxylation at the phenol ring produce three active metabolites with beta-receptor blocking activity. Based on pre-clinical studies, the 4`-hydroxyphenyl metabolite is approximately 13 times more potent than carvedilol for beta-blockade.
Compared to carvedilol, the three active metabolites exhibit weak vasodilating activity. Plasma concentrations of the active metabolites are about one-tenth of those observed for carvedilol and have pharmacokinetics similar to the parent.
Carvedilol undergoes stereoselective, first-pass metabolism with plasma levels of R(+)-carvedilol approximately two to three 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.
Heart Failure : Steady-state plasma concentrations of carvedilol and its enantiomers increased proportionally over the 6.25 to 50 mg dose range in patients with heart failure. Compared to healthy subjects, heart failure patients had increased mean AUC and C max values of carvedilol and its enantiomers, with up to 50% to 100% higher values observed in 6 patients with NYHA class IV heart failure. The mean apparent terminal elimination half-life for carvedilol was similar to that observed in healthy subjects.
Special Populations
Elderly : Plasma levels of carvedilol average about 50% higher in the elderly compared to young subjects.
Hepatic Impairment : Compared to healthy subjects, patients with cirrhotic liver disease exhibit significantly higher concentrations of carvedilol (approximately 4- to 7-fold) following single-dose therapy. 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.
INDICATIONS
• Heart failure
• Left ventricular dysfunction following myocardial infarction
• Hypertension
DOSAGE AND ADMINISTRATION
Carvedilol should be taken with food to slow the rate of absorption and reduce the incidence of orthostatic effects.
Heart Failure
DOSAGE MUST BE INDIVIDUALIZED AND CLOSELY MONITORED BY A PHYSICIAN DURING UP-TITRATION. Prior to initiation of carvedilol, fluid retention should be minimized. The recommended starting dose of carvedilol is 3.125 mg twice daily for two weeks. If tolerated, patients may have their dose increased to 6.25, 12.5, and 25 mg twice daily over successive intervals of at least 2 weeks. Patients should be maintained on lower doses if higher doses are not tolerated. A maximum dose of 50 mg twice daily has been administered to patients with mild-to-moderate heart failure weighing over 85 kg (187 lbs).
Patients should be advised that initiation of treatment and (to a lesser extent) dosage increases may be associated with transient symptoms of dizziness or lightheadedness (and, rarely, syncope) within the first hour after dosing. Vasodilatory symptoms often do not require treatment, but it may be useful to separate the time of dosing of carvedilol from that of the ACE inhibitor or to reduce temporarily the dose of the ACE inhibitor. The dose of carvedilol should not be increased until symptoms of worsening heart failure or vasodilation have been stabilized. Fluid retention (with or without the transient worsening heart failure symptoms) should be treated by an increase in the dose of diuretics. If patients experience bradycardia (pulse rate below 55 beats/min), the dose of carvedilol should be reduced. Episodes of dizziness or fluid retention during initiation of carvedilol can generally be managed without discontinuation of treatment and do not preclude subsequent successful titration of, or a favorable response to, carvedilol.
Left Ventricular Dysfunction Following Myocardial Infarction
DOSAGE MUST BE INDIVIDUALIZED AND MONITORED DURING UP-TITRATION. Treatment with carvedilol may be started as an in-patient or outpatient and should be started after the patient is hemodynamically stable and fluid retention has been minimized. It is recommended that carvedilol be started at 6.25 mg twice daily, increased after 3 to 10 days, based on tolerability, to 12.5 mg twice daily, and 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 (eg, 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 intravenous (IV) or oral beta-blocker during the acute phase of the myocardial infarction.
Hypertension
DOSAGE MUST BE INDIVIDUALIZED. The recommended starting dose of carvedilol 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 m
CONTRAINDICATIONS
• Carvedilol is contraindicated in patients with bronchial asthma or related bronchospastic conditions, second- or third-degree atrioventricular (AV) block, sick sinus syndrome, severe bradycardia ,in patients with cardiogenic shock or who have decompensated heart failure
• Carvedilol is also contraindicated in patients with severe hepatic impairment or patients with a history of serious hypersensitivity to any component of the product
WARNINGS AND PRECAUTIONS
• Bradycardia
• Hypotension
• Peripheral Vascular Disease
• Anesthesia and Major Surgery
• Diabetes and Hypoglycemia
• Thyrotoxicosis
• Non-allergic bronchospasm
• Pheochromocytoma
• Renal Impairment
• Hepatic Impairment
• Pregnancy
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.
• Lactation
It is not known whether this drug is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from beta-blockers, especially bradycardia, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
• Pediatric Use
Safety and efficacy in patients younger than 18 years of age have not been established.
UNDESIRABLE EFFECTS
• Carvedilol is generally well tolerated.
• The commonly observed adverse effects include fatigue, bradycardia, postural hypotension, diarrhea, headache and dizziness.
• These are usually mild, transient and occur early in the course of treatment.
• Diminished peripheral circulation, dry eyes, and flu-like symptoms have occurred occasionally.
• Rarely, AV block or exacerbation of symptoms in intermittent claudication may occur.
PACKAGING INFORMATION
• CARLOC-12.5 ...................Blister pack of 10 tablets
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