Dilatrend

Dilatrend

carvedilol

Manufacturer:

Cheplapharm

Distributor:

DKSH
Full Prescribing Info
Contents
Carvedilol.
Action
Pharmacology: Mechanism of Action: Carvedilol is a multiple action adrenergic receptor-blocker with α1, β1 and β2 adrenergic receptor blockade properties. Carvedilol has been shown to have organ-protective effects. Carvedilol is a potent antioxidant and a scavenger of reactive oxygen radicals. It is racemic, and both R(+) and S(-) enantiomers have the same α-adrenergic receptor-blocking properties and antioxidant properties. Carvedilol has antiproliferative effects on human vascular smooth muscle cells.
A decrease in oxidative stress has been shown in clinical studies by measuring various markers during chronic treatment of patients with carvedilol.
Carvedilol's β-adrenergic receptor-blocking properties are nonselective for the β1- and β2-adrenoceptors and are associated with the levorotatory S(-) enantiomer.
Carvedilol has no intrinsic sympathomimetic activity and (like propranolol) it has membrane-stabilizing properties. Carvedilol suppresses the renin-angiotensin-aldosterone system through β-blockade, which reduces the release of renin, thus making fluid retention rare.
Carvedilol reduces the peripheral vascular resistance via selective blockade of α1-adrenoceptors. It attenuates the increase in blood pressure induced by phenylephrine, an α1-adrenoceptor agonist, but not that induced by angiotensin II.
Carvedilol has no adverse effect on the lipid profile. A normal ratio of high-density lipoproteins to low-density lipoproteins (HDL/LDL) is maintained.
Efficacy: Clinical studies showed the following results for carvedilol: Hypertension: Carvedilol lowers blood pressure in hypertensive patients by a combination of β-blockade and α1-mediated vasodilation. A reduction in blood pressure is not associated with a concomitant increase in total peripheral resistance, as observed with pure β-blocking agents. Heart rate is slightly decreased. Renal blood flow and renal function are maintained in hypertensive patients. Carvedilol has been shown to maintain stroke volume and reduce total peripheral resistance. Blood supply to distinct organs and vascular beds including kidneys, skeletal muscles, forearms, legs, skin, brain or the carotid artery is not compromised by carvedilol. There is a reduced incidence of cold extremities and early fatigue during physical activity. The long-term effect of carvedilol on hypertension is documented in several double-blind controlled studies.
Coronary Heart Disease: In patients with coronary heart disease, carvedilol has demonstrated anti-ischemic (improved total exercise time, time to 1 mm ST segment depression and time to angina) and anti-anginal properties that were maintained during long-term treatment. Acute hemodynamic studies have demonstrated that carvedilol significantly decreases myocardial oxygen demand and sympathetic overactivity. It also decreases the myocardial preload (pulmonary artery pressure and pulmonary capillary wedge pressure) and afterload (total peripheral resistance).
Chronic Heart Failure: Carvedilol significantly reduces all causes of mortality and the need for cardiovascular hospitalization. Carvedilol also increases ejection fraction and improves symptoms in patients with ischemic or non-ischemic chronic heart failure. The effect of carvedilol is dose-dependent.
Pharmacokinetics: Absorption: Following oral administration, carvedilol is rapidly absorbed. In healthy volunteers, the maximum serum concentration is reached after approximately 1 hr. The absolute bioavailability of carvedilol in humans is approximately 25%.
Distribution: Carvedilol is a highly lipophilic compound, approximately 98-99% bound to plasma proteins. The distribution volume is approximately 2 L/kg.
Metabolism: In humans, carvedilol is extensively metabolized into a variety of metabolites that are eliminated mainly in the bile. The first-pass effect after oral administration amounts to about 60-75%. Enterohepatic circulation of the parent substance has been shown in animals.
Carvedilol is metabolized extensively by the liver and glucuronidation is one of the major reactions. Demethylation and hydroxylation at the phenol ring produce 3 metabolites with β-adrenergic receptor-blocking activity. Based on preclinical studies, the 4'-hydroxyphenol metabolite is approximately 13 times more potent than carvedilol for β-blockade. Compared to carvedilol, the 3 active metabolites exhibit weak vasodilating activity. In humans, the concentrations of the 3 active metabolites are about 10 times lower than that of the parent substance. Two (2) of the hydroxycarbazole metabolites of carvedilol are extremely potent antioxidants, demonstrating a 30- to 80-fold greater potency than carvedilol.
Elimination: The average elimination half-life of carvedilol is approximately 6 hrs. Plasma clearance is approximately 500-700 mL/min. The primary route of excretion is via the feces. Elimination is mainly biliary. A minor part is eliminated via the kidneys in the form of various metabolites.
Pharmacokinetics in Special Populations: Patients with Renal Impairment: The autoregulatory blood supply is preserved and the glomerular filtration is unchanged during chronic treatment with carvedilol.
In patients with hypertension and renal insufficiency, the area under plasma level-time curve, elimination half-life and maximum plasma concentration does not change significantly. Renal excretion of the unchanged drug decreases in the patients with renal insufficiency; however, changes in pharmacokinetic parameters are modest.
Several open studies have shown that carvedilol is an effective agent in patients with renal hypertension. The same is true in patients with chronic renal failure, or those on hemodialysis or after renal transplantation. Carvedilol causes a gradual reduction in blood pressure both on dialysis and nondialysis days, and the blood pressure-lowering effects are comparable with those seen in patients with normal renal function. Carvedilol is not eliminated during dialysis because it does not cross the dialysis membrane, probably due to its high plasma protein-binding.
On the basis of results obtained in comparative trials on hemodialyzed patients, it was concluded that carvedilol was more effective than calcium-channel blockers and was better tolerated.
Patients with Hepatic Impairment: In patients with cirrhosis of the liver, the systemic availability of the drug is increased by up to 80% because of a reduction in the first-pass effect. Therefore, carvedilol is contraindicated in patients with clinically manifest liver dysfunction (see Contraindications).
Geriatric Use: The pharmacokinetics of carvedilol in hypertensive patients was not affected by age. A study in elderly hypertensive patients showed that there was no difference in the adverse event profile. Another study which included elderly patients with coronary heart disease showed no difference in the adverse events reported:
Pediatric Use: There is limited data available on pharmacokinetics in people <18 years.
Diabetic Patients: In hypertensive patients with non-insulin-dependent diabetes, no influence of carvedilol on fasting or postprandial blood glucose concentration, glycolated hemoglobin A1 or need for change of the dose of antidiabetic agents was found.
In patients with non-insulin-dependent diabetes, carvedilol had no statistically significant influence on the glucose tolerance test. In hypertensive nondiabetic patients with impaired insulin sensitivity (syndrome X) carvedilol improved the insulin sensitivity. The same results were found in hypertensive patients with non-insulin-dependent diabetes.
Toxicology: Preclinical Safety Data: In carcinogenicity studies conducted in rats and mice employing dosages up to 75 mg/kg/day and 200 mg/kg/day, respectively [38-100 times the maximum recommended human dose (MRHD)], carvedilol had no carcinogenic effect.
Carvedilol was not mutagenic in in vitro or in vivo mammalian tests and non-mammalian tests.
Administration of carvedilol to pregnant rats at maternally toxic doses (≥200 mg/kg, ≥100 times MRHD) resulted in impairment of fertility (poor mating, fewer corpora lutea, implants and embryonic responses). Doses >60 mg/kg (>30 times MRHD) caused delays in physical growth/development of offspring. There was embryotoxicity (increased post-implantation deaths) but no malformations in rabbits and rats at doses of 75 and 200 mg/kg, respectively (38-100 times MRHD).
Indications/Uses
Hypertension: Dilatrend is indicated primarily for the management of essential hypertension: It can be used alone or in combination with other antihypertensive agents (eg, calcium-channel blockers, diuretics).
Coronary Heart Disease: Carvedilol has demonstrated clinical efficacy in coronary heart disease. Preliminary data shows efficacy and safety in patients with unstable angina and silent myocardial ischemia.
Chronic Heart Failure: Unless a contraindication exists, carvedilol is indicated for the treatment of all patients with stable and symptomatic, mild, moderate and severe chronic heart failure of ischemic or non-ischemic etiology in combination with standard therapy (including ACE inhibitors and diuretics with or without digitalis).
Left ventricular dysfunction following acute myocardial infarction. Long-term treatment following myocardial infarction complicated by left ventricular dysfunction [left ventricular ejection fraction (LVEF) ≤40% or wall motion index ≤1.3], in combination with ACE inhibitors and other treatments recommended in the management of patients after myocardial infarction.
Dosage/Direction for Use
Duration of Treatment: Treatment with carvedilol is a long-term therapy. Treatment should not be stopped abruptly but rather gradually reduced at weekly intervals. This is particularly important in the case of patients with concomitant coronary heart disease.
Essential Hypertension: The recommended dose for initiation of therapy is 12.5 mg once a day for the first 2 days. Thereafter, the recommended dosage is 25 mg once a day. If necessary, the dosage may subsequently be increased at intervals of at least 2 weeks to the recommended maximum daily dose of 50 mg given once daily or in divided doses (twice daily).
Coronary Heart Disease: The recommended dose for initiation of therapy is 12.5 mg twice a day for the first 2 days. Thereafter the recommended dosage is 25 mg twice a day. If necessary, the dosage may thereafter be increased at intervals of at least 2 weeks, up to the recommended maximum daily dose of 100 mg given in divided doses (twice daily).
Symptomatic, Stable, Chronic Heart Failure: Dosage must be tailored to suit the individual and closely monitored by a physician during up-titration.
For those patients receiving digitalis, diuretics and ACE inhibitors, dosing of these drugs should be stabilized before initiation of Dilatrend treatment.
The recommended dose for initiation of therapy is 3.125 mg twice daily for 2 weeks. If this dose is tolerated, the dose may thereafter be increased, at intervals of not less than 2 weeks, to 6.25, 12.5 and 25 mg twice daily. Doses should be increased to the highest level tolerated by the patient.
The maximum recommended dose is 25 mg twice daily for all patients with severe CHF and for patients with mild to moderate CHF weighing <85 kg (187 lbs). In patients with mild or moderate CHF weighing >85 kg, the maximum recommended dose is 50 mg twice daily.
Before each dose increase, the patient should be evaluated by the physician for symptoms of vasodilation or worsening heart failure.
Transient worsening of heart failure or fluid retention should be treated with increased doses of diuretics. Occasionally, it may be necessary to lower the dose of Dilatrend and, in rare cases, temporarily discontinue Dilatrend treatment.
If Dilatrend treatment is discontinued for >1 week, therapy should be recommenced at a lower dose level (twice daily) and up-titrated in line with the above dosing recommendation. If Dilatrend is discontinued for >2 weeks, therapy should be recommenced at 3.125 mg in line with the previously mentioned dosing recommendation.
Symptoms of vasodilation may be managed initially by a reduction in the dose of diuretics. If symptoms persist, the dose of ACE inhibitor (if used) may be reduced, followed by a reduction in the dose of carvedilol if necessary. Under these circumstances, the dose of carvedilol should not be increased until symptoms of worsening heart failure or vasodilation have been stabilized.
Left Ventricular Dysfunction Following Acute Myocardial Infarction: Dosage must be individualized and closely monitored by a physician during up-titration.
Treatment may be started as an inpatient or outpatient when the patient is hemodynamically stable and fluid retention has been minimized.
Prior to initiating carvedilol: Hemodynamically stable patients should have received an ACE inhibitor for at least 48 hrs, given at a stable dose during at least the preceding 24 hrs. Carvedilol can then be started between day 3 and day 21 after the myocardial infarction.
First dose of carvedilol: The initial recommended dose is 6.25 mg. Patients should remain under close medical supervision for at least 3 hrs following the initial dose (see Precautions).
Subsequent doses of carvedilol: If the patient has tolerated the 1st dose (ie, heart rate >50 beats/min, systolic blood pressure >80 mmHg, and absence of clinical signs of intolerance), the dose should be increased to 6.25 mg twice daily and maintained for 3-10 days.
The dose should be reduced to 3.125 mg twice daily if the patient develops signs of intolerance during this period, in particular bradycardia <50 beats/min, systolic blood pressure <80 mmHg or fluid retention. If this dose is not tolerated, treatment should be stopped. If it is well tolerated, it should be increased again to 6.25 mg twice daily after 3-10 days.
Subsequent up-titration: If the dose of 6.25 mg twice daily is well tolerated, the dose should be increased at intervals of 3-10 days to 12.5 mg twice daily and then to 25 mg twice daily. The maintenance dose is the maximum dose tolerated by the patient. The maximum recommended dose is 25 mg twice daily, irrespective of the patient's weight.
Special Dosage Instructions: Renal Impairment: Available pharmacokinetic data in patients with varying degrees of renal impairment (including renal failure) suggest no changes in Dilatrend dosing recommendations are warranted in patients with moderate to severe renal insufficiency.
Hepatic Impairment: Dilatrend is contraindicated in patients with clinical manifestations of liver dysfunction (see Contraindications).
Elderly: There is no evidence to support dose adjustment.
Administration: The tablets are to be swallowed with sufficient liquid.
Overdosage
Symptoms: In the event of overdosage, there may be severe hypotension, bradycardia, heart failure, cardiogenic shock and cardiac arrest. There may also be respiratory problems, bronchospasm, vomiting, disturbed consciousness and generalized seizures.
Treatment: In addition to general procedures, the vital parameters must be monitored and corrected, if necessary, under intensive care conditions. The following supportive therapies can be used:
Patients should be placed in the supine position.
Atropine: 0.5-2 mg IV (for excessive bradycardia).
Glucagon: Initially, 1-10 mg IV then 2-5 mg/hr as a long-term infusion (to support cardiovascular function).
Sympathomimetics According to Body Weight and Effect: Dobutamine, isoprenaline, orciprenaline or adrenaline. If positive inotropic effect is required, phosphodiesterase inhibitors (PDE) eg, milrinone should be considered.
If peripheral vasodilation dominates the intoxication profile then norepinephrine or noradrenaline should be administered with continuous monitoring of the circulatory conditions.
In the case of drug-resistant bradycardia, pacemaker therapy should be initiated.
Treatment of Bronchospasm: For bronchospasm, β-sympathomimetics (as aerosol or IV) or aminophylline IV should be given.
Treatment of Seizures: In the event of seizures, slow IV injection of diazepam or clonazepam is recommended.
Important Note: In cases of severe intoxication with shock, supportive treatment must be continued for a sufficiently long period, as a prolongation of elimination half-life and redistribution of carvedilol from deeper compartments are to be expected. The duration of the supportive/antidote therapy depends on the severity of the overdosage. The supportive treatment should therefore be continued until the patient's condition has stabilized.
Contraindications
Patients with hypersensitivity to carvedilol or to any component of the Dilatrend; unstable/decompensated heart failure; clinically manifest liver dysfunction.
As with other β-blockers, Dilatrend must not be used in patients with: 2nd and 3rd degree AV block (unless a permanent pacemaker is in place); severe bradycardia (<50 beats/min); sick sinus syndrome (including sinoatrial block); severe hypotension (systolic blood pressure <85 mmHg); cardiogenic shock; and history of bronchospasm or asthma.
Special Precautions
Chronic Congestive Heart Failure: In chronic heart failure patients, worsening cardiac failure or fluid retention may occur during up-titration of Dilatrend. If such symptoms occur, diuretics should be increased and the Dilatrend dose should not be advanced until clinical stability resumes. Occasionally, it may be necessary to lower the Dilatrend dose or, in rare cases, temporarily discontinue it. Such episodes do not preclude subsequent successful titration of Dilatrend. Dilatrend should be used with caution in combination with digitalis glycosides, as both drugs slow AV conduction.
Renal Function in Congestive Heart Failure: Reversible deterioration of renal function has been observed with Dilatrend therapy in chronic heart failure patients with low blood pressure (systolic BP <100 mmHg), ischemic heart disease and diffuse vascular disease and/or underlying renal insufficiency.
Left Ventricular Dysfunction Following Acute Myocardial Infarction: Before treatment with carvedilol is initiated, the patient must be clinically stable and should have received an ACE inhibitor for at least the preceding 48 hrs, and the dose of the ACE inhibitor should have been stable for at least the preceding 24 hrs (see Dosage & Administration).
Chronic Obstructive Pulmonary Disease (COPD): Dilatrend should be used with caution in patients with COPD with a bronchospastic component who are not receiving oral or inhaled medication, and only if the potential benefit outweighs the potential risk.
In patients with a tendency to bronchospasm, respiratory distress can occur as a result of a possible increase in airway resistance. Patients should be closely monitored during initiation and up-titration of Dilatrend and the dose of Dilatrend should be reduced if any evidence of bronchospasm is observed during treatment.
Diabetes: Care should be taken in the administration of Dilatrend to patients with diabetes mellitus, as the early signs and symptoms of acute hypoglycemia may be masked or attenuated. In chronic heart failure patients with diabetes, the use of Dilatrend may be associated with worsening control of blood glucose.
Peripheral Vascular Disease: Dilatrend should be used with caution in patients with peripheral vascular disease as β-blockers can precipitate or aggravate symptoms of arterial insufficiency.
Raynaud's Phenomenon: Dilatrend should be used with caution in patients suffering from peripheral circulatory disorders (eg, Raynaud's phenomenon) as there may be exacerbation of symptoms.
Thyrotoxicosis: Dilatrend, like other agents with β-blocking properties, may obscure the symptoms of thyrotoxicosis.
Anesthesia and Major Surgery: Caution should be exercised in patients undergoing general surgery, because of the synergistic negative inotropic effects of Dilatrend and anesthetic drugs.
Bradycardia: Dilatrend may induce bradycardia. If the patient's pulse rate decreases to <55 beats/min, the dosage of Dilatrend should be reduced.
Hypersensitivity: Care should be taken in administering Dilatrend to patients with a history of serious hypersensitivity reactions and in those undergoing desensitisation therapy, as β-blockers may increase both the sensitivity towards allergens and the seriousness of anaphylactic reactions.
Psoriasis: Patients with a history of psoriasis associated with β-blocker therapy should take Dilatrend only after consideration of the risk-benefit ratio.
Concomitant Use of Calcium-Channel Blockers: Careful monitoring of ECG and blood pressure is necessary in patients receiving concomitant therapy with calcium-channel blockers of the verapamil or diltiazem type or other antiarrhythmic drugs.
Pheochromocytoma: In patients with pheochromocytoma, an α-blocking agent should be initiated prior to the use of any β-blocking agent. Although Dilatrend has both α- and β-blocking pharmacological activities, there is no experience with its use in this condition. Caution should therefore be taken in the administration of Dilatrend to patients suspected of having pheochromocytoma.
Prinzmetal's Variant Angina: Agents with nonselective β-blocking activity may provoke chest pain in patients with Prinzmetal's variant angina. There is no clinical experience with Dilatrend in these patients although the α-blocking activity of Dilatrend may prevent such symptoms. Caution should, however, be taken in the administration of Dilatrend to patients suspected of having Prinzmetal's variant angina.
Contact Lenses: Wearers of contact lenses should bear in mind the possibility of reduced lacrimation.
Withdrawal Syndrome: Dilatrend treatment should not be discontinued abruptly, particularly in patients suffering from ischemic heart disease. The withdrawal of Dilatrend should be gradual (over a period of 2 weeks).
Effects on the Ability to Drive or Operate Machinery: Fitness to Drive: No studies have been performed on the effects of Dilatrend on patients' fitness to drive or to operate machinery.
Because of individually variable reactions (eg, dizziness, tiredness), the ability to drive, operate machinery or work without firm support may be impaired. This applies particularly at the start of treatment, after dose increases, on changing products and in combination with alcohol.
Use in pregnancy: β-Blockers reduce placental perfusion, which may result in intrauterine fetal death, and immature and premature deliveries. In addition, adverse effects (especially hypoglycemia and bradycardia) may occur in the fetus and neonate. There may be an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period. There is no evidence from animal studies that Dilatrend has any teratogenic effects.
There is no adequate clinical experience with Dilatrend in pregnant women.
Dilatrend should not be used during pregnancy unless the potential benefit outweighs the potential risk.
Use in lactation: Animal studies demonstrated that Dilatrend or its metabolites are excreted in breast milk. It is not known whether Dilatrend is excreted in human milk. Breastfeeding is therefore not recommended during administration of Dilatrend.
Use in children: The safety and efficacy of Dilatrend in patients <18 years have not been established.
Adverse Reactions
Adverse Event (AE) Frequency: Very common: ≥10%; common: ≥1% and <10%; uncommon: ≥0.1% and <1%; rare: ≥0.01% and <0.1%; very rare including isolated cases: <0.01%.
The frequency of adverse experiences is not dose-dependent, with the exception of dizziness, abnormal vision and bradycardia.
Undesirable Effects in Chronic Heart Failure: Adverse experiences most frequently observed in the Dilatrend group in clinical trials in chronic heart failure patients and not seen at an equivalent incidence among placebo-treated patients are described as follows.
Central Nervous System: Very Common: Dizziness, headaches are usually mild and occur particularly at the start of treatment. Asthenia (including fatigue) also occurs very commonly.
Cardiovascular System: Common: Bradycardia, postural hypotension, hypotension, edema (including generalized, peripheral, dependent and genital edema, edema of the legs, hypervolemia and fluid overload). Uncommon: Syncope (including presyncope), AV-block and cardiac failure during up-titration.
Gastrointestinal System: Common: Nausea, diarrhea and vomiting.
Hematology: Rare: Thrombocytopenia. Leucopenia has been reported in isolated cases.
Metabolic: Common: Weight increase and hypercholesterolemia. Hyperglycemia, hypoglycemia and worsening control of blood glucose are also common in patients with preexisting diabetes mellitus (see Precautions).
Others: Common: Vision abnormalities. Rarely, renal failure and renal function abnormalities in patients with diffuse vascular disease and/or impaired renal function (see Precautions).
Undesirable effects in left ventricular dysfunction following acute myocardial infarction: In a phase III, randomized, double-blind, parallel group study, the effects of carvedilol on mortality and morbidity in patients with left ventricular dysfunction following acute myocardial infarction with or without clinical evidence of heart failure was investigated. Adverse events observed with ≥2% incidence in the carvedilol arm or that had a higher incidence than the placebo arm are listed in the table. (See table.)

Click on icon to see table/diagram/image

Undesirable Effects in Hypertension and the Long-Term Management of Coronary Heart Disease: The profile of adverse events associated with the use of Dilatrend in the treatment of hypertension and the long-term management of coronary heart disease is consistent with that observed in chronic heart failure. The incidence of adverse events in these patient populations is lower, however.
Adverse experiences reported in clinical trials in patients with hypertension and coronary heart disease are:
Central Nervous System: Common: Dizziness, headaches and fatigue, which are usually mild and occur particularly at the beginning of treatment. Uncommon: Depressed mood, sleep disturbance, paresthesia.
Cardiovascular System: Common: Bradycardia, postural hypotension and uncommonly syncope, especially at the beginning of treatment. Uncommon: Disturbances of peripheral circulation (cold extremities, PVD, exacerbation of intermittent claudication and Raynaud's phenomenon), AV-block, angina pectoris (including chest pain), symptoms of heart failure and peripheral edema.
Respiratory System: Common: Asthma and dyspnea in predisposed patients. Rare: Stuffy nose.
Gastrointestinal System: Common: Gastrointestinal upset (with symptoms eg, nausea, abdominal pain, diarrhea). Uncommon: Constipation and vomiting.
Skin and Appendages: Uncommon: Skin reactions (eg, allergic exanthema, dermatitis, urticaria and pruritus).
Blood Chemistry and Hematology: Isolated cases of increases in ALAT, ASAT and γ-GT, thrombocytopenia and leucopenia.
Others: Commonly, pain in the extremities. Common: Reduced lacrimation and eye irritation. Uncommon: Cases of sexual impotence and disturbed vision. Rare: Dryness of the mouth and disturbances of micturition. Isolated cases of allergic reactions have been reported.
Class Effect: Due to the β-blocking properties, it is also possible for latent diabetes mellitus to become manifest, manifest diabetes to be aggravated and blood glucose counter-regulation to be inhibited.
Drug Interactions
(See also Precautions.)
Pharmacokinetic Interactions: Digoxin: Digoxin concentrations are increased by about 15% when digoxin and carvedilol are administered concomitantly. Both digoxin and carvedilol slow AV conduction. Increased monitoring of digoxin levels is recommended when initiating, adjusting or discontinuing carvedilol.
Insulin or Oral Hypoglycemics: Agents with β-blocking properties may enhance the blood sugar-reducing effect of insulin and oral hypoglycemics. The signs of hypoglycemia may be masked or attenuated (especially tachycardia). In patients taking insulin or oral hypoglycemics, regular monitoring of blood glucose is therefore recommended.
Inducers and Inhibitors of Hepatic Metabolism: Rifampicin reduced plasma concentrations of carvedilol by about 70%. Cimetidine increased AUC by about 30% but caused no change in Cmax. Care may be required in those patients receiving inducers of mixed function oxidases eg, rifampicin, as serum levels of carvedilol may be reduced or inhibitors of mixed function oxidases eg, cimetidine, as serum levels of carvedilol may be increased.
However, based on the relatively small effect of cimetidine on carvedilol drug levels, the likelihood of any clinically important interaction is minimal.
Catecholamine-Depleting Agents: Patients taking both agents with β-blocking properties and a drug that can deplete catecholamines (eg, reserpine and monoamine oxidase inhibitors) should be observed closely for signs of hypotension and/or severe bradycardia.
Cyclosporin: Modest increases in mean trough cyclosporin 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 cyclosporin had to be reduced in order to maintain cyclosporin concentrations within the therapeutic range, while in the remainder no adjustment was needed. On average, the dose of cyclosporin was reduced about 20% in these patients. Due to wide interindividual variability in the dose adjustment required, it is recommended that cyclosporin concentrations be monitored closely after initiation of carvedilol therapy and that the dose of cyclosporin be adjusted as appropriate.
Verapamil, Diltiazem or Other Antiarrhythmics: In combination with carvedilol can increase the risk of AV conduction disturbances (see Precautions).
Pharmacodynamic Interactions: Clonidine: 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.
Calcium-Channel Blockers (See Precautions): Isolated cases of conduction disturbance (rarely with hemodynamic compromise) have been observed when carvedilol is co-administered with diltiazem. As with other agents with β-blocking properties, if carvedilol is to be administered orally with calcium-channel blockers of the verapamil or diltiazem type, it is recommended that ECG and blood pressure be monitored.
As with other agents with β-blocking activity, carvedilol may potentiate the effect of other concomitantly administered drugs that are antihypertensive in action (eg, α1-receptor antagonists) or have hypotension as part of their adverse effect profile.
Careful attention must be paid during anesthesia to the synergistic negative inotropic and hypotensive effects of carvedilol and anesthetic drugs.
Storage
Store in the original container (sensitive to light).
MIMS Class
ATC Classification
C07AG02 - carvedilol ; Belongs to the class of alpha and beta blocking agents. Used in the treatment of cardiovascular diseases.
Presentation/Packing
Tab 6.25 mg (round, yellow, with bilateral scoreline) x 100's. 12.5 mg (round, pale peach, with bilateral scoreline) x 100's. 25 mg (round, white, with bilateral scoreline) x 100's.
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