Dilatrend

Dilatrend

carvedilol

Manufacturer:

Cheplapharm

Distributor:

DKSH
Full Prescribing Info
Contents
Carvedilol.
Description
One 12.5 mg tablet contains 12.5 mg carvedilol.
One 25 mg tablet contains 25 mg carvedilol.
Sterile/Radioactive Statement: Not applicable.
Action
Pharmacotherapeutic Group: Alpha (α) and (β) adrenergic receptor blocking agents.
Pharmacology: Pharmacodynamics: 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. Carvedilol 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 non-selective for the β1 and β2-adrenoceptors and are associated with the S(-) enantiomer.
Carvedilol has no intrinsic sympathomimetic activity and (like propranolol) it has membrane stabilising 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. Carvedilol 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.
Clinical/Efficacy Studies: 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.
Renal impairment: 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 haemodialysis or after renal transplantation. Carvedilol causes a gradual reduction in blood pressure both on dialysis and non-dialysis days, and the blood pressure-lowering effects are comparable with those seen in patients with normal renal function.
On the basis of results obtained in comparative trials on haemodialysed patients, it was concluded that carvedilol was more effective than calcium channel blockers and was better tolerated.
Coronary heart disease: In patients with coronary heart disease, carvedilol has demonstrated anti-ischemic (improved total exercise time, time to 1mm 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 cause 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.
Renal impairment: Carvedilol reduces morbidity and mortality in dialysis patients with dilated cardiomyopathy. A meta-analysis of placebo-controlled clinical trials including a large number of patients (>4000) with mild to moderate chronic kidney disease supports carvedilol treatment of patients with left ventricular dysfunction with or without symptomatic heart failure to reduce rates of all cause of mortality as well as heart failure related events.
Pharmacokinetics: Absorption: Following oral administration of a 25 mg capsule to healthy subjects, carvedilol is rapidly absorbed with a peak plasma concentration Cmax of 21 mg/L reached after approximately 1.5 hour (tmax). The Cmax values are linearly related to the dose. Following oral administration, carvedilol undergoes extensive first pass metabolism that results in an absolute bioavailability of about 25% in healthy male subjects. Carvedilol is a racemate and the S-(-)- enantiomer appears to be metabolized more rapidly than the R-(+)- enantiomer, showing an absolute oral bioavailability of 15% compared to 31% for the R-(+)- enantiomer. The maximal plasma concentration of R-carvedilol is approximately 2 fold higher than that of S-carvedilol.
In vitro studies have shown that carvedilol is a substrate of the efflux transporter P-glycoprotein. The role of P-glycoprotein in the disposition of carvedilol was also confirmed in vivo in healthy subjects.
Distribution: Carvedilol is a highly lipophilic compound, showing a plasma protein binding of around 95%. The distribution volume ranges between 1.5 and 2 L/kg.
Metabolism: In humans, carvedilol is extensively metabolised into a variety of metabolites that are eliminated mainly in the bile. Enterohepatic circulation of the parent substance has been shown in animals.
Carvedilol is metabolised 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 three active metabolites exhibit weak vasodilating activity. In humans, the concentrations of the three active metabolites are about 10 times lower than that of the parent substance. Two of the hydroxy-carbazole metabolites of carvedilol are extremely potent antioxidants, demonstrating a 30- to 80-fold greater potency than carvedilol.
Pharmacokinetic studies in human have shown that the oxidative metabolism of carvedilol is stereoselective. The results of an in vitro study suggested that different cytochrome P450 isoenzymes may be involved in the oxidation and hydroxylation processes including CYP2D6, CYP3A4, CYP2E1, CYP2C9, as well as CYP1A2. Studies in healthy volunteers and in patients have shown that the R-enantiomer is predominantly metabolized by CYP2D6. The S-enantiomer is mainly metabolized by CYP2D6 and CYP2C9.
Genetic polymorphism: The results of clinical pharmacokinetic studies in human subjects have shown that CYP2D6 plays a major role in the metabolism of R and of S-carvedilol. As a consequence plasma concentrations of R and S-carvedilol are increased in CYP2D6 slow metabolisers. The importance of CYP2D6 genotype in the pharmacokinetics of R and S-carvedilol was confirmed in population pharmacokinetics studies, whereas other studies did not confirm this observation. It was concluded that CYP2D6 genetic polymorphism may be of limited clinical significance.
Elimination: The average elimination half-life of carvedilol is approximately 6 hours and the plasma clearance is approximately 500-700ml/min for oral administration. Following a single oral administration of 50 mg carvedilol, around 60% are secreted into the bile and eliminated with the faeces in the form of metabolites within 11 days. Following a single oral dose, only about 16% are excreted into the urine in form of carvedilol or its metabolites. The urinary excretion of unaltered drug represents less than 2%. After intravenous infusion of 12.5 mg to healthy volunteers, the plasma clearance of carvedilol reaches around 600 mL/min and the elimination half-life around 2.5 hours. The elimination half-life of a 50 mg capsule observed in the same individuals was 6.5 hours corresponding indeed to the absorption half-life from the capsule. Following oral administration, the total body clearance of the S-carvedilol is approximately two times larger than that of the R-carvedilol.
Pharmacokinetics in Special Populations: Renal impairment: 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. Carvedilol is not eliminated during dialysis because it does not cross the dialysis membrane, probably due to its high plasma protein binding.
Hepatic impairment: See Contraindications and Hepatic Impairment under Precautions.
Elderly: Age has no statistically significant effect on the pharmacokinetics of carvedilol in hypertensive patients.
Children: Investigation in paediatrics has shown that the weight-adjusted clearance is significantly larger in paediatrics as compared to adults (see Special Dosage Instructions: Children under Dosage & Administration and Use in Children under Precautions).
Heart failure: In a study in 24 Japanese patients with heart failure, the clearance of R-and S-carvedilol was significantly lower than previously estimated in healthy volunteers. These results suggested that the pharmacokinetics of R-and S-carvedilol is significantly altered by heart failure.
Toxicology: Preclinical Safety: Carcinogenicity: In carcinogenicity studies conducted in rats and mice, employing dosages up to 75 mg/kg/day and 200 mg/kg/day respectively (38 to 100 times the maximum recommended human dose [MRHD]), carvedilol had no carcinogenic effect.
Mutagenicity: Carvedilol was not mutagenic in in vitro or in vivo mammalian tests and non-mammalian tests.
Impairment of Fertility: 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).
Teratogenicity: 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 mg/kg and 200 mg/kg, respectively (38 to 100 times MRHD).
Indications/Uses
Hypertension: Dilatrend is indicated for the management of essential hypertension. It can be used alone or in combination with other antihypertensive agents (e.g.calcium channel blockers, diuretics).
Treatment of angina pectoris.
Treatment of symptomatic chronic heart failure: Dilatrend is indicated for the treatment of symptomatic chronic heart failure (CHF) to reduce mortality and cardiovascular hospitalisations, improve patient well-being and slow the progression of the disease.
Dilatrend may be used as adjunct to standard therapy, but may also be used in those patients unable to tolerate an ACE inhibitor, or those who are not receiving digitalis, hydralazine or nitrate therapy.
Dosage/Direction for Use
Route of Administration: Oral.
Method of administration: The tablets are to be swallowed with sufficient fluid.
Duration of treatment: Treatment with carvedilol is a long-term therapy. As with all β-blockers, 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.
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 two weeks to the recommended maximum daily dose of 50 mg given once or twice daily.
Angina pectoris: 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 two weeks, up to the recommended maximum daily dose of 100 mg given in divided doses (twice daily).
Symptomatic 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 two weeks, to 6.25 mg, 12.5 mg 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 less than 85 kg (187 lbs). In patients with mild or moderate CHF weighing more than 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 more than one 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 more than two weeks, therapy should be recommenced at 3.125 mg in line with the above 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.
Special Dosage Instructions: Renal impairment: Available pharmacokinetic data and published clinical studies 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.
Children: The safety and efficacy of carvedilol in children and adolescents (<18 years) has not been established (see Use in Children under Precautions and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions).
Overdosage
Symptoms and signs of overdose: 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 generalised seizures.
Treatment of overdose: The patients should be monitored for the above mentioned signs and symptoms and managed according to the best judgment of the treating physicians and according to standard practice for patients with β-blocker overdose (e.g. atropine, transvenous pacing, glucagon, phosphodiesterase inhibitor such as amiodarone or milrinone, β-sympathomimetics).
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 overdose. The supportive treatment should therefore be continued until the patient's condition has stabilised.
Contraindications
Dilatrend must not be used in patients with: hypersensitivity to carvedilol or any component of the product; 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 atrioventricular (AV) block (unless a permanent pacemaker is in place); Severe bradycardia (< 50 bpm); Sick sinus syndrome (including sino-atrial block); Severe hypotension (systolic blood pressure < 85 mmHg); Cardiogenic shock; History of bronchospasm or asthma.
Special Precautions
General: Chronic 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 further increased 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 up-titration of Dilatrend. Dilatrend should be used with caution in combination with digitalis glycosides, as both drugs slow AV conduction.
Renal function in chronic 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.
Chronic obstructive pulmonary disease: Dilatrend should be used with caution, in patients with chronic obstructive pulmonary disease (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 it may be associated with worsening control of blood glucose, or the early signs and symptoms of acute hypoglycemia may be masked or attenuated.
Peripheral vascular disease and Raynaud's phenomenon: Dilatrend should be used with caution in patients with peripheral vascular disease (e.g. Raynaud's phenomenon) as β-blockers can precipitate or aggravate symptoms of arterial insufficiency.
Thyrotoxicosis: Dilatrend, like other agents with β-blocking properties, may obscure the symptoms of thyrotoxicosis.
Bradycardia: Dilatrend may induce bradycardia. If the patient's pulse rate decreases to less than 55 beats per minute, 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 patients undergoing desensitisation therapy, as β-blockers may increase both the sensitivity towards allergens and the severity of hypersensitivity reactions.
Severe cutaneous adverse reactions (SCARs): Very rare cases of severe cutaneous adverse reactions such as toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) have been reported during treatment with carvedilol (see Postmarketing under Adverse Reactions).
Carvedilol should be permanently discontinued in patients who experience severe cutaneous adverse reactions possibly attributable to carvedilol.
Psoriasis: Patients with a history of psoriasis associated with β-blocker therapy should take Dilatrend only after consideration of the risk-benefit ratio.
Pheochromocytoma: In patients with pheochromocytoma, an α-blocking agent should be initiated prior to the use of any β-blocking agent. Although Dilatrend has 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 non-selective 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 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 two weeks).
Interactions with other medicinal products: There are a number of important pharmacokinetic and pharmacodynamic interactions with other drugs (e.g., digoxin, cyclosporin, rifampicin, anaesthetic drugs, antiarrhythmic drugs), see Interactions, for further details.
Ability to Drive and Use Machines: Fitness to drive: No studies on the effects on the ability to drive and to use machines have been performed.
Because of individually variable reactions (e.g. 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.
Renal Impairment: The autoregulatory renal blood supply is preserved and the glomerular filtration is unchanged during chronic treatment with carvedilol. In patients with moderate to severe renal insufficiency, no changes in carvedilol dosage recommendations are warranted (see Special Dosage Instructions under Dosage & Administration).
Hepatic Impairment: Carvedilol is contraindicated in patients with clinically manifest liver dysfunction (see Contraindications). A pharmacokinetic study in cirrhotic patients has shown that exposure (AUC) to carvedilol was increased by 6.8-folds in patients with liver impairment as compared to healthy subjects.
Diabetic Patients: Beta-blockers may increase insulin resistance and mask hypoglycaemic symptoms. However, numerous studies have established that vasodilating ß-blockers like carvedilol are associated with more favorable effects on glucose and lipid profiles. Carvedilol has been shown to exhibit modest insulin-sensitizing properties and can relieve some manifestations of the metabolic syndrome.
Use in Children: See Special Dosage Instructions under Dosage & Administration.
Use in the Elderly: A study in elderly hypertensive patients showed that there was no difference in the adverse event profile as compared to younger patients. Another study, which included elderly patients with coronary heart disease, showed no difference in the adverse events reported vs those reported by younger patients. Therefore, no dose adjustment of the starting dose is required in the geriatric population (see Special Dosage Instructions under Dosage & Administration).
Use In Pregnancy & Lactation
Pregnancy: Studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical Safety under Actions). The potential risk for humans is unknown.
Beta-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.
Nursing Mothers: Animal studies demonstrated that Dilatrend and/or its metabolites are excreted in rat breast milk. The excretion of carvedilol in human milk has not been established.However, most β-blockers, in particular lipophilic compounds, will pass into human breast milk although to a variable extent. Breast feeding is therefore not recommended following administration of carvedilol.
Adverse Reactions
Clinical Trials: Adverse Drug Reactions (ADRs) are listed according to MedDRA system organ class and CIOMS frequency category: Very common ≥1/10.
Common ≥1/100 and <1/10.
Uncommon ≥1/1,000 and <1/100.
Rare ≥1/10,000 and <1/1,000.
Very rare <1/10,000.
The table as follows summarizes undesirable effects that have been reported in association with the use of carvedilol in pivotal clinical trials with following indications: chronic heart failure, left ventricular dysfunction following acute myocardial infarction, hypertension and the long term management of coronary heart disease. (See table.)

Click on icon to see table/diagram/image

Description of selected adverse reactions: The frequency of adverse reactions is not dose-dependent, with the exception of dizziness, abnormal vision and bradycardia. Dizziness, headache and asthenia are usually mild and along with syncope are more likely to occur at the beginning of the treatment.
In patients with congestive heart failure, worsening cardiac failure and fluid retention may occur during up-titration of carvedilol dose (see Precautions).
Cardiac failure was a very commonly reported adverse event in both placebo (14.5%) and carvedilol-treated (15.4%) patients, in patients with left ventricular dysfunction following acute myocardial infarction.
Reversible deterioration of renal function has been observed with carvedilol therapy in chronic heart failure patients with low blood pressure, ischaemic heart disease and diffuse vascular disease and/or underlying renal insufficiency (see Precautions).
Post Marketing: The following adverse events have been identified during post-marketing use of carvedilol. Because these events are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency and/or establish a causal relationship to drug exposure.
Metabolism and Nutrition disorder: 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 counterregulation to be inhibited.
Skin and subcutaneous tissue disorders: Alopecia: Severe cutaneous adverse reactions (Toxic epidermal necrolysis, Stevens-Johnson syndrome) (see Precautions).
Drug Interactions
(Also see Precautions).
Pharmacokinetic interactions: Effects of Carvedilol on the pharmacokinetics of other drugs: Digoxin: An increased exposure of digoxin of up to 56% has been shown in some studies in patients with heart failure. A significantly larger effect has been seen in male patients compared to female patients. Therefore monitoring of digoxin levels is recommended when initiating, adjusting or discontinuing carvedilol (see General under Precautions). Carvedilol had no effect on digoxin administered intravenously.
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 e.g. rifampicin, as serum levels of carvedilol may be reduced, or inhibitors of mixed function oxidases e.g. 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.
Cyclosporin: Two studies in renal and cardiac transplant patients receiving oral cyclosporin have shown an increase in cyclosporin plasma concentration following the initiation of carvedilol. It appears that carvedilol increases exposure to oral cyclosporin by around 10 to 20%. In an attempt to maintain therapeutic cyclosporin levels, an average 10-20% reduction of the cyclosporin dose was necessary. The mechanism for the interaction is not known but inhibition of intestinal P glycoprotein by carvedilol may be involved. Due to wide interindividual variability of cyclosporin levels, it is recommended that cyclosporin concentrations are monitored closely after initiation of carvedilol therapy and that the dose of cyclosporin be adjusted as appropriate. In case of IV administration of cyclosporin, no interaction with carvedilol is expected.
Effects of other drugs on the pharmacokinetics of Carvedilol: Inhibitors as well as inducers of CYP2D6 and CYP2C9 can modify the systemic and/or presystemic metabolism of carvedilol stereoselectively, leading to increased or decreased plasma concentrations of R and S-carvedilol (see Pharmacology: Pharmacokinetics: Metabolism under Actions). Some examples observed in patients or in healthy subjects are listed below but the list is not exhaustive.
Amiodarone: An in vitro study with human liver microsomes has shown that amiodarone and desethylamiodarone inhibited the oxidation of R and S-carvedilol. The trough concentration of R and S-carvedilol was significantly increased by 2.2- fold in heart failure patients receiving carvedilol and amiodarone concomitantly as compared to patients receiving carvedilol monotherapy. The effect on S-carvedilol was attributed to desethylamiodarone, a metabolite of amiodarone, which is a strong inhibitor of CYP2C9. A monitoring of the β-blockade activity in patients treated with the combination carvedilol and amiodarone is advised.
Rifampicin: In a study in 12 health subjects, exposure to carvedilol decreased by around 60% during concomitant administration with rifampicin and a decrease effect of carvedilol on the systolic blood pressure was observed. The mechanism for the interaction is not known but it may be due to the induction of the intestinal P glycoprotein by rifampicin. A close monitoring of the β-blockade activity in patients receiving concomitant administration of carvedilol and rifampicin is appropriate.
Fluoxetine and Paroxetine: In a randomized, cross-over study in 10 patients with heart failure, co-administration of fluoxetine, a strong inhibitor of CYP2D6, resulted in stereoselective inhibition of carvedilol metabolism with a 77% increase in mean R(+) enantiomer's AUC, and a non-statistically 35% increase of the S(-) enantiomer's AUC as compared to the placebo group. However, no differences in adverse events, blood pressure or heart rate were noted between treatment groups. The effect of single dose paroxetine, a strong CYP2D6 inhibitor, on carvedilol pharmacokinetics was investigated in 12 healthy subjects following single oral administration. Despite significant increase in R and S-carvedilol exposure, no clinical effects were observed in these healthy subjects.
Pharmacodynamic interactions: 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.
Catecholamine-depleting 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.
Digoxin: The combined use of beta-blockers and digoxin may result in additive prolongation of atrioventricular (AV) conduction time.
Non-dihydropyridines calcium channel blockers,amiodarone or other antiarrhythmics: In combination with carvedilol can increase the risk of AV conduction disturbances. Isolated cases of conduction disturbance (rarely with haemodynamic 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 non-dihydropyridines calcium channel blockers of the verapamil or diltiazem type, amiodarone or other antiarrhythmics it is recommended that ECG and blood pressure be monitored.
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.
Antihypertensives: As with other agents with β-blocking activity, carvedilol may potentiate the effect of other concomitantly administered drugs that are antihypertensive in action (e.g. α1-receptor antagonists) or have hypotension as part of their adverse effect profile.
Anesthetic agents: Careful attention must be paid during anesthesia to the synergistic negative inotropic and hypotensive effects of carvedilol and anesthetic drugs.
NSAIDs: The concurrent use of non-steroidal anti-inflammatory drugs (NSAIDs) and beta-adrenergic blockers may result in an increase in blood pressure and impairment of blood pressure control.
Beta-agonist bronchodilators: Non-cardioselective beta blockers oppose the bronchodilator effects of beta-agonist bronchodilators. Careful monitoring of patients is recommended.
Storage
Stability: 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 12.5 mg (uncoated, round, biconvex with a bilateral scoreline, pale peach) x 30's. 25 mg (uncoated, round, biconvex with a bilateral scoreline, white) x 100's.
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