Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2023 Publisher: Milpharm Limited, Ares, Odyssey Business Park, West End Road, South Ruislip HA4 6QD, United Kingdom
In chronic heart failure patients carvedilol should be administered principally in addition to diuretics, ACE inhibitors, digitalis and/or vasodilators. Initiation of therapy should be under the supervision of a hospital physician. Therapy should only be initiated, if the patient is stabilized on conventional basic therapy for at least 4 weeks. Patients with severe heart failure, salt and volume depletion, elderly or patients with low basic blood pressure should be monitored for approximately 2 hours after the first dose or after dose increase as hypotension may occur. Hypotension due to excessive vasodilatation is initially treated by reducing the dose of the diuretic. If symptoms still persist, the dose of any ACE inhibitor may be reduced. At the start of therapy or during up-titration of Carvedilol worsening of heart failure or fluid retention may occur. In these cases, the dose of diuretic should be increased. However, sometimes it will be necessary to reduce or withdraw Carvedilol medication. The carvedilol dose should not be increased before symptoms due to the worsening of heart failure or hypotension due to vasodilatation are under control.
Since, to date, there are few data in patients with congestive heart failure class IV of the NYHA, if it is necessary to treat this group of patients with carvedilol, it should be done with special precaution. It is recommended to follow the instructions indicated in this section.
Reversible deterioration of renal function has been observed during carvedilol therapy in heart failure patients with low blood pressure (systolic <100 mmHg), ischaemic heart disease and generalized atherosclerosis, and/or underlying renal insufficiency. In heart failure patients with these risk factors, renal function should be monitored during dose titration of carvedilol. If significant worsening of renal function occurs, the carvedilol dose must be reduced or therapy must be discontinued.
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 thepast 48 hours, and the dose of the ACE inhibitor should have been stable for at least the past 24 hours.
In patients with chronic heart failure treated with digitalis, carvedilol should be given with caution, as digitalis and carvedilol both lengthen the AV conduction time (see section 4.5).
Agents with non-selective beta-blocking activity may provoke chest pain in patients with Prinzmetal’s variant angina. There is no clinical experience with carvedilol in these patients, although the alpha-blocking activity of carvedilol may prevent such symptoms. However, caution should be taken in the administration of carvedilol to patients suspected of having Prinzmetal’s variant angina.
Patients with a chronic obstructive pulmonary disease with a tendency towards bronchospasms who are not treated with oral or inhalation medicine should only be given carvedilol if the expected improvement outweighs the possible risk. Patients should be monitored closely in the initial phase, and titration of carvedilol and carvedilol dose should be reduced in case of bronchospasms.
Carvedilol may mask symptoms and signs of acute hypoglycaemia. Impaired blood glucose control may occasionally occur in patients with diabetes mellitus and heart failure in connection with the use of carvedilol. Therefore, close monitoring of diabetic patients receiving carvedilol is required by means of regular blood glucose measurements, especially during dose titration, and adjustment of antidiabetic medication as necessary (see section 4.5). Blood glucose levels should also be closely monitored after a longer period of fasting.
On the other hand, numerous studies have demonstrated that vasodilating ß-blockers, such as carvedilol, have a more favorable effect on glucose and lipid profiles. Carvedilol has shown modest insulin-sensitizing properties and may alleviate some manifestations of metabolic syndrome.
Carvedilol may mask features (symptoms and signs) of thyrotoxicosis.
Carvedilol may cause bradycardia. If there is a decrease in pulse rate to less than 55 beats per minute, and symptoms associated with bradycardia occur, the carvedilol dose should be reduced.
When carvedilol is used concomitantly with calcium channel blocking agents such as verapamil and diltiazem or with other antiarrhythmics, specifically amiodarone, the patient’s blood pressure and ECG have to be monitored. Intravenous co-administration should be avoided (see section 4.5).
Cimetidine should be administered only with caution concomitantly as effects of carvedilol may be increased (see section 4.5).
Persons wearing contact lenses should be advised of a possible reduction of the secretion of lacrimal fluid.
Care should be taken in administrating carvedilol to patients with a history of serious hypersensitivity reactions and in those undergoing desensitisation therapy as beta-blockers may increase both the sensitivity towards allergens and the seriousness of anaphylactic reactions. Cautions should be exercised when prescribing beta-blockers to patients with psoriasis since skin reactions may be aggravated.
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 section 4.8). Carvedilol should be permanently discontinued in patients who experience severe cutaneous adverse reactions possibly attributable to Eucardic.
Carvedilol should be used with caution in patients with peripheral vascular diseases, as beta-blockers may aggravate symptoms of the disease. The same also applies to those with Raynaud’s syndrome, as there may be exacerbation or aggravation of symptoms.
Patients who are known as poor metabolizers of debrisoquine, should be closely monitored during initiation of therapy (see section 5.2).
Since there is limited clinical experience, carvedilol should not be administered in patients with labile or secondary hypertension, orthostasis, acute inflammatory heart disease, haemodynamic relevant obstruction of heart valves or outflow tract, end-stage peripheral arterial disease, concomitant treatment with α1-receptor antagonist or α2-receptor agonist.
In patients with phaeochromocytoma, an initial treatment with alpha-blockers should be started before using any betablocker. Although carvedilol exercises alpha and beta blockade there is not sufficient experience in this disease, therefore caution should be advised in these patients.
Because of its negative dromotropic action, carvedilol should be given with caution to patients with first degree heart block.
Beta-blockers reduce the risk of arrhythmias at anasthesia, however the risk of hypotension may be increased as well. Caution should therefore be observed with the use of certain anaesthetic medicines. Newer studies suggest however, a benefit of beta-blockers in preventing perioperative cardiac morbidity and reduction of the incidence of cardiovascular complications.
As with other beta-blockers, carvedilol should not be discontinued abruptly. This applies in particular to patients with ischaemic heart disease. Carvedilol therapy must be discontinued gradually within two weeks, e.g. by reducing the daily dose to half every three days. If necessary, at the same time replacement therapy should be initiated to prevent exacerbation of angina pectoris.
Carvedilol contains lactose monohydrate and sucrose. Patients with rare hereditary problems of galactose intolerance, fructose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, sucrase-isomaltase insufficiency should not take this medicine.
Isolated cases of conduction disturbance (rarely compromised haemodynamics) have been reported, if oral carvedilol and oral diltiazem verapamil and/or amiodarone are given concomitantly. As with other beta-blockers, ECG and blood pressure should be monitored closely when concomitantly administering calcium-channel-blockers of the verapamil and diltiazem type due to the risk of AV conduction disorder or risk of cardiac failure (synergetic effect). Close monitoring should be done in case of co-administration of carvedilol, and amiodarone therapy (oral) or class I antiarrhythmics. Bradycardia, cardiac arrest, and ventricular fibrillation have been reported shortly after initiation of beta-blocker treatment in patients receiving amiodarone. There is a risk of cardiac failure in case of class Ia or Ic antiarrhythmics concomitant intravenous therapy.
Concomitant treatment with reserpine, guanethidine, methyldopa, guanfacine and monoamine oxidase inhibitors (exception MAO-B inhibitors) can lead to additional decrease in heart rate. And hypotension Monitoring of vital signs is recommended.
The administration of dihydropyridines and carvedilol should be done under close supervision as heart failure and severe hypotension have been reported.
Increased hypotensive effects.
An increase of steady state digoxin levels by approximately 16% and of digitoxin by approximately 13% has been seen in hypertensive patients in connection with the concomitant use of carvedilol and digoxin. Monitoring of plasma digoxin concentrations is recommended when initiating, discontinuing or adjusting treatment with carvedilol.
Carvedilol may potentiate the effects of other concomitantly administered antihypertensives (e.g. α1-receptor antagonists) and medicines with antihypertensive adverse reactions such as barbiturates, phenothiazines, tricyclic antidepressants, vasodilating agents and alcohol.
Modest increases in mean trough cyclosporine concentrations were observed following the initiation of carvedilol treatment in 21 renal transplant patients suffering from chronic vascular rejection. In about 30% of patients, the dose of cyclosporine had to be reduced in order to maintain cyclosporine concentrations with the therapeutic range, while in the remainder no adjustment was needed. On average, the dose of cyclosporine was reduced about 20% in these patients. Due to wide interindividual variability in the dose adjustments required, it is recommended that cyclosporine concentrations be monitored closely after initiation of carvedilol therapy and that the dose of cyclosporine be adjusted as appropriate.
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 section 5.2). Some examples observed in patients or in healthy subjects are listed below but the list is not exhaustive.
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. 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 AUC, and a non-statistically 35% increase of the S(-) enantiomer’s AUC as compared to the placebo group. However, no difference 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.
The blood sugar-lowering effect of insulin and oral diabetic medicines may be intensified. Symptoms of hypoglycaemia may be masked. In diabetic patients regular monitoring of blood glucose levels is necessary.
Concomitant administration of clonidine with agents with beta-blocking properties may potentiate blood pressure and heart rate lowering effects. When concomitant treatment with agents with beta-blocking properties and clonidine is to be terminated, the beta-blocking agent should be discontinued first. Clonidine therapy can then be discontinued several days later by gradually decreasing the dosage.
Caution is advised in case of anaesthesia due to synergistic, negative inotrope and hypotensive effect of carvedilol and certain anaesthetics.
The antihypertensive effect of carvedilol is decreased due to water and sodium retention.
Patients receiving medicines that induce (e.g. rifampicin and barbiturates) or inhibit (e.g. cimetidine, ketoconazole, fluoxetine, haloperidol, verapamil, erythromycine) cytochrome P450 enzymes have to be monitored closely during concomitant treatment with carvedilol as serum carvedilol concentrations may be reduced by the first agents and increased by the enzyme inhibitors.
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 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.
Risk of hypertension and excessive bradycardia.
Vasoconstriction increased.
Increased neuromuscular block.
Non-cardioselective beta blockers oppose the bronchodilator effects of beta-agonist bronchodilators.
There are no adequate data from the use of carvedilol in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). 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 reactions (especially hypoglycaemia, hypotension, bradycardia, respiratory depression and hypothermia) may occur in the fetus and neonate. There is an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period. Carvedilol should not be used during pregnancy unless clearly necessary (that is if the potential benefit for the mother outweighs the potential risk for the fetus/neonate). The treatment should be stopped 2-3 days before expected birth. If this is not possible the new-born has to be monitored for the first 2-3 days of life.
Carvedilol is lipophilic and according to results from studies with lactating animals, carvedilol and its metabolites are excreted in breast milk and, therefore, mothers receiving carvedilol should not breast-feed.
This medicinal product has minor influence on the ability to drive and use machines. Some individuals may have reduced alertness especially on initiation and adjustment of medication.
The frequency of adverse reactions is not dose-dependent, with the exception of dizziness, abnormal vision and bradycardia.
The risk of most adverse reactions associated with carvedilol is similar across all indications. Exceptions are described in subsection.
Frequency categories are as follows: 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.
Common: Bronchitis, pneumonia, upper respiratory tract infection, urinary tract infection
Common: Anaemia
Rare: Thrombocytopaenia
Very rare: Leukopenia
Very rare: Hypersensitivity (allergic reaction)
Common: Weight increase, hypercholesterolaemia, impaired blood glucose control (hyperglycaemia, hypoglycaemia) in patients with pre-existing diabetes
Common: Depression, depressed mood
Uncommon: Sleep disorders, confusion
Very common: Dizziness, headache
Uncommon: Presyncope, syncope, paraesthesia
Common: Visual impairment, lacrimation decreased (dry eye), eye irritation
Very common: Cardiac failure
Common: Bradycardia, oedema, hypervolaemia, fluid overload
Uncommon: Atrioventricular block, angina pectoris
Very common: Hypotension
Common: Orthostatic hypotension, disturbances of peripheral circulation (cold extremities, peripheral vascular disease, exacerbation of intermittent claudication and Reynaud’s phenomenon), Hypertension.
Common: Dyspnoea, pulmonary oedema, asthma in predisposed patients
Rare: Nasal congestion
Common: Nausea, diarrhoea, vomiting, dyspepsia, abdominal pain
Rare: dry mouth
Very rare: Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gammaglutamyltransferase (GGT) increased
Uncommon: Skin reactions (e.g. allergic exanthema, dermatitis, urticaria, pruritus, psoriatic and lichen planus like skin lesions and increased sweating), alopecia
Very rare: Severe cutaneous adverse reactions (e.g. Erythema multiforme, Stevens-Johnson syndrome, Toxic epidermal necrolysis)
Common: Pain in extremities
Common: Renal failure and renal function abnormalities in patients with diffuse vascular disease and/or underlying renal insufficiency, micturition disorders
Very rare: Urinary incontinence in women
Uncommon: Erectile dysfunction
Very common: Asthenia (fatigue)
Common: Pain, Oedema
Dizziness, syncope, headache and asthenia are usually mild and are more likely to occur at the beginning of treatment.
In patients with congestive heart failure, worsening cardiac failure and fluid retention may occur during up-titration of carvedilol dose (see section 4.4).
Cardiac failure is a commonly reported adverse event in both placebo and carvedilol-treated patients (14.5% and 15.4% respectively, 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 section 4.4).
As a class, beta-adrenergic receptor blockers may cause latent diabetes to become manifest, manifest diabetes to be aggravated, and blood glucose counter-regulation to be inhibited.
Carvedilol may cause urinary incontinence in women which resolves upon discontinuation of the medication.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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