EUCARDIC Tablet Ref.[51666] Active ingredients: Carvedilol

Chronic congestive heart failure

In congestive heart failure patients, worsening cardiac failure or fluid retention may occur during up-titration of Eucardic. If such symptoms occur, diuretics should be increased and the Eucardic dose should not be further increased until clinical stability resumes. Occasionally it may be necessary to lower the Eucardic dose or, in rare cases, temporarily discontinue it. Such episodes do not preclude subsequent successful up-titration of Eucardic.

Eucardic should be used with caution in combination with digitalis glycosides, since both medicinal products slow AV conduction (see section 4.5).

Renal function in congestive heart failure

Reversible deterioration of renal function has been observed with Eucardic therapy in chronic heart failure patients with low blood pressure (systolic BP < 100 mmHg), ischaemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency. In CHF patients with these risk factors, renal function should be monitored during up-titration of Eucardic and the medicinal product discontinued or dosage reduced if worsening of renal failure occurs.

Chronic obstructive pulmonary disease

Carvedilol 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 carvedilol and the dose of Eucardic should be reduced if any evidence of bronchospasm is observed during treatment.

Diabetes

Care should be taken in the administration of Eucardic to patients with diabetes mellitus, as it may be associated with worsening control of blood glucose. Furthermore, the early signs and symptoms of acute hypoglycaemia may be masked or attenuated. Alternatives to beta-blocking agents are generally preferred in insulin-dependent patients. Therefore, regular monitoring of blood glucose is required in diabetics when Eucardic is initiated or up-titrated and hypoglycaemic therapy adjusted accordingly (see section 4.5).

Peripheral vascular disease and Raynaud’s phenomenon

Eucardic should be used with caution in patients with peripheral vascular disease (e.g. Raynaud’s phenomenon) as beta-blockers can precipitate or aggravate symptoms of arterial insufficiency.

Thyrotoxicosis

Eucardic may obscure the symptoms of thyrotoxicosis.

Bradycardia

Eucardic may induce bradycardia. If the patient’s pulse rate decreases to less than 55 beats per minute, the dosage of Eucardic should be reduced.

Hypersensitivity

Care should be taken in administering Eucardic to patients with a history of serious hypersensitivity reactions and in patients undergoing desensitisation therapy as beta-blockers may increase both the sensitivity towards allergens and the severity of hypersensitivity reactions.

Risk of Anaphylactic Reaction

While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.

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 Eucardic (see section 4.8). Eucardic should be permanently discontinued in patients who experience severe cutaneous adverse reactions possibly attributable to Eucardic.

Psoriasis

Patients with a history of psoriasis associated with beta-blocker therapy should be given Eucardic only after consideration of the risk-benefit ratio.

Interactions with other medicinal products

There are a number of important pharmacokinetic and pharmacodynamic interactions with other medicinal products (e.g., digoxin, ciclosporin, rifampicin, anaesthetics, antiarrhythmics. See section 4.5).

Phaeochromocytoma

In patients with phaeochromocytoma, an alpha-blocking agent should be initiated prior to the use of any beta-blocking agent. Although Eucardic has both alpha- and beta-blocking pharmacological activities, there is no experience of the use of carvedilol in this condition. Therefore, caution should be taken in the administration of Eucardic to patients suspected of having phaeochromocytoma.

Prinzmetal’s variant angina

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 Eucardic may prevent such symptoms. Caution should be taken in the administration of Eucardic to patients suspected of having Prinzmetal’s variant angina.

Contact lenses

Wearers of contact lenses should be advised of the possibility of reduced lacrimation.

Withdrawal syndrome

Although angina has not been reported on stopping treatment, discontinuation should be gradual (over a period of 2 weeks), particularly in patients with ischaemic heart disease, as Eucardic has beta-blocking activity.

Lactose

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sucrose

This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Pharmacokinetic interactions

Effects of Eucardic on the pharmacokinetics of other medicinal products

Carvedilol is a substrate as well as an inhibitor of P-glycoprotein. Therefore, the bioavailability of drugs transported by P-glycoprotein may be increased with concomitant administration of carvedilol. In addition, the bioavailability of carvedilol can be modified by inducers or inhibitors of P-glycoprotein.

Digoxin: An increased exposure of digoxin of up to 20% has been shown in some studies in healthy subjects and 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 section 4.4). Carvedilol had no effect on digoxin administered intravenously.

Ciclosporin and tacrolimus: Two studies in renal and cardiac transplant patients receiving oral ciclosporin have shown an increase in ciclosporin plasma concentration following the initiation of carvedilol. It appears that carvedilol increases exposure to oral ciclosporin by around 10 to 20%. In an attempt to maintain therapeutic ciclosporin levels, an average 10 to 20% reduction of the ciclosporin 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 ciclosporin levels, it is recommended that ciclosporin concentrations are monitored closely after initiation of carvedilol therapy and that the dose of ciclosporin be adjusted as appropriate. In case of intravenous administration of ciclosporin, no interaction with carvedilol is expected. Furthermore, there is evidence that CYP3A4 is involved in the metabolism of carvedilol. As tacrolimus is a substrate of P-glycoprotein and CYP3A4, its pharmacokinetics may also be affected by carvedilol through these interaction mechanisms.

Effects of other medicinal products and substances 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 section 5.2). Some examples observed in patients or in healthy subjects are listed below but the list is not exhaustive.

Rifampicin: In a study in 12 healthy subjects, exposure to carvedilol decreased by around 60% during concomitant administration with rifampicin and a decreased 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 beta-blockade activity in patients receiving concomitant administration of carvedilol and rifampicin is appropriate.

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 beta-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, coadministration 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-significant 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.

Alcohol: Alcohol intake is shown to have acute hypotensive effects which may augment the blood pressure reduction caused by carvedilol. As carvedilol is soluble in ethanol, the presence of alcohol could affect the rate and/or extent of intestinal absorption of carvedilol. Also, carvedilol is partly metabolized by CYP2E1, an enzyme known to be induced and inhibited by alcohol.

Grapefruit juice: Consumption of a single dose of 300 ml grapefruit juice results in a 1.2-fold increase of the AUC of carvedilol in comparison to water. While clinical relevance is unclear, patients should avoid concomitant intake of grapefruit juice at least until a stable dose-response relationship is established.

Pharmacodynamic interactions

Insulin or oral hypoglycaemics: Agents with beta-blocking properties may enhance the blood-sugar-reducing effect of insulin and oral hypoglycaemics. The signs of hypoglycaemia may be masked or attenuated (especially tachycardia). In patients taking insulin or oral hypoglycaemics, regular monitoring of blood glucose is therefore recommended (see section 4.4).

Catecholamine-depleting agents: Patients taking both agents with beta-blocking properties and a medicinal product 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-dihydropyridine calcium channel blockers, amiodarone or other antiarrhythmics: The combined use of non-dihydropyridine calcium channel blockers, amiodarone or other antiarrhythmics with carvedilol can increase the risk of AV conduction disturbances (see section 4.4). Isolated cases of conduction disturbance (rarely with haemodynamic compromise) have been observed when carvedilol is co-administered with diltiazem. As with other agents with beta-blocking properties, if carvedilol is to be administered orally with non-dihydropyridinecalcium 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 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.

Antihypertensives: As with other agents with beta-blocking activity, Eucardic may potentiate the effect of other concomitantly administered medicinal products that are anti-hypertensive in action (e.g. alpha1-receptor antagonists) or have hypotension as part of their adverse effect profile.

Anaesthetic agents: Careful attention must be paid during general anaesthesia to the synergistic negative inotropic and hypotensive effects of carvedilol and anaesthetics (see section 4.4).

Non-steroidal anti-inflammatory 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.

Pregnancy

There is no adequate clinical experience with carvedilol in pregnant women. Animal studies demonstrated effects on pregnancy, embryonal/foetal development, parturition, reproductive toxicity and postnatal development (see section 5.3). The potential risk for humans is unknown.

Carvedilol should not be used during pregnancy unless the potential benefit outweighs the potential risk. Beta-blockers reduce placental perfusion which may result in intrauterine foetal death and immature and premature deliveries. In addition, adverse effects (especially hypoglycaemia and bradycardia) may occur in the foetus and neonate. There may be an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period. Animal studies have not shown substantive evidence of teratogenicity with carvedilol (see also section 5.3).

Breastfeeding

Animal studies demonstrated that carvedilol and/or its metabolites are excreted in rat breast milk. The excretion of carvedilol in human milk has not been established. However, most beta-blockers, in particular lipophilic compounds, will pass into human breast milk although to a variable extent. Breastfeeding is therefore not recommended following administration of carvedilol.

No studies of the effects on ability to drive and use machines have been performed.

As for other medicinal products which produce changes in blood pressure, patients taking carvedilol should be warned not to drive or operate machinery if they experience dizziness or related symptoms. This applies particularly when starting, dose increasing or changing treatment and in conjunction with alcohol.

(a) Summary of the safety profile

The frequency of adverse reactions is not dose-dependent except for dizziness, visual disturbances and bradycardia.

(b) Table of adverse reactions

The risk of most adverse reactions associated with carvedilol is similar for all indications. The exceptions are described in subsection ©.

The following undesirable effects have been reported (e.g. from clinical trials, post-authorisation safety studies or spontaneous reporting) to occur when carvedilol is administered:

Frequency categories are as follows: Very common ≥1/10, Common ≥1/100 to <1/10, Uncommon ≥1/1,000 to <1/100, Rare ≥1/10,000 to <1/1,000, Very rare <1/10,000.

Table 1. Adverse Reactions:

(c) Description of selected adverse reactions

The frequency of adverse reactions is not dose-dependent, with the exception of dizziness, abnormal vision and bradycardia. Dizziness, syncope, headache and asthenia are usually mild and are more likely to occur at the beginning of treatment.

In congestive heart failure patients, worsening cardiac failure and fluid retention may occur during up-titration of carvedilol dose (see section 4.4).

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 section 4.4).

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 medicinal product exposure:

Metabolism and nutrition disorders: 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.

Psychiatric disorders: Carvedilol may cause hallucinations.

Cardiac disorders: Sinus arrest may occur in predisposed patients (e.g. elderly patients or patients with pre-existing bradycardia, sinus node dysfunction or atrioventricular block).

Skin and subcutaneous tissue disorders: Severe cutaneous adverse reactions (Toxic epidermal necrolysis, Stevens-Johnson syndrome (see section 4.4)). Hyperhidrosis.

Renal and urinary disorders: Carvedilol may cause urinary incontinence in women which resolves upon discontinuation of the medication.

Reporting of suspected adverse reactions

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 theHPRA Pharmacovigilance Website: www.hpra.ie.

Not applicable.