DILATREND Tablet Ref.[51031] Active ingredients: Carvedilol

DILATREND should not be given to patients with bronchospasm or obstructive airways disease, allergic conditions involving the airways (e.g. allergic rhinitis, glottis oedema), metabolic acidosis, sinus bradycardia, or partial heart block. It should be given to patients with congestive heart failure only after having achieved adequate clinical control, and then only with great caution. Patients with phaeochromocytoma should first be adequately controlled by alpha blockade before initiating therapy with DILATREND. It should be used with caution in patients with renal impairment.

Chronic congestive heart failure

In congestive heart failure patients, worsening cardiac effects or fluid retention may occur during up-titration of DILATREND. If such symptoms occur, the dose of diuretics should be increased and the DILATREND dose should not be further increased until clinical stability resumes, or it may be necessary to lower the DILATREND dose or temporarily discontinue it. Such episodes do not preclude subsequent successful up-titration of DILATREND. In patients who have congestive heart failure controlled with digoxin, diuretics and/or an ACE inhibitor, DILATREND should be used with caution as both digoxin and DILATREND slow A-V conduction. See CONTRAINDICATIONS.

Left ventricular dysfunction following uncomplicated acute myocardial infarction

Before treatment with DILATREND is initiated the patient must be clinically stable and should have received an ACE inhibitor for at least the preceding 48 hours, and the dose of the ACE inhibitor should have been stable for at least the preceding 24 hours. See DOSAGE AND DIRECTIONS FOR USE.

Withdrawal syndrome

DILATREND treatment should not be discontinued abruptly, particularly in patients suffering from ischaemic heart disease. The withdrawal of DILATREND in these patients should be over the course of one to two weeks.

Bradycardia

DILATREND may induce bradycardia. If the pulse rate drops to less than 55 beats/min, the dosage must be reduced.

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 hypoglycaemia may be masked or attenuated. Regular monitoring of blood glucose is therefore required in diabetics when DILATREND is initiated or up-titrated and hypoglycaemic therapy adjusted accordingly.

Thyrotoxicosis

It is to be expected that DILATREND may mask the symptoms of thyrotoxicosis.

Renal function in congestive heart failure (CHF)

Patients with renal insufficiency require no dosage adjustment since DILATREND is cleared mainly by the liver. Reversible deterioration of renal function has been observed with DILATREND therapy in CHF patients with low blood pressure (systolic <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 DILATREND and the medicine discontinued or dosage reduced if worsening of renal function occurs.

Chronic obstructive pulmonary disease (COPD)

DILATREND should not be used in patients with COPD with a bronchospastic component. See CONTRAINDICATIONS. Patients with COPD should be closely monitored during initiation and up-titration of DILATREND and DILATREND should be discontinued if any evidence of bronchospasm is observed during treatment.

Contact lenses

Wearers of contact lenses should bear in mind the possibility of reduced lacrimation.

Peripheral vascular disease and Raynaud’s phenomenon

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

Anaesthesia and major surgery

Caution should be exercised in patients undergoing general surgery, because of the synergistic negative inotropic effects of DILATREND and anaesthetic medicines.

Hypersensitivity

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

Severe cutaneous adverse reactions (SCARs)

Severe cutaneous adverse reactions such as toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) have been reported during treatment with DILATREND, see SIDE EFFECTS, Post-Marketing. DILATREND should be permanently discontinued in patients who experience severe cutaneous adverse reactions possibly attributable to DILATREND.

Psoriasis

Patients with a history of psoriasis associated with ß-blocker therapy should take DILATREND 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 medicines (e.g. digoxin, ciclosporin, rifampicin, anaesthetic medicines, anti-dysrhythmic medicines). See INTERACTIONS.

Phaeochromocytoma

In patients with phaeochromocytoma, an alpha-blocking agent should be initiated prior to the use of DILATREND.

Prinzmetal’s variant angina

DILATREND may provoke chest pain in patients with Prinzmetal’s variant angina. However, there is no clinical experience with DILATREND in these patients, and caution should be exercised in the administration of DILATREND to patients suspected of having Prinzmetal’s variant angina.

Vagal influences

The patient can be protected against vagal influences by the intravenous administration of 1-2 mg atropine. In case of severe postural hypotension DILATREND should be discontinued in these patients.

Lactose

DILATREND contains lactose, therefore patients with rare hereditary problems of galactose intolerance, e.g. galactosaemia, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take DILATREND.

Sucrose

DILATREND contains sucrose, therefore patients with rare hereditary problems of fructose intolerance, glucosegalactose malabsorption or sucrase-isomaltase insufficiency should not take DILATREND.

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and to use machines have been performed. Patients taking DILATREND should be warned not to drive or operate machinery if they experience dizziness or related symptoms. This applies particularly when starting or changing treatment and in conjunction with alcohol.

Pharmacokinetic interactions

DILATREND may potentiate the effect of other concomitantly administered medicines that are antihypertensive in action or have hypotension as part of their adverse effect profile.

Effects of DILATREND on the pharmacokinetics of other medicines

DILATREND is a substrate as well as an inhibitor of P-glycoprotein. Therefore, the bioavailability of medicines transported by P-glycoprotein may be increased with concomitant administration of DILATREND. In addition, the bioavailability of DILATREND 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. Therefore monitoring of digoxin levels is recommended when initiating, adjusting or discontinuing DILATREND, see WARNINGS AND SPECIAL PRECAUTIONS.

Cimetidine: Concomitant therapy with cimetidine may result in increased systemic bioavailability (about 30%) but causes no change in C_max of carvedilol.

Phenothiazines: The concurrent use of phenothiazines and beta-blockers may result in a rise in the plasma levels of both medicines, since phenothaizines are inhibitors of cytochrome P450 isoenzyme CYP2D6 and may inhibit the metabolism of DILATREND, which is a substrate for this isoenzyme. Both DILATREND and phenothiazines can cause hypotension, and these effects could be additive.

Ciclosporin: Two studies in renal and cardiac transplant patients receiving oral ciclosporin have shown an increase in ciclosporin plasma concentration following the initiation of DILATREND. It appears that DILATREND increases the exposure to oral ciclosporin by around 10 to 20%. In an attempt to maintain therapeutic ciclosporin levels, an average of 10-20% reduction of the ciclosporin dose was necessary. The mechanism for the interaction is not known but inhibition of intestinal P-glycoprotein by DILATREND may be involved. Due to wide inter-individual variability of ciclosporin levels, it is recommended that ciclosporin concentrations be monitored closely after initiation of DILATREND therapy and that the dose of ciclosporin be adjusted as appropriate. In case of IV administration of ciclosporin, no interaction with DILATREND is expected.

Effects of other medicines on the pharmacokinetics of DILATREND

Inhibitors as well as inducers of CYP2D6 and CYP2C9 can modify the systemic and/or presystemic metabolism of DILATREND stereo-selectively, leading to increased or decreased plasma concentrations of R and Scarvedilol. See Pharmacokinetics, Metabolism. 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 DILATREND decreased by around 60% during concomitant administration with rifampicin and a decreased effect of DILATREND 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 DILATREND 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 Scarvedilol was significantly increased by 2,2-fold in heart failure patients receiving DILATREND and amiodarone concomitantly as compared to patients receiving DILATREND monotherapy. The effect on S-carvedilol was attributed to desethylamiodarone, a metabolite of amiodarone, which is a strong inhibitor of CYP2C9. A monitoring of β-blockade activity in patients treated with the combination DILATREND and amiodarone is advised.

Fluoxetine and Paroxetine: In a randomised cross-over study in 10 patients with heart failure, co-administration of fluoxetine, a strong inhibitor of CYP2D6, resulted in stereo-selective inhibition of DILATREND metabolism with a 77% increase in mean R(+) enantiomer AUC, and a non-statistically 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 a single dose paroxetine, a strong CYP2D6 inhibitor, on DILATREND 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 hypoglycaemics: The effects of insulin or oral hypoglycaemics may be enhanced. 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 WARNINGS AND SPECIAL PRECAUTIONS.

Catecholamine-depleting agents: Patients taking both agents with β-blocking properties and a medicine 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 β-blockers and digoxin may result in additive prolongation of atrioventricular (AV) conduction time. See WARNINGS AND SPECIAL PRECAUTIONS.

Clonidine: Concomitant administration of clonidine with agents with β-blocking properties may potentiate bloodpressure- and heart-rate-lowering effects. When concomitant treatment with DILATREND and clonidine is to be terminated, DILATREND should be discontinued first. Clonidine therapy can then be discontinued several days later by gradually decreasing the dosage.

Non-dihydropyridine calcium channel blockers, amiodarone or other anti-dysrhythmics: In combination with DILATREND can increase the risk of AV conduction disturbances. Cases of conduction disturbance (some with haemodynamic compromise) have been observed when DILATREND is co-administered with diltiazem. If DILATREND is to be administered orally with non-dihydropyridine calcium channel blockers of the verapamil or diltiazem type, amiodarone or other anti-dysrhythmics it is recommended that ECG and blood pressure be monitored.

α- and β- adrenoreceptor-stimulating agents: The effects of DILATREND are diminished by β-adrenoreceptorstimulating agents such as isoprenaline; the hypotensive effects of DILATREND may be dangerously reversed and the peripheral vasoconstrictor effects enhanced by α-adrenoreceptor-stimulating agents such as noradrenaline or those with mixed α- and β-adrenoreceptor-stimulating properties such as adrenaline; bradycardia can also occur.

Anti-hypertensives: DILATREND may potentiate the effect of other concomitantly administered medicines with anti-hypertensive action (e.g. α1-receptor antagonists) or have hypotension as part of their adverse effect profile.

Anaesthetic agents: Careful monitoring of vital signs is recommended during anaesthesia due to the synergistic negative inotropic and hypotensive effects of DILATREND and anaesthetic medicines. See WARNINGS AND SPECIAL PRECAUTIONS. DILATREND should be discontinued 48 hours prior to anaesthesia.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The concurrent use of NSAIDs and DILATREND may result in an increase in blood pressure and impairment of blood pressure control.

Beta-agonist bronchodilators: DILATREND opposes the bronchodilator effects of β-agonist bronchodilators. Careful monitoring of patients is recommended.

Hydralazine and alcohol may increase the plasma concentration of DILATREND because it is metabolised in the liver.

Pregnancy

There is no adequate clinical experience with DILATREND in pregnant women. DILATREND should not be used in pregnant women.

β-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. There is no evidence from animal studies that DILATREND has any teratogenic effects.

Lactation

DILATREND and/or its metabolites are excreted in breast milk; breast-feeding is therefore not recommended during administration of DILATREND.

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, <1/10); uncommon (≥1/1 000, <1/100); rare (≥1/10 000, <1/1 000); very rare (<1/10 000); including isolated reports.

The table 1 below summarises undesirable effects that have been reported in association with the use of DILATREND 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.

Table 1. Adverse Drug Reactions in Clinical Trials:

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 patients with congestive heart failure, worsening cardiac failure and fluid retention may occur during uptitration of DILATREND dose. See WARNINGS AND SPECIAL PRECAUTIONS.

Cardiac failure was a very commonly reported adverse event in patients with left ventricular dysfunction following acute myocardial infarction.

Reversible deterioration of renal function has been observed with DILATREND therapy in chronic heart failure patients with low blood pressure, ischaemic heart disease and diffuse vascular disease and/or underlying renal insufficiency. See WARNINGS AND SPECIAL PRECAUTIONS.

Post-Marketing

The following adverse events have been identified during post-marketing use of DILATREND. 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 medicine exposure.

Renal and urinary disorders: Cases of urinary incontinence in women, which may resolve upon discontinuation of the medication, have been reported.

Skin and subcutaneous tissue disorders: Alopecia.

Severe cutaneous adverse reactions (toxic epidermal necrolysis, Stevens-Johnson syndrome). See WARNINGS AND SPECIAL PRECAUTIONS.

Metabolism and nutrition disorders: 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.