DILATREND - PACKAGE LEAFLET - LEAFLETS

Home / leaflets / 2021

Dilatrend - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Carvedilol

Dilatrend 3.125 mg tablets

Dilatrend package inserts are available for pack sizes:

Dilatrend 3.125 mg tablets
Dilatrend 6.25 mg tablets
Dilatrend 12.5 mg tablets
Dilatrend 25 mg tablets
Dilatrend 50 mg tablets

Indications Why is Dilatrend used? What is it for?

Pharmacotherapeutic group

Unassociated beta-blockers, alpha - and beta - adrenergic receptor blockers.

Therapeutic indications

Treatment of essential arterial hypertension: Carvedilol is indicated for the treatment of essential arterial hypertension. It can be used alone or in combination with other antihypertensives, especially with thiazide diuretics. Treatment of angina pectoris.

Treatment of heart failure.

Contraindications When Dilatrend should not be used

Hypersensitivity to carvedilol or to any of the excipients

Unstable / decompensated heart failure, NYHA Class IV heart failure (New York Heart Association classification) unresponsive to standard therapy requiring intravenous inotropic therapy

Clinically manifest liver dysfunction

Feeding time

2nd and 3rd degree atrioventricular block (unless a permanent peacemaker has been placed)

Severe bradycardia (

Sinus node disease (including sino-atrial block)

Severe hypotension (systolic pressure

Cardiogenic shock

History of bronchospasm or asthma

Pheochromocytoma not controlled with alpha-blockers

Metabolic acidosis.

Precautions for use What you need to know before you take Dilatrend

Chronic congestive heart failure

In patients with congestive heart failure, worsening of heart failure or fluid retention may occur during the carvedilol titration phase. If these symptoms occur, the diuretic dosage should be increased and the carvedilol dose should not be increased up to until stabilization of clinical signs has been achieved. Occasionally, it may be necessary to reduce the dose of carvedilol or, in rare cases, to temporarily stop taking it. These episodes do not preclude the possibility of subsequent effective titration of carvedilol.
In patients with digitalis controlled heart failure, diuretics and / or ACE inhibitors, carvedilol should be used with caution as both digitalis and carvedilol slow atrioventricular conduction (see Interactions section).

Renal function in congestive heart failure

Reversible worsening of renal function has been observed during therapy with
carvedilol in chronic heart failure patients with low blood pressure (blood pressure
systolic ischemic heart disease and diffuse vascular disease; and / or underlying renal failure. In heart failure patients with these risk factors, renal function should be monitored during the steps of increasing the carvedilol dosage and treatment should be stopped, or the dosage reduced, if worsening of renal function is observed. .

Left ventricular dysfunction after acute myocardial infarction

Before starting treatment with carvedilol the patient must be clinically stable and
you must have received an ACE inhibitor for at least the past 48 hours, and the ACE inhibitor dose must have been stable for at least the past 24 hours.

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 taking medicinal products by mouth or inhalation, and only if the potential benefits outweigh the potential risks. In patients with a predisposition to bronchospasm, respiratory distress may occur as a result of a possible increase in airway resistance. Patients should be closely monitored during the initial and dose-adjustment phases of carvedilol, and the carvedilol dose should be reduced if symptoms of bronchospasm are observed during treatment (see Interactions section).

Diabetes

Caution should be exercised in administering carvedilol to patients with diabetes mellitus, as the initial signs and symptoms of acute hypoglycaemia may be masked or attenuated. In patients with insulin-dependent diabetes mellitus, however, alternatives to beta-blockers are preferred.
In diabetic patients with chronic heart failure, the use of carvedilol may be associated with worsening of blood glucose control. Regular blood glucose control is therefore necessary in diabetic patients and hypoglycemic therapy should be adjusted accordingly.

Peripheral vascular disease

Carvedilol should be used with caution in patients with peripheral vascular disease as beta-blockers may aggravate the symptoms of arterial insufficiency.

Raynaud's phenomenon

Carvedilol should be used with caution in patients suffering from peripheral circulatory disorders (e.g. Raynaud's phenomenon) as aggravation of symptoms may occur.

Thyrotoxicosis

Carvedilol can mask the symptoms of thyrotoxicosis.

Anesthesia and major surgery

Caution should be exercised in patients undergoing general surgery due to the synergy of the negative inotropic effects of carvedilol and anesthetics.

Bradycardia

Carvedilol can induce bradycardia. If the patient's pulse rate decreases to less than 55 beats per minute, the carvedilol dosage should be reduced.

Hypersensitivity

Caution should be exercised in administering carvedilol to patients with a history of severe hypersensitivity reactions and to patients undergoing desensitization therapy as beta-blockers may increase both sensitivity to allergens and the severity of anaphylactic reactions.

Psoriasis

Patients with a history of psoriasis associated with beta-blocker therapy should only take carvedilol after a "careful benefit / risk assessment".

Concomitant use of calcium channel blockers

Close monitoring of electrocardiographic (ECG) and blood pressure is necessary in patients receiving concomitantly carvedilol in combination with calcium channel blockers of the verapamil or diltiazem type, or other antiarrhythmic drugs (see section Interactions).

Pheochromocytoma

In patients with pheochromocytoma, an alpha-blocking agent should be started before using any beta-blocking agent. Although carvedilol has both alpha- and beta-blocking pharmacological activities, there is no experience with its use in this condition. Therefore, particular caution should be exercised in administering carvedilol to patients with suspected pheochromocytoma.

Prinzmetal's variant angina

Medicinal products with non-selective beta-blocking activity may cause 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 these symptoms. . However, caution should be exercised in administering carvedilol to patients with suspected Prinzmetal's variant angina.

Contact lenses

Contact lens wearers should be aware of the possibility of reduced lacrimation.

Withdrawal syndrome

Treatment with carvedilol should not be stopped abruptly, especially in patients with ischemic heart disease. Withdrawal of carvedilol should be done gradually (over two weeks).

Carvedilol should be used with caution in patients with labile or secondary hypertension until further clinical experience is available.

If in the course of heart failure therapy, deterioration in clinical status or signs of worsening of heart failure occur compared to the previous visit, alternative therapy should be instituted.

Interactions Which drugs or foods can modify the effect of Dilatrend

Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.

Pharmacokinetic interactions

Carvedilol is a substrate and inhibitor of P-glycoprotein. Therefore, the bioavailability of drugs transported by P-glycoprotein can be increased by concomitant administration of carvedilol. Furthermore, the bioavailability of carvedilol can be modified by inducers or inhibitors of P-glycoprotein.

Inhibitors as well as inducers of CYP2D6 and CYP2C9 may stereoselectively modify the systemic and / or presystemic metabolism of carvedilol, resulting in increased or decreased plasma concentrations of R-carvedilol and S-carvedilol (see section 5.2). Some examples seen in patients or healthy subjects are listed below, but the list is not exhaustive.

Digoxin: Digoxin concentrations are increased by approximately 15% when digoxin and carvedilol are administered concomitantly. Both digoxin and carvedilol slow AV conduction. Closer monitoring of digoxin levels is recommended when initiating, adjusting or discontinuing carvedilol therapy (see section Special warnings and precautions for use).

Inducers and inhibitors of hepatic metabolism:

Rifampicin: In a study carried out on 12 healthy subjects, the administration of rifampicin reduced the plasma levels of carvedilol by about 70%, most likely following the induction of P-glycoprotein which led to a decrease in intestinal absorption of Carvedilol and a decrease in the antihypertensive effect. Particular attention is required in patients being treated with inducers of mixed function oxidase, such as rifampicin, as serum levels of carvedilol may be reduced.

Cimetidine: Cimetidine increased the AUC by approximately 30%, but did not cause any change in Cmax. Particular attention is required in patients being treated with mixed function oxidase inhibitors, such as cimetidine, since plasma levels of carvedilol However, based on the relatively small effect of cimetidine on carvedilol levels, the likelihood of a clinically important interaction is minimal.

Ciclosporin: Two studies in renal or cardiac transplant patients treated with oral cyclosporine have shown increased plasma concentrations of cyclosporine after initiation of Carvedilo treatment. Modest increases in mean trough concentrations of cyclosporine have been observed following "initiation of carvedilol treatment in 21 renal transplant patients suffering from chronic vascular rejection. In approximately 30% of patients, the dose of cyclosporine was reduced to keep cyclosporin concentrations within the therapeutic range, while in the rest of the patients no adjustment was necessary. On average, the dose of cyclosporine in these patients was reduced by approximately 20%. Due to the large individual variability in the dose adjustment required, it is recommended that plasma concentrations of cyclosporin be closely monitored following initiation of carvedilol therapy and that the cyclosporin dose be adjusted appropriately.

Amiodarone: In patients with heart failure, amiodarone caused a reduction in the elimination of S-carvedilol, possibly as a result of inhibition of CYP2C9. The mean plasma concentration of R-carvedilol did not change. Consequently, there is a potential risk of increased beta blockade caused by an "increased concentration of S-carvedilol in plasma.

Fluoxetine: In a randomized cross-sectional study in 10 patients with heart failure, concomitant administration of fluoxetine, a strong CYP2D6 inhibitor, resulted in a stereoselective inhibition of carvedilol metabolism with a 77% increase in the mean AUC of the enantiomer. R (+) However, no differences were observed between treatment groups in adverse events, blood pressure and heart rate.

Pharmacodynamic interactions

Insulin or oral hypoglycemic agents: Agents with beta-blocking properties may potentiate the hypoglycemic action of insulin or oral hypoglycemic agents.

The signs of hypoglycemia may be masked or attenuated (especially tachycardia). Regular blood glucose monitoring is therefore recommended in patients taking insulin or oral hypoglycemic agents (see section Special warnings and precautions for use).

Catecholamine-lowering agents: Patients taking both agents with beta-blocking properties and a medicinal product that can reduce catecholamines (e.g. reserpine and monoamine oxidase inhibitors) should be carefully monitored for signs of hypotension and / or severe bradycardia.

Digoxin: Combined use of beta-blockers and digoxin may result in further prolongation of atrioventricular (AV) conduction time.

Verapamil, diltiazem, amiodarone and other antiarrhythmics: in combination with carvedilol may increase the risk of AV conduction disturbances (see section Special warnings and precautions for use).

Clonidine: Concomitant administration of clonidine and agents with beta-blocking properties may potentiate the blood pressure and heart rate lowering effects.

When concomitant treatment with agents having beta-blocking properties and clonidine is to be discontinued, the beta-blocker should be discontinued first. Clonidine therapy can be stopped a few days later by gradually decreasing the dosage.

Calcium channel blockers (see section Special warnings and precautions for use)

Isolated cases of conduction disturbance (rarely with haemodynamic impairment) have been observed when carvedilol is administered in combination with diltiazem. As observed for other agents with beta-blocking properties, if carvedilol is administered orally with calcium channel blockers of the verapamil or diltiazem type, ECG and blood pressure monitoring is recommended.

Antihypertensives: As observed for other agents with beta-blocking activity, carvedilol may potentiate the effect of other drugs administered in combination with antihypertensive action (eg α1 receptor antagonists) or that of drugs for which hypotension is part of the profile of their own. side effects.

Anesthetic Agents: Particular attention must be paid during anesthesia due to the synergy between the negative and hypotensive inotropic effects of carvedilol and anesthetics.

NSAIDs: The concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) and beta-blocking drugs can cause an increase in blood pressure levels and a reduction in blood pressure control.

Beta-Agonist Bronchodilators: Non-cardio-selective beta-blocking drugs oppose the bronchodilator effects of beta-agonists. Close monitoring of patients in these conditions is recommended (see section Special warnings and precautions for use).

The administration of carvedilol in combination with inotropic drugs has not been studied.

Warnings It is important to know that:

For those who carry out sporting activities: the use of the drug without therapeutic necessity constitutes doping and can in any case determine positive anti-doping tests.

Fertility, pregnancy and breastfeeding

Ask your doctor or pharmacist for advice before taking any medicine.

Animal studies are insufficient with regard to effects on pregnancy, embryonal / fetal development, parturition and postnatal development. The potential risk for humans is unknown.

For carvedilol, embryotoxicity was observed only after high doses in rabbits. The clinical relevance of these findings is uncertain. Furthermore, animal studies have shown that carvedilol or its metabolites cross the placental barrier and is excreted in milk, so the possible consequences of alpha and beta receptor blockade in the human fetus and neonate must always be kept in mind. It is not known whether carvedilol is excreted in human breast milk. Breastfeeding is therefore contraindicated while taking carvedilol.

With other alpha- and beta-blocking agents, effects included perinatal and neonatal stress (bradycardia, hypotension, respiratory depression, hypoglycemia and hypothermia).

Carvedilol should not be given during pregnancy unless the potential benefits outweigh the potential risks.

Beta-blockers reduce placental perfusion, which can cause intrauterine fetal death and immature and premature births. In addition, adverse reactions (especially hypoglycaemia 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.

Animal studies have shown no substantial evidence of teratogenicity with carvedilol.

Effects on ability to drive and use machines

No studies on the effects of carvedilol on patients' fitness to drive or operate machinery have been performed.

Due to variable individual reactions (e.g. dizziness, tiredness) the ability to drive, or to operate machinery, or to work without solid support may be impaired. This is particularly true at the start of treatment, after dose increases, with product changes and in combination with alcohol.

Important information about some of the ingredients

Dilatrend contains sucrose and lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

Dosage and method of use How to use Dilatrend: Dosage

The tablets should be taken with a sufficient amount of liquid. It is not necessary to take the tablets with meals; however, in patients with heart failure, carvedilol should be administered with meals to slow absorption and reduce the incidence of postural effects such as orthostatic hypotension.

Essential arterial hypertension

Adults

The recommended dosage for initiation of therapy is 12.5 mg once daily for the former
two days. Thereafter, the recommended dosage is 25 mg once a day. If necessary, the dosage can be gradually increased at intervals of not less than two weeks, until the maximum recommended dose of 50 mg per day is reached, to be taken in a single administration or divided into 25 mg twice a day.

Senior citizens

The recommended dose for initiation of therapy is 12.5 mg once a day. This has allowed for adequate control of blood pressure values in some patients. If the response is inadequate, the dose can be increased. at intervals of not less than two weeks until the maximum recommended dose of 50 mg is reached, to be taken divided into 25 mg twice a day.

Angina pectoris

Adults

The recommended initiation dosage is 12.5 mg twice daily for the first two days. Thereafter, the recommended dosage is 25 mg twice daily. It is recommended not to exceed this dosage.

Senior citizens

The recommended dose for initiation of therapy is 12.5 mg twice daily. Thereafter the dose may be increased after an interval of at least two days to 25 mg twice daily (maximum dose not to be exceeded).

Heart failure

The decision to initiate therapy with carvedilol for heart failure should be made by a physician experienced in the management of this disease, after a "careful evaluation of the patient's condition. Patients should always be clinically stable and should not present with deterioration of clinical status or signs of decompensation since previous visit In patients receiving digitalis, diuretics and ACE inhibitors, the dosage of these drugs should be stabilized before starting treatment with carvedilol.

THE DOSAGE MUST BE CUSTOMIZED AND THE PATIENT MUST BE CAREFULLY FOLLOWED BY THE DOCTOR DURING THE WHOLE PERIOD NECESSARY TO REACH THE ADEQUATE DOSAGE.

The recommended dose for initiation of therapy is 3.125 mg twice daily for at least two weeks. If this dose is well tolerated, the dose may then be increased at intervals of not less than two weeks, and first increased to 6. , 25 mg twice daily, then to 12.5 mg twice daily and finally to 25 mg twice daily The dosage should be increased to the highest tolerated dose by the patient.

The maximum recommended dose is 25 mg twice daily in all patients with severe heart failure and in patients with mild or moderate heart failure with a body weight of less than 85 kg. In patients with mild or moderate heart failure who weigh more than 85 kg the maximum recommended dose is 50 mg twice daily.

Before each dose increase, the patient should be examined by the physician for any signs of worsening heart failure or vasodilation. Temporary worsening of heart failure or fluid retention should be treated with an increase in the dosage of diuretics. although occasionally it may be necessary to decrease the dose of carvedilol or temporarily stop taking it.

In the event that the treatment with carvedilol is interrupted for more than two weeks, the therapy should be restarted with the intake of 3.125 mg twice a day and subsequently the dosage should be increased taking into account the previous recommendations.

Symptoms of vasodilation can initially be treated with a reduction in the dosage of diuretics. If symptoms persist, the dose of ACE inhibitor (if used) may be decreased and, if deemed necessary, a reduction in the carvedilol dose may subsequently be made. In such circumstances, the carvedilol dose should not be increased until symptoms of worsening heart failure or vasodilation have stabilized.

Tolerability and efficacy of carvedilol in patients under 18 years of age have not been established.

Overdose What to do if you have taken too much Dilatrend

In case of accidental ingestion / intake of an excessive dose of Dilatrend, notify your doctor immediately or go to the nearest hospital.

Symptoms and signs

Severe hypotension, bradycardia, heart failure, cardiogenic shock and cardiac arrest can occur in the event of overdose. There may also be breathing problems, bronchospasm, vomiting, altered consciousness and generalized seizures.

Treatment

In addition to normal intervention protocols, vital signs should be monitored and corrected, if necessary, in intensive care conditions.

Atropine can be used in cases of excessive bradycardia while intravenous glucagon or sympathomimetics (dobutamine, isoprenaline, orciprenaline or adrenaline) are recommended to support ventricular function.

If a positive inotropic effect is required, phosphodiesterase inhibitors (PDEs) should be considered.

If peripheral vasodilation dominates the intoxication profile, norfenephrine, adrenaline or noraradrenaline should be administered while continuously monitoring the circulation.

In case of bradycardia resistant to drug therapy, pacemaker treatment should be initiated.

In case of bronchospasm, beta-sympathomimetic drugs (by aerosol or intravenously) or intravenous aminophylline should be administered. given by injection or slow infusion.

In case of seizures, administration of diazepam or clonazepam by slow intravenous injection is recommended.

In case of severe overdose with symptoms of shock, supportive treatment with antidotes should be continued for a sufficiently long period of time, i.e. until the patient's condition has stabilized, in consideration of a prolongation of the elimination half-life. and the redistribution of carvedilol from deeper compartments. The duration of antidote therapy is related to the extent of the overdose; therapy and supportive measures should be continued until the patient has stabilized.

IF YOU HAVE ANY DOUBT ABOUT USING DILATREND, CONTACT YOUR DOCTOR OR PHARMACIST.

Side Effects What are the side effects of Dilatrend

Side effects

Like all medicines, Dilatrend can cause side effects, although not everybody gets them.

(a) Summary of the safety profile

The frequency of adverse reactions is not dose-dependent, with the exception of dizziness, abnormal vision and bradycardia.

(b) List of adverse reactions

The risk of most adverse reactions associated with carvedilol is similar across all indications. The exceptions are described in subsection (c).

The categories of attendance are as follows:

Very common ≥ 1/10

Common ≥ 1/100 e

Uncommon ≥ 1/1. 000 and

Rare ≥ 1 / 10,000 e

Very rare

Infections and infestations

Common: bronchitis, pneumonia, upper respiratory tract infections, urinary tract infections

Disorders of the blood and lymphatic system

Common: Anemia

Rare: thrombocytopenia

Very rare: leukopenia

Disorders of the immune system

Very rare: hypersensitivity (allergic reaction)

Metabolism and nutrition disorders

Common: Weight gain, hypercholesterolaemia, impaired glycemic control (hyperglycemia, hypoglycemia) in patients with pre-existing diabetes

Psychiatric disorders

Common: depression, depressed mood

Uncommon: sleep disturbances

Pathology of the nervous system

Very common: dizziness, headache

Uncommon: pre-syncope, syncope, paraesthesia. Eye disorders

Common: visual impairment, reduced lacrimation (dry eyes), eye irritation

Cardiac pathologies

Very common: heart failure

Common: bradycardia, edema, hypervolemia, excess fluid

Uncommon: atrioventricular block, angina pectoris

Vascular pathologies

Very common: hypotension

Common: orthostatic hypotension, peripheral circulation disorders (cold extremities, peripheral vascular disease, exacerbation of intermittent claudication and Reynaud's phenomenon)

Respiratory, thoracic and mediastinal disorders

Common: dyspnoea, pulmonary edema, asthma in predisposed patients

Rare: nasal congestion

Gastrointestinal disorders

Common: nausea, diarrhea, vomiting, dyspepsia, abdominal pain

Hepatobiliary disorders

Very rare: increased alanine aminotransferase (ALT), aspartate aminotransferase (AST)
and gammaglutamyltransferase (GGT)

Skin and subcutaneous tissue disorders

Uncommon: skin reactions (e.g. allergic rash, dermatitis, urticaria, pruritus, psoriatic skin lesions and skin lesion-like lichen planus), alopecia

Very rare: severe skin adverse reactions (e.g. erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis)

Musculoskeletal and connective tissue disorders

Common: pain in the extremities

Renal and urinary disorders

Common: renal failure and changes in renal function in patients with diffuse vascular disease and / or baseline renal failure, urination disturbances

Very rare: urinary incontinence in women

Diseases of the reproductive system and breast

Uncommon: erectile dysfunction

General disorders and administration site conditions

Very common: asthenia (fatigue)

Common: pain

(c) Description of selected adverse reactions

Vertigo, syncope, headache and asthenia are usually mild and are more likely to occur at the start of treatment.

In patients with congestive heart failure, worsening of heart failure and fluid retention may occur in the dose titration phase of carvedilol (see section Special warnings and precautions for use).

Heart failure is a commonly reported event in both placebo and carvedilol-treated patients (14.5% and 15.4%, respectively, in patients with left ventricular dysfunction after acute myocardial infarction).

Reversible worsening of renal function has been observed with carvedilol therapy in chronic heart failure patients with low blood pressure, ischemic heart disease and diffuse vascular disease and / or underlying renal insufficiency (see section Special warnings and precautions for use).

As a class effect, beta-adrenergic receptor antagonists can cause the onset of latent diabetes, worsening of overt diabetes, and inhibition of the blood glucose regulation center.

Carvedilol can cause urinary incontinence in women which resolves upon discontinuation of treatment.

Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Undesirable effects can also be reported directly via the national reporting system
at "the address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse". By reporting side effects you can help provide more information on the safety of this medicine

Expiry and Retention

Expiry: see the expiry date printed on the package.

The expiry date refers to the product in intact packaging, correctly stored.

Warning: do not use the medicine after the expiry date shown on the package.

Store at a temperature not exceeding 30 ° C.Store in the original container.

Medicines should not be disposed of via wastewater or household waste.

Ask your pharmacist how to throw away medicines you no longer use.

This will help protect the environment.

Keep this medicine out of the reach and sight of children.

Composition and pharmaceutical form

Composition

One 3.125 mg tablet contains: 3.125 mg carvedilol

Excipients: sucrose, lactose monohydrate, povidone K25, anhydrous colloidal silica, crospovidone type A, magnesium stearate, red iron oxide (E 172).

Pharmaceutical form and content

Box of 28 divisible tablets of 3.125 mg

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Dilatrend can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications Pregnancy 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction 04.6 Pregnancy and lactation 04.7 Effects on ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER 08.0 MARKETING AUTHORIZATION NUMBER ON THE MARKET 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIOPharmaceuticals, FURTHER DETAILED INSTRUCTIONS AND PRE-DETAILED QUALITY CONTROLS

01.0 NAME OF THE MEDICINAL PRODUCT

DILATREND

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

One 3.125 mg tablet contains: 3.125 mg carvedilol

One 6.25 mg tablet contains: 6.25 mg carvedilol.

One 12.5 mg tablet contains: 12.5 mg carvedilol.

One 25mg tablet contains: Carvedilol 25mg.

One 50mg tablet contains: 50mg carvedilol.

For excipients, see 6.1

03.0 PHARMACEUTICAL FORM

Divisible tablets of 3.125 mg; 6.25 mg; 12.5 mg; 25 mg and 50 mg, for oral administration.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Treatment of essential arterial hypertension:

Carvedilol is indicated for the treatment of essential arterial hypertension. It can be used alone or in combination with other antihypertensives, especially with thiazide diuretics.

Treatment of angina pectoris.

Treatment of heart failure.

04.2 Posology and method of administration

The tablets should be taken with a sufficient amount of liquid.

It is not necessary to take the tablets with meals; however, in patients with heart failure, carvedilol should be administered with meals to slow absorption and reduce the incidence of postural effects such as orthostatic hypotension.

Treatment of essential arterial hypertension

Adults: The recommended initiation dosage is 12.5 mg once daily for the first two days. Thereafter, the recommended dosage is 25 mg once daily. Dosage can be gradually increased at intervals if necessary. not less than two weeks, until reaching the maximum recommended dose of 50 mg per day to be taken in a single administration or divided into 25 mg twice a day.

Senior citizens: The recommended dose for initiation of therapy is 12.5 mg once a day. This dosage has allowed for adequate control of blood pressure values in some patients. If the response is inadequate, the dosage may be increased at intervals of not less than two weeks until the maximum recommended dose of 50 mg is reached, to be taken divided into 25 mg twice daily.

Treatment of angina pectoris

Adults: The recommended initiation dosage is 12.5 mg twice daily for the first two days. Thereafter, the recommended dosage is 25 mg twice daily.

It is recommended not to exceed this dosage.

Senior citizens: the recommended starting dose is 12.5 mg twice a day. Thereafter the dose can be increased, after an interval of at least two days, to 25 mg twice a day (maximum dose not to be exceeded) .

Treatment of heart failure

THE DOSAGE MUST BE CUSTOMIZED AND THE PATIENT MUST BE CAREFULLY FOLLOWED BY THE DOCTOR DURING THE WHOLE PERIOD NECESSARY TO REACH THE ADEQUATE DOSAGE.

Symptoms of vasodilation can initially be treated with a reduction in the dosage of diuretics. If symptoms persist, the dose of ACE inhibitor (if used) can be decreased and, if deemed necessary, a reduction of the carvedilol dose can be made afterwards. In such circumstances, the carvedilol dose should not be increased until symptoms of worsening heart failure or vasodilation have stabilized.

Tolerability and efficacy of carvedilol in patients under 18 years of age have not been established.

04.3 Contraindications

Hypersensitivity to carvedilol or to any of the excipients

Unstable / decompensated heart failure, NYHA Class IV heart failure (New York Heart Association classification) unresponsive to standard therapy requiring intravenous inotropic therapy

Clinically manifest liver dysfunction

Pregnancy

2nd and 3rd degree atrioventricular block (unless a permanent peacemaker has been placed)

Severe bradycardia (

Sinus node disease (including sino-atrial block)

Severe hypotension (systolic pressure

Cardiogenic shock

Pheochromocytoma not controlled with alpha-blockers

Metabolic acidosis

History of bronchospasm or asthma

04.4 Special warnings and appropriate precautions for use

Chronic congestive heart failure

In patients with digitalis controlled heart failure, diuretics and / or ACE inhibitors, carvedilol should be used with caution as both digitalis and carvedilol slow atrioventricular conduction (see section 4.5).

Renal function in congestive heart failure

Reversible worsening of renal function has been observed during carvedilol therapy in chronic heart failure patients with low blood pressure (systolic pressure ischemic heart disease and diffuse vascular disease, and / or underlying renal insufficiency. such risk factors, renal function should be monitored during the phases of increasing the carvedilol dosage and treatment should be suspended, or the dosage reduced, if worsening of renal function is observed.

Left ventricular dysfunction after acute myocardial infarction

Prior to initiating carvedilol treatment the patient must be clinically stable and must have received an ACE inhibitor for at least the past 48 hours, and the ACE inhibitor dose must be stable for at least the past 24 hours.

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 taking medicinal products by mouth or inhalation and only if the potential benefits outweigh the potential risks. In patients with a predisposition to bronchospasm, respiratory distress may occur as a result of a possible increase in airway resistance. Patients should be closely monitored during the initial and dose-adjustment phases of carvedilol, and the carvedilol dose should be reduced if symptoms of bronchospasm are observed during treatment (see section 4.5).

Diabetes

In diabetic patients with chronic heart failure, the use of carvedilol may be associated with worsening of glycemic control. Regular glycemic control is therefore necessary in diabetics both when carvedilol therapy is initiated and when its dosage is increased; hypoglycemic therapy must be adjusted accordingly.

Peripheral vascular disease

Carvedilol should be used with caution in patients with peripheral vascular disease as beta-blockers may precipitate or aggravate symptoms of arterial insufficiency.

Raynaud's phenomenon

Carvedilol should be used with caution in patients suffering from peripheral circulatory disorders (e.g. Raynaud's phenomenon) as aggravation of symptoms may occur.

Thyrotoxicosis

Carvedilol can mask the symptoms of thyrotoxicosis.

Anesthesia and major surgery

Caution should be exercised in patients undergoing general surgery due to the synergy of the negative inotropic effects of carvedilol and anesthetics.

Bradycardia

Carvedilol can induce bradycardia. If the patient's pulse rate decreases to less than 55 beats per minute, the carvedilol dosage should be reduced.

Hypersensitivity

Caution should be exercised in administering carvedilol to patients with a history of severe hypersensitivity reactions and to patients undergoing desensitization therapy, as beta-blockers may increase both sensitivity to allergens and the severity of anaphylactic reactions.

Psoriasis

Patients with a history of psoriasis associated with beta blocker therapy should only take carvedilol after a "careful benefit / risk assessment."

Concomitant use of calcium channel blockers

Pheochromocytoma

In patients with pheochromocytoma, an alpha-blocking agent should be started before using any beta-blocking agent. Although carvedilol has both alpha and beta blocking pharmacological activities, there is no experience with its use in this condition. Therefore, particular caution should be exercised in administering carvedilol to patients with suspected pheochromocytoma.

Prinzmetal's variant angina

Medicinal products with non-selective beta-blocking activity may cause 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 these symptoms. However, caution should be exercised in administering carvedilol to patients with suspected Prinzmetal's variant angina.

Contact lenses

Contact lens wearers should be aware of the possibility of reduced lacrimation.

Withdrawal syndrome

Carvedilol treatment should not be stopped abruptly, especially in patients with ischemic heart disease. Withdrawal of carvedilol should be done gradually (over two weeks).

Carvedilol should be used with caution in patients with labile or secondary hypertension until further clinical experience is available.

If in the course of heart failure therapy, deterioration in clinical status or signs of worsening of heart failure occur compared to the previous visit, alternative therapy should be instituted.

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

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.

04.5 Interactions with other medicinal products and other forms of interaction

Pharmacokinetic interactions

Digoxin: Digoxin concentrations are increased by approximately 15% when digoxin and carvedilol are administered concomitantly. Both digoxin and carvedilol slow AV conduction. Closer monitoring of digoxin levels is recommended when initiating, adjusting or discontinuing carvedilol therapy (see section 4.4).

Inducers and inhibitors of hepatic metabolism:

• Rifampicin: in a study carried out on 12 healthy subjects, the administration of rifampicin reduced the plasma levels of carvedilol by about 70%, most likely following the induction of P-glycoprotein which led to a decrease in intestinal absorption of carvedilol and a decrease in the antihypertensive effect. Particular attention is required in patients being treated with inducers of mixed function oxidases, eg rifampicin, since serum levels of carvedilol may be reduced.

• Cimetidine: Cimetidine increased the AUC by approximately 30%, but did not cause any change in Cmax. Particular attention is required in patients being treated with mixed function oxidase inhibitors, eg cimetidine, as plasma levels of carvedilol may However, based on the relatively small effect of cimetidine on carvedilol levels, the likelihood of a clinically important interaction is minimal.

Ciclosporin: Two studies in renal or cardiac transplant patients treated with oral cyclosporine showed increased plasma concentrations of cyclosporine after initiation of carvedilol treatment. Modest increases in mean trough concentrations of ciclosporin were observed after initiation treatment with carvedilol in 21 renal transplant patients suffering from chronic vascular rejection. In approximately 30% of patients, the dose of cyclosporine was reduced to keep cyclosporin concentrations within the therapeutic range, while in the rest of the patients no adjustment was necessary. On average, the dose of cyclosporine in these patients was reduced by approximately 20%. Due to the large individual variability in the dose adjustment required, it is recommended that plasma concentrations of cyclosporin be closely monitored following initiation of carvedilol therapy and that the cyclosporin dose be adjusted appropriately.

Amiodarone: In patients with heart failure, amiodarone caused a reduction in the elimination of S-carvedilol, possibly as a result of inhibition of CYP2C9. The mean plasma concentration of R-carvedilol did not change. Consequently, there is a risk potential for increased beta blockade caused by an "increased concentration of S-carvedilol in plasma.

Fluoxetine: In a randomized cross-sectional study in 10 patients with heart failure, the concomitant administration of fluoxetine, a strong inhibitor of CYP2D6, resulted in a stereoselective inhibition of carvedilol metabolism with a 77% increase in the mean AUC of the R-enantiomer (+) However, no differences were observed between treatment groups in adverse events, blood pressure and heart rate.

Pharmacodynamic interactions Insulin or oral hypoglycemic agents: Agents with beta-blocking properties may potentiate the hypoglycemic action of insulin or oral hypoglycemic agents.

Agents that reduce catecholamines: Patients taking both agents with beta-blocking properties and a medicinal product that may reduce catecholamines (e.g. reserpine and monoamine oxidase inhibitors) should be carefully monitored for signs of hypotension and / or severe bradycardia.

Digoxin: The combined use of beta-blockers and digoxin may result in a further prolongation of atrioventricular (AV) conduction time.

Verapamil, diltiazem, amiodarone and other antiarrhythmics: in combination with carvedilol they may increase the risk of AV conduction disturbances (see section 4.4).

Clonidine: Concomitant administration of clonidine and agents with beta-blocking properties may potentiate the blood pressure and heart rate lowering effects.

Calcium channel blockers (see section 4.4)

Antihypertensives: as observed for other agents with beta-blocking activity, carvedilol may potentiate the effect of other drugs administered in combination with antihypertensive action (eg α1 receptor antagonists) or that of drugs for which hypotension is part of the profile of their effects unwanted.

Anesthetic agents: Particular attention must be paid during anesthesia due to the synergy between the negative and hypotensive inotropic effects of carvedilol and anesthetics.

NSAIDs: The concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) and beta-blocking drugs can cause an increase in blood pressure levels and a reduction in blood pressure control.

Beta-agonist bronchodilators: Non-cardio-selective beta-blocking drugs oppose the bronchodilator effects of beta-agonists. Close monitoring of patients in these conditions is recommended (see section 4.4).

The administration of carvedilol in combination with inotropic drugs has not been studied.

04.6 Pregnancy and lactation

There is no adequate clinical experience with the use of carvedilol in pregnant women.

Animal studies are insufficient with respect to effects on pregnancy, embryonal / fetal development, parturition and postnatal development (see section 5.3). The potential risk for humans is unknown.

With other alpha- and beta-blocking agents, effects included perinatal and neonatal stress (bradycardia, hypotension, respiratory depression, hypoglycemia and hypothermia).

Carvedilol should not be given during pregnancy unless the potential benefits outweigh the potential risks.

Animal studies have shown no substantial evidence of teratogenicity with carvedilol (see also section 5.3).

04.7 Effects on ability to drive and use machines

No studies on the effects of carvedilol on patients' fitness to drive or operate machinery have been performed.

Due to variable individual reactions (e.g. dizziness, tiredness) the ability to drive, use machines, or work without solid support may be impaired. This is particularly true at the start of treatment, after dose increases, with product changes and in combination with alcohol.

04.8 Undesirable effects

(a) Summary of the safety profile

The frequency of adverse reactions is not dose-dependent, with the exception of dizziness, abnormal vision and bradycardia.

(b) List of adverse reactions

The risk of most adverse reactions associated with carvedilol is similar across all indications. The exceptions are described in subsection (c).

The categories of attendance are as follows:

Very common ≥ 1/10

Common ≥ 1/100 e

Uncommon ≥ 1/1. 000 and

Rare ≥ 1 / 10,000 e

Very rare

Infections and infestations

Common: bronchitis, pneumonia, upper respiratory tract infections, urinary tract infections

Disorders of the blood and lymphatic system

Common: Anemia

Rare: thrombocytopenia

Very rare: leukopenia

Disorders of the immune system

Very rare: hypersensitivity (allergic reaction)

Metabolism and nutrition disorders

Common: Weight gain, hypercholesterolaemia, impaired glycemic control (hyperglycemia, hypoglycemia) in patients with pre-existing diabetes

Psychiatric disorders

Common: depression, depressed mood

Uncommon: sleep disturbances

Pathology of the nervous system

Very common: dizziness, headache

Uncommon: pre-syncope, syncope, paraesthesia

Eye disorders

Common: visual impairment, reduced lacrimation (dry eyes), eye irritation

Cardiac pathologies

Very common: heart failure

Common: bradycardia, edema, hypervolemia, excess fluid

Uncommon: atrioventricular block, angina pectoris

Vascular pathologies

Very common: hypotension

Common: orthostatic hypotension, peripheral circulation disorders (cold extremities, peripheral vascular disease, exacerbation of intermittent claudication and Reynaud's phenomenon)

Respiratory, thoracic and mediastinal disorders

Common: dyspnoea, pulmonary edema, asthma in predisposed patients

Rare: nasal congestion

Gastrointestinal disorders

Common: nausea, diarrhea, vomiting, dyspepsia, abdominal pain

Hepatobiliary disorders

Very rare: increased alanine aminotransferase (ALT), aspartate aminotransferase (AST)

and gammaglutamyltransferase (GGT)

Skin and subcutaneous tissue disorders

Uncommon: skin reactions (e.g. allergic rash, dermatitis, urticaria, pruritus, psoriatic skin lesions and skin lesion-like lichen planus), alopecia

Very rare: severe skin adverse reactions (e.g. erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis)

Musculoskeletal and connective tissue disorders

Common: pain in the extremities

Renal and urinary disorders

Common: renal failure and changes in renal function in patients with diffuse vascular disease and / or baseline renal failure, urination disturbances

Very rare: urinary incontinence in women

Diseases of the reproductive system and breast

Uncommon: erectile dysfunction

General disorders and administration site conditions

Very common: asthenia (fatigue)

Common: pain

(c) Description of selected adverse reactions

Vertigo, syncope, headache and asthenia are usually mild and are more likely to occur at the start of treatment.

In patients with congestive heart failure, worsening of heart failure and fluid retention may occur in the carvedilol dose titration phase (see section 4.4).

As a class effect, beta-adrenergic receptor antagonists can cause the onset of latent diabetes, worsening of overt diabetes, and inhibition of the blood glucose regulation center.

Carvedilol can cause urinary incontinence in women which resolves upon discontinuation of treatment.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous 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. "address http://www.agenziafarmaco.gov.it/it/responsabili.

04.9 Overdose

Symptoms and signs

Severe hypotension, bradycardia, heart failure, cardiogenic shock and cardiac arrest can occur in the event of overdose. In addition, breathing problems, bronchospasm, vomiting, alterations of consciousness and generalized seizures may occur.

Treatment

In addition to normal intervention protocols, vital signs should be monitored and corrected, if necessary, in intensive care conditions.

If a positive inotropic effect is required, phosphodiesterase inhibitors (PDEs) should be considered.

If peripheral vasodilation dominates the intoxication profile, norfenephrine, adrenaline or noradrenaline should be administered while continuously monitoring the circulation.

In case of bradycardia resistant to drug therapy, pacemaker treatment should be initiated.

In case of bronchospasm, beta-sympathomimetic drugs (by aerosol or intravenously) or intravenous aminophylline should be administered, administered by injection or slow infusion.

In case of seizures, administration of diazepam or clonazepam by slow intravenous injection is recommended.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: alpha and beta-adrenergic receptor blockers,

ATC code: C07AG02

Carvedilol is a non-selective beta-blocker which exerts vasodilating activity mediated mainly through a selective block of alpha1-adrenergic receptors, and is endowed with antioxidant properties.

Carvedilol reduces peripheral vascular resistance by vasodilation and depresses the renin-angiotensin-aldosterone system by beta-blockade. Plasma renin activity is reduced and fluid retention is rare.

Carvedilol has no intrinsic sympathomimetic activity and, like propranolol, has membrane stabilizing activity.

Carvedilol is a racemic mixture of two stereoisomers. In animal models, both enantiomers possess blocking activity against alpha adrenergic receptors.

The beta-adrenergic blocking properties are not selective for beta-1 or beta-2 adrenoceptors and are associated with the levorotatory enantiomer of carvedilol.

Carvedilol is a powerful antioxidant and has a "scavenger" activity against oxygen radicals.

The antioxidant properties of carvedilol and its metabolites have been demonstrated in studies in vitro and in vivo in animal models, ed in vitro in different types of human cells.

Clinical studies have shown that the combined vasodilation and beta-blocking activities possessed by carvedilol produce the following effects:

In hypertensive patients, the reduction in blood pressure is not associated with a concomitant increase in total peripheral resistance, as is instead observed with pure beta-blocker drugs. Heart rate decreased slightly. Renal blood flow and renal function are maintained. Peripheral blood flow is maintained, therefore cold extremities (often seen with beta-blocker drugs) are a rare event.

Acute hemodynamic studies have shown that carvedilol is able to reduce ventricular pre- and afterload.

In patients with heart failure, carvedilol has been shown to produce favorable effects on hemodynamics and improve both the ejection fraction and the size of the left ventricle.

The normal ratio of high and low density lipoproteins (HDL / LDL) is not changed. The plasma electrolyte picture is not changed.

In a large, multicenter, double-blind, placebo-controlled study (COPERNICUS), 2289 patients with stable severe heart failure of ischemic or non-ischemic origin, on standard therapy, were randomized to receive carvedilol (1156 patients) or placebo (1133 patients).

Patients had left ventricular systolic dysfunction with a mean ejection fraction of less than 20%. In the carvedilol group, mortality was reduced by 35% compared to the placebo group (12.8% vs 19.7%, p = 0.00013). In the carvedilol group, the reduction in mortality was observed in all patient subgroups studied; furthermore, sudden deaths were reduced by 41% compared to the placebo group (4.2% vs 7.8%).

The combined secondary endpoints of mortality or hospitalizations for heart failure, mortality or hospitalization for cardiovascular causes and mortality or hospitalizations from all causes were all significantly lower in the carvedilol group than in the placebo group (with reductions of 31%, 27% and 24%, p

During the study, the incidence of serious adverse events was lower in the carvedilol group (39% vs 45.4%). At the start of treatment, the incidence of worsening heart failure was similar in both groups. L "incidence of severe worsening of heart failure was lower in the carvedilol group (14.5% vs 21.1%).

05.2 Pharmacokinetic properties

Absorption

Carvedilol is a substrate of the intestinal transporter P-glycoprotein, which plays an important role in the bioavailability of certain drugs.

The absolute bioavailability of carvedilol in humans is about 25%.The plasma peak is reached approximately 1 hour after oral administration. There is a linear relationship between dose and plasma concentration. Meals do not change bioavailability or maximum plasma concentration, although the time to reach maximum plasma concentration is delayed.

Distribution

Carvedilol is highly lipophilic; approximately 98% - 99% of the drug is bound to plasma proteins. The volume of distribution is approximately 2 L / kg and increases in patients with liver cirrhosis.

Matabolism

The "first pass effect" after oral administration is approximately 60-75%; entero-hepatic recirculation of the unchanged drug has been demonstrated in the animal.

In all animal species studied and also in humans, carvedilol is extensively metabolized in the liver by oxidation and conjugation with the production of various metabolites which are mainly eliminated with the bile.

In patients with impaired hepatic function the bioavailability may be increased up to 80% due to a reduced first pass effect.

The oxidative metabolism of carvedilol is stereoselective. The R-enantiomer is predominantly metabolised by CYP2D6 and CYP1A2, while the S-enantiomer is mainly metabolised by CYP2C9 and to a lesser extent by CYP2D6. Other CYP450 isoenzymes involved in the metabolism of carvedilol include CYP3A4, CYP2E1 and CYP2C19. The maximum plasma concentration of R-carvedilol is approximately 2 times higher than that of S-carvedilol.

The R-enantiomer is mainly metabolised by hydroxylation.

In poor metabolisers of CYP2D6, an increase in the plasma concentration of carvedilol, mainly the R-enantiomer, may occur, leading to an increase in alpha-blocking activity.

Demethylation and hydroxylation of the phenolic ring produce three active metabolites with beta-blocking activity. The metabolite 4 "-hydroxyphenol was found, in preclinical tests, about thirteen times more active than carvedilol in terms of beta-blocking activity. The three active metabolites show, when compared to carvedilol, a weak vasodilating action. In humans, their concentrations are approximately. ten times lower than that of carvedilol. Furthermore, two of the hydroxy-carbazole metabolites are particularly powerful antioxidants, with an antioxidant activity from 30 to 80 times greater than that of carvedilol.

Elimination

The mean elimination half-life of carvedilol is between 6 and 10 hours.

Plasma clearance is approximately 590 mL / min. Elimination occurs primarily via the biliary route. The major route of excretion is via the faeces. A smaller amount is eliminated by the kidney in the form of various metabolites.

Pharmacokinetics in special populations

The pharmacokinetics of carvedilol change with age; carvedilol plasma levels in elderly patients are approximately 50% higher than those seen in young patients. In a study conducted in patients with liver cirrhosis, the bioavailability of carvedilol was found to be was four times higher and the plasma peak was five times higher than that observed in healthy volunteers.

In hypertensive patients with moderate (creatinine clearance 20-30 ml / min) to severe (creatinine clearance) renal impairment

In a study of 24 patients with heart failure, the clearance of R and S-carvedilol was significantly lower than previously estimated in healthy volunteers. These results suggest that the pharmacokinetics of R and S-carvedilol are significantly altered by heart failure.

05.3 Preclinical safety data

In carcinogenicity studies performed in rats and mice using doses up to 75 mg / kg / day and 200 mg / kg / day, respectively (38 to 100 times the maximum recommended human dose), carvedilol was not found to be carcinogenic.

Carvedilol has been shown not to possess mutagenic activity in tests conducted on mammals and non-mammals either in vitro and in vivo.

The administration of carvedilol in pregnant female rats at maternally toxic dosages (200 mg / kg equal to more than 100 times the maximum recommended dose in humans) resulted in impaired fertility (poor mating, fewer corpora lutea and fewer implants , and embryos) Dosages 60 mg / kg (30 times the maximum recommended dose in humans) caused a delay in the growth and development of the offspring. An embryotoxic effect (increased post-implantation loss) was observed but no malformations were observed in rats and rabbits up to doses of 200 mg / kg and 75 mg / kg, respectively (100 times and 38 times the maximum recommended dose. in man).

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

3.125 mg tablets:

Sucrose, lactose monohydrate, povidone K25, anhydrous colloidal silica, crospovidone type A, magnesium stearate, red iron oxide (E 172).

6.25 mg tablets:

Sucrose, lactose monohydrate, povidone K25, anhydrous colloidal silica, crospovidone type A, magnesium stearate, yellow iron oxide (E 172).

12.5 mg tablets:

Sucrose, lactose monohydrate, povidone K25, anhydrous colloidal silica, crospovidone type A, magnesium stearate, yellow iron oxide (E 172), red iron oxide (E 172).

25 mg tablets:

Sucrose, lactose monohydrate, povidone K25, anhydrous colloidal silica, crospovidone type A, magnesium stearate.

50 mg tablets:

Sucrose, lactose monohydrate, povidone K25, anhydrous colloidal silica, crospovidone type A, magnesium stearate.

06.2 Incompatibility

Not relevant.

06.3 Period of validity

The following validity periods are intended for product stored in the original packaging.

50 mg tablets 2 years

25 mg tablets 5 years

12.5 mg tablets 4 years

6.25 mg tablets 3 years

3.125 mg tablets 3 years

06.4 Special precautions for storage

3.125 mg, 12.5 mg and 50 mg tablets

Store at a temperature not exceeding 30 ° C. Store in the original container.

6.25 mg and 25 mg tablets

Store in the original package to protect from light and moisture.

06.5 Nature of the immediate packaging and contents of the package

The tablets are packed in blisters.

06.6 Instructions for use and handling

Disposal of expired / unused drugs

The release of drugs into the environment should be minimized. Medicines should not be disposed of via wastewater or household waste. Use dedicated collection systems, if available.