Carvedilol 12.5 mg Tablets – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Carvedilol 12.5 mg Tablets.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Carvedilol 12.5 mg tablet contains 12.5 mg carvedilol.

Excipient with known effect: Each tablet contains 62.94 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Uncoated tablet.

Cream coloured, circular, biconvex tablets marked '12' on one face and plain on reverse face.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Symptomatic chronic heart failure (CHF)

Carvedilol is indicated for the treatment of stable mild, moderate and severe chronic heart failure as adjunct to standard therapies e.g. diuretics, digoxin and ACE inhibitors in patients with euvolemia.

Hypertension

Carvedilol is indicated for the treatment of hypertension.

Angina

Carvedilol is indicated for the prophylactic treatment of stable angina.

4.2 Posology and method of administration

For oral administration. The tablets should be taken with fluid. For CHF patients carvedilol should be given with food.

Symptomatic chronic heart failure

Initiation of therapy with carvedilol should only be under the supervision of a hospital physician, following a thorough assessment of the patients' condition.

Prior to any subsequent titration of the dose, the patient must be clinically evaluated on the day of up - titration by a health-care professional experienced in the management of heart failure to ensure that the clinical status has remained stable. The dose of carvedilol should not be increased in any patient with deteriorating heart failure since last visit or with signs of decompensated or unstable chronic heart failure.

The dosage must be titrated to individual requirements.

For those patients receiving diuretics and/or digoxin and/or ACE inhibitors, dosing of these other drugs should be stabilized prior to initiation of carvedilol treatment.

Adults

The recommended dose for the initiation of therapy is 3.125 mg twice a day for two weeks. If this dose is tolerated, the dosage should be increased subsequently, at intervals of not less than two weeks, to 6.25 mg twice daily, followed by 12.5 mg twice daily and thereafter 25 mg twice daily. Dosing should be increased to the highest level tolerated by the patient.

The recommended maximum daily dose is 25 mg given twice daily for all patients with severe CHF and for patients with mild to moderate CHF weighing less than 85 kg (187 lbs). In patients with mild or moderate CHF weighing more than 85 kg, the recommended maximum dose is 50 mg twice daily.

During up-titration of the dose in patients with systolic blood pressure < 100mmHg, deterioration of renal and/or cardiac functions may occur. Therefore, before each dose increase these patients should be evaluated by the physician for renal function and symptoms of worsening heart failure or vasodilation. Transient worsening of heart failure, vasodilation or fluid retention may be treated by adjusting doses of diuretics or ACE inhibitors or by modifying or temporarily discontinuing carvedilol treatment. Under these circumstances, the dose of carvedilol should not be increased until symptoms of worsening heart failure or vasodilation have been stabilised.

If carvedilol is discontinued for more than two weeks, therapy should be recommenced at 3.125 mg twice daily and up-titrated in line with the above dosing recommendation.

Elderly

As for adults.

Children

Safety and efficacy in children (under 18 years) has not been established.

Hypertension

Once daily dosing is recommended.

Adults

The recommended dose for initiation of therapy is 12.5 mg once a day for the first two days. Thereafter the recommended dosage is 25 mg once a day. Although this is an adequate dose in most patients, if necessary the dose may be titrated up to a recommended daily maximum dose of 50 mg given once a day or in divided doses.

Dose titration should occur at intervals of at least two weeks.

Elderly

An initial dose of 12.5 mg daily is recommended. This has provided satisfactory control in some cases. If the response is inadequate the dose may be titrated up to the recommended daily maximum dose of 50 mg given once a day or in divided doses.

Children

Safety and efficacy in children (under 18 years) has not been established.

Angina

Adults

The recommended dose for initiation of therapy is 12.5 mg twice a day for the first two days. Thereafter, the recommended dosage is 25 mg twice a day.

Elderly

The recommended maximum daily dose is 50 mg given in divided doses.

Children

Safety and efficacy in children (under 18 years) has not been established.

Patients with co-existing hepatic disease

Carvedilol is contra-indicated in patients with hepatic dysfunction (see sections 4.3 Contra-indications and 5.2 Pharmacokinetic properties).

Patients with co-existing renal dysfunction

No dose adjustment is anticipated as long as systolic blood pressure is above 100 mmHg (see also sections 4.4 Special warnings and precautions for use and 5.2 Pharmacokinetic properties).

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Carvedilol is contra-indicated in patients with marked fluid retention or overload requiring intravenous inotropic support.
• Patients with obstructive airways disease, unstable/decompensated heart failure, clinically manifested liver dysfunction.

• As with other beta-blocking agents: History of bronchospasm or asthma, 2nd and

  3rd degree A-V heart block (unless a permanent pacemaker is in place), severe bradycardia (< 50 bpm), cardiogenic shock, sick sinus syndrome (including sino-atrial block), severe hypotension (systolic blood pressure < 85 mmHg), metabolic acidosis and phaeochromocytoma (unless adequately controlled by alpha blockade).

• Prinzmetal's angina.
• Severe peripheral arterial circulatory disturbances.
• Concomitant intravenous treatment with verapamil or diltiazem (see section 4.5).

• Unsuitable for patients with lactase insufficiency, galactosaemia or

  glucose/galactose malabsorption syndrome.

4.4 Special warnings and precautions for use

Chronic Heart Failure

In chronic heart failure patients, worsening cardiac failure or fluid retention may occur during up-titration of carvedilol. If such symptoms occur, the dose of diuretics should be increased and the carvedilol dose should not be advanced until clinical stability resumes. Occasionally it may be necessary to lower the carvedilol dose or, in rare cases, temporarily discontinue it. Such episodes do not preclude subsequent successful titration of carvedilol. Carvedilol should be used with caution in combination with digitalis glycosides, as both drugs slow AV conduction (see section 4.5).

In hypertensive patients who have chronic heart failure controlled with digoxin, diuretics and/or an ACE inhibitor, carvedilol should be used with caution since both digoxin and carvedilol may slow A-V conduction.

Renal function in Chronic Heart Failure

Reversible deterioration of renal function has been observed with carvedilol 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 patients with these risk factors, renal function should be monitored during up-titration of Carvedilol and the drug discontinued or dosage reduced if worsening of renal failure occurs.

Left ventricular dysfunction following acute myocardial infarction

Before treatment with Carvedilol is initiated the patient must be clinically stable and should have received an ACE inhibitor for at least the preceding 48 hours, and the dose of the ACE inhibitor should have been stable for at least the preceding 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 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 carvedilol should be reduced if any evidence of bronchospasm is observed during treatment.

Diabetes

Care should be taken in the administration of Carvedilol to patients with diabetes mellitus, as 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. In chronic heart failure patients with diabetes, the use of Carvedilol may be associated with worsening control of blood glucose. Therefore, regular monitoring of blood glucose is required in diabetics when Carvedilol is initiated or up-titrated and hypoglycaemic therapy adjusted accordingly.

Peripheral vascular disease

Carvedilol should be used with caution in patients with peripheral vascular disease as beta-blockers can precipitate or aggravate symptoms of arterial insufficiency. However as Carvedilol also has alpha-blocking properties this effect is largely counterbalanced.

Raynaud’s phenomenon

Carvedilol should be used with caution in patients suffering from the peripheral circulatory disorder (e.g Raynaud's phenomenon) as there may be exacerbation of symptoms.

Patients who are known as poor metabolizers of debrisoquine, should be closely monitored during initiation of therapy (see section 5.2).

Thyrotoxicosis

Carvedilol may obscure the symptoms of thyrotoxicosis.

Anesthesia and major surgery

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

Bradycardia

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

Hypersensitivity

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

Psoriasis

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

Concomitant use of calcium channel blockers

Careful monitoring of ECG and blood pressure is necessary in patients receiving concomitant therapy with calcium channel blockers of the verapamil of diltiazem type or other antiarrhythmic drugs.

Phaeochromocytoma

In patients with phaeochromocytoma, an alpha-blocking agent should be initiated prior to the use of any beta-blocking agent. Although Carvedilol 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 Carvedilol 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 carvedilol may prevent such symptoms. However, caution should be taken in the administration of Carvedilol 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, carvedilol treatment should not be discontinued abruptly, particularly in patients suffering from ischaemic heart disease. The withdrawal of carvedilol should be gradual (over a period of two weeks).

Lactose

The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

In patients with a tendency to bronchospastic reactions, respiratory distress can occur as a result of a possible increase in airway resistance. The following warnings will be included on the outer packaging and leaflet:

Packaging

Do not take this medicine if you have a history of wheezing due to asthma or other lung diseases.

Leaflet

Do not take this medicine if you have a history of asthma or other lung diseases unless you have consulted your doctor or pharmacist first.

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacokinetic interactions

Digoxin and cardiac glycosides

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

Dihydropyridines

The administration of dihydropyridines and carvedilol should be done under close supervision as heart failure and severe hypotension have been reported.

Nitrates

Increased hypotensive effects.

Mixed function oxidase inducers or inhibitors

Inducers and inhibitors of hepatic metabolism: In a study in 12 healthy subjects, Rifampicin reduced plasma concentrations of carvedilol by about 70%, most likely by induction of P-glycoprotein leading to a decrease of the intestinal absorption of carvedilol. Cimetidine increased AUC by about 30% but caused no change in Cmax. Care may be required in those receiving inducers of mixed function oxidases e.g. rifampicin, as serum levels of carvedilol may be reduced, or inhibitors of mixed function oxidases e.g. cimetidine, as serum levels may be increased.

However, based on the relatively small effect of cimetidine on carvedilol drug levels, the likelihood of any clinically important interaction is minimal.

These interactions arise from the extensive metabolism of carvedilol by the cytochrome P450 enzyme system. Induction or inhibition of these enzymes by drugs such as rifampicin or cimetidine, respectively, may thus affect the biotransformation of carvedilol, with consequent effects on the therapeutic response and toleration of the beta-blocker.

Cyclosporin

Two studies in renal and cardiac transplant patients receiving oral cyclosporin have shown an increase in cyclosporin plasma concentrations following initiation of carvedilol treatment. In about 30% of patients, the dose of cyclosporin had to be reduced in order to maintain cyclosporin concentrations within the therapeutic range, while in the remainder no adjustment was needed. On average, the dose of cyclosporin was reduced about 20% in these patients.

Due to wide inter individual variability in the dose adjustment required, it is recommended that cyclosporin concentrations be monitored closely after initiation of carvedilol therapy and that the dose of cyclosporin can be adjusted as appropriate.

Amiodarone

In patients with heart failure, amiodarone decreased the clearance of S-carvedilol likely by inhibition of CYP2C9. The mean R-carvedilol plasma concentration was not altered. Consequently there is a potential risk of increased beta-blockade caused by a raise of the S-carvedilol concentration

Fluoxetine

In a randomised, cross over study in 10 patients with heart failure, co-administration of fluoxetine, a strong inhibitor of CYP2D6, resulted in stereoselective inhibition of carvedilol metabolism with a 77% increase in mean (R)+ enantiomer AUC. However no difference in adverse events, blood pressure or heart rate were noticed between treatment groups.

Phenylalkylamine or benzothiazepine calcium channel blockers, class I anti-arrhythmic drugs Verapamil, diltiazem, or other antiarrhythmics

In combination with Carvedilol can increase the risk of AV conduction disturbances (see section 4.4). Isolated cases of conduction disturbance (rarely with haemodynamic disruption) have been observed when carvedilol and diltiazem were given concomitantly. Therefore, as with other drugs with beta-blocking activity, careful monitoring of ECG and blood pressure should be undertaken when co-administering calcium channel blockers of the verapamil or diltiazem type, or class I anti-arrhythmic drugs. These types of drugs should not be co-administered intravenously in patients receiving carvedilol.

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). The effects of insulin or oral hypoglycaemics may be intensified. Regular monitoring of blood glucose is therefore recommended (see section 4.4).

Drugs with beta-blocking or catecholamine-depleting properties

Catecholamine-depleting agents

Patients taking an agent with beta-blocking properties and a drug that can deplete catecholamines (e.g. reserpine and monoamine-oxidase inhibitors) should be observed closely for signs of hypotension and/or severe bradycardia.

Digoxin

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

Veramapril, diltiazem, amiodarone or other antiarrhythmics

In combination with carvedilol can increase the risk of AV conduction disturbances (see section 4.4).

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 together is to be terminated, the beta-blocking agent should be withdrawn first. Clonidine therapy can be discontinued several days later by gradually decreasing the dosage.

Calcium-channel blockers (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 calcium channel blockers of the verapamil or diltiazem type, it is recommended that ECG and blood pressure be monitored.

Anti-hypertensive drugs

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

Other antihypertensive medicine

Carvedilol may potentiate the effects of other concomitantly administered antihypertensives (e.g. α1-receptor antagonists) and medicines with antihypertensive adverse reactions such as barbiturates, phenothiazines, tricyclic antidepressants, vasodilating agents and alcohol.

Anaesthetic agents

Careful monitoring of vital signs must be paid during general anaesthesia to the synergistic negative inotropic and hypotensive effects of carvedilol and anaesthetic drugs (see section 4.4).

NSAIDs

The concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs) and beta- adrenergic blockers may result in an increase in blood pressure and lower blood pressure control.

Estrogens and corticosteroids

The antihypertensive effect of carvedilol is decreased due to water and sodium retention.

Beta-agonist bronchodilators

Non-cardioselective beta-blockers oppose the bronchodilator effects of beta-agonist bronchodilators. Careful monitoring of patients is recommended.

Ergotamine

Vasoconstriction increased.

Neuromuscular blocking agent

Increased neuromuscular block.

4.6 Fertility, pregnancy and lactation

Pregnancy

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

Animal studies are insufficient with respect to effects on pregnancy, embryonal/foetal development, parturition 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).

Breast-feeding

Animal studies demonstrated that carvedilol or its metabolites are excreted in breast milk. It is not known whether carvedilol is excreted in human milk.

Breast feeding is therefore not recommended during the administration of carvedilol.

4.7 Effects on ability to drive and use machines

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

Because of individually variable reactions (e.g. dizziness, tiredness), the ability to drive, operate machinery, or work without firm support may be impaired. This applies particularly at the start of treatment, after dose increases, on changing products, and in combination with alcohol.

4.8 Undesirable effects

1. a) Summary of the safety profile

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

1. b) Tabulated list of adverse reactions

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

Frequency categories are as follows: Adverse drug reactions are listed below by system organ class and frequency.

Frequencies are defined as:

Very common ≥ 1/10; Common ≥ 1/100 and < 1/10; Uncommon ≥ 1/1,000 and < 1/100; Rare ≥ 1/10,000 and < 1/1,000; Very rare < 1/10,000.

In patients with chronic heart failure

* Common in patients with pre-existing diabetes mellitus (see section 4.5)

In patients with hypertension and angina

The profile is similar to that observed in chronic heart failure although the incidence of events is generally lower in patients with hypertension or angina treated with carvedilol.

1. c) Description of selected adverse reactions

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

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

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

Reversible deterioration of renal function has been observed with carvedilol therapy in chronic heart failure patients with low blood pressure, ischaemic heart disease and diffuse vascular disease and/or underlying renal insufficiency (see section 4.4).

As a class, beta-adrenergic receptor blockers may cause latent diabetes to become manifest, manifest diabetes to be aggravated, and blood glucose counter regulation to be inhibited.

Carvedilol may cause urinary incontinence in women which resolves upon discontinuation of the medication.

Reporting 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 professional are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms and signs

In the event of overdose, there may be severe hypotension, bradycardia, heart failure, cardiogenic shock and cardiac arrest. There may also be respiratory problems, bronchospasm, vomiting, disturbed consciousness and generalised seizures.

Treatment

In addition to general supportive treatment, the vital parameters must be monitored and corrected, if necessary under intensive care conditions.

Atropine can be used for excessive bradycardia, while to support ventricular function intravenous glucagon or sympathomimetics (dobutamine, isoprenaline) are recommended. If positive inotropic effect is required, phosphodiesterase inhibitors (PDE) should be considered. If peripheral vasodilation dominates the intoxication profile then norfenephrine or noradrenaline should be administered with continuous monitoring of the circulation. In the case of drug-resistant bradycardia, pacemaker therapy should be initiated.

For bronchospasm beta-sympathomimetics (as aerosol or intravenous) should be given, or aminophylline may be administered intravenously by slow injection or infusion. In the event of seizures, slow i.v. injection of diazepam or clonazepam is recommended.

In cases of severe overdose with symptoms of shock, supportive treatment must be continued for a sufficiently long period of time, i.e. until the patient’s condition is stabilised, as a prolongation of elimination half-life and redistribution of carvedilol from deeper compartments can be expected.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC Code C07A G02 (Cardiovascular system – Beta-blocking agents – Alpha- and beta-blocking agents).

Mechanism of action

Carvedilol is a vasodilating non-selective beta blocking agent with antioxidant properties. It has antagonist activity at both alpha1- and beta-adrenoceptors, with a higher affinity for the latter.

Pharmacodynamic effects

Vasodilation is predominantly mediated through alpha1 receptor antagonism.

Carvedilol reduces the peripheral vascular resistance through vasodilation and suppresses the renin-angiotensin-aldosterone system through beta blockade.

The activity of plasma renin is reduced and fluid retention is rare.

Carvedilol has no intrinsic sympathomimetic activity and like propranolol, it has membrane stabilising properties.

Carvedilol is a racemate of two stereoisomers. Beta-blockade is attributed to the S(-) enantiomer; in contrast, both enantiomers exhibit the same α1-blocking activity.

Carvedilol is a potent antioxidant, a scavenger of reactive oxygen radicals and an anti-proliferative agent. The properties of carvedilol and its metabolites have been demonstrated in in vitro and in vivo animal studies and in vitro in a number of human cell types.

Clinical efficacy

Clinical studies have shown that the balance of vasodilation and beta-blockade provided by carvedilol results in the following effects:

• In hypertensive patients, a reduction in blood pressure is not associated with a concomitant increase in total peripheral resistance, as observed with pure beta-blocking agents. Heart rate is slightly decreased. Renal blood flow and renal function are maintained. Peripheral blood flow is maintained, therefore, cold extremities, often observed with drugs possessing beta-blocking activity, are rarely seen.
• In patients with stable angina, carvedilol has demonstrated anti-ischaemic and anti-anginal properties. Acute haemodynamic studies demonstrated that carvedilol reduces ventricular pre- and after-load.

Serum lipid profile and electrolytes are not affected.

5.2 Pharmacokinetic properties

The absolute bioavailability of carvedilol is approximately 25% in humans.

Bioavailability is stereo-selective, 30% for the R-form and 15% for the S-form. Serum levels peak at approximately 1 hour after an oral dose. There is a linear relationship between the dose and serum concentrations. Food does not affect bioavailability or the maximum serum concentration although the time to reach maximum serum concentration is delayed. carvedilol is highly lipophilic, approximately 98% to 99% is bound to plasma proteins. The distribution volume is approximately 2 l/kg and increased in patients with liver cirrhosis. The first pass effect after oral administration is approximately 60 - 75%; enterohepatic circulation of the parent substance has been shown in animals.

Carvedilol exhibits a considerable first pass effect. The metabolite pattern reveals intensive metabolism with glucuronidation as one of the major steps. Demethylation and hydroxylation at the phenol ring produce three metabolites with beta-receptor blocking activity.

The average elimination half-life ranges from 6 to 10 hours. Plasma clearance is approximately 590 ml/min. Elimination is mainly biliary. The primary route of excretion is via the faeces. A minor portion is eliminated via the kidneys in the form of various metabolites.

The pharmacokinetics of carvedilol are affected by age; plasma levels of carvedilol are approximately 50% higher in the elderly compared to young subjects. In a study in patients with cirrhotic liver disease, the bioavailability of carvedilol was four times greater and the peak plasma level five times higher than in healthy subjects. Since carvedilol is primarily excreted via the faeces, significant accumulation in patients with renal impairment is unlikely. In patients with impaired liver function, bioavailability is raised to as much as 80% due to a reduced first pass effect.

5.3 Preclinical safety data

Animal studies revealed no special findings relevant to clinical use (although see section 4.6).

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate

Microcrystalline cellulose

Low substituted hydroxypropyl cellulose

Maize starch

Yellow iron oxide (E172)

Colloidal anhydrous silica

Talc

Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store in the original package.

6.5 Nature and contents of container

Packs of 28 tablets.

Blister strips comprising of PVC/PVdC/Aluminium foil enclosed in an outer carton.

6.6 Special precautions for disposal

Not applicable.

7 MARKETING AUTHORISATION HOLDER

Relonchem Limited,

Cheshire House,

Gorsey Lane,

Widnes,

Cheshire,

WA8 0RP,

United Kingdom.

8 MARKETING AUTHORISATION NUMBER(S)

PL 20395/0335

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

10/07/2023

10 DATE OF REVISION OF THE TEXT

21/04/2026