Document: Karvedilol Mylan film-coated tablet ENG SmPC change

• Karvedilol Mylan, film-coated tablet, Marknadsförs ej för närvarande, SmPC
• Karvedilol Mylan film-coated tablet ENG SmPC

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1. NAME OF THE MEDICINAL PRODUCT

Karvedilol Mylan 3.125 mg Film-coated Tablets

Karvedilol Mylan 6.25 mg Film-coated Tablets

Karvedilol Mylan 12.5 mg Film-coated Tablets

Karvedilol Mylan 25 mg Film-coated Tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 3.125 mg, 6.25 mg, 12.5 mg or 25 mg carvedilol.

Excipient with known effect:

Each film-coated tablet contains 12.5 mg, 25 mg, 50 mg or 100 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL form

Film-coated tablet

3.125 mg film-coated tablets: white, oval, smooth on both sides.

6.25 mg film-coated tablets: white, oval, scored on both sides and marked "6.25" on one side.

12.5 mg film-coated tablets: white, oval, scored on both sides and marked "12.5" on one side.

25 mg film-coated tablets: white, oval, scored on both sides and marked "25" on one side

The 6.25 mg, 12.5 mg and 25 mg tablets can be divided into equal doses.

4. Clinical particulars

4.1 Therapeutic indications

Chronic stable angina pectoris

Adjunctive treatment in moderate to severe stable heart failure

4.2 Posology and method of administration

Karvedilol Mylan is available in 4 strengths: 3.125 mg, 6.25 mg, 12.5 mg and 25 mg

Essential hypertension

Carvedilol may be used for the treatment of hypertension alone or in combination with other antihypertensives, especially thiazide diuretics. Once daily dosing is recommended, however the recommended maximum single dose is 25 mg and the recommended maximum daily dose is 50 mg.

Adults:

The recommended initial dose is 12.5 mg once a day for the first two days. Thereafter, the treatment is continued at the dose 25 mg/day. If necessary, the dose may be further increased gradually at intervals of at least two weeks.

Elderly:

The recommended initial dose in hypertension is 12.5 mg once a day, which may also be sufficient for continued treatment.However, if the therapeutic response is inadequate at this dose, the dose may be further increased gradually at intervals of at least two weeks.

Chronic stable angina pectoris

Adults:

The recommended initial dose is 12.5 mg twice daily for two days. Thereafter, the treatment is continued at the dose 25 mg twice daily. If necessary, the dose may be further increased gradually at intervals of at least two weeks. The recommended maximum daily dose is 100 mg in two doses (50 mg twice daily).

Elderly:

The recommended initial dose is 12.5 mg twice daily for two days. Thereafter, the treatment is continued at the dose 25 mg twice daily, which is the recommended maximum daily dose.

Heart failure

Treatment of moderate to severe heart failure in addition to conventional basic therapy with diuretics, ACE inhibitors, digitalis, and/or vasodilators. The patient should be clinically stable (no change in NYHA-class, no hospitalisation due to heart failure) and the basic therapy must be stabilised for at least 4 weeks prior to treatment. Additionally the patient should have a reduced left ventricular ejection fraction and heart frequency should be > 50 bpm and systolic blood pressure > 85 mm Hg (see section 4.3).

The initial dose is 3.125 mg twice a day for two weeks. If the initial dose is well tolerated, the carvedilol dose can be increased at intervals of at least two weeks, first to 6.25 mg twice daily, then 12.5 mg twice daily followed by 25 mg twice daily. It is recommended that the dose is increased to the highest level tolerated by the patient.

The recommended maximum dose is 25 mg given twice daily for patients weighing less than 85 kg and 50 mg twice daily for patients weighing more than 85 kg, provided that the heart failure is not severe. A dose increase to 50 mg twice daily should be performed carefully under close medical supervision of the patient.

Transient worsening of symptoms of heart failure may occur at the beginning of treatment, or due to a dose increase, especially in patients with severe heart failure and/or under high dose diuretic treatment. This does not usually call for discontinuation of treatment, but the dose should not be increased. The patient should be monitored by a physician/cardiologist after starting carvedilol treatment or increasing the dose. Before each dose increase, an examination should be performed for potential symptoms of worsening heart failure or for symptoms of excessive vasodilation (e.g. renal function, body weight, blood pressure, heart rate and heart rhythm). Worsening of heart failure or fluid retention is treated by increasing the dose of diuretic, and the dose of carvedilol should not be increased until the patient is stabilised. If bradycardia appears or in case of lengthening of AV conduction, the level of digoxin should first be monitored. Occasionally it may be necessary to reduce the carvedilol dose or temporarily discontinue treatment altogether. Even in these cases, carvedilol dose titration can often be successfully continued.

If carvedilol therapy is discontinued for more than two weeks, it should be reinitiated at 3.125 mg twice daily and increased gradually in accordance with the above recommendation.

Renal insufficiency

Dosage must be determined for each patient individually, but according to pharmacokinetic parameters there is no evidence that dose adjustment of carvedilol in patients with renal failure is necessary.

Moderate hepatic dysfunction

Dose adjustment may be required.

Children and adolescents

There is insufficient data on the efficacy and safety of carvedilol in children and adolescents under 18 years of age.

Elderly

Elderly patients may be more susceptible to the effects of carvedilol and should be monitored more carefully.

As with other beta-blockers and especially in coronary patients, treatment with carvedilol should be withdrawn gradually (see section 4.4).

Method of administration

The tablets do not need to be taken with a meal. However, it is recommended that heart failure patients take their carvedilol medication with food to allow the absorption to be slower and the risk of orthostatic hypotension to be reduced.

4.3 Contraindications

• Hypersensitivity to carvedilol or to any of the excipients listed in section 6.1

• Unstable/decompensated heart failure

• Clinically manifest liver dysfunction

• 2nd and 3rd degree AV block (unless a permanent pacemaker is in place)

• Severe bradycardia (<50 bpm)

• Sick sinus syndrome (including sino-atrial block)

• Severe hypotension (systolic blood pressure <85 mmHg)

• Cardiogenic shock

• History of bronchospasm or asthma

4.4 Special warnings and precautions for use

Chronic congestive heart failure

Carvedilol should be administered principally in addition to diuretics, ACE inhibitors, digitalis and/or vasodilators. Therapy should only be initiated if the patient is stabilised on conventional basic therapy for at least 4 weeks. Decompensated patients have to be re-compensated. Patients with severe heart failure, salt and volume depletion, elderly patients or patients with low basic blood pressure should be monitored for approximately 2 hours after the first dose or after dose increase as hypotension may occur.

In congestive heart failure patients, worsening cardiac failure or fluid retention may occur during up-titration of carvedilol. If such symptoms occur, 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).

Renal function in congestive 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 heart failure patients with these risk factors, renal function should be monitored during dose titration of carvedilol. If significant worsening of renal function occurs, the carvedilol dose must be reduced or therapy must be discontinued.

Left ventricular dysfunction following acute myocardial infarction

Before treatment with carvedilol is initiated the patient must be clinically stable and should have received an ACE inhibitor for at least the preceding 48 hours, and the dose of the ACE inhibitor should have been stable for at least the preceding 24 hours.

First degree AV block

Because of its negative dromotropic action, carvedilol should be administered with caution to patients with first degree heart block.

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. In chronic heart failure patients with diabetes, the use of carvedilol may be associated with worsening control of blood glucose. Therefore, close monitoring of diabetic patients receiving carvedilol is required by means of regular blood glucose measurements and adjustment of antidiabetic medication as necessary (see section 4.5).

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.

Raynaud's phenomenon

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

Thyrotoxicosis

Carvedilol may obscure the symptoms of thyrotoxicosis.

Anaesthesia 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 take 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 or diltiazem type or other antiarrhythmic drugs, specifically amiodarone. Intravenous administration of verapamil in patients on beta-blocker treatment may lead to profound hypotension and atrio-ventricular block.

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 with its use in this condition. Caution should therefore 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. Caution should, however, be taken in the administration of carvedilol to patients suspected of having Prinzmetal's variant angina.

Metabolic acidosis

Carvedilol should be usedwith caution in patients with metabolic acidosis.

Contact lenses

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

Withdrawal syndrome

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).

Poor metabolisers of debrisoquine

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

Other

Since there is limited clinical experience, carvedilol should not be administered in patients with labile or secondary hypertension, orthostasis, acute inflammatory heart disease, haemodynamically relevant obstruction of heart valves or outflow tract, end-stage peripheral arterial disease, concomitant treatment with alpha₁-receptor antagonist or alpha₂-receptor agonist.

Excipients

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

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacokinetic interactions

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

Inhibitors as well as inducers of CYP2D6 and CYP2C9 can modify the systemic and/or presystemic metabolism of carvedilol stereoselectively, leading to increased or decreased plasma concentrations of R and S-carvedilol. Patients receiving medicines that induce (e.g.rifampicin, carbamazepine and barbiturates) or inhibit (e.g.paroxetine, fluoxetine, quinidine, cinacalcet, bupropion, amiodarone and fluconazole) these CYP enzymes have to be monitored closely during concomitant treatment with carvedilol. Some examples observed in patients or in healthy subjects are listed below but the list is not exhaustive.

Digoxin:

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).

Rifampicin and cimetidine:

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 patients receiving inducers of mixed function oxidases e.g. rifampicin, as serum levels of carvedilol may be reduced, or inhibitors of mixed function oxidases e.g. cimetidine, as serum levels of carvedilol 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.

Ciclosporin:

Two studies in renal and cardiac transplant patients receiving oral ciclosporin have shown an increase in ciclosporin plasma concentrations following initiation of carvedilol treatment. In about 30% of patients, the dose of ciclosporin had to be reduced in order to maintain ciclosporin concentrations within the therapeutic range, while in the remainder no adjustment was needed. On average, the dose of ciclosporin was reduced by about 20% in these patients. Due to wide interindividual variability in the dose adjustment required, it is recommended that ciclosporin concentrations be monitored closely after initiation of carvedilol therapy and that the dose of ciclosporin 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 β-blockade caused by a raise of the plasma S-carvedilol concentration.

Fluoxetine:

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

Pharmacodynamic interactions

Digoxin:

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

Clonidine:

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

Antiarrythmics and calcium channel blockers:

In combination with carvedilol these medicines can increase the risk of AV conduction disturbances (see section 4.4).Isolated cases of conduction disturbance (rarely with haemodynamic compromise) have been observed when carvedilol is co-administered with diltiazem, verapamil and/or amiodarone. 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 monitoredas the risk of AV conduction disorders or risk of cardiac failure are increased (synergistic effect). Intravenous administration of verapamil in patients on beta-blocker treatment may lead to profound hypotension and atrio-ventricular block. Close monitoring should be done when co-administering carvedilol, and either a class I antiarrhythmic or amiodarone (oral).Bradycardia, cardiac arrest, and ventricular fibrillation have been reported shortly after initiation of beta-blocker treatment in patients receiving amiodarone.

Antihypertensives:

As with other agents with beta-blocking activity, carvedilol may potentiate the effect of other concomitantly administered drugs that are antihypertensive in action (e.g. alpha₁-receptor antagonists) or have hypotension as part of their adverse effect profile such as barbiturates, phenothiazines, tricyclic antidepressants, vasodilating agents and alcohol.

Anaesthetic agents:

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

Insulin or oral hypoglycaemics:

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

Catecholamine-depleting agents:

Patients taking both agents 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.

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.

NSAIDs, oestrogens and corticosteroids:

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

Nitrates:

Increased hypotensive effects.

Ergotamine:

Vasoconstriction increased.

Neuromuscular blocking agents:

Increased neuromuscular block.

Sympathomimetics with alpha-mimetic and beta-mimetic effects:

Risk of hypertension and excessive bradycardia.

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

4.6 Pregnancy and lactation

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. The treatment should be stopped 2-3 days before expected birth. If this is not possible the newborn has to be monitored for the first 2-3 days of life.

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).

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 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

(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) 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:

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

Infections and infestations

Common: Bronchitis, pneumonia, upper respiratory tract infection, urinary tract infection

Blood and lymphatic system disorders

Common: Anaemia

Rare: Thrombocytopenia

Very rare: Leukopenia

Immune system disorders

Very rare: Hypersensitivity (allergic reaction)

Metabolism and nutrition disorders

Common: Weight increase, hypercholesterolaemia, impaired blood glucose control (hyperglycaemia, hypoglycaemia) in patients with pre-existing diabetes

Psychiatric disorders

Common: Depression, depressed mood

Uncommon: Sleep disorders

Nervous system disorders

Very common: Dizziness, headache

Uncommon: Presyncope, syncope, paraesthesia

Eye disorders

Common: Visual impairment, lacrimation decreased (dry eye), eye irritation

Cardiac disorders

Very common: Cardiac failure

Common: Bradycardia, oedema, hypervolaemia, fluid overload

Uncommon: Atrioventricular block, angina pectoris

Vascular disorders

Very common: Hypotension

Common: Orthostatic hypotension, disturbances of peripheral circulation (cold extremities, peripheral vascular disease, exacerbation of intermittent claudication and Raynaud’s phenomenon)

Respiratory, thoracic and mediastinal disorders

Common: Dyspnoea, pulmonary oedema, asthma in predisposed patients

Rare: Nasal congestion

Gastrointestinal disorders

Common: Nausea, diarrhoea, vomiting, dyspepsia, abdominal pain

Uncommon: Constipation

Very rare: Dry mouth

Hepatobiliary disorders

Very rare: Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT) increased

Skin and subcutaneous tissue disorders

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

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

Musculoskeletal and connective tissue disorders

Common: Pain in extremities

Renal and urinary disorders

Common: Renal failure and renal function abnormalities in patients with diffuse vascular disease and/or underlying renal insufficiency, micturition disorders

Very rare: Urinary incontinence in women

Reproductive system and breast disorders

Very common: Genital oedema

Uncommon: Erectile dysfunction

General disorders and administration site conditions

Very common: Asthenia (fatigue)

Common: Pain

(c) Description of selected adverse reactions

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

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

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

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

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

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via [to be completed nationally].

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 norfenefrine 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 intravenous injection of diazepam or clonazepam is recommended.

Carvedilol is highly protein-bound. Therefore, it cannot be eliminated by dialysis.

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

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: beta- and alpha₁-receptor blocking agents

ATC code: C07AG02

Carvedilol is a vasodilatory non-selective beta-blocker, which reduces the peripheral vascular resistance by selective alpha₁- receptor blockade and suppresses the renin-angiotensin system through non-selective beta-blockade. Plasma renin activity is reduced and fluid retention is rare.

Carvedilol has no intrinsic sympathomimetic activity (ISA). Like propranolol, it has membrane stabilising properties.

Carvedilol is a racemate of two stereoisomers. Both enantiomers were found to have

alpha-adrenergic blocking activity in animal models. Non-selective beta₁- and beta₂-

adrenoceptor blockade is attributed mainly to the S(-) enantiomer.

The antioxidant properties of carvedilol and its metabolites have been demonstrated in in vitroand in vivoanimal studies and in vitroin a number of human cell types.

In hypertensive patients, a reduction in blood pressure is not associated with a concomitant increase in peripheral resistance, as observed with pure beta-blocking agents. Heart rate is slightly decreased. Stroke volume remains unchanged. Renal blood flow and renal function remain normal, as does peripheral blood flow, therefore, cold extremities, often observed with beta-blockers, are rarely seen. In hypertensive patients carvedilol increases the plasma norepinephrine concentration.

In prolonged treatment of patients with angina, carvedilol has been seen to have an anti-ischaemic effect and to alleviate pain. Haemodynamic studies demonstrated that carvedilol reduces ventricular pre- and after-load. In patients with left ventricular dysfunction or congestive heart failure, carvedilol has a favourable effect on haemodynamics and left ventricular ejection fraction and dimensions.

Carvedilol has no negative effect on the serum lipid profile or electrolytes. The ratio of HDL (high-density lipoproteins) and LDL (low-density lipoproteins) remains normal.

5.2 Pharmacokinetic properties

Absorption

The absolute bioavailability of orally administered carvedilol is approximately 25 %. Plasma levels peak at approximately 1 hour after dosing. In patients with slow hydroxylation of debrisoquine, plasma carvedilol concentrations increased up to 2- to 3-fold compared to rapid debrisoquine metabolisers. Food does not affect bioavailability although the time to reach maximum plasma concentration is delayed.

Distribution

Carvedilol is a highly lipophilic compound. Approximately 98 % to 99 % of carvedilol is bound to plasma proteins. Its volume of distribution is approximately 2 L/kg.

Biotransformation

The first pass effect after oral administration is approximately 60 to 75 %.

Carvedilol is found to be extensively metabolised into various metabolites, which are mainly eliminated in bile. Carvedilol is metabolised in the liver mainly through aromatic ring oxidation and glucuronidation. Demethylation and hydroxylation at the phenol ring yield three active metabolites with beta-blocking activity. Compared to carvedilol, these three active metabolites have a weak vasodilatory effect. On the basis of preclinical studies, the 4’-hydroxyphenol metabolite has a beta-blocking activity 13 times more potent than that of carvedilol. However, the metabolite concentrations in humans are approximately 10 times lower than those of carvedilol. Two of the hydroxycarbazole metabolites of carvedilol are highly potent antioxidants, with a 30- to 80-fold potency compared to carvedilol.

Elimination

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

Linearity

There is linear correlation between the dose and plasma concentrations.

Properties in the patient

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 liver cirrhosis, the bioavailability of carvedilol was four times greater and the peak plasma level five times higher and the volume of distribution three times higher than in healthy subjects.

In some of the hypertensive patients with moderate (creatinine clearance 20 to 30 mL/min) or severe (creatinine clearance < 20 mL/min) renal insufficiency, an increase in plasma carvedilol concentrations of approximately 40 to 55 % was seen compared to patients with normal renal function. However, there was a large variation in the results.

5.3 Preclinical safety data

Studies on rats and mice revealed no carcinogenic potential of carvedilol at doses of 75 mg/kg and 200 mg/kg (38 to 100 times the human maximum daily dose). Carvedilol demonstrated no mutagenic potential in studies conducted on mammals or other animals in vitro or in vivo.

When high doses of carvedilol were administered to pregnant rats ( 200 mg/kg =  100 times the human maximum daily dose), undesirable effects on pregnancy and fertility were observed. Physical growth and development of the foetus were delayed at doses of  60 mg/kg ( 30 times the human maximum daily dose). Embryotoxicity (increased mortality after implantation of the embryo) occurred, but there were no deformations in rats or rabbits at doses of 200 mg/kg and 75 mg/kg, respectively (38 to 100 times the human maximum daily dose).

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Cellulose, microcrystalline

Lactose monohydrate

Crospovidone

Povidone

Silica, colloidal anhydrous

Magnesium stearate

Tablet coating:

Hypromellose

Titanium dioxide (E 171)

Triethyl citrate

Macrogol

Polydextrose

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store in the original package, in order to protect from light.

Do not store above 30C.

6.5 Nature and contents of container

PVC/Aluminium foil blisters or HDPE bottles with PP lids, available in packs containing 10, 14, 28, 30, 50, 56, 98, 100 and 250 (plastic bottle only) tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7. MARKETING AUTHORISATION HOLDER

[To be completed nationally]

8. MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

[To be completed nationally]

10. DATE OF REVISION OF THE TEXT

2014-03-07