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Document: Carveratio tablet ENG SmPC change

• Carveratio tablet SmPC
• Carveratio tablet ENG SmPC

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SUMMARY OF PRODUCT CHARACTERISTICS

Carveratio 6.25 mg tablet

Carveratio 12.5 mg tablet

Carveratio 25 mg tablet

One tablet contains 6.25 mg, 12.5 mg or 25 mg carvedilol.

Excipient with known effect:89 mg/86 mg/171 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

Tablet

6.25 mg tablets: white, biconvex, capsule shaped tablets debossed “C” with breakline and “2” on one side and plain on the other.

12.5 mg tablets: white, biconvex, capsule shaped tablets debossed “C” with breakline and “3” on one side and plain on the other.

25 mg tablets: white, biconvex, capsule shaped tablets debossed “C” with breakline and “4” on one side and plain on the other.

The tablets can be divided into equal doses.

Essential hypertension.

Chronic stable angina pectoris.

Adjunctive treatment in moderate to severe stable heart failure.

Carveratio is available in 3 strengths: 6.25 mg, 12.5 mg and 25 mg.

Posology

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 two weeks or more rarely.

Older people

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 two weeks or more rarely.

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 two weeks or more rarely. The recommended maximum daily dose is 100 mg in divided doses (twice daily).

Older people

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 two weeks or more rarely, 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 in patients weighing less than 85 kg and 50 mg twice daily in 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 usually not 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 vasodilatation (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 time, 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.

Paediatric population

There is no experience in children and adolescents.

Older people

Older people may be more susceptible to the effects of carvedilol and should be monitored more carefully.

As with other β-blockers and especially in coronary patients, the withdrawal of carvedilol should be done 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.

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• Unstable/decompensated heart failure.

• Clinically manifest liver dysfunction.

• Metabolic acidosis.

• Second and third 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.

Chronic Congestive Heart Failure

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.

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 mm Hg), ischaemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency.

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.

Labile or secondary hypertension

Since there is limited clinical experience, carvedilol should not be administered in patients with labile or secondary hypertension.

First degree heart 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 patientswith 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.

Peripheral vascular disease

Carvedilol should be used with caution in patients with peripheral vascular disease as β-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.

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 β-blockers may increase both the sensitivity towards allergens and the seriousness of anaphylactic reactions.

Psoriasis

Patients with a history of psoriasis associated with β-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).

Pheochromocytoma

In patients with pheochromocytoma, an α-blocking agent should be initiated prior to the use of any β-blocking agent. Although carvedilol has both α-and β-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 pheochromocytoma.

Prinzmetal's variant angina

Agents with non-selective β-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 α-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.

Contact lenses

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

Debrisoquine metabolism

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

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).

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

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. rifampicine, carbamazepine and barbiturates) or inhibit (e.g. paroxetine, fluoxetine, quinidine, cinacalcet, bupropion, amiodarone or fluconazole) these CYP enzymeshave to be monitored closely during concomitant treatment with carvedilol as serum carvedilol concentrations may be reduced by enzyme inducers and increased by the enzyme inhibitors. Some examplesobserved in patients or in healthy subjects are listed below but the list is not exhaustive.

Cardiac glycosides:Digoxin concentrations are increased by about 15% and digitoxin concentrations by approximately 13% in hypertensive patients when digoxin or respectively digitoxin 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: In a study in 12 healthy subjects, rifampicin administration decreased the carvedilol plasma levels by about 70%, most likely by induction of P-glycoprotein leading to a decrease of the intestinal absorption of carvedilol.

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 interindividual 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 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 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 noted between treatment groups.

Pharmacodynamic interactions

Insulin or oral hypoglycaemics:Agents with β-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 β-blocking properties and a drug that can deplete catecholamines (e.g. reserpine, guanethidine, methyldopa, guanfacine and monoamine oxidase inhibitors) should be observed closely for signs of hypotension and/or severe bradycardia.

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

Verapamil,diltiazem, amiodaroneorother antiarrhythmics:Combination with carvedilol can increase therisk of AV conduction disturbances (see section 4.4). Close monitoring should be done when co-administering carvedilol, and either a class I antiarrhythmicor amiodarone (oral). Bradycardia, cardiac arrest, and ventricular fibrillation have been reported shortly after initiation of β-blocker treatment in patients receiving amiodarone. There is a risk of cardiac failure in case of class Ia or Ic antiarrhythmics concomitant intravenous therapy.

Clonidine: Concomitant administration of clonidine with agents with β-blocking properties may potentiate blood-pressure- and heart-rate-lowering effects. When concomitant treatment with agents with β-blocking properties and clonidine is to be terminated, the β-blocking agent should be discontinued first. Clonidine therapy can then 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 β-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. 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.

Antihypertensive drugs: Aswith other agents with β-blocking activity, carvedilol may potentiate the effectof other concomitantly administered drugs that are antihypertensive in action(e.g. α₁-receptor antagonists) or have hypotension as part of their adverse effect profilesuch as barbiturates, phenothiazines, tricyclic antidepressants, vasodilating agents and alcohol.

Anaesthetic agents: Carefulmonitoring of vital signsis recommended during anaesthesia dueto the synergisticnegative inotropic and hypotensive effectsof carvedilol and anaesthetic drugs (see section 4.4).

NSAIDs: The concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs) and β-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.

Sympathomimetics with α-mimetic and β-mimetic effects: Risk of hypertension and excessive bradycardia.

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

Ergotamine: Vasoconstriction increased.

Neuromuscular blocking agents: Increased neuromuscular block.

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.

β-Blockersreduce placental perfusion which may result in intrauterine foetal death and immature and premature deliveries. In addition, adverse effects(especially hypoglycaemiaand 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 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 administration of carvedilol.

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.

(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).

The frequencies of adverse eventsare ranked according to the following: verycommon ( 1/10), common ( 1/100 to  1/10), uncommon ( 1/1,000 to  1/100), rare ( 1/10,000 to  1/1,000), very rare ( 1/10,000), not known (cannot be estimated from the available data).

System organ class	Very common (≥1/10)	Common (≥1/100 to <1/10)	Uncommon (≥1/1,000 to <1/100)	Rare (≥1/10,000 to <1/1,000)	Very rare ( 1/10,000)
Infections and infestations		Bronchitis, pneumonia, upper respiratory tract infection, urinary tract infection
Blood and lymphatic system disorders		Anaemia		Thrombocytopaenia	Leukopenia
Immune system disorders					Hypersensitivity (allergic reaction)
Metabolism and nutrition disorders		Weight increase, hypercholesterolaemia, impaired blood glucose control (hyperglycaemia, hypoglycaemia) in patients with pre-existing diabetes
Psychiatric disorders		Depression, depressed mood	Sleep disorders, confusion
Nervous system disorders	Dizziness, headache		Presyncope, syncope, paraesthesia
Eye disorders		Visual impairment, lacrimation decreased (dry eye), eye irritation
Cardiac disorders	Cardiac failure	Bradycardia, oedema, hypervolaemia, fluid overload	Atrioventricular block, angina pectoris
Vascular disorders	Hypotension	Orthostatic hypotension, disturbances of peripheral circulation (cold extremities, peripheral vascular disease, exacerbation of intermittent claudication and Reynaud’s phenomenon)
Respiratory, thoracic and mediastinal disorders		Dyspnoea, pulmonary oedema, asthma in predisposed patients		Nasal congestion
Gastrointestinal disorders		Nausea, diarrhoea, vomiting, dyspepsia, abdominal pain		Dry mouth
Hepatobiliary disorders					Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma- glutamyltransferase (GGT) increased
Skin and subcutaneous tissue disorders			Skin reactions (e.g. allergic exanthema, dermatitis, urticaria, pruritus, psoriatic and lichen planus like skin lesions and increased sweating), alopecia		Severe cutaneous adverse reactions (e.g. Erythema multiforme, Stevens-Johnson syndrome, Toxic epidermal necrolysis)
Musculoskeletal and connective tissue disorders		Pain in extremities
Renal and urinary disorders		Renal failure and renal function abnormalities in patients with diffuse vascular disease and/or underlying renal insufficiency, micturition disorders			Urinary incontinence in women
Reproductive system and breast disorders			Erectile dysfunction
General disorders and administration site conditions	Asthenia (fatigue)	Pain

(c) Description of selected adversereactions

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,β-adrenergic receptor blockers may cause latent diabetes to becomemanifest, manifest diabetes to beaggravated,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 the national reporting system listed in[To be completed nationally].

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 andcorrected, if necessary, underintensive 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, β-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.

Pharmacotherapeutic group: Alpha and beta blocking agents, ATC code: C07AG02

Carvedilol is a vasodilatory non-selective β-blocker, which reduces the peripheral vascular resistance by selective α1- receptor blockade and suppresses the renin-angiotensin system through non-selective β-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 α-adrenergic blocking activity in animal models. Non-selective β₁- and β₂-adrenoceptor blockade is attributed mainly to the S(-) enantiomer.

The antioxidant properties of carvedilol and its metabolites have been demonstrated in in vitro and in vivo animal 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 β-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 β-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.

General description:The absolute bioavailability of orally administered carvedilol is approximately 25 %. Plasma levels peak at approximately 1 hour after dosing. There is linear correlation between the dose and plasma concentrations. In patients with slow hydroxylation of debrisoquine, plasma carvedilol concentrations increased up to 2 – 3 -fold compared to rapid debrisoquine metabolisers. Food does not affect bioavailability although the time to reach maximum plasma concentration is delayed. 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. The first pass effect after oral administration is approximately 60 – 75 %.

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.

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 β-blocking activity. Compared to carvedilol, these three active metabolites have a weak vasodilatory effect. On the basis of preclinical studies, the 4’-hydroxyphenolmetabolite has a β-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 - 80-fold potency compared to carvedilol.

Properties in the patient:The pharmacokinetics of carvedilol isaffected 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 - 30 ml/min) or severe (creatinine clearance < 20 ml/min) renal insufficiency, an increase in plasma carvedilol concentrations of approximately 40 – 55 % was seen compared to patients with normal renal function. However, there was a large variation in the results.

Carvedilol was not teratogenic in rats and rabbits. Embryo/fetotoxic effects occurred in rabbits at dose levels not toxic to the dose.

Standard in vitro and in vivo tests did not show any relevant mutagenic or carcinogenic potential of carvedilol.

Cellulose microcrystalline

Lactose monohydrate

Crospovidone

Povidone

Silica,colloidal anhydrous

Magnesium stearate

Not applicable.

Blister (PVC/PVdC-Aluminium):

6.25 mg: 18 months

12.5 mg and 25 mg: 2 years

Blister (OPA/Aluminium/PVC-Aluminium)):

2 years

Blister (PVC/PVdC-Aluminium)

6.25 mg:

Do not store above 30°C

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

12.5 mg and 25 mg:

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

This medicinal product does not require any special temperature storage conditions.

Blister (OPA/Aluminium/PVC-Aluminium)

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

This medicinal product does not require any special temperature storage conditions.

Blister (PVC/PVdC-Aluminium) or blister (OPA/Aluminium/PVC-Aluminium)

Pack sizes: 10, 14, 28, 30, 50, 56, 60, 98, 100 and 105 tablets.

Not all pack sizes may be marketed.

No special requirements.

[To be completed nationally]

[To be completed nationally]

[To be completed nationally]

29 July 2015