Carvedilol 12.5mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
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.
For excipients, see 6.1.
3 PHARMACEUTICAL FORM
Uncoated tablet.
Cream coloured round tablet marked ‘NEO’ on one face and ‘C12’ on the 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 3.125mg 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 6.25mg twice daily, followed by 12.5mg twice daily and thereafter 25mg twice daily. Dosing should be increased to the highest level tolerated by the patient.
The recommended maximum daily dose is 25mg given twice daily for all patients with severe CHF and for patients with mild to moderate CHF weighing less than 85kg (187 lbs). In patients with mild or moderate CHF weighing more than 85kg, the recommended maximum dose is 50mg 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 3.125mg 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 12.5mg once a day for the first two days. Thereafter the recommended dosage is 25mg 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 50mg given once a day or in divided doses.
Dose titration should occur at intervals of at least two weeks.
Elderly
An initial dose of 12.5mg 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 50mg 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 12.5mg twice a day for the first two days. Thereafter, the recommended dosage is 25mg twice a day.
Elderly
The recommended maximum daily dose is 50mg 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 100mmHg (see also sections 4.4 Special warnings and precautions for use and 5.2 Pharmacokinetic properties).
4.3. Contraindications
Carvedilol is contra-indicated in patients with:
• marked fluid retention or overload requiring intravenous inotropic support.
• unstable/decompensated heart failure
• patients with obstructive airways disease
• clinically manifest liver dysfunction
• hypersensitivity to carvedilol or any other constituents of the tablets.
• 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 < 85mmHg)
• metabolic acidosis
• phaeochromocytoma (unless adequately controlled by alpha blockade).
4.4 Special warnings and precautions for use
Chronic congestive heart failure
In chronic 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.
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.
Bronchospastic reactions
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 patient information leaflet:
Outer packaging:
Do not take this medicine if you have a history of wheezing due to asthma or other lung diseases.
Patient Information Leaflet:
Do not take this medicine if you have a history of wheezing due to asthma or other lung diseases. Consult your doctor or pharmacist first.
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.
As with other drugs with beta-blocking activity, carvedilol may mask or attenuate the early signs of acute hypoglycaemia in patients with diabetes mellitus. 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 (see section 4.5 Interaction with other medicinal products and other forms of interaction).
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 < 100mmHg), ischaemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency. In CHF patients with these risk factors, renal function should be monitored during up-titration of 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.
Contact lenses
Wearers of contact lenses should be advised of the possibility of reduced lacrimation.
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
Withdrawal syndrome
Carvedilol treatment should not be discontinued adruptly, particularly in patients suffering from ischemic heart disease. Although angina has not been reported on stopping treatment, discontinuation should be gradual (1 - 2 weeks) particularly in patients with ischaemic heart disease, as carvedilol has beta-blocking activity.
Peripheral vascular disease
Carvedilol should be used with caution in patients with peripheral vascular disease. Pure beta-blockers can precipitate or aggravate symptoms of arterial insufficiency. However as carvedilol also has alpha-blocking properties this effect is largely counterbalanced.
Thyrotoxicosis
Carvedilol, as with other agents with beta-blocking activity, may mask the symptoms of thyrotoxicosis.
Bradycardia
If carvedilol induces a decrease in pulse rate to less than 55 beats per minute and symptoms associated with bradycardia occur, 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.
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.
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 (see section 4.5 Interaction with other medicinal products and other forms of interaction).
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 properties, 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.
Lactose
The tablets contain lactose (see section 6.1 List of excipients). 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 stereo selectively, leading to increased or decreased plasma concentrations of R and S-carvedilol (see section 5.2 Pharmacokinetic properties). Some examples observed in patients or in healthy subjects are listed below bit 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. Concomitant administration of carvedilol and cardiac glycosides may prolong AV conduction time.
Rifampicin:
In a study of 12 healthy subjects rifampicin administration decreased the carvedilol plasma levels most likely by induction of P-glycoprotein leading to a decrease of the intestinal absorption of carvedilol and a decrease of hypertensive effect.
Cimetidine:
Care may be required in those receiving inhibitors of mixed function oxidases e.g. cimetidine. Plasma concentrations of carvedilol may be increased by such drugs.
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 about 20% in these patients. Due to wide inter individual 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 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 was noticed between treatment groups.
Pharmacodynamic interactions
Insulin or oral hypoglycaemics:
Agents with P-blocking properties may enhance the blood-sugar-reducing effect of insulin and oral hypoglycaemics. Carvedilol may mask or attenuate symptoms and signs of hypoglycaemia (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 p-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 or other antiarrhythmics:
In combination with carvedilol can increase the risk of AV conduction disturbances (see section 4.4 Special warnings and precautions for use).
Clonidine:
Concomitant administration of clonidine with agents with beta-blocking properties may potentiate blood-pressure and heart-rate-lowering effects. When concomitant treatment 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 before gradually decreasing the dosage of clonidine
Calcium-channel blockers and anti-arrhythmics:
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 (see section 4.4 Special warnings and precautions for use).
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.
Anaesthetic agents:
Careful monitoring of vital signs is recommended during anaesthesia due to the synergistic negative inotropic and hypertensive effects of carvedilol and anaesthetic drugs (see section 4.4 Special warnings and precautions for use).
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.
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
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 post natal development (see section 5.3 Preclinical safety data). The potential risk for humans is unknown.
Carvedilol should not be used in pregnancy unless the anticipated benefits outweigh the potential risks.
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 Preclinical safety data).
Lactation
Animal studies have shown that carvedilol and 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 of the effects on ability to drive and use machines have been performed.
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 when starting or changing treatment and in conjunction with alcohol.
4.8 Undesirable effects
a) Summary of the safety profile
The frequency of adverse experiences 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 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
Hepatobiliary disorders
Very rare: alanine aminotransferase (ALT) aspartate aminotransferase (AST) and gammaglutamyltransferase (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 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 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 Special warnings and precautions for use).
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 Special warnings and precautions for use).
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.
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
Gastric lavage or induced emesis may be useful in the first few hours after ingestion.
In addition to general supportive treatment, the vital signs must be monitored and corrected, if necessary under intensive care conditions.
Patients should be placed in the supine position. Atropine, 0.5mg to 2mg i.v. and/or glucagon 1 to 10 mg i.v. (followed by a slow i.v. infusion of 2 to 5mg/hour if necessary) may be given when bradycardia is present. 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. Pacemaker therapy may be necessary in case of drug-resistent bradycardia. For excessive hypotension, intravenous fluids may be administered. If peripheral vasodilation dominates the intoxication profile then norfenephrine or noradrenaline should be administered with continuous monitoring of the circulation. In addition, norepinephrine may be given, either 5 to 10 micrograms i.v., repeated according to blood pressure response, or 5 micrograms per minute by infusion titrated to blood pressure.
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 as described should be continued for a sufficiently long period of time, i.e. until the patient stabilises, since prolonged elimination half-life and redistribution of carvedilol from deeper compartments can be expected.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC Code CO7A G02.
Carvedilol is a vasodilating non-selective beta blocking agent with antioxidant properties. 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 ^-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 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.
In patients with left ventricular dysfunction or chronic heart failure, carvedilol has demonstrated favourable effects on haemodynamics and improvements in left ventricular ejection fraction and dimensions.
In a large, multi-centre, double-blind, placebo-controlled mortality trial, 2289 patients with severe stable CHF of ischaemic or nonischaemic origin, on standard therapy, were randomised to either carvedilol (1156 patients) or placebo (1133 patients). Patients had left ventricular systolic dysfunction with a mean ejection fraction of < 20%. All-cause mortality was reduced by 35% from 19.7% in the placebo group to 12.8% in the carvedilol group (Cox proportional hazards, p = 0.00013).
Combined secondary endpoints of mortality or hospitalisation for heart failure, mortality or cardiovascular hospitalisation and mortality or all cause hospitalisation were all significantly lower in the carvedilol group than placebo (31%, 27% and 24% reductions, respectively, all p < 0.00004).
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 590ml/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
There is no evidence from animal studies that Carvedilol has any teratogenic effects. Embryotoxicity was observed only after large doses in rabbits. The relevance of these findings for humans is uncertain. Betablockers reduce placental perfusion which may result in intrauterine foetal death and immature and premature deliveries. In addition, animal studies have shown that carvedilol crosses the placental barrier and therefore the possible consequences of alpha and beta-blockade in the human foetus and neonate should also be borne in mind. With other alpha and beta-blocking agents, effects have included perinatal and neonatal distress (bradycardia, hypotension, respiratory depression, hypoglycaemia, hypothermia). There is an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate
microcyrstalline 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
2 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
Fannin (UK) Limited 42-46 Booth Drive Park Farm South Wellingborough Northamptonshire NN8 6GT UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 20417/0015
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 17/01/2077
10
DATE OF REVISION OF THE TEXT
07/01/2014