Carvedilol 12.5 Mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Carvedilol 12.5mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 12.5mg carvedilol.
Excipients with known effect: Each tablet contains 55.5 mg of lactose (as lactose monohydrate)
For the full list of excipients, see 6.1
3 PHARMACEUTICAL FORM
Tablet.
Red/brown, round, convex, scored tablet encoded C3 on one side with an approximate size of 7mm.
The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Essential hypertension Chronic stable angina pectoris
Adjunctive treatment in moderate to severe stable heart failure
4.2 Posology and method of administration
Posology
Carvedilol is available in 4 strengths: 3.125mg, 6.25mg, 12.5mg and 25mg.
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. The recommended maximum daily dose is 50mg.
Adults: The recommended initial dose is 12.5mg once daily for two days. Thereafter, the treatment is continued at the dose 25mg/day. If necessary, the dose may be further increased gradually to a recommended daily maximum dose of 50mg given once a day or in divided doses at intervals of two weeks or more rarely.
Elderly: The recommended initial dose in hypertension is 12.5mg once daily, 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 up to the recommended daily maximum dose of 50mg given once a day or in divided doses at intervals of two weeks or more rarely.
Paediatric population: Safety and efficacy in children (under 18 years) has not been established.
Chronic stable angina pectoris:
Adults: The recommended initial dose is 12.5mg twice daily for two days. Thereafter, the treatment is continued at the dose 25mg twice daily. If necessary, the dose may be further increased gradually at intervals of not less than two weeks or more rarely. The recommended maximum daily dose is 100mg in divided doses (twice daily).
Elderly: The recommended initial dose is 12.5mg twice daily for two days. Thereafter, the treatment is continued at the dose 25mg twice daily, which is the recommended maximum daily dose.
Heart failure: The dosage must be titrated to individual requirements and monitored during up-titration. For Congestive Heart Failure (CHF) patients carvedilol should be given with food to slow the rate of absorption and reduce the incidence of orthostatic effects.
For those patients receiving diuretics and/or digoxin and/or ACE inhibitors, dosing of these other drugs should be stabilised prior to initiation of carvedilol treatment. 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 4.3 “Contraindications ”).
The initial dose is 3.125mg twice daily 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 6.25mg twice daily, then 12.5mg twice daily followed by 25mg twice daily. It is recommended that the dose is increased to the highest level tolerated by the patient.
The recommended maximum dose is 25mg given twice daily in patients weighing less than 85 kg and 50mg twice daily in patients weighing more than 85 kg, provided that the heart failure is not severe. A dose increase to 50mg 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 dose should not be increased. The patient should be monitored by a physician/cardiologist after starting 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 - rhythm). Worsening of heart failure or fluid retention is treated by increasing the dose of diuretic or ACE inhibitors or by modifying or temporarily discontinuing carvedilol treatment and the dose of carvedilol should not be increased until symptoms of worsening heart failure or vasodilation in 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 3.125mg 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 heart failure is necessary.
Moderate hepatic dysfunction: Dose adjustment may be required.
Children and adolescents (< 18 years): There is insufficient data of the efficacy and safety of carvedilol.
Elderly: As for adults elderly patients may be more susceptible to the effects of carvedilol and should be monitored more carefully.
As with other betablockers and especially in coronary patients, the withdrawal of carvedilol should be done gradually (see 4.4 “Special warning and special precautions for use”).
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.
The tablets should be taken with fluid.
4.3 Contraindications
Hypersensitivity to active substance or to any of the excipients listed in section 6.1.
Unstable/decompensated heart failure requiring intravenous inotropic support Clinically Manifest hepatic dysfunction.
As with other beta-blocking agents:
History of bronchospasm or asthma
Second or third degree AV block. (unless a permanent pacemaker is in place)
Severe bradycardia (< 50 bpm).
Cardiogenic shock
Sick sinus syndrome (including sinoatrial blocks).
Severe hypotension (systolic blood pressure below 85 mmHg). Metabolic acidosis.
Prinzmetal's angina.
Untreated phaeochromocytoma.
Severe peripheral arterial circulatory disturbances.
Concomitant intravenous treatment with verapamil or diltiazem (see 4.5 “Interaction with other medicinal products and other forms of interaction”).
4.4 Special warnings and precautions for use
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.
Warnings to be considered particularly in heart failure patients. Carvedilol should be administered principally in addition to diuretics, ACE inhibitors, and/or vasodilators. Therapy should only be initiated, if the patient is stabilized 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 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. Hypotension due to excessive vasodilatation is initially treated by reducing the dose of the diuretic. If symptoms still persist, the dose of any ACE inhibitor may be reduced. The carvedilol dose may be further reduced or temporarily discontinued, if necessary. The carvedilol dose should not be increased again before symptoms due to the worsening of heart failure or vasodilatation are under control.
Renal function in Congestive Heart Failure
Reversible deterioration of renal function has been observed during carvedilol therapy in chronic heart failure patients with low blood pressure (systolic < 100 mm Hg), ischaemic heart disease and diffuse vascular disease (generalised atherosclerosis), 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.
During concomitant administration of carvedilol and digitalis, it has to be kept in mind that both digitalis and carvedilol lengthen the atrioventricular conduction time (see 4.5 “Interaction with other medicinal products and other forms of interaction”).
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
Other warnings as regards carvedilol and beta-blockers in general.
Subjects with chronic obstructive pulmonary disease with a bronchospastic component using no oral or inhaled medication should not use carvedilol unless the benefit outweighs the potential risks of use. If carvedilol is given to these patients, respiratory distress can occur as a result of a possible increase in airway resistance. They have to be monitored carefully when carvedilol therapy is initiated and during dose up-titration. The carvedilol dose must be reduced if the patient exhibits signs of bronchial obstruction or bronchospasm during treatment.
Diabetes
Carvedilol may mask or attenuate symptoms and signs of acute hypoglycaemia. Alternatives to beta-blocking agents are generally preferred in insulin-dependent patients. Impaired blood glucose control may occasionally occur in patients with diabetes mellitus and chronic heart failure in connection with the use of carvedilol. 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 4.5 “Interaction with other medicinal products and other forms of interaction”).
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.
Since carvedilol is a vasodilatory beta-blocker, the aggravation of peripheral vascular disease is more unlikely than with conventional beta-blockers. However, there is little clinical experience in this patient group so far.
Raynaud's phenomenon
The same also applies to those with peripheral circulatory disorders (eg Raynaud’s syndrome), but there may be exacerbation of symptoms.
Thyrotoxicosis
Carvedilol may mask symptoms and signs 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 cause bradycardia. If there is a decrease in pulse rate to less than 55 beats per minute, and symptoms associated with bradycardia occur, the carvedilol dose should be reduced.
Hypersensitivity
Care should be taken in administrating 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
Cautions should be exercised when prescribing beta-blockers to patients with history of psoriasis associated with P-blocker therapy since skin reactions may be aggravated and should take carvedilol only after consideration of the risk-benefit ratio.
Concomitant use of calcium channel blockers
When carvedilol is used concomitantly with calcium channel blocking agents such as verapamil and diltiazem or with other antiarrhythmics, specifically amiodarone, the patient’s blood pressure and ECG have to be monitored. Intravenous co-administration should be avoided (see 4.5 “Interaction with other medicinal products and other forms of interaction”).
Pheochromocytoma
In patients with pheochromocytoma, 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 pheochromocytoma.
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
Patients who are known as poor metabolisers of debrisoquine, should be closely monitored during initiation of therapy (see 5.2 “Pharmacokinetic properties”).
Since there is limited clinical experience, carvedilol should not be administered in patients with labile or secondary hypertension, orthostasis, acute inflammatory heart disease, haemodynamic relevant obstruction of heart valves or outflow tract, end-stage peripheral arterial disease, concomitant treatment with a1-receptor antagonist or a2-receptor agonist.
Because of its negative dromotropic action, carvedilol should be given with caution to patients with first degree heart block.
Contact lenses
Wearers of contact lenses should be advised of the possibility of reduced lacrimation.
Withdrawal syndrome
As with other beta-blockers, carvedilol should not be discontinued abruptly. This applies in particular to patients with ischaemic heart disease.
Although angina has not been reported on stopping treatment, carvedilol therapy must be discontinued gradually within two weeks, e.g. by reducing the daily dose to half every three days. If necessary, at the same time replacement therapy should be initiated to prevent exacerbation of angina pectoris.
Lactose
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.
Usage of carvedilol in patients with symptomatic congestive heart failure has not been shown to reduce mortality.
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. Some examples observed in patients or in healthy subjects are listed below but the list is not exhaustive.
Cardiac glycosides (Digoxin). An increase of steady state digoxin levels by approximately 15% and of digitoxin by approximately 13% has been seen in hypertensive patients in connection with the concomitant use of carvedilol and digoxin. Monitoring of plasma digoxin concentrations is recommended when initiating, discontinuing or adjusting treatment with carvedilol. Both digoxin and carvedilol slow AV conduction i.e. may result in additive prolongation of atrioventricular (AV) conduction time.
Medicines inducing or inhibiting cytochrome P450 enzymes.
Patients receiving medicines (e.g. rifampicin and barbiturates) that induces cytochrome P450 enzymes should be monitored for plasma concentrations of carvedilol which may be reduced by 70% or inhibitors (e.g. cimetidine, ketoconazole, fluoxetine, haloperidol, verapamil, erythromycin) cytochrome P450 enzymes have to be monitored closely during concomitant treatment with carvedilol as serum carvedilol concentrations may be reduced by the first agents and increased by the enzyme inhibitors. Cimetidine increased AUC by about 30% but caused no change in Cmax.
However, based on the relatively small effect of cimetidine on carvedilol drug levels, the likelihood of any clinically important interaction is minimal.
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. Modest increases in mean trough cyclosporin concentrations were observed following initiation of carvedilol treatment in 21 renal transplant patients suffering from chronic vascular rejection. It appears that carvedilol increases the absorption of ciclosporin po through inhibition of P-glycoprotein activity in the intestine. 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 10-20% 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. In case of iv administration of ciclosporin, no interaction with carvedilol is expected.
Rifampicin: In a study in 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.
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 P-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
Antidiabetics including insulin. The blood sugar lowering effect of insulin and oral diabetic drugs may be intensified. The signs of hypoglycaemia may be masked or attenuated (especially tachycardia). In diabetic patients on insulin or oral hypoglycaemics, regular monitoring of blood glucose levels is necessary.
Catecholamine-depleting agents: Patients taking both agents with P-blocking properties and a drug that can deplete catecholamines (eg reserpine and monoamine oxidase inhibitors) should be observed closely for signs of hypotension and/or severe bradycardia.
Clonidine. Concomitant administration of clonidine with agents with P-blocking properties may potentiate blood-pressure- and heart-rate-lowering effects. When combination treatment with carvedilol and clonidine is discontinued, carvedilol should be withdrawn several days before gradually decreasing the dose of clonidine.
Calcium channel blockers (see section 4.4 Special warnings and precautions for use).
Isolated cases of conduction disturbance (rarely with haemodynamic compromise) have been observed when carvedilol is co-administered with diltiazem. As with other agents with P-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. These drugs should not be administered intravenously.
Other antihypertensive drugs. As with other agents with P-blocking activity, carvedilol may potentiate the effects of other concomitantly administered antihypertensives (e.g. a1-receptor antagonists) and drugs with antihypertensive side effects such as barbiturates, phenothiazines, tricyclic antidepressants, vasodilating agents and alcohol.
Antiarrhythmics. Isolated cases of conduction disturbance, rarely with haemodynamic disruption, have been observed in patients taking carvedilol and (oral) diltiazem, verapamil and/or amiodarone. As with other beta-blockers, careful monitoring of the ECG and blood pressure should be undertaken when co-administering calcium channel blockers of the verapamil and diltiazem type, as risk of AV conduction disorder or risk of cardiac failure is increased (synergistic effect). Close monitoring should be done in case of co-administration of carvedilol, and class I antiarrhythmics or amiodarone therapy (oral). Bradycardia, cardiac arrest, and ventricular fibrillation have been reported shortly after initiation of beta-blocker treatment in patients receiving amiodarone. There is a risk of cardiac failure in case of class Ia or Ic antiarrhythmics concomitant intravenous therapy.
Concomitant treatment with reserpine, guanethidine, methyldopa, guanfacin and monoamine-oxidase inhibitors (exception MAO-B-inhibitors) can lead to additional decrease in heart rate. Monitoring of vital signs is recommended.
Dihydropyridines. The administration of dihydropyridines and carvedilol should be done under close supervision as heart failure and severe hypotension have been reported.
Nitrates. Increased hypotensive effects.
Inhalational anaesthetics. Careful monitoring of vital signs is recommended. Attention should be paid during general anaesthesia to the potential negative inotropic and hypotensive interactions of carvedilol and anaesthetics in association with anaesthesia.
NSAIDs, estrogens and corticosteroids. The antihypertensive effect of carvedilol is decreased due to water and sodium retention.
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.
Sympathomimetics with alpha-mimetic and beta-mimetic effects. Risk of hypertension and excessive bradycardia.
Ergotamine. Vasoconstriction increased.
Neuromuscular blocking agents. Increased neuromuscular block.
Beta-agonist bronchodilators: Non-cardioselective beta blockers oppose the bronchodilator effects of beta-agonist bronchodilators. Careful monitoring of patients is recommended.
4.6 Fertility, pregnancy and lactation
Pregnancy
There is no adequate clinical experience with carvedilol in pregnant women. Use of carvedilol is not recommended during pregnancy and lactation.
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 did not demonstrate any substantive evidence of teratogenic effects in animal reproduction studies, but there is insufficient clinical evidence of its safety in pregnant women (see 5.3 ”Preclinicalsafety data”).
Beta-blockers reduce placental perfusion which may result in intrauterine foetal death and immature and premature deliveries. In addition, adverse reactions (especially hypoglycaemia bradycardia, respiratory depression and hypothermia) may occur in the foetal and neonate). There is an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period. Carvedilol should only be used for pregnant women, if the potential benefit for the mother outweighs the potential risk for the foetal/neonate. The treatment should be stopped 2-3 days before expected birth. If this is not possible the new-born has to be monitored for the first 2-3 days of life.
Breast-feeding
Carvedilol is lipophilic and according to results from studies with lactating animals, carvedilol and its metabolites are excreted in breast milk and, therefore, mothers receiving carvedilol should not breast-feed. It is not known whether carvedilol is excreted in human milk.
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.
As for other drugs which produce changes in blood pressure, patients taking carvedilol should be warned that 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: Thrombocytopaenia 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
Rare: Oedema peripheral
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 (including generalised, peripheral, dependent and genital oedema, oedema of the legs), 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 Reynaud’s phenomenon)
Respiratory, thoracic and mediastinal disorders
Common: Dyspnoea, pulmonary oedema, asthma in predisposed patients
Rare: Nasal congestion, flu-like symptoms Gastrointestinal disorders
Common: Nausea, diarrhoea, vomiting, dyspepsia, abdominal pain Rare: Constipation Very rare: Dry mouth
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
Investigations:
Rare: Serum transaminase increased
(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).
Carvedilol may cause urinary incontinence in women which resolves upon discontinuation of the medication.
The frequency of adverse reactions is not dose dependent, with the exception of dizziness, visual disturbance, bradycardia and aggravation of heart insufficiency.
Cardiac contractility may be decreased during dose titration but this is rare.
Respiratory, thoracic and mediastinal disorders. Asthmatic dyspnoea has been observed commonly in predisposed patients.
Psoriatic skin lesions may occur or existing lesions may be aggravated.
Non-selective beta-blockers in particular may also result in latent diabetes mellitus becoming manifest, manifest diabetes being aggravated, and blood glucose control being disturbed. Mild disturbances of glucose balance are possible, however not common, also during treatment with carvedilol.
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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard
4.9 Overdose
Symptoms. Overdose may cause severe hypotension, bradycardia, heart failure, cardiogenic shock and cardiac arrest. There may also be respiratory problems, bronchospasm, vomiting, disturbed consciousness and generalised convulsions.
Treatment. The benefit of gastric decontamination is uncertain. Consider activated charcoal (charcoal dose: 50 g for adults;1 g/kg for children) if the patient presents within 1 hour of ingestion of more than a potentially toxic dose. Alternatively consider gastric lavage in adults within 1 hour of a potentially life-threatening overdose.In addition to normal treatment procedures, vital signs must be monitored and, if necessary, corrected at an intensive care unit. The following supportive measures may be taken:
Patients should be placed in the supine position. Atropine: 0.5 - 2mg intravenously and/or glucagon initially 1 to 10mg i.v. (followed if necessary by a slow infusion of 2 - 5mg/hour) (for treatment of severe bradycardia).
To support ventricular function intravenous glucagon or sympathomimetics according to their efficacy and the patient’s weight: dobutamine, isoprenalin or adrenaline.
If positive inotropic effect is required, phosphodiesterase inhibitors (PDE) should be considered. If peripheral vasodilatation is the dominant symptom of overdose, the patient has to be given noradneraline or norfenephrine or etilefrine. The patient’s circulation must be monitored continuously. Norepinephrine or noradrenaline should be administered, either 5 to 10 micrograms i.v., repeated according to blood pressure response, or 5 micrograms per minute by infusion titrated to blood pressure.
If the patient has bradycardia unresponsive to pharmacotherapy, pacemaker therapy should be started. For the treatment of bronchospasm, the patient must be given beta-sympathomimetics (as aerosol or intravenously, if the aerosol does not provide adequate effect) or theophylline intravenously or aminophylline may be administered intravenously by slow injection or infusion. If the patient has convulsions, diazepam or clonazepam may be administered as a slow intravenous injection.
Carvedilol is highly protein-bound. Therefore, it cannot be eliminated by dialysis.
Important! In cases of severe overdose when the patient is in shock, supportive treatment should be continued for a sufficiently long period of time, since the elimination and redistribution of carvedilol from deeper compartments are likely to be slower than normal.
Duration of the antidote treatment depends on the seriousness of the overdose; supportive treatment must be continued until the patient stabilises.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: alpha- and beta-blocking agents ATC code: C07AG02
Carvedilol is a vasodilatory non-selective beta-blocker, which reduces the peripheral vascular resistance by selective alpha 1- receptor blockade and suppresses the renin-angiotensin through non-selective beta-blockade. Plasma rennin 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 betai- and beta2-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 vitro in 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 betablocking 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 reduces mortality and need for cardiovascular hospitalisations in patients with heart failure.
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
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 betablocking activity. Compared to carvedilol, these three active metabolites have a weak vasodilatory effect. On the basis of preclinical studies, the 4’-hydroxyphenolmetabolite 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 - 80-fold potency compared to carvedilol.
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 - 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.
5.3 Preclinical safety data
Studies on rats and mice revealed no carcinogenic potential of carvedilol at doses of 75mg/kg and 200mg/kg (38 - 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.
There is no evidence from animal studies that carvedilol has any teratogenic effects. When high doses of carvedilol were administered to pregnant rats (> 200mg/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 > 60mg/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 200mg/kg and 75mg/kg, respectively (38 - 100 time the human maximum daily dose). The relevance of these findings for humans is uncertain. 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 (although see section 4.6).
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate. Cellulose, microcrystalline. Crospovidone.
Povidone K30.
Silica, colloidal anhydrous. Magnesium stearate. Colouring agents:
Ferric oxide, red (E172) Ferric oxide, yellow (E172)
6.2 Incompatibilities
Not applicable
6.3 Shelf life
4 years
6.4 Special precautions for storage
Polyethylene (PE-HD) containers and closures: Store in the original container. Blister (Al/PVC): Store in the original package.
Nature and contents of container
6.5
Polyethylene (PE/HD) containers and closures: 28, 30, 60, 100, 250 and 500 tablets.
Blister (Al/PVC): 14, 20, 28, 30, 50, 50x1, 56, 60, 98, 98x1 and 100 tablets. Not all pack size and pack types may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements for disposal.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
TILLOMED LABORATORIES LTD
3 HOWARD ROAD
EATON SOCON
ST. NEOTS
CAMBRIDGESHIRE
PE198ET
8 MARKETING AUTHORISATION NUMBER(S)
PL 11311/0482
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
DATE OF REVISION OF THE TEXT
10
31/03/2015