Carvedilol 6.25mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Carvedilol 6.25mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains Carvedilol 6.25mg
Excipient with known effect: Also contains Lactose monohydrate 7mg For the full list of excipients, see Section 6.1
3 PHARMACEUTICAL FORM
Tablets.
Cream coloured, circular, biconvex uncoated tablets with ‘C’ breakline ‘2’ embossed on one side and plain on the other.
The scoreline is not intended for breaking the tablet.
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
Posology
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 patient's 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 and monitored during up-titration.
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.
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 (187lbs). 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 with increased 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.
Older people
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.
Older people
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.
Older people
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 hepatic impairment
Carvedilol is contra-indicated in patients with hepatic dysfunction (see sections 4.3 and 5.2).
Patients with renal impairment
No dose adjustment is anticipated as long as systolic blood pressure is above 100mmHg (see also sections 4.4 and 5.2).
Method of administration
The tablets should be taken with fluid. For CHF patients Carvedilol should be given with food to slow the rate of absorption and reduce the incidence of orthostatic effects.
4.3 Contraindications
■ Hypersensitivity to the active substance or to any of the excipients listed in Section 6.1.
■ Unstable /decompensated heart failure requiring intravenous inotropic support
■ Marked fluid retention or overload requiring intravenous support
■ Obstructive airways disease
■ Clinically manifest liver dysfunction.
■
As with other beta-blocking agents:
■ History of bronchospasm or asthma
■ 2nd and 3rd degree atrioventricularA-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 congestive heart failure patients, worsening cardiac failure or fluid retention may occur during up-titration of Carvedilol. If such symptoms occur, the dose of diuretic should be increased and the Carvedilol dose should not be further increased d 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 up-titration of Carvedilol.
Carvedilol should be used with caution in combination with digitalis glycosides since both drugs may slow A -V conduction (see section-4.5)
Diabetes
Care should be taken in the administration of carvedilol to patients with diabetes mellitus, as it may be associated with worsening control of blood glucose, or the early signs and symptoms of acute hypoglycaemia may be masked or attenuated. Alternatives to beta-blocking agents are generally preferred in insulin-dependent patients. 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).
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.
Contact lenses
Wearers of contact lenses should be advised of the possibility of reduced lacrimation.
Peripheral vascular disease and Raynaud’s phenomenon
Carvedilol should be used with caution in patients with peripheral vascular disease as pure beta-blockers can precipitate or aggravate symptoms of arterial insufficiency (e.g. Raynaud’s phenomenon).
Thyrotoxicosis
Carvedilol, as with other agents with beta-blocking activity, may obscure the symptoms of thyrotoxicosis.
Bradycardia
If Carvedilol induces bradycardia, with a decrease in pulse rate 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 patients undergoing desensitisation therapy as beta-blockers may increase both the sensitivity towards allergens and the severity of hypersensitivity reactions.
Severe cutaneous adverse reactions (SCARs)
Very rare cases of severe cutaneous adverse reactions such as toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) have been reported during treatment with Eucardic (see section 4.8). Eucardic should be permanently discontinued in patients who experience severe cutaneous adverse reactions possibly attributable to Eucardic.
Psoriasis
Patients with a history of psoriasis associated with beta-blocker therapy should be given Carvedilol only after consideration of the risk-benefit ratio.
Interactions with other medicinal products
There are a number of important pharmacokinetic and pharmacodynamic interactions with other drugs (e.g., digoxin, ciclosporin, rifampicin, anaesthetic drugs, anti-arrhythmic drug. See section 4.5).
Phaeochromocytoma
In patients with phaeochromocytoma, an alpha-blocking agent should be initiated prior to the use of any beta-blocking agent. Although carvedilol has both alpha- and beta- blocking pharmacological activities, there is no experience of the use of carvedilol in this condition. Therefore, caution should be taken in the administration of Carvedilol to patients suspected of having phaeochromocytoma.
Prinzmetal's variant angina
Agents with non-selective beta-blocking activity may provoke chest pain in patients with Prinzmetal's variant angina. There is no clinical experience with Carvedilol in these patients, although the alpha-blocking activity of Carvedilol may prevent such symptoms. Caution should be taken in the administration of Carvedilol to patients suspected of having Prinzmetal's variant angina.
Withdrawal syndrome
Although angina has not been reported on stopping treatment, Carvedilol treatment should not be discontinued abruptly, particularly in patients suffering from ischaemic heart disease, as Carvedilol has beta-blocking activity. The withdrawal of carvedilol should be gradual (over a period of two weeks).
Lactose
This product contains the excipient lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
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.
Bronchospatic reactions: In patients with a tendency to bronchospastic reactions, 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. The following warnings will be included on the outer packaging and leaflet.
Packaging
Do not take this medicine if you have a history of wheezing due to asthma or other lung diseases.
Leaflet
Do not take this medicine if you have a history of wheezing due to asthma or other lung diseases. If you are not sure, talk to your doctor or pharmacist before taking carvedilol.
4.5 Interaction with other medicinal products and other forms of interaction
Pharmacokinetic interactions
Effects of Carvedilol on the _ pharmacokinetics of other drugs
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. (see section 5.2). Some examples observed in patients or in healthy subjects are listed below but the list is not exhaustive.
Digoxin:
An increased exposure of digoxin of up to 20% has been shown in some studies in healthy subjects and patients with heart failure. A significantly larger effect has been seen in male patients compared to female patients. Therefore monitoring of digoxin levels is recommended when initiating, adjusting or discontinuing carvedilol (see section 4.4). Carvedilol had no effect on digoxin administered intravenously.
Inducers and inhibitors of hepatic metabolism:
Rifampicin reduced plasma concentrations of carvedilol by about 70% Cimetidine increased AUC by about 30% but caused no change in Cmax.
Care may be required in those receiving inducers of mixed function oxidases e.g. rifampicin, as serum levels of carvedilol may be reduced or inhibitors of mixed function oxidases e.g. cimetidine, as serum levels may be increased.
However, based on the relatively small effect of cimetidine on carvedilol drug levels, the likelihood of any clinically important interaction is minimal.
Ciclosporin:
Two studies in renal and cardiac transplant patients receiving oral ciclosporin have shown an increase in ciclosporin plasma concentration following the initiation of carvedilol. It appears that carvedilol increases exposure to oralciclosporinby around 10 to 20%. In an attempt to maintain therapeutic ciclosporin levels, an average 10-20% reduction of the ciclosporin dose was necessary. The mechanism for the interaction is not known but inhibition of intestinal P glycoprotein by carvedilol may be involved. Due to wide interindividual variability of ciclosporin levels, it is recommended that ciclosporin concentrations are monitored closely after initiation of carvedilol therapy and that the dose of ciclosporin be adjusted as appropriate. In case of IVadministration of ciclosporin, no interaction with carvedilol is expected.
Effects of other drugs on the pharmacokinetics of Carvedilol
Rifampicin:
In a study in 12 healthy subjects, exposure to carvedilol decreased by around 60% during concomitant administration with rifampicin and a decrease effect of carvedilol on the systolic blood pressure was observed. The mechanism for the interaction is not known but it may be due to the induction of the intestinal P glycoprotein by rifampicin. A close monitoring of the P-blockade activity in patients receiving concomitant administration of carvedilol and rifampicin is appropriate.
Amiodarone:
An in vitro study with human liver microsomes has shown that amiodarone and desethylamiodarone inhibited the oxidation of R and S-carvedilol. The trough concentration of R and S-carvedilol was significantly increased by 2.2-fold in heart failure patients receiving carvedilol and amiodarone concomitantly as compared to patients receiving carvedilol monotherapy. The effect on S-carvedilol was attributed to desethylamiodarone, a metabolite of amiodarone, which is a strong inhibitor of CYP2C9. A monitoring of the P-blockade activity in patients treated with the combination carvedilol and amiodarone is advised.
In a randomized, cross-over study in 10 patients with heart failure, coadministration of fluoxetine, a strong inhibitor of CYP2D6, resulted in stereoselective inhibition of carvedilol metabolism with a 77% increase in mean R(+) enantiomer AUC and a non-statistically 35% increase of the S(-) enantiomer's AUC as compared to the placebo group. However, no difference in adverse events, blood pressure or heart rate were noted between treatment groups. The effect of single dose paroxetine, a strong CYP2D6 inhibitor, on carvedilol pharmacokinetics was investigated in 12 healthy subjects following single oral administration. Despite significant increase in R and S-carvedilol exposure, no clinical effects were observed in these healthy subjects.
Pharmacodynamic interactions
Insulin or oral hypoglycaemics:
Agents with beta-blocking properties may enhance the blood-sugar-reducing effect of insulin and oral hypoglycaemics. The signs of hypoglycaemia may be masked or attenuated (especially tachycardia). In patients taking insulin or oral hypoglycaemics, regular monitoring of blood glucose is therefore recommended (see section 4.4).
Catecholamine-depleting agents:
Patients taking both agents with beta-blocking properties and a drug that can deplete catecholamines (e.g. reserpine and monoamine oxidase inhibitors) should be observed closely for signs of hypotension and/or severe bradycardia.
Digoxin:
The combined use of beta-blockers and digoxin may result in additive prolongation of atrioventricular (AV) conduction time.
Non-dihydropyridines calcium channel blockers or other antiarrhythmics:In combination with Carvedilol can increase the risk of AV conduction disturbances (see section 4.4). Isolated cases of conduction disturbance (rarely with haemodynamic compromise) have been observed when carvedilol is coadministered with diltiazem. As with other agents with P-blocking properties, if carvedilol is to be administered orally with non-dihydropyridines calcium channel blockers of the verapamil or diltiazem type, amiodarone or other antiarrhythmics it is recommended that ECG and blood pressure be monitored.
Antihypertensives:
As with other agents with beta-blocking activity, Carvedilol may potentiate the effect of other concomitantly administered drugs that are anti-hypertensive in action (e.g. alpha1-receptor antagonists) or have hypotension as part of their adverse effect profile.
Clonidine:
Concomitant administration of clonidine with agents with P-blocking properties may potentiate blood-pressure- and heart-rate-lowering effects.
When concomitant treatment with Beta-blockers and clonidine together is to be terminated, Carvedilol should be withdrawn first.Clonidine therapy can then be discontinued several days later by gradually decreasing the dosage.
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).
NSAIDs:
The concurrent use of non-steroidal anti-inflammatory drugs (NSAIDs) and betaadrenergic blockers may result in an increase in blood pressure and impairment of blood pressure control.
Beta-agonist bronchodilatators:
Non-cardioselective beta blockers oppose the bronchodilator effects of beta-agonist bronchodilators.
4.6 Fertility, pregnancy and lactation
Pregnancy
There is no adequate experience with Carvedilol in pregnant women.
Carvedilol should not be used during pregnancy unless the potential benefit outweighs the potential risk.
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.
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)
Lactation:
Animal studies demonstrated that carvedilol and/or its metabolites are excreted in rat breast milk. The excretion of carvedilol in human milk has not been established. However, most P-blockers, in particular lipophilic compounds, will pass into human breast milk although to a variable extent. 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.
As for other drugs which produce changes in blood pressure, patients taking Carvedilol should be warned not to drive or operate machinery if they experience dizziness or related symptoms. This applies particularly when starting or changing treatment, after dose increases and in conjunction with alcohol
4.8 Undesirable effects
The following undesirable effects have been reported to occur when carvedilol is administered:
Frequency categories are as follows:
Very >1/10
common
Common >1/100 and <1/10
Very rare <1/10,000
Table 1 Adverse Drug Reactions
|
System Organ Class |
Adverse Reaction |
Frequency |
|
Blood and Lymphatic System Disorders |
Anaemia |
Common |
|
Thrombocytopenia |
Rare | |
|
Leukopenia |
Very rare | |
|
Cardiac Disorders |
Cardiac failure |
Very common |
|
Bradycardia |
Common | |
|
Hypervolaemia |
Common | |
|
Fluid overload |
Common | |
|
Oedema |
Common | |
|
Atrioventricular block |
Uncommon | |
|
Angina pectoris |
Uncommon | |
|
Eye Disorders |
Visual impairment |
Common |
|
Lacrimation decreased (dry eye) |
Common | |
|
Eye irritation |
Common | |
|
Gastrointestinal Disorders |
Nausea |
Common |
|
Diarrhoea |
Common | |
|
Vomiting |
Common | |
|
Dyspepsia |
Common | |
|
Abdominal pain |
Common |
|
Constipation |
Uncommon | |
|
Dry mouth |
Rare | |
|
General Disorders and Administration Site Conditions |
Asthenia (fatigue) |
Very common |
|
Oedema |
Common | |
|
Pain |
Common | |
|
Hepatobiliary disorders |
Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT) increased |
Very rare |
|
Immune System Disorders |
Hypersensitivity (allergic reactions) |
Very rare |
|
Infections and Infestations |
Pneumonia |
Common |
|
Bronchitis |
Common | |
|
Upper respiratory tract infection |
Common | |
|
Urinary tract infection |
Common | |
|
Metabolism and Nutrition Disorders |
Weight increase |
Common |
|
Hyp ercholesterolaemia |
Common | |
|
Impaired blood glucose control (hyperglycaemia, hypoglycaemia) in patients with pre-existing diabetes |
Common | |
|
Musculoskeletal and Connective Tissue Disorders |
Pain in extremities |
Common |
|
Nervous System |
Dizziness |
Very |
|
Disorders |
common | |
|
Headache |
Very Common | |
|
Syncope, presyncope |
Common | |
|
Paraesthesia |
Uncommon | |
|
Psychiatric Disorders |
Depression, depressed mood |
Common |
|
Sleep disorders |
Uncommon | |
|
Renal and urinary disorders |
Renal failure and renal function abnormalities in patients with diffuse vascular disease and/or underlying renal insufficiency |
Common |
|
Micturition disorders |
Rare | |
|
Urinary incontinence in women |
Very rare | |
|
Reproductive system and breast disorders |
Erectile dysfunction |
Uncommon |
|
Respiratory, Thoracic and Mediastinal Disorders |
Dyspnoea |
Common |
|
Pulmonary oedema |
Common | |
|
Asthma in predisposed patients |
Common | |
|
Nasal congestion, flu-like symptoms |
Rare | |
|
Skin and Subcutaneous Disorders |
Skin reactions (e.g. allergic exanthema, dermatitis, urticaria, pruritus, psoriatic and lichen planus like skin lesions), alopecia |
Uncommon |
|
Vascular Disorders |
Hypotension |
Very |
|
common | ||
|
Orthostatic hypotension, |
Common | |
|
Disturbances of peripheral circulation (cold extremities, peripheral vascular disease, exacerbation of intermittent claudication and Reynaud's phenomenon) |
Common | |
|
Hypertension |
Common |
Description of selected adverse reactions
The frequency of adverse reactions is not dose-dependent, with the exception of dizziness, abnormal vision and bradycardia. 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 4.2 Warnings and Precautions).
Cardiac failure was a very commonly reported adverse event in both placebo (14.5%) and carvedilol-treated (15.4%) patients, 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 4.2 Warnings and Precautions).
The following adverse events have been identified during post-marketing use of carvedilol. Because these events are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency and/or establish a causal relationship to drug exposure:
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.
Severe cutaneous adverse reactions (Toxic epidermal necrolysis, Stevens-Johnson syndrome (see section 4.4).
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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
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
The patients should be monitored for the above mentioned signs and symptoms and managed according to the best judgment of the treating physicians and according to standard practice for patients with P-blocker overdose (e.g. atropine, transvenous pacing, glucagon, phosphodiesterase inhibitor such as amrinone or milrinone, P-sympathomimetics).
Gastric lavage or induced emesis may be useful in the first few hours after ingestion.
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
Pharmacotherapeutic group: Alpha and beta blocking agents.
ATC code: C07AG02
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. Some of the limitations of traditional P-blockers do not appear to be shared by some of the vasodilating P-blockers, such as carvedilol.
Carvedilol has no intrinsic sympathomimetic activity and like propranolol, it has membrane stabilising properties.
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 left ventricular dysfunction or chronic heart failure, carvedilol has demonstrated favourable effects on haemodynamics and improvements in left ventricular ejection fraction and dimensions.
Clinical efficacy
Renal impairment
Several open studies have shown that carvedilol is an effective agent in patients with renal hypertension. The same is true in patients with chronic renal failure or those on haemodialysis or after renal transplantation. Carvedilol causes a gradual reduction in blood pressure both on dialysis and non-dialysis days, and the blood pressure-lowering effects are comparable with those seen in patients with normal renal function.
On the basis of results obtained in comparative trials on haemodialysed patients, it was concluded that carvedilol was more effective than calcium channel blockers and was better tolerated.
Carvedilol reduces morbidity and mortality in dialysis patients with dilated cardiomyopathy. A meta-analysis of placebo-controlled clinical trials including a large number of patients (>4000) with mild to moderate chronic kidney disease supports carvedilol treatment of patients with left ventricular dysfunction with or without symptomatic heart failure to reduce rates of all cause of mortality as well as heart failure related events.
Absorption
Following oral administration of a 25 mg capsule to healthy subjects, carvedilol is rapidly absorbed with a peak plasma concentration Cmax of 21 mg/L reached after approximately 1.5 hour (tmax). The Cmax values are linearly related to the dose. Following oral administration, carvedilol undergoes extensive first pass metabolism that results in an absolute bioavailability of about 25% in healthy male subjects. Carvedilol is a racemate and the S-(-)-enantiomer appears to be metabolized more rapidly than the R-(+)-enantiomer, showing an absolute oral bioavailability of 15% compared to 31% for the R-(+)- enantiomer. The maximal plasma concentration of R-carvedilol is approximately 2 fold higher than that of S-carvedilol.
In vitro studies have shown that carvedilol is a substrate of the efflux transporter P-glycoprotein. The role of P-glycoprotein in the disposition of carvedilol was also confirmed in vivo in healthy subjects. Food does not affect bioavailability or the maximum serum concentration although the time to reach maximum serum concentration is delayed.
Distribution
Carvedilol is highly lipophilic, showing a plasma protein of around 95%. The distribution volume ranges between 1.5 and 2L/kg and increased in patients with liver cirrhosis.
Metabolism
In humans, carvedilol is extensively metabolized in the liver via oxidation and conjugation into a variety of metabolites that are eliminated mainly in the bile. Enterohepatic circulation of the parent substance has been shown in animals.
Pharmacokinetic studies in human have shown that the oxidative metabolism of carvedilol is stereoselective. The results of an in vitro study suggested that different cytochrome P450 isoenzymes may be involved in the oxidation and hydroxylation processes including CYP2D6, CYP3A4, CYP2E1, CYP2C9, as well as CYP1A2.
Studies in healthy volunteers and in patients have shown that the R-enantiomer is predominantly metabolized by CYP2D6. The S-enantiomer is mainly metabolized by CYP2D6 and CYP2C9.
Genetic polymorphism
The results of clinical pharmacokinetic studies in human subjects have shown that CYP2D6 plays a major role in the metabolism of R and of S-carvedilol.
As a consequence plasma concentrations of R and S-carvedilol are increased in CYP2D6 slow metabolisers. The importance of CYP2D6 genotype in the
pharmacokinetics of R and S-carvedilol was confirmed in population pharmacokinetics studies, whereas other studies did not confirm this observation. It was concluded that CYP2D6 genetic polymorphism may be of limited clinical significance.
Elimination
Following a single oral administration of 50 mg carvedilol, around 60% are secreted into the bile and eliminated with the faeces in the form of metabolites within 11 days. Following a single oral dose, only about 16% are excreted into the urine in form of carvedilol or its metabolites. The urinary excretion of unaltered drug represents less than 2%. After intravenous infusion of 12.5 mg to healthy volunteers, the plasma clearance of carvedilol reaches around 600 mL/min and the elimination half-life around 2.5 hours. The elimination halflife of a 50 mg capsule observed in the same individuals was 6.5 hours corresponding indeed to the absorption half-life from the capsule. Following oral administration, the total body clearance of the S-carvedilol is approximately two times larger than that of the R-carvedilol.
Special populations
Elderly: Age has no statistically significant effect on the pharmacokinetics of carvedilol in hypertensive patients.
Children: Investigation in paediatrics has shown that the weight-adjusted clearance is significantly larger in paediatrics as compared to adults.
Hepatic impairment: 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.
Renal impairment: Since carvedilol is primarily excreted via the faeces, significant accumulation in patients with renal impairment is unlikely.
Heart failure: In a study in 24 Japanese patients with heart failure, the clearance of R-and S-carvedilol was significantly lower than previously estimated in healthy volunteers. These results suggested that the pharmacokinetics of R-and S-carvedilol is significantly altered by heart failure in Japanese patients.
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. 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).
6.1 List of excipients
Maize starch
Lactose monohydrate Sodium starch glycollate Microcrystalline cellulose Colloidal silicon dioxide Magnesium stearate Polysorbate -80 Colourant:
Yellow ferric oxide (E172)
6.2 Incompatibilities
Not applicable.
6.3. Shelf Life
3 years
6.4 Special precautions for storage
Do not store above 25°C.
Store in the original package to protect from moisture.
Keep blister in outer carton to protect from light.
6.5 Nature and contents of container
Al /PVC/PVDC blister, pack sizes of 14, 28, 56, 84 tablets.
6.6 Special precautions for disposal
No special requirements
7 MARKETING AUTHORISATION HOLDER
Bristol Laboratories Ltd.
Unit 3, Canalside, Northbridge Road, Berkhamsted, Herts, HP4 1EG,
UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 17907/0098
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
27/12/2007
10 DATE OF REVISION OF THE TEXT
03/07/2015