Carvedilol 12.5 Mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Carvedilol 12.5 mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 12.5 mg of Carvedilol Excipients: Each tablet contains 62.94 mg of lactose For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablet
Carvedilol Tablets are cream coloured, circular, biconvex tablets, 8.30 mm-8.70 mm in diameter, marked ‘C12’ on one face and plain 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.
Carvedilol is indicated for the prophylactic treatment of stable angina.
This medicinal product is indicated in adults and the elderly.
4.2 Posology and method of administration 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.
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 3.125 mg 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 6.25 mg twice daily, followed by 12.5 mg twice daily and thereafter 25 mg twice daily. Dosing should be increased to the highest level tolerated by the patient.
The recommended maximum daily dose is 25 mg given twice daily for all patients with severe CHF and for patients with mild to moderate CHF weighing less than 85 kg (187 lbs). In patients with mild or moderate CHF weighing more than 85 kg, the recommended maximum dose is 50 mg twice daily.
During up-titration of the dose in patients with systolic blood pressure < 100 mm Hg, 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 3.125 mg 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 12.5 mg once a day for the first two days. Thereafter the recommended dosage is 25 mg 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 50 mg given once a day or in divided doses.
Dose titration should occur at intervals of at least two weeks.
Elderly:
An initial dose of 12.5 mg 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 50 mg given once a day or in divided doses.
Children:
Safety and efficacy in children (under 18 years) has not been established.
The recommended dose for initiation of therapy is 12.5 mg twice a day for the first two days. Thereafter, the recommended dosage is 25 mg twice a day.
Elderly:
The recommended maximum daily dose is 50 mg 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 contraindicated in patients with hepatic dysfunction (see sections 4.3 and section 5.2).
Patients with co-existing renal dysfunction
No dose adjustment is anticipated as long as systolic blood pressure is above 100 mm Hg (see also sections 4.4 and section 5.2).
Method of administration:
The tablets should be taken with fluid. For CHF patients, Carvedilol should be given with food.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Carvedilol is contraindicated in patients with marked fluid retention or overload requiring intravenous inotropic support.
Patients with obstructive airways disease, liver dysfunction.
As with other beta-blocking agents: 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 < 85 mm Hg), metabolic acidosis and phaeochromocytoma (unless adequately controlled by alpha blockade).
Due to the presence of lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
4.4 Special warnings and precautions for use
In chronic 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 adjusted and the carvedilol dose should not be advanced until clinical stability resumes. Occasionally it may be necessary to lower the carvedilol dose or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of carvedilol.
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.
As with other drugs with beta-blocking activity, carvedilol may mask the early signs of acute hypoglycaemia in patients with diabetes mellitus. Alternatives to betablocking agents are generally preferred in insulin-dependent patients. In 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.
Reversible deterioration of renal function has been observed with carvedilol therapy in chronic heart failure patients with low blood pressure (systolic BP < 100 mm Hg), ischaemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency. 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.
Wearers of contact lenses should be advised of the possibility of reduced lacrimation.
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.
Carvedilol may be used in patients with peripheral vascular disease. Pure beta-blockers can precipitate or aggravate symptoms of arterial insufficiency. However, as carvedilol also has an alpha-blocking property, this effect is largely counterbalanced.
Carvedilol, as with other agents with beta-blocking activity, may mask the symptoms of thyrotoxicosis.
If carvedilol induces bradycardia, with a decrease in pulse rate to less than 55 beats per minute, the dosage of carvedilol should be reduced.
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.
In patients suffering from the peripheral circulatory disorder Raynaud's phenomenon, there may be exacerbation of symptoms.
Patients with a history of psoriasis associated with beta-blocker therapy should be given carvedilol only after consideration of the risk-benefit ratio.
In patients with phaeochromocytoma, an alpha-blocking agent should be initiated prior to the use of any beta-blocking agent. 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.
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.
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 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. Consult your doctor or pharmacist first.
4.5 Interaction with other medicinal products and other forms of interaction
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.
Patients taking an agent 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.
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 antiarrhythmic drugs. These types of drugs should not be co-administered intravenously in patients receiving carvedilol.
The effects of insulin or oral hypoglycaemics may be intensified. Regular monitoring of blood glucose is therefore recommended.
Trough plasma digoxin levels may be increased by approximately 16% in hypertensive patients co-administered carvedilol and digoxin. 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.
When treatment with carvedilol and clonidine together is to be terminated, carvedilol should be withdrawn first, several days before gradually decreasing the dosage of clonidine.
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.
During general anaesthesia, attention should be paid to the potential synergistic negative inotropic effects of carvedilol and anaesthetic drugs.
Modest increases in mean trough cyclosporin concentrations were observed following initiation of carvedilol treatment in 21 renal transplant patients suffering from chronic vascular rejection. In about 30% of patients, the dose of cyclosporin had to be reduced in order to maintain cyclosporin concentrations within the therapeutic range, while in the remainder no adjustment was needed. On average, the dose of cyclosporin was reduced about 20% in these patients. Due to wide interindividual variability in the dose adjustment required, it is recommended that cyclosporin concentrations be monitored closely after initiation of carvedilol therapy and that the dose of cyclosporin be adjusted as appropriate.
4.6 Fertility, Pregnancy and Lactation
Pregnancy
There are no adequate data from the use of carvedilol in pregnant women.
Animal studies are insufficient with respect to effects on pregnancy, embryonal/foetal development, parturition and postnatal development (see section 5.3). The potential risk for humans is unknown.
Carvedilol should not be used during pregnancy unless clearly necessary (i.e. unless the anticipated benefits outweigh the potential risks).
Lactation
It is unknown whether carvedilol is excreted in human breast milk. Animal studies have shown excretion of carvedilol or its metabolites in breast milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with carvedilol should be made taking into account the benefit of breast-feeding to the child and the benefit of carvedilol therapy to the woman.
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 and in conjunction with alcohol.
4.8 Undesirable effects
The most commonly reported adverse reactions during treatment are dizziness, headache and asthenia (including fatigue) which are usually mild and occur at the start of the treatment.
The following terminologies have been used in order to classify the occurrence of undesirable effects. VERY COMMON (>1/10); COMMON (>1/100 to < 1/10); UNCOMMON (>1/1000 to <1/100); RARE (>1/10000 to <1/1000)
Adverse events are listed separately for CHF because of differences in the background diseases
In chronic heart failure:
Rare: thrombocytopenia.
Not known (cannot be estimated from the available data): Leucopenia.
Metabolism and nutrition disorders
Common: Weight increases and hypercholesterolaemia. Hyperglycaemia and hypoglycaemia are also common in patients with pre-existing diabetes mellitus (see section 4.5).
Nervous system disorders
Very common: dizziness, headaches are usually mild and occur particularly at the start of treatment. Asthenia (including fatigue)
Eye disorders
Common: vision abnormalities.
Cardiac disorders
Common: bradycardia, oedema (including generalised, peripheral, dependent and genital oedema, oedema of the legs, hypervolaemia and fluid overload).
Uncommon: AV-block and cardiac failure during up-titration, syncope (including presyncope)
Vascular disorders
Common: postural hypotension, hypotension Gastrointestinal disorders
Common: nausea, diarrhoea, and vomiting. Skin and subcutaneous tissue disorders
Dermatitis and increased sweating
Rare: acute renal failure and renal function abnormalities in patients with diffuse vascular disease and/or impaired renal function (see section 4.4).
The frequency of adverse experiences is not dose dependent, with the exception of dizziness, abnormal vision and bradycardia.
In hypertension and angina:
The profile is similar to that observed in chronic heart failure although the incidence of events is generally lower in patients with hypertension or angina treated with carvedilol.
Blood and lymphatic system disorders
Not known (cannot be estimated from the available data): thrombocytopenia and leucopenia.
Metabolism and nutrition disorders
Due to the beta-blocking properties it is also possible for latent diabetes mellitus to become manifest, manifest diabetes to be aggravated, and blood glucose counterregulation to be inhibited.
Nervous system disorders
Common: dizziness, headaches and fatigue, which are usually mild and occur particularly at the beginning of treatment.
Uncommon: depressed mood, sleep disturbance, paraesthesia, asthenia.
Eye disorders
Common reduced lacrimation
Uncommon: disturbed vision
Rare: eye irritation.
Common: bradycardia
Uncommon: syncope, hypotension, AV-block, angina pectoris (including chest pain), symptoms of heart failure and peripheral oedema.
Vascular disorders
Common: postural hypotension, especially at the beginning of treatment.
Uncommon: disturbances of peripheral circulation (cold extremities, PVD, exacerbation of intermittent claudication and Raynauds phenomenon.
Respiratory, thoracic and mediastinal disorders
Common: asthma and dyspnoea in predisposed patients.
Rare: stuffy nose, wheezing and flu-like symptoms.
Gastrointestinal disorders
Common: gastro-intestinal upset (with symptoms such as nausea, abdominal pain, diarrhoea).
Uncommon: constipation and vomiting.
Skin and subcutaneous tissue disorders
Uncommon: skin reactions (e.g. allergic exanthema, dermatitis, urticaria, pruritus, lichen planus-like reactions, and increased sweating). Psoriatic skin lesions may occur or existing lesions exacerbated.
Renal and urinary disorders
Rare: disturbances of micturition
Reproductive system and breast disorders
Uncommon: cases of sexual impotence
General disorders and administration site conditions
Common: pain in the extremities.
Rare: dryness of the mouth.
Not known (cannot be estimated from the available data): allergic reactions Investigations
Not known (cannot be estimated from the available data): changes in serum transaminases
Post-marketing experience
Not known (cannot be estimated from the available data): urinary incontinence in women, which resolved upon discontinuation of the medication.
4.9 Overdose
Symptoms and signs
Profound cardiovascular effects such as hypotension and bradycardia would be expected after massive overdose. Heart failure, cardiogenic shock and cardiac arrest may follow. 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 procedures, vital signs must be monitored and corrected, if necessary under intensive care conditions.
Patients should be placed in the supine position. Atropine, 0.5 mg to 2 mg i.v. and/or glucagon 1 to 10 mg i.v. (followed by a slow i.v. infusion of 2 to 5 mg/hour if necessary) may be given when bradycardia is present. Pacemaker therapy may be
necessary. For excessive hypotension, intravenous fluids may be administered. 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. Bronchospasm may be treated using salbutamol or other beta2-agonists given as aerosol or, if necessary, by the intravenous route. 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
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 alphai 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 betablocking 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 (COPERNICUS), 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).
The incidence of serious adverse events during the study was lower in the carvedilol group (39.0% vs 45.4%). During initiation of treatment, the incidence of worsening heart failure was similar in both carvedilol and placebo groups. The incidence of serious worsening heart failure during the study was lower in the carvedilol group (14.6% vs 21.6%).
Serum lipid profile and electrolytes are not affected.
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 3 metabolites with beta-receptor blocking activity.
The average elimination half-life ranges from 6 to 10 hours. Plasma clearance is approximately 590 ml/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. Beta-blockers 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 Microcrystalline cellulose (Avicel pH 102) Low-substituted hydroxypropyl cellulose (E463) Maize starch
Yellow iron oxide (E172)
Colloidal anhydrous silica Purified talc
Magnesium stearate (E572)
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in the original package in order to protect from moisture
6.5 Nature and contents of container
Blister packs, PVC/PVDC Aluminium foil of 14, 28, 30, 56 or 100 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Not applicable
7 MARKETING AUTHORISATION HOLDER
APTIL Pharma Limited 9th Floor, CP House 97 - 107 Uxbridge Road Ealing, London W5 5TL
8 MARKETING AUTHORISATION NUMBER(S)
PL 40378/0138
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
16/11/2012
10 DATE OF REVISION OF THE TEXT
16/11/2012