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CARVEDILOL 25 MG FILM-COATED TABLETS

Active substance(s): CARVEDILOL

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Carvedilol 25 mg film-coated tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Carvedilol 25 mg film-coated tablets:
Each tablet contains 25 mg carvedilol.
Excipients: Each tablet contains 229 mg lactose monohydrate and 5 mg
sucrose.
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Film-coated tablet.
Carvedilol 25 mg film-coated tablets:
White to off-white, oval shaped, film-coated tablets, debossed with F59 on
one side and deep break line on the other side.
The tablet can be divided into equal halves.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Essential hypertension
Chronic stable angina pectoris
Adjunctive treatment of moderate to severe stable chronic heart failure

4.2

Posology and method of administration
Oral use.
Essential hypertension:
Carvedilol may be used for the treatment of hypertension alone or in
combination with other antihypertensives, especially thiazide diuretics. Once
daily dosing is recommended, however the recommended maximum single
dose is 25 mg and the recommended maximum daily dose is 50 mg.

Adults
The recommended initial dose is 12.5 mg once a day for the first two days.
Thereafter, the treatment is continued at the dose 25 mg/day. If necessary, the
dose may be further increased gradually at intervals of two weeks or more
rarely.
Elderly
The recommended initial dose in hypertension is 12.5 mg once a day which
may also be sufficient for continued treatment.
However, if the therapeutic response is inadequate at this dose, the dose may
be further increased gradually at intervals of two weeks or more rarely.
Chronic stable angina pectoris:
A twice-daily regimen is recommended.
Adults
The recommended initial dosage is 12.5 mg twice a day for the first two days.
Thereafter, the treatment is continued at the dose 25 mg twice a day. If
necessary, the dose may be further increased gradually at intervals of two
weeks or more rarely to the recommended maximum dose of 100 mg a day
divided into two doses (twice daily).
Elderly

The recommended initial dose is 12.5 mg twice daily for two days. Thereafter,
the treatment is continued at the dose 25 mg twice daily, which is the
recommended maximum daily dose.
Heart failure:
Carvedilol is given in 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 NYHAclass, no hospitalisation due to heart failure) and the basic therapy must be
stabilized for at least 4 weeks prior to treatment. Additionally the patient
should have a reduced left ventricular ejection fraction and heart rate should
be > 50 bpm and systolic blood pressure > 85 mm Hg (see section 4.3).
The initial dose is 3.125 mg twice a day for two weeks. If this dose is
tolerated, the dose may be increased slowly with intervals of not less than two
weeks up to 6.25 mg twice a day, then up to 12.5 mg twice a day and finally
up to 25 mg twice a day. The dosage should be increased to the highest
tolerable level.
The recommended maximum dosage is 25 mg twice a day for patients with a
body weight of less than 85 kg, and 50 mg twice a day for patients with a body
weight above 85 kg, provided that the heart failure is not severe. A dose
increase to 50 mg twice daily should be performed carefully under close
medical supervision of the patient.
Transient worsening of symptoms of heart failure may occur at the beginning
of treatment or due to a dose increase, especially in patients with severe heart
failure and/or under high dose diuretic treatment. This does usually not call for
discontinuation of treatment, but dose should not be increased. The patient
should be monitored by a physician/cardiologist for two hours 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, and the dose of carvedilol should
not be increased until the patient is stabilized. 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.
Renal function, thrombocytes and glucose (in case of NIDDM and/or IDDM)
should be monitored regularly during dose titration. However, after dose
titration the frequency of monitoring can be reduced.
If carvedilol has been withdrawn for more than two weeks, the therapy should
be reinitiated with 3.125 mg twice a day and increased gradually according to
the above recommendations.
Renal insufficiency

Dosage must be determined for each patient individually, but according to
pharmacokinetic parameters there is no evidence that dose adjustment of
carvedilol in patients with renal impairment is necessary.
Moderate hepatic dysfunction
Dose adjustment may be required.
Children and adolescents (< 18 years)
Carvedilol is not recommended for the use in children below 18 years of age
due to insufficient data on the efficacy and safety of carvedilol.
Elderly
Elderly patients may be more susceptible to the effects of carvedilol and
should be monitored more carefully.
As with other beta-blockers and especially in patients with coronary disease,
the withdrawal of carvedilol should be done gradually (see section 4.4).
Methods of administration
The tablets should be taken with the adequate supply of fluid. 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.

4.3

Contraindications
Hypersensitivity to the carvedilol or to any of the excipients of Carvedilol .
Heart failure belonging to NYHA Class IV of the heart failure classification
with marked fluid retention or overload requiring intravenous inotropic
treatment.
Chronic obstructive pulmonary disease with bronchial obstruction (see
section 4.4).
Clinically significant hepatic dysfunction.
Bronchial asthma.
AV block, degree II or III (unless a permanent pacemaker is in place).
Severe bradycardia (<50 bpm).
Sick sinus syndrome (incl. sino-atrial block).
Cardiogenic shock.
Severe hypotension (systolic blood pressure below 85 mmHg).
Prinzmetal's angina.
Untreated phaeochromocytoma.
Metabolic acidosis.
Severe peripheral arterial circulatory disturbances.

Concomitant intravenous treatment with verapamil or diltiazem (see section
4.5).

4.4

Special warnings and precautions for use
Warnings to be considered particularly in heart failure patients
In chronic heart failure patients carvedilol should be administered principally
in addition to diuretics, ACE inhibitors, digitalis and/or vasodilators. Initiation
of therapy should be under the supervision of a hospital physician. Therapy
should only be initiated, if the patient is stabilized on conventional basic
therapy for at least 4 weeks. 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. At the start of therapy or
during up-titration of Carvedilol worsening of heart failure or fluid retention
may occur. In these cases, the dose of diuretic should be increased. However,
sometimes it will be necessary to reduce or withdraw Carvedilol medication.
The carvedilol dose should not be increased before symptoms due to the
worsening of heart failure or hypotension due to vasodilatation are under
control.
Reversible deterioration of renal function has been observed during carvedilol
therapy in heart failure patients with low blood pressure (systolic < 100 mm
Hg), ischaemic heart disease and generalized 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.
In patients with chronic heart failure treated with digitalis, carvedilol should
be given with caution, as digitalis and carvedilol both lengthen the AV
conduction time (see section 4.5).
Other warnings as regards carvedilol and beta-blockers in general
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.
Patients with a chronic obstructive pulmonary disease with a tendency towards
bronchospasms who are not treated with oral or inhalation medicine should

only be given carvedilol if the expected improvement outweighs the possible
risk. Patients should be monitored closely in the initial phase, and titration of
carvedilol and carvedilol dose should be reduced in case of bronchospasms.
Carvedilol may mask symptoms and signs of acute hypoglycaemia. Impaired
blood glucose control may occasionally occur in patients with diabetes
mellitus and 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, especially during dose titration, and
adjustment of antidiabetic medication as necessary (see section 4.5). Blood
glucose levels should also be closely monitored after a longer period of
fasting.
Carvedilol may mask features (symptoms and signs) of thyrotoxicosis.
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.
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 section 4.5).
Cimetidine should be administered only with caution concomitantly as effects
of carvedilol may be increased (see section 4.5).
Persons wearing contact lenses should be advised of a possible reduction of
the secretion of lacrimal fluid.
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. Cautions should be exercised
when prescribing beta-blockers to patients with psoriasis since skin reactions
may be aggravated.
Carvedilol should be used with caution in patients with peripheral vascular
diseases, as beta-blockers may aggravate symptoms of the disease. The same
also applies to those with Raynaud s syndrome, as there may be exacerbation
or aggravation of symptoms.
Patients who are known as poor metabolizers of debrisoquine, should be
closely monitored during initiation of therapy (see section 5.2).
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 1-receptor antagonist or 2-receptor agonist.

In patients with phaeochromocytoma, an initial treatment with alpha-blockers
should be started before using any beta-blocker. Although carvedilol exercises
alpha and beta blockade there is not sufficient experience in this disease,
therefore caution should be advised in these patients.
Because of its negative dromotropic action, carvedilol should be given with
caution to patients with first degree heart block.
Beta-blockers reduce the risk of arrhythmias at anasthesia, however the risk of
hypotension may be increased as well. Caution should therefore be observed
with the use of certain anaesthetic medicines. Newer studies suggest however,
a benefit of beta-blockers in preventing perioperative cardiac morbidity and
reduction of the incidence of cardiovascular complications.
As with other beta-blockers, carvedilol should not be discontinued abruptly.
This applies in particular to patients with ischaemic heart disease. 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.
Carvedilol contains lactose monohydrate and sucrose. Patients with rare
hereditary problems of galactose intolerance, fructose intolerance, the Lapp
lactase deficiency or glucose-galactose malabsorption, sucrase-isomaltase
insufficiency should not take this medicine.

4.5

Interaction with other medicinal products and other forms of interaction
Antiarrhythmics.
Isolated cases of conduction disturbance (rarely compromised
haemodynamics) have been reported, if oral carvedilol and oral diltiazem
verapamil and/or amiodarone are given concomitantly. As with other betablockers, ECG and blood pressure should be monitored closely when
concomitantly administering calcium-channel-blockers of the verapamil and
diltiazem type due to the risk of AV conduction disorder or risk of cardiac
failure (synergetic effect). Close monitoring should be done in case of coadministration of carvedilol, and amiodarone therapy (oral) or class I
antiarrhythmics. 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, guanfacine
and monoamine oxidase inhibitors (exception MAO-B inhibitors) can lead to

additional decrease in heart rate. And hypotension 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.
Cardiac glycosides.
An increase of steady state digoxin levels by approximately 16% 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.
Other antihypertensive medicines.
Carvedilol may potentiate the effects of other concomitantly administered
antihypertensives (e.g. 1-receptor antagonists) and medicines with
antihypertensive adverse reactions such as barbiturates, phenothiazines,
tricyclic antidepressants, vasodilating agents and alcohol.
Cyclosporin.
The plasma level of cyclosporin is increased when carvedilol is coadministered. It is recommended that cyclosporin concentrations are carefully
monitored.
Antidiabetics including insulin.
The blood sugar-lowering effect of insulin and oral diabetic medicines may be
intensified. Symptoms of hypoglycaemia may be masked. In diabetic patients
regular monitoring of blood glucose levels is necessary.
Clonidine.
In case of withdrawal of both carvedilol and clonidine, carvedilol should be
withdrawn several days before the stepwise withdrawal of clonidine.
Inhalational anaesthetics.
Caution is advised in case of anaesthesia due to synergistic, negative inotrope
and hypotensive effect of carvedilol and certain anaesthetics.
NSAIDs, estrogens and corticosteroids.
The antihypertensive effect of carvedilol is decreased due to water and sodium
retention.
Medicines inducing or inhibiting cytochrome P450 enzymes.

Patients receiving medicines that induce (e.g. rifampicin and barbiturates) or
inhibit (e.g. cimetidine, ketoconazole, fluoxetine, haloperidol, verapamil,
erythromycine) 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.
Sympathomimetics with alpha-mimetic and beta-mimetic effects.
Risk of hypertension and excessive bradycardia.
Ergotamine.
Vasoconstriction increased.
Neuromuscular blocking agents.
Increased neuromuscular block.

4.6

Pregnancy and lactation
Pregnancy
There are no adequate data from the use of carvedilol in pregnant women.
Studies in animals have shown reproductive toxicity (see section 5.3). The
potential risk for humans is unknown.

Beta-blockers reduce placental perfusion which may result in intrauterine fetal
death and immature and premature deliveries. In addition, adverse reactions
(especially hypoglycaemia, hypotension, bradycardia, respiratory depression
and hypothermia) may occur in the fetus and neonate. There is an increased
risk of cardiac and pulmonary complications in the neonate in the postnatal
period. Carvedilol should not be used during pregnancy unless clearly
necessary (that is if the potential benefit for the mother outweighs the potential
risk for the fetus/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.
Lactation
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.

4.7

Effects on ability to drive and use machines
This medicinal product has minor influence on the ability to drive and use
machines. Some individuals may have reduced alertness especially on
initiation and adjustment of medication.

4.8

Undesirable effects
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 ( 1/1,000 to <1/100)
Rare ( 1/10,000 to <1/1,000)
Very rare (<1/10,000), not known (cannot be established from the available
data).
Adverse reactions occur mainly at the beginning of treatment.
Adverse reactions in heart failure patients reported from clinical studies.
Adverse reactions that occurred in heart failure patients, in clinical studies, and
not seen as commonly in subjects who received placebo are listed below.
Cardiac disorders
Common: bradycardia, postural hypotension, hypotension, oedema (including
generalised, peripheral, dependent and genital oedema, oedema of the legs,
hypervolaemia and fluid overload).
Uncommon: syncope (including presyncope), AV-block and aggravation of
heart insufficiency during up-titration.
Blood and lymphatic system disorder
Rare: thrombocytopenia.
Very rare: leucopenia.
Nervous system disorders
Very common: dizziness*, headache* (usually mild), asthenia (including
fatigue).
Eye disorders
Common: vision abnormalities.

Gastrointestinal disorders
Common: nausea, diarrhoea, and vomiting.
Renal and Urinary disorders
Rare: acute renal failure and renal function abnormalities in patients with
diffuse vascular disease and/or impaired renal function (see section 4.4).
Metabolism and nutrition disorders
Common: weight increase, hypercholesterolemia, hyperglycaemia,
hypoglycaemia and worsening control of blood glucose (in patients with preexisting diabetes mellitus) (see section 4.4).
* Occuring particularly at the start of treatment.
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.
Adverse reactions in patients with hypertension and angina pectoris reported
from clinical studies
The adverse reaction profile in patients with hypertension and angina is similar
to that observed in patients with heart failure. However, the frequency of
adverse reactions is lower in patients with hypertension and angina pectoris.
Cardiac disorders
Common: bradycardia*, postural hypotension*
Uncommon: syncope*, disturbances of peripheral circulation (cold extremities,
PVD, exacerbation of intermittent claudication and Raynauds phenomenon).
AV-block, angina pectoris (including chest pain), symptoms of heart failure
and peripheral oedema.
Blood and lymphatic system disorders
Very rare: Increase of ALAT, ASAT and gamma-GT, thrombocytopenia,
leucopenia.
Nervous system disorder
Common: dizziness*, headaches* and fatigue*
Uncommon: paraesthesia
Eye disorder
Common: reduced lacrimation (in particular in patients wearing contact
lenses), eye irritation
Uncommon: disturbed vision.
Respiratory disorders:
Common: asthma and dyspnoea in predisposed patients.
Rare: stuffy nose.

Gastrointestinal disorders
Common: nausea, abdominal pain, diarrhoea
Uncommon: constipation and vomiting.
Rare: dryness of the mouth
Renal and urinary disorders
Rare: disturbances of micturition
Skin and subcutaneous disorders
Uncommon: skin reactions (e.g. allergic exanthema, dermatitis, urticaria,
pruritus, lichen planus-like reactions, and increased sweating). Psoriatic skin
lessions may occur or existing lesions exacerbated.
Musculoskeletal and connective tissue disorders
Common: pain in the extremeties
General disorders and administration site conditions
Isolated cases of allergic reactions
Reproductive system and breast disorders
Uncommon: impotence
Psychiatric disorder
Uncommon: sleep disturbance, depression, hallucination, confusion
Very rare: psychosis
* Occuring particularly at the start of treatment.
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.
The frequency of adverse reactions is not dose dependent, with the exception
of dizziness, visual disturbance, bradycardia and aggravation of heart
insufficiency.

4.9

Overdose
Symptoms
Overdose may cause serious hypotension, bradycardia, heart failure,
cardiogenic shock and cardiac arrest. There may also be respiratory problems,
bronchospasm, vomiting, reduced consciousness and convulsions.
Treatment

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: Atropine: 0.5 - 2 mg intravenously (for treatment of
severe bradycardia). Glucagon: initially 1 - 10 mg intravenously followed if
necessary by a slow infusion of 2 5 mg/hour (in order to maintain
cardiovascular function).
Sympathomimetics according to their efficacy and the patient s weight:
dobutamine, isoprenaline or adrenaline.
If peripheral vasodilatation is the dominant symptom of overdose, the patient
has to be given noradneraline or etilefrine. The patient s circulation must be
monitored continuously.
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. If the patient
has convulsions, diazepam 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 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: C07A G02
Carvedilol is a vasodilatory non-selective beta-blocker, which reduces the
peripheral vascular resistance by selective alpha1-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
beta1-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 betablockers, are rarely seen. In hypertensive patients carvedilol increases the
plasma norepinephrine concentration.
In prolonged treatment of patients with angina, carvedilol has been seen to
have an anti-ischaemic effect and to alleviate pain. Haemodynamic studies
demonstrated that carvedilol reduces ventricular pre- and after-load. In
patients with left ventricular dysfunction or congestive heart failure, carvedilol
has a favourable effect on haemodynamics and left ventricular ejection
fraction and dimensions.
Carvedilol has no negative effect on the serum lipid profile or electrolytes. The
ratio of HDL (high-density lipoproteins) and LDL (low-density lipoproteins)
remains normal.

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 a
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 2l/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
Carvedilol demonstrated no mutagenic or carcinogenic potential.
High doses of carvedilol impaired fertility and affected pregnancy in rats
(increased resorptions). Decreased fetal weight and delayed skeletal
development were also seen in rats. Embryotoxicity (increased postimplantation loss) occurred in rats and rabbits.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tablet Core
Lactose monohydrate
Silica Colloidal anhydrous
Crospovidone (Type A)
Crospovidone (Type B)
Povidone 30
Sucrose
Magnesium stearate
Film-coating
Macrogol 400
Polysorbate 80
Titanium dioxide (E171)
Hypromellose

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
2 years

6.4

Special precautions for storage
Store below 25 C.

6.5

Nature and contents of container
PVC/PE/PVDC Aluminium blister packs:
Pack sizes: 10, 14, 28, 30, 50, 56, 60, 98 [Carvedilol 6.25 mg and 25 mg only]
and 100 film-coated tablets.
HDPE bottle with white opaque polypropylene stock ribbed closure:
Pack sizes: 30 and 1000 film-coated tablets.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER
Pfizer Limited

Ramsgate Road
Sandwich
Kent CT13 9NJ
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 00057/1073

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
29 / 04 / 2010

10

DATE OF REVISION OF THE TEXT
06/10/2011

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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