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

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 NYHA-class, 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)
Carvidol 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.

• Hypersensitivity to the carvedilol or to any of the excipients of Carvedilol listed in section 6.1. • 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).

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
carvedilol. Carvedilol should be permanently discontinued in patients who experience
severe cutaneous adverse reactions possibly attributable to carvedilol.
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).

ersons 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 betablockers
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 α1-receptor antagonist or α2-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.

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 beta-blockers, 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 co-administration 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.
α1-receptor antagonists) and medicines with antihypertensive adverse reactions such as
barbiturates, phenothiazines, tricyclic antidepressants, vasodilating agents and alcohol.

Cyclosporin.
Modest increases in mean trough cyclosporine concentrations were observed following the
initiation of carvedilol treatment in 21 renal transplant patients suffering from chronic vascular rejection. In about 30% of patients, the dose of cyclosporine had to be reduced in order to
maintain cyclosporine concentrations with the therapeutic range, while in the remainder no
adjustment was needed. On average, the dose of cyclosporine was reduced about 20% in these
patients. Due to wide interindividual variability in the dose adjustments required, it is
recommended that cyclosporine concentrations be monitored closely after initiation of carvedilol
therapy and that the dose of cyclosporine be adjusted as appropriate.

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.
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 patients
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.

Sympathomimetics with alpha-mimetic and beta-mimetic effects.
Risk of hypertension and excessive bradycardia.
Ergotamine.
Vasoconstriction increased.
Neuromuscular blocking agents.
Increased neuromuscular block.

Pregnancy
Pregnancy category: C
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.

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

a) Summary of the safety profile
The frequency of adverse reactions is not dose-dependent, with the exception of dizziness,
abnormal vision and bradycardia.
(b) Tabulated list of adverse reactions
The risk of most adverse reactions associated with carvedilol is similar across all indications.
Exceptions are described in subsection (c).
Frequency categories are as follows:
Very common ≥ 1/10
Common ≥ 1/100 and < 1/10
Uncommon ≥ 1/1,000 and < 1/100
Rare ≥ 1/10,000 and < 1/1,000
Very rare < 1/10,000
Infections and infestations
Common: Bronchitis, pneumonia, upper respiratory tract infection, urinary tract infection
Blood and lymphatic system disorders
Common: Anaemia
Rare: Thrombocytopaenia
Very rare: Leukopenia
Immune system disorders
Very rare: Hypersensitivity (allergic reaction)
Metabolism and nutrition disorders
Common: Weight increase, hypercholesterolaemia, impaired blood glucose control
(hyperglycaemia, hypoglycaemia) in patients with pre-existing diabetes, Hyperkalaemia.

Psychiatric disorders
Common: Depression, depressed mood
Uncommon: Sleep disorders, confusion
Nervous system disorders
Very common: Dizziness, headache
Uncommon: Presyncope, syncope, paraesthesia
Eye disorders
Common: Visual impairment, lacrimation decreased (dry eye), eye irritation
Cardiac disorders
Very common: Cardiac failure
Common: Bradycardia, oedema, hypervolaemia, fluid overload
Uncommon: Atrioventricular block, angina pectoris
Vascular disorders
Very common: Hypotension
Common: Orthostatic hypotension, disturbances of peripheral circulation (cold extremities,
peripheral vascular disease, exacerbation of intermittent claudication and Reynaud's
phenomenon)
Respiratory, thoracic and mediastinal disorders
Common: Dyspnoea, pulmonary oedema, asthma in predisposed patients
Rare: Nasal congestion
Gastrointestinal disorders
Common: Nausea, diarrhoea, vomiting, dyspepsia, abdominal pain
Rare: dry mouth
Hepatobiliary disorders

Very rare: Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and
gammaglutamyltransferase (GGT) increased
Skin and subcutaneous tissue disorders
Very rare: Severe cutaneous adverse reactions (Toxic epidermal necrolysis,
Stevens-Johnson syndrome (see section 4.4 Warnings and Precautions)
Uncommon: Skin reactions (e.g. allergic exanthema, dermatitis, urticaria, pruritus, psoriatic and
lichen planus like skin lesions and increased sweating), alopecia
Musculoskeletal and connective tissue disorders
Common: Pain in extremities
Renal and urinary disorders
Common: Renal failure and renal function abnormalities in patients with diffuse vascular disease
and/or underlying renal insufficiency, micturition disorders
Very rare: Urinary incontinence in women
Reproductive system and breast disorders
Uncommon: Erectile dysfunction
General disorders and administration site conditions
Very common: Asthenia (fatigue)
Common: Pain
(c) Description of selected adverse reactions
Dizziness, syncope, headache and asthenia are usually mild and are more likely to occur at the
beginning of treatment.
In patients with congestive heart failure, worsening cardiac failure and fluid retention may occur
during up-titration of carvedilol dose (see section 4.4).
Cardiac failure is a commonly reported adverse event in both placebo and carvedilol-treated
patients (14.5% and 15.4% respectively, in patients with left ventricular dysfunction following
acute myocardial infarction).
Reversible deterioration of renal function has been observed with carvedilol therapy in chronic
heart failure patients with low blood pressure, ischaemic heart disease and diffuse vascular disease and/or underlying renal insufficiency (see section 4.4).
As a class, beta-adrenergic receptor blockers may cause latent diabetes to become manifest,
manifest diabetes to be aggravated, and blood glucose counter-regulation to be inhibited.
Carvedilol may cause urinary incontinence in women which resolves upon discontinuation of the
medication.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization 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:

To report any side effect(s):
The National Pharmacovigilance and Drug Safety Centre (NPC)
o Fax: +966-11-205-7662
o Call NPC at +966-11-2038222, Exts: 2317-2356-2340.
o Reporting hotline: 19999.
o E-mail: npc.drug@sfda.gov.sa
o Website: www.sfda.gov.sa/npc

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 generalized seizures.
Treatment
In addition to general supportive treatment, the vital parameters must be monitored and
corrected, if necessary, under intensive care conditions.
Atropine can be used for excessive bradycardia, while to support ventricular function intravenous
glucagon, or sympathomimetics (dobutamine, isoprenaline) are recommended. If positive
inotropic effect is required, phosphodiesterase inhibitors (PDE) should be considered. If
peripheral vasodilation dominates the intoxication profile then norfenephrine or noradrenaline
should be administered with continuous monitoring of the circulation. In the case of drugresistant
bradycardia, pacemaker therapy should be initiated.

For bronchospasm, β-sympathomimetics (as aerosol or intravenous) should be given, or
aminophylline may be administered intravenously by slow injection or infusion. In the event of
seizures, slow intravenous injection of diazepam or clonazepam is recommended.
Carvedilol is highly protein-bound. Therefore, it cannot be eliminated by dialysis.
In cases of severe overdose with symptoms of shock, supportive treatment must be continued for
a sufficiently long period, i.e. until the patient's condition has stabilised, as a prolongation of
elimination half-life and redistribution of carvedilol from deeper compartments are to be
expected.

Pharmacotherapeutic group: Alpha and beta blocking agents..
ATC code: C07AG02
Carvedilol is a vasodilatory non-selective beta-blocker, which reduces the peripheral vascular
resistance by selective alpha 1- receptor blockade and suppresses the renin-angiotensin system
through non-selective beta-blockade. Plasma renin 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 alphaadrenergic
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 beta-blocking agents. Heart rate is
slightly decreased. Stroke volume remains unchanged. Renal blood flow and renal function
remain normal, as does peripheral blood flow, therefore, cold extremities, often observed with
beta-blockers, are rarely seen. In hypertensive patients carvedilol increases the plasma
norepinephrine concentration.
In prolonged treatment of patients with angina, carvedilol has been seen to have an antiischaemic
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.

Absorption
Carvedilol is rapidly absorbed after oral administration. In healthy subjects, maximum serum
concentration is achieved approximately 1 hour after administration. The absolute bioavailability
of carvedilol in humans is approximately 25%.
There is a linear relationship between dose and serum concentrations of carvedilol. Food intake
did not affect the bioavailability or the maximum serum concentration, although the time needed
to reach maximum serum concentration is prolonged.
Distribution
Carvedilol is highly lipophilic. The plasma protein binding is about 98 to 99%. The volume of
distribution is approximately 2 l / kg and increases in patients with liver cirrhosis.
Metabolism
In humans and in animal species studied, carvedilol is extensively metabolized to several
metabolites which are excreted primarily in bile. The first pass effect after oral administration is
about 60-75%. The enterohepatic circulation of the parent substance was demonstrated in
animals.
Carvedilol is extensively metabolized in the liver, glucuronidation being one of the main
reactions. The demethylation and hydroxylation at the phenol ring produce 3 active metabolites
with blocking activity of beta-adrenergic receptors.
According to preclinical studies, the beta-blocking activity of the metabolite 4 - hydroxyphenol is
approximately 13 times higher than that of carvedilol. The three active metabolites have a weak
vasodilating activity, compared with carvedilol. In humans, their concentrations are about 10
times lower than the parent substance. Two of the carbazole-hydroxy metabolites are extremely
potent antioxidants, showing a potency 30-80 times that of carvedilol. Elimination
The average half-life of elimination of carvedilol is approximately 6 hours. The plasma clearance
is approximately 500-700 ml / min. Elimination is mainly via the bile, and excretion mainly via
the faeces. A minor part is eliminated renally in the form of various metabolites.
Pharmacokinetics in Special Populations
Patients with renal impairment
In some of the hypertensive patients with moderate to severe renal impairment (creatinine
clearance < 30 ml/min), an increase in plasma carvedilol concentrations of approximately 40-50
% was seen compared to patients with normal renal function. Peak plasma concentrations in
patients with renal insufficiency increased also by an average of 10-20 %. However, there was a
large variation in the results. Since carvedilol is primarily excreted via the faeces, significant
accumulation in patients with renal impairment is unlikely.
In patients with moderate to severe renal impairment there is no need to modify carvedilol
dosage (see section 4.2).
Patients with liver failure
In patients with liver cirrhosis, the systemic availability of carvedilol is increased 80% due to
reduced first pass effect. Therefore, carvedilol is contraindicated in patients with clinically
manifest hepatic impairment (see section 4.3 Contraindications).
Use in elderly
Age had a statistically significant effect on pharmacokinetic parameters of carvedilol in
hypertensive patients. A study in elderly hypertensive patients showed no difference between the
adverse event profile of this group and younger patients. Another study involving elderly patients
with coronary artery disease showed no difference in reported adverse reactions vs. those that
were reported by younger patients.
Use in pediatrics
The available information on pharmacokinetics in subjects younger than 18 years is limited.
Diabetic patients
In hypertensive patients with type 2 diabetes was not observed effect of carvedilol on blood
glucose (fasting or postprandial) and glycosylated haemoglobin A1, it was not necessary to
change the dose of antidiabetic drugs.
In patients with type 2 diabetes, carvedilol had no statistically significant influence on the glucose tolerance test. In nondiabetic hypertensive patients with altered insulin sensitivity
(Syndrome X), carvedilol increased insulin sensitivity. The same results were observed in
hypertensive patients with type 2 diabetes.
Heart failure
In a study in 24 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.

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 post-implantation loss) occurred in rats and rabbits.

Lactose Maize Starch Microcrystalline Cellulose (Avicel pH 102) Low-Substituted Hydroxypropyl Cellulose Colloidal Silicon Dioxide Magnesium Stearate Purified Talc Iron Oxide Red

Not applicable

For Carvidol 25 mg: 48Months/4Years For Carvidol 6.25 & 12.5 mg: 36 month /3 years

Store below 25°C

Package size: 30 tablets

No Special Disposal