Carvedilol Krka 25 mg Tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

Buy It Now

Active ingredient:
Carvedilol
Available from:
Krka d.d., Novo mesto
ATC code:
C07AG; C07AG02
INN (International Name):
Carvedilol
Dosage:
25 milligram(s)
Pharmaceutical form:
Tablet
Prescription type:
Product subject to prescription which may be renewed (B)
Therapeutic area:
Alpha and beta blocking agents; carvedilol
Authorization status:
Marketed
Authorization number:
PA1347/037/004
Authorization date:
2003-08-22

Package leaflet: Information for the patient

Carvedilol Krka 3.125 mg tablets

Carvedilol Krka 6.25 mg tablets

Carvedilol Krka 12.5 mg tablets

Carvedilol Krka 25 mg tablets

Carvedilol

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in

this leaflet

What Carvedilol Krka is and what it is used for

What you need to know before you take Carvedilol Krka

How to take Carvedilol Krka

Possible side effects

How to store Carvedilol Krka

Contents of the pack and other information

1.

What Carvedilol Krka is and what it is used for

Carvedilol Krka contains a medicine called carvedilol. This belongs to a group of medicines called

‘betablockers’.

Carvedilol Krka 3.125 mg and 6.25 mg tablets are used to treat the following:

Congestive heart failure.

High blood pressure (hypertension).

Carvedilol Krka 12.5 mg and 25 mg tablets are used to treat the following:

Congestive heart failure.

High blood pressure (hypertension).

Angina (chest pain or discomfort that happens when your heart isn’t getting enough oxygen).

Carvedilol Krka works by making your blood vessels relax and widen.

This helps to lower your blood pressure.

If you have congestive heart failure, this makes it easier for your heart to pump blood around your

body.

If you have angina, this will help stop the chest pain.

Your doctor may give you other medicines as well as Carvedilol Krka to help treat your condition.

2.

What you need to know before you take Carvedilol Krka

Do not take Carvedilol Krka:

if you are allergic (hypersensitive) to carvedilol or any of the

other ingredients of this medicine

(listed in section 6).

if your heart failure has worsened recently (you have severe fluid retention and are breathless,

even when sitting) and you are receiving intravenous medication to help your heart work.

if you have a history of wheezing due to asthma.

if you have liver disease.

if you have a conduction defect of the heart (or ‘heart block’).

if you have a slow heartbeat (less than 50 beats per minute).

if you have sick sinus sydrome (irregular heartbeat).

if you suffer from cardiogenic shock (a state in which a weakened heart is unable to pump

enough blood to meet the body’s needs).

if you have very low blood pressure (systolic blood pressure below 85 mm Hg).

If any of the above apply to you, consult your doctor or pharmacist before taking Carvedilol Krka.

Warnings and precautions

Check with your doctor or pharmacist before taking Carvedilol Krka if:

you have a condition called Prinzmetal's angina (cardiac chest pain that occurs at rest)

you suffer from any other heart problems.

you have lung disease (this includes asthma and chronic obstructive pulmonary disease). This

medicine may cause wheezing or spasm in the lung.

you have had any problems with your liver, kidneys or thyroid.

you have diabetes (high blood sugar). Symptoms of low blood sugar may be masked if you are

taking carvedilol.

you have a skin condition known as psoriasis, after taking beta-blocker medicines.

you have a circulation disorder (usually affecting the fingers) called Raynaud's phenomenon.

you have an allergy and are having treatment to desensitize you.

you have ever had a serious allergic reaction (for example, sudden swelling causing difficulty

breathing or swallowing, swelling of the hands, feet or ankles, or a severe rash).

you wear contact lenses (you may notice that your eyes become drier than usual).

you have problems with your blood vessels (peripheral vascular disease).

you have phaeochromocytoma (a tumour of the adrenal gland causing high blood pressure). An

initial treatment with appropriate medicines (alpha-blockers) should be started before using any

beta-blocker.

Other medicines and Carvedilol Krka

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other

medicines.

Be sure to advise if you are taking any of the following medicines:

calcium channel blockers e.g. verapamil or diltiazem (for irregular heartbeat)

antiarrhythmics, e.g. amiodarone (for irregular heartbeat)

any other medicine that may additionally decrease the heart rate, e.g. reserpine

medicines known as monoamine oxidase inhibitors e.g. isocarboxide and phenelzine (for

depression)

fluoxetine and paroxetine (used to treat depression)

digoxin (for heart failure)

medicines for your blood pressure, including diuretics (water tablets) (Carvedilol Krka may

intensify the effect of these medicines)

antidiabetic medicines (metformin) or insulin (Carvedilol Krka may intensify the effects of

these medicines)

clonidine (for migraine, menopausal flushing, high blood pressure or Tourette’s syndrome)

ciclosporin (for preventing rejection of a transplanted organ)

rifampicin (used to treat bacterial infections, including tuberculosis)

non-steroidal anti-inflammatory drugs (NSAIDs)

beta-agonist bronchodilators (used to treat chest tightness and wheezing due to asthma or other

chest conditions).

Operations

Tell your hospital doctor you are taking carvedilol if you need to have an anaesthetic for surgery.

Beta-blockers reduce the risk of arrhythmias during anaesthesia; however, the risk of hypotension (low

blood pressure) may be increased.

Carvedilol Krka with food and drink

Take the tablets with a drink of water, without chewing or crushing them. Patients with congestive

heart failure should take Carvedilol Krka with food.

Pregnancy, fertility and breast-feeding

Ask your doctor or pharmacist for advice before taking any medicine. If you are pregnant, trying to get

pregnant or breast feeding,

do not take

this medicine until you have talked to your doctor. Consult

your doctor immediately if you become pregnant while taking this medicine.

Driving and using machines

If you feel tired or dizzy while taking your tablets, you should not drive or operate machinery. This is

more likely when you start treatment or if your treatment is changed, and when you drink alcohol.

Consumption of alcohol should be avoided, as these symptoms may be made worse. If this happens to

you, do not drive or use any tools or machines. Talk to your doctor if you notice any other problems

that might affect driving, using tools or machines while you are taking Carvedilol Krka.

Carvedilol Krka contains lactose and sucrose

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor

before taking this medicinal product.

3.

How to take Carvedilol krka

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor

or pharmacist if you are not sure.

Carvedilol Krka 3.125 mg, 6.25 mg, 12.5 mg and 25 mg tablets are used to treat High blood pressure

and Congestive heart failure:

High blood pressure:

In patients with high blood pressure, the recommended maximum single dose is 25 mg and the

recommended maximum daily dose is 50 mg.

Adults:

The usual starting dose is 12.5 mg once a day for the first two days, increasing to 25 mg once a day. If

necessary, your doctor may gradually increase the dose further at intervals of two weeks or more.

Elderly:

Your doctor will usually start you on 12.5 mg a day and continue with this dose for the length of your

treatment. However, if necessary, your doctor may gradually increase your dose at intervals of two

weeks or more.

Congestive heart failure:

Adults and elderly

While taking Carvedilol Krka, make sure that you continue with your other treatments for

heart failure as advised by your doctor.

In heart failure patients, treatment with Carvedilol Krka is recommended to be started and supervised

by a hospital specialist.

The tablets should be taken twice a day – in the morning and in the evening.

The usual starting dose is one 3.125 mg tablet twice a day for two weeks.

Your doctor will then increase the dose slowly, over several weeks, up to 25 mg twice a day.

For patients with a body weight of less than 85 kg, the recommended maximum single dose is 25 mg

and the recommended maximum daily dose is 50 mg.

For patients with a body weight above 85 kg, the recommended maximum single dose is 50 mg and

the recommended maximum daily dose is 100 mg.

Carvedilol Krka 12.5 mg and 25 mg tablets are used to treat Angina:

Angina:

Adults

The usual starting dose is 12.5 mg twice a day for two days.

After two days the dose is usually 25 mg, twice a day.

If your angina is not under control, your doctor may increase your dose slowly, over several weeks up

to 50 mg twice a day.

Elderly

Your doctor will decide both your starting dose and the best dose for you to take in the longer term.

The usual maximum dose is 50 mg each day, taken in smaller amounts (divided doses).

Patients with kidney problems

Dose adjustment may be required, depending on your blood pressure. Your doctor will decide which

dose is best suited for you.

Patients with liver disease

Carvedilol Krka should not be taken by patients with liver problems.

Patients undergoing surgery

Tell your hospital doctor you are taking Carvedilol Krka if you need to have an anaesthetic for

surgery. This is because some anaesthetics can lower your blood pressure and it may become too low.

Use in children and adolescents

Carvedilol Krka tablets are not recommended for use in children under 18 years of age.

If you take more Carvedilol Krka than you should

If you accidentally take too many tablets (overdose), you or someone else should contact your nearest

hospital casualty department or tell your doctor immediately.

The following effects may happen if you have taken more tablets than you should: being sick, a slow

heartbeat or even sudden cessation of heart beating, feeling dizzy or light headed, becoming

breathless, convulsions (a person's body shakes rapidly and uncontrollably), feeling wheezy or

extremely tired.

In cases of severe overdose, urgent treatment in a hospital Intensive Care Unit is necessary.

Duration of the antidote treatment depends on the seriousness of the overdose; supportive treatment

must be continued until the patient stabilises.

If you forget to take Carvedilol Krka

Do not take a double dose to make up for a forgotten tablet. Take another as soon as you remember.

Take your next tablet at the normal time but do not take a double dose to make up for a forgotten

tablet.

If you stop taking Carvedilol Krka

You should always consult with your doctor before stopping Carvedilol Krka treatment. You should

not stop Carvedilol Krka treatment abruptly as this can temporarily make your condition worse. Your

doctor may want you to stop taking Carvedilol Krka slowly over a period of two weeks.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. The

possible side effects and how likely you are to get them will depend on the reason you are being

treated with Carvedilol Krka.

If you experience any of the following, contact your doctor or go to a hospital immediately:

Severe allergic reactions.

Signs may include sudden swelling of the throat, face, lips and mouth. This

may make it difficult to breathe or swallow.

Chest pains

accompanied by shortness of breath, sweating and feeling sick.

Passing water (urinating) less often

with swelling of legs, indicating problems with your kidneys.

Very low blood sugar (hypoglycaemia)

which might cause seizures or unconsciousness.

Skin reactions Very rarely, severe skin conditions (erythema multiforme, Stevens-Johnson syndrome

and toxic epidermal necrolysis) can occur. Redness, often associated with blisters may appear on the

skin or mucous membranes, such as the inside of the mouth, the genital areas or the eyelids. These can

appear initially as circular patches often with central blisters, which may progress to widespread

peeling of the skin and can be life threatening. These serious skin reactions are often preceded by

headache, fever and body aches (flu-like symptoms).

Very common (affect more than 1 in 10 people):

Feeling dizzy.

Headache.

Feeling weak and tired.

Problems with your heart. The signs include chest pains, tiredness, shortness of breath and

swelling of your arms and legs.

Low blood pressure. The signs include feeling dizzy or lightheaded.

Feeling dizzy, having a headache and feeling weak and tired are usually mild and more likely to

happen at the beginning of your treatment.

Common (affect less than 1 in 10 people):

Infections of the airway (bronchitis), lung (pneumonia), nose and throat (upper respiratory

tract). The signs include wheezing, shortness of breath, chest tightness and sore throat.

Infections of the urinary tract which can cause problems in passing water.

Low numbers of red blood cells (anaemia). The signs include feeling tired, pale skin, a

fluttering sensation in your heart (palpitations) and being short of breath.

Increase in weight.

Increase in cholesterol levels (shown by a blood test).

Loss of control of blood sugar in people with diabetes.

Feeling depressed.

Problems with your sight, sore or dry eyes due to fewer tears being made.

A slow heart beat.

Feeling dizzy or light-headed after standing up.

Fainting.

Fluid retention. The signs include: overall swelling of your body, swelling of parts of your

body, for example your hands, feet, ankles and legs, and an increase in how much blood you

have in your body.

Problems with blood circulation in your arms and legs. The signs include cold hands and feet,

whiteness, tingling and pain in your fingers and a pain in your leg which gets worse when you

walk.

Breathing problems or asthma.

Fluid build-up in the lungs (pulmonary oedema).

Feeling sick or being sick.

Diarrhoea.

Stomach pain/indigestion.

Pain, possibly in your hands and feet.

Problems with your kidneys, including changes to how often you pass urine.

Uncommon (affect less than 1 in 100 people):

Disturbed sleep.

Tingling or numbness of your hands or feet.

Chest pain (angina pectoris).

Heart failure.

Problems with your skin, including skin rashes which may cover a lot of your body, a lumpy

rash (hives), feeling itchy and dry skin patches.

Hair loss.

Being unable to get an erection (erectile dysfunction).

Constipation.

Rare (affect less than 1 in 1,000 people):

Low number of platelets in your blood. The signs include bruising easily and nose bleeds.

A stuffy nose, wheezing and flu-like symptoms.

A dry mouth.

Very rare (affect less than 1 in 10,000 people):

Low numbers of all types of white blood cells. The signs include infections of the mouth, gums,

throat and lungs.

Allergic (hypersensitivity) reactions. The signs may include difficulty breathing or swallowing

caused by sudden swelling of the throat, or face or swelling of your hands, feet and ankles or

severe skin reactions.

Changes in liver function which show up in a blood test.

Some women may have difficulty with bladder conotrol when they pass water (urinary

incontinence). This normally will get better when treatment is stopped.

Carvedilol Krka can also cause development of the signs of diabetes in people who have a very mild

form of diabetes called ‘latent diabetes’.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet. You can also report side effects directly via HPRA Pharmacovigilance,

Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517; Website: www.hpra.ie,

e-mail: medsafety@hpra.ie

By reporting side effects you can help provide more information on the safety of this medicine.

5.

How to store Carvedilol krka

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the package and blister. The expiry

date refers to the last day of that month.

Store in the original package.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Carvedilol Krka contains

The active substance is carvedilol. Each tablet contains 3.125 mg, 6.25 mg, 12.5 mg or 25 mg tablet.

The other ingredients are sucrose, lactose monohydrate, povidone K25, colloidal anhydrous silica,

crospovidone and magnesium stearate.

What Carvedilol Krka looks like and contents of the pack

Carvedilol Krka 3.125 mg tablets are round, slightly biconvex white bevel-edged tablets.

Carvedilol Krka 6.25 mg tablets are oval, slightly biconvex white tablets, marked with S2 on one side

and scored on the reverse.

Carvedilol Krka 12.5 mg tablets are oval, slightly biconvex white tablets, marked with S3 on one side

and scored on the reverse.

Carvedilol Krka 25 mg tablets are round, slightly biconvex white bevel-edged tablets, scored on one

side.

Carvedilol Krka is supplied in packs of 28 tablets.

Marketing Authorisation Holder and Manufacturer

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

This leaflet was last revised in

Health Products Regulatory Authority

18 October 2019

CRN008JX7

Page 1 of 12

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Carvedilol Krka 25 mg Tablets.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One tablet contains 25 mg carvedilol.

Excipients: Each tablet contains 85 mg lactose monohydrate and 60 mg sucrose.

For a full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Tablets.

Appearance:

Round, slightly biconvex, white bevel edged tablet scored on one side.

The tablet can be divided into two equal halves.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Adjunctive therapy for the treatment of symptomatic congestive heart failure to reduce morbidity and increase patient

well-being.

Treatment of hypertension.

Long-term management of stable angina pectoris.

4.2 Posology and method of administration

Posology

Symptomatic congestive heart failure

The dosage must be titrated to individual requirements and patients' clinical status should be monitored for 2 - 3 hours after

initiation and any dose increase 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 Krka 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 in patients weighing less than 85 kg (187 lbs) and 50 mg twice

daily in patients weighing more than 85 kg. During up-titration of the dose in patients with systolic blood pressure < 100

mmHg, 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 Krka treatment. Under these circumstances, the dose of Carvedilol Krka should not be

increased until symptoms of worsening heart failure or vasodilation have been stabilised.

If Carvedilol Krka is discontinued for more than two weeks, therapy should be recommenced at 3.125 mg twice daily and

uptitrated in line with the above dosing recommendation.

Elderly

Health Products Regulatory Authority

18 October 2019

CRN008JX7

Page 2 of 12

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 of age have 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. If necessary, the dose may be titrated up to 50mg twice a day. Dose titration should occur at

intervals of at least two weeks.

Elderly

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 co-existing hepatic disease

Carvedilol Krka is contra-indicated in patients with hepatic dysfunction (see sections 4.3 and 5.2).

Patients with co-existing renal dysfunction

No dose adjustment is anticipated as long as systolic blood pressure is above 100 mmHg (see also sections 4.4 and 5.2).

Method of administration

The tablets should be taken with fluid. For CHF patients Carvedilol Krka should be given with food to slow the rate of

absorption and reduce the incidence of orthostatic effects.

4.3 Contraindications

Carvedilol Krka is contra-indicated in patients with:

hypersensitivity to carvedilol or to any of the excipients listed in section 6.1,

unstable/decompensated heart failure requiring intravenous inotropic support,

clinically manifest liver dysfunction,As with other beta-blocking agents:

history of bronchospasm or asthma,

2nd and 3rd degree atrioventricular A-V heart block (unless a permanent pacemaker is in place),

severe bradycardia (<50 bpm),

cardiogenic shock,

sick sinus syndrome (including sino-atrial block),

Health Products Regulatory Authority

18 October 2019

CRN008JX7

Page 3 of 12

severe hypotension (systolic blood < 85 mmHg).

4.4 Special warnings and precautions for use

Chronic Congestive Heart Failure

In congestive heart failure patients, worsening cardiac failure or fluid retention may occur during up-titration of carvedilol. If

such symptoms occur, diuretic should be increased and the carvedilol dose should not be further increased 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 Krka should be used with caution in combination with digitalis glycosides, as both drugs slow AV conduction.

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.

Diabetes

Care should be taken in the administration of Carvedilol Krka 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 Krka 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 Krka therapy in chronic heart failure patients with

low blood pressure (systolic BP < 100 mmHg), 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 Krka

and the drug discontinued or dosage reduced if worsening of renal failure occurs.

Contact lenses

Wearers of contact lenses should be advised of the possibility of reduced lacrimation.

Withdrawal syndrome

Carvedilol treatment should not be discontinued abruptly, particularly in patients suffering from ischaemic heart disease. The

withdrawal of Carvedilol Krka should be gradual (over a period of two weeks).

Lactose

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase

deficiency or glucose-galactose malabsorption should not take this medicine.

Sucrose

This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucosegalactose

malabsorption or sucrose-isomaltase insufficiency should not take this medicine.

Peripheral vascular disease and Raynaud's phenomenon

Carvedilol Krka should be used with caution in patients with peripheral vascular disease (e.g. Raynaud's phenomenon). Pure

beta-blockers can precipitate or aggravate symptoms of arterial insufficiency. However, as Carvedilol Krka also has

alpha-blocking properties, this effect is largely counterbalanced.

Thyrotoxicosis

Carvedilol Krka, as with other agents with beta-blocking activity, may mask/obscure the symptoms of thyrotoxicosis.

Bradycardia

If Carvedilol Krka induces bradycardia, with a decrease in pulse rate to less than 55 beats per minute, the dosage of Carvedilol

Krka should be reduced.

Hypersensitivity

Care should be taken in administering Carvedilol Krka 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.

Health Products Regulatory Authority

18 October 2019

CRN008JX7

Page 4 of 12

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 (see section 4.8). Carvedilol should be permanently discontinued in

patients who experience severe cutaneous adverse reactions possibly attributable to carvedilol.

Psoriasis

Patients with a history of psoriasis associated with beta-blocker therapy should be given Carvedilol Krka 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).

Pheochromocytoma

In patients with phaeochromocytoma, an alpha-blocking agent should be initiated prior to the use of any beta-blocking agent.

Although Carvedilol Krka has both α and β-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 Krka 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 Krka in these patients, although the alpha-blocking activity of Carvedilol Krka may

prevent such symptoms. However, caution should be taken in the administration of Carvedilol Krka to patients suspected of

having Prinzmetal's variant angina.

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.

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.

Usage of carvedilol in patients with symptomatic congestive heart failure has not been shown to reduce mortality.

4.5 Interaction with other medicinal products and other forms of interactions

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. 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.

Cyclosporin: Two studies in renal and cardiac transplant patients receiving oral cyclosporin have shown an increase in

cyclosporin plasma concentrations following initiation of carvedilol treatment. It appears that carvedilol increases exposure to

oral ciclosporin by 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 in the dose adjustment required, it is recommended that

Health Products Regulatory Authority

18 October 2019

CRN008JX7

Page 5 of 12

cyclosporin concentrations be monitored closely after initiation of carvedilol therapy and that the dose of cyclosporin be

adjusted as appropriate. In case of IV administration of ciclosporin, no interaction with carvedilol is expected.

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 beta-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 β-blockade activity in patients treated with the combination carvedilol and amiodarone is advised.

Fluoxetine and Paroxetine: In a randomized, cross-over study in 10 patients with heart failure, co-administration of fluoxetine, a

strong inhibitor of CYP2D6, resulted in stereoselective inhibition of carvedilol metabolism with a 77% increase in mean R(+)

enantiomer's AUC, and a non-statistically 35% increase of the S(-) enantiomer's AUC as compared to the placebo group.

However, no differences 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 β-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.

Catecholamine-depleting agents: Patients taking both agents with β-blocking properties and a drug that can deplete

catecholamines (eg reserpine and monoamine oxidase inhibitors) should be observed closely for signs of hypotension and/or

severe bradycardia.

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 co-administered with diltiazem. As with other agents with β-blocking

properties, if carvedilol is to be administered orally with non-dihydropyridinescalcium channel blockers of the verapamil or

diltiazem type, amiodarone or other antiarrhythmics it is recommended that ECG and blood pressure be monitored.

Clonidine: Concomitant administration of clonidine with agents withβ-blocking properties may potentiate bloodpressure- and

heart-rate-lowering effects. When treatment with agents with β-blocking properties and clonidine together is to be terminated,

the β-blocking agent 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 to the synergistic negative inotropic

and hypotensive effects of carvedilol and anaesthetic drugs (see section 4.4).

Antihypertensives: As with other agents with -blocking activity, carvedilol may potentiate the effect of other concomitantly

administered drugs that are antihypertensive in action (e.g. alpha

-receptor antagonists) or have hypotension as part of their

adverse effect profile.

NSAIDs: The concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs) and beta-adrenergic blockers may result in an

increase in blood pressure and impairment of lower blood pressure control.

Health Products Regulatory Authority

18 October 2019

CRN008JX7

Page 6 of 12

Beta-agonist bronchodilators: Non-cardioselective beta blockers oppose the bronchodilator effects of beta-agonist

bronchodilators. Careful monitoring of patients is recommended.

4.6 Fertility, pregnancy and lactation

Pregnancy

There is no adequate experience with Carvedilol Krka 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 Krka should not be used during pregnancy unless the potential benefit outweighs the potential risk.

Beta blockers reduce placental perfusion which may result in intrauterine foetal death and immature and premature deliveries.

In addition, adverse effects (especially hypoglycaemiaand 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).

Breastfeeding

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 β-blockers, in particular lipophilic compounds, will pass into human

breast milk although to a variable extent. Breast feeding is therefore not recommended following administration of carvedilol.

4.7 Effects on ability to drive and use machines

No studies have been performed on the effects of carvedilol on patients' fitness to drive or to operate machinery.

Because of individually variable reactions (e.g. dizziness, tiredness), the ability to drive, operate machinery, or work without firm

support may be impaired. This applies particularly at the start of treatment, after dose increases, on changing products, and in

combination with alcohol.

4.8 Undesirable effects

The following undesirable effects have been reported to occur when carvedilol is administered:

Frequency categories are as follows:

very common ≥1/10;

common ≥ 1/100 to <1/10;

uncommon ≥ 1/1000 to < 1/100;

rare ≥1/10,000 to < 1/1000;

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 mellitus (see section 4.4).

Psychiatric disorders

Common: Depression, depressed mood

Uncommon: Sleep disorders

Health Products Regulatory Authority

18 October 2019

CRN008JX7

Page 7 of 12

Nervous system disorders

Very common: dizziness, headaches

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 and 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), hypertension

Respiratory, thoracic and mediastinal disorders

Common: Dyspnoea, pulmonary oedema, asthma in predisposed patients

Rare: Nasal congestion, flu-like symptoms

Gastro-intestinal disorders

Common: nausea, diarrhoea, dyspepsia, vomiting and abdominal pain.

Uncommon: constipation

Rare: dry mouth

Hepatobiliary disorders

Very rare: Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyltransferase (GGT) increased

Skin and subcutaneous tissue disorders

Uncommon: Skin reactions (e.g. allergic exanthema, dermatitis, urticaria, pruritus, psoriatic and lichen planus like skin lesions),

alopecia

When Carvedilol is taken for Hypertension, Psoriatic skin lesions may occur or existing lesions exacerbated.

Musculoskeletal and connective tissue disorders

Common: Pain in extremities

Renal and urinary disorders

Common: acute renal failure and renal function abnormalities in patients with diffuse vascular disease and/or underlying renal

insufficiency (see section 4.4)

Rare: micturition disorder.

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: Oedema, pain

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 4.4).

Health Products Regulatory Authority

18 October 2019

CRN008JX7

Page 8 of 12

Cardiac failure was a very 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

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 online reporting option (preferred method) accessible from the IMB homepage (www.imb.ie). A

downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the

IMB via 'freepost' (see details below). Alternatively, the traditional post-paid 'yellow card' option may also be used.

FREEPOST

Pharmacovigilance Section

Irish Medicines Board

Kevin O'Malley House

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

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 b-blocker overdose (e.g. atropine,

transvenous pacing, glucagon, phosphodiesterase inhibitor such as amrinone or milrinone, β-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 are to be expected.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: beta- and alpha

-receptor blockers, ATC code: C07 AG02

Health Products Regulatory Authority

18 October 2019

CRN008JX7

Page 9 of 12

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-angiotensinaldosterone

system through beta blockade. The activity of plasma renin is reduced and fluid retention is rare. Some of the limitations of

traditional β-blockers do not appear to be shared by some of the vasodilating β-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 congestive heart failure, carvedilol has demonstrated favourable

effects on haemodynamics and improvements in left ventricular ejection fraction and dimensions.Serum lipid

profile and electrolytes are not affected.

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.

In patients with stable angina, carvedilol has demonstrated anti-ischaemic and anti-anginal properties. Acute haemodynamic

studies demonstrated that carvedilol reduces both cardiac pre-load and after- load with consequent improvement in left

ventricular systolic and diastolic function without substantial changes in the cardiac output.

Carvedilol has no adverse affects on the metabolic risk factors of coronary heart disease. It does not impair the normal serum

lipid profile and in hypertensive patients with dyslipidaemia favourable effects on the serum lipids have been reported after six

months of oral therapy.

In two studies, carvedilol 25mg b.i.d. was compared with other anti-anginal drugs of recognised value in patients with chronic

Health Products Regulatory Authority

18 October 2019

CRN008JX7

Page 10 of 12

stable exertional angina. The dose regimens that were chosen were those widely used in clinical practice. Both trials had a

double-blind, parallel group design. The primary objective was total exercise time (TET).

Report no:

Control (dose)

Patient numbers carvedilol/comparator drug

Duration of treatment

Verapamil (120mg t.i.d.)

126/122

12 weeks

ISDN s.r. (40mg b.i.d.)

93/94

12 weeks

The results of both trials clearly demonstrated that for TET at trough blood drug levels after 12 weeks of therapy there was no

statistically significant difference between treatment groups. However the risk ratios obtained from the Cox proportional

hazards model showed a trend in favour of carvedilol indicating that on average carvedilol was 114% as effective as verapamil

(90% CI: 85-152%) and 134% as effective as ISDN (90%CI: 96-185%). This was also true for time to angina (TTA) and

ST-segment depression (TST) at trough. The increase in TET was about 50 seconds in all groups; the improvements for TTA and

TST were about 30 seconds, which is clinically relevant.

In study 060, 48h Holter monitoring data measurements demonstrated a reduction of number and duration of ST-segment

depressions (silent myocardial ischaemia) in both treatment groups. Carvedilol also decreased premature atrial and ventricular

contractions (PAC, PVC), couplets and runs.

5.2 Pharmacokinetic properties

Absorption

Following oral administration of a 25 mg capsule to healthy subjects, carvedilol is rapidly absorbed with a peak plasma

concentration C

of 21 mg/L reached after approximately 1.5 hour (t

). The C

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 metabolised in the liver via oxidation and conjugation into a variety of various metabolites,

which are mainly eliminated in bile.

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

Health Products Regulatory Authority

18 October 2019

CRN008JX7

Page 11 of 12

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 half-life 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.

5.3 Preclinical safety data

Animal studies revealed no special findings relevant to clinical use (although see section 4.6).

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sucrose

Lactose monohydrate

Povidone K25

Colloidal anhydrous silica

Magnesium Stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 years.

6.4 Special precautions for storage

HDPE container and PP closures: Store in the original container.

Blister (OPA/A1/PVC foil-aluminium foil): Store in the original blister.

6.5 Nature and contents of container

Blister (laminated OPA/A1/PVC foil – aluminium foil) and HDPE containers (PP closure and desiccant insert of PE filled with

silica gel) containing 14, 28, 30, 50, 56, 60, and 100 tablets.

Not all pack sizes may be marketed.

Health Products Regulatory Authority

18 October 2019

CRN008JX7

Page 12 of 12

6.6 Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal

product and other handling of the product

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Krka d.d

Novo mesto

Šmarješka cesta 6

8501 Novo mesto

Slovenia

8 MARKETING AUTHORISATION NUMBER

PA1347/037/004

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 22 August 2003

Date of last renewal: 22 August 2008

10 DATE OF REVISION OF THE TEXT

October 2019

Similar products

Search alerts related to this product

View documents history

Share this information