Dicarz

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Carvedilol 12.5 mg
Available from:
Mylan New Zealand Ltd
INN (International Name):
Carvedilol 12.5 mg
Dosage:
12.5 mg
Pharmaceutical form:
Film coated tablet
Composition:
Active: Carvedilol 12.5 mg Excipient: Colloidal silicon dioxide Crospovidone Lactose monohydrate Magnesium stearate Microcrystalline cellulose Opadry white YS-22-18096 Povidone
Units in package:
Blister pack, PVC/aluminium blister strip - 90 tablets, 90 tablets
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Moehs Catalana SL
Therapeutic indications:
Hypertension Dicarz is indicated for the management of essential hypertension. It can be used alone or in combination with other antihypertensive agents (e.g. calcium channel blockers, diuretics).
Product summary:
Package - Contents - Shelf Life: Blister pack, PVC/aluminium blister strip - 60 tablets - 24 months from date of manufacture stored at or below 25°C - Blister pack, PVC/aluminium blister strip - 90 tablets - 24 months from date of manufacture stored at or below 25°C - Bottle, plastic, HDPE bottle, PP cap with permaseal liner - 90 tablets - 12 months from date of manufacture stored at or below 25°C
Authorization number:
TT50-7240b
Authorization date:
2004-04-29

Page 1 of 5

NEW ZEALAND CONSUMER MEDICINE INFORMATION

DICARZ

Carvedilol Film-coated Tablets

6.25 mg, 12.5 mg & 25 mg

What is in this leaflet

This leaflet answers some common

questions about Dicarz.

It does not contain all the available

information. It does not take the

place of talking to your doctor or

pharmacist.

All medicines have risks and

benefits. Your doctor has weighed

the risks of you taking Dicarz

against the benefits they expect it

will have for you.

If you have any concerns about

taking this medicine, ask your

doctor or pharmacist.

Keep this leaflet with the

medicine. You may need to read it

again.

What Dicarz is used

for

Dicarz is used to treat:

high blood pressure.

angina (a type of severe

chest pain).

heart failure.

heart failure following a

recent heart attack.

It may be used in combination with

other heart medications.

Dicarz contains the active ingredient

carvedilol. It belongs to a group of

medicines called beta blockers.

These medicines work by relaxing

tightened blood vessels and slowing

the rate of your heart beat.

Dicarz is different from conventional

beta blockers as it has additional

effects of being an alpha blocker

and an antioxidant.

This means your heart does not

have to pump as hard to move the

blood around the body. When you

place extra demands on your heart,

such as during exercise, the heart

may cope better so you may not get

short of breath as easily.

Ask your doctor if you have any

questions about why this

medicine has been prescribed for

you.

Your doctor may have prescribed it

for another reason.

This medicine is available only with

a doctor’s prescription.

There is not enough information to

recommend the use of this medicine

for people under the age of 18

years.

Before you take

Dicarz

When you must not take

it

Do not take Dicarz if you have an

allergy to:

any medicine containing

carvedilol.

any of the ingredients listed

at the end of this leaflet.

Some of the symptoms of an

allergic reaction may include:

shortness of breath; wheezing or

difficulty breathing; swelling of the

face, lips, tongue or other parts of

the body; rash, itching or hives on

the skin.

Do not take Dicarz if you have:

asthma or other condition

that makes you short of

breath from time to time

a history of a very slow

heart rate or uneven heart

beating

very low blood pressure

certain other heart

conditions. Your doctor will

know what these conditions

are.

liver problems, including

liver failure.

Do not take this medicine after

the expiry date printed on the

pack or if the packaging is torn or

shows signs of tampering.

If it has expired or is damaged,

return it to your pharmacist for

disposal.

If you are not sure whether you

should start taking this medicine,

talk to your doctor.

Before you start to take

it

Tell your doctor if you have

allergies to any other medicines,

foods, preservatives or dyes.

Tell your doctor if you have or

have had any of the following

medical conditions:

a history of poor kidney

function

lung disease (called chronic

obstructive pulmonary

disease)

low blood pressure

diabetes

very poor circulation to your

fingers and/or toes (called

peripheral vascular disease

or Raynaud’s phenomenon)

thyroid disorders

a history of severe allergic

reactions causing swelling

and/or difficulty breathing

a history of psoriasis when

taking beta-blockers

a rare cancer called

pheochromocytoma

angina or chest

pain/tightness which occurs

even when you are at rest

(called unstable angina).

Page 2 of 5

Tell your doctor if you are

pregnant or plan to become

pregnant or are breast-feeding.

Your doctor can discuss with you

the risks and benefits involved.

If you have not told your doctor

about any of the above, tell

him/her before you start taking

Dicarz.

Taking other medicines

Tell your doctor or pharmacist if

you are taking any other

medicines, including any that you

get without a prescription from

your pharmacy, supermarket or

health food shop.

Some medicines and Dicarz may

interfere with each other. These

include:

cimetidine, a medicine used

to treat stomach ulcers or

reflux

digoxin, a medicine used to

treat heart failure

cyclosporine, a medicine

used to treat certain

problems with the immune

system

rifampicin, a medicine used

to treat tuberculosis

fluoxetine and paroxetine,

medicines used to treat

depression

insulin injections,

glibenclamide, metformin,

gliclazide or glipizide,

medicines used in the

treatment of diabetes

reserpine, a medicine used

to treat high blood pressure

or severe agitation

associated with some

mental disorders

monoamine oxidase

inhibitors, medicines used

to treat depression (e.g.

moclobemide, phenelzine

and tranylcypromine)

medicines for when your

heart doesn’t beat smoothly

(e.g. quinidine, lignocaine,

flecainide, amiodarone and

propafenone)

diltiazem, a medicine used

to treat high blood pressure

or angina

verapamil, a medicine used

to treat high blood pressure,

angina or fast heart rate

clonidine, a medicine used

to treat high blood pressure,

migraine or menopausal

symptoms

aspirin and other pain

relievers or non-steroidal

anti-inflammatory medicines

such as ibuprofen or

naproxen

medicines which may

relieve asthma, or help you

breathe better, such as

salbutamol and salmeterol.

These medicines may be affected

by Dicarz or may affect how well it

works. You may need different

amounts of your medicines, or you

may need to take different

medicines.

Your doctor and pharmacist have

more information on medicines to

be careful with or avoid while taking

this medicine.

How to take Dicarz

Follow all directions given to you

by your doctor or pharmacist

carefully.

They may differ from the information

contained in this leaflet.

If you do not understand the

instructions on the box/bottle,

ask your doctor or pharmacist for

help.

How much to take

Take Dicarz exactly as your

doctor has prescribed.

Your doctor will tell you how many

Dicarz tablets to take each day.

This depends on your condition and

whether or not you are taking other

medicines.

High Blood Pressure

The usual dose is 12.5 mg (one

12.5 mg tablet or half a 25 mg

tablet) once a day for the first two

days, then one 25 mg tablet once a

day.

If necessary, after at least another

two weeks, the dose may be

increased to 50 mg per day, taken

either as two 25 mg tablets at the

same time once a day, or one 25

mg tablet taken in the morning and

another 25 mg tablet taken in the

evening.

Angina

The usual dose is 12.5 mg (one

12.5 mg tablet or half a 25 mg

tablet) twice a day for the first two

days, then 25 mg twice a day (one

25 mg tablet in the morning and

another 25 mg tablet in the

evening).

If necessary, the dose may be

increased gradually up to a

maximum daily dose of 50 mg (two

25 mg tablets) twice a day – a total

of four 25 mg tablets per day.

Heart Failure

The usual starting dose is 3.125 mg

(half a 6.25 mg tablet) twice daily.

The dose is usually increased every

two weeks to 6.25 mg twice daily

(one 6.25 mg tablet in the morning

and another 6.25 mg tablet in the

evening), then 12.5 mg twice daily

and then 25 mg twice daily.

Some patients may require up to

two 25 mg tablets (50 mg) twice

daily. However, this dosage

increase may be done more slowly

if side effects occur.

If the tablets slow your heart too

much you may go back to a lower

dose.

Heart Failure Following a Recent

Heart Attack

The usual starting dose is 6.25 mg.

If the first dose is tolerated, the

dose is increased to 6.25 mg twice

a day (one 6.25 mg tablet in the

morning and another 6.25 mg tablet

in the evening) and maintained for 3

to 10 days.

If the 6.25 mg twice a day dose is

well tolerated, the dose can be

increased to 12.5 mg twice a day

and maintained for 3 to 10 days.

The maximum daily dose is 25 mg

twice a day. The final dose will be

determined by how well you feel

while taking Dicarz.

Your doctor will decide which dose

is best for you and monitor you

carefully each time the dose is

increased or changed.

How to take it

Page 3 of 5

Swallow the tablets whole or

halved with a full glass of water.

Do not crush or chew the tablets.

When to take it

Take your medicine at about the

same time each day, during or

immediately after a meal.

Taking Dicarz at the same time

each day will have the best effect. It

will also help you remember when

to take it.

If you take it on an empty stomach,

it may increase some side effects.

How long to take it

Continue taking your medicine

for as long as your doctor tells

you.

This medicine helps to control your

condition, but does not cure it. It is

important to keep taking your

medicine even if you feel well.

Treatment with Dicarz is usually

long term.

It is very important that Dicarz

treatment is not stopped

suddenly.

If you are to stop taking Dicarz your

doctor will advise you to reduce the

dose slowly over approximately two

weeks.

If you forget to take it

Do not take a double dose to

make up for the dose that you

missed.

Wait until the next dose and take

your normal dose then.

If you are not sure what to do,

ask your doctor or pharmacist.

If you have trouble remembering to

take your medicine, ask your

pharmacist for some hints.

If you take too much

(overdose)

Immediately telephone your

doctor or the National Poisons

Information Centre (0800 POISON

or 0800 764 766) for advice, or go

to Accident and Emergency at

the nearest hospital, if you think

that you or anyone else may have

taken too much Dicarz. Do this

even if there are no signs of

discomfort or poisoning.

You may need urgent medical

attention.

Symptoms of an overdose may

include:

low blood pressure causing

dizziness or fainting

a very slow heart rate

difficulty breathing

vomiting

shock

seizures.

Keep telephone numbers for

these places handy.

If you are not sure what to do,

contact your doctor or

pharmacist.

While you are taking

Dicarz

Things you must do

If you are about to be started on

any new medicine, remind your

doctor and pharmacist that you

are taking Dicarz.

Tell any other doctors, dentists,

and pharmacists who treat you

that you are taking this medicine.

If you are going to have surgery,

tell the surgeon or anaesthetist

that you are taking this medicine.

Your surgeon and anaesthetist

should know well ahead of the date

of your surgery so they can allow for

your conditions and medications.

If you become pregnant while

taking this medicine, tell your

doctor immediately.

If you are about to have any

laboratory tests, tell your doctor

that you are taking this medicine.

It may interfere with the results of

some tests.

Keep all of your doctor’s

appointments so that your

progress can be checked.

Your doctor may examine your

eyes, and test your blood glucose

and kidney function from time to

time, to make sure the medicine is

working and to prevent unwanted

side effects.

Things you must not do

Do not stop taking Dicarz or

lower the dosage without

checking with your doctor.

If you stop taking it suddenly, your

condition may worsen or you may

have unwanted side effects.

Dicarz should only be reduced

gradually over a period of about

two weeks before stopping

completely.

Do not use Dicarz to treat any

other complaints unless your

doctor tells you to.

Do not give your medicine to

anyone else, even if they have

the same condition as you.

Things to be careful of

Be careful driving or operating

machinery until you know how

Dicarz affects you.

This medicine may cause tiredness,

dizziness or light-headedness in

some people, especially after the

first dose or when dosage is

increased. If any of these occur, do

not drive, operate machinery or do

anything else that could be

dangerous.

Be careful getting up from a

sitting or lying position.

Dizziness, light-headedness or

fainting may occur, especially when

you get up quickly. Getting up

slowly may help. If this problem

continues, talk to your doctor.

Be careful when drinking alcohol

while you are taking this

medicine.

If you drink alcohol, the tiredness,

dizziness or light-headedness may

be worse.

If you wear contact lenses you

may notice less tear fluid in your

eyes.

You may find you have to use your

contact lenses less or switch to

glasses.

Lifestyle measures that

help reduce heart

disease risk

Page 4 of 5

By following these simple

measures, you can further reduce

the risk from heart disease.

Quit smoking and avoid

second hand smoke.

Limit alcohol intake.

Enjoy healthy eating by:

eating plenty of vegetables

and fruit;

reducing your saturated fat

intake (eat less fatty meats,

full fat dairy products,

butter, coconut and palm

oils, most take-away foods,

commercially-baked

products).

Be active. Progress, over time,

to at least 30 minutes of

moderate intensity physical

activity on 5 or more days each

week. Can be accumulated in

shorter bouts of 10 minutes

duration. If you have been

prescribed anti-angina

medicine, carry it with you

when being physically active.

Maintain a healthy weight.

Discuss your lifestyle and

lifestyle plans with your doctor.

Do this before starting any

exercise programme.

Know warning signs of heart

attack and what to do:

Tightness, fullness, pressure,

squeezing, heaviness or pain

in your chest, neck, jaw, throat,

shoulders, arms or back.

You may also have difficulty

breathing, or have a cold sweat

or feel dizzy or light headed or

feel like vomiting (or actually

vomit).

If you have heart attack

warning signs that are severe,

get worse or last for 10

minutes even if they are mild,

call triple one (111). Every

minute counts.

Side effects

Tell your doctor or pharmacist as

soon as possible if you do not

feel well while you are taking

Dicarz.

This medicine helps most people

but it may have unwanted side

effects in a few people.

All medicines can have side effects.

Sometimes they are serious, most

of the time they are not. You may

need medical attention if you get

some of the side effects.

Do not be alarmed by the

following lists of side effects.

You may not experience any of

them.

Ask your doctor or pharmacist to

answer any questions you may

have.

Tell your doctor or pharmacist if

you notice any of the following

and they worry you:

fatigue, dizziness,

headache (these side

effects often occur at the

beginning of treatment)

feeling faint

oedema (swelling)

abnormal heart beat,

including slow or fast heart

beat

nausea (feeling sick),

vomiting, stomach pain,

diarrhoea

weight increase

vision abnormalities

dry or sore eyes

lightheadedness on

standing

pain in your fingers and/or

toes

if you are diabetic,

worsening control of your

blood glucose levels

unusual hair loss or

thinning.

The above list includes the more

common side effects of your

medicine.

They are usually mild.

Tell your doctor immediately or

go to Accident and Emergency at

your nearest hospital if you

notice any of the following:

shortness of breath

swelling of the mouth or

tongue

irregular heart beat

swelling of the feet or legs

due to fluid build-up

bleeding or bruising more

easily than normal

cold extremities

chest pain

depressed mood

sleep disturbances or

nightmares

loss of bladder control

severe skin reactions -

blisters and bleeding in the

lips, eyes, mouth, nose and

genitals.

The above list includes serious side

effects. You may need urgent

medical attention or hospitalisation.

These side effects are rare.

This is not a complete list of all

possible side effects. Others may

occur in some people and there

may be some side effects not yet

known.

After taking Dicarz

Storage

Keep your tablets in the blister

pack until it is time to take them.

If you take the tablets out of the

blister pack they may not keep well.

Keep your tablets in a cool dry

place where the temperature

stays below 25°C.

Do not store Dicarz or any other

medicine in the bathroom or near a

sink. Do not leave it on a window sill

or in the car.

Heat and dampness can destroy

some medicines.

Keep it where children cannot

reach it.

A locked cupboard at least one-and-

a half metres above the ground is a

good place to store medicines.

Disposal

If your doctor tells you to stop

taking this medicine or the expiry

date has passed, ask your

pharmacist what to do with any

medicine that is left over.

Product description

What it looks like

Dicarz is available in three tablet

strengths.

Dicarz 6.25 mg - White, oval

shaped, film-coated tablets, with

break line on both sides imprinted

"6.25" on one side. Available in

blister pack of 60.

Page 5 of 5

Dicarz 12.5 mg - White, oval

shaped, film-coated tablets, with

break line on both sides, imprinted

"12.5" on one side. Available in

blister pack of 60.

Dicarz 25 mg - White, oval shaped,

film-coated tablets, with break line

on both sides, imprinted "25" on one

side. Available in blister pack of 60.

Ingredients

The active ingredient of Dicarz is

carvedilol.

The tablets also contains:

microcrystalline cellulose

lactose

crospovidone

povidone

colloidal silicon dioxide

magnesium stearate

hypromellose

titanium dioxide

polydextrose

triethyl citrate

polyethylene glycol.

The tablets are sucrose and gluten

free.

If you want to know

more

Should you have any questions

regarding this product, please

contact your pharmacist or doctor.

Who supplies this

medicine

Distributed in New Zealand by:

Mylan New Zealand Ltd,

PO Box 11183,

Ellerslie,

Auckland.

Telephone: (09) 579 2792

Date of Information

11 February 2015

(Based on datasheet dated 06

January 2015)

Page 1 of 15

NEW ZEALAND DATA SHEET

DICARZ

Carvedilol film-coated tablets

3.125 mg, 6.25 mg, 12.5 mg and 25 mg

Presentation

DICARZ 3.125 mg: White, oval shaped, film-coated tablet, plain on both sides.

DICARZ 6.25 mg: White, oval shaped, film-coated tablet with a breakline on both sides, imprinted

“6.25” on one side.

DICARZ 12.5 mg: White, oval shaped, film-coated tablet, with a breakline on both sides, imprinted

“12.5” on one side.

DICARZ 25 mg: White, oval shaped, film-coated tablet, with a breakline on both sides, imprinted

“25” on one side.

Indications

Hypertension

DICARZ is indicated for the management of essential hypertension. It can be used alone or in

combination with other antihypertensive agents (e.g. calcium channel blockers, diuretics).

Treatment of angina pectoris

DICARZ is efficacious in the treatment of chronic stable angina and unstable angina.

Chronic heart failure (CHF)

Unless a contraindication exists, DICARZ is indicated for the treatment of all patients with stable and

symptomatic mild, moderate and severe chronic heart failure of ischaemic or non-ischaemic

aetiology in combination with standard therapy (including ACE inhibitors and diuretics with or without

digitalis).

Left ventricular dysfunction following acute myocardial infarction

Long term treatment following myocardial infarction complicated by left ventricular dysfunction (LVEF

40% or wall motion index

1.3), including well controlled heart failure, in combination with ACE

inhibitors and other treatments recommended in the management of patients after myocardial

infarction.

Dosage and Administration

Method of administration

The tablets are to be swallowed with sufficient fluid. It is not necessary to take the dose in relation to

meals, however, for chronic heart failure patients, DICARZ should be taken with food to slow the

rate of absorption and reduce the incidence of orthostatic effects.

Page 2 of 15

Duration of treatment

Treatment with DICARZ is a long-term therapy. As with all

-blockers, treatment should not be

stopped abruptly but rather gradually reduced at weekly intervals. This is particularly important in the

case of patients with concomitant coronary heart disease.

Hypertension

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. If necessary, the dosage may

subsequently be increased at intervals of at least two weeks up to a maximum daily dose of 50 mg.

This may be given as 50 mg once daily or 25 mg twice daily.

Angina pectoris

The recommended dose for initiation of therapy is 12.5 mg twice a day for the first 2 days. Thereafter

the recommended dosage is 25 mg twice a day. If necessary, the dosage may subsequently be

increased at intervals of at least two weeks up to a maximum daily dose of 100 mg. This may be

given as 50 mg twice daily.

Chronic Heart Failure

Dosage must be tailored to suit the individual, and closely monitored by a physician during

up-titration. For those patients receiving digitalis, diuretics and ACE inhibitors, dosing of these

medicines should be stabilised prior to initiation of DICARZ treatment.

The recommended dose for initiation of therapy is 3.125 mg twice daily for two weeks. If this dose is

tolerated, the dose may thereafter be increased, at intervals of not less than two weeks, to 6.25 mg,

12.5 mg and 25 mg twice daily. Doses should be increased to the highest level tolerated by the

patient. The maximum recommended dose is 25 mg twice daily for all patients with severe CHF and

for patients with mild to moderate CHF weighing less than 85 kg. In patients with mild to moderate

CHF weighing more than 85 kg, the maximum recommended daily dose is 50 mg twice daily.

Before each dose increase, the patient should be evaluated by the physician for symptoms of

worsening heart failure or vasodilation. Transient worsening of heart failure or fluid retention should

be treated with increased doses of diuretics. Occasionally it may be necessary to lower the dose of

DICARZ and, in rare cases, temporarily discontinue DICARZ treatment.

If DICARZ treatment is discontinued for more than one week, therapy should be recommenced at a

lower dose level (twice daily) and up-titrated in line with the above dosing recommendation. If

DICARZ treatment is discontinued for more than two weeks, therapy should be recommenced at

3.125 mg in line with the above dosing recommendation.

Symptoms of vasodilation may be managed initially by a reduction in the dose of diuretics. If

symptoms persist, the dose of ACE inhibitor (if used) may be reduced, followed by a reduction in the

dose of carvedilol if necessary. Under these circumstances, the dose of DICARZ should not be

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

Left ventricular dysfunction following acute myocardial infarction

Dosage must be individualised and closely monitored by a physician during up-titration.

Treatment may be started as an inpatient or outpatient when the patient is haemodynamically stable

and fluid retention has been minimised.

Prior to initiating

treatment

Haemodynamically stable patients should have received an ACE inhibitor for at least 48 hours, given

at a stable dose during at least the preceding 24 hours. DICARZ can then be started between day

3 and day 21 after the myocardial infarction.

Page 3 of 15

First dose

The initial recommended dose is 6.25 mg. Patients should remain under close medical supervision

for at least 3 hours following the initial dose (see Warnings and Precautions; General).

Subsequent doses

If the patient has tolerated the first dose (i.e. heart rate > 50 beats/minute, systolic blood pressure

> 80 mmHg, and absence of clinical signs of intolerance), the dose should be increased to 6.25 mg

twice daily and maintained for 3 to 10 days.

The dose should be reduced to 3.125 mg twice daily if the patient develops signs of intolerance

during this period, in particular bradycardia < 50 beats/minute, systolic blood pressure < 80 mmHg

or fluid retention. If this dose is not tolerated, treatment should be stopped. If it is well tolerated, it

should be increased again to 6.25 mg twice daily after 3 to 10 days.

Subsequent up-titration

If the dose of 6.25 mg twice daily is well tolerated, the dose should be increased at intervals of 3 to

10 days to 12.5 mg twice daily and then to 25 mg twice daily. The maintenance dose is the maximum

dose tolerated by the patient. The maximum recommended dose is 25 mg twice daily, irrespective

of the patient's weight.

Special dosage instructions

Renal impairment

Available pharmacokinetic data and published clinical studies in patients with varying degrees of

renal impairment (including renal failure) suggest no changes in carvedilol dosing recommendations

are warranted in patients with moderate to severe renal insufficiency.

Hepatic impairment

DICARZ

contraindicated

patients

with

clinical

manifestations

liver

dysfunction

(see

Contraindications).

Elderly

There is no evidence to support dose adjustment.

Children

The safety and efficacy of carvedilol in children and adolescents (<18 years) has not been

established (see Use in Special Populations: Paediatric Use and Pharmacokinetics in Special

Populations: Children).

Contraindications

DICARZ must not be used in patients with:

hypersensitivity to carvedilol or any component of the product (see Further Information)

unstable/decompensated heart failure

clinically manifest liver dysfunction.

As with other

-blockers, DICARZ must not be used in patients with:

2nd and 3rd degree atrioventicular (AV) block (unless a permanent pace maker is in place)

severe bradycardia (< 50 bpm)

sick sinus syndrome (including sino-atrial block)

severe hypotension (systolic blood pressure < 85 mm Hg)

Page 4 of 15

cardiogenic shock

history of bronchospasm or asthma

history of other obstructive lung disorders.

Warnings and Precautions

General

There are a number of important pharmacokinetic and pharmacodynamics interactions with other

drugs

(e.g.

digoxin,

cyclosporine,

rifampicin,

anaesthetic

drugs,

anti-arrhythmic

drugs)

(see

Interactions).

Chronic heart failure

In chronic heart failure patients, worsening cardiac failure or fluid retention may occur during up-

titration of carvedilol. If such symptoms occur, diuretics 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

carvedilol.

Carvedilol

should

used

with

caution

combination with digitalis glycosides, as both medicines slow atrioventricular (AV) conduction (see

Interactions).

Renal function in congestive heart failure

Reversible deterioration of renal function has been observed with carvedilol therapy in chronic heart

failure patients with low blood pressure (systolic BP <100 mmHg), ischaemic heart disease and

diffuse vascular disease, and/or underlying renal insufficiency.

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 (see Dosage and Administration).

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 bronchospasm, 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.

Diabetes

Care should be taken in the administration of carvedilol to patients with diabetes mellitus, as it may

be associated with worsening control of blood glucose, or the early signs and symptoms of acute

hypoglycaemia may be masked or attenuated (see Interactions and Use in Special Populations).

Peripheral vascular disease and Raynaud's phenomenon

Carvedilol should be used with caution in patients with peripheral vascular disease (e.g. Reynaud’s

phenomenon) as

-blockers can precipitate or aggravate symptoms of arterial insufficiency.

Thyrotoxicosis

Carvedilol, like other agents with

-blocking properties, may obscure the symptoms of thyrotoxicosis.

Page 5 of 15

Bradycardia

Carvedilol may induce bradycardia. If the patient's pulse rate decreases to less than 55 beats per

minute, the dosage of carvedilol should be reduced.

Hypersensitivity

Care should be taken in administering carvedilol to patients with a history of serious hypersensitivity

reactions, and in patients undergoing desensitisation therapy, as

-blockers may increase both the

sensitivity towards allergens and the severity of hypersensitivity reactions.

Severe cutaneous adverse reactions (SCARs)

Very rare cases of severe cutaneous adverse reactions such as toxic epidermal necrolysis (TEN)

and Stevens-Johnson syndrome (SJS) have been reported during treatment with carvedilol (see

Undesirable Effects, Post-Marketing experience). 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

-blocker therapy should take carvedilol only after

consideration of the risk-benefit ratio.

Pheochromocytoma

In patients with pheochromocytoma, an

-blocking agent should be initiated prior to the use of any

-blocking agent. Although carvedilol has both

- and

-blocking pharmacological activities, there is

no experience with its use in this condition. Caution should therefore be taken in the administration

of carvedilol to patients suspected of having pheochromocytoma.

Prinzmetal's variant angina

Agents with non-selective

-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

-blocking activity of carvedilol may prevent such symptoms. Caution should, however, be taken in

the administration of carvedilol to patients suspected of having Prinzmetal’s variant angina.

Contact lenses

Wearers of contact lenses should bear in mind 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 should be gradual (over a period of two

weeks).

Ability to drive and use machines

No studies on the effects on the ability to drive or to use machines have been performed.

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.

Interactions

Pharmacokinetic interactions

Effects of carvedilol on the pharmacokinetics of other drugs

Page 6 of 15

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.

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 Warnings and Precautions). Carvedilol had no effect on digoxin

administered intravenously.

Cyclosporin:

Two studies in renal and cardiac transplant patients receiving oral cyclosporine have shown an

increase in cyclosporin plasma concentration following the initiation of carvedilol. It appears that

carvedilol increases exposure to oral cyclosporine by around 10 to 20 %. In an attempt to maintain

therapeutic cyclosporine levels, an average 10 - 20% reduction of the cyclosporine dose was

necesary. The mechanism for the interaction is not known but inhibition of intestinal P glycoprotein

by carvedilol may be involved. Due to wide inter-individual variability of cyclosporine levels, it is

recommended that cyclosporin concentrations are monitored closely after initiation of carvedilol

therapy and that the dose of cyclosporin be adjusted as appropriate. In case of I.V. administration of

cyclosporin, no interaction with carvedilol is expected.

Effects of other drugs on the pharmacokinetics of carvedilol

Inhibitors as well as inducers of CYP2D6 and CYP2C9 can modify the systemic and/or presystemic

metabolism of carvedilol stereoselectively, leading to increased or decreased plasma concentrations

of R and S-carvedilol (see Pharmacokinetic Properties; Metabolism). Some examples observed in

patients or in healthy subjects are listed below but the list is not exhaustive.

Rifampicin:

In a study in 12 healthy subjects, exposure to carvedilol decreased by around 60% during

concomitant administration with rifampicin and a decrease effect of carvedilol on the systolic blood

pressure was observed. The mechanism for the interaction is not known but it may be due to the

induction of the intestinal P glycoprotein by rifampicin. A close monitoring of the p-blockade activity

in patients receiving concomitant administration of carvedilol and rifampicin is appropriate.

Amiodarone:

An in vitro study with human liver microsomes has shown that amiodarone and desethylamiodarone

inhibited the oxidation of R and S-carvedilol. The trough concentration of R and S-carvedilol was

significantly increased by 2.2 fold in heart failure patients receiving carvedilol and amiodarone

concomitantly as compared to patients receiving carvedilol monotherapy. The effect on S-carvedilol

was attributed to desethylamiodarone, a metabolite of amiodarone, which is a strong inhibitor of

CYP2C9. A monitoring of the

-blockade activity in patients treated with the combination carvedilol

and amiodarone is advised.

Fluoxetine and Paroxetine:

In a randomised, 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

-blocking properties may enhance the blood-sugar-reducing effect of insulin and oral

Page 7 of 15

hypoglycaemics.

signs

hypoglycaemia

masked

attenuated

(especially

tachycardia). In patients taking insulin or oral hypoglycaemics, regular monitoring of blood glucose

is therefore recommended (see Warnings and Precautions; General).

Catecholamine-depleting agents:

Patients

taking

both

agents

with

-blocking

properties

medicine

that

deplete

catecholamines (e.g. reserpine and monoamine oxidase inhibitors) should be observed closely for

signs of hypotension and/or severe bradycardia.

Non-dihydropyridines calcium channel blockers, amiodarone or other antiarrhythmics:

In combination with carvedilol can increase the risk of AV conduction disturbances. Isolated cases

of conduction disturbance (rarely with haemodynamic compromise) have been observed when

carvedilol is co-administered with diltiazem. As with other agents with

-blocking properties, if

carvedilol is to be administered orally with non-dihydropyridines calcium channel blockers of the

verapamil or diltiazem type, amiodarone or other antiarrhythmics it is recommended that ECG and

blood pressure be monitored.

Clonidine:

Concomitant administration of clonidine with agents with

-blocking properties may potentiate

blood-pressure and heart-rate-lowering effects. When concomitant treatment with agents with

-blocking properties and clonidine is to be terminated, the

-blocking agent should be discontinued

first. Clonidine therapy can then be discontinued several days later by gradually decreasing the

dosage.

Antihypertensives:

with

other

agents with

-blocking

activity,

carvedilol may

potentiate

effect

other

concomitantly

administered

medicines

that

anti-hypertensive

action

(e.g.

-receptor

antagonists) or have hypotension as part of their adverse effect profile.

Anaesthetic agents:

Careful monitoring of vital signs is recommended during anaesthesia due to the synergistic negative

inotropic and hypotensive effects of carvedilol and anaesthetic medicines.

Non-steroidal anti-inflammatory drugs (NSAIDs):

The concurrent use of NSAIDs and

-adrenergic blockers may result in an increase in blood pressure

and impairment of blood pressure control.

Beta-agonist bronchodilators:

Non-cardioselective

-blockers oppose the bronchodilator effects of

-agonist bronchodilators.

Careful monitoring of patients is recommended.

Digoxin:

The combined use of

-blockers and digoxin may result in additive prolongation of atrioventricular

(AV) conduction time.

Use in Special Populations

Pregnancy

Studies in animals have shown reproductive toxicity (see Preclinical Safety). The potential risk for

humans is unknown.

Beta-blockers reduce placental perfusion, which may result in intrauterine foetal death, and immature

and premature deliveries. In addition, adverse effects (especially hypoglycaemia and bradycardia)

may occur in the foetus and neonate. There may be an increased risk of cardiac and pulmonary

complications in the neonate in the postnatal period. There is no evidence from animal studies that

carvedilol has any teratogenic effects.

There is no adequate clinical experience with carvedilol in pregnant women.

Page 8 of 15

Carvedilol should not be used during pregnancy unless the potential benefit outweighs the potential

risk.

Nursing mothers

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

-blockers, in

particular lipophilic compounds, will pass into human breast milk although to a variable extent.

Breastfeeding is therefore not recommended during administration of carvedilol.

Paediatric Use

See Dosage and Administration: Special dosage instructions

Elderly Use

A study in elderly hypertensive patients showed that there was no difference in the adverse event

profile as compared to younger patients. Another study, which included elderly patients with coronary

heart disease, showed no difference in the adverse events reported vs. those reported by younger

patients. Therefore, no dose adjustment of the starting dose is required in the elderly population (see

Dosage and Administration: Special dosage instructions).

Renal Impairment

The autoregulatory renal blood supply is preserved and the glomerular filtration is unchanged during

chronic treatment with carvedilol. In patients with moderate to severe renal insufficiency, no changes

in carvedilol dosage recommendations are warranted (see Dosage and Administration: Special

dosage instructions).

Hepatic Impairment

Carvedilol

contraindicated

patients

with

clinically

manifest

liver

dysfunction

(see

Contraindications). A pharmacokinetic study in cirrhotic patients has shown that exposure (AUC) to

carvedilol was increased by 6.8 folds in patients with liver impairment as compared to healthy

subjects.

Diabetic Patients

Beta-blockers may increase insulin resistance and mask hypoglycaemic symptoms. However,

numerous studies have established that vasodilating

-blockers like carvedilol are associated with

more favourable effects on glucose and lipid profiles. Carvedilol has been shown to exhibit modest

insulin-sensitising properties and can relieve some manifestations of the metabolic syndrome.

Adverse Effects

Clinical Trials

Adverse Drug Reactions (ADRs) are listed according to MedDRA system organ class and CIOMS

frequency category: Very common

1/10; Common

1/100 and

1/10; Uncommon

1/1000 and

1/100; Rare

1/10,000 and

1/1000; Very rare

1/10,000.

Table 1 below summarises undesirable effects that have been reported in associated with the use

of carvedilol in pivotal clinical trials with the following indications: chronic heart failure, left ventricular

dysfunction following acute myocardial infarction, hypertension and the long term management of

coronary heart disease:

Page 9 of 15

Table 1: Adverse Drug Reactions in Clinical Trials

System Organ Class

Adverse Reaction

Frequency

Blood and Lymphatic System

Disorders

Anaemia

Common

Thrombocytopenia

Rare

Cardiac Disorders

Cardiac failure

Very common

Bradycardia

Common

Hypovolaemia

Common

Fluid overload

Common

Atrioventricular block

Uncommon

Angina pectoris

Uncommon

Eye Disorders

Visual impairment

Common

Lacrimation decreased (dry eye)

Common

Eye irritation

Common

Gastrointestinal Disorders

Nausea

Common

Diarrhoea

Common

Vomiting

Common

Dyspepsia

Common

Abdominal pain

Common

Constipation

Uncommon

Dry mouth

Rare

General Disorders and

Administration Site Conditions

Asthenia (fatigue)

Very common

Oedema

Common

Pain

Common

Hepatobiliary Disorders

Alanine

aminotransferase

(ALT),

aspartate

aminotransferase

(AST)

gamma-glutamyltransferase

(GGT) increased

Very rare

Immune System Disorders

Hypersensitivity (allergic reactions)

Very rare

Infections and Infestations

Pneumonia

Common

Bronchitis

Common

Upper respiratory tract infection

Common

Urinary tract infection

Common

Metabolism and Nutrition

Disorders

Weight increase

Common

Hypercholesterolaemia

Common

Impaired

blood

glucose

control

(hyperglycaemia, hypoglycaemia) in

patients with pre-existing diabetes

Common

Musculoskeletal and

Connective Tissue Disorders

Pain in extremities

Common

Nervous System Disorders

Dizziness

Very common

Headache

Very common

Syncope, presyncope

Common

Paraesthesia

Uncommon

Psychiatric Disorders

Depression, depressed mood

Common

Page 10 of 15

System Organ Class

Adverse Reaction

Frequency

Sleep disorders

Uncommon

Renal and Urinary Disorders

Renal

failure

renal

function

abnormalities in patients with diffuse

vascular disease and/or underlying

renal insufficiency

Common

Micturition disorders

Rare

Reproductive

System

Breast Disorders

Erectile dysfunction

Uncommon

Respiratory,

Thoracic

Mediastinal Disorders

Dyspnoea

Common

Pulmonary oedema

Common

Asthma in predisposed patients

Common

Nasal congestion

Rare

Skin

Subcutaneous

Disorders

Skin

reactions

(e.g.

allergic

exanthema,

dermatitis,

urticarial,

pruritus, psoriatic and lichen planus

like skin lesions)

Uncommon

Vascular Disorders

Hypotension

Very common

Orthostatic hypotension

Common

Disturbances of peripheral circulation

(cold extremities, peripheral vascular

disease, exacerbation of intermittent

claudication

Reynaud’s

phenomenon)

Common

Hypertension

Common

Description of selected adverse reactions

The frequency of adverse reactions is not dose-dependent, with the exception of dizziness, abnormal

vision and bradycardia. Dizziness, syncope, headache and asthenia are usually mild and are more

likely to occur at the beginning of treatment.

In patients with congestive heart failure, worsening cardiac failure and fluid retention may occur

during up-titration of carvedilol dose (see Warnings and Precautions).

Cardiac failure was a very commonly reported adverse event in both placebo (14.5%) and

carvedilol-treated (15.4%) patients, in patients with left ventricular dysfunction following acute

myocardial infarction.

Reversible deterioration of renal function has been observed with carvedilol therapy in chronic heart

failure patients with low blood pressure, ischaemic heart disease and diffuse vascular disease and/or

underlying renal insufficiency (see Warnings and Precautions).

Post-marketing experience

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.

Renal and urinary disorders

Isolated cases of urinary incontinence in women, which resolved upon discontinuation of the

medication, have been reported.

Page 11 of 15

Skin and subcutaneous tissue disorders

Alopecia

Severe cutaneous adverse reactions (toxic epidermal necrolysis, Stevens-Johnson syndrome) (see

Warnings and Precautions).

Metabolism and nutrition disorders

Due to the

-blocking properties, it is also possible for latent diabetes mellitus to become manifest,

manifest diabetes to be aggravated, and blood glucose counter-regulation to be inhibited.

Overdose

Symptoms and signs of overdose

In the event of overdosage, 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 of overdose

The patient should be monitored for the above mentioned signs and symptoms and managed

according to the best judgement of the treating physicians and according to standard practice for

patients with

-blocker overdose (e.g. atropine, transvenous pacing, glucagon, phosphodiesterase

inhibitors such as amrinone or milrinone,

-sympathomimetics).

For further advice on management of overdose please contact the National Poisons Information

Centre (0800 POISON or 0800 764 766).

Important note

In cases of severe intoxication with shock, supportive treatment must be continued for a sufficiently

long period, as a prolongation of elimination half-life and redistribution of carvedilol from deeper

compartments are to be expected. The duration of the supportive/antidote therapy depends on the

severity of the overdosage. The supportive treatment should therefore be continued until the patient's

condition has stabilised.

Pharmacological Properties and Effects

Pharmacodynamic Properties

Mechanism of action

Carvedilol is a multiple action adrenergic receptor blocker with

adrenergic receptor

blockade properties. Carvedilol has been shown to have organ-protective effects. Carvedilol is a

potent antioxidant and a scavenger of reactive oxygen radicals. Carvedilol is racemic, and both R(+)

and S(-) enantiomers have the same

-adrenergic receptor blocking properties and antioxidant

properties. Carvedilol has anti-proliferative effects on human vascular smooth muscle cells.

A decrease in oxidative stress has been shown in clinical studies by measuring various markers

during chronic treatment of patients with carvedilol.

Carvedilol's

-adrenergic

receptor

blocking

properties

non-selective

-adrenoceptors and are associated with the laevorotatory S(-) enantiomer.

Carvedilol has no intrinsic sympathomimetic activity and (like propranolol) it has membrane

stabilising properties. Carvedilol suppresses the renin-angiotensin-aldosterone system through

-blockade, which reduces the release of renin, thus making fluid retention rare.

Page 12 of 15

Carvedilol reduces the peripheral vascular resistance via selective blockade of

-adrenoceptors.

Carvedilol attenuates the increase in blood pressure induced by phenylephrine, an

-adrenoceptor

agonist, but not that induced by angiotensin II.

Carvedilol has no adverse effect on the lipid profile. A normal ratio of high-density lipoproteins to low

density lipoproteins (HDL:LDL) is maintained.

Clinical/efficacy studies

Clinical studies showed the following results for carvedilol:

Hypertension

Carvedilol lowers blood pressure in hypertensive patients by a combination of

-blockade and

mediated vasodilation. Some of the limitations of traditional

-blockers do not appear to be shared

by some of the vasodilating

-blockers, such as carvedilol. A reduction in blood pressure is not

associated with a concomitant increase in total peripheral resistance, as observed with pure

-blocking agents. Heart rate is slightly decreased. Renal blood flow and renal function are

maintained in hypertensive patients. Carvedilol has been shown to maintain stroke volume and

reduce total peripheral resistance. Blood supply to distinct organs and vascular beds including

kidneys, skeletal muscles, forearms, legs, skin, brain or the carotid artery is not compromised by

carvedilol. There is a reduced incidence of cold extremities and early fatigue during physical activity.

The long-term effect of carvedilol on hypertension is documented in several double-blind controlled

studies.

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.

Coronary heart disease

In patients with coronary heart disease, carvedilol has demonstrated anti-ischaemic (improved total

exercise time, time to 1mm ST segment depression and time to angina) and anti-anginal properties

that were maintained during long-term treatment. Acute haemodynamic studies have demonstrated

that carvedilol significantly decreases myocardial oxygen demand and sympathetic overactivity. It

also decreases the myocardial preload (pulmonary artery pressure and pulmonary capillary wedge

pressure) and afterload (total peripheral resistance).

Chronic heart failure

Carvedilol significantly reduces mortality and hospitalisations and improves symptoms and left

ventricular function in patients with ischaemic or non-ischaemic chronic heart failure. The effect of

carvedilol is dose dependent.

Renal impairment

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.

Left ventricular dysfunction following acute myocardial infarction

In a double-blind placebo-controlled study in 1959 patients with a recent myocardial infarction and

left ventricular ejection fraction

40% or wall motion index

1.3 (with or without symptomatic heart

Page 13 of 15

failure), carvedilol did not show a statistically significant reduction of the co-primary endpoint;

all-cause mortality or cardiovascular hospitalisation (8% reduction vs. placebo, p = 0.297), but

significantly reduced all-cause mortality by 23% (p = 0.031), all-cause mortality or non-fatal

myocardial infarction by 29% (p = 0.002), mortality due to cardiovascular causes by 25% (p = 0.024)

and hospitalisation for non-fatal myocardial infarction by 41% (p = 0.014). Additionally a post-hoc

analysis showed that carvedilol significantly reduced death or major cardiovascular hospitalisation

by 17% (p = 0.019).

Pharmacokinetic Properties

Absorption

Following oral administration of a 25 mg capsule in healthy subjects, carvedilol is rapidly absorbed

with a peak plasma concentration C

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

). The

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 metabolised 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.

Distribution

Carvedilol is a highly lipophilic compound, showing a plasma protein binding of around 95%. The

distribution volume ranges between 1.5 and 2 L/kg.

Metabolism

In humans, carvedilol is extensively metabolised in the liver via oxidation and conjugation into a

variety of metabolites that are mainly eliminated in the bile. Enterohepatic circulation of the parent

substance has been shown in animals.

Demethylation and hydroxylation at the phenol ring produce 3 metabolites with

-adrenergic receptor

blocking activity. Based on pre-clinical studies, the 4'-hydroxyphenol metabolite is approximately

13 times more potent than carvedilol for

-blockade. Compared to carvedilol, the three active

metabolites exhibit weak vasodilating activity. In humans, the concentrations of the three active

metabolites are about 10 times lower than that of the parent substance. Two of the hydroxy-

carbazole metabolites of carvedilol are extremely potent antioxidants, demonstrating a 30 to 80 fold

greater potency than carvedilol.

Pharmacokinetic studies in humans have shown that the oxidative metabolism of carvedilol is

stereoselective.

results

in

vitro

study

suggested

that

different

cytochrome

P450

isoenzymes

involved

oxidation

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

metabolised by CYP2D6. The S-enantiomer is mainly metabolised 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 S-carvedilol. As a consequence, plasma concentrations of

S-carvedilol

increased

CYP2D6

slow

metabolisers.

importance

CYP2D6 genotype in the pharmacokinetics of R and S-carvedilol was confirmed in population

pharmacokinetics studies, whereas other studies did not confirm this observation. It was concluded

that CYP2D6 genetic polymorphism may be of limited clinical significance.

Elimination

Following a single oral administration of 50 mg carvedilol, around 60% is secreted into the bile and

eliminated with the faeces in the form of metabolites within 11 days. Following a single oral dose,

Page 14 of 15

only about 16% are excreted into the urine in the 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 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.

Pharmacokinetics in Special Populations

Renal impairment

In patients with hypertension and renal insufficiency, the area under plasma level-time curve,

elimination half-life and maximum plasma concentration does not change significantly. Renal

excretion of unchanged carvedilol decreases in the patients with renal insufficiency; however

changes in pharmacokinetic parameters are modest.

Carvedilol is not eliminated during dialysis because it does not cross the dialysis membrane,

probably due to its high plasma protein binding.

Hepatic impairment

See Contraindications and Use in Special Populations sections.

Heart failure

In a study in 24 Japanese patients with heart failure, the clearance of R-and S-carvedilol was

significantly lower than previously estimated in healthy volunteers. These results suggested that the

pharmacokinetics of R-and S-carvedilol is significantly altered by heart failure.

Elderly use

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.

Preclinical Safety

Carcinogenicity

In carcinogenicity studies conducted in rats and mice, employing dosages up to 75 mg/kg/day and

200 mg/kg/day respectively (38 to 100 times the maximum recommended human dose [MRHD]),

carvedilol had no carcinogenic effect.

Mutagenicity

Carvedilol was not mutagenic in in vitro or in vivo mammalian tests and non-mammalian tests.

Impairment of fertility

Administration of carvedilol to adult female rats at maternally toxic doses (

200 mg/kg,

100 times

MRHD) resulted in impairment of fertility (poor mating, fewer corpora lutea, and fewer implants).

Teratogenicity

There is no evidence from animal studies that carvedilol has any teratogenic effects. Doses

> 60 mg/kg (> 30 times MRHD) caused delays in physical growth/development of offspring. There

was embryotoxicity (increased post-implantation deaths) but no malformations in rats and rabbits at

doses of 200 mg/kg and 75 mg/kg, respectively (38 to 100 times MRHD).

Page 15 of 15

Pharmaceutical Precautions

Store in a dry place below 25°C and protect from li ght.

Medicine Classification

Prescription medicine.

Package Quantities

DICARZ 3.125 mg:

Blister and bottle packs of 90 tablets.

DICARZ 6.25 mg:

Blister packs of 60 and 90 tablets; bottles of 90 tablets.

DICARZ 12.5mg:

Blister packs of 60 and 90 tablets; bottles of 90 tablets.

DICARZ 25 mg:

Blister packs of 60 and 90 tablets; bottles of 90 tablets.

Not all strengths, pack types or pack sizes may be marketed.

Further Information

Composition

DICARZ film coated tablets contain lactose. They are gluten and sugar free.

Active Ingredient

Each DICARZ film coated tablet contains 3.125 mg, 6.25 mg, 12.5 mg or 25 mg of carvedilol.

Inactive Ingredients

Each

DICARZ film coated tablet

contains the following

inactive

ingredients: microcrystalline

cellulose,

lactose,

crospovidone,

povidone,

colloidal

silicon

dioxide,

magnesium

stearate,

hypromellose, titanium dioxide, polydextrose, triethyl citrate and polyethylene glycol.

Name and Address

Mylan New Zealand Limited

PO Box 11-183

Ellerslie

AUCKLAND

Telephone: 09 579 2792

Date of Preparation

6 January 2015

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