Dilatrend

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Carvedilol 12.5 mg
Available from:
Pharmaco (NZ) Ltd
INN (International Name):
Carvedilol 12.5 mg
Dosage:
12.5 mg
Pharmaceutical form:
Tablet
Composition:
Active: Carvedilol 12.5 mg Excipient: Colloidal silicon dioxide Crospovidone Iron oxide red Iron oxide yellow Lactose monohydrate Magnesium stearate Povidone Sucrose
Units in package:
Blister pack, Alu-PVC or Alu-polyamide-PVC, 30 tablets
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Moehs Catalana SL
Therapeutic indications:
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, Alu-PVC or Alu-polyamide-PVC - 30 tablets - 48 months from date of manufacture stored at or below 30°C - Blister pack, Alu-PVC or Alu-polyamide-PVC - 100 tablets - 48 months from date of manufacture stored at or below 30°C
Authorization number:
TT50-4979a
Authorization date:
1996-05-08

Dilatrend

-October 2018

New Zealand Consumer Medicine Information

DILATREND

®

Carvedilol

6.25 mg, 12.5 mg and 25 mg tablets

What is in this leaflet

Please read this leaflet carefully before you start using DILATREND.

This leaflet answers some common questions about DILATREND tablets.

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 DILATREND

tablets against the benefits expected 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 DILATREND is used for

DILATREND contains the active ingredient carvedilol.

DILATREND is used to treat:

high blood pressure

angina (a type of severe chest pain)

heart failure

heart failure following a recent heart attack

DILATREND may be used in combination with other “heart” medicines. DILATREND is a long-term

treatment.

DILATREND belongs to a group of medicines called beta blockers. These medicines work by relaxing

tightened blood vessels and slowing the rate of heart beat. DILATREND is different from conventional

beta blockers as it has additional effects of being an alpha blocker (which also relaxes and widens

your blood vessels) and an antioxidant.

Heart failure occurs when the heart can no longer pump blood strongly enough for the body’s needs.

Often the heart gets bigger to try to improve the blood flow, but this can make heart failure worse.

Symptoms of heart failure include shortness of breath and swelling of the feet and/or legs due to fluid

build-up.

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DILATREND, when used with other “heart” medicines, reduces the pressure that the heart has to

pump against as well as controlling the heart rate. Over time this will reduce the size of an oversized

heart and increase its efficiency.

DILATREND helps to stop heart failure getting worse and reduces the chances of you being admitted

to hospital and/or dying from this disease.

Your doctor, however, may have prescribed DILATREND for another purpose.

Ask your doctor if you have any questions about why DILATREND has been prescribed for

you.

There is not enough information to recommend the use of DILATREND for people under the age of 18

years.

This medicine is available only with a doctor’s prescription.

Before you use DILATREND

When you must not take it

Do not take DILATREND if:

1.

you have had an allergic reaction to DILATREND or any ingredients listed at the end of this

leaflet

2.

you have asthma, or a history of asthma

3.

you have wheeziness/difficulty in breathing or a history of lung disorders

4.

you have liver disease

5.

you have a history of a very slow heart rate (bradycardia) or uneven heart beating (heart

block)

6.

you have very low blood pressure (hypotension)

7.

the package is torn or shows signs of tampering

8.

the expiry date (EXP) printed on the pack has passed

If you take this medicine after the expiry date has passed, it may not work as well.

If you are not sure if you should be taking DILATREND, talk to your doctor.

Before you start to use it

Tell your doctor if:

1.

you are pregnant or plan to become pregnant

It is not known whether DILATREND is harmful to an unborn baby when taken by a pregnant

woman. If there is a need to take DILATREND when you are pregnant your doctor will discuss the

risks and benefits to you and the unborn baby.

2.

you are breastfeeding or plan to breastfeed

It is not known if DILATREND passes into breast milk. Breast feeding is not recommended if you

are taking DILATREND.

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-October 2018

3.

you have any other health problems, especially the following:

diabetes

low blood pressure

very poor circulation to your fingers and/or toes (called peripheral vascular disease or

Raynaud’s phenomenon)

angina or chest pain/tightness which occurs even when you are at rest (called unstable

angina)

a history of poor kidney function

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

lung disease (called chronic obstructive pulmonary disease)

4.

you are allergic to any other medicines, foods, dyes or preservatives

5.

you react badly to lactose, sucrose or milk before you start taking DILATREND. DILATREND

tablets contain lactose and sucrose.

6.

you plan to have surgery

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 have not told your doctor about any of the above, you should do so before your start

taking DILATREND.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you have bought

without a prescription from a pharmacy, supermarket or health food shop.

You should also tell any health professional who is prescribing a new medication for you that

you are taking DILATREND.

Some medicines may interfere with DILATREND. These medicines include:

rifampicin

cimetidine

reserpine

a group of medicines called monoamine oxidase inhibitors that includes moclobemide, phenelzine

and tranylcypromine

cyclosporin

digoxin

diltiazem

verapamil

clonidine

medicines for diabetes such as insulin injections, glibenclamide, metformin , gliclazide , glipizide,

medicines for when your heart doesn’t beat smoothly, including quinidine, lignocaine, flecainide,

amiodarone and propafenone

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

fluoxetine and paroxetine

These medicines may be affected by DILATREND, or may affect how well it works. You may need to

use different amounts of your medicines or you may need to take different medicines. Your doctor will

advise you.

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-October 2018

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking

DILATREND.

Ask your doctor or pharmacist if you are not sure about this list of medicines.

How to use DILATREND

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

How much to take

Take DILATREND exactly as your doctor has prescribed.

Your doctor will tell you how many DILATREND tablets to take each day.

The usual dose for hypertension (high blood pressure) 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.

The usual dose for angina (severe chest pain) 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, after at least another two weeks, the dose may be

increased to 50 mg (two 25 mg tablets) twice a day – a total of four 25 mg tablets per day.

The usual starting dose in heart failure 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.

The usual starting dose for heart failure following a recent heart attack 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 DILATREND.

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

Swallow the tablets whole or halved with a glass of water.

Do not crush or chew the tablets.

When to take it

Take DILATREND during or immediately after a meal, at about the same time each day.

If you take DILATREND on an empty stomach, it may increase the risk of some side effects.

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-October 2018

How long to take it

Treatment with DILATREND is usually long term treatment.

Continue taking DILATREND until your doctor tells you to stop.

It is very important that DILATREND treatment is not stopped suddenly.

If you are to stop taking DILATREND your doctor will advise you to reduce the dose slowly over

approximately two weeks.

If you forget to take it

Do not take an extra dose. Wait until the next dose and take your normal dose then.

Do not try to make up for the dose that you missed by taking more than one dose at a time.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering your dose, ask your pharmacist for some hints.

While you are taking DILATREND

Things you must do

If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly.

If you are about to be started on any new medicine tell your doctor and pharmacist that you are

taking DILATREND.

Tell all doctors, dentists and pharmacists who are treating you that you are taking DILATREND.

If you are having surgery, be sure to tell your surgeon and anaesthetist that you are taking

DILATREND.

Tell your doctor if you become pregnant while taking DILATREND.

Tell your doctor that you are taking DILATREND if you are going to have any laboratory tests.

Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed.

Otherwise your doctor may think that it was not effective and change your treatment unnecessarily.

Tell your doctor if you feel that the tablets are not helping your condition.

Be sure to keep all of your appointments with your doctor 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.

Things you must not do

Do not stop taking DILATREND or change the dose without first checking with your doctor.

Do not let yourself run out of medicine over the weekend or on holidays.

DILATREND should only be stopped by gradually reducing the amount you are taking as directed by

your doctor.

Do not give DILATREND to anyone else even if they have the same condition as you.

Do not use DILATREND to treat other complaints unless your doctor says to.

Dilatrend

-October 2018

Do not take any other medicines whether they require a prescription or not without first telling

your doctor or consulting a pharmacist.

Things to be careful of

Be careful driving or operating machinery until you know how DILATREND affects you.

DILATREND may affect your ability to drive a car or operate machinery when you start taking it, or

when the dosage is increased, or in combination with alcohol.

If you wear contact lenses you may also notice less tear fluid in your eyes. You may find you have to

use your contact lenses less or switch to glasses.

If you are not sure what to do, contact your doctor or pharmacist.

In case of an overdose

If you take too much (overdose)

Immediately telephone your doctor or National Poisons Centre (telephone 0800 POISON or

0800 764 766) or go to your nearest Accident and Emergency Centre if you think that you or

anyone else may have taken too much DILATREND.

Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

The following are some symptoms which may or may not occur.

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.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking

DILATREND.

DILATREND 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 treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor 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

Dilatrend

-October 2018

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.

These are the more common side effects of DILATREND. Mostly these are mild.

Tell your doctor immediately or go to your nearest Accident and Emergency Centre if you

notice any of the following:

shortness of breath

swelling of the mouth or tongue

uneven heart beating

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/nightmares

loss of bladder control

severe skin reactions - blisters and bleeding in the lips, eyes, mouth, nose and genitals

These may be serious side effects. You may need urgent medical attention. Serious side effects are

rare.

This is not a complete list of all possible side effects. Other adverse effects not listed above may also

occur in some patients.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on

this list.

Ask your doctor or pharmacist if you don’t understand anything in this list.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After using DILATREND

Storage

Keep your tablets in the blister until it is time to take them.

If you take the tablets out of the blister pack they may not keep well.

Keep DILATREND in a cool dry place where the temperature stays below 30

°

C.

Do not store it or any other medicine in a bathroom or near a sink or any other place where

there is high humidity.

Do not leave it in the car or on windowsills.

Heat and dampness can destroy some medicines.

Keep DILATREND where young 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

Dilatrend

-October 2018

If your doctor tells you to stop taking DILATREND, or the tablets have passed their expiry date, ask

your pharmacist what to do with any tablets that are left over.

Product description

Availability

DILATREND comes in three tablet strengths – 6.25 mg, 12.5 mg and 25 mg.

All strengths of DILATREND come in packs of 30.

What DILATREND looks like

6.25 mg tablet – yellow round tablet with raised centre, scored and with BM on one side and F1 on the

other.

12.5 mg tablet – light brown round tablet with raised centre, scored and with BM on one side and H3

on the other.

25 mg tablet – white to pale yellowish beige round tablet with raised centre, scored and with BM on

one side and D5 on the other.

Ingredients

Active ingredient – carvedilol

each 6.25 mg tablet contains 6.25 mg carvedilol

each 12.5 mg tablet contains 12.5 mg carvedilol

each 25 mg tablet contains 25 mg carvedilol

Inactive ingredients – each strength of tablet contains:

Lactose

Sucrose

Povidone

Crospovidone

Colloidal silicon dioxide

Magnesium stearate

Yellow iron oxide (6.25 mg and 12.5 mg tablets only)

Red iron oxide (12.5 mg tablets only)

DILATREND tablets contain lactose and sucrose.

DILATREND tablets are gluten free.

Sponsor details

DILATREND is supplied in New Zealand by:

Pharmaco (NZ) Ltd

4 Fisher Crescent

Mt Wellington

Auckland 1060

Telephone: 09 377 3336

Date of preparation

This leaflet was prepared on 24 October 2018.

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October 2018

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DILATREND® tablets

Carvedilol

1 PRODUCT NAME

Dilatrend 6.25 mg tablets

Dilatrend 12.5 mg tablets

Dilatrend 25 mg tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 tablet contains 6.25 mg, 12.5 mg or 25 mg carvedilol.

Excipient(s) with known effect: Lactose, sucrose.

For full list of excipients, see Section 6.1 List of excipients.

3 PHARMACEUTICAL FORM

Tablets for oral administration.

Dilatrend 6.25 mg tablet: yellow, round biconvex tablet, with a bilateral scoreline engraved with 'BM'

on one side and 'F1' on the other side.

Dilatrend 12.5 mg tablet: light brown, round biconvex tablet, with a bilateral scoreline engraved with

'BM' on one side and 'H3' on the other side.

Dilatrend 25 mg tablet: white to pale yellowish beige, round biconvex tablet, with a bilateral

scoreline engraved with 'BM' on one side and 'D5' on the other side.

4 CLINICAL PARTICULARS

4.1

Therapeutic indications

Hypertension

Dilatrend 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

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

Chronic heart failure (CHF)

Unless a contraindication exists, Dilatrend 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

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

infarction.

4.2

Dose and method of 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, Dilatrend should be taken with food to slow the

rate of absorption and reduce the incidence of orthostatic effects.

Duration of treatment

Treatment with Dilatrend is a long-term therapy. As with all β-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

recommended

dosage

once

day.

necessary,

dosage

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

recommended

dosage

twice

day.

necessary,

dosage

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.

those

patients

receiving

digitalis,

diuretics

inhibitors,

dosing

these

medicines should be stabilised prior to initiation of Dilatrend 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

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

If Dilatrend 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

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Dilatrend 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 Dilatrend 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 Dilatrend

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. Dilatrend can then be started between day 3

and day 21 after the myocardial infarction.

First dose of Dilatrend

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 Section 4.4 Special warnings and precautions for

use; General).

Subsequent doses of Dilatrend

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

80 mm Hg, 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 Dilatrend dosing recommendations

are warranted in patients with moderate to severe renal insufficiency.

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Hepatic impairment

Dilatrend is contraindicated in patients with clinical manifestations of liver dysfunction (see Section

4.3 Contraindications).

Elderly

There is no evidence to support dose adjustment.

Paediatric population

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

(see Section 5.2 Pharmacokinetic properties; Pharmacokinetics in special populations; Children).

4.3

Contraindications

Dilatrend must not be used in patients with:

hypersensitivity to carvedilol or any component of the product.

unstable/decompensated heart failure.

clinically manifest liver dysfunction.

As with other β–blockers, Dilatrend must not be used in patients with:

2nd and 3rd degree atrioventricular (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 mmHg)

cardiogenic shock

history of bronchospasm or asthma

history of other obstructive lung disorders

4.4

Special warnings and precautions for use

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 Section

4.5 Interaction with other medicines and other forms of interaction).

Chronic heart failure

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

titration of Dilatrend. If such symptoms occur, diuretics should be increased and the Dilatrend dose

should not be further increased until clinical stability resumes. Occasionally, it may be necessary to

lower the Dilatrend dose or, in rare cases, temporarily discontinue it. Such episodes do not preclude

subsequent

successful

up-titration

Dilatrend.

Dilatrend

should

used

with

caution

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

Section 4.5 Interaction with other medicines and other forms of interaction).

Renal function in congestive heart failure

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Reversible deterioration of renal function has been observed with Dilatrend 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 Dilatrend 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 Section 4.2 Dose and method of

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 Dilatrend should be reduced if any evidence of bronchospasm is

observed during treatment.

Diabetes

Care should be taken in the administration of Dilatrend 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 Section 4.5 Interaction with other medicines and

other

forms

interaction

Special

warnings

precautions

use;

special

populations).

Peripheral vascular disease and Raynaud’s phenomenon

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

phenomenon) as β-blockers can precipitate or aggravate symptoms of arterial insufficiency.

Thyrotoxicosis

Dilatrend, like other agents with β-blocking properties, may obscure the symptoms of thyrotoxicosis.

Bradycardia

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

minute, the dosage of Dilatrend should be reduced.

Hypersensitivity

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

reactions, and in patients undergoing desensitisation therapy, as β-blockers may increase both the

sensitivity towards allergens and the severity of hypersensitivity reactions.

Severe cutaneous adverse reactions (SCARs)

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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 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 β-blocker therapy should take Dilatrend only after

consideration of the risk-benefit ratio.

Pheochromocytoma

In patients with pheochromocytoma, an α- blocking agent should be initiated prior to the use of any

β-blocking agent. Although Dilatrend has α- and β-blocking pharmacological activities, there is no

experience with its use in this condition. Caution should therefore be taken in the administration of

Dilatrend to patients suspected of having pheochromocytoma.

Prinzmetal's variant angina

Agents with non-selective β-blocking activity may provoke chest pain in patients with Prinzmetal's

variant angina. There is no clinical experience with Dilatrend in these patients although the α-

blocking

activity

Dilatrend

prevent

such

symptoms.

Caution

should

taken

administration of Dilatrend 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

Dilatrend treatment should not be discontinued abruptly, particularly in patients suffering from

ischaemic heart disease. The withdrawal of Dilatrend should be gradual (over a period of two

weeks).

Use in special populations

Paediatric use

See Section 4.2 Dose and method of 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 Section 4.2 Dose and method of 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

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changes in carvedilol dosage recommendations are warranted (see Section 4.2 Dose and method of

administration; Special dosage instructions.

Hepatic impairment

Carvedilol is contraindicated in patients with clinically manifest liver dysfunction (see Section 4.3

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

increase

insulin

resistance

mask

hypoglycaemic

symptoms.

However,

numerous studies have established that vasodilating β-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.

Lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-

galactose malabsorption should not take this medicine.

Sucrose

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or

sucrase-isomaltase insufficiency should not take this medicine.

4.5

Interaction with other medicines and other forms of interaction

Pharmacokinetic interactions

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

S-carvedilol

(see

Section

Pharmacokinetic

Properties;

Biotransformation).

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 β-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.

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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.

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

P-glycoprotein

increased

with

concomitant

administration

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

female

patients.

Therefore

monitoring

digoxin

levels

recommended

when

initiating, adjusting or discontinuing carvedilol (see Section 4.4 Special warnings and precautions for

use). 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 concentration following the initiation of carvedilol. It

appears that carvedilol increases exposure to oral cyclosporin by around 10 to 20 %. In an attempt to

maintain therapeutic cyclosporin levels, an average 10 - 20% reduction of the cyclosporin 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 inter-individual variability of cyclosporin 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.

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).

patients

taking

insulin

oral

hypoglycaemics,

regular

monitoring of blood glucose is therefore recommended (see Section 4.4 Special warnings and

precautions for use; General).

Catecholamine-depleting agents: Patients taking both agents with β-blocking properties and a

medicine that can 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:

combination with Dilatrend 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 β-blocking properties, if

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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 β-blocking properties may

potentiate

blood-pressure-

heart-rate-lowering

effects.

When concomitant

treatment with

agents with β-blocking properties and clonidine is to be terminated, the β-blocking agent should be

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

decreasing the dosage.

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

of other concomitantly administered medicines that are anti-hypertensive in action (e.g. α

-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 Dilatrend and anaesthetic medicines.

Non-steroidal anti-inflammatory drugs (NSAIDs): The concurrent use of NSAIDs and β-adrenergic

blockers may result in an increase in blood pressure and impairment of blood pressure control.

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

β-agonist bronchodilators. Careful monitoring of patients is recommended.

Digoxin:

combined

β-blockers

digoxin

result

additive

prolongation

atrioventricular (AV) conduction time.

4.6

Fertility, pregnancy and lactation

Pregnancy

Studies in animals have shown reproductive toxicity (see Section 5.3 Preclinical safety data). The

potential risk for humans is unknown.

Beta

blockers

reduce

placental

perfusion,

which

result

intrauterine

foetal

death,

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.

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

risk.

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.

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4.7

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and 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.

4.8

Undesirable 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:

Table 1: Adverse drug reactions in clinical trials

Very common

(≥1/10)

Common

(1/100 to ˂1/10)

Uncommon

(1/1,000 to <1/100)

Rare

(1/10,000 to

<1/1000)

Very Rare

(<1/10,000)

Infections and

Infestations

Pneumonia, Bronchitis,

Upper respiratory tract

infection, Urinary tract

infection

Blood and

Lymphatic System

Disorders

Anaemia

Thrombocytope

Leukopenia

Immune System

Disorders

Hypersensitivity

(allergic

reactions)

Metabolism and

Nutrition Disorders

Weight increase,

Hypercholesterolaemia,

Impaired blood glucose

control (hyperglycaemia,

hypoglycaemia) in

patients with pre-existing

diabetes

Psychiatric

Disorders

Depression, depressed

mood

Sleep disorders

Nervous System

Disorders

Dizziness,

Headache,

Syncope, presyncope

Paraesthesia

Eye Disorders

Visual impairment,

Lacrimation decreased

(dry eye), Eye irritation

Cardiac Disorders

Cardiac failure

Bradycardia,

Hypovolaemia, Fluid

overload

Atrioventricular

block, Angina

pectoris

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Very common

(≥1/10)

Common

(1/100 to ˂1/10)

Uncommon

(1/1,000 to <1/100)

Rare

(1/10,000 to

<1/1000)

Very Rare

(<1/10,000)

Vascular Disorders

Hypotension

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

Dyspnoea, Pulmonary

oedema, Asthma in

predisposed patients

Nasal

congestion

Gastrointestinal

Disorders

Nausea, Diarrhoea,

Vomiting, Dyspepsia,

Abdominal pain

Constipation

Dry mouth

Hepatobiliary

Disorders

Alanine

aminotransferase

(ALT), aspartate

aminotransferase

(AST) and gamma-

glutamyltransfera

se (GGT)

increased

Skin and

Subcutaneous

Disorders

Skin reactions (e.g.

allergic exanthema,

dermatitis,

urticarial, pruritus,

psoriatic and lichen

planus like skin

lesions)

Musculoskeletal

and Connective

Tissue Disorders

Pain in extremities

Renal and Urinary

Disorders

Renal failure and renal

function abnormalities in

patients with diffuse

vascular disease and/or

underlying renal

insufficiency

Micturition

disorders

Reproductive

System and Breast

Disorders

Erectile dysfunction

General Disorders

and Administration

Site Conditions

Asthenia

(fatigue)

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.

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

during up-titration of carvedilol dose (see Section 4.4 Special warnings and precautions for use).

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 Section 4.4 Special warnings and precautions for use).

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.

Skin and subcutaneous tissue disorders:

Alopecia

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

Section 4.4 Special warnings and precautions for use).

Metabolism and nutrition disorders

Due to the β-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.

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows

continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are

asked to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/

4.9

Overdose

Symptoms and signs of overdose

In the event of overdosage, there may be severe hypotension, bradycardia, heart failure, cardiogenic

shock

cardiac

arrest.

There

also

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

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

inhibitors such as amrinone or milrinone, β-sympathomimetics).

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 overdose. The supportive treatment should therefore be continued until the patient’s

condition has stabilised.

For advice on the management of overdose please contact the National Poisons Centre on 0800

POISON (0800 764766).

5 PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Alpha and beta blocking agents

ATC code: C07AG02

Mechanism of action

Carvedilol is a multiple action adrenergic receptor blocker with α

and β

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 antiproliferative 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

β-adrenergic

receptor

blocking

properties

non-selective

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

Carvedilol

intrinsic

sympathomimetic

activity

(like

propranolol)

membrane

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

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

Carvedilol

reduces

peripheral

vascular

resistance

selective

blockade

-adrenoceptors.

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

-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 Dilatrend:

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Hypertension

Dilatrend lowers blood pressure in hypertensive patients by a combination of β-blockade and α

mediated vasodilation. Some of the limitations of traditional β-blockers do not appear to be shared

by some of the vasodilating β-blockers, such as carvedilol. A reduction in blood pressure is not

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

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

in hypertensive patients. Dilatrend 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 Dilatrend. There is a

reduced incidence of cold extremities and early fatigue during physical activity. The long-term effect

of Dilatrend on hypertension is documented in several double-blind controlled studies.

Renal impairment

Several

open

studies

have

shown

that

carvedilol

effective

agent

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, Dilatrend has demonstrated anti-ischaemic (improved total

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

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

that Dilatrend 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

Dilatrend 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

Dilatrend 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

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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 failure), Dilatrend 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

(p = 0.031),

all-cause

mortality

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 Dilatrend significantly reduced death or major cardiovascular hospitalisation by

17% (p = 0.019).

5.2

Pharmacokinetic properties

Absorption

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

with a peak plasma concentration Cmax of 21mg/L reached after approximately 1.5 hours (tmax).

The Cmax 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.

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.

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.

Biotransformation

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 β-adrenergic

receptor

blocking

activity.

Based

pre-clinical

studies,

4’-hydroxy-phenol

metabolite

approximately 13 times more potent than carvedilol for β-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

vitro

study

suggested

that

different

cytochrome

P450

isoenzymes

involved

oxidation

hydroxylation

processes

including

CYP2D6,

CYP3A4, CYP2E1, CYP2C9 as well as CYP1A2.

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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 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

Following a single oral administration of 50mg 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,

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 12.5mg to healthy

volunteers, the plasma clearance of carvedilol reaches around 600mL/min and the elimination half-

life around 2.5 hours. The elimination half-life of a 50mg capsule observed in the same individuals

hours

corresponding

absorption

half-life

from

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

maximum

plasma

concentration

does

change

significantly.

Renal

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

changes in pharmacokinetic parameters are modest.

Carvedilol is

eliminated during

dialysis

because

does

cross

the dialysis membrane,

probably due to its high plasma protein binding.

Hepatic impairment

See Section 4.3 Contraindications and 4.4 Special warnings and precautions for use; Use in special

populations.

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.

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Children

Investigation in paediatrics has shown that the weight-adjusted clearance is significantly larger in

paediatrics as compared to adults.

5.3

Preclinical safety data

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).

6 PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Lactose

Sucrose

Povidone

Crospovidone

Colloidal silicon dioxide

Magnesium stearate

Yellow iron oxide (6.25 mg and 12.5 mg tablets only)

Red iron oxide (12.5 mg tablets only)

6.2

Incompatibilities

Not applicable

6.3

Shelf life

Tablets 6.25 mg – 36 months

Tablets 12.5 mg – 48 months

Tablets 25 mg – 60 months

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6.4

Special precautions for storage

Dilatrend tablets should be stored in a dry place below 30 °C and protected from light.

Dilatrend tablets should not be used after the expiry date printed on the pack.

6.5

Nature and contents of container

Tablets 6.25 mg – blister pack of 30 (pack of 100 not available), Alu-PVC or Alu-polyamide-PVC

Tablets 12.5 mg – blister pack of 30 (pack of 100 not available), Alu-PVC or Alu-polyamide-PVC

Tablets 25 mg – blister pack of 30 (pack of 100 not available), Alu-PVC or Alu-polyamide-PVC

6.6

Special precautions for disposal

The release of medicines into the environment should be minimised. Medicines should not be

disposed of via wastewater and disposal through household waste should be avoided. Unused or

expired medicine should be returned to a pharmacy for disposal.

7 MEDICINE SCHEDULE

Prescription medicine

8 SPONSOR

Pharmaco (NZ) Ltd

4 Fisher Crescent

Mt Wellington

Auckland 1060

Telephone: 09 377 3336

9 DATE OF FIRST APPROVAL

Tablets 6.25 mg – 17 Apr 1997

Tablets 12.5 mg – 17 Apr 1997

Tablets 25 mg – 05 May 1994

10 DATE OF REVISION OF THE TEXT

24 October 2018

[CDS 6.0. Dated March 2014]

SUMMARY TABLE OF CHANGES

Section changed

Summary of new information

Reformatted to new SPC format, references to 3.125mg tablet removed as

approval has lapsed

Section 2 & 4.4

Addition of excipients with known effect and associated warnings

Section 4.8

Addition of Leukopenia in Table 1: Adverse drug reactions in clinical trials

Section 8

Details updated to reflect change in sponsorship

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