Candestar

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Candesartan cilexetil 16 mg;  
Available from:
Mylan New Zealand Ltd
INN (International Name):
Candesartan cilexetil 16 mg
Dosage:
16 mg
Pharmaceutical form:
Tablet
Composition:
Active: Candesartan cilexetil 16 mg   Excipient: Carmellose calcium Hyprolose Lactose monohydrate Magnesium stearate Mannitol
Units in package:
Blister pack, cold form, OPA/Al/PVC, hard tempered Al foil, 30 tablets
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Zhejiang Huahai Pharmaceutical Co Ltd
Therapeutic indications:
Hypertension
Product summary:
Package - Contents - Shelf Life: Blister pack, cold form, OPA/Al/PVC, hard tempered Al foil - 30 tablets - 24 months from date of manufacture stored at or below 25°C - Blister pack, cold form, OPA/Al/PVC, hard tempered Al foil - 90 tablets - 24 months from date of manufacture stored at or below 25°C - Bottle, HDPE, white, with opaque screw, absorbent cotton and desiccant - 30 tablets - 24 months from date of manufacture stored at or below 25°C - Bottle, HDPE, white, with opaque screw, absorbent cotton and desiccant - 90 tablets - 24 months from date of manufacture stored at or below 25°C
Authorization number:
TT50-8582b
Authorization date:
2010-05-27

Page 1 of 4

NEW ZEALAND CONSUMER MEDICINE INFORMATION

CANDESTAR

Candesartan cilexetil

4 mg, 8 mg, 16 mg and 32 mg tablets

What is in this leaflet

This leaflet answers some common

questions about Candestar.

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 will have

weighed the risks of you taking

Candestar 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 Candestar is

used for

Candestar contains the active

ingredient candesartan cilexetil. It

belongs to a group of medicines

called angiotensin II receptor

blockers, or ARBs.

Candestar is used to treat:

high blood pressure

(hypertension)

heart failure patients with

reduced heart muscle

function

Candestar works by blocking the

effects of the hormone, angiotensin

II. This causes relaxation or

widening of the blood vessels which

results in a lowering of the blood

pressure.

It also helps with heart failure by

widening the blood vessels, so that

the heart does not have to pump as

hard to move the blood around the

body. This also means that 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.

Before you take

Candestar

When you must not take

it:

Do not take Candestar if you

have an allergy to:

any medicine containing

candesartan

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 this medicine if you

have or have had any of the

following medical conditions:

severe liver problems

diabetes (type I or II) or

moderate to severe kidney

problems, and also taking

any aliskiren- containing

medicines

Do not take this medicine if you

are pregnant.

It may affect your developing baby if

you take it during pregnancy.

Do not breast-feed if you are

taking this medicine.

It is not known whether the active

ingredient in Candestar passes into

breast milk.

Do not give Candestar to

children.

Safety and effectiveness in children

has not been established.

Do not take this medicine after

the expiry date, or if the bottle

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:

heart problems

mild to moderate liver

problems

mild kidney problems

If you have not told your doctor

about any of the above, tell

him/her before you start taking

Candestar.

Taking other medicines

Tell your doctor or pharmacist if

you are taking any other

medicines, including any that you

Page 2 of 4

get without a prescription from

your pharmacy, supermarket or

health food shop.

Some medicines and Candestar

may interfere with each other.

These include:

other medicines used to

treat high blood pressure

including angiotensin

converting enzyme (ACE)

inhibitors and other

angiotensin II receptor

blockers (ARBs)

any medicine containing

potassium, including

potassium-sparing diuretics,

potassium supplements,

salt substitutes or

medicines that may

increase potassium levels

(e.g. heparin or

cotrimoxazole)

lithium, a medicine used to

treat mood swings and

some types of depression

non-steroidal anti-

inflammatory drugs

(NSAIDs), used to treat

pain and inflammation

any medicine containing

aliskiren used in patients

with diabetes (type I or II) or

who have moderate to

severe kidney problems

These medicines may be affected

by Candestar 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

Candestar.

How to take

Candestar

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 bottle, ask

your doctor or pharmacist for

help.

How much to take

Hypertension:

The usual adult starting dose is 8

mg once daily. Your doctor may

increase this dose to 16 mg once a

day and further up to 32 mg once a

day depending on blood pressure

response.

In some patients, such as those

with liver or kidney problems, your

doctor may prescribe a lower

starting dose.

Heart Failure:

The usual adult starting dose is 4

mg once daily. Your doctor may

increase your dose up to 32 mg

once a day over intervals of at least

2 weeks.

How to take it

Swallow the tablets whole with a

full glass of water.

Candestar tablets may be broken in

half if required.

When to take it

Take your medicine at about the

same time each day.

Taking it at the same time each day

will have the best effect. It will also

help you remember when to take it.

It does not matter if you take

Candestar with or without food.

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.

If you forget to take it

If it is almost time for your next

dose, skip the dose you missed

and take your next dose when

you are meant to. Otherwise, take

it as soon as you remember, and

then go back to taking your

medicine as you would normally.

Do not take a double dose to

make up for the dose that you

missed.

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 Candestar. Do

this even if there are no signs of

discomfort or poisoning. You may

need urgent medical attention.

While you are using

Candestar

Things you must do

If you are about to be started on

any new medicines, remind your

doctor and pharmacist that you

are taking Candestar.

Tell any other doctors, dentists,

and pharmacists who treat you

that you are taking Candestar.

If you are going to have surgery,

tell the surgeon or anaesthetist

that you are taking this medicine.

If you become pregnant while

taking this medicine, tell your

doctor immediately.

If you are about to have any

blood tests, tell your doctor that

you are taking this medicine.

Candestar may interfere with the

results of some tests.

Keep all of your doctor’s

appointments so that your

progress can be checked.

Things you must not do

Do not take Candestar 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.

Do not stop taking your medicine

or lower the dosage without

Page 3 of 4

checking with your doctor.

Things to be careful of

Be careful driving or operating

machinery until you know how

Candestar affects you.

This medicine may cause dizziness

or drowsiness in some people. If

you feel dizzy or drowsy, do not

drive, operate machinery or do

anything else that could be

dangerous.

If you feel light-headed, dizzy or

faint when getting out of bed or

standing up, get up slowly.

Standing up slowly, especially when

you get up from bed or chairs, will

help your body get used to the

change in position and blood

pressure. If this problem continues

or gets worse, talk to your doctor.

Side effects

Tell your doctor or pharmacist as

soon as possible if you do not

feel well while you are taking

Candestar.

Candestar 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:

dizziness, lightheadedness

cough

back pain

The above list includes the more

mild side effects of Candestar.

If any of the following happen,

tell your doctor immediately or

go to Accident and Emergency at

your nearest hospital:

swelling of the face, lips,

tongue or throat which may

cause difficulty in

swallowing or breathing

severe and sudden onset of

rash, itchiness, hives (itchy

swellings on the skin)

worsening of kidney

function (symptoms may

include passing little or no

urine, nausea or vomiting,

loss of appetite and

weakness)

nausea, diarrhoea, muscle

weakness and changes in

heart rhythm (these

symptoms may indicate

high potassium levels in the

blood)

frequent infections such as

fever, severe chills, sore

throat or mouth ulcers

jaundice (yellowing of the

skin and / or eyes)

The above list includes very serious

side effects. You may need urgent

medical attention or hospitalisation.

Tell your doctor or pharmacist if

you notice anything that is

making you feel unwell.

Other side effects not listed above

may also occur in some people.

Some side effects such as changes

in your potassium, sodium or white

blood cell levels can only be found

when your doctor does tests to

check your progress. It is important

you keep all of your doctor’s

appointments so that your progress

can be checked.

After using

Candestar

Storage

Keep your tablets in the bottle

until it is time to take them.

If you take the tablets out of the

bottle they may not keep well.

Keep your tablets in a cool dry

place where the temperature stays

below 25°C.

Do not store Candestar 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 Candestar 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

Candestar 4 mg tablets are white to

off white, round tablets marked with

“M” over “C1” on one side, and plain

with a break line on the other side.

Candestar 8 mg tablets are white to

off white, round tablets marked with

“M” over “C5” on one side, and plain

with a break line on the other side.

Candestar 16 mg tablets are white

to off white, round tablets marked

with “M” over “C6” on one side, and

plain with a break line on the other

side.

Candestar 32 mg tablets are white

to off white, round tablets marked

with “M” over “C7” on one side, and

plain with a break line on the other

side.

Ingredients

Candestar contains 4 mg, 8 mg, 16

mg or 32 mg of candesartan cilexetil

as the active ingredient.

The tablets also contain:

lactose

mannitol

carmellose calcium

hydroxypropyl cellulose

magnesium stearate

This medicine does not contain

sucrose, gluten, tartrazine or any

other azo dyes.

If you want to know

more

Page 4 of 4

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

13 February 2018

(Based on datasheet dated 13

February 2018)

Page 1 of 12

NEW ZEALAND DATA SHEET

CANDESTAR

1. Product Name

Candestar, 4 mg, 8 mg, 16 mg and 32 mg tablets.

2. Qualitative and Quantitative Composition

Each tablet contains 4 mg, 8 mg, 16 mg or 32 mg of candesartan cilexetil.

Contains lactose.

For the full list of excipients, see section 6.1.

3. Pharmaceutical Form

Candestar 4 mg: White to off white, round, biconvex tablet debossed with “M” over “C1” on one

side, and plain with a break line on the other side.

Candestar 8 mg: White to off white, round, biconvex tablet debossed with “M” over “C5” on one

side, and plain with a break line on the other side.

Candestar 16 mg: White to off white, round, biconvex tablet debossed with “M” over “C6” on one

side, and plain with a break line on the other side.

Candestar 32 mg: White to off white, round, biconvex tablet debossed with “M” over “C7” on one

side, and plain with a break line on the other side.

The tablet can be divided into equal doses.

4. Clinical Particulars

4.1

Therapeutic indications

Hypertension

Treatment of patients with heart failure and left ventricular systolic dysfunction. Treatment

with candesartan cilexetil reduces mortality, reduces hospitalisation due to heart failure,

and improves symptoms.

4.2

Dose and method of administration

Dosage in hypertension

The recommended initial and maintenance dose of Candestar is 8 mg once daily. The dose may

be increased to 16 mg once daily. In patients who require further blood pressure reduction, the

dose may be increased to 32 mg once daily.

Page 2 of 12

Therapy should be adjusted according to blood pressure response. The maximal antihypertensive

effect is attained within 4 weeks after initiation of treatment.

In patients with less than optimal blood pressure reduction on Candestar, combination with a

thiazide diuretic is recommended.

Use in the elderly

No initial dosage adjustment is necessary for elderly patients.

Use in impaired renal function

No initial dosage adjustment is necessary in patients with mild to moderate impaired renal function

(i.e. creatinine clearance ≥ 30-80 mL/min/1.73 m

BSA). In patients with severe impaired renal

function (i.e. creatinine clearance <30 mL/ min/1.73 m

BSA), including patients on haemodialysis a

lower initial dose of 4 mg should be considered.

Use in impaired hepatic function

Patients with hepatic impairment: Dose titration is recommended in patients with mild to moderate

chronic liver disease, and a lower initial dose of 4 mg should be considered. Candestar should not

be used in patients with severe hepatic impairment and/or cholestasis (see section 4.3).

Concomitant therapy

Candestar may be administered with other antihypertensive agents (see section 5.1)

Dosage in heart failure

The usual recommended initial dose for Candestar is 4 mg once daily. Up-titration to the target

dose of 32 mg once daily or the highest tolerated dose is done by doubling the dose at intervals of

at least 2 weeks (see section 4.4).

Special patient populations

No initial dose adjustment is necessary for elderly patients.

Concomitant therapy

Candestar can be administered with other heart failure treatment, including ACE inhibitors, beta-

blockers, diuretics and digitalis or a combination of these medicinal products (see section 4.4 and

5.2).

Method of administration

Candestar should be taken once daily with or without food.

Use in Children

The safety and efficacy of Candestar have not been established in children.

4.3

Contraindications

Hypersensitivity to any component present in Candestar tablets.

Pregnancy and lactation.

Severe hepatic impairment and/or choleostasis.

The use of candesartan cilexetil in combination with aliskiren-containing medicines in patients with

diabetes mellitus (type I or II) or moderate to severe renal impairment (GFR <60 mL/min/1.73m

Page 3 of 12

4.4

Special warnings and precautions for use

Hypotension

Hypotension may occur during treatment with candesartan cilexetil in heart failure patients. As

described for other agents acting on the renin-angiotensin-aldosterone system, it may also occur in

hypertensive patients with intravascular volume depletion. Caution should be observed when

initiating therapy and correction of hypovolaemia should be attempted.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or

aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including

acute renal failure). Dual blockade of RAAS through the combined use of candesartan cilexetil

with

an ACE-inhibitor or aliskiren is therefore not recommended (see section 4.5).

dual

blockade

therapy

considered

necessary,

this

should

only

occur

under

specialist

supervision and subject to frequent close monitoring of renal function, electrolytes and blood

pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients

with diabetic nephropathy. The use of candesartan cilexetil with aliskiren is contraindicated in

patients

with

diabetes

mellitus

(type

moderate

severe

renal

impairment

(GFR<60ml/min/1.73m

) (see section 4.3).

Use in heart failure

Triple combination of candesartan cilexetil with an ACE-inhibitor and a mineralocorticoid receptor

antagonist used in heart failure is also not recommended. Use of these combinations should be

under specialist supervision and subject to frequent close monitoring of renal function, electrolytes

and blood pressure.

Renal artery stenosis

Other drugs that affect the renin-angiotensin-aldosterone system,

i.e. angiotensin converting

enzyme (ACE) inhibitors, may increase blood urea and serum creatinine in patients with bilateral

renal artery stenosis or stenosis of the artery to a solitary kidney. A similar effect may be

anticipated with angiotensin II receptor antagonists.

Renal impairment

As with other agents inhibiting the renin-angiotensin-aldosterone system, changes in renal function

may be anticipated in susceptible patients treated with candesartan cilexetil.

When candesartan cilexetil is used in hypertensive patients with severe renal impairment, periodic

monitoring of serum potassium and creatinine levels should be considered. There is very limited

experience in patients with very severe or end-stage renal impairment (i.e. creatinine clearance

<15 mL/min/1.73 m

BSA).

Evaluation of patients with heart failure should include periodic assessments of renal function.

During dose titration of candesartan cilexetil, monitoring of serum creatinine and potassium is

recommended.

Kidney transplantation

There

is limited clinical

evidence regarding

candesartan

cilexetil

patients

have

undergone renal transplant.

Haemodialysis

During dialysis the blood pressure may be particularly sensitive to AT

-receptor blockade as a

result of reduced plasma volume and activation of the renin-angiotensin-aldosterone system.

Page 4 of 12

Therefore, candesartan cilexetil should be carefully titrated with thorough monitoring of blood

pressure in patients on haemodialysis. (see section 4.2).

Hepatic impairment

There is only limited experience in patients with severe hepatic impairment and/or cholestasis.

Aortic and mitral valve stenosis (or Obstructive hypertrophic cardiomyopathy)

As with other vasodilators, special caution is indicated in patients suffering from haemodynamically

relevant aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy.

Hyperkalaemia

Based on experience with the use of other drugs that affect the renin-angiotensin-aldosterone

system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes

containing

potassium

other

drugs

that

increase

potassium

levels

(e.g.

heparin,

cotrimoxazole) may lead to increases in serum potassium in hypertensive patients.

In heart failure patients treated with candesartan cilexetil, hyperkalaemia may occur. During

treatment with candesartan cilexetil in patients with heart failure, periodic monitoring of serum

potassium

recommended,

especially

when

taken

concomitantly

with

inhibitors

potassium-sparing diuretics such as spironolactone.

Anaesthesia and surgery

Hypotension may occur during anaesthesia and surgery in patients treated with angiotensin II

antagonists due to blockage of the renin-angiotensin system. Very rarely, hypotension may be

severe such that it may warrant the use of intravenous fluids and/or vasopressors.

General

In patients whose vascular tone and renal function depend predominantly on the activity of the

renin-angiotensin-aldosterone

system

(e.g.

patients

with

severe

congestive

heart

failure

underlying renal disease, including renal artery stenosis), treatment with drugs that affect this

system has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal

failure.

As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic

heart disease or atherosclerotic cerebrovascular disease could result in a myocardial infarction or

stroke.

4.5

Interaction with other medicines and other forms of interaction

Clinical trial data has shown that dual blockade of the RAAS through the combined use of ACE-

inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of

adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute

renal failure) compared to the use of a single RAAS-acting agent (see section 4.3 and 4.4).

Compounds

which

have

been

investigated

clinical

pharmacokinetic

studies

include

hydrochlorothiazide, warfarin, digoxin, oral contraceptives (i.e. ethinyloestradiol / levonorgestrel),

glibenclamide, nifedipine and enalapril.

No pharmacokinetic interactions of clinical significance

were identified in these studies.

Reversible increases in serum lithium concentrations and toxicity have been reported during

concomitant

administration

lithium

with

inhibitors.

similar

effect

occur

with

angiotensin II receptor antagonists (AIIRAs)

and careful monitoring of serum lithium levels is

recommended during concomitant use.

The antihypertensive effect of angiotension II receptor antagonists, including candesartan may be

attenuated by NSAIDs; including selective COX-2 inhibitors and acetylsalicylic acid.

Page 5 of 12

As with ACE inhibitors, concomitant use of AIIRAs and NSAIDs may lead to an increased risk of

worsening of renal function, including possible acute renal failure, and an increase in serum

potassium, especially in patients with poor pre-existing renal function. The combination should be

administered with caution, especially in older patients and in volume depleted patients. Patients

should be adequately hydrated and consideration should be given to monitoring renal function after

initiation of concomitant therapy and periodically thereafter.

The antihypertensive effect of candesartan cilexetil may be enhanced by other antihypertensives.

The bioavailability of candesartan is not affected by food.

4.6

Fertility, pregnancy and lactation

Pregnancy

The use of candesartan cilexetil

is contraindicated during pregnancy (see section 4.3). Patients

receiving

candesartan

should

made

aware

that

before

contemplating

possibility

becoming pregnant so that they can discuss appropriate options with their treating physician.

When pregnancy is diagnosed, treatment with candesartan cilexetil

must be stopped immediately

and if appropriate, alternative therapy should be started.

When used in pregnancy, medicines that act directly on the renin-angiotensin system can cause

foetal and neonatal injury and death. Exposure to angiotensin II receptor antagonist therapy is

known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification

retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3).

Breast-feeding

It is not known whether candesartan cilexetil

is excreted in human milk. However, candesartan is

excreted in the milk of lactating rats. Because of the potential for adverse effects on the nursing

infant, breast feeding should be discontinued if the use of candesartan cilexetil is considered

essential (see section 4.3).

Fertility

No data available. For pre-clinical fertility data refer to section 5.3.

4.7

Effects on ability to drive and use machines

The effect of candesartan cilexetil on the ability to drive and use machines has not been studied,

but based on its pharmacodynamic properties candesartan cilexetil is unlikely to affect this ability.

When driving vehicles or operating machines, it should be taken into account that dizziness or

weariness may occur during treatment.

4.8

Undesirable effects

Treatment of hypertension

Candesartan cilexetil

was well tolerated in controlled clinical studies showing an adverse event

profile comparable to that of placebo. Generally adverse events were mild and transient.

The overall incidence of adverse events showed no association with dose, age or gender.

Withdrawals from treatment due to adverse events were similar with candesartan cilexetil (3.1%)

and placebo (3.2%).

Laboratory findings

In general, there were no clinically important influences of candesartan cilexetil on routine

laboratory variables. As for other inhibitors of the renin-angiotensin-aldosterone system, small

decreases in haemoglobin have been seen. Increases in creatinine, urea or potassium and

decreases in sodium have been observed. Increases in S-ALAT (S-GPT) were reported as

adverse events slightly more often with candesartan cilexetil than with placebo (1.3% vs 0.5%). No

Page 6 of 12

routine monitoring of laboratory variables is necessary for patients receiving candesartan cilexetil.

However, in patients with severe renal impairment, periodic monitoring of serum potassium and

creatinine levels should be considered.

Treatment of Heart Failure

The adverse experience profile of candesartan cilexetil in heart failure patients was consistent with

the pharmacology of the drug and the health status of the patients. In the CHARM clinical

programme, comparing candesartan cilexetil in doses up to 32 mg (n=3,803) to placebo (n=3,796),

21.0% of the candesartan cilexetil group and 16.1% of the placebo group discontinued treatment

because of adverse events. Adverse reactions commonly (≥ 1/100, <1/10) seen were:

Vascular disorders:

Hypotension.

Metabolism and nutrition disorders:

Hyperkalaemia.

Renal and urinary disorders:

Renal impairment.

Laboratory findings

Increases

creatinine,

urea

potassium.

Periodic

monitoring

serum

creatinine

potassium is recommended (see section 4.4).

Post-marketing

The following adverse reactions have been reported very rarely (<1/10,000) in post marketing

experience:

Blood and lymphatic system disorders:

Leukopenia, neutropenia and agranulocytosis.

Metabolism and nutrition disorders:

Hyperkalaemia, hyponatraemia.

Nervous system disorders:

Dizziness.

Respiratory, thoracic and mediastinal disorders:

Cough.

Hepato-biliary disorders:

Increased liver enzymes, abnormal hepatic function or hepatitis.

Skin and subcutaneous tissue disorders:

Angioedema, rash, urticaria, pruritus.

Musculoskeletal, connective tissue and bone disorders:

Back pain.

Renal and urinary disorders:

Renal impairment, including renal failure in susceptible patients (see section 4.4).

Page 7 of 12

Although causality to candesartan has not been established, palpitation has been very rarely

reported as an adverse event during post-marketing surveillance.

Reporting of suspected adverse reactions

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

Based on pharmacological considerations, the main manifestation of an overdose is likely to be

symptomatic hypotension and dizziness.

In single case reports of overdose (up to 672 mg candesartan cilexetil), patient recovery was

uneventful.

Management

If symptomatic hypotension should occur, symptomatic treatment should be instituted and vital

signs monitored. The patient should be placed supine with the legs elevated. If this is not sufficient,

plasma

volume

should

increased

infusion

example,

isotonic

saline

solution.

Sympathomimetic drugs may be administered if the above-mentioned measures are not sufficient.

Candesartan cilexetil cannot be removed by haemodialysis.

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

Centre (0800 POISON or 0800 764 766).

5. Pharmacological Properties

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Angiotensin II antagonists, plain, ATC code: C09CA06

Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and

plays

significant

role

pathophysiology

hypertension,

heart

failure

other

cardiovascular

disorders.

also

important

role

pathogenesis

organ

hypertrophy

damage.

major

physiological

effects

angiotensin

such

vasoconstriction, aldosterone stimulation, regulation of salt and water homeostasis and stimulation

of cell growth, are mediated via the type 1 (AT

) receptor.

Candesartan cilexetil

is a prodrug suitable for oral use. It is rapidly converted to the active drug,

candesartan, by ester hydrolysis during absorption from the gastrointestinal tract. Candesartan is

an angiotensin II receptor antagonist, selective for AT

receptors, with tight binding to and slow

dissociation from the receptor. It has no agonist activity.

Candesartan does not inhibit ACE, which converts angiotensin I to angiotensin II and degrades

bradykinin. Since there is no effect on the degradation of bradykinin, angiotensin II receptor

antagonists are unlikely to be associated with cough. In controlled clinical studies comparing

candesartan cilexetil with ACE inhibitors, the incidence of cough was lower in patients receiving

candesartan cilexetil.

Candesartan does not bind to or block other hormone receptors or ion channels known to be

important in cardiovascular regulation. The antagonism of the angiotensin II (AT

) receptors results

in dose related increases in plasma renin activity, angiotensin I and angiotensin II concentrations

and a decrease in plasma aldosterone concentration.

Page 8 of 12

Clinical efficacy and safety

Hypertension

In hypertension, candesartan cilexetil

causes a dose-dependent, long-lasting reduction in arterial

blood pressure. The antihypertensive action is due to decreased systemic peripheral resistance,

while heart rate, stroke volume and cardiac output are not affected.

There is no indication of serious or exaggerated first dose hypotension or rebound effect after

cessation of treatment.

After administration of a single dose of candesartan cilexetil onset of antihypertensive effect

generally occurs within 2 hours.

With continuous treatment, the maximum reduction in blood pressure with any dose is generally

attained within four weeks and is sustained during long-term treatment.

Candesartan cilexetil

once daily provides effective and smooth blood pressure reduction over 24

hours, with little difference between maximum and trough effects during the dosing interval. In two

8-week randomised, double-blind studies, the blood pressure lowering effects of candesartan

cilexetil

losartan

were

evaluated

total

1,268

patients

with

mild

moderate

hypertension.

both

studies,

reduction

systolic

diastolic

blood

pressure

significantly greater with candesartan cilexetil (32 mg once daily). In a pooled analysis, the trough

blood pressure reduction (systolic/diastolic) was 13.1/10.5 mmHg with candesartan cilexetil and

10.0/8.7 mmHg with losartan potassium (100 mg once daily). The mean difference in blood

pressure reduction was 3.1/1.8 mmHg (p<0.0001/p<0.0001).

Candesartan cilexetil

can be used as monotherapy or in combination with other antihypertensive

drugs, such as thiazide diuretics, dihydropyridine calcium antagonists and lisinopril, for enhanced

efficacy.

Candesartan cilexetil

is similarly effective in patients irrespective of age and gender. Candesartan

cilexetil

is effective in reducing blood pressure regardless of race, although the effect is somewhat

less in black patients (usually a low-renin population). This is generally true for drugs that block the

renin-angiotensin-aldosterone system.

Candesartan

cilexetil

increases

renal

blood

flow

either

effect

increases

glomerular

filtration

rate

while

renal

vascular

resistance

filtration

fraction

reduced.

Candesartan cilexetil also reduces urinary albumin excretion in patients with type II diabetes

mellitus, hypertension and microalbuminuria. In hypertensive patients with type II diabetes mellitus,

12 weeks treatment with candesartan cilexetil 8 mg to 16 mg had no adverse effects on blood

glucose or lipid profile.

In a trial, the effects of candesartan cilexetil based antihypertensive treatment on cardiovascular

morbidity and mortality, cognitive function and quality of life were assessed in 4,937 elderly

patients (aged 70-89 years) with hypertension (SBP 160-179 mmHg and/or DBP 90-99 mmHg).

The table shows the study results for the primary endpoint (major cardiovascular events) and its

components. Both treatment regimens lowered systolic and diastolic blood pressure effectively and

were generally well tolerated. Cognitive function and quality of life were well maintained in both

treatment arms.

Candesartan cilexetil*

No. of pts with

a first event

(N=2477)

Control*

No. of pts with a

first event

(N=2460)

Relative risk

(95% CI)

P-value

Major CV events

0.89

(0.75-1.06)

0.19

- CV mortality

0.95

0.63

Page 9 of 12

Candesartan cilexetil*

No. of pts with

a first event

(N=2477)

Control*

No. of pts with a

first event

(N=2460)

Relative risk

(95% CI)

P-value

(0.75-1.19)

- Non-fatal

stroke

0.72

(0.53-0.99)

0.04

- Non-fatal MI

1.14

(0.77-1.68)

0.52

*Any

previous

antihypertensive

treatment

standardized

hydrochlorothiazide

12.5

once

daily

before

randomisation. Other antihypertensive treatment was added to the double-blind study medication (candesartan cilexetil

8-16 mg or corresponding placebo once daily) if SBP remained ≥ 160 mmHg and/or DBP ≥ 90 mmHg.

Heart Failure

In patients with chronic heart failure (CHF) and depressed left ventricular systolic function (left

ventricular ejection fraction, LVEF ≤ 40%), candesartan cilexetil decreases systemic vascular

resistance

pulmonary

capillary

wedge

pressure,

increases

plasma

renin

activity

angiotensin II concentration, and decreases aldosterone levels.

Treatment

with

candesartan

cilexetil

reduces

mortality

hospitalisation

improves symptoms as shown in the Candesartan in Heart failure - Assessment of Reduction in

Mortality and morbidity (CHARM) programme. This multinational, placebo controlled, double-blind

study programme in CHF patients with NYHA functional class II to IV consisted of three separate

studies: CHARM-Alternative (n=2,028) in patients with LVEF ≤ 40% not treated with an ACE

inhibitor because of intolerance, CHARM-Added (n=2,548) in patients with LVEF ≤ 40% and

treated with an ACE inhibitor, and CHARM-Preserved (n=3,023) in patients with LVEF >40%.

Patients on optimal baseline therapy were randomised to placebo or candesartan cilexetil (titrated

from 4 mg or 8 mg once daily to 32 mg once daily or the highest tolerated dose, mean dose 24 mg)

and followed for a median of 37.7 months.

The composite endpoint of cardiovascular mortality or first CHF hospitalisation was significantly

reduced with candesartan cilexetil in comparison with placebo in CHARM-Alternative (hazard ratio

(HR) 0.77, 95% CI 0.67-0.89, p<0.001) and in CHARM-Added (HR 0.85, 95% CI 0.75-0.96,

p=0.011). This corresponds to a relative risk reduction of 23% and 15% respectively. A reduction,

although statistically non-significant, was also achieved in CHARM-Preserved (HR 0.89, 95% CI

0.77-1.03, p=0.118).

The composite endpoint of all-cause mortality or first CHF hospitalisation was also significantly

reduced with candesartan cilexetil in CHARM-Alternative (HR 0.80, 95% CI 0.70-0.92, p=0.001)

and CHARM-Added (HR 0.87, 95% CI 0.78-0.98, p=0.021), and a similar trend was observed in

CHARM-Preserved (HR 0.92, 95% CI 0.80-1.05, p=0.221).

Both the mortality and morbidity (CHF hospitalisation) components of the composite endpoints

contributed to the favourable effects of candesartan cilexetil in CHARM-Alternative and CHARM-

Added.

favourable

effects

indicated

CHARM-Preserved

were

reduced

hospitalisation.

All-cause mortality was also assessed in pooled populations, CHARM-Alternative and CHARM-

Added (HR 0.88, 95% CI

0.79-0.98, p=0.018) and all three studies (HR 0.91, 95% CI 0.83-1.00,

p=0.055).

Treatment with candesartan cilexetil resulted in improved NYHA functional class in CHARM-

Alternative and CHARM-Added (p=0.008 and p=0.020, respectively).

The beneficial effects of candesartan cilexetil on cardiovascular mortality and CHF hospitalisation

were consistent irrespective of age, gender and concomitant medication. Candesartan cilexetil

Page 10 of 12

effective also in patients taking both beta-blockers and ACE inhibitors at the same time, and the

benefit was obtained whether or not patients were taking ACE inhibitors at the target dose

recommended by treatment guidelines.

5.2

Pharmacokinetic properties

Absorption and distribution

Following oral administration, candesartan cilexetil is converted to the active drug candesartan.

absolute

bioavailability

candesartan

approximately

after

oral

solution

candesartan cilexetil. The relative bioavailability of the tablet formulation compared with the same

oral solution is approximately 34% with very little variability. The mean peak serum concentration

) is reached 3 to 4 hours following tablet intake. The candesartan serum concentrations

increase linearly with increasing doses in the therapeutic dose range.

No gender related differences in the pharmacokinetics of candesartan have been observed.

area

under

serum

concentration

versus

time

curve

(AUC)

candesartan

significantly affected by food.

Candesartan is highly bound to plasma protein (more than 99%). The apparent volume of

distribution of candesartan is 0.1 L/kg.

Biotransformation and elimination

Candesartan is mainly eliminated unchanged via urine and bile and only eliminated by hepatic

metabolism (CYP2C9) to a minor extent. Available interaction studies indicate no effect on

CYP2C9 and CYP3A4. Based on in vitro data, no interaction would be expected to occur in vivo

with

drugs

whose

metabolism

dependent

upon

cytochrome

P450

isoenzymes

CYP1A2,

CYP2A6,

CYP2C9,

CYP2C19,

CYP2D6,

CYP2E1

CYP3A4.

terminal

half-life

candesartan is approximately 9 hours. There is no accumulation following multiple doses.

Total plasma clearance of candesartan is about 0.37 mL/min/kg, with a renal clearance of about

0.19 mL/min/kg. The renal elimination of candesartan is both by glomerular filtration and active

tubular secretion. Following an oral dose of

C-labelled candesartan cilexetil approximately 26% of

the dose is excreted in the urine as candesartan and 7% as an inactive metabolite while

approximately 56% of the dose is recovered in the faeces as candesartan and 10% as the inactive

metabolite.

Pharmacokinetics in special populations

In the elderly (over 65 years) both C

and AUC of candesartan are increased by approximately

50% and 80% respectively, in comparison to young subjects. However, the blood pressure

response and the incidence of adverse events are similar after a given dose of candesartan

cilexetil in young and elderly patients.

In patients with mild to moderate renal impairment C

and AUC of candesartan increased during

repeated dosing by approximately 50% and 70%, respectively, but t

was not altered compared to

patients with normal renal function. The corresponding changes in patients with severe renal

impairment were approximately 50% and 110% respectively. The terminal t

of candesartan was

approximately doubled in patients with severe renal impairment. The AUC of candesartan in

patients undergoing haemodialysis was similar to that in patients with severe renal impairment (see

section 4.2).

In patients with mild to moderate hepatic impairment, there was an increase in the AUC of

candesartan of approximately 20%. In patients with moderate to severe hepatic impairment, the

increase in the AUC of candesartan was approximately 80%. There is only limited experience in

patients with severe hepatic impairment and/or cholestasis (see section 4.2).

5.3

Preclinical safety data

Page 11 of 12

In a variety of preclinical safety studies conducted in several species, expected exaggerated

pharmacological

effects,

modification

renin-angiotensin-aldosterone

system

homeostasis, have been observed. The incidence and severity of the effects induced were dose

and time related and have been shown to be reversible in adult animals. Animal studies with

candesartan cilexetil

have

demonstrated

late

foetal

neonatal

injury

the kidney.

mechanism is believed to be pharmacologically mediated through effects on the renin-angiotensin-

aldosterone system.

There was no evidence of mutagenicity, clastogenicity or carcinogenicity.

6. Pharmaceutical Particulars

6.1

List of excipients

Lactose, mannitol, carmellose calcium, hydroxypropyl cellulose and magnesium stearate.

Candestar is gluten free.

6.2

Incompatibilities

Not applicable

6.3

Shelf life

Blister packs and bottles: 24 months.

6.4

Special precautions for storage

Store at or below 25°C.

6.5

Nature and contents of container

Candestar 4 mg tablet: Blister packs of 30 and 90 tablets; Bottle of 30 and 90 tablets

Candestar 8 mg tablet: Blister packs of 30 and 90 tablets; Bottle of 30 and 90 tablets

Candestar 16 mg tablet: Blister packs of 30 and 90 tablets; Bottle of 30 and 90 tablets

Candestar 32 mg tablet: Blister packs of 30 and 90 tablets; Bottle of 30 and 90 tablets

Not all pack types and sizes may be marketed

6.6

Special precautions for disposal

Not applicable.

7. Medicines Schedule

Prescription Medicine

8. Sponsor Details

Mylan New Zealand Ltd

PO Box 11183

Ellerslie

AUCKLAND

Telephone 09-579-2792

Page 12 of 12

9. Date of First Approval

26 May 2011

10. Date of Revision of the Text

13 February 2018 Update to SmPC format

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