CANDESARTAN GH candesartan cilexetil 16 mg tablet blister pack

Main information

  • Trade name:
  • CANDESARTAN GH candesartan cilexetil 16 mg tablet blister pack
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CANDESARTAN GH candesartan cilexetil 16 mg tablet blister pack
    Australia
  • Language:
  • English

Status

  • Source:
  • Dept. of Health,Therapeutic Goods Administration - Australia
  • Authorization status:
  • Registered
  • Authorization number:
  • 195485
  • Last update:
  • 21-05-2019

Public Assessment Report

Public Summary

Summary for ARTG Entry:

195485

CANDESARTAN GH candesartan cilexetil 16 mg tablet blister pack

ARTG entry for

Medicine Registered

Sponsor

Lupin Australia Pty Limited

Postal Address

Generic Health Pty Ltd,Level 1 1102 Toorak Road,CAMBERWELL, VIC, 3124

Australia

ARTG Start Date

2/05/2013

Product category

Medicine

Status

Active

Approval area

Drug Safety Evaluation Branch

Conditions

Conditions applicable to all therapeutic goods as specified in the document "Standard Conditions Applying to Registered or Listed Therapeutic Goods

Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Conditions applicable to the relevant category and class of therapeutic goods as specified in the document "Standard Conditions Applying to Registered

or Listed Therapeutic Goods Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Products

1. CANDESARTAN GH candesartan cilexetil 16 mg tablet blister pack

Product Type

Single Medicine Product

Effective date

16/08/2017

Warnings

See Product Information and Consumer Medicine Information for this product

Standard Indications

Specific Indications

Treatment of hypertension.,Treatment of patients with heart failure and impaired left ventricular systolic function (left ventricular ejection fraction

<=40percent) as add-on therapy to ACE inhibitors or when ACE inhibitors are not tolerated.

Additional Product information

Container information

Type

Material

Life Time

Temperature

Closure

Conditions

Blister Pack

PVC/PE/PVDC/Al

24 Months

Store below 25

degrees Celsius

Not recorded

Store in Original

Container

Blister Pack

Al/Al

24 Months

Store below 25

degrees Celsius

Not recorded

Store in Original

Container

Pack Size/Poison information

Pack Size

Poison Schedule

30 tablets

(S4) Prescription Only Medicine

Components

1. CANDESARTAN GH candesartan cilexetil 16 mg tablet blister pack

Dosage Form

Tablet, uncoated

Route of Administration

Oral

Visual Identification

Light pink, round, biconvex uncoated mottled tablets debossed with L293

on one side and break line on other side.

Active Ingredients

Candesartan cilexetil

16 mg

© Commonwealth of Australia.This work is copyright.You are not permitted to re-transmit, distribute or commercialise the material without obtaining prior

written approval from the Commonwealth.Further details can be found at http://www.tga.gov.au/about/website-copyright.htm.

Public Summary

Page 1 of

Produced at 28.11.2017 at 04:09:00 AEDT

This is not an ARTG Certificate document.

The onus is on the reader to verify the current accuracy of the information on the document subsequent to the date shown.

Visit www.tga.gov.au for contact information

Summary of Product characteristics: dosage, interactions, side effects

Candesartan GH PI v5.0

Page 1 of 15

PRODUCT INFORMATION

Candesartan GH

Candesartan cilexetil 4mg, 8mg, 16mg & 32mg tablets

Name of the medicine

Candesartan

cilexetil.

chemical

name

candesartan

cilexetil

(1RS)-1-

[[(Cyclohexyloxy)carbonyl]oxy]ethyl

2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-

benzimidazole-7-carboxylate. Its structural formula is:

Molecular weight: 611

CAS No.: 145040-37-5

Description

Candesartan cilexetil is a white or almost white powder and is practically insoluble in water, freely

soluble in methylene chloride and slightly soluble in anhydrous ethanol. Three polymorphic forms

have been identified; crystal form I, crystal form II and an amorphous form. Crystalline form I is

used in CANDESARTAN GH.

CANDESARTAN GH tablets come in four strengths and contain 4 mg, 8 mg, 16 mg or 32 mg of

candesartan cilexetil. The tablets also contain lactose monohydrate, carmellose calcium, maize

starch, macrogol 8000, hyprolose, magnesium stearate and Pigment Blend PB-24880 Pink (ARTG

108327) which contains iron oxide red and lactose. The tablets are gluten free.

Pharmacology

Pharmacodynamics

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

Candesartan GH PI v5.0

Page 2 of 15

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 angiotensin converting enzyme (ACE), which converts angiotensin I to

angiotensin II and degrades bradykinin. Since there is no effect on ACE and no potentiation of

bradykinin or substance P, angiotensin II receptor antagonists are unlikely to be associated with

cough. This has been confirmed in controlled clinical studies with candesartan. Candesartan does

bind

block

other

hormone

receptors

channels

known

important

cardiovascular regulation.

In hypertension, candesartan 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.

Candesartan

effective

hypertension.

After

administration

single

dose,

onset

antihypertensive

effect

generally

occurs

within

hours.

With

continuous

treatment,

maximum reduction in blood pressure with any dose is generally attained within four weeks and is

sustained during long-term treatment. It provides effective and smooth blood pressure reduction

over the 24 hours dosing interval, with a trough/peak ratio confirming once daily dosing.

Candesartan can be used as monotherapy, or in combination with other antihypertensive drugs,

such as thiazide diuretics, calcium antagonists and lisinopril, for improved blood pressure control.

Age and gender have no influence on the efficacy of candesartan.

Candesartan

favourable

renal

haemodynamic

effects.

increases

renal

blood

flow

maintains or increases glomerular filtration rate while renal vascular resistance and filtration

fraction are reduced. Candesartan reduces urinary protein excretion in hypertensive patients with

microalbuminuria or nephropathy of different aetiology. Candesartan has no adverse effect on

blood glucose or lipid profile. In a variety of preclinical safety studies conducted in several species,

expected exaggerated pharmacological effects (eg. renal changes leading to juxtaglomerular cell

hypertrophy, adrenal gland zona glomerulosa atrophy and reduced heart weight related to reduced

afterload), due to modification of the 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. Foetotoxicity has been observed in late

pregnancy (see Precautions, Use in pregnancy, Use during lactation).

Pharmacokinetics

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

Candesartan GH PI v5.0

Page 3 of 15

oral

solution

approximately

34%,

with

little

variability.

absolute

bioavailability

candesartan following administration of the tablet is approximately 14%. The mean peak serum

concentration

reached

hours

after

taking

tablet.

candesartan

serum

concentrations increase linearly with increasing doses in the therapeutic dose range. The area

under the serum concentration versus time curve (AUC) of candesartan is not significantly affected

by food. The peak concentration (C

) is increased by 26% and the rate of absorption is increased

when taken with food. These changes are unlikely to result in clinically significant effects.

Candesartan

highly

bound

plasma

protein

(more

than

99%).

apparent

volume

distribution (V

) of candesartan is 0.1 L/kg.

Metabolism and elimination

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

metabolism only to a minor extent. The terminal half-life of 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 about 30% and 70%

of the total radioactivity is recovered in the urine and faeces, respectively.

Pharmacokinetics in special populations

In the elderly (over 65 years) both C

and AUC of candesartan are increased in comparison to

young subjects. An initial dose of 8 mg is recommended (see Dosage and administration).

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 was approximately 50% and 110% respectively. The terminal t

of candesartan was

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

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

In patients with mild to moderate hepatic impairment, there was a 23% increase in the AUC of

candesartan. No initial dosage adjustment is necessary in these patients.

Clinical trials

Hypertension

Candesartan and

Lisinopril Microalbuminuria

(CALM)

study

was a

24-week double

blind,

parallel group trial (n=199) to evaluate the effects of candesartan and lisinopril alone and in

combination

urinary

albumin

excretion

(UAE)

patients

with

type

diabetes

mellitus,

hypertension and microalbuminuria. Patients were randomly allocated to four treatment regimens:

weeks

candesartan

monotherapy

(1/3

patients);

weeks

lisinopril

monotherapy (1/3 of the patients); 3) 12 weeks of candesartan monotherapy, followed by 12 weeks

of candesartan + lisinopril combination therapy (1/6 of the patients); and 4) 12 weeks of lisinopril

monotherapy, followed by 12 weeks of lisinopril + candesartan combination therapy (1/6 of the

Candesartan GH PI v5.0

Page 4 of 15

patients). Thus, after 12 weeks, half of the patients were treated with candesartan monotherapy

(n=99) and half with lisinopril monotherapy (n=98). After 24 weeks, 1/3 of the patients still in the

study were on candesartan monotherapy (n=49), 1/3 on lisinopril monotherapy (n=46), and 1/3 on

combination therapy (candesartan + lisinopril, n=25; lisinopril + candesartan, n=24).

Baseline

Change at 12 weeks

Change at 24 weeks

SBP mmHg

DBP mmHg

SBP mmHg

DBP mmHg

SBP mmHg

DBP mmHg

Candesartan 16 mg (n=49)

Lisinopril 20 mg (n=46)

Candesartan 16 mg + Lisinopril

20 mg from 12 weeks (n=25)

-22*

-16*

Lisinopril 20 mg + Candesartan

16 mg from 12 weeks (n=24)

-28***

-17***

* p<0.05, *** p<0.001 for the additional blood pressure reduction at 24 weeks compared with 12 weeks.

Significant reduction in urinary albumin/creatinine ratio (UACR), in both monotherapy treatment

groups was observed, although no significant difference between treatment groups was seen.

Combination therapy following monotherapy for 12 weeks showed significantly greater reduction in

UACR (mean reduction of 50%) than candesartan cilexetil 16 mg monotherapy (mean reduction in

UACR 24%) and numerically greater reduction than lisinopril 20 mg monotherapy (mean reduction

in UACR 39%).

All treatment regimens reduced both systolic and diastolic blood pressure significantly. The blood

pressure reductions were significantly greater with combination therapy than with monotherapy,

whether lisinopril was added to candesartan, or candesartan was added to lisinopril (see table).

antihypertensive

effects

candesartan

cilexetil

losartan

potassium

their

highest

recommended doses administered once daily were compared in two randomised, double-blind

trials. In a total of 1,268 patients with mild to moderate hypertension who were not receiving other

antihypertensive therapy, candesartan cilexetil 32 mg lowered systolic and diastolic blood pressure

by 2 to 3 mmHg on average more than losartan potassium 100 mg, when measured at the time of

either peak or trough effect.

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 and pulmonary capillary wedge pressure, increases plasma renin activity and 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 comprising 3 studies (CHARM-Alternative, CHARM-

Added

CHARM-Preserved).

studies,

patients

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.

Candesartan GH PI v5.0

Page 5 of 15

CHARM-Alternative

CHARM-Alternative was a multinational, randomised, double-blind placebo controlled study in CHF

patients (NYHA class II-IV, n=2,028) with a LVEF ≤40% not treated with an ACE inhibitor because of

intolerance.

Effect of candesartan versus placebo on composite endpoints and their components in CHARM-

Alternative

Endpoint

Absolute Risk

Reduction (%)

Hazard Ratio

(HR)

95% CI

Relative Risk

Reduction (%)

CV mortality or CHF hospitalisation

0.77

0.67-0.89,

p<0.001

CV mortality

0.85

0.71-1.02,

p=0.072

CHF hospitalisation

0.68

0.57-0.81,

p<0.001

All-cause mortality or CHF

hospitalisation

0.80

0.70-0.92,

p=0.001

All-cause mortality

0.87

0.74-1.03,

p=0.104

CHARM-Added

CHARM-Added was a multinational, randomised, double-blind placebo controlled study in CHF

patients (NYHA class II-IV, n=2,548) with a LVEF ≤40% treated with ACE inhibitors.

Effect of candesartan versus placebo on composite endpoints and their components in CHARM-

Added

Endpoint

Absolute Risk

Reduction (%)

Hazard Ratio (HR)

95% CI

Relative Risk

Reduction (%)

CV mortality or CHF hospitalisation

0.85

0.75-0.96,

p=0.011

CV mortality

0.84

0.72-0.98,

p=0.029

CHF hospitalisation

0.83

0.71-0.96,

p=0.013

All-cause mortality or CHF

hospitalisation

0.87

0.78-0.98,

p=0.021

All-cause mortality

0.89

0.77-1.02,

p=0.086

CHARM-Preserved

CHARM-Preserved was a multinational, randomised, double-blind placebo controlled study in CHF

patients (n=3,023, NYHA class II-IV) with a LVEF >40%, approximately 20% of whom received an ACE

inhibitor. In the CHARM-Preserved study there was no effect of candesartan upon mortality.

Candesartan GH PI v5.0

Page 6 of 15

Endpoint

Absolute Risk

Reduction (%)

Hazard Ratio (HR)

95% CI

Relative Risk

Reduction (%)

CV mortality or CHF hospitalisation

0.89

0.77-1.03,

p=0.118

CV mortality

0.99

0.80-1.22,

p=0.918

CHF hospitalisation

0.85

0.72-1.01,

p=0.071

All-cause mortality or CHF

hospitalisation

0.92

0.80-1.05,

p=0.221

All-cause mortality

1.02

0.85-1.22,

p=0.836

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). This corresponds to a relative risk reduction of 12% and 9% respectively and an absolute

risk reduction of 2.9 and 1.6% respectively.

Treatment

with

candesartan

cilexetil

resulted

improved

NYHA

functional

class

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 was

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.

Indications

Treatment of hypertension.

Treatment

patients

with

heart

failure

impaired

left

ventricular

systolic

function

(left

ventricular ejection fraction ≤40%) as add-on therapy to ACE inhibitors or when ACE inhibitors are

not tolerated.

Contraindications

Hypersensitivity to any component of CANDESARTAN GH.

Pregnancy and lactation (see Precautions - Use in pregnancy).

Candesartan GH PI v5.0

Page 7 of 15

Precautions

General

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

renin-angiotensin-aldosterone

system

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 cardiopathy or ischaemic cerebrovascular disease could result in a myocardial infarction

or stroke.

Kidney transplantation

There is no experience regarding the administration of candesartan in patients with a recent kidney

transplantation.

Renal artery stenosis

Other

drugs

that

affect

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.

Aortic and mitral valve stenosis (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.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism will not generally respond to antihypertensive drugs

acting

through

inhibition

renin-angiotensin-aldosterone

system.

Therefore,

candesartan in these patients is not recommended.

Hypotension

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

other

agents

acting

renin-angiotensin-aldosterone

system,

also

occur

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

initiating therapy and correction of hypovolemia should be attempted.

Hyperkalaemia

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

system, concomitant use of candesartan with potassium-sparing diuretics, potassium supplements,

salt substitutes containing potassium, or other drugs that may increase potassium levels (e.g.

heparin) may lead to increases in serum potassium in hypertensive patients. In heart failure

patients

treated

with

candesartan,

hyperkalaemia

occur.

During

treatment

with

CANDESARTAN

in patients

with

heart

failure,

periodic

monitoring

serum potassium is

recommended, especially when taken concomitantly with ACE inhibitors and potassium-sparing

diuretics such as spironolactone.

Renal impairment

Candesartan GH PI v5.0

Page 8 of 15

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

may be anticipated in susceptible patients treated with candesartan. When CANDESARTAN GH is

used

hypertensive

patients

with

severe

renal

impairment,

periodic

monitoring

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 GH, monitoring of serum creatinine and potassium is

recommended.

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. Therefore,

CANDESARTAN GH should be carefully titrated with thorough monitoring of blood pressure in

patients on haemodialysis (see Dosage and Administration).

Hepatic impairment

There is no experience in patients with severe hepatic impairment and/or cholestasis; caution is

advised in these patients. There have been reports of clinically significant liver disease occurring

with other angiotensin II receptor antagonists. No such cases have been reported to date with

candesartan.

Anaesthesia and surgery

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

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

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

Combination use of ACE inhibitors or angiotensin receptor antagonists, anti-inflammatory drugs

and thiazide diuretics

The use of an ACE inhibiting drug (ACE-inhibitor or angiotensin receptor antagonist), an anti-

inflammatory drug (NSAID or COX-2 inhibitor) and a thiazide diuretic at the same time increases the

risk of renal impairment. This includes use in fixed-combination products containing more than one

class of drug. Combined use of these medications should be accompanied by increased monitoring

of serum creatinine, particularly at the institution of the combination. The combination of drugs

from these three classes should be used with caution particularly in elderly patients or those with

pre-existing renal impairment.

Effects on Fertility

Candesartan cilexetil had no adverse effects on the reproductive performance of male or female

rats at oral doses up to 300 mg/kg/day.

Use in pregnancy (Category D

1

)

The use of CANDESARTAN GH is contraindicated during pregnancy (see Contraindicationa). Patients

receiving CANDESARTAN GH should be made aware of that before contemplating a possibility of

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

Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal

malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be

consulted for further details.

Candesartan GH PI v5.0

Page 9 of 15

When pregnancy is diagnosed, treatment with CANDESARTAN GH must be stopped immediately

and if appropriate, alternative therapy should be started.

Drugs that act on the renin-angiotensin system (RAS) can cause foetal and neonatal morbidity and

death when administered to pregnant women. Exposure to angiotensin II receptor antagonist

therapy is known to induce human feototoxicity (decreased renal function, oligohydramnios, skull

ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).

Use in lactation

It is not known whether candesartan 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 GH is considered essential.

Carcinogenicity

There was no evidence of carcinogenicity when candesartan cilexetil was orally administered to

mice and rats for up to 104 weeks at doses up to 100 and 1000 mg/kg/day, respectively. Rats

received the drug by gavage whereas mice received the drug by dietary administration. These

(maximally tolerated) doses of candesartan cilexetil provided systematic exposures to candesartan

(AUCs) that were, in mice, approximately 7 times and, in rats, more than 70 times the exposure in

man at the maximum recommended daily human dose (32 mg).

Genotoxicity

Candesartan showed no evidence of genotoxic potential in a series of assay for gene mutations

(Salmonella

typhimurium,

Escherichia

coli,

Mouse

L5178Y

cells

cells),

chromosomal

aberrations

(mouse

nucleus

assay)

unscheduled

synthesis.

active

metabolite,

candesartan, caused an increase in chromosomal aberrations in vitro (CHL cells) but not in vivo

(mouse micronucleus assay).

Effects on ability to drive and use machines

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

weariness may occur during treatment.

Interactions with other medicines

Food

Food

increases

rate

absorption

candesartan

however,

extent

absorption

candesartan is not affected by food.

Lithium

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 and careful monitoring of serum lithium levels is recommended

during concomitant use.

Other drugs

Candesartan GH PI v5.0

Page 10 of 15

Compounds

which

have

been

investigated

clinical

pharmacokinetic

studies

include

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

glibenclamide and nifedipine and enalapril. No pharmacokinetic interactions of clinical significance

were identified in these studies.

Attenuation of the antihypertensive effect may occur when simultaneously administering AIIRAs

and non-steroidal anti-inflammatory drugs (NSAIDs; i.e. selective COX-2 inhibitors, acetylsalicylic

acid (> 3 g/day) and non-selective NSAIDs).

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.

Candesartan is eliminated only to a minor extent by hepatic metabolism (CYP2C9). Available

interaction studies indicate no effect on CYP2C9 and CYP3A4 but the effect on other cytochrome

P450 isoenzymes is presently unknown.

CANDESARTAN GH may be administered with other antihypertensive agents.

Adverse effects

Hypertension

Candesartan was well tolerated in clinical studies showing an adverse event profile comparable to

that of placebo. Generally adverse events were mild and transient. The overall incidence of

adverse effects 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%).

Information on adverse events was obtained from 39 Phase I to Phase III clinical studies, involving a

total of 5,464 subjects. Candesartan was administered as mono or combination therapy to 2,061

hypertensive patients. The crude frequency of the most commonly occurring adverse events,

irrespective of causality, reported for those patients and the 573 placebo comparators are given

below.

Adverse Event

Monotherapy Studies

Combination Studies

Placebo

Candesartan

Placebo

Candesartan

Candesartan

+ HCTZ

(n=573)

(n=1388)

(n=205)

(n=444)

(n=673)

Cardiovascular

peripheral oedema

Gastrointestinal

nausea

Candesartan GH PI v5.0

Page 11 of 15

Adverse Event

Monotherapy Studies

Combination Studies

Placebo

Candesartan

Placebo

Candesartan

Candesartan

+ HCTZ

(n=573)

(n=1388)

(n=205)

(n=444)

(n=673)

abdominal pain

diarrhoea

vomiting

Musculo-skeletal

back pain

Nervous system

headache

10.7

10.9

dizziness

Other

influenza-like symptoms

inflicted injury

fatigue

Respiratory

URTI

bronchitis

coughing

pharyngitis

rhinitis

HCTZ – hydrochlorothiazide

Median (mean) duration of exposure: placebo 57 (68 days) and candesartan cilexetil: 56 (78 days).

Laboratory findings

In general there were no clinically important effects 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. In clinical trials, elevations of ALT occurred in 1.3% of candesartan-treated

patients and 0.5% of those treated with placebo. The incidence of AST elevation was 0.4% with

candesartan

and 0%

with placebo.

routine

monitoring

laboratory

variables

usually

necessary

for patients receiving

CANDESARTAN

However,

patients

with

severe

renal

impairment, periodic monitoring of serum potassium and creatinine levels should be considered.

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

Candesartan GH PI v5.0

Page 12 of 15

Metabolism and nutrition disorders:

Hyperkalaemia

Renal and urinary disorders:

Renal impairment

Laboratory findings:

Increases in creatinine, urea and potassium. Periodic monitoring of serum creatinine and potassium

is recommended (see Precautions).

Post marketing

following

adverse

reactions

have

been

reported

very

rarely

(<0.01%)

post

marketing

experience:

Blood and lymphatic system disorders:

Leukopenia, neutropenia and agranulocytosis

Metabolism and nutrition disorders:

Hyperkalaemia, hyponatraemia

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, myalgia

Renal and urinary disorders:

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

Rare reports of rhabdomyolysis have been reported in patients receiving angiotension II receptor

blockers.

Although causality to candesartan has not been established, the following neuropsychiatric and

cardiovascular

adverse

reactions

have

been

very

rarely

reported

during

post-marketing

surveillance.

These

were:

agitation,

anxiety,

depression,

insomnia,

somnolence,

nervousness,

nightmare, sleep disorder and palpitations.

Dosage and administration

CANDESARTAN GH should be taken once daily with or without food.

Paediatrics

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

Candesartan GH PI v5.0

Page 13 of 15

Hypertension

The recommended maintenance dose of candesartan is 8 mg or 16 mg once daily. The maximal

antihypertensive effect is attained within 4 weeks following initiation of treatment. For those

patients who start on 8 mg and require further blood pressure reduction, a dose increase to 16 mg

is recommended. An initial dose of 16 mg is also well tolerated. Some patients may receive an

additional benefit by increasing the dose to 32 mg once daily.

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

thiazide diuretic is recommended.

Geriatrics

An initial dose of 8 mg is recommended.

Hepatic insufficiency

No initial dosage adjustment is necessary in patients with mild to moderately chronic liver disease.

No experience is available to date in patients with severely impaired hepatic function (e.g. cirrhotic

patients).

Renal insufficiency

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

(i.e.

creatinine

clearance

≥30

mL/min/1.73m

BSA).

patients

with

severely

impaired

renal

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

BSA) including patients on haemodialysis a

lower initial dose of 4 mg should be considered.

Heart failure

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

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

intervals of at least 2 weeks (see Precautions).

Special patient populations

No initial dose adjustment is necessary for elderly patients or in patients with renal or hepatic

impairment.

Concomitant therapy

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

blockers, diuretics and digitalis or a combination of these medicines (see also Pharmacology -

Pharmacodynamics).

Overdosage

Symptoms

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

symptomatic

hypotension,

dizziness.

single

case

reports

overdose

candesartan cilexetil) patient recovery was uneventful.

Management

Candesartan GH PI v5.0

Page 14 of 15

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

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

sufficient, plasma volume should be increased by the infusion of, for example, isotonic saline

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

sufficient.

Candesartan is not removed by haemodialysis.

For information on the management of an overdose, contact the Poisons Information Centre on 13

11 26 (Australia).

Presentation and storage conditions

CANDESARTAN GH Candesartan cilexetil 4 mg tablet;

Light pink, mottled, round biconvex uncoated tablet with ‘291’ on one side and a scoreline on the

other

side.

PVC/PE/PVDC/Al

or Al/Al blister packs

HDPE

bottles

with

child-resistant

closures. Packs of 30 tablets.

CANDESARTAN GH Candesartan cilexetil 8 mg tablet;

Light pink, mottled, round biconvex uncoated tablet with ‘292’ on one side and a scoreline on the

other

side.

PVC/PE/PVDC/Al

or Al/Al blister packs

HDPE

bottles

with

child-resistant

closures. Packs of 30 tablets.

CANDESARTAN GH Candesartan cilexetil 16 mg tablet;

Light pink, mottled, round biconvex uncoated tablet with ‘L293’ on one side and a scoreline on the

other

side.

PVC/PE/PVDC/Al

or Al/Al blister packs

HDPE

bottles

with

child-resistant

closures. Packs of 30 tablets.

CANDESARTAN GH Candesartan cilexetil 32 mg tablet;

Light pink, mottled, round biconvex uncoated tablet with ‘L294’ on one side and a scoreline on the

other

side.

PVC/PE/PVDC/Al

or Al/Al blister packs

HDPE

bottles

with

child-resistant

closures. Packs of 30 tablets.

Note: Not all packaging presentations will be available.

Store below 25°C.

Store in original container.

Name and address of the sponsor

Lupin Australia Pty Ltd

Level 1, 1102 Toorak Road

Camberwell VIC 3124

Candesartan GH PI v5.0

Page 15 of 15

Poison schedule of the medicine

PRESCRIPTION ONLY MEDICINES - S4

Date of first inclusion in the Australian Register of Therapeutic Goods (the ARTG)

2 May 2013

Date of most recent amendment

31 January 2017