Consumer medicine information

APO-Candesartan Tablets

Candesartan cilexetil

BRAND INFORMATION

Brand name

APO-Candesartan Tablets

Active ingredient

Candesartan cilexetil

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Candesartan Tablets.

What is in this leaflet

Read this leaflet carefully before taking your medicine.

This leaflet answers some common questions about candesartan. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the last page. More recent information on this medicine may be available.

Ask your doctor or pharmacist:

  • if there is anything you do not understand in this leaflet,
  • if you are worried about taking your medicine, or
  • to obtain the most up-to-date information.

You can also download the most up to date leaflet from www.apotex.com.au.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits they expect it will have for you.

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

Keep this leaflet with your medicine. You may want to read it again.

What this medicine is used for

The name of your medicine is APO-Candesartan. It contains the active ingredient candesartan cilexetil.

It is used to treat:

  • high blood pressure, also called hypertension.
  • heart failure - increase survival, reduce hospitalisation and improve symptoms. It is used in combination with other medicines to treat your condition.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed this medicine for another reason.

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

There is no evidence that this medicine is addictive.

How it works

Candesartan is a type of medicine called an angiotensin II receptor inhibitor (or antagonist).

Hypertension:
All people have blood pressure. This pressure helps to push blood all around your body. Your blood pressure changes during the day, depending on how busy you are or how you are feeling.

You have hypertension (high blood pressure) when your blood pressure stays higher than is needed, even when you are calm and relaxed.

Regular blood pressure checks are the only way of knowing that you have hypertension. There are usually no symptoms of hypertension and you may feel fine. If hypertension is not treated, serious health problems such as stroke or heart attack and heart or kidney failure may occur.

Candesartan lowers blood pressure by dilating (expanding) small blood vessels from the heart, letting the blood be pumped around the body more easily.

Heart Failure:
Heart failure means that the heart muscle cannot pump blood strongly enough to supply all the blood needed throughout the body. Heart failure is not the same as heart attack and does not mean that the heart stops working.

Heart failure may start off with no symptoms, but as the condition progresses, patients may feel short of breath or may get tired easily after light physical activity such as walking. Some patients may wake up short of breath at night. Fluid may collect in different parts of the body, often first noticed as swollen ankles and feet.

Candesartan helps to treat heart failure and may improve your symptoms.

One of the ways candesartan helps heart failure is that it widens 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.

When used to treat heart failure, candesartan is almost always used with other medicines called diuretics or fluid tablets. These medicines help the kidney to get rid of excess fluid from the body.

Use in children

There is no information about its use in children, so candesartan is not recommended for children.

Before you use this medicine

When you must not use it

Do not use this medicine if you have an allergy to:

  • candesartan cilexetil or any of the ingredients listed at the end of this leaflet.
  • angiotensin II receptor inhibitor (or antagonist), e.g. telmisartan, irbesartan, olmesartan etc.
    Symptoms of an allergic reaction may include: shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin.
    If you think you are having an allergic reaction, contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital.
  • Do not use candesartan if you are also taking aliskiren-containing medications and have kidney problems or diabetes.
  • Do not use candesartan if you have severe hepatic impairment and/or cholestasis (a condition where bile does not flow from the liver).
  • Do not use candesartan if you are pregnant.
    It may affect your baby if you take it during pregnancy.
  • Do not breast-feed if you are taking candesartan.
    It is not known if candesartan passes into breast milk.
  • Do not use this medicine if the expiry date (EXP) printed on the pack has passed.
  • Do not use this medicine if the packaging is torn, shows signs of tampering or it does not look quite right.

Before you start to take it

Before you start taking this medicine, tell your doctor if:

  1. You have allergies to:
    - any other medicines
    - any other substances, such as foods, preservatives or dyes.
  2. You have or have had any medical conditions, especially the following:
    - kidney problems
    - liver problems
    - heart or blood vessel problems
    - a condition called primary hyperaldosteronism.
    You may have to take a lower dose of candesartan if you have these conditions.
  3. You are planning to have surgery or an anaesthetic.

If you have not told your doctor about any of the above, tell them before you use this medicine.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy at the chemist, supermarket or health food shop.

Some medicines and candesartan may interfere with each other. These include:

  • any medicines containing potassium, including salt substitutes
  • diuretics (fluid tablets)
  • lithium, a medicine used to treat mood swings and some types of depression
  • non-steroidal anti-inflammatory drugs (NSAIDs), medicines used to relieve pain, swelling and other symptoms of inflammation, including arthritis
  • angiotensin converting enzyme (ACE) inhibitors e.g. perindopril, ramipril and captopril.

These medicines may be affected by candesartan or may affect the way candesartan works. You may need different amounts of your medicines, or may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

It may be necessary to have regular blood tests done if you take any of these medicines.

How to take this medicine

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

Their instructions may be different to the information in this leaflet.

If you are not sure how to take this medicine, ask your doctor or pharmacist for help.

How to take it

Your doctor or pharmacist will tell you how much of this medicine you should take. This will depend on your condition and whether you are taking any other medicines.

Do not stop taking your medicine or change your dosage without first checking with your doctor.

Take candesartan once a day, at about the same time each day.

Taking candesartan at the same time each day will help you remember when to take it.

It does not matter whether you take candesartan with food or on an empty stomach.

How long to take it

Continue taking this medicine for as long as your doctor tells you.

This medicine controls 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 to take your next dose, skip the missed dose and take your next dose at the usual time.

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 missed doses.

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

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively go to the Accident and Emergency Department at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you take too many candesartan you will probably get a headache and feel sick (nausea), dizzy and very tired.

While you are using this medicine

Things you must do

  • If you become pregnant while you are using this medicine, tell your doctor.
  • Tell all doctors, dentists and pharmacists who are treating you that you are using this medicine.
  • If you are about to be started on any new medicine, tell your doctor or pharmacist that you are using this medicine.
  • If you are going to have surgery, inform your doctor and tell the surgeon or anaesthetist that you are using this medicine.

Things you must not do

Do not:

  • Give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Take your medicine to treat any other condition unless your doctor or pharmacist tells you to.
  • Stop taking your medicine, or change the dosage, without first checking with your doctor.

Things to be careful of

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

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

You may feel dizzy when you start taking candesartan.

If you are taking candesartan for high blood pressure, drink plenty of water during exercise and hot weather, especially if you sweat a lot. If you do not drink enough water while taking candesartan, you may faint or feel light-headed or sick. This is because your body doesn't have enough fluid and your blood pressure is low. If you continue to feel unwell, tell your doctor.

If you are taking candesartan for heart failure, restricted fluid intake is generally recommended. Speak with your doctor about how much water you should drink.

Please talk to your doctor or pharmacist about any concerns you may have about the above.

Possible side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using this medicine.

Your doctor will decide whether any change in your treatment is needed.

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. If you are over 65 years of age, you may have an increased chance of getting side effects.

Candesartan helps most people, but it may have side effects in a few people.

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

Tell your doctor if you notice any of the following:

  • headache
  • chest or throat infection
  • flu-like symptoms
  • feeling sick (nausea, vomiting)
  • back pain
  • dizziness.

These are all mild side effects of candesartan.

The following side effects have been reported very rarely by patients taking candesartan: palpitations, agitation, anxiety, depression, trouble sleeping (insomnia), drowsiness (somnolence), nervousness, nightmare and sleep disorder. It is not known if these side effects are caused by candesartan.

Tell your doctor as soon as possible if you notice any of the following:

  • aching muscles, tenderness or weakness in the muscle.

The above list includes serious side effects that may require medical attention. These side effects are rare.

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
  • harsh sounds when breathing
  • signs of frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • jaundice (yellowing of the skin and/or eyes)
  • unusual skin reactions (severe and sudden onset of rash), itchiness, hives (itchy swellings on the skin)
  • bruising easily
  • extreme fatigue, tiredness, weakness
  • worsening kidney function, including passing little or no urine, drowsiness, nausea, vomiting, breathlessness, loss of appetite and weakness (especially in patients with existing kidney problems or heart failure)
  • changes in your potassium, sodium and red or white blood cell levels may occur. Such changes are usually detected by a blood test
  • symptoms that may indicate high potassium levels in the blood include nausea, diarrhoea, muscle weakness and changes in heart rhythm.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

These side effects are very rare.

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

Other side effects not listed above may occur in some people. Tell your doctor if you notice any other side effects.

Storage and disposal

Storage

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

If you take candesartan out of the blister pack it will not keep well.

Keep your tablets in a cool dry place where the temperature will stay below 30°C.

Do not store your medicine, 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 this medicine 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 or pharmacist tells you to stop taking this medicine or they have passed their expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What APO-Candesartan looks like

  • APO-Candesartan 4 mg tablets: Light pink, round, biconvex tablet with '291' on one side and a break line on the other side.
  • APO-Candesartan 8 mg tablets: Light pink, round, biconvex, uncoated mottled tablet with '292' on one side and a break line on the other side.
  • APO-Candesartan 16 mg tablets: Light pink, round, biconvex uncoated mottled tablet with 'L293' on one side and a break line on the other side
  • APO-Candesartan 32 mg tablets: Light pink, , round, biconvex uncoated mottled tablet with 'L294' on one side and a break line on the other side.

Ingredients

Each tablet contains 4 mg or 8 mg or 16 mg or 32 mg of the active ingredient candesartan cilexetil.

It also contains the following inactive ingredients:

  • lactose
  • maize starch
  • hydroxypropylcellulose
  • carmellose calcium
  • magnesium stearate
  • Pigment Blend PB-24880 Pink (iron oxide red and lactose)
  • macrogol 8000.

This medicine is gluten-free, sucrose-free, tartrazine-free and free of other azo dyes.

APO-Candesartan is available in:
Blister packs of 7, 28 and 30 tablets.

Not all strengths, pack types and/or pack sizes may be available.

Australian Registration Numbers

  • APO-Candesartan 4 mg blister pack:
    AUST R 210529
  • APO-Candesartan 8 mg blister pack:
    AUST R 210530
  • APO-Candesartan 16 mg blister pack:
    AUST R 210531
  • APO-Candesartan 32 mg blister pack:
    AUST R 210532

Sponsor

Apotex Pty Ltd
16 Giffnock Ave
Macquarie Park, NSW 2113
Australia

APO and APOTEX are registered trade marks of Apotex Inc.

This leaflet was prepared in July 2014.

BRAND INFORMATION

Brand name

APO-Candesartan Tablets

Active ingredient

Candesartan cilexetil

Schedule

S4

 

1 Name of Medicine

Candesartan cilexetil.

6.7 Physicochemical Properties

It is a white to off white powder and is practically insoluble in water. It has a pKa of 6.3, corresponding to deprontonation of the tetrazole ring. The partition coefficient of candesartan cilexetil is as follows (see Table 6):
Three polymorphic forms have been identified; crystal form I, crystal form II and an amorphous form. Crystalline form I is used in APO-Candesartan.
Chemical Name: (±)-1-(cyclohexyloxycarbonyl-oxy) ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl]-1H-benzimadozole-7-carboxylate. Molecular Formula: C33H34N6O6. Molecular Weight: 610.7.

Chemical structure.


CAS number.

145040-37-5.

2 Qualitative and Quantitative Composition

Each candesartan tablet contains candesartan cilexetil as the active ingredient. In addition, each candesartan tablet contains the following inactive ingredients: lactose, carmellose calcium, maize starch, macrogol 8000, hydroxypropylcellulose, magnesium stearate and Pigment Blend PB-24880 Pink (ARTG 108327) which contains iron oxide red and lactose. The tablets are gluten free.

3 Pharmaceutical Form

4 mg tablets.

Light pink, mottled, round biconvex uncoated tablet with '291' on one side and a scoreline on the other side.

8 mg tablets.

Light pink, mottled, round biconvex uncoated tablet with '292' on one side and a scoreline on the other side.

16 mg tablets.

Light pink, mottled, round biconvex uncoated tablet with 'L293' on one side and a scoreline on the other side.

32 mg tablets.

Light pink, mottled, round biconvex uncoated tablet with 'L294' on one side and a scoreline on the other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Angiotensin II is the primary vasoactive hormone of the renin angiotensin aldosterone system and plays a significant role in the pathophysiology of hypertension, heart failure and other cardiovascular disorders. It also has an important role in the pathogenesis of end organ hypertrophy and damage. The major physiological effects of angiotensin II, such as vasoconstriction, aldosterone stimulation, regulation of salt and water homeostasis and stimulation of cell growth, are mediated via the type 1 (AT1) receptor.
Candesartan 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 AT1 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 not bind to or block other hormone receptors or ion channels known to be important in 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 is effective in hypertension. After administration of a single dose, onset of antihypertensive effect generally occurs within two 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. 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 has favourable renal haemodynamic effects. It increases renal blood flow and 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 (e.g. 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. Fetotoxicity has been observed in late pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation).

Clinical trials.

Hypertension.

The 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 on urinary albumin excretion (UAE) in patients with type II diabetes mellitus, hypertension and microalbuminuria. Patients were randomly allocated to four treatment regimens: 1) 24 weeks of candesartan monotherapy (1/3 of the patients); 2) 24 weeks of 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 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).
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 2).
The antihypertensive effects of candesartan cilexetil and losartan potassium at 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 decreases systemic vascular resistance and pulmonary capillary wedge pressure, increases plasma renin activity and angiotensin II concentration, and decreases aldosterone levels.
Treatment with candesartan reduces mortality and hospitalisation due to CHF and 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 and CHARM-Preserved). In all 3 studies, patients on optimal baseline therapy were randomised to placebo or candesartan (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.

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. See Table 3.

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. See Table 4.

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. See Table 5.
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 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 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.

5.2 Pharmacokinetic Properties

In studies comparing candesartan 8 mg and 32 mg tablets with the innovator, the two products were shown to be bioequivalent.

Absorption.

Following oral administration, candesartan cilexetil is converted to the active drug candesartan. The absolute bioavailability of candesartan is approximately 40% after an oral solution of candesartan cilexetil. The relative bioavailability of the tablet formulation compared with the same oral solution is approximately 34%, with little variability. The absolute bioavailability of candesartan following administration of the tablet is approximately 14%. The mean peak serum concentration (Cmax) is reached 3-4 hours after taking a tablet. The 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 (Cmax) 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.

Distribution.

Candesartan is highly bound to plasma protein (more than 99%). The apparent volume of distribution (Vss) of candesartan is 0.1 L/kg.

Metabolism.

Candesartan is mainly eliminated unchanged via urine and bile and is eliminated by hepatic metabolism only to a minor extent.

Excretion.

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 14C-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 Cmax and AUC of candesartan are increased in comparison to young subjects. An initial dose of 8 mg is recommended (see Section 4.2 Dose and Method of Administration).
In patients with mild to moderate renal impairment Cmax and AUC of candesartan increased during repeated dosing by approximately 50% and 70% respectively, but t1/2 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 t1/2 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.

5.3 Preclinical Safety Data

Genotoxicity.

Candesartan showed no evidence of genotoxic potential in a series of assay for gene mutations (Salmonella typhimurium, Escherichia coli, mouse L5178Y cells and CHO cells), chromosomal aberrations (mouse nucleus assay) and unscheduled DNA synthesis. The active metabolite, candesartan, caused an increase in chromosomal aberrations in vitro (CHL cells) but not in vivo (mouse micronucleus assay).

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 systemic 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).

4 Clinical Particulars

4.1 Therapeutic Indications

APO-Candesartan is indicated for the treatment of:
hypertension;
patients with heart failure and impaired left ventricular systolic function (left ventricular ejection fraction ≤ 40%) as add-on therapy to ACE inhibitors or when ACE inhibitors are not tolerated.

4.3 Contraindications

Patients with known hypersensitivity to candesartan cilexetil or any of the excipients.
Pregnancy and lactation (see Section 4.6 Fertility, Pregnancy and Lactation).
Severe hepatic impairment and/or cholestasis.
The use of candesartan cilexetil in combination with aliskiren containing medicines in patients with diabetes mellitus (type I or II) or with moderate to severe renal impairment (GFR < 60 mL/min/1.73 m2).

4.4 Special Warnings and Precautions for Use

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 or 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.

Kidney transplantation.

There is limited clinical experience regarding candesartan use in patients who have undergone renal transplant.

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.

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 of the renin angiotensin aldosterone system. Therefore, the use of candesartan in these patients is not recommended.

Hypotension.

Hypotension may occur during treatment with candesartan 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 hypovolemia should be attempted.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with aliskiren-containing medicines.

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 Interactions with Other Medicines and Other Forms of Interactions).
If dual blockade therapy is 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 with aliskiren is contraindicated in patients with diabetes mellitus (type I or II) or moderate to severe renal impairment (GFR < 60 mL/min/1.73 m2) (see Section 4.3 Contraindications).

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.

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 may occur. During treatment with candesartan in patients with heart failure, periodic monitoring of serum potassium is recommended, especially when taken concomitantly with ACE inhibitors and 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 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.

Use in hepatic impairment.

There is limited clinical experience in patients with severe hepatic impairment and/or cholestasis. Use in patients with severe hepatic impairment is contraindicated. Caution is advised in patients with mild to moderate hepatic impairment. 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.

Use in 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. When candesartan 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 endstage renal impairment (i.e. creatinine clearance < 15 mL/min/1.73 m2 BSA). Evaluation of patients with heart failure should include periodic assessments of renal function. During dose titration of candesartan, monitoring of serum creatinine and potassium is recommended.

Haemodialysis.

During dialysis the blood pressure may be particularly sensitive to AT1 receptor blockade as a result of reduced plasma volume and activation of the renin angiotensin aldosterone system. Therefore, candesartan should be carefully titrated with thorough monitoring of blood pressure in patients on haemodialysis (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

An initial dose of 8 mg is recommended.

Paediatric use.

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

Effects on laboratory tests.

In general there were no clinically important effects of candesartan 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. No routine monitoring of laboratory variables is usually necessary for patients receiving candesartan. However, in patients with severe renal impairment, periodic monitoring of serum potassium and creatinine levels should be considered.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Dual blockade of the renin angiotensin aldosterone system (RAAS) with aliskiren containing medicines.

The combination of candesartan cilexetil with aliskiren-containing medicine is contraindicated in patients with diabetes mellitus (type I or II) or moderate to severe renal impairment (GFR < 60 mL/min/1.73 m2) and is not recommended in other patients. 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 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Food.

Food increases the rate of absorption of candesartan however the extent of absorption of candesartan is not affected by food.

Lithium.

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. A similar effect may occur with angiotensin II receptor antagonists and careful monitoring of serum lithium levels is recommended during concomitant use.

Other medicines.

Compounds which have been investigated in 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 nonsteroidal anti-inflammatory drugs (NSAIDs; i.e. selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) and nonselective 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 may be administered with other antihypertensive agents.

4.6 Fertility, Pregnancy and Lactation

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.
(Category D1)
The use of candesartan is contraindicated during pregnancy (see Section 4.3 Contraindications). Patients receiving candesartan should be made aware of that before contemplating a possibility of becoming pregnant so that they can discuss appropriate options with their treating physician. When pregnancy is diagnosed, treatment with candesartan must be stopped immediately and if appropriate, alternate therapy should be started.
Drugs that act on the renin angiotensin system (RAS) can cause fetal and neonatal morbidity and death when administered to pregnant women. 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).
1Category D - 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.
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, breastfeeding should be discontinued if the use of candesartan is considered essential.

4.8 Adverse Effects (Undesirable 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 in Table 1.

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. No routine monitoring of laboratory variables is usually necessary for patients receiving candesartan cilexetil. However, in patients with severe renal impairment, periodic monitoring of serum potassium and creatinine levels should be considered.

Heart failure.

The adverse experience profile of candesartan 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 in doses up to 32 mg (n = 3,803) to placebo (n = 3,796), 21.0% of the candesartan 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 in creatinine, urea and potassium. Periodic monitoring of serum creatinine and potassium is recommended (see Section 4.4 Special Warnings and Precautions for Use).

Post marketing experience.

The following adverse reactions have been reported very rarely (< 0.01%) in postmarketing experience.

Blood and lymphatic system disorders.

Leukopenia, neutropenia and agranulocytosis.

Metabolism and nutrition disorders.

Hyperkalaemia, hyponatraemia.

Hepatobiliary 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 Section 4.4 Special Warnings and Precautions for Use).
Rare reports of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
*Although causality to candesartan has not been established, the following neuropsychiatric and cardiovascular adverse reactions have been very rarely reported during postmarketing surveillance. These were: agitation, anxiety, depression, insomnia, somnolence, nervousness, nightmare, sleep disorder and palpitations.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

APO-Candesartan should be taken once daily with or without food.

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.

Dose titration is recommended in patients with mild to moderate chronic liver disease, and a lower initial dose of 4 mg should be considered.
Candesartan should not be used in patients with severe hepatic impairment and/or cholestasis (see Section 4.3 Contraindications).

Renal insufficiency.

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 m2 BSA). In patients with severely impaired renal function (i.e. creatinine clearance < 30 mL/min/1.73 m2 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 Section 4.4 Special Warnings and Precautions for Use).

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 Section 5.1 Pharmacodynamic Properties).

4.7 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.

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 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. Contact the Poisons Information Centre for advice on management.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

4 mg tablets.

Blister pack (PVC/PE/PVDC/Al) of 7, 28 and 30 tablets. AUST R 210529.

8 mg tablets.

Blister pack (PVC/PE/PVDC/Al) blister packs 7, 28 and 30 tablets. AUST R 210530.

16 mg tablets.

Blister pack (PVC/PE/PVDC/Al) of 7, 28 and 30 tablets. AUST R 210531.

32 mg tablets.

Blister pack (PVC/PE/PVDC/Al) of 7, 28 and 30 tablets. AUST R 210532.
Not all strengths and/or pack sizes may be available.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes