Consumer medicine information

BTC Candesartan

Candesartan cilexetil

BRAND INFORMATION

Brand name

BTC Candesartan

Active ingredient

Candesartan cilexetil

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using BTC Candesartan.

SUMMARY CMI

BTC Candesartan

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using BTC Candesartan?

BTC Candesartan contains the active ingredient candesartan cilexetil. BTC Candesartan is used to treat high blood pressure (hypertension) and heart failure (in combination with other medicines to treat your condition).

For more information, see Section 1. Why am I using BTC Candesartan? in the full CMI.

2. What should I know before I use BTC Candesartan?

Do not use if you have ever had an allergic reaction to BTC Candesartan or any of the ingredients listed at the end of the CMI. Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use BTC Candesartan? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with BTC Candesartan and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use BTC Candesartan?

  • Your doctor will tell you how many tablets to take each day. The usual dose is 8 mg or 16 mg once daily. This dose may be increased to 32 mg once daily.
  • Swallow the tablets whole with a glass of water at about the same time each day

More instructions can be found in Section 4. How do I use BTC Candesartan? in the full CMI.

5. What should I know while using BTC Candesartan?

Things you should do
  • Remind any doctor, dentist, or pharmacist you visit that you are taking BTC Candesartan.
  • If you are taking this medicine for high blood pressure, drink plenty of water during exercise and hot weather, especially if you sweat a lot. If you are taking BTC Candesartan for heart failure, restricted fluid intake is generally recommended. Speak with your doctor about how much water you should drink.
  • Move slowly when getting out of bed or standing up if you feel faint, dizzy or light-headed.
Things you should not do
  • Do not stop taking BTC Candesartan or lower the dosage without checking with your doctor.
Driving or using machines
  • Be careful driving or operating machinery until you know how BTC Candesartan affects you. BTC Candesartan may cause nausea, dizziness and tiredness in some people. If this occurs, do not drive, operate machinery or do anything else that could be dangerous.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
Looking after your medicine
  • Keep BTC Candesartan below 30°C.
  • Keep your tablets in the original packaging until it is time to take them.

For more information, see Section 5. What should I know while using BTC Candesartan? in the full CMI.

6. Are there any side effects?

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

Serious side effects: swelling of the face, lips, tongue or throat which may cause difficulty in swallowing or breathing; swelling of the hands, feet or ankles; aching muscles, tenderness of weakness in the muscles, worsening of the 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).

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

BTC Candesartan

Active ingredient(s): Candesartan cilexetil

Consumer Medicine Information (CMI)

This leaflet provides important information about using BTC Candesartan. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using BTC Candesartan.

Where to find information in this leaflet:

1. Why am I using BTC Candesartan?
2. What should I know before I use BTC Candesartan?
3. What if I am taking other medicines?
4. How do I use BTC Candesartan?
5. What should I know while using BTC Candesartan?
6. Are there any side effects?
7. Product details

1. Why am I using BTC Candesartan?

BTC Candesartan contains the active ingredient candesartan cilexetil.

BTC Candesartan belongs to a group of medicines called angiotensin II receptor antagonists (or blocker).

BTC Candesartan is used to treat

  • high blood pressure, also called hypertension.
  • heart failure, in combination with other medicines to treat your condition.

2. What should I know before I use BTC Candesartan?

Warnings

Do not use BTC Candesartan if:

  • you are allergic to candesartan cilexetil, any medicine containing an angiotensin II receptor antagonist (blocker) or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
    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.
  • you have severe liver disease and/or conditions associated with impaired bile flow (cholestasis)
  • you are taking blood pressure medicine containing aliskiren, especially if you have diabetes mellitus or have kidney problems.

Check with your doctor if you:

  • have any other medical conditions
    - kidney problems
    - liver problems
    - heart problems
    - recent excessive vomiting or diarrhoea
    - a condition called primary hyperaldosteronism.
  • take medicines for any other condition
  • During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Use in Children

BTC Candesartan should not be given to children. There is not enough information to recommend the use of this medicine for children.

Pregnancy and breastfeeding

Do not take BTC Candesartan if you are pregnant or planning to become pregnant.

It may affect your developing baby if you take it during pregnancy.

Do not breastfeed if you are taking this medicine.

Talk to your doctor if you intend to breastfeed. It is not known if this medicine passes into breast milk.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins, or supplements that you buy without a prescription from your pharmacy, supermarket, or health food shop.

Some medicines may interfere with BTC Candesartan and affect how it works. 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, medicines used to help lower blood pressure, especially if you have diabetes related kidney problems
  • Mineralocorticoid receptor antagonists (MRAs), such as spironolactone and eplerenone, medicines used to treat heart failure.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins, or supplements you are taking and if these affect BTC Candesartan.

4. How do I use BTC Candesartan?

How much to take

  • The usual dose is 8 or 16 mg taken once daily. Sometimes an increase in dose to 32 mg once daily is needed.
  • Follow the instructions your doctor or pharmacist give you. If you take the wrong dose, BTC Candesartan may not work as well, and your problem may not improve.

When to take BTC Candesartan

  • BTC Candesartan should be taken once a day, 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

How to take BTC Candesartan

Swallow the tablets whole with a full glass of water. It does not matter whether you take this medicine with food or on an empty stomach.

How to long to take BTC Candesartan

Continue taking BTC Candesartan 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 use BTC Candesartan

If you miss your dose at the usual time, take it as soon as you remember (as long as it is at least 12 hours before your next dose is due), and continue to take it as you would normally.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed. This may increase the chance of you getting an unwanted side effect.

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 use too much BTC Candesartan

If you think that you have used too much BTC Candesartan, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

Symptoms of overdose may include a headache, feel sick (nausea), dizziness or tiredness.

5. What should I know while using BTC Candesartan?

Things you should do

  • Take BTC Candesartan exactly as your doctor has told you to. Your blood pressure will not be well controlled if you do not.
  • If you are about to be started on any new medicine, remind your doctor or pharmacist that you are taking BTC Candesartan
  • If you are going to have surgery (even at the dentist) that needs a general anaesthetic, tell the surgeon or anaesthetist that you are taking this medicine.
  • Be sure to keep all of your doctor's appointments so that your progress can be checked. Your doctor will check your progress and may want to take some test (e.g., blood tests, blood pressure) from time to time. These tests may help to prevent side effects.

Call your doctor straight away if you:

  • become pregnant while taking this medicine. You should not take this medicine if you are pregnant or thinking about becoming pregnant. Your doctor can discuss different treatment options with you.

Remind any doctor, dentist, or pharmacist you visit that you are using BTC Candesartan.

Things you should not do

  • Do not take BTC Candesartan 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 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.
  • If you are taking this medicine 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 this medicine, 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 this medicine for heart failure, restricted fluid intake is generally recommended. Speak with your doctor about how much water you should drink.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how BTC Candesartan affects you. This medicine may cause nausea, dizziness, and tiredness in some people. If you have any of these symptoms, do not drive, operate machinery, or do anything else that could be dangerous.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

  • Keep BTC Candesartan in the original container.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place below 30°C away from moisture, heat, or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date or if the packaging is torn or shows signs of tampering.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Infection related:
  • chest or throat infection
  • flu-like symptoms
Gut or Gastrointestinal related:
  • feeling sick (nausea/vomiting)
Muscle-joint related:
  • back pain
General disorders:
  • headache
  • dizziness
Speak to your doctor if you have any of these less serious side effects and they worry you.

They are generally mild and do not cause patients to stop taking BTC Candesartan.

Serious side effects

Serious side effectsWhat to do
Allergy related:
  • swelling of the face, lips, tongue or throat which may cause difficulty in swallowing or breathing
General disorders:
  • extreme fatigue, tiredness, weakness
Skin related:
  • Unusual skin reactions (severe and sudden onset of rash, itchiness, hives (itchy swellings on the skin)
Muscle-joint related:
  • aching muscles, not caused by exercise, tenderness in the muscle
  • muscle pain or weakness
Kidney related:
  • worsening of the 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)
Electrolytes related:
  • symptoms that may indicate high potassium levels in the blood, include nausea, diarrhoea, muscle weakness, change in heart rhythm
  • changes in your potassium, sodium and red or white blood cell levels may occur. Such changes are usually detected by a blood test.
Liver related:
  • jaundice (yellowing of the skin and/or eyes)
Infection related:
  • signs of frequent infections such as fever, severe chills, sore throat, or mouth ulcers.
Blood related:
  • easy bruising or bleeding more easily than normal
Lungs related:
  • harsh sounds when breathing
Others:
  • swelling of hands, feet, or ankles
Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What BTC Candesartan contains

Active ingredient
(main ingredient)		candesartan cilexetil
Other ingredients
(inactive ingredients)
  • iron oxide red (8 mg, 16 mg, and 32 mg tablets only)
  • titanium dioxide (8 mg, 16 mg, and 32 mg tablets only)
  • lactose monohydrate
  • maize starch
  • povidone
  • carrageenan
  • croscarmellose sodium magnesium stearate
Potential allergens
  • sugars as lactose

This medicine does not contain sucrose, gluten, tartrazine, or any other azo dyes.

Do not take this medicine if you are allergic to any of these ingredients.

What BTC Candesartan looks like

BTC Candesartan 4 mg - white, round biconvex tablet, debossed with 4 on one side and scored on the other side (AUST R 396088).

BTC Candesartan 8 mg - pink, mottled, round biconvex tablet, debossed with 8 on one side and scored on the other side (AUST R 396085).

BTC Candesartan 16 mg - pink, mottled, round biconvex tablet, debossed with 16 on one side and scored on the other side (AUST R 396089).

BTC Candesartan 32 mg - pink, mottled, round biconvex tablet, debossed with 32 on one side and scored on the other side (AUST R 396087).

Available in blisters of 30 tablets.

Who distributes BTC Candesartan

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park, NSW 2113
Tel: 1800 726 369

This leaflet was prepared in January 2023.

Published by MIMS July 2023

BRAND INFORMATION

Brand name

BTC Candesartan

Active ingredient

Candesartan cilexetil

Schedule

S4

 

1 Name of Medicine

Candesartan cilexetil.

2 Qualitative and Quantitative Composition

Each BTC Candesartan 4 mg tablet contains 4 mg candesartan cilexetil.
Each BTC Candesartan 8 mg tablet contains 8 mg candesartan cilexetil.
Each BTC Candesartan 16 mg tablet contains 16 mg candesartan cilexetil.
Each BTC Candesartan 32 mg tablet contains 32 mg candesartan cilexetil.

Excipient with known effect.

Sugars as lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

BTC Candesartan 4 mg tablets are white, round biconvex tablets, debossed with 4 on one side and scored on the other.
BTC Candesartan 8 mg tablets are pink, mottled, round biconvex tablets, debossed with 8 on one side and scored on the other.
BTC Candesartan 16 mg tablets are pink, mottled, round biconvex tablets, debossed with 16 on one side and scored on the other.
BTC Candesartan 32 mg tablets are pink, mottled, round biconvex tablets, debossed with 32 on one side and scored on the other.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of hypertension.
Treatment of patients with heart failure and impaired left ventricular systolic function (left ventricular ejection fraction ≤ 40%) as add on therapy to angiotensin converting enzyme (ACE) inhibitors or when ACE inhibitors are not tolerated.

4.2 Dose and Method of Administration

Dosage.

BTC Candesartan should be taken once daily with or without food.

Hypertension.

The recommended maintenance dose of BTC Candesartan is 8 or 16 mg once daily. The maximal antihypertensive effect is attained within four 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 BTC Candesartan, combination with a thiazide diuretic is recommended.

Heart failure.

The usual recommended initial dose of BTC 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).

Dosage adjustment.

Renal impairment.

No initial dosage adjustment is necessary in patients with mild to moderate impaired renal function (i.e. creatinine clearance 30 - 80 mL/minute/1.73 m2 body surface area (BSA)). In patients with severely impaired renal function (i.e. creatinine clearance < 30 mL/minute/1.73 m2 BSA), including patients on haemodialysis, a lower initial dose of 4 mg should be considered.

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.
BTC Candesartan should not be used in patients with severe hepatic impairment and/or cholestasis (see Section 4.3 Contraindications).

Elderly.

An initial dose of 8 mg is recommended.

Paediatrics.

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

Concomitant therapy.

BTC 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 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties).

4.3 Contraindications

Hypersensitivity to any component of BTC Candesartan.
Pregnancy and lactation (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
Severe hepatic impairment and/or cholestasis.
The use of candesartan in combination 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

In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone-system (RAAS) (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with medicines 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 medicines that affect the RAAS, i.e. 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 (AIIRAs).

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.

Primary hyperaldosteronism.

Patients with primary hyperaldosteronism will not generally respond to antihypertensive medicines acting through inhibition of the RAAS. 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 RAAS, 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 RAAS.

There is evidence that the concomitant use of ACE-inhibitors, AIIRAs or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of the RAAS through the combined use of candesartan with and 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 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 medicines that affect the RAAS, concomitant use of candesartan with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other medicines that may increase potassium levels (e.g. heparin, trimethoprim/sulfamethoxazole) 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 AIIRAs due to blockade of the renin-angiotensin system (RAS). 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 medicine (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 medicine. Combined use of these medications should be accompanied by increased monitoring of serum creatinine, particularly at the institution of the combination. The combination of medicines 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 AIIRAs. No such cases have been reported to date with candesartan.

Use in renal impairment.

As with other agents inhibiting the RAAS, 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 end-stage renal impairment (i.e. creatinine clearance < 15 mL/minute/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 RAAS. 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.

No data available.

Paediatric use.

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

Effects on laboratory tests.

In general, there were no clinically important effects of candesartan cilexetil on routine laboratory variables. As for other inhibitors of the RAAS, 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 alanine aminotransferase (ALT) occurred in 1.3% of candesartan treated patients and 0.5% of those treated with placebo. The incidence of aspartate aminotransferase (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.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Dual blockade of the RAAS.

The combination of candesartan 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/1.7 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 blocker 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 AIIRAs 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, nifedipine and enalapril. No pharmacokinetic interactions of clinical significance were identified in these studies.
The antihypertensive effect of AIIRAs, including candesartan, may be attenuated by NSAIDs, including COX-2 inhibitors and acetylsalicylic acid.
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 D)
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, alternative therapy should be started.
Drugs that act on the 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).
 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.

4.7 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.

4.8 Adverse Effects (Undesirable Effects)

Hypertension.

Candesartan cilexetil 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 cilexetil was administered as monotherapy 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.

Heart failure.

The adverse experience profile of candesartan cilexetil in heart failure patients was consistent with the pharmacology of the medicine and the health status of the patients. In the CHARM clinical program, 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 as follows:

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).

Postmarketing.

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

Blood and lymphatic system disorders.

Leucopenia, 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, Renal impairment).
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 www.tga.gov.au/reporting-problems.

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.

Treatment.

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, e.g. isotonic saline solution. Sympathomimetic medicines may be administered if the above-mentioned measures are not sufficient.
Candesartan is not removed by haemodialysis.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Candesartan cilexetil is an AIIRA.
Angiotensin II is the primary vasoactive hormone of the RAAS 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 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 AIIRA, selective for AT1 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 ACE and no potentiation of bradykinin or substance P, AIIRAs are unlikely to be associated with cough. This has been confirmed in controlled clinical studies with candesartan cilexetil. Candesartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
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.
Candesartan cilexetil 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-hour dosing interval, with a trough/ peak ratio confirming once daily dosing.
Candesartan can be used as monotherapy or in combination with other antihypertensive medicines, such as thiazide diuretics, calcium antagonists and lisinopril, for improved blood pressure control. Age and gender have no influence on the efficacy of candesartan cilexetil.
Candesartan cilexetil 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 cilexetil reduces urinary protein excretion in hypertensive patients with microalbuminuria or nephropathy of different aetiology. Candesartan cilexetil 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 RAAS 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, Use in pregnancy, Use in 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 2 diabetes mellitus, hypertension and microalbuminuria. Patients were randomly allocated to four treatment regimens: 1) 24 weeks of candesartan monotherapy (one-third of the patients); 2) 24 weeks of lisinopril monotherapy (one-third of the patients); 3) 12 weeks of candesartan monotherapy, followed by 12 weeks of candesartan + lisinopril combination therapy (one-sixth of the patients); and 4) 12 weeks of lisinopril monotherapy, followed by 12 weeks of lisinopril and candesartan combination therapy (one-sixth 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, one-third of the patients still in the study were on candesartan monotherapy (n = 49), one-third on lisinopril monotherapy (n = 46), and one-third on combination therapy (candesartan and lisinopril (n = 25), lisinopril and candesartan (n = 24). (See Table 2.)
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 less than or equal to 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 and hospitalisation due to CHF and improves symptoms as shown in the Candesartan in Heart failure - Assessment of Reduction in Mortality and morbidity (CHARM) program comprising three studies (CHARM-Alternative, CHARM-Added and CHARM-Preserved). In all three studies, patients on optimal baseline therapy were randomised to placebo or candesartan cilexetil (titrated from 4 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 (New York Heart Association (NHYA) class II to IV, n = 2,028) with a LVEF less than or equal to 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 to IV, n = 2,548) with a LVEF less than or equal to 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 to 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 to 0.98, p = 0.018) and all three studies (HR 0.91, 95% CI: 0.83 to 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 in improved NYHA functional class in CHARM-Alternative and CHARM-Added (p = 0.008 and 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.

5.2 Pharmacokinetic Properties

Absorption and distribution.

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 three to four hours after taking a tablet. The point estimate of Cmax is 103.83% with associated confidence interval of [96.65%, 111.55%]. 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.
In case of AUC0-t, the point estimate is 95.45% with associated confidence interval of [91.14%, 99.96%] and AUC0-∞ has point estimate of 94.96% and corresponding associated confidence interval of [90.73%, 99.37%].
Candesartan is highly bound to plasma protein (more than 99%). The apparent volume of distribution (Vss) 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 nine hours. There is no accumulation following multiple doses.
Total plasma clearance of candesartan is about 0.37 mL/minute/kg, with a renal clearance of about 0.19 mL/minute/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 were 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.
Following oral administration of BTC Candesartan 16 mg to healthy subjects under fasting conditions, a mean peak plasma concentration (Cmax) of candesartan of approximately 118.18 nanogram/mL was achieved within approximately 4.02 hours (Tmax).

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 medicine by gavage whereas mice received the medicine 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 humans at the maximum recommended daily human dose (32 mg).

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, iron oxide red (8 mg, 16 mg and 32 mg tablets only), titanium dioxide (8 mg, 16 mg and 32 mg tablets only), maize starch, povidone, carrageenan, croscarmellose sodium, magnesium stearate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For information on interactions with other medicines and other forms of interactions, see Section 4.5.

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 30°C. Store in the original packaging.

6.5 Nature and Contents of Container

BTC Candesartan is available in Al/Al blister packs of 30 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

The chemical name of Candesartan cilexetil is (±)-1-(cyclohexyloxycarbonyl-oxy) ethyl 2ethoxy- 1-[[2'-(1H-tetrazol-5-yl)-biphenyl-4-yl]methyl]-1H-benzimadozole-7-carboxylate. Its empirical formula is C33H34N6O6 (MW: 610.7) and its chemical structure is:

CAS number.

145040-37-5.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes