Consumer medicine information

Adesan

Candesartan cilexetil

BRAND INFORMATION

Brand name

Adesan

Active ingredient

Candesartan cilexetil

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Adesan.

What is in this leaflet

This leaflet answers some common questions about ADESAN.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking ADESAN against the benefits expected for you.

If you have any concerns about taking this medicine, talk to your doctor or pharmacist.

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

What ADESAN is used for

ADESAN is a type of medicine called an angiotensin II receptor antagonist (or blocker).

ADESAN is used to treat high blood pressure, also called hypertension.

ADESAN is also used to treat heart failure. It is used in combination with other medicines to treat your condition.

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.

ADESAN 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.

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

One of the ways ADESAN 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, ADESAN is almost always used with other medicines called diuretics or fluid tablets. These medicines help the kidney get rid of excess fluid from the body.

Your doctor will have explained why you are being treated with ADESAN and told you what dose to take.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may prescribe it for another reason.

This medicine is not addictive.

It is available only with a doctor's prescription.

This medicine may affect your ability to drive a car or operate machinery.

There is not enough information to recommend the use of this medicine for children.

Before you take ADESAN

When you must not take it

Do not take ADESAN if you have an allergy to:

  • any medicine containing candesartan cilexetil
  • any of the ingredients listed at the end of this leaflet
  • any medicine containing an angiotensin II receptor antagonist (or blocker)

Some of the symptoms of an allergic reaction may include

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not take ADESAN if you have:

  • severe liver disease and/or conditions associated with impaired bile flow (cholestasis)

Do not take ADESAN if you are taking blood pressure medicine containing aliskiren, especially if you have diabetes mellitus or have kidney problems.

Do not take this medicine if you are pregnant or planning to become pregnant. It may affect your baby if you take it during pregnancy.

Do not breast-feed if you are taking this medicine. It is not known if ADESAN passes into breast milk.

Do not give ADESAN to children. There is no information about its use in children, so ADESAN is not recommended for children.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should take this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have any of the following medical conditions:

  • kidney problems
  • liver problems
  • heart problems
  • recent excessive vomiting or diarrhoea
  • a condition called primary hyperaldosteronism

You may have to take a lower dose of ADESAN if you have these conditions.

If you have not told your doctor about any of the above, tell him/her before you start taking ADESAN.

Taking other medicines

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

Some medicines and ADESAN 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, 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

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

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

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

How to take ADESAN

Follow all directions given to you by your doctor and pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box/bottle, ask your doctor or pharmacist for help.

How much to take

The usual dose is one 8 mg tablet or one 16 mg tablet taken daily. Sometimes an increase in dose to 32 mg once daily is needed. Your doctor will tell you the dose of ADESAN you should take.

How to take it

Swallow the tablets whole with a full glass of water.

Do not crush or chew the tablets.

When to take it

Take ADESAN 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.

It does not matter if you take ADESAN with food or on an empty stomach.

How long to take it

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

This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take it

If you forget to take a dose, take it as soon as you remember, as long as it is at least 12 hours before your next dose is due. Then go back to taking your medicine as you would normally.

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

Do not take a double dose to make up for the dose you missed.

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

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much ADESAN. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of an overdose may include headache and feel sick (nausea), dizzy and very tired.

While you are taking ADESAN

Things you must do

Take ADESAN exactly as your doctor has told you, 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 and pharmacist that you are taking ADESAN.

Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.

If you plan to have surgery (even at the dentist) that needs a general anaesthetic, tell your doctor or dentist that you are taking this medicine. It may affect other medicines used during surgery.

Tell your doctor immediately if you become pregnant or plan to become pregnant while taking this ADESAN. You should not use ADESAN if you are pregnant or thinking about becoming pregnant. Your doctor can discuss treatment options with you.

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 do some tests (e.g. blood tests, blood pressure) from time to time. These tests may help to prevent side effects.

Things you must not do

Do not take ADESAN 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 change the dosage unless you have discussed it with your doctor.

Things to be careful of

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

Be careful driving or operating machinery until you know how ADESAN affects you. You may feel dizzy when you start taking ADESAN.

If you are taking ADESAN 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 ADESAN, 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 ADESAN 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 these possibilities if you think they may bother you.

Lifestyle measures that help reduce heart disease risk

By following these simple measures, you can further reduce the risk from heart disease.

  • Quit smoking and avoid second-hand smoke.
  • Limit alcohol intake.
  • Enjoy healthy eating by:
    - eating plenty of vegetables and fruit;
    - reducing your saturated fat intake (eat less fatty meats, full fat dairy products, butter, coconut and palm oils, most take-away foods, commercially-baked products).
  • Be active. Progress, over time, to at least 30 minutes of moderate-intensity physical activity on 5 or more days each week. Can be accumulated in shorter bouts of 10 minutes duration. If you have been prescribed anti-angina medicine, carry it with you when you are being physically active.
  • Maintain a healthy weight.
  • Discuss your lifestyle and lifestyle plans with your doctor.
  • For more information and tools to improve your heart health, call Heartline, the Heart Foundation's national telephone information service, on 1300 36 27 87 (local call cost).

Know warning signs of heart attack and what to do:

  • Tightness, fullness, pressure, squeezing, heaviness or pain in your chest, neck, jaw, throat, shoulders, arms or back.
  • You may also have difficulty breathing, or have a cold sweat or feel dizzy or light headed or feel like vomiting (or actually vomit).
  • If you have heart attack warning signs that are severe, get worse or last for 10 minutes even if they are mild, call triple zero (000). Every minute counts.

Side effects

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

This medicine helps most people but it may have unwanted side effects in a few people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by the following list of side effects. You may not experience any of them.

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

Tell your doctor if you notice any of the following and they worry you:

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

These side effects are usually mild.

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. Serious 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
  • swelling of the hands, feet or ankles
  • harsh sounds when breathing
  • rash, itchiness or hives
  • jaundice (yellowing of the skin and/or eyes).
  • easy bruising or bleeding more easily than normal
  • extreme fatigue, tiredness, weakness
  • signs of frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • 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).
  • 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.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people.

After taking ADESAN

Storage

Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 25°C. Protect from light.

Do not store ADESAN 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 it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

ADESAN 4 mg: A white to off white round, biconvex tablet debossed with M on left side of the breakline and C on the right side of the breakline on one side of the tablet and 24 on the other side.

ADESAN 8 mg: A mottled pink, round, biconvex tablet debossed with M on left side of the breakline and C on right side of the breakline on one side of the tablet and 25 on the other side.

ADESAN 16 mg: A mottled pink, round, biconvex tablet debossed with M on left side of the breakline and C on right side of the breakline on one side of the tablet and 31 on the other side.

ADESAN 32 mg: A mottled pink, round, biconvex tablet debossed with MC above the breakline and 32 below the break line on one side of the tablet and plain on the other side.

All strengths are available in blister pack of 30 tablets.

Ingredients

ADESAN tablet contains 4, 8, 16 or 32 mg of candesartan cilexetil as the active ingredient.

It also contains the following inactive ingredients:

  • lactose monohydrate
  • carmellose calcium
  • glyceryl monostearate
  • hydroxypropylcellulose
  • iron oxide red CI77491
  • maize starch
  • magnesium stearate
  • ADESAN tablets contain lactose.

Supplier

ADESAN is supplied in Australia by:

Alphapharm Pty Limited
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.mylan.com.au

Australian registration numbers:

ADESAN 4 mg: AUST R 171019

ADESAN 8 mg: AUST R 171022

ADESAN 16 mg: AUST R 171016

ADESAN 32 mg: AUST R 171017

This leaflet was prepared in December 2019.

ADESAN_cmi\Nov19/00

Published by MIMS February 2020

BRAND INFORMATION

Brand name

Adesan

Active ingredient

Candesartan cilexetil

Schedule

S4

 

1 Name of Medicine

Candesartan cilexetil.

6.7 Physicochemical Properties

Molecular formula: C33H34N6O6.
Molecular weight: 610.67.

Chemical structure.


CAS number.

145040-37-5.
Candesartan cilexetil a white to off white powder and is practically insoluble in water. Three polymorphic forms have been identified; crystal form I, crystal form II and an amorphous form. Crystalline form I is used in Adesan.

2 Qualitative and Quantitative Composition

Adesan 4 mg.

Contains 4 mg of candesartan cilexetil as the active ingredient.
A white to off white round, biconvex tablet debossed with M on left side of the breakline and C on the right side of the breakline on one side of the tablet and 24 on the other side.

Adesan 8 mg.

Contains 8 mg of candesartan cilexetil as the active ingredient.
A mottled pink, round, biconvex tablet debossed with M on left side of the breakline and C on right side of the breakline on one side of the tablet and 25 on the other side.

Adesan 16 mg.

Contains 16 mg of candesartan cilexetil as the active ingredient.
A mottled pink, round, biconvex tablet debossed with M on left side of the breakline and C on right side of the breakline on one side of the tablet and 31 on the other side.

Adesan 32 mg.

Contains 32 mg of candesartan cilexetil as the active ingredient.
A mottled pink, round, biconvex tablet debossed with MC above the breakline and 32 below the break line on one side of the tablet and plain on the other side.
Adesan also contains sugars (as lactose).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

See Section 2 Qualitative and Quantitative Composition.

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 cilexetil is a prodrug suitable for oral use. It is rapidly converted to the active drug, candesartan, by ester hydrolysis during absorption from the gastrointestinal tract. Candesartan is an angiotensin II receptor antagonist, selective for 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) program 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 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

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 plasma concentration (Cmax) is reached 3-4 hours after taking a tablet. The candesartan plasma concentrations increase linearly with increasing doses in the therapeutic dose range.
The area under the plasma 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.
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 excretion.

Candesartan is mainly eliminated unchanged via urine and bile and is eliminated by hepatic metabolism only to a minor extent (CYP2C9). 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 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.

Pharmacokinetic results of the bioequivalence study.

A bioavailability study was conducted comparing the generic candesartan cilexetil 32 mg tablet with that of the originator. The generic and originator mean Cmax for candesartan was 5.476 nanogram/mL and 5.530 nanogram/mL respectively. The Cmax point estimate for candesartan was 94.75% with the 90% confidence interval between 87.80% and 102.37%. The AUC0-t of the generic is 7.907 nanogram.hr/mL, and the mean AUC0-t point estimate for candesartan was 90.98% with the 90% confidence interval between 86.34% and 95.87%. The Tmax for the generic and originator tablets was 3.9 hours and 4.3 hours respectively.

5.3 Preclinical Safety Data

Genotoxicity.

Mutagenicity.

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 systematic exposures to candesartan (AUCs) that were, in mice, approximately 7 times and, in rats, more than 70 times the exposure in man at the maximum recommended daily human dose (32 mg).

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 ACE inhibitors or when ACE inhibitors are not tolerated.

4.3 Contraindications

Hypersensitivity to any component of Adesan.
Pregnancy and lactation (see Section 4.6 Fertility, Pregnancy and Lactation).
Severe hepatic impairment and/or cholestasis.
The use of Adesan 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, an excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke.

Kidney transplantation.

There is limited clinical experience regarding the administration of candesartan 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 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 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 the renin-angiotensin-aldosterone system 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 Adesan 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 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, 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.

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).

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 end-stage 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.

Use in the elderly.

There are special dosage recommendations for use of candesartan cilexetil in elderly patients (see Section 4.2 Dose and Method of Administration).

Paediatric use.

Safety and efficacy have not been established in children.

Effects on laboratory tests.

No data available.

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 Adesan 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 (AIIRAs) and careful monitoring of serum lithium levels is recommended during concomitant use.

Other drugs.

Compounds which have been investigated in clinical pharmacokinetic studies include hydrochlorothiazide, warfarin, digoxin, oral contraceptives (i.e. ethinylestradiol/ levonorgestrel), glibenclamide and nifedipine and enalapril. No pharmacokinetic interactions of clinical significance were identified in these studies.
The antihypertensive effect of angiotensin II receptor antagonists, 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)
Category 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.
The use of candesartan cilexetil is contraindicated during pregnancy (see Section 4.3 Contraindications). Patients receiving candesartan cilexetil 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 cilexetil must be stopped immediately and if appropriate, alternative 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).
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 cilexetil 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 influences of candesartan cilexetil on routine laboratory variables. As for other inhibitors of the renin-angiotensin-aldosterone system, small decreases in haemoglobin have been seen. Increases in creatinine, urea or potassium and decreases in sodium have been observed. 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.

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 program, comparing candesartan in doses up to 32 mg (n = 3,803) to placebo (n = 3,796), 21.0% of the candesartan cilexetil group and 16.1% of the placebo group discontinued treatment because of adverse events. Adverse reactions commonly (≥ 1/100, < 1/10) seen were:

Vascular disorders.

Hypotension.

Metabolism and nutrition disorders.

Hyperkalaemia.

Renal and urinary disorders.

Renal impairment.

Laboratory findings.

Increases 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.

The following adverse reactions have been reported very rarely (< 0.01%) in post marketing experience:

Blood and lymphatic system disorders.

Leukopenia, neutropenia and agranulocytosis.

Metabolism and nutrition disorders.

Hyperkalaemia, hyponatraemia.

Hepato-biliary disorders.

Increased liver enzymes, abnormal hepatic function or hepatitis.

Skin and subcutaneous tissue disorders.

Angioedema, rash, urticaria, pruritus.

Musculoskeletal, connective tissue and bone disorders.

Back pain, myalgia.

Renal and urinary disorders.

Renal impairment, including renal failure in susceptible patients (see 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 post-marketing 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.

4.2 Dose and Method of Administration

Candesartan should be taken once daily with or without food.

Paediatrics.

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

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.
Adesan 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 4.4 Special Warnings and Precautions for Use; 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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

In addition to candesartan cilexetil, Adesan tablets also contain lactose monohydrate, carmellose calcium, glyceryl monostearate, hydroxypropylcellulose, iron oxide red CI77491, maize starch, magnesium stearate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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 in original container. Protect from light.

6.5 Nature and Contents of Container

Container type: Blister pack.
Pack sizes: 7*, 28*, 30
*Some strengths, pack sizes and/or pack types may not be marketed.

6.6 Special Precautions for Disposal

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

Summary Table of Changes