Consumer medicine information

Candesartan/ HCT Sandoz

Candesartan cilexetil; Hydrochlorothiazide

BRAND INFORMATION

Brand name

Candesartan/HCT Sandoz

Active ingredient

Candesartan cilexetil; Hydrochlorothiazide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Candesartan/ HCT Sandoz.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Candesartan/HCT Sandoz.

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

All medicines have risks and benefits. Your doctor has weighed the risk of you taking Candesartan/HCT Sandoz against the benefits it is expected to have for you.

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

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

WHAT CANDESARTAN/HCT SANDOZ IS USED FOR

This medicine is used to treat high blood pressure.

It contains the active ingredients candesartan cilexetil and hydrochlorothiazide.

Candesartan cilexetil belongs to a group of medicines called angiotensin II - receptor antagonists (or blocker). It works by causing relaxation of blood vessels.

Hydrochlorothiazide belongs to a group of medicines called diuretics. It works by reducing the amount of excess fluid in the body.

Using these two medicines together will lower your blood pressure more than using either one on its own.

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

Follow all directions given to you by your doctor carefully

Your doctor may have prescribed it for another reason.

They may differ from the information contained in this leaflet.

This medicine is not addictive.

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

BEFORE YOU TAKE CANDESARTAN/HCT SANDOZ

When you must not take it

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

  • candesartan cilexetil and hydrochlorothiazide, the active ingredients, or to any of the other ingredients listed at the end of this leaflet under Product Description
  • any other similar medicines (such as Irbesartan), angiotensin II receptor antagonist
  • any sulphur drugs (sulphonamides) such as some antibiotics or some medicines to treat diabetes.

Some of the symptoms of an allergic reaction may include:

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

Do not take this medicine if you have or have had any of the following medical conditions:

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

Do not use Candesartan/HCT Sandoz 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 are 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. Your baby can take in components of Candesartan/HCT Sandoz from breast milk if you are breastfeeding.

Do not give this medicine to children. There is no information about its use in 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 start taking this medicine, talk to your doctor.

Before you start to take it

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

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

  • kidney problems
  • liver problems
  • heart problems
  • diabetes
  • recent excessive vomiting or diarrhoea
  • systemic Lupus Erythematosus (SLE), a disease affecting the skin, joints and kidneys
  • a salt restricted diet
  • a condition called primary hyperaldosteronism
  • a past operation known as sympathectomy.

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

Taking other medicines

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

Some medicines and Candesartan/HCT Sandoz may interfere with each other. These include:

  • other blood pressure lowering medicines, particularly diuretics (fluid tablets) and ACE-inhibitors, especially if you have diabetes-related kidney problems
  • any medicine containing potassium, including salt substitutes
  • digoxin, a medicine used to treat heart failure
  • non-steroidal anti-inflammatory drugs (NSAIDs), medicines used to relieve pain, swelling and other symptoms of inflammation, including arthritis
  • colestipol and cholestyramine, medicines used to treat high blood cholesterol levels
  • lithium, a medicine used to treat mood swings and some types of depression
  • alcohol
  • strong pain killers such as codeine, morphine, dextropropoxyphene
  • barbiturates, used to treat epilepsy, such as phenobarbitone
  • medicines like insulin used to treat diabetes
  • calcium supplements, or medicines containing calcium
  • vitamin D supplements
  • medicines to treat irregular heart beats
  • corticosteroids such as prednisone, cortisone, dexamethasone.
  • laxatives
  • medicines used to treat cancer such as cyclophosphamide
  • methotrexate a medicine used to treat arthritis and some cancers
  • amantadine, a medicine used to treat Parkinson's Disease.
  • Ciclosporin

These medicines may be affected by Candesartan/HCT Sandoz or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

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

HOW TO TAKE CANDESARTAN/HCT SANDOZ

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

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

How much to take

The standard dose for this medicine is one tablet once daily.

Your doctor may have prescribed a different dose.

Ask your doctor or pharmacist if you are unsure of the correct dose for you. They will tell you exactly how much to take.

Follow the instructions they give you. If you take the wrong dose, Candesartan/HCT Sandoz may not work as well and your problem may not improve.

How to take it

Swallow the tablet whole with a full glass of water.

When to take Candesartan/HCT Sandoz

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

It does not matter whether you take Candesartan/HCT Sandoz with food or on an empty stomach.

How long to take Candesartan/HCT Sandoz

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

If you forget to take it

If 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 it as you would normally.

If it is less than 12 hours to 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 that 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 take too much (overdose)

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

If you take too many Candesartan/HCT Sandoz tablets you will probably get a headache, feel sick (nausea), dizzy, thirsty and very tired.

WHILE YOU ARE USING CANDESARTAN/HCT SANDOZ

Things you must do

Take Candesartan/HCT Sandoz 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 and pharmacist that you are taking Candesartan/HCT Sandoz.

Tell your doctor if you have excessive vomiting or diarrhoea while taking Candesartan/HCT Sandoz. You may lose too much water and your blood pressure may become too low.

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

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you become pregnant while taking this medicine or plan to become pregnant, tell your doctor immediately. You should not use Candesartan/HCT Sandoz if you are pregnant or thinking about becoming pregnant. Your doctor can discuss different treatment options with you.

If you plan to have a surgery (even at the dentist) that needs a general anaesthetic, tell your doctor or dentist that you are taking Candesartan/HCT Sandoz.

Tell your doctor if you plan to have an examination such as an x-ray or a scan requiring injection of iodinated contract (dye) that you are taking Candesartan/HCT Sandoz.

If you have had skin cancer or if you develop a suspicious skin lesion during treatment with Candesartan/HCT Sandoz, tell your doctor or pharmacist. Treatment with hydrochlorothiazide, particularly long-term use with high doses, may increase the risk of some types of skin and lip cancer (non-melanoma skin cancer). Limit exposure to sunlight and protect your skin when exposed to sun while taking Candesartan/HCT Sandoz.

Be sure to keep all your doctor's appointment so that your progress can be checked. Your doctor will check your progress and may want to take 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 Candesartan/HCT Sandoz 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 Candesartan/HCT Sandoz 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. Standing up slowly, especially when you get up from bed or chairs, will help your body get used to the change in position and blood pressure. If this problem continues or gets worse, talk to your doctor

Be careful driving or operating machinery until you know how Candesartan/HCT Sandoz affects you. This medicine may cause dizziness when you start taking it and this is due to the drop in your blood pressure.

Drink plenty of water while you are using Candesartan/HCT Sandoz, especially if you sweat a lot.

Please talk to your doctor or pharmacist about these possibilities if you think they may bother you.

SIDE EFFECTS

Tell your doctor or pharmacist as soon as possible if you do not feel well while taking Candesartan/HCT Sandoz.

Candesartan/HCT Sandoz helps most people with high blood pressure, but it may have unwanted side effects in a few people.

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

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

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

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

  • headache or dizziness
  • flu-like symptoms or infections
  • chest, throat or sinus infections
  • feeling sick (nausea) or vomiting
  • back pain
  • urinary tract infection
  • rapid heartbeats
  • feeling tired
  • stomach ache
  • symptoms of sunburn which happens more quickly than normal

These are all mild side effects of Candesartan/HCT Sandoz.

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

  • rapid heartbeats
  • aching muscles, tenderness or weakness in the muscle
  • suspicious skin lesions

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, itching or hives
  • easy bruising or bleeding more easily than normal
  • feel extremely tired
  • yellowing of the skin and eyes
  • 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. If you have them, you may have had a serious reaction to Candesartan/HCT Sandoz. You may need urgent medical attention or hospitalisation. These side effects are very rare.

Tell your doctor or pharmacist 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 CANDESARTAN/HCT SANDOZ

Storage

Keep your medicine in the original container.

If you take it out of its original container it may not keep well.

Keep your medicine in a cool dry place where the temperature stays below 25°C.

Do not store Candesartan/HCT Sandoz 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

Candesartan/HCT Sandoz comes in three types of tablets:

Candesartan/HCT Sandoz 16mg/12.5 mg - apricot, mottled, oval biconvex scored on both sides.

Candesartan/HCT Sandoz 32mg/12.5mg - light brown, mottled, oblong, biconvex tablet, debossed with 32 on one side and with score line on both sides

Candesartan/HCT Sandoz 32mg/25mg - reddish brown, mottled, oblong, biconvex tablet, debossed with H 32 on one side and with score line on both sides.

Available in blister packs of 30 tablets.

Ingredients

Active ingredients:

  • Candesartan cilexetil
  • hydrochlorothiazide

Inactive ingredients:

  • lactose monohydrate
  • iron oxide red
  • iron oxide yellow
  • maize starch
  • povidone
  • carrageenan
  • croscarmellose sodium
  • magnesium stearate.

Additionally, Candesartan/HCT Sandoz 32mg/12.5mg and 32mg/25mg also contains iron oxide black.

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

Supplier/Distributor

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

This leaflet was prepared in August 2019.

Australian Register Numbers:

16mg/12.5mg tablet: AUST R 157942 (blisters)

32mg/12.5mg tablet: AUST R 195279 (blisters)

32mg/25mg tablet: AUST R 195278 (blisters)

Published by MIMS October 2019

BRAND INFORMATION

Brand name

Candesartan/HCT Sandoz

Active ingredient

Candesartan cilexetil; Hydrochlorothiazide

Schedule

S4

 

1 Name of Medicine

Candesartan cilexetil/hydrochlorothiazide.

6.7 Physicochemical Properties

Candesartan cilexetil.

The chemical name of candesartan cilexetil is (+/-)-1-(cyclohexyloxycarbonyl-oxy) ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl]-1H-benzimidazole-7-carboxylate. Its empirical formula is C33H34N6O6 (MW: 610.7).

Hydrochlorothiazide.

The chemical name of hydrochlorothiazide is 6-chloro- 3,4-dihydro- 2H-1,2,4-benzo-thiadiazine -7-sulfonamide 1,1-dioxide. Its empirical formula is C7H8ClN3O4S2 (MW: 297.7).

Chemical structure.


CAS number.

Candesartan cilexetil.

58-93-5.

Hydrochlorothiazide.

1450-40-37-5.

2 Qualitative and Quantitative Composition

Candesartan/HCT Sandoz 16 mg/12.5 mg contains candesartan cilexetil 16 mg and hydrochlorothiazide 12.5 mg.
Candesartan/HCT Sandoz 32 mg/12.5 mg contains candesartan cilexetil 32 mg and hydrochlorothiazide 12.5 mg.
Candesartan/HCT Sandoz 32 mg/25 mg contains candesartan cilexetil 32 mg and hydrochlorothiazide 25 mg.
Candesartan cilexetil is a white to off white powder and is practically insoluble in water.
Hydrochlorothiazide (HCT) is a sulfonamide derived medicine. It is a white or almost white crystalline powder and is very slightly soluble in water.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Candesartan/HCT Sandoz 16 mg/12.5 mg tablets are apricot, mottled, oval biconvex tablets, scored on both sides.
Candesartan/HCT Sandoz 32 mg/12.5 mg tablets are light brown, mottled, oblong, biconvex tablets, debossed with 32 on one side and with score line on both sides.
Candesartan/HCT Sandoz 32 mg/25 mg tablets are reddish brown, mottled, oblong, biconvex tablets, debossed with H 32 on one side and with score line on both sides.

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 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 medicine, 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 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.
Hydrochlorothiazide inhibits the active reabsorption of sodium, mainly in the distal kidney tubules, and promotes the excretion of sodium, chloride and water. The renal excretion of potassium and magnesium increases dose dependently, while calcium is reabsorbed to a greater extent. Hydrochlorothiazide decreases plasma volume and extracellular fluid and reduces cardiac output and blood pressure. During long-term therapy, reduced peripheral resistance contributes to the blood pressure reduction.
Candesartan and hydrochlorothiazide have additive antihypertensive effects. In hypertensive patients, candesartan/HCT causes an effective and long lasting reduction in arterial blood pressure without reflex increase in heart rate. There is no indication of serious or exaggerated first dose hypotension or rebound effect after cessation of treatment.
After administration of a single dose of candesartan/HCT, onset of the antihypertensive effect generally occurs within two hours. With continuous treatment, most of the reduction in blood pressure is attained within four weeks and is sustained during long-term treatment.
Candesartan/HCT once daily provides effective and smooth blood pressure reduction over 24 hours, with little difference between maximum and trough effects during the dosing interval. In double blind, randomised studies, the incidence of cough was lower during treatment with candesartan cilexetil/ hydrochlorothiazide than during treatment with combinations of ACE inhibitors and hydrochlorothiazide.
Age and gender have no influence on the efficacy of candesartan/HCT.
Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the risk for cardiovascular morbidity and mortality. There are no data regarding the effects of candesartan cilexetil and candesartan cilexetil/ hydrochlorothiazide on morbidity and mortality in hypertensive patients.
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. Addition of hydrochlorothiazide caused a potentiation of the nephrotoxicity seen with candesartan alone, however, without any qualitatively new findings.

Clinical trials.

In a randomised, double blind, parallel group, 8 week clinical study, including 1975 randomised patients not adequately controlled on 32 mg candesartan cilexetil once daily, the addition of 12.5 mg or 25 mg hydrochlorothiazide resulted in additional blood pressure reductions of 7/3 mmHg and 9/4 mmHg respectively over 32 mg monotherapy. The candesartan cilexetil/ hydrochlorothiazide 32/12.5 mg and 32/25 mg combinations produced overall mean blood pressure reductions of 13/9 mmHg and 16/10 mmHg, respectively. This study also demonstrated that the 32/25 mg combination was significantly more effective than the 32/12.5 mg combination.
In two 8 week clinical studies (randomised, double blind, placebo controlled, parallel group) including 275 and 1524 randomised patients respectively, the candesartan cilexetil/ hydrochlorothiazide combinations 32/12.5 mg and 32/25 mg resulted in blood pressure reductions of 21/14 mmHg for the highest dose, and were significantly more effective than the respective monotherapy components.
Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the risk for cardiovascular morbidity and mortality. There are no data regarding the effects of candesartan cilexetil and candesartan cilexetil/ hydrochlorothiazide on morbidity and mortality in hypertensive patients.

Non-melanoma skin cancer (NMSC).

Based on available data from epidemiological studies, cumulative dose-dependent association between hydrochlorothiazide and NMSC has been observed. One study included a population comprised of 71,553 cases of BCC and of 8,629 cases of SCC matched to 1,430,883 and 172,462 population controls, respectively. High hydrochlorothiazide use (≥ 50,000 mg cumulative) was associated with an adjusted OR of 1.29 (95% CL: 1.23-1.35) for BCC and 3.98 (95% CL: 3.68-4.31) for SCC. A clear cumulative dose response relationship was observed for both BCC and SCC. Another study showed a possible association between lip cancer (SCC) and exposure to hydrochlorothiazide: 633 cases of lip-cancer were matched with 63,067 population controls, using a risk-set sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR 2.1 (95% CL: 1.7-2.6) increasing to OR 3.9 (3.0-4.9) for high use (~25,000 mg) and OR 7.7 (5.7-10.5) for the highest cumulative dose (~100,000 mg). (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

5.2 Pharmacokinetic Properties

The individual pharmacokinetic profiles of candesartan and hydrochlorothiazide were not clinically significantly affected when given in combination.

Absorption.

Candesartan cilexetil.

Following oral administration, candesartan cilexetil is converted to the active medicine 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 three to four 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.

Hydrochlorothiazide.

Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract with an absolute bioavailability of approximately 70%. Concomitant intake of food increases the absorption by approximately 15%. The bioavailability may decrease in patients with cardiac failure and pronounced oedema.

Distribution.

Candesartan cilexetil.

Candesartan is highly bound to plasma protein (more than 99%). The apparent volume of distribution (Vss) of candesartan is 0.1 L/kg.
Following oral administration of a single dose of Candesartan/HCT Sandoz 16 mg/12.5 mg to healthy male subjects under fasting conditions, a mean peak plasma concentration (Cmax) of candesartan cilexetil compared to the reference product was 119.93% (confidence interval 111.67%-128.79%) which was achieved within approximately 3.94 hours (Tmax). The ratios of the areas under the plasma concentration versus time curve (AUC) of candesartan cilexetil compared to the reference product was 103.96% (confidence interval 99.53%-108.59%).

Hydrochlorothiazide.

The plasma protein binding of hydrochlorothiazide is approximately 60%. The apparent volume of distribution is approximately 0.81 L/kg.
Following oral administration of a single dose of Candesartan/HCT Sandoz 16 mg/12.5 mg to healthy male subjects under fasting conditions, a mean peak plasma concentration (Cmax) of hydrochlorothiazide compared to the reference product was 99.23% (confidence interval 96.61%-102.11%) which was achieved within approximately 1.90 hours (Tmax). The ratios of the areas under the plasma concentration versus time curve (AUC) for hydrochlorothiazide compared to the reference product was 99.32% (confidence interval 94.05%-104.71%).

Metabolism.

Candesartan cilexetil.

The half-life of candesartan remains unchanged (approximately nine hours) after administration of candesartan cilexetil in combination with hydrochlorothiazide. There is a clinically nonsignificant increase in AUC (15 to 18%) and Cmax (23 to 24%) of candesartan when given together with hydrochlorothiazide. No accumulation of candesartan occurs after repeated doses of the combination compared to monotherapy.

Excretion.

Candesartan cilexetil.

Candesartan cilexetil 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 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.

Hydrochlorothiazide.

Hydrochlorothiazide is not metabolised and is excreted almost entirely as unchanged drug by glomerular filtration and active tubular secretion. The terminal t1/2 of hydrochlorothiazide is approximately eight hours. Approximately 70% of an oral dose is eliminated in the urine within 48 hours. The half-life of hydrochlorothiazide remains unchanged (approximately eight hours) after administration of hydrochlorothiazide in combination with candesartan cilexetil. No accumulation of hydrochlorothiazide occurs after repeated doses of the combination compared to monotherapy.

Pharmacokinetics in special populations.

Candesartan cilexetil.

Elderly.

In the elderly (over 65 years) both Cmax and AUC of candesartan are increased by approximately 50 and 80%, respectively, in comparison to young subjects. However, the blood pressure response and the incidence of adverse events are similar after a given dose of candesartan/HCT 16 mg/12.5 mg in young and elderly patients.

Renal impairment.

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. The pharmacokinetics in patients undergoing haemodialysis were similar to those in patients with severe renal impairment.

Hydrochlorothiazide.

The terminal t1/2 of hydrochlorothiazide is prolonged in patients with renal impairment.

Hepatic impairment.

In patients with mild to moderate hepatic impairment, there was a 23% increase in the AUC of candesartan. No initial dosage adjustment is necessary in these patients.

5.3 Preclinical Safety Data

Genotoxicity.

Candesartan cilexetil alone or in combination with hydrochlorothiazide showed no evidence of genotoxic potential in a series of assays for gene mutations (Salmonella typhimurium and Escherichia coli), chromosomal aberrations (mouse micronucleus assay) and DNA damage (unscheduled DNA synthesis in rat liver). In addition, candesartan cilexetil alone showed no evidence of genotoxic potential in further assays for gene mutations (mouse L5178Y cells and Chinese hamster ovary cells). The active metabolite, candesartan, caused an increase in chromosomal aberrations in vitro (Chinese hamster lung cells) but not in vivo (mouse micronucleus test and chromosomal aberrations in rat bone marrow). However, hydrochlorothiazide had mutagenic activity in a mammalian cell assay (mouse L5178Y cells) and caused an increase in chromosomal aberrations in vitro (Chinese hamster lung cells). Candesartan at subclastogenic concentration did not modify these effects of hydrochlorothiazide. Hydrochlorothiazide also had a genotoxic activity in the sister chromatid exchange assay in Chinese hamster ovary cells and a nondisjunction assay in Aspergillus nidulans.

Carcinogenicity.

The carcinogenic potential of candesartan cilexetil in combination with hydrochlorothiazide has not been evaluated in animal studies. Candesartan cilexetil alone was not carcinogenic when administered orally to rats and mice for 2 years at doses up to 100 and 1000 mg/kg/day corresponding to ca. 7 times and 260 times the clinical exposure at the maximum recommended daily dose of 32 mg (based on AUC, respectively).
Hydrochlorothiazide alone was not carcinogenic in female mice in doses ca. 600 mg/kg/day, or in male and female rats at doses up to ca. 100 mg/kg/day in two year feeding studies. These doses correspond to ca. 110 times (female mice) or 40 times (male and female rats) the clinical exposure at the maximum recommended daily human dose of 25 mg (based on BSA). However, there was equivocal evidence for hepatocarcinogenicity in male mice that received ca. 600 mg/kg/day.

4 Clinical Particulars

4.1 Therapeutic Indications

The treatment of hypertension. Treatment should not be initiated with this fixed dose combination.

4.3 Contraindications

Hypersensitivity to any component of Candesartan/HCT Sandoz or to sulfonamide derived medicines.
Pregnancy and lactation.
Severe renal impairment (creatinine clearance < 30 mL/minute/1.73 m2 body surface area).
Severe hepatic impairment and/or cholestasis.
Gout.
The use of candesartan/HCT 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 (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.

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

There is evidence that the concomitant use of angiotensin converting enzyme (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 RAAS through the combined use of candesartan/HCT with ACE inhibitors, angiotensin II receptor blockers 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/HCT 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).

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.

Aortic and mitral valve stenosis (obstructive hypertrophic cardiomyopathy).

As with other vasodilators, special caution is indicated in patients suffering from haemodynamically relevant aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy.

Primary hyperaldosteronism.

Patients with primary hyperaldosteronism will not generally respond to antihypertensive medicines acting through inhibition of the renin angiotensin aldosterone system. Therefore, the use of candesartan/HCT in these patients is not recommended.

Fluid and electrolyte imbalance.

As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.
Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypercalcaemia, hypokalaemia, hyponatraemia, hypomagnesaemia and hypochloraemic alkalosis).
Hydrochlorothiazide dose dependently increases urinary potassium excretion which may result in hypokalaemia. This effect of hydrochlorothiazide seems to be less evident when combined with candesartan cilexetil. The risk of hypokalaemia may be increased in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients with an inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or adrenocorticotropic hormone (ACTH).
Based on experience with the use of other medicines that affect the RAAS, concomitant use of Candesartan/HCT Sandoz and ACE inhibitors, aliskiren, potassium sparing diuretics, potassium supplements or salt substitutes or other medicines that may increase serum potassium levels may lead to increases in serum potassium.

Non-melanoma skin cancer.

An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide exposure has been observed in two epidemiological studies based on Danish National Cancer Registry (see Clinical trials). Photosensitizing actions of hydrochlorothiazide could act as a possible mechanism for NMSC.
Patients taking hydrochlorothiazide should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. The use of hydrochlorothiazide may also need to be reconsidered in patients who have experienced previous NMSC (see Section 4.8 Adverse Effects (Undesirable Effects).

Metabolic and endocrine effects.

Treatment with a thiazide diuretic may impair glucose tolerance. Dosage adjustment of antidiabetic medicines, including insulin, may be required. Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure linked to hydrochlorothiazide.
Latent diabetes mellitus may become manifest during thiazide therapy. Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy. However, at the doses contained in Candesartan/HCT Sandoz, only minimal effects were observed. Thiazide diuretics increase serum uric acid concentration and may precipitate gout in susceptible patients.

Hypotension, volume depleted patients.

Candesartan/HCT like all antihypertensive agents may cause symptomatic hypotension in some patients. Symptomatic hypotension may be expected to occur more frequently in patients who have been sodium and/or volume depleted by vigorous diuretic therapy and/or dietary salt restrictions, or vomiting and/or diarrhoea or haemodialysis. Sodium and/or volume depletion should be corrected prior to administration of Candesartan/HCT Sandoz.

Postsympathectomy.

The antihypertensive effects of thiazide diuretics may be increased in the postsympathectomy patient.

Systemic lupus erythematosus.

Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics.

Anaesthesia and surgery.

Hypotension may occur during anaesthesia and surgery in patients treated with angiotensin II antagonists due to blockade of the RAAS. 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 medicines and thiazide diuretics.

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

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. There is no clinical experience with Candesartan/HCT Sandoz in patients with hepatic impairment. Use in patients with severe hepatic impairment is contraindicated. Caution is advised in patients with mild to moderate hepatic impairment.

Use in renal impairment.

When Candesartan/HCT Sandoz is used in patients with renal impairment, periodic monitoring of serum potassium, creatinine and uric acid levels is recommended. Loop diuretics are preferred to thiazides in this population.
As with other agents inhibiting the RAAS, changes in renal function may be anticipated in susceptible patients treated with candesartan/HCT (see Section 4.3 Contraindications).

Kidney transplantation.

There is limited clinical experience regarding the administration of Candesartan/HCT Sandoz in patients who have undergone kidney transplantation.

Use in the elderly.

For dosage recommendations for use of Candesartan/HCT Sandoz in elderly patients please see Section 4.2 Dose and Method of Administration.

Paediatric use.

Safety and efficacy have not been established in children.

Effects on laboratory tests.

In general, there were no clinically important influences of candesartan cilexetil/ hydrochlorothiazide on routine laboratory variables. Increases in creatinine, urea, potassium, uric acid, glucose and ALAT (SGPT) and decreases in sodium have been observed. Minor decreases in haemoglobin and increases in ASAT (SGOT) have been observed in single patients.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The antihypertensive effect of Candesartan/HCT Sandoz may be enhanced by other antihypertensives.

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

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).

Candesartan cilexetil.

No medicine interactions of clinical significance have been identified with candesartan cilexetil. Compounds which have been investigated include hydrochlorothiazide, warfarin, digoxin (see Hydrochlorothiazide below), oral contraceptives (i.e. ethinyloestradiol/ levonorgestrel), glibenclamide and nifedipine.
Attenuation of the antihypertensive effect of angiotensin II receptor antagonists, including candesartan may occur when simultaneously administering AIIRAs and nonsteroidal anti-inflammatory medicines (NSAIDs, i.e. selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) and nonselective NSAIDs).
As with ACE inhibitors, concomitant use of AIIRAs and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in older patients and in volume depleted patients. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy and periodically thereafter.
Candesartan is eliminated only to a minor extent by hepatic metabolism (CYP2C9).
Interaction studies performed to date show no effect of candesartan on the metabolising capacity of CYP2C9 and CYP3A4. Based on in vitro data, no interaction would be expected to occur in vivo with medicines whose metabolism is dependent upon cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4.

Hydrochlorothiazide.

Alcohol, barbiturates, opioids and anaesthetics.

Potentiation of thiazide diuretic induced orthostatic hypotension may occur.

Antidiabetic agents (oral and insulin).

Thiazides may increase blood glucose concentration and adjustment of antidiabetic medication may be required.

Cardiac glycosides and other antiarrhythmics.

Thiazide induced hypokalaemia and hypomagnesaemia predisposes to the potential cardiotoxic effects of digitalis glycosides and antiarrhythmics.
Periodic monitoring of serum potassium is recommended when Candesartan/HCT Sandoz is administered with such active substances, and with the following active substances that could induce torsades de pointes:
Class Ia antiarrhythmics (e.g. quinidine, hydroquinidine, disopyramide);
Class III antiarrhythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide);
Some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamenmazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
Others (e.g. bepridil, cisapride, diphemanil, erythromycin iv, halofantrin, ketanserin, mizolastin, pentamidine, sparfloxacin, terfenadine, vincamine iv).

Calcium salts and vitamin D.

Thiazide diuretics may increase the serum calcium concentration due to decreased excretion. If calcium or vitamin D is prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly.

Cholestyramine resin and colestipol hydrochloride.

The absorption of thiazide may be delayed or decreased in the presence of bile acids sequestrants. Candesartan/HCT Sandoz should be taken at least one hour before or after such medicines.

Lithium.

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

Nonsteroidal anti-inflammatory medicines (NSAIDs).

The diuretic, natriuretic and antihypertensive effect of hydrochlorothiazide is blunted by NSAIDs.

Hypokalaemic agents.

The potassium depleting effect of hydrochlorothiazide could be expected to be potentiated by other medicines associated with potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, amphotericin, carbenoxolone, salicylic acid derivatives).

Potassium sparing agents.

Based on experience with the use of other medicines that affect the renin angiotensin aldosterone system, concomitant use of Candesartan/HCT Sandoz and potassium sparing diuretics, potassium supplements or salt substitutes or other medicines that may increase serum potassium levels (e.g. heparin sodium, trimethoprim/ sulfamethoxazole) may lead to increases in serum potassium.

Nondepolarising muscle relaxants (e.g. tubocurarine).

The effect of nondepolarising skeletal muscle relaxants (e.g. tubocurarine) may be potentiated by hydrochlorothiazide.

Pressor amines.

Hydrochlorothiazide may cause the arterial response to pressor amines to decrease but not enough to exclude a pressor effect.

Iodinated contrast media.

Hydrochlorothiazide may increase the risk of acute renal insufficiency especially with high doses of iodinated contrast media.

Corticosteroids, ACTH.

The risk for hypokalaemia may be increased during concomitant use of steroids or ACTH.

Amantadine.

Thiazides may increase the risk of adverse effects caused by amantadine.

Beta-blockers and diazoxide.

The hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides.

Anticholinergic agents (e.g. atropine).

Anticholinergic agents (e.g. atropine, biperiden) may increase the bioavailability of thiazide diuretics by decreasing gastrointestinal motility and stomach emptying rate.

Cytotoxic medicines (e.g. cyclophosphamide, methotrexate).

Thiazides may reduce the renal excretion of cytotoxic medicines (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.

Ciclosporin.

Concomitant treatment with ciclosporin may increase the risk of hyperuricaemia and gout type complications.

Baclofen, amifostin, tricyclic antidepressants or neuroleptics.

Concomitant treatment may lead to enhancement of the antihypertensive effect and may induce hypotension.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of hydrochlorothiazide alone or in combination with candesartan cilexetil on fertility have not been evaluated in animal studies. However, candesartan cilexetil alone had no adverse effects on the reproductive performance of male or female rats at oral doses up to 300 mg/kg/day.
(Category D)
Medicines 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 medicines may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.
The use of Candesartan/HCT Sandoz is contraindicated in pregnancy (see Section 4.3 Contraindications). Patients receiving Candesartan/HCT Sandoz 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/HCT Sandoz must be stopped immediately and if appropriate, alternative therapy should be started.
The use of medicines that act directly on the RAAS during the second and third trimesters of human pregnancy has been associated with fetal and neonatal injury, including hypotension, hyperkalaemia, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation and hypoplastic lung development. Prematurity, intrauterine growth retardation, skull ossification retardation and patent ductus arteriosus have also been reported. 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).
There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Hydrochlorothiazide can reduce the plasma volume as well as the uteroplacental blood flow. Based on the pharmacological mechanism of action of hydrochlorothiazide, its use during pregnancy may compromise foetoplacental perfusion and may cause fetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.
In retrospective data, first trimester use of ACE inhibitors has been associated with a potential risk of birth defects. There have been reports of spontaneous abortion, oligohydramnios and newborn renal dysfunction, when pregnant women have inadvertently taken the angiotensin II antagonist valsartan. As for any medicine that also acts directly on the RAAS, candesartan cilexetil should not be used during pregnancy (see Section 4.3 Contraindications) or in women planning to become pregnant.
Healthcare professionals prescribing any agents acting on the RAAS should counsel women of childbearing potential about the potential risk of these agents during pregnancy.
If pregnancy is detected during therapy, candesartan cilexetil should be discontinued as soon as possible, and if appropriate, alternative therapy should be started.
It is not known whether candesartan is excreted in human milk. However, candesartan is excreted in the milk of lactating rats. Hydrochlorothiazide passes into human milk. Because of the potential for adverse effects on the breastfed infant, breastfeeding should be discontinued if the use of Candesartan/HCT Sandoz is considered essential.

4.8 Adverse Effects (Undesirable Effects)

Adverse events were mild and transient and comparable to placebo in controlled clinical studies with various doses of candesartan cilexetil/ hydrochlorothiazide (candesartan cilexetil up to 32 mg and hydrochlorothiazide up to 25 mg). The overall incidence of adverse events showed no association with age or gender. Withdrawals from treatment due to adverse events were similar with candesartan cilexetil/ hydrochlorothiazide (2.3%-3.3%) and placebo (2.7%-4.3%).
Clinical adverse events, regardless of causal relationship, with a cumulative eight week incidence rate of greater than or equal to 1% during treatment with candesartan cilexetil/ hydrochlorothiazide up to 16 mg/12.5 mg in the double blind, placebo controlled trials are presented in Table 1.
The following clinical adverse events occurred with a frequency of 0.5% to < 1% with no occurrence in the placebo group: A-V block, vomiting.
Clinical adverse events, regardless of causal relationship, occurring in ≥ 1% of the patients during 8 week randomised treatment with candesartan cilexetil/ hydrochlorothiazide 32/12.5 mg and 32/25 mg in double blind clinical trials are presented in Table 2.

Adverse events on individual components.

Candesartan cilexetil.

The following clinical adverse events, regardless of whether attributed to therapy, have been reported to occur with a cumulative eight week incidence rate of ≥ 1% in placebo controlled clinical trials with candesartan cilexetil monotherapy: cough, diarrhoea, peripheral oedema and rhinitis. Angioedema, urticaria, pruritus and rash have been reported very rarely in patients treated with candesartan cilexetil. Very rare cases of increased liver enzymes, abnormal hepatic function or hepatitis have also been reported. Very rare adverse reactions include hyponatraemia, hyperkalaemia and renal impairment, including renal failure in susceptible patients (see Section 4.4 Special Warnings and Precautions for Use). Other adverse events reported for candesartan cilexetil where a causal relationship could not be established include very rare cases of leukopenia, neutropenia and agranulocytosis.

Hydrochlorothiazide.

The following clinical adverse events have been reported to occur with hydrochlorothiazide monotherapy: anorexia, loss of appetite, gastric irritation, diarrhoea, constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis, leucopenia, neutropenia/ agranulocytosis, thrombocytopenia, aplastic anaemia, haemolytic anaemia, bone marrow depression, photosensitivity reactions, fever, rash, cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus, urticaria, necrotising angiitis (vasculitis, cutaneous vasculitis), anaphylactic reactions, toxic epidermal necrolysis, respiratory distress (including pneumonitis and pulmonary oedema), hyperglycaemia, glycosuria, hyperuricaemia, electrolyte imbalance (including hyponatraemia and hypokalaemia), increases in cholesterol and triglycerides, increases in blood urea nitrogen (BUN) and serum creatinine, renal dysfunction, interstitial nephritis, muscle spasm, weakness, restlessness, transient blurred vision, lightheadedness, postural hypotension, vertigo, paraesthesia, cardiac arrhythmias, sleep disturbances, depression, acute myopia, acute angle closure glaucoma.

Laboratory findings.

In general, there were no clinically important influences of candesartan cilexetil/ hydrochlorothiazide on routine laboratory variables. Increases in creatinine, urea, potassium, uric acid, glucose and ALAT (SGPT) and decreases in sodium have been observed. Minor decreases in haemoglobin and increases in ASAT (SGOT) have been observed in single patients.

Postmarketing.

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

Musculoskeletal, connective tissue and bone disorders.

Myalgia.

Respiratory, thoracic and mediastinal disorders.

Cough.
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.
The following adverse reactions have been reported post-marketing with hydrochlorothiazide, regardless of causality:
Neoplasms benign, malignant and unspecified (including cysts and polyps).

Frequency “not known”.

Non-melanoma skin cancer (Basal cell carcinoma and squamous cell carcinoma) (see Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties, Clinical trials).
Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Dosage.

The dose of Candesartan/HCT Sandoz must be determined by careful titration of the dose of each of the individual components.

Method of administration.

The recommended dose of Candesartan/HCT Sandoz is one tablet once daily, taken with or without food. Candesartan/HCT Sandoz tablets should not be divided.
Candesartan/HCT Sandoz 16 mg/12.5 mg may be administered in patients whose blood pressure is not optimally controlled with hydrochlorothiazide alone or with candesartan 16 mg monotherapy.
Candesartan/HCT Sandoz 32 mg/12.5 mg or 32 mg/25 mg may be administered in patients whose blood pressure is not optimally controlled with hydrochlorothiazide alone or Candesartan Sandoz 32 mg monotherapy, or at a lower dose of Candesartan/HCT Sandoz. Dose titration of candesartan cilexetil is recommended when adding on to hydrochlorothiazide monotherapy.
Most of the antihypertensive effect is usually attained within four weeks of initiation of treatment.
Candesartan/HCT Sandoz should not be used to initiate treatment.

Dosage adjustment in:

Infants and children.

The safety and efficacy of Candesartan/HCT Sandoz have not been established in children.

Elderly.

Dose titration of candesartan cilexetil is recommended before treatment with Candesartan/HCT Sandoz.

Hepatic impairment.

Dose titration of candesartan cilexetil is recommended before treatment with Candesartan/HCT Sandoz in patients with mild to moderate hepatic impairment.
Candesartan/HCT Sandoz should not be used in patients with severe hepatic impairment and/or cholestasis (see Section 4.3 Contraindications).

Renal impairment.

Loop diuretics are preferred to thiazides in this population. Dose titration of candesartan cilexetil is recommended before treatment with Candesartan/HCT Sandoz in patients with renal impairment whose creatinine clearance is greater than or equal to 30 mL/minute/1.73 m2 body surface area (BSA). Candesartan/HCT Sandoz should not be used in patients with severe renal impairment (creatinine clearance < 30 mL/minute/1.73 m2 BSA).

Intravascular volume depletion.

Patients who are severely volume and/or sodium depleted should have this corrected before being treated with Candesartan/HCT Sandoz.

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 of hypertension.

4.9 Overdose

Symptoms.

Based on pharmacological considerations, the main manifestation of an overdose of candesartan cilexetil is likely to be symptomatic hypotension and dizziness. In two case reports of overdose (candesartan cilexetil 160 and 432 mg) patient recovery was uneventful.
The main manifestation of an overdose of hydrochlorothiazide is acute loss of fluid and electrolytes. Symptoms such as dizziness, hypotension, thirst, tachycardia, ventricular arrhythmias, sedation/ impairment of consciousness and muscle cramps can also be observed.

Treatment.

No specific information is available on the treatment of overdosage with Candesartan/HCT Sandoz. The following measures are however suggested in case of overdosage.
Administration of activated charcoal with or without gastric lavage. If symptomatic hypotension should occur, symptomatic treatment should be instituted and vital signs monitored. The patient should be placed supine with the legs elevated. If this is not sufficient, plasma volume should be increased by infusion of isotonic saline solution. Serum electrolyte and acid balance should be checked and corrected if needed. Sympathomimetic medicines may be administered if the abovementioned measures are not sufficient.
Activated charcoal may reduce absorption of the medicine if given within one or two hours after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected.
Candesartan cannot be removed by haemodialysis. It is not known to what extent hydrochlorothiazide is removed by haemodialysis.
For information on the management of overdose, contact the Poisons Information Centre on 131 126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Candesartan/HCT Sandoz 16 mg/12.5 mg tablets also contain the following excipients ingredients: lactose monohydrate, iron oxide red, iron oxide yellow, maize starch, povidone, carrageenan, croscarmellose sodium and magnesium stearate.
Candesartan/HCT Sandoz 32 mg/12.5 mg tablets also contain the following excipients ingredients: lactose monohydrate, iron oxide red, iron oxide yellow, iron oxide black, maize starch, povidone, carrageenan, croscarmellose sodium and magnesium stearate.
Candesartan/HCT Sandoz 32 mg/25 mg tablets also contain the following excipients ingredients: lactose monohydrate, iron oxide red, iron oxide black, titanium dioxide, maize starch, povidone, carrageenan, croscarmellose sodium and 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 25°C. Store in the original package.

6.5 Nature and Contents of Container

Candesartan/HCT Sandoz tablets (all strengths) are available in blister packs and bottles of 30 tablets.
Not all presentations may be marketed in Australia.

6.6 Special Precautions for Disposal

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

Summary Table of Changes