Consumer medicine information

APO-Olmesartan HCTZ

Olmesartan medoxomil; Hydrochlorothiazide

BRAND INFORMATION

Brand name

APO-Olmesartan/HCTZ

Active ingredient

Olmesartan medoxomil; Hydrochlorothiazide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Olmesartan HCTZ.

SUMMARY CMI

APO-OLMESARTAN HCTZ

Consumer Medicine Information (CMI) summary

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

1. Why am I taking APO-OLMESARTAN HCTZ?

APO-OLMESARTAN HCTZ contains the active ingredients olmesartan and hydrochlorothiazide (HCTZ). APO-OLMESARTAN HCTZ is used to treat high blood pressure (hypertension).

For more information, see Section 1. Why am I taking APO-OLMESARTAN HCTZ? in the full CMI.

2. What should I know before I take APO-OLMESARTAN HCTZ?

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

For more information, see Section 2. What should I know before I take APO-OLMESARTAN HCTZ? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with APO-OLMESARTAN HCTZ and affect how it works.

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

4. How do I take APO-OLMESARTAN HCTZ?

  • The usual dose is one tablet taken once a day. Your doctor will tell you how much medicine you will need to take each day, depending on your condition and if you are taking any other medicines.
  • Follow all directions given to you by your doctor or pharmacist carefully.
    More instructions can be found in Section 4. How do I take APO-OLMESARTAN HCTZ? in the full CMI.

5. What should I know while taking APO-OLMESARTAN HCTZ?

Things you should do
  • Remind any doctor, dentist, pharmacist or other health practitioner that you visit that you are using APO-OLMESARTAN HCTZ.
  • If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are taking APO-OLMESARTAN HCTZ.
  • If you need to have any blood tests, tell your doctor you are taking APO-OLMESARTAN HCTZ tablets may affect the results of some laboratory tests.
Things you should not do
  • Do not give this medicine to anyone else, even if they have the same condition as you.
  • Do not take this medicine to treat any other complaints unless your doctor or pharmacist tells you to.
  • Do not stop taking this medicine, or change the dosage, without checking with your doctor.
Driving or using machines
  • Be careful driving or operating machinery until you know how this medicine affects you. APO-OLMESARTAN HCTZ may cause dizziness, light-headedness or tiredness in some people. If this occurs do not drive. If you drink alcohol, dizziness or light-headedness may be worse.
Drinking alcohol
  • Tell your doctor if you drink alcohol while using this medicine.
Looking after your medicine
  • Store APO-OLMESARTAN HCTZ below 25°C in a cool dry place.
  • Do not store your medicine, or any other medicine, in a bathroom or near a sink. Do not leave it on a windowsill or in the car.

For more information, see Section 5. What should I know while taking APO-OLMESARTAN HCTZ? in the full CMI.

6. Are there any side effects?

There are a number of side effects associated with APO-OLMESARTAN HCTZ. It is important to be aware of them so that you can identify any symptoms if they occur.

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



FULL CMI

APO-OLMESARTAN HCTZ

Active ingredient(s): Olmesartan medoxomil and hydrochlorothiazide

Consumer Medicine Information (CMI)

This leaflet provides important information about taking APO-OLMESARTAN HCTZ. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using APO-OLMESARTAN HCTZ.

Where to find information in this leaflet:

1. Why am I taking APO-OLMESARTAN HCTZ?
2. What should I know before I take APO-OLMESARTAN HCTZ?
3. What if I am taking other medicines?
4. How do I take APO-OLMESARTAN HCTZ?
5. What should I know while taking APO-OLMESARTAN HCTZ?
6. Are there any side effects?
7. Product details

1. Why am I taking APO-OLMESARTAN HCTZ?

APO-OLMESARTAN HCTZ contains the active ingredient olmesartan and hydrochlorothiazide (HCTZ). OLMESARTAN belongs to a group of medicines known as angiotensin-II receptor antagonists. Angiotensin-II is a substance produced in the body which causes blood vessels to tighten. Olmesartan blocks the action of angiotensin-II and therefore relaxes your blood vessels. This helps lower your blood pressure. HCTZ is a diuretic which reduces the amount of fluid in the body. This also helps to lower blood pressure.

APO-OLMESARTAN HCTZ is used to treat high blood pressure (hypertension).

Everyone has blood pressure. This pressure helps push blood all around your body. Your blood pressure changes at different times of the day, depending on how busy or worried you are. You have high blood pressure when your blood pressure stays higher than is needed, even when you are calm and relaxed.

There are usually no symptoms of high blood pressure. The only way of knowing that you have high blood pressure is to have your blood pressure checked on a regular basis. Untreated high blood pressure can lead to serious health problems, including stroke, heart disease and kidney failure.

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

Your doctor may have prescribed this medicine for another reason.

This medicine is not addictive.

The safety and effectiveness of olmesartan/HCTZ in children has not been established.

2. What should I know before I take APO-OLMESARTAN HCTZ?

Warnings

Do not use APO-OLMESARTAN HCTZ if:

  • you are allergic to olmesartan, sulfonamide derived medicines (e.g. thiazide diuretic), or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.
  • Some of the symptoms of an allergic reaction may include skin rash, itchiness, shortness of breath swelling of the face, lips or tongue, muscle pain or tenderness, joint pain.

Check with your doctor if you:

  • have any other medical conditions:
    - kidney or liver problems,
    - low potassium or sodium levels in the blood,
    - high calcium or uric acid levels in the blood,
    - diabetes and are taking a medicine called aliskiren to reduce blood pressure.

Pregnancy and breastfeeding

Do not take this medicine if you are pregnant or breastfeeding. This medicine may enter your womb, or it may pass into the breast milk, and there is the possibility that your baby may be affected. If pregnancy is discovered, this medicine should be discontinued as soon as possible.

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:

  • to any other medicines,
  • or any other substances, such as foods, preservatives or dyes.

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

  • kidney, liver or heart problems
  • diabetes
  • recent excessive vomiting or diarrhoea
  • gout
  • systemic lupus erythematosus (SLE)
  • high levels of potassium in your blood
  • adrenal gland problems

You must also tell your doctor if you:

  • are following a very low salt diet
  • are or intend to become pregnant or plan to breastfeed
  • are taking potassium supplements, potassium-sparing agents, potassium-containing salt substitutes or other medicines that may increase serum potassium (e.g. trimethoprim-containing products)
  • have skin cancer or if you develop a new skin lesion during treatment. 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). Discuss with your doctor how to protect your skin from sun exposure, and avoid artificial tanning.

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

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

3. What if I am taking other medicines?

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

Some medicines may interfere with APO-OLMESARTAN HCTZ and affect how it works.

These include:

  • medicines used to treat high blood pressure
  • diuretics, also known as fluid or water tablets
  • non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors, used to relieve pain, swelling and other symptoms of inflammation, including arthritis
  • potassium supplements or potassium-containing salt substitutes
  • other medicines that may increase potassium levels in the blood (e.g. trimethoprim-containing products)
  • lithium or antidepressant medicines
  • insulin and tablets used to treat diabetes
  • antacids, used to treat heartburn and indigestion
  • medicines which lower your immune system (e.g., corticosteroids and cytotoxic medicines used to treat cancer, including radiation therapy)
  • alcohol
  • laxatives, used to treat constipation
  • medicines used to relieve pain
  • medicines used to treat epilepsy
  • antiarrhythmics which treat irregular heart beats
  • muscle relaxants
  • cholestyramine and colestipol, used to treat high cholesterol.
  • medicines that contain aliskiren
  • any medicines that contain colesevelam

These medicines may be affected by APO-OLMESARTAN HCTZ or may affect how well it works. You may need different amounts of your medicine, or you may need to take different medicines.

Other medicines not listed above may also interfere with APO-OLMESARTAN HCTZ.

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

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect APO-OLMESARTAN HCTZ.

Use in Children

The safety and effectiveness of APO-OLMESARTAN HCTZ in children has not been established.

4. How do I take APO-OLMESARTAN HCTZ?

How much to take

  • 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 on the box,ask your doctor or pharmacist for help.
  • Your doctor will tell you how much medicine you will need to take each day, depending on your condition and if you are taking any other medicines.
  • The usual dose is one tablet taken once a day.

How to take

  • Swallow the tablet whole with a full glass of water.
  • Do not chew the tablets.

When to take

  • Take this medicine at about the same time each day.
    Taking your tablets at the same time each day will have the best effect. It will also help you remember when to take the tablets.
  • It does not matter whether you take it with or without food.

How long to take

  • Continue taking your medicine for as long as your doctor tells you.
  • APO-OLMESARTAN HCTZ helps 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 APO-OLMESARTAN HCTZ

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

Otherwise, take it as soon as you remember and then go back to taking your medicine as you would normally.

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

This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist. If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you use too much APO-OLMESARTAN HCTZ

If you think that you have used too much APO-OLMESARTAN HCTZ, you may need urgent medical attention.

You should immediately:

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

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

If you take too much of APO-OLMESARTAN HCTZ, you may feel light-headed, have a fast heartbeat, feel dizzy or you may faint.

5. What should I know while taking APO-OLMESARTAN HCTZ?

Things you should do

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are taking this medicine.

Make sure you drink enough water during exercise and hot weather when you are taking this medicine, especially if you sweat a lot.

If you do not drink enough water while taking this medicine, you may feel faint, light-headed or sick. This is because your blood pressure is dropping suddenly. If you continue to feel unwell, tell your doctor.

Call your doctor straight away:

  • if you have excess vomiting and/or diarrhoea while taking this medicine. You may lose too much water and salt, and your blood pressure may drop too much.
  • if you feel light-headed or dizzy after taking your first dose of this medicine, or when your dose is increased.
  • if you become pregnant while taking this medicine.
  • that you are taking this medicine if you are about to have any blood tests. APO-OLMESARTAN HCTZ may interfere with the results of some tests.
  • if photosensitivity reactions occur during your treatment.
  • if you develop an unexpected skin lesion during the treatment. Treatment with hydrochlorothiazide, particularly long-term use with high doses, may increase the risk of some types of skin and lip cancer (nonmelanoma skin cancer). Protect your skin from sun exposure and UV rays while taking this medicine.
  • in case of acute onset of decreased visual acuity or ocular pain. These could be symptoms of fluid accumulation in the vascular layer of the eye (choroidal effusion) or an increase of pressure in your eye and can happen within hours to weeks of taking APO-OLMESARTAN HCTZ. This can lead to permanent vision loss, if not treated.
  • if you experience any fever, severe shortness of breath, breathing faster than normal, difficulty breathing, slightly blue fingertips and lips after taking this medicine. Stop the medication and seek medical attention immediately

Tell your doctor or dentist that you are taking this medicine if you plan to have surgery that needs a general anaesthetic, as your blood pressure may drop suddenly.

Keep all your doctor's appointments.

Your doctor may occasionally do blood tests to check your potassium levels and see how your kidneys are working, as well as to check your blood pressure.

Things you should not do

  • Do not give this medicine to anyone else, even if they have the same condition as you.
  • Do not take this medicine to treat any other complaints unless your doctor or pharmacist tells you to.
  • Do not stop taking this medicine, or change the dosage, without checking 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.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how APO-OLMESARTAN HCTZ affects you.

APO-OLMESARTAN HCTZ may cause dizziness, light-headedness or tiredness in some people. If this occurs do not drive. If you drink alcohol, dizziness or light-headedness may be worse

Drinking alcohol

Tell your doctor if you drink alcohol.

They may advise you to limit your alcohol intake.

Things that would be helpful for your blood pressure

Some self-help measures suggested below may help your condition. Talk to your doctor or pharmacist about these measures and for more information

  • Alcohol - your doctor may advise you to limit your alcohol intake.
  • Weight - your doctor may suggest losing some weight to help lower your blood pressure and help lessen the amount of work your heart must do. Some people may need a dietician's help to lose weight.
  • Diet - eat a healthy diet which includes plenty of fresh vegetables, fruit, bread (preferably wholegrain), cereals and fish. Also eat less sugar and fat (especially saturated fat) which includes sausages, fatty meats, full cream dairy product, biscuits, cakes, pastries, chocolates, chips and coconut.
  • Salt - your doctor may advise you to watch the amount of salt in your diet. To reduce your salt intake, you should avoid using salt in cooking or at the table and avoid cooked or processed foods containing high sodium (salt) levels.
  • Exercise – regular exercise helps to reduce blood pressure and helps get the heart fitter. Before starting any exercise, ask your doctor about the best kind of programme for you.
  • Smoking - your doctor may advise you to stop smoking or at least cut down. Ask your doctor or pharmacist for further information and advice.

Looking after your medicine

  • Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack, they will not keep well.
  • Keep your tablets in a cool dry place where the temperature stays below 25°C.

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

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

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

Heat and dampness can destroy some medicines.

Keep it where young children cannot reach it.

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

When to discard this medicine

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

Getting rid of any unwanted medicine

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

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

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

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

Hydrochlorothiazide, a component of this medicine, increases sensitivity of the skin to the sun and may increase the risk of sone types of skin and lip cancer (non-melanoma skin cancer).

Hydrochlorothiazide, a component of this medicine, may cause a decrease in vision or pain in your eyes due to high pressure (possible signs of fluid accumulation in the vascular layer of the eye (choroidal effusion) or acute angle-closure glaucoma).

Hydrochlorothiazide, a component of this medicine, may cause fever, severe shortness of breath, breathing faster than normal, difficulty breathing, slightly blue fingertips and lips.

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

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

Less serious side effects

Less serious side effectsWhat to do
  • feeling light-headed, dizzy, faint, or headache
  • stomach problems, including nausea, vomiting, pain, diarrhoea, constipation, or an uncomfortable feeling in the stomach
  • unusual tiredness or weakness, fatigue
  • 'flu-like' symptoms, runny or blocked nose, sneezing, cough or bronchitis
  • swelling of the hands, feet or ankles
  • back pain
  • urinary tract infection
  • blurred vision
  • skin rashes or eczema
  • sleep disturbance
  • depression
Speak to your doctor if you have any of these less serious side effects and they worry you.

The above list includes the more common side effects of your medicine. They are generally mild.

Serious side effects

Serious side effectsWhat to do
  • sore throat and discomfort when swallowing (pharyngitis)
  • jaundice
  • skin rash or itchiness
  • aching, tender or weak muscles not caused by exercise
  • painful joints
  • fast heartbeat
  • shortness of breath or tightness in the chest
  • swelling of the hands, feet or ankles
  • yellowing of the whites of the eyes, dark urine and itching of the skin
  • nausea, diarrhoea, muscle weakness, change in heart rhythm (symptoms that may indicate high potassium levels in the blood)
These may be serious side effects. You may need medical attention. Serious side effects are rare.		Tell your doctor as soon as possible if you notice any of the following
  • swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing (signs of an allergic reaction)
  • chest pain
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

These are very serious side effects. 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 may be making you feel unwell.

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

Reporting side effects

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

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

7. Product details

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

What APO-OLMESARTAN HCTZ contains

Active ingredient
(main ingredient)
  • APO-OLMESARTAN/HCTZ TABLETS 20/12.5 - 20mg olmesartan medoxomil and 12.5mg hydrochlorothiazide
  • APO-OLMESARTAN/HCTZ TABLETS 40/12.5 - 40mg olmesartan medoxomil and 12.5mg hydrochlorothiazide
  • APO-OLMESARTAN/HCTZ TABLETS 40/25 - 40mg olmesartan medoxomil and 25mg hydrochlorothiazide
Other ingredients
(inactive ingredients)
  • lactose monohydrate
  • microcrystalline cellulose
  • hyprolose
  • magnesium stearate
  • Opadry Yellow 03F82788
Potential allergensContains sugars as lactose.

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

What APO-OLMESARTAN HCTZ looks like

APO-OLMESARTAN HCTZ 20/12.5 is a yellow film coated, round, biconvex tablets debossed with ‘346’ on one side and ‘L’ on other side. (Aust R 221116).

APO-OLMESARTAN HCTZ 40/12.5 is a yellow film coated, oval shape, biconvex tablets debossed with ‘L347’ on one side and plain on other side. (Aust R 221118).

APO-OLMESARTAN HCTZ 40/25 is a yellow film coated, oval shape, biconvex tablets debossed with ‘L348’ on one side and plain on other side (Aust R 221121).

Blister pack of 30 film-coated tablets.

Who distributes APO-OLMESARTAN HCTZ

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel Street
Cremorne VIC 3121
Australia
www.arrotex.com.au

This leaflet was prepared in October 2024.

Published by MIMS February 2025

BRAND INFORMATION

Brand name

APO-Olmesartan/HCTZ

Active ingredient

Olmesartan medoxomil; Hydrochlorothiazide

Schedule

S4

 

1 Name of Medicine

Olmesartan medoxomil/hydrochlorothiazide.

2 Qualitative and Quantitative Composition

APO-Olmesartan HCTZ 20/12.5 film coated tablets contain 20 mg of olmesartan medoxomil and 12.5 mg of hydrochlorothiazide.
APO-Olmesartan HCTZ 40/12.5 film coated tablets contain 40 mg of olmesartan medoxomil and 12.5 mg of hydrochlorothiazide.
APO-Olmesartan HCTZ 40/25 film coated tablets contain 40 mg of olmesartan medoxomil and 25 mg of hydrochlorothiazide.

Excipients with known effect.

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

3 Pharmaceutical Form

APO-Olmesartan HCTZ 20/12.5.

Yellow film coated, round, biconvex tablets debossed with '346' on one side and 'L' on other side.

APO-Olmesartan HCTZ 40/12.5.

Yellow film coated, oval shape, biconvex tablets debossed with 'L347' on one side and plain on other side.

APO-Olmesartan HCTZ 40/25.

Yellow film coated, oval shape, biconvex tablets debossed with 'L348' on one side and plain on other side.

4 Clinical Particulars

4.1 Therapeutic Indications

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

4.2 Dose and Method of Administration

Dosage.

Adults. APO-Olmesartan HCTZ is administered once daily, with or without food, in patients whose blood pressure is not adequately controlled by olmesartan medoxomil or HCTZ alone.
APO-Olmesartan HCTZ is registered in the combination of 20/12.5 mg, 40/12.5 mg and 40/25 mg. Olmesartan HCTZ 20/25 mg is registered in alternative brands.
Dosing should be individualised and dependent on the patient's condition. Depending on the blood pressure response, the dose may be titrated after 4 weeks.
If blood pressure is not adequately controlled on olmesartan medoxomil alone, HCTZ may be added with a starting dose of 12.5 mg. Should blood pressure still remain inadequately controlled, either up-titration of HCTZ to 25 mg or olmesartan to 40 mg dose may be advisable.
If blood pressure is not adequately controlled on HCTZ alone, olmesartan medoxomil may be added with a starting dose of 20 mg with up-titration to 40 mg should blood pressure still remain inadequately controlled.
Doses of APO-Olmesartan HCTZ above 40/25 mg are not recommended.
Special populations.

Elderly.

No dosage adjustment is necessary.
If up-titration to the maximum dose of 40 mg daily is required, blood pressure should be closely monitored.

Renal impairment.

No adjustment of dosage is necessary for patients with mild (creatinine clearance of 50-80 mL/min) to moderate (creatinine clearance of 30 - < 50 mL/min) renal impairment. When APO-Olmesartan HCTZ is used in such patients, periodic monitoring of renal function is advised (see Section 4.4 Special Warnings and Precautions for Use). APO-Olmesartan HCTZ is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see Section 4.3 Contraindications).

Intravascular volume depletion.

For patients with possible depletion of intravascular volume, particularly those with impaired renal function, APO-Olmesartan HCTZ should be administered under close medical supervision.
If a patient becomes volume depleted whilst taking APO-Olmesartan HCTZ, blood pressure and renal function should be closely monitored until the situation resolves.

Hepatic impairment.

No adjustment of dosage is necessary for patients with mild (Child-Pugh score 5-6) to moderate (Child-Pugh score 7-9) hepatic impairment. Close monitoring of blood pressure and renal function is advised in hepatically-impaired patients who are already receiving diuretics and/or other antihypertensive agents. There is no experience of olmesartan medoxomil in patients with severe (Child-Pugh score 10-15) hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).
APO-Olmesartan HCTZ should not be used in patients with severe hepatic impairment, cholestasis and biliary obstruction (see Section 4.3 Contraindications).
If up-titration of the olmesartan medoxomil component to the maximum dose of 40 mg daily is required, blood pressure should be closely monitored.

Children and adolescents.

The safety and efficiency of APO-Olmesartan HCTZ in children have not been established.

4.3 Contraindications

APO-Olmesartan HCTZ is contraindicated in:
patients who are hypersensitive to olmesartan medoxomil, sulfonamide derived drugs (e.g. thiazides), or any other component of this medication;
pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy);
patients with anuria or severe renal impairment (creatinine clearance < 30 mL/min) (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment and kidney transplantation);
patients with severe hepatic impairment (Child-Pugh score 10-15), cholestasis or biliary obstruction (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment);
patients who are breastfeeding;
patients with refractory hypokalaemia, hypercalcaemia, hyponatraemia, and symptomatic hyperuricaemia (see Section 4.4 Special Warnings and Precautions for Use, Electrolyte imbalance);
patients with diabetes who are taking aliskiren (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Intravascular volume depletion.

Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of olmesartan medoxomil/HCTZ.

Other conditions with stimulation of the renin-angiotensin-aldosterone system.

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 ACE inhibitors and angiotensin receptor antagonists has been associated with acute hypotension, azotaemia, oliguria or, rarely with acute renal failure and/or death. The possibility of similar effects cannot be excluded with olmesartan medoxomil.

Renovascular hypertension.

There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system.

Hyperkalaemia.

As with other angiotensin receptor antagonists and ACE inhibitors, hyperkalaemia may occur during treatment with APO-Olmesartan HCTZ especially in the presence of renal impairment and/or heart failure. This is because APO-Olmesartan HCTZ contains olmesartan medoxomil, a drug which inhibits the renin-angiotensin system (RAS) and drugs that inhibit the RAS can cause hyperkalaemia. Concomitant use of APO-Olmesartan HCTZ with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products which may increase the potassium level (e.g. trimethoprim containing medicines) may lead to an increase in serum potassium. Close monitoring of serum potassium levels in at risk patients is recommended.

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 (HCTZ) exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. Photosensitizing actions of HCTZ could act as a possible mechanism for NMSC.
Patients taking HCTZ 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 HCTZ may also need to be reconsidered in patients who have experienced previous NMSC.

Use in renal impairment and kidney transplantation.

APO-Olmesartan HCTZ should not be used in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see Section 4.2 Dose and Method of Administration). No dosage adjustment is necessary in patients with mild (creatinine clearance 50-80 mL/min) to moderate (creatinine clearance 30 - < 50 mL/min) renal impairment. In such patients APO-Olmesartan HCTZ should be administered with caution and periodic monitoring of serum potassium, creatinine and uric acid levels is recommended. Thiazide diuretic-associated azotaemia may occur in patients with impaired renal function. There is no experience of the administration of olmesartan medoxomil/HCTZ in patients with recent kidney transplantation.
The pharmacokinetics of APO-Olmesartan HCTZ or coadministered olmesartan medoxomil and HCTZ have not been studied in patients with renal impairment.

Sprue-like enteropathy.

Severe, chronic diarrhoea with substantial weight loss has been reported in patients taking olmesartan medoxomil months to years after drug initiation. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan medoxomil, exclude other etiologies. Consider discontinuation of APO-Olmesartan HCTZ in cases where no other etiology is identified.

Use in hepatic impairment.

APO-Olmesartan HCTZ should be used with caution in patients with impaired hepatic function or progressive liver disease since minor alterations of fluid and electrolyte balance during thiazide therapy may precipitate hepatic coma. Use of olmesartan medoxomil in patients with severe hepatic impairment (Child-Pugh score 10-15), cholestasis and biliary obstruction is contraindicated (see Section 4.3 Contraindications).
The pharmacokinetics of APO-Olmesartan HCTZ or coadministered olmesartan medoxomil and HCTZ have not been studied in patients with hepatic impairment.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy.

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

Primary aldosteronism.

Patients with primary aldosteronism generally will not respond to anti-hypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of olmesartan medoxomil and HCTZ is not recommended in such patients.

Metabolic and endocrine effects.

Thiazide therapy may impair glucose tolerance. In diabetic patients, dosage adjustments of insulin or oral hypoglycaemic agents may be required (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Latent diabetes mellitus may become manifest during thiazide therapy.
Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy. Hyperuricaemia may occur or frank gout may be precipitated in some patients receiving thiazide therapy.

Electrolyte imbalance.

As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.
Thiazides, including HCTZ, can cause fluid or electrolyte imbalance (including hypokalaemia, hyponatraemia and hypochloraemic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, seizures, confusion, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting (see Section 4.8 Adverse Effects (Undesirable Effects)).
Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with olmesartan medoxomil may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or ACTH. Conversely, due to antagonism at the angiotensin-II receptors (AT1) through the olmesartan medoxomil component of APO-Olmesartan HCTZ hyperkalaemia may occur, especially in the presence of renal impairment and/or heart failure, and diabetes mellitus. This is because olmesartan medoxomil inhibits the renin-angiotensin system (RAS) and drugs that inhibit the RAS can cause hyperkalaemia. Adequate monitoring of serum potassium in patients at risk is recommended. Potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes should be co-administered cautiously with APO-Olmesartan HCTZ (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
There is no evidence that olmesartan medoxomil would reduce or prevent diuretic-induced hyponatraemia.
Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia.
Dilutional hyponatraemia may occur in oedematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt, except in rare instances when the hyponatraemia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.
Metabolic acidosis may occur. Although a chloride deficit in a particular patient is generally mild and usually does not require specific treatment, except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis.

Angioedema.

Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue has been reported in patients treated with olmesartan medoxomil; some of these patients previously experienced angioedema with other drugs including ACE inhibitors. APO-Olmesartan HCTZ should be immediately discontinued in patients who develop angioedema, and APO-Olmesartan HCTZ should not be re-administered.

Acute respiratory toxicity.

Very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS) have been reported after taking hydrochlorothiazide. Pulmonary oedema typically develops within minutes to hours after hydrochlorothiazide intake. At the onset, symptoms include dyspnoea, fever, pulmonary deterioration and hypotension. If diagnosis of ARDS is suspected, APO-Olmesartan HCTZ should be withdrawn and appropriate treatment given. Hydrochlorothiazide should not be administered to patients who previously experienced ARDS following hydrochlorothiazide intake.

Photosensitivity.

Cases of photosensitivity reactions have been reported with thiazide diuretics. If photosensitivity reaction occurs during treatment with APO-Olmesartan HCTZ, it is recommended to stop the treatment. If a re-administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.

Ethnic differences.

As with all other angiotensin receptor antagonists, the blood pressure lowering effect of olmesartan medoxomil can be somewhat less in black patients than in non-black patients, possibly because of a higher prevalence of low-renin status in the black hypertensive population.

Lithium.

The co-administration of APO-Olmesartan HCTZ and lithium is not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Choroidal effusion, acute myopia and secondary angle-closure glaucoma.

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in choroidal effusion with visual field defect, acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Concomitant use of ACE inhibitors or angiotensin receptor antagonists and anti-inflammatory drugs and thiazide diuretics.

The use of ACE-inhibitors or angiotensin receptor antagonists, and 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 with fixed-combination products containing more than one class of drug. Concomitant use of all three classes of these medications should be accompanied by increased monitoring of serum creatinine, particularly at the institution of the treatment. The concomitant use of drugs from these three classes should be used with caution particularly in elderly patients or those with pre-existing renal impairment.

Other.

As with any anti-hypertensive agent, excessive blood pressure decrease in patients with ischaemic heart disease or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke.
Caution should be exercised in patients who have shown prior hypersensitivity to other angiotensin II receptor antagonists. Hypersensitivity reactions to HCTZ may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics.

Paediatric use.

The safety and effectiveness of olmesartan medoxomil/HCTZ in children have not been established.

Use in the elderly.

Clinical Studies of olmesartan medoxomil/HCTZ of 415 subjects aged 65 and over determined that the elderly do not respond differently from younger subjects. In general dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant diseases or other drug therapy.

Effects on laboratory tests.

Olmesartan medoxomil.

In post-marketing experience, increased blood creatinine levels and hyperkalaemia have been reported.

HCTZ.

Laboratory adverse events reports with HCTZ include the following: Hyperglycaemia, glycosuria, hyperuricaemia, electrolyte imbalance (including hyponatraemia and hypokalaemia), increases in cholesterol and triglycerides.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effects of other medicinal products on olmesartan medoxomil/HCTZ.

Medicinal products affecting potassium levels.

The potassium-depleting effect of HCTZ may be potentiated by the co-administration of other medicinal products associated with potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, corticosteroids, ACTH, amphotericin, benzyl penicillin sodium or salicylic acid derivatives).
Conversely, based on experience with the use of other drugs that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other drugs that may increase serum potassium levels (e.g. heparin, trimethoprim containing medicines) may lead to increases in serum potassium (see Section 4.4 Special Warnings and Precautions for Use).
If drugs which affect potassium levels are to be prescribed in combination with olmesartan medoxomil/HCTZ, monitoring of potassium plasma levels is advised.

Other antihypertensive medications.

The blood pressure lowering effect of olmesartan medoxomil/HCTZ can be increased by concomitant use of other antihypertensive medications.

Non-steroidal anti-inflammatory drugs (NSAIDs).

NSAIDs (including acetylsalicylic acid at doses > 3 g/day and also COX-2 inhibitors) and angiotensin-II receptor antagonists may act synergistically by decreasing glomerular filtration. The risk of the concomitant use of NSAIDs and angiotensin II antagonists is the occurrence of acute renal failure. Monitoring of renal function at the beginning of treatment should be recommended as well as regular hydration of the patient. Additionally, concomitant treatment can reduce the antihypertensive effect of angiotensin II receptor antagonists, leading to their partial loss of efficacy.
In some patients the administration of NSAIDs reduces the diuretic, natriuretic and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when APO-Olmesartan HCTZ tablets and NSAIDs are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

Dual blockade of the renin-angiotensin system (RAS).

Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalaemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on olmesartan medoxomil/HCTZ and other agents that affect the RAS.
Do not co-administer aliskiren with olmesartan medoxomil/HCTZ in patients with diabetes (see Section 4.3 Contraindications). Avoid use of aliskiren with olmesartan medoxomil/HCTZ in patients with renal impairment (GFR < 60 mL/min).

Colesevelam hydrochloride.

Concomitant administration of 40 mg olmesartan medoxomil and 3750 mg colesevelam hydrochloride in healthy subjects resulted in 28% reduction in Cmax and 39% reduction in AUC of olmesartan. Lesser effects, 4% and 15% reduction in Cmax and AUC, respectively, were observed when olmesartan medoxomil was administered 4 hours prior to colesevelam hydrochloride. Consider administering olmesartan medoxomil 4 hours before the colesevelam hydrochloride dose.

Other drugs.

After treatment with antacid (aluminium magnesium hydroxide), a modest reduction in bioavailability of olmesartan was observed. Co-administration of warfarin and digoxin had no effect on the pharmacokinetics of olmesartan medoxomil.

Alcohol, barbiturates, narcotics or antidepressants.

Potentiation of orthostatic hypotension may occur.

Baclofen, amifostine.

Potentiation of antihypertensive effect may occur.

Cholestyramine and colestipol resins.

Absorption of HCTZ is impaired in the presence of anionic exchange resins.

Anticholinergic agents (e.g. atropine, biperiden).

Increase of the bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate.

Effects of olmesartan medoxomil/HCTZ on other medicinal products.

Lithium.

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors and angiotensin II antagonists. Therefore, use of olmesartan medoxomil and lithium in combination is not recommended (see Section 4.4 Special Warnings and Precautions for Use, Lithium). If use of the combination proves necessary, careful monitoring of serum lithium levels is recommended.

Medicinal products affected by serum potassium disturbances.

Periodic monitoring of serum potassium and ECG is recommended when olmesartan medoxomil/HCTZ is administered with drugs affected by serum potassium disturbances (e.g. digitalis glycosides and antiarrhythmics) and with the following torsades de pointes-inducing medicinal products (including some antiarrhythmics), hypokalaemia being a predisposing factor to 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, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
others (e.g. bepridil, cisapride, diphemanil, erythromycin IV, halofantrine, mizolastine, pentamidine, sparfloxacin, terfenadine, vincamine IV).

Digitalis glycosides.

Thiazide-induced hypokalaemia or hypomagnesaemia may favour the onset of digitalis-induced cardiac arrhythmias.

Antidiabetic drugs (oral agents and insulin).

The treatment with a thiazide may influence the glucose tolerance. Dosage adjustment of the antidiabetic drug may be required.

Metformin.

Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure linked to HCTZ.

Beta-blockers and diazoxide.

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

Pressor amines (e.g. noradrenaline).

The effect of pressor amines may be decreased.

Non-depolarizing skeletal muscle relaxants (e.g. tubocurarine).

The effect of non-depolarizing skeletal muscle relaxants may be potentiated by HCTZ.

Medicinal products used in the treatment of gout (probenecid, sulfinpyrazone and allopurinol).

Dosage adjustment of uricosuric medications may be necessary since HCTZ may raise the level of serum uric acid. Increase in dosage of probenecid or sulfinpyrazone may be necessary. Co-administration of a thiazide may increase the incidence of hypersensitivity reactions to allopurinol.

Calcium salts.

Thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium supplements must be prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly.

Amantadine.

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

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

Thiazides may reduce the renal excretion of cytotoxic drugs and potentiate their myelosuppressive effects.

Additional information.

Concomitant administration of olmesartan medoxomil and HCTZ had no clinically relevant effects on the pharmacokinetics of either component in healthy subjects.
Olmesartan medoxomil had no significant effect on the pharmacokinetics or pharmacodynamics of warfarin or the pharmacokinetics of digoxin.
Co-administration of olmesartan medoxomil with pravastatin had no clinically relevant effects on the pharmacokinetics of either component in healthy subjects.
Olmesartan had no clinically relevant inhibitory effects on human cytochrome P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1 and 3A4 in vitro, and had no or minimal inducing effects on rat cytochrome P450 activities. No clinically relevant interactions between olmesartan and drugs metabolised by the above cytochrome P450 enzymes are expected.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of olmesartan medoxomil and HCTZ in combination on fertility have not been investigated.
Fertility of rats was unaffected by administration of olmesartan medoxomil at dose levels as high as 1,000 mg/kg/day (relative plasma exposure of 7-8 times that anticipated at the MRHD based on AUC) in a study in which dosing was begun 2 (female) or 9 (male) weeks prior to mating.
No animal fertility studies are available for HCTZ.
(Category D)

Olmesartan medoxomil.

Drugs that act directly on the renin-angiotensin system can cause foetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature of patients who were taking ACE inhibitors. When pregnancy is detected, APO-Olmesartan HCTZ should be discontinued as soon as possible.
The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with foetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure and death. Oligohydramnios has also been reported, presumably resulting from decreased foetal function; oligohydramnios in this setting has been associated with foetal limb contractures, craniofacial deformation and hypoplastic lung development. Prematurity, intrauterine growth retardation and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.
These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and foetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. If pregnancy occurs during therapy, APO-Olmesartan HCTZ must be discontinued as soon as possible.
Rarely (probably less often than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin system will be found. In these rare cases, the mothers should be apprised of the potential hazards to their foetuses and serial ultrasound examinations should be performed to assess the intra-amniotic environment.
If oligohydramnios is observed, APO-Olmesartan HCTZ should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a nonstress test (NST) or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the foetus has sustained irreversible injury.
Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria and hyperkalaemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.
There is no clinical experience with the use of olmesartan medoxomil/HCTZ in pregnant women. No teratogenic effects were observed when olmesartan medoxomil was administered to pregnant rats at oral doses up to 1,000 mg/kg/day (7 times clinical exposure to olmesartan at MRHD based on AUC) or pregnant rabbits at oral doses up to 1 mg/kg/day (half the MRHD on a mg/m2 basis; higher doses could not be evaluated for effects on foetal development as they were lethal to the does). In rats, significant decreases in pup birth weight and weight gain were observed at doses ≥ 1.6 mg/kg/day, and delays in developmental milestones (delayed separation of ear auricula, eruption of lower incisors, appearance of abdominal hair, descent of testes, and separation of eyelids) and dose-dependent increases in the incidence of dilation of the renal pelvis were observed at doses ≥ 8 mg/kg/day. The no observed adverse effect dose for developmental toxicity in rats is 0.3 mg/kg/day, about one-tenth the MRHD of 40 mg/day.

Thiazide diuretics.

Thiazides cross the placental barrier and appear in cord blood. They may cause foetal electrolyte disturbances and possible other reactions that have occurred in adults. Cases of neonatal thrombocytopenia, or foetal or neonatal jaundice have been reported with maternal thiazide therapy.
 It is not known whether olmesartan is excreted in human milk, but olmesartan is secreted at low concentration in the milk of lactating rats. Thiazides appear in human milk.
Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug.

4.7 Effects on Ability to Drive and Use Machines

The effect of olmesartan medoxomil/HCTZ on the ability to drive and use machines has not been specifically studied. However, it should be borne in mind that dizziness or fatigue may occasionally occur in patients taking antihypertensive therapy.

4.8 Adverse Effects (Undesirable Effects)

Olmesartan medoxomil and HCTZ.

The safety profile of olmesartan medoxomil/HCTZ has been evaluated in 2,341 hypertensive patients. This experience included 941 patients treated for at least 6 months, and 642 patients treated for at least 1-year.
Treatment with olmesartan medoxomil/HCTZ was well tolerated, with an incidence of adverse events similar to placebo. Events generally were mild, transient and had no relationship to the dose of olmesartan medoxomil/HCTZ.
In the clinical trials, the overall frequency of adverse events was not dose-related. Analysis of gender, age and race groups demonstrated no differences between olmesartan medoxomil/HCTZ and placebo-treated patients. The rate of withdrawals due to adverse events in all trials of hypertensive patients was 2.0% of patients treated with olmesartan medoxomil/HCTZ and 2.0% of patients treated with placebo. The only adverse event which was statistically significantly more frequent on olmesartan medoxomil/HCTZ than on placebo was dizziness (2.9% versus 1.3%). The incidence of dizziness was not dose related.
Incidence of adverse events reported in all clinical trials with a greater than or equal to 1% incidence is shown in Table 1.
Adverse events reported across all clinical trials with olmesartan medoxomil/HCTZ (including trials with active as well as placebo control, irrespective of causality or incidence relative to placebo) include the events listed below. Frequencies are defined as: common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000).

Cardiac disorders.

Uncommon: palpitations.

Nervous system disorders.

Uncommon: syncope.

General disorders.

Uncommon: weakness.

Investigations.

Uncommon: blood potassium decreased, blood potassium increased, blood urea increased, increase SGOT, increase SGPT.

Metabolism and nutrition disorders.

Common: creatinine phosphokinase increased.
Uncommon: hyperuricaemia, hypertriglyceridaemia.

Musculoskeletal and connective tissue disorders.

Uncommon: Arthritis.

Skin and subcutaneous tissue disorders.

Uncommon: rash, eczema.

Renal and urinary disorders.

Uncommon: Haematuria.

Vascular disorders.

Uncommon: hypotension, orthostatic hypotension.
Laboratory parameters. In clinical trials, clinically important changes in standard laboratory parameters were rarely associated with olmesartan medoxomil/HCTZ.

Creatinine, blood urea nitrogen.

Increases in blood urea nitrogen (BUN) and serum creatinine of > 50% were observed in 1.3% of patients. No patients were discontinued from clinical trials of olmesartan medoxomil/HCTZ due to increased BUN or creatinine.

Haemoglobin and haematocrit.

A greater than 20% decrease in haemoglobin and haematocrit was observed in 0.0% and 0.4% (n = 1 patient), respectively, of olmesartan medoxomil/HCTZ patients, compared with 0.0% and 0.0%, respectively, in placebo-treated patients. No patients were discontinued due to anaemia.
Use in elderly. Olmesartan medoxomil/HCTZ has been evaluated for safety in 415 patients aged 65 years or older of whom, 105 were aged 75 years or older. Overall, the incidence of adverse events in the elderly is comparable to that of the adult population. The number of withdrawals due to olmesartan medoxomil/HCTZ-related adverse effects was low (8/415; 1.9%).
Adverse events reported with olmesartan medoxomil/HCTZ combination therapy in the elderly with a greater than 1% incidence are shown in Table 2.
The most common adverse events considered to be treatment related in elderly patients on 20 mg olmesartan medoxomil with HCTZ were headache (2.0%) and cough (1.0%). The most common adverse event considered to be treatment related in elderly patients on 40 mg olmesartan medoxomil with HCTZ was dizziness (1.3%).
Post-marketing experience. The following adverse reactions have been reported in post-marketing experience:

General disorders and administration site conditions.

Asthenic conditions, such as asthenia, fatigue, lethargy, malaise.

Gastrointestinal disorders.

Abdominal pain; nausea; vomiting.

Investigations.

Hepatic enzymes increased; blood calcium increased; blood lipids increased; increased blood creatinine levels.

Metabolism and nutrition disorders.

Hyperkalaemia; hypercholesterolaemia.

Musculoskeletal and connective tissue disorders.

Rhabdomyolysis; myalgia; muscle spasm.

Nervous system disorders.

Headache; disturbances in consciousness; postural dizziness; somnolence.

Reproductive system and breast disorders.

Erectile dysfunction.

Respiratory, thoracic and mediastinal disorders.

Cough.

Skin and subcutaneous tissue disorders.

Angioedema; alopecia; rash; pruritus; urticaria.

Renal and urinary disorders.

Acute renal failure.

Vascular disorders.

Flushing.

Additional information on individual components.

Undesirable effects previously reported with either of the individual components may be potential undesirable effects with olmesartan medoxomil/HCTZ, even if not observed in clinical trials with this product.

Olmesartan medoxomil.

In double-blind, placebo-controlled monotherapy studies, the overall incidence of treatment-emergent adverse events was similar on olmesartan medoxomil and on placebo. In long-term (2-year) treatment, the incidence of withdrawals due to adverse events on olmesartan medoxomil 20 mg once daily was 3%.
In placebo-controlled monotherapy studies, the only adverse drug reaction that was unequivocally related to treatment was dizziness (2.5% incidence on olmesartan medoxomil and 0.9% on placebo).
The following adverse events have been reported across all clinical trials with olmesartan medoxomil irrespective of causality or incidence relative to placebo. They are listed under body system and ranked under headings of frequency using the conventions described above:

Cardiovascular.

Uncommon: tachycardia.
Rare: hypotension.

Central nervous system.

Common: dizziness.
Uncommon: vertigo.

Gastrointestinal.

Common: abdominal pain, diarrhoea, dyspepsia, gastroenteritis, nausea.

General.

Common: chest pain, fatigue, headache, influenza-like symptoms, peripheral oedema, pain.

Musculoskeletal.

Common: arthritis, back pain, skeletal pain.
Uncommon: arthralgia, myalgia.

Myo/endo/pericardial and valve disorders.

Uncommon: angina pectoris.

Respiratory system.

Common: bronchitis, cough, pharyngitis, rhinitis, sinusitis.

Skin and appendages.

Uncommon: rash.

Urinary system.

Common: haematuria, urinary tract infection.
Laboratory parameters. In placebo-controlled monotherapy studies the incidence was somewhat higher on olmesartan medoxomil compared with placebo for hypertriglyceridaemia (2.0% versus 1.1%) and for raised creatine phosphokinase (1.3% versus 0.7%).
Laboratory adverse events reported across all clinical trials with olmesartan medoxomil (including trials without a placebo control), irrespective of causality or incidence relative to placebo, included.

Metabolic and nutritional.

Common: increased creatine phosphokinase, hyperglycaemia, hypertriglyceridaemia, hyperuricaemia, blood urea increased.
Uncommon: Hypercholesterolaemia, hyperlipidaemia.
Rare: hyperkalaemia.

Liver and biliary.

Common: liver enzyme elevations.

Investigations.

Decrease in haemoglobin and haematocrit.
Post-marketing experience. The following adverse reactions have been reported in post-marketing experience:

Blood and lymphatic system disorders.

Thrombocytopenia.

General disorders and administration site conditions.

Peripheral oedema; asthenic conditions, such as asthenia, fatigue, lethargy, malaise.

Gastrointestinal disorders.

Abdominal pain; nausea; vomiting; diarrhoea; sprue-like enteropathy.

Hepatobiliary disorders.

Autoimmune hepatitis.

Immune system disorders.

Anaphylactic reactions.

Investigations.

Hepatic enzymes increased; increased blood creatinine levels; blood urea increased.

Metabolic and nutritional disorders.

Hyperkalaemia.

Musculoskeletal and connective tissue disorders.

Rhabdomyolysis; myalgia; muscle spasm.

Nervous systems disorders.

Headache.

Respiratory, thoracic and mediastinal disorders.

Cough.

Skin and subcutaneous tissue disorders.

Angioedema; alopecia; rash; pruritus; urticaria; allergic dermatitis; exanthema.

Renal and urinary disorders.

Acute renal failure.

Vascular disorders.

Flushing.
ROADMAP/ORIENT. Two postmarketing studies were conducted to determine the effects of olmesartan on renal disease in diabetic patients. In both of these studies, cardiovascular events were exploratory secondary efficacy endpoints. Cardiovascular deaths occurred in higher proportions of patients treated with olmesartan than placebo, but the risk of non-fatal myocardial infarction was lower with olmesartan.
The Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study in 4447 patients with type 2 diabetes, normoalbuminuria and at least one additional cardiovascular risk factor, investigated whether treatment with olmesartan could prevent or delay the onset of microalbuminuria. This is not an approved indication in Australia. During the median follow-up duration of 3.2 years, patients received either olmesartan 40 mg or placebo once daily in addition to other antihypertensive agents, except ACE inhibitors or angiotensin receptor blockers (ARBs).
In this study, cardiovascular events were exploratory secondary efficacy endpoints. The endpoints were classed as cardiovascular (CV) morbidity endpoints and CV mortality endpoints. The CV morbidity endpoints included acute coronary syndrome (ACS), congestive heart failure (CHF), silent myocardial infarction (MI), coronary revascularisation (percutaneous transluminal coronary angioplasty [PTCA] or coronary artery bypass graft [CABG]), stroke, peripheral vascular disease (PVD), new-onset atrial fibrillation (AF), and transient ischaemic attack (TIA). The CV Mortality endpoints includes: sudden cardiac death, fatal MI, fatal stroke, CHF death, death post-PTCA or CABG, recent MI on autopsy. The study was not designed to formally compare the treatment groups in relation to these endpoints.
Cardiovascular events occurred in 96 patients (4.3%) with olmesartan and in 94 patients (4.2%) with placebo. There was a finding of increased cardiovascular mortality in the olmesartan group, compared with the placebo group (15 patients (0.7%) vs 3 patients (0.1%)) (HR 4.9, 95% CI (1.4, 17.1), exploratory p value = 0.0115). Conversely, a smaller proportion of patients had a non-fatal myocardial infarction in the olmesartan group compared with the placebo group (17 patients (0.8%) vs 26 patients (1.2%)), (HR 0.64, 95% CI (0.35, 1.18)) and the same proportions of patients in each treatment group were reported with non-cardiovascular mortality (11 patients (0.5%) vs 12 patients (0.5%)). Non-fatal stroke was reported in 14 patients (0.6%) in the olmesartan group and 8 patients (0.4%)) in the placebo group. Overall mortality with olmesartan was numerically increased compared with placebo (26 patients (1.2%) vs 15 patients (0.7%)), which was mainly driven by a higher number of fatal cardiovascular events (sudden cardiac death (7 (0.3%) vs 1 (0.0%)) and fatal myocardial infarction (5 (0.2%) vs 0 (0.0%)).
The Olmesartan Reducing Incidence of End-stage Renal Disease in Diabetic Nephropathy Trial (ORIENT) primarily investigated the suppressive effect of olmesartan on the progression of diabetic nephropathy in 577 randomized Japanese and Chinese type 2 diabetic patients with overt nephropathy. This is not an approved indication in Australia. During a median follow-up of 3.1 years, patients received either olmesartan or placebo in addition to other antihypertensive agents including ACE inhibitors. The once daily dose of olmesartan was up-titrated from 10 mg to 20 mg to 40 mg, subject to tolerability and safety. Not all patients received the 40 mg dose. The study (undertaken in Japan and in Hong Kong) was not designed to formally compare the treatment groups in relation to cardiovascular endpoints. The composite cerebro/ cardiovascular endpoint, an exploratory secondary efficacy endpoint, occurred in 40 olmesartan-treated patients (14.2%) and 53 placebo-treated patients (18.7%). This composite endpoint included cardiovascular death, non-fatal stroke, and non-fatal myocardial infarction as well as additional individual endpoints. Cardiovascular death was reported in 10 patients (3.5%) receiving olmesartan compared with 3 patients (1.1%) receiving placebo. Sudden death occurred in 5 patients (1.8%) in the olmesartan group compared with 2 patients (0.7%) in the placebo group. Overall mortality, non-fatal stroke and non-fatal myocardial infarction were reported, however, in lower proportions of patients treated with olmesartan compared with placebo (overall mortality 19 patients (6.7%) vs 20 patients (7.0%), non-fatal stroke 8 patients (2.8%) vs 11 patients (3.9%) and non-fatal myocardial infarction 3 patients (1.1%) vs 7 patients (2.5%) (olmesartan vs placebo, respectively)).
Use in elderly patients. Olmesartan medoxomil has been evaluated for safety in 1646 patients aged 65 years or older of whom, 454 were aged 75 years or older. Overall, the incidence of adverse events in the elderly is comparable to that of the adult population. The number of withdrawals due to olmesartan medoxomil-related adverse effects was very low (6/1206; 0.5%) compared to the placebo (1/85; 1.2%) or losartan (0/184; 0.0%).
The most common adverse events considered to be treatment related in elderly patients were headache (1.5%) and dizziness (1.1%) on 40 mg olmesartan medoxomil.

HCTZ.

HCTZ may cause or exacerbate volume depletion, which may lead to electrolyte imbalance (see Section 4.4 Special Warnings and Precautions for Use).
Adverse events reported with the use of HCTZ alone include:

Blood and lymphatic system disorders.

Leukopenia, neutropenia/agranulocytosis, thrombocytopenia, aplastic anaemia, haemolytic anaemia, bone marrow depression.

Cardiac disorders.

Cardiac arrhythmias.

Ear and labyrinth disorders.

Vertigo.

Nervous system disorders.

Light-headedness, paraesthesia, headache, paresis, convulsions, dizziness.

Eye disorders.

Xanthopsia, transient blurred vision, diplopia, lacrimation decreased, worsening of pre-existing myopia, acute-closure glaucoma, choroidal effusion (frequency not known). Cases of choroidal effusion with visual field defect have been reported after the use of thiazide diuretics.

Gastrointestinal disorders.

Gastric irritation, diarrhoea, constipation, pancreatitis, abdominal pain, meteorism, paralytic ileus, vomiting, nausea, cramping.

General disorders and administration site conditions.

Fever.

Hepatobiliary disorders.

Jaundice (intrahepatic cholestatic jaundice), acute cholecystitis.

Immune system disorders.

Anaphylactic reactions.

Infections and infestations.

Sialadenitis.

Investigations.

Blood creatinine increased, blood urea increased.

Metabolism and nutritional disorders.

Loss of appetite, hypercholesterolaemia, hyperuricaemia, hypertriglyceridaemia, glycosuria, hypercalcaemia, hyperglycaemia, hypokalaemia, hypomagnesaemia, hyponatraemia, hyperamylasaemia, hypochloraemic alkalosis, hypochloraemia.

Musculoskeletal and connective tissue disorders.

Muscle spasm, muscular weakness.

Psychiatric disorders.

Sleep disturbances, depression, anorexia, restlessness, confusional state, apathy.

Reproductive system and breast disorders.

Erectile dysfunction.

Respiratory, thoracic and mediastinal disorders.

Respiratory distress, pneumonitis, pulmonary oedema, dyspnoea and interstitial pneumonia. Acute respiratory distress has been reported in very rare instances (see Section 4.4 Special Warnings and Precautions for Use).

Skin and subcutaneous tissue disorders.

Photosensitivity reactions, rash, cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus, urticaria, erythema multiforme, exfoliative dermatitis including Stevens-Johnson syndrome and toxic epidermal necrolysis, erythema, pruritus, purpura.

Renal and urinary disorders.

Renal failure, renal dysfunction, interstitial nephritis.

Vascular disorders.

Postural hypotension, embolism, thrombosis, necrotising angiitis (vasculitis, cutaneous vasculitis).

Neoplasms benign, malignant and unspecified (incl cysts and polyps).

Frequency 'not known': Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma).

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 and contact Arrotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

No specific information is available on the effects or treatment of APO-Olmesartan HCTZ overdosage. The patient should be closely monitored, and the treatment should be symptomatic and supportive. Management depends upon the time since ingestion and the severity of the symptoms. Activated charcoal may be useful in the treatment of overdosage. Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a supine position, with salt and volume replacements given quickly.
The most likely manifestations of olmesartan medoxomil overdosage are expected to be hypotension and tachycardia; bradycardia might also occur. Overdosage with HCTZ is associated with electrolyte depletion (hypokalaemia, hypochloraemia) and dehydration resulting from excessive diuresis. The most common signs and symptoms of overdosage are nausea and somnolence. Hypokalaemia may result in muscle spasm and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalis glycosides or certain anti-arrhythmic drugs.
No information is available regarding the dialysability of olmesartan or HCTZ.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

APO-Olmesartan HCTZ is a combination of an angiotensin II receptor antagonist, olmesartan medoxomil, and a thiazide diuretic, HCTZ. The combination of these ingredients has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.
Once daily dosing with APO-Olmesartan HCTZ provides an effective and smooth reduction in blood pressure over the 24-hour dose interval.
Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan medoxomil is an orally active angiotensin II receptor (type AT1) antagonist. It has more than a 12,500-fold greater affinity for the AT1 receptor than for the AT2 receptor. It is expected to block all actions of angiotensin II mediated by the AT1 receptor, regardless of the source or route of synthesis of angiotensin II. The selective antagonism of the angiotensin II (AT1) receptors results in increases in plasma renin levels and angiotensin I and II concentrations, and some decrease in plasma aldosterone concentrations.
Angiotensin II plays a significant role in the pathophysiology of hypertension via the type 1 (AT1) receptor.
In hypertension, olmesartan medoxomil causes a dose-dependent, long-lasting reduction in arterial blood pressure. There has been no evidence of first-dose hypotension, of tachyphylaxis during long-term treatment, or of rebound hypertension after cessation of therapy.
With continuous treatment, maximum reductions in blood pressure are achieved by 8 weeks after the initiation of therapy, although a substantial proportion of the blood pressure lowering effect is already observed after 2 weeks of treatment. When used together with HCTZ, the reduction in blood pressure is additive and co-administration is well tolerated.
The effect of olmesartan medoxomil on mortality and morbidity is not yet known.
HCTZ is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazide diuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. The diuretic action of HCTZ reduces plasma volume, increases plasma renin activity and increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II and therefore co-administration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with thiazide diuretics. With HCTZ, onset of diuresis occurs at about 2 hours and peak effect occurs at about 4 hours post-dose, whilst the action persists for approximately 6-12 hours.
The combination of olmesartan medoxomil and HCTZ produces additive reductions in blood pressure, which generally increase with the dose of each component. In pooled placebo-controlled studies, administration of the 20/12.5 mg, 20/25 mg, 40/12.5 mg, and 40/25 mg combinations of olmesartan medoxomil/HCTZ resulted in mean placebo-subtracted systolic/diastolic blood pressure reductions at trough ranging from 12/7 to 16/9 mmHg. Age and gender had no clinically relevant effect on response to treatment with olmesartan medoxomil/HCTZ combination therapy.
Administration of 12.5 mg and 25 mg HCTZ in patients insufficiently controlled by olmesartan medoxomil 20 mg monotherapy gave additional reductions in 24-hour systolic/diastolic blood pressures measured by ambulatory blood pressure monitoring of 7/5 mmHg and 12/7 mmHg, respectively, compared with olmesartan medoxomil monotherapy baseline. The additional mean systolic/diastolic blood pressure reductions at trough compared with baseline, measured conventionally, were 11/10 mmHg and 16/11 mmHg, respectively. The addition of 12.5 mg HCTZ in patients not achieving target blood pressure (≤ 130/85 mmHg) on olmesartan medoxomil 40 mg decreased systolic/diastolic blood pressure by an additional 13/6 mmHg, and titration of the HCTZ dose to 25 mg in non-achievers at the lower add-on dose resulted in a further blood pressure decrease of 9/5 mmHg. Conversely, addition of olmesartan medoxomil 10-20 mg in patients with moderate to severe hypertension insufficiently controlled by HCTZ 25 mg monotherapy provided mean systolic/diastolic blood pressure reductions at trough of 21/18 mmHg compared with HCTZ monotherapy baseline.
The effectiveness of olmesartan medoxomil/HCTZ combination therapy was maintained over long-term (1-year) treatment. Withdrawal of olmesartan medoxomil therapy, with or without concomitant HCTZ therapy, did not result in rebound hypertension.
The effects of fixed dose combination of olmesartan medoxomil/HCTZ on mortality and cardiovascular morbidity are currently unknown.

Non-melanoma skin cancer.

Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ 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 HCTZ use (≥ 50,000 mg cumulative) was associated with an adjusted OR of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 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 HCTZ: 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% CI: 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).

Clinical trials.

Olmesartan medoxomil.

The antihypertensive effects of olmesartan have been demonstrated in seven placebo-controlled studies at doses ranging from 2.5 to 80 mg for 6 to 12 weeks. Approximately 2,800 patients with essential hypertension were studied. The blood pressure lowering effect of olmesartan tended to increase with time and to increase with dose up to the 40 mg dose. Olmesartan medoxomil 10 mg (n = 521), 20 mg (n = 513), and 40 mg (n = 195) once daily produced statistically significant reductions in peak and trough blood pressure compared with placebo (n = 543) at every time point from week 2 to week 12 (sSBP p < 0.001 and sDBP p < 0.001). The blood pressure lowering effect was maintained throughout the 24-hour period with olmesartan medoxomil once daily, with trough-to-peak ratios for systolic and diastolic response between 60 and 80%.
The blood pressure lowering effect of olmesartan, with and without HCTZ, was maintained in patients treated for up to 1-year. There was no evidence of tachyphylaxis during long-term treatment with olmesartan or rebound effect following abrupt withdrawal of olmesartan medoxomil after 1-year of treatment.
The antihypertensive effect of olmesartan was similar in men and women and in patients older and younger than 65 years. The effect was smaller in black patients (usually a low-renin population), as has been seen with other ACE inhibitors, angiotensin receptor blockers and beta-blockers. Olmesartan had an additional blood pressure lowering effect when added to HCTZ.

Olmesartan medoxomil and HCTZ.

In clinical trials, 1,230 patients were exposed to the combination of olmesartan medoxomil (2.5 mg to 40 mg) and HCTZ (12.5 mg to 25 mg). These trials included one placebo-controlled factorial trial (n = 502) in mild-moderate hypertensives with combinations of olmesartan medoxomil (10 mg, 20 mg, 40 mg or placebo) and HCTZ (12.5 mg, 25 mg or placebo). The antihypertensive effect of the combination on trough blood pressure was related to the dose of each component (see Table 3).
Once daily dosing with 20 mg olmesartan medoxomil and 12.5 mg HCTZ, 40 mg olmesartan medoxomil and 12.5 mg HCTZ or 40 mg olmesartan medoxomil and 25 mg HCTZ produce mean placebo-adjusted blood pressure reductions at trough (24 hours post-dosing) ranging from 17/8 to 24/14 mmHg.
The onset of the antihypertensive effect occurred within 1-week and was near maximal at 4 weeks. The antihypertensive effect was independent of gender, but there were too few subjects to identify response differences based on race or age greater than or less than 65 years. No appreciable changes in trough heart rate were observed with combination therapy in the placebo-controlled trial.

Use in the elderly.

The antihypertensive effects of olmesartan medoxomil and HCTZ were investigated in a randomised, double-blind, parallel group with losartan in elderly patients (65 years or older; olmesartan medoxomil n = 251 whom 69 were > 75 years; losartan n = 130 whom 48 were > 75 years) with essential hypertension for 52 weeks. Patients were initiated on a starting dose of 20 mg olmesartan. At 4 week intervals, the treatment was titrated to achieve target BP. The results obtained for those on olmesartan medoxomil and HCTZ were similar to those in the losartan group.

5.2 Pharmacokinetic Properties

Absorption.

Olmesartan medoxomil.

Olmesartan medoxomil is a prodrug. It is rapidly converted to the pharmacologically active metabolite, olmesartan, by esterases in the gut mucosa and in portal blood during absorption from the gastrointestinal tract. No intact olmesartan medoxomil or intact side chain medoxomil moiety have been detected in plasma or excreta. The mean absolute bioavailability of olmesartan from a tablet formulation was 25.6%.
The mean peak plasma concentration (Cmax) of olmesartan is reached within about 2 hours after oral dosing with olmesartan medoxomil, and olmesartan plasma concentrations increase approximately linearly with increasing single oral doses up to about 80 mg.
Food had minimal effect on the bioavailability of olmesartan and, therefore, olmesartan medoxomil may be administered with or without food.

Distribution.

Olmesartan medoxomil.

The mean volume of distribution after intravenous dosing is in the range of 16-29 litres. Olmesartan is highly bound to plasma proteins (99.7%), but the potential for clinically significant protein binding displacement interactions between olmesartan and other highly bound co-administered drugs is low (as confirmed by the lack of a clinically significant interaction between olmesartan medoxomil and warfarin). The binding of olmesartan to blood cells is negligible.
In rats, olmesartan crossed the blood-brain barrier poorly, if at all. Olmesartan crossed the placental barrier in rats and was distributed to the foetus. Olmesartan was distributed to milk at low levels in rats.

HCTZ.

Following oral administration of olmesartan medoxomil and HCTZ in combination, the median time to peak concentrations of HCTZ was 1.5 to 2 hours after dosing. HCTZ is 68% protein bound in the plasma and its apparent volume of distribution is 0.83-1.14 L/kg.

Metabolism.

Olmesartan medoxomil.

Following the rapid and complete conversion of olmesartan medoxomil to olmesartan during absorption, there is virtually no further metabolism of olmesartan.

Excretion.

Olmesartan medoxomil.

Total plasma clearance was typically 1.3 L/h (CV, 19%) and was relatively slow compared with hepatic blood flow (approximately 90 L/h). Approximately 30% to 50% of the systemically absorbed drug is excreted in the urine whilst the remainder is excreted in faeces (via the bile).
The terminal elimination half-life of olmesartan varied between 10 and 15 hours after multiple oral dosing. Steady-state was reached after the first few doses and no further accumulation was evident after 14 days of repeated dosing. Renal clearance was approximately 0.5-0.7 L/h and was independent of dose.

HCTZ.

HCTZ is not metabolised in man and is excreted almost entirely as unchanged drug in urine. About 60% of the oral dose is eliminated as unchanged drug within 48 hours. Renal clearance is about 250-300 mL/min. The terminal elimination half-life of HCTZ is 10-15 hours.

Pharmacokinetics in special populations.

Elderly.

In hypertensive patients, the AUC at steady-state was increased by approximately 33% in elderly patients (65-75 years old) and by approximately 31% (adjusted for gender and body mass index) in very elderly patients (≥ 75 years old) compared with the younger age group (see Section 4.2 Dose and Method of Administration).

Paediatric.

The pharmacokinetics of olmesartan medoxomil have not been investigated in patients < 18 years of age.

Gender.

Minor differences were observed in the pharmacokinetics of olmesartan medoxomil in women compared with men. AUC and Cmax were 10-15% higher in women than in men. Female patients had approximately 20% smaller clearances of hydrochlorothiazide than male patients.

Renal impairment.

In patients with renal insufficiency, serum concentrations of olmesartan were elevated compared to subjects with normal renal function. After repeated dosing, the AUC was approximately tripled in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment and kidney transplantation).
The pharmacokinetics of olmesartan medoxomil in patients undergoing haemodialysis has not been studied.

Hepatic impairment.

Mean olmesartan AUC after single oral administration to patients with moderate hepatic impairment (Child-Pugh score 7-9) was increased by about 48% compared with healthy controls (total group), or by about 60% when compared with matched controls only. Following repeated dosing, a similar increase in olmesartan mean AUC was observed in patients with moderate hepatic impairment (Child-Pugh score 7-9) when compared with matched healthy controls. Olmesartan mean Cmax values were similar in hepatically-impaired and healthy subjects. Olmesartan medoxomil has not been evaluated in patients with severe hepatic impairment (Child-Pugh score 10-15) (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

5.3 Preclinical Safety Data

Genotoxicity.

Olmesartan medoxomil.

Both olmesartan medoxomil and olmesartan tested negative in the in vitro Syrian hamster embryo cell transformation assay and showed no evidence of genetic toxicity in the Ames (bacterial mutagenicity) test. However, both were shown to induce chromosomal aberrations in cultured cells in vitro (Chinese hamster lung) and tested positive for thymidine kinase mutations in the in vitro mouse lymphoma assay. Olmesartan medoxomil tested negative in vivo for mutations in the intestine and kidney of a mutagenic susceptible mouse (MutaMouse) and for clastogenicity in mouse bone marrow (micronucleus test) at oral doses of up to 2,000 mg/kg/day. Olmesartan not tested in this mouse model. On balance, the weight-of-evidence indicates that olmesartan medoxomil does not pose a genotoxic risk at clinically relevant doses.

HCTZ.

HCTZ was negative in several different assays of gene mutation and chromosomal aberration. However, positive test results were obtained in the in vitro CHO sister chromatid exchange (clastogenicity) assay and the mouse lymphoma (mutagenicity) assay at HCTZ concentrations of 43-1,200 microgram/mL.

Olmesartan medoxomil and HCTZ.

Olmesartan medoxomil/HCTZ in a ratio of 20:12.5 was negative in the bacterial reverse mutation test up to the maximum recommended plate concentration for the standard assays. As expected, positive clastogenicity responses were observed with either drug or the combination (40:12.5, 20:12.5, 10:12.5) in Chinese hamster lung cells but no synergistic clastogenicity was observed. However, the combination (20:12.5) was negative in the in vivo mouse micronucleus test at oral doses (1,935/1,209 mg/kg) that were likely to achieve high relative systemic exposure (> 33-700-fold based on AUC) to both components.

Carcinogenicity.

The carcinogenic potential of olmesartan medoxomil and HCTZ in combination has not been investigated.
Olmesartan medoxomil was not carcinogenic when administered by dietary administration to rats for up to 2 years. The highest dose tested (2,000 mg/kg/day) corresponded to a relative systemic exposure to olmesartan that was about 30 times that anticipated at the maximum recommended human dose (MRHD) of 40 mg/day (based on AUC). Two carcinogenicity studies conducted in mice, a 6-month gavage study in the p53 knockout mouse and a 6-month dietary administration study in the Hras2 transgenic mouse, at doses of up to 1,000 mg/kg/day (about 11 times anticipated clinical exposure to olmesartan at the MRHD, based on AUC in Hras2), revealed no evidence of a carcinogenic effect of olmesartan medoxomil.
Two-year feeding studies in mice and rats showed no evidence of carcinogenic potential for HCTZ in female mice at doses up to approximately 600 mg/kg/day, or in male and female rats at doses up to approximately 100 mg/kg/day. There was equivocal evidence for hepatocarcinogenicity in male mice treated with HCTZ at approximately 600 mg/kg/day.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, lactose monohydrate, hyprolose, magnesium stearate, hypromellose, Opadry complete film coating system 03F82788 Yellow.

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.

6.5 Nature and Contents of Container

APO-Olmesartan HCTZ 20/12.5 film coated tablets.

Aluminium/Aluminium blister packs or PVC/PVDC/Al blister packs containing 30 film-coated tablets. AUST R 221116.

APO-Olmesartan HCTZ 40/12.5 film coated tablets.

Aluminium/Aluminium blister packs or PVC/PVDC/Al blister packs containing 30 film-coated tablets. AUST R 221118.

APO-Olmesartan HCTZ 40/25 film coated tablets.

Aluminium/Aluminium blister packs or PVC/PVDC/Al blister packs containing 30 film-coated tablets. AUST R 221121.
Not all strengths may be available.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Olmesartan medoxomil is a prodrug, hydrolysed to olmesartan during absorption from the gastrointestinal tract. Olmesartan is a selective AT1 subtype angiotensin II receptor antagonist. HCTZ is a thiazide diuretic.
Olmesartan medoxomil is a white to light yellowish-white powder or crystalline powder with a molecular weight of 558.59. It is practically insoluble in water and sparingly soluble in methanol.
HCTZ is a white, or almost white, crystalline powder, with a molecular weight of 297.7. HCTZ is very slightly soluble in water, soluble in acetone, sparingly soluble in alcohol. It dissolves in dilute solutions of alkali hydroxides.

Chemical structure.

Olmesartan medoxomil.


Chemical name: 2,3-dihydroxy-2- butenyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[p-(o-1H-tetrazol-5-ylphenyl) benzyl] imidazole-5-carboxylate, cyclic 2,3-carbonate.
Molecular formula: C29H30N6O6.

CAS number.

144689-63-4.

Chemical structure.

Hydrochlorothiazide.


Chemical name: 6-chloro-3,4-dihydro-2H-1,2,4- benzothiadiazine-7-sulfonamide 1,1-dioxide.
Molecular formula: C7H8ClN3O4S2.

CAS number.

58-93-5.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes