Consumer medicine information

APO-Olmesartan

Olmesartan medoxomil

BRAND INFORMATION

Brand name

APO-Olmesartan

Active ingredient

Olmesartan medoxomil

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

SUMMARY CMI

APO-Olmesartan

Consumer Medicine Information (CMI) summary

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

1. Why am I using APO-Olmesartan?

APO-Olmesartan contains the active ingredient olmesartan medoxomil. APO-Olmesartan is used to treat high blood pressure, which is sometimes called hypertension.

For more information, see Section 1. Why am I using APO-Olmesartan? in the full CMI.

2. What should I know before I use APO-Olmesartan?

Do not use if you have ever had an allergic reaction to APO-Olmesartan or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

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

3. What if I am taking other medicines?

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

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

4. How do I use APO-Olmesartan?

  • The usual starting dose is 20mg once daily
  • For children 6-18 years of age, (weighing more than 35 kg or more), the usual dose is 20mg once daily
  • Do not give to children under one (1) year of age

More instructions can be found in Section 4. How do I use APO-Olmesartan? in the full CMI.

5. What should I know while using APO-Olmesartan?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using APO-Olmesartan.
  • Tell your doctor immediately if you feel light-headed or dizzy after taking your first dose of APO-Olmesartan or when your dose is increased
  • Make sure you drink enough water during exercise and hot weather when you are taking APO-Olmesartan
Things you should not do
  • Do not stop using this medicine suddenly
  • Do not lower the dosage without checking with your doctor
Driving or using machines
  • APO-Olmesartan may cause dizziness, light-headedness or tiredness in some people
  • Be careful before you drive or operate machinery until you know how APO-Olmesartan affects you
Drinking alcohol
  • Alcohol may increase dizziness or light-headedness
Looking after your medicine
  • Keep in a cool dry place where the temperature stays below 25°C

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

6. Are there any side effects?

Call your doctor immediately or go to the nearest emergency department if you feel any chest pains or develop any anaphylactic reactions; swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing.

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

Active ingredient: olmesartan medoxomil

Consumer Medicine Information (CMI)

This leaflet provides important information about using APO-Olmesartan. 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.

Where to find information in this leaflet:

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

1. Why am I using APO-Olmesartan?

APO-Olmesartan contains the active ingredient olmesartan medoxomil. APO-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. APO-Olmesartan blocks the action of angiotensin-II and therefore relaxes the blood vessels. This helps lower blood pressure.

APO-Olmesartan is used to treat high blood pressure which is also known as hypertension.

There are usually no symptoms of hypertension. The only way of knowing that you have hypertension is to have your blood pressure checked on a regular basis. If high blood pressure is not treated it can lead to serious health problems, including stroke, heart disease and kidney failure.

Your doctor may have prescribed APO-Olmesartan for another reason. Ask your doctor if you have any questions about why APO-Olmesartan has been prescribed for you.

This medicine is not addictive and is only available with a doctor's prescription.

2. What should I know before I use APO-Olmesartan?

Warnings

Do not use APO-Olmesartan if:

  • you have serious problems with your kidneys
  • you have serious problems with your liver
  • you have diabetes and are taking a medicine called aliskiren to reduce blood pressure
  • it is past its expiry date oriented on the pack or if the packaging is torn or shows sign of tampering
  • you are allergic to olmesartan medoxomil, or any of the ingredients listed at the end of this leaflet.

Always check the ingredients to make sure you can use this medicine.

Symptoms of an allergic reaction to APO-Olmesartan may include skin rash, itchiness, shortness of breath, swelling of the face, lips or tongue, muscle pain or tenderness or joint pain.

Check with your doctor if you:

  • have kidney problems
  • have liver problems
  • have heart problems
  • have excessive vomiting or diarrhoea
  • have high levels of potassium in your blood
  • have problems with your adrenal glands (small glands above the kidneys)
  • are following a very low salt diet
  • are allergic to any other medicines, foods, dyes or preservatives
  • are taking any medicine for any other condition

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

Pregnancy and breastfeeding

Do not take APO-Olmesartan if you are pregnant or breastfeeding. APO-Olmesartan may enter the womb or it may pass into breast milk and there is the possibility that your baby may be affected.

If pregnancy is discovered, speak to your doctor immediately as APO-Olmesartan should be discontinued as soon as possible.

Use in Children

The safety and effectiveness of APO-Olmesartan in children aged less than 1 year has not been established.

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.

The medicines listed below may be affected by APO-Olmesartan or may affect how well APO-Olmesartan works. You may need different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

  • 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, medicines used to relieve pain, swelling and other symptoms of inflammation, including arthritis
  • potassium supplements, potassium-sparing agents, potassium-containing salt substitutes
  • medicines that may increase serum potassium (eg. trimethoprim-containing products)
  • lithium, a medicine used to treat mood swings and some types of depression
  • any medicines that contain aliskiren
  • any medicines that contain colesevelam

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.

4. How do I use APO-Olmesartan?

How much to take / use

Adults: The usual starting dose of APO-Olmesartan is 20mg once daily. The dose may be increased to 40mg once a day if necessary.

Children 6-18 years (weighing 35 kg or more): The usual dose is one APO-Olmesartan 20mg tablet daily.

Children 6-18 years (weighing less than 35 kg): The usual dose is 10 mg once daily. APO-Olmesartan tablets cannot be divided to accommodate 10 mg dosing. Olmesartan 10 mg tablets are available from alternative brands if the 10 mg strength is required.

Children 1-5 years (weighing 5 kg or more): The dose will vary depending on your child's weight.

Children under 1 year of age: Do not give APO-Olmesartan to children under 1 of age.

Follow the instructions provided and take APO-Olmesartan until your doctor tells you to stop.

Swallow APO-Olmesartan tablets with a full glass of water. Do not chew the tablets.

When to take / use APO-Olmesartan

  • Take APO-Olmesartan at the about the same time each day. Taking it at the same time each day will have the best effect and will also help you remember when to take it.
  • It does not matter if you take APO-Olmesartan before or after food.

If you forget to use APO-Olmesartan

If you miss your dose at the usual time and 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.

If you use too much APO-Olmesartan

If you think that you have used too much APO-Olmesartan, you may feel light-headed, dizzy or you may feint. You may also have a fast heartbeat.

If you think that you have taken too much APO-Olmesartan, 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.

5. What should I know while using APO-Olmesartan?

Things you should do

Make sure you drink enough water during exercise and hot weather when you are taking APO-Olmesartan, especially if you sweat a lot. If you do not drink enough water while taking APO-Olmesartan, 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.

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.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are taking APO-Olmesartan. Your blood pressure may drop suddenly.

If you are about to have any blood tests, tell your doctor that you are taking APO-Olmesartan. APO-Olmesartan may interfere with the results of some tests.

Go to your doctor regularly for a check-up. Your doctor may occasionally do a blood test to check your potassium levels and see how your kidneys are working.

Have your blood pressure checked when your doctor says, to make sure APO-Olmesartan is working.

Call your doctor straight away if you:

  • feel light-headed or dizzy after taking your first dose of APO-Olmesartan, or when your dose is increased
  • become pregnant whilst taking APO-Olmesartan
  • have excess vomiting and/or diarrhoea while taking APO-Olmesartan. You may lose too much water and salt and your blood pressure may drop too much.

Remind any doctor, dentist or pharmacist you visit that you are using APO-Olmesartan.

Things you should not do

  • Do not stop using APO-Olmesartan suddenly or lower the dosage without checking with your doctor
  • Do not take APO-Olmesartan to treat any other complaints unless your doctor or pharmacist tells you
  • Do not give APO-Olmesartan to anyone else, even if they have the same condition as you

Driving or using machines

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

As with other medicines in this class, APO-Olmesartan may cause dizziness, light-headedness or tiredness in some people. Make sure you know how you react to APO-Olmesartan before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed.

Drinking alcohol

Tell your doctor if you drink alcohol. Alcohol may increase dizziness or light-headedness.

Looking after your medicine

  • Store 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.

Keep it where young children cannot reach it.

When to discard your medicine

If your doctor or pharmacist tells you to stop taking APO-Olmesartan or the tablets have passed their expiry date, ask your pharmacist what to do with any that are 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 APO-Olmesartan 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.

Less serious side effects

Less serious side effectsWhat to do
Body as a whole:
  • Back pain
  • Fatigue, unusual tiredness, or weakness
  • Headache
  • Influenza-like symptoms
Central & peripheral nervous system:
  • Dizziness
Gastrointestinal system:
  • Diarrhoea
  • Nausea or vomiting
  • Abdominal pain
Respiratory system:
  • Bronchitis
  • Coughing
  • Inflammation of the back of the throat
  • Rhinitis
Urinary system:
  • Urinary tract infection
Speak to your doctor if you have any of these less serious side effects and they worry you.
Body as a whole:
  • Swelling of legs or hands
Skin and subcutaneous tissue:
  • Skin rash or itchiness
Musculoskeletal system:
  • Joint pain
  • Aching, tender or weak muscles not caused by exercise
Cardiovascular system:
  • Fast heartbeat
  • Shortness of breath or tightness in the chest
Tell your doctor as soon as possible if you notice any of the following

Serious side effects

Serious side effectsWhat to do
Body as a whole:
  • Chest pain
Immune system:
  • Anaphylactic reactions such as swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing
Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

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

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

Reporting side effects

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

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

7. Product details

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

What APO-Olmesartan contains

Active ingredient
(main ingredient)		olmesartan medoxomil
Other ingredients
(inactive ingredients)
  • lactose monohydrate
  • microcrystalline cellulose
  • low-substituted hydroxypropylcellulose
  • hydroxypropylcellulose
  • magnesium stearate
  • Opadry Yellow 03F82788
Potential allergenssugars (as lactose)

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

What APO-Olmesartan looks like

20 mg tablets (AUST R 221052):
Yellow film coated, round, biconvex tablets debossed with '323' on one side and 'L' on other side.

40 mg tablets (AUST R 221603):
Yellow film coated, oval shape, biconvex tablets debossed with 'L324' on one side and plain on other side. AUST R 221063.

Available in blister packs of 30 tablets.

Who distributes APO-Olmesartan

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

This leaflet was prepared in December 2023.

Published by MIMS March 2024

BRAND INFORMATION

Brand name

APO-Olmesartan

Active ingredient

Olmesartan medoxomil

Schedule

S4

 

1 Name of Medicine

Olmesartan medoxomil.

2 Qualitative and Quantitative Composition

APO-Olmesartan contains the active ingredient olmesartan medoxomil.
APO-Olmesartan is available for oral use as film-coated tablets containing 20 mg, or 40 mg olmesartan medoxomil.

Excipients with known effect.

Lactose monohydrate.
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

20 mg tablet.

Yellow film coated, round, biconvex tablets debossed with 323 on one side and L on the other side.

40 mg tablet.

Yellow film coated, oval shape, biconvex tablets debossed with L324 on one side and plain on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

APO-Olmesartan is indicated for the treatment of hypertension.

4.2 Dose and Method of Administration

Dosage.

Adults. Dosage must be individualised. The optimal recommended starting dose of APO-Olmesartan is 20 mg once daily when used as monotherapy in patients who are not volume-contracted. If additional blood pressure reduction is required, the dose of APO-Olmesartan may be increased to a maximum of 40 mg daily.
APO-Olmesartan may be administered with or without food. In order to assist compliance, it is recommended that APO-Olmesartan tablets be taken at about the same time each day. Twice-daily dosing offers no advantage over the same total dose given once daily.
The antihypertensive effect of olmesartan medoxomil is substantially present within 2 weeks of initiating therapy and is maximal by about 8 weeks after initiating therapy. This should be borne in mind when considering changing the dose regimen for any patient.
Hydrochlorothiazide therapy should be considered in those patients requiring additional blood pressure control beyond 40 mg daily. APO-Olmesartan may be administered with other antihypertensive agents.
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 required for patients with mild (creatinine clearance of 50-80 mL/min, eGFR 60-89 mL/min/1.73 m2) to moderate (creatinine clearance of 30 - < 50 mL/min, eGFR 30-59 mL/min/1.73 m2) renal impairment. The use of APO-Olmesartan in patients with severe renal impairment (creatinine clearance < 30 mL/min, eGFR < 30 mL/min/1.73 m2) is not recommended, since there is only limited experience in this patient group (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment and kidney transplantation). There are no data on the use of olmesartan in children with eGFR less than 25 mL/min/1.73 m2.

Intravascular volume depletion.

For patients with possible depletion of intravascular volume, particularly those with impaired renal function, APO-Olmesartan should be administered under close medical supervision. In these patients a lower starting dose of 10 mg once daily is recommended (see Section 4.4 Special Warnings and Precautions for Use, Intravascular volume depletion) (see Section 6.5 Nature and Contents of Container for marketed strengths). APO-Olmesartan tablets cannot be divided to accommodate 10 mg dosing. Olmesartan 10 mg tablets are available from alternative brands when the 10 mg strength is required.
If a patient becomes volume depleted whilst taking APO-Olmesartan, blood pressure and renal function should be closely monitored until the situation resolves.

Hepatic impairment.

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

Paediatric use.

Dosing must be individualised. The recommended starting dose of APO-Olmesartan is based on age and/or weight (see dosing recommendation in Table 1). If after 2 weeks of therapy further reduction in blood pressure is required, the dose of APO-Olmesartan may be increased to a maximum of either 20 mg or 40 mg (see dosing recommendation in Table 1).
There are limited data available for the pharmacokinetics of olmesartan in children aged less than 6 years (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations, Paediatric) and there are no pharmacokinetic data available in children with renal impairment (see Section 4.2 Dose and Method of Administration, Renal impairment).
For children who cannot swallow tablets, the equivalent dose may be given as an extemporaneous suspension. This brand of product has not been approved for use as an extemporaneous suspension. An alternative brand approved for use to compound an extemporaneous suspension is to be used if treatment is required in the suspension form.

4.3 Contraindications

APO-Olmesartan is contraindicated in:
Patients who are hypersensitive to either olmesartan medoxomil or any component of this medication.
Pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
Patients with 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) or biliary obstruction (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).
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.

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 drugs that affect the renin-angiotensin-aldosterone system.

Use in renal impairment and kidney transplantation.

When olmesartan medoxomil is used in patients with impaired renal function, periodic monitoring of serum potassium and creatinine levels is recommended. Use of olmesartan medoxomil is not recommended in patients with severe renal impairment (creatinine clearance < 30 mL/min, eGFR < 30 mL/min/1.73 m2) (see Section 4.2 Dose and Method of Administration). There is no experience of the administration of olmesartan medoxomil in patients with a recent kidney transplant or in patients with end-stage renal impairment (i.e. creatinine clearance < 12 mL/min, eGFR < 15 mL/min/1.73 m2). There are no data on the use of olmesartan in children with eGFR less than 25 mL/min/1.73 m2.

Use in hepatic impairment.

There is no experience in patients with severe hepatic impairment (Child-Pugh score 10 - 15) and therefore use of APO-Olmesartan in this patient group is not recommended (see Section 4.2 Dose and Method of Administration).

Hyperkalaemia.

As with other angiotensin receptor antagonists and ACE inhibitors, hyperkalaemia may occur during treatment with APO-Olmesartan, especially in the presence of renal impairment and/or heart failure. This is because the tablets contains olmesartan medoxomil, a drug which inhibits the renin-angiotensin system (RAS) and drugs that inhibit the RAS can cause hyperkalaemia.
Concomitant use of olmesartan medoxomil 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 and should therefore be co-administered cautiously with Olmetec in patients where such coadministration is considered necessary.
Close monitoring of serum potassium levels in at risk patients is recommended.

Lithium.

As with other angiotensin receptor antagonists, the combination of lithium and olmesartan medoxomil is not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Aortic or mitral valve stenosis; obstructive hypertrophic cardiomyopathy.

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

Primary aldosteronism.

Patients with primary aldosteronism generally will not respond to antihypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of APO-Olmesartan is not recommended in such patients.

Ethnic differences.

As with all other angiotensin receptor antagonists, the blood pressure lowering effect of APO-Olmesartan is 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.

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.

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 olmesartan medoxomil in cases where no other etiology is identified.

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. Olmesartan medoxomil should be immediately discontinued in patients who develop angioedema, and olmesartan medoxomil should not be re-administered.

General.

Caution should be exercised in patients who have shown prior hypersensitivity to other angiotensin II receptor antagonists.

Other.

As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic heart disease or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke.

Use in the elderly.

Of the total number of hypertensive patients receiving olmesartan medoxomil in clinical studies, including two studies investigating safety and efficacy in the elderly, more than 40% were 65 years of age and over, while more than 10% were 75 years of age and older. No overall differences in effectiveness or safety were observed between elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Paediatric use.

Not to be used for children aged below 1 year of age. Pharmacokinetic information is limited in patients less than 6 years.

Effects on laboratory tests.

Olmesartan medoxomil.

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

4.5 Interactions with Other Medicines and Other Forms of Interactions

Drugs that affect olmesartan medoxomil.

Potassium supplements and potassium sparing diuretics.

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. Such concomitant use is therefore not recommended.

Other antihypertensive medications.

The blood pressure lowering effect of olmesartan medoxomil 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 receptor antagonists may act synergistically by decreasing glomerular filtration. The risk of the concomitant use of NSAIDs and angiotensin receptor 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 receptor antagonists, leading to their partial loss of efficacy.

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 and other agents that affect the RAS.
Do not co-administer aliskiren with olmesartan medoxomil in patients with diabetes (see Section 4.3 Contraindications). Avoid use of aliskiren with olmesartan medoxomil 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. Coadministration of warfarin and digoxin had no effect on the pharmacokinetics of olmesartan medoxomil.

Drugs that are affected by olmesartan medoxomil.

Lithium.

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors and angiotensin receptor 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.

Other drugs.

Drugs, which have been investigated in specific clinical studies in healthy volunteers, include warfarin, digoxin, an antacid (magnesium aluminium hydroxide), hydrochlorothiazide and pravastatin. No clinically relevant interactions were observed and in particular olmesartan medoxomil had no significant effect on the pharmacokinetics or pharmacodynamics of warfarin or the pharmacokinetics of digoxin.
Olmesartan had no clinically relevant inhibitory effects on in vitro human cytochrome P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1 and 3A4, and had no or minimal inducing effects on rat cytochrome P450 activities. Therefore in vivo interaction studies with known cytochrome P450 enzyme inhibitors and inducers were not conducted, and 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.

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.
(Category D)
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, olmesartan medoxomil 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 receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of olmesartan medoxomil 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, olmesartan medoxomil 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 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 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 effect dose for developmental toxicity in rats is 0.3 mg/kg/day, about one-tenth the MRHD of 40 mg/day.
 It is not known whether olmesartan is excreted in human milk, but olmesartan is secreted at low concentration in the milk of lactating rats. 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 on the ability to drive has not been specifically studied. With respect to driving vehicles or operating machines, it should be taken into account that occasionally dizziness or fatigue may occur in patients taking antihypertensive therapy.

4.8 Adverse Effects (Undesirable Effects)

Olmesartan medoxomil has been evaluated for safety in more than 3,825 patients/subjects, including more than 3,275 patients treated for hypertension in controlled trials. This experience included about 900 patients treated for at least 6 months and more than 525 for at least 1 year.
Treatment with olmesartan medoxomil 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.
The overall frequency of adverse events was not dose-related. Analysis of gender, age and race groups demonstrated no differences between olmesartan medoxomil and placebo-treated patients. The rate of withdrawals due to adverse events in all trials of hypertensive patients was 2.4% (i.e. 79/3,278) of patients treated with olmesartan medoxomil and 2.7% (i.e. 32/1,179) of control patients. In placebo-controlled trials, the only adverse event that occurred in more than 1% of patients treated with olmesartan medoxomil and at a higher incidence versus placebo was dizziness (2.5% versus 0.9%).
Adverse events reported in placebo-controlled monotherapy studies with a greater than 1% incidence are shown in Table 2.
Other adverse events of potential clinical relevance reported in the clinical trials are listed below. Adverse events reported across all clinical trials with olmesartan medoxomil (including trials with active as well as placebo control), irrespective of causality or incidence relative to placebo, included those 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).

Cardiovascular.

Uncommon: Tachycardia; Rare: Hypotension.

Central nervous system.

Uncommon: Vertigo.

Gastro-intestinal.

Common: Abdominal pain.

Myo/endo/pericardial and valve disorders.

Uncommon: Angina pectoris.

Musculoskeletal.

Uncommon: Myalgia.

Skin and appendages.

Uncommon: Rash.

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: Blood urea increased; Uncommon: Hypercholesterolaemia, hyperlipaemia; Rare: Hyperkalaemia.

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.

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

Gastrointestinal disorders.

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

Immune system disorders.

Anaphylactic reactions.

Investigations.

Hepatic enzymes increased, increased blood creatinine levels.

Hepatobiliary disorders.

Autoimmune hepatitis.

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, exanthema, allergic dermatitis.

Renal and urinary disorders.

Acute renal failure.

Vascular disorders.

Flushing.
ROADMAP/ORIENT. Two post marketing 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%).
Adverse events reported with olmesartan medoxomil monotherapy in the elderly with a greater than 1% incidence are shown in Table 3.
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.

Paediatric use.

No clinically relevant differences were identified between the adverse experience profile for paediatric patients aged 1 to 18 years and that previously reported for adult patients.
In placebo-controlled period, the only adverse event that occurred in more than 2% of patients treated with olmesartan medoxomil and at a higher incidence versus placebo was pseudohyperkalaemia (Cohort A: 1.1% versus 2.3%; Cohort C: 0% versus 7.1%). (See Table 4.)

Reporting suspected adverse effects.

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

4.9 Overdose

Only limited information is available regarding overdosage in humans. The most likely effect of overdosage is hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurs. In the event of overdosage, the patient should be carefully monitored and treatment should be symptomatic and supportive.
No information is available regarding the dialysability of olmesartan.
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.

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.
Once daily dosing with olmesartan medoxomil provides an effective and smooth reduction in blood pressure over the 24-hour dose interval. Once daily dosing produced similar decreases in blood pressure as twice daily dosing at the same total daily dose.
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 hydrochlorothiazide, the reduction in blood pressure is additive and coadministration is well tolerated.
The effect of olmesartan on mortality and morbidity is not yet known.

Clinical trials.

The antihypertensive effects of olmesartan medoxomil 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 medoxomil tended to increase with time and to increase with dose up to the 40 mg dose (see Table 5). 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).
Data above from seven placebo-controlled studies also confirm that 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%.
In a 4-month, open-label, extension study, all patients received 20 mg olmesartan medoxomil, which was titrated to 40 mg as required. If sitting diastolic blood pressure (sDBP) remained uncontrolled, hydrochlorothiazide 12.5-25 mg was then added. By Week 16, the majority of patients remained on 20 mg olmesartan medoxomil therapy (56.8%). Mean blood pressures generally continued to decrease in each treatment group from Week 4 to Week 16, as expected from the study design, which allowed treatment to be individually tailored to achieve blood pressure control (see Table 6).
The blood pressure lowering effect of olmesartan medoxomil, with and without hydrochlorothiazide, was maintained in patients treated for up to 1-year. There was no evidence of tachyphylaxis during long-term treatment with olmesartan medoxomil or rebound effect following abrupt withdrawal of olmesartan medoxomil after 1-year of treatment.
The antihypertensive effect of olmesartan medoxomil 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 medoxomil had an additional blood pressure lowering effect when added to hydrochlorothiazide.

Use in elderly.

The antihypertensive effects of olmesartan medoxomil were investigated in a randomised, double-blind, parallel group with losartan in elderly patients (65 years or older; olmesartan 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 medoxomil and if required, titrated to 40 mg after 4 weeks. If after 4 weeks on 40 mg olmesartan medoxomil target blood pressure was not achieved then hydrochlorothiazide was added. The results obtained for those on olmesartan medoxomil were similar to those in the losartan group.

Paediatric use.

The antihypertensive effect of olmesartan medoxomil once daily was evaluated in a randomised, double-blind study involving 361 hypertensive paediatric patients (1-5 years n = 59, 6-16 years n = 302). Renal and urinary disorders with/ without obesity were the most common underlying causes of hypertension in these patients enrolled in this study. See Table 7 for a summary of the baseline demographic characteristics of study participants.
The study included three periods: a 3 week double-blind, randomised, dose-response period for patients aged 6-16 years or, for patients aged 1-5 years, an open-label dose period; up to 2 week double-blind, randomised, placebo-controlled withdrawal period; and a 46 week open-label safety and efficacy period. The primary endpoints were the dose response in systolic blood pressure or in diastolic blood pressure for subjects 6 to 16 years of age at the end of this period. This study was not a clinical outcome study.
In the dose-response period, patients aged 6-16 years were randomised to receive either low or high dose of olmesartan medoxomil based on their weight. Patients weighing 20 to < 35 kg received 2.5 mg (low) or 20 mg (high); those weighing ≥ 35 kg, received 5 mg (low) or 40 mg (high). Patients aged 1-5 years who weighed ≥ 5 kg received a dose of 0.3 mg/kg.
At the end of this period, olmesartan medoxomil reduced both systolic and diastolic blood pressure in a dose-dependent manner. In patients aged 6-16 years the low and high doses of olmesartan medoxomil significantly reduced systolic blood pressure by 6.63 and 11.87 mmHg from the baseline, respectively. Patients aged 1-5 years of age had a clinically, and a statistically significant change from baseline reduction in systolic blood pressure of 13.31 mmHg.
In the placebo-controlled withdrawal period, patients who continued on olmesartan medoxomil had smaller increases in their systolic and diastolic blood pressure compared to patients switched to placebo. The difference between placebo and olmesartan medoxomil was statistically significant in patients aged 6-16 years, but was not statistically significant in patients aged 1-5 years. See Table 8 for a summary of the mean change in SeSBP and SeDBP for both groups during the open-label (1-5 year age group)/double-blind (6-16 year age group) and placebo-controlled withdrawal periods of the study.
At the end of the open-label efficacy and safety period, compared to baseline, the mean systolic and diastolic blood pressure were reduced at all visits for all patient age groups. However data in children 1-5 years are limited due to small numbers of patients enrolled in the clinical studies. Overall the clinical trials were unable to demonstrate that olmesartan medoxomil was significantly better than placebo in reducing blood pressure in children 1-5 years of age.

5.2 Pharmacokinetic Properties

Absorption.

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 has minimal effect on the bioavailability of olmesartan and therefore olmesartan medoxomil may be administered with or without food.

Distribution.

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 coadministered 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.

Metabolism.

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

Excretion.

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.

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.

Paediatric.

The single-dose pharmacokinetics of olmesartan was investigated in an open-label study in paediatric hypertensive patients aged 1 to 16 years. See Table 9 for a summary of PK parameters. The clearance of olmesartan in paediatric patients was similar to that in adult patients when adjusted by body weight. There are, however, very limited data on the pharmacokinetics of olmesartan in children less than 6 years (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).

Gender.

Minor differences were observed in the pharmacokinetics of olmesartan in women compared with men. AUC and Cmax were 10-15% higher in women than in men.

Renal impairment.

In patients with renal insufficiency, serum concentrations of olmesartan were elevated compared with subjects with normal renal function. After repeated dosing, the AUC was approximately tripled in patients with severe renal impairment (creatinine clearance < 30 mL/min).
The pharmacokinetics of olmesartan 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).

5.3 Preclinical Safety Data

Genotoxicity.

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. 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.

Carcinogenicity.

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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, microcrystalline cellulose, hyprolose, hypromellose, magnesium stearate, 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

20 mg tablet.

Aluminium/Aluminium blister pack of 30 tablets. AUST R 221052.

40 mg tablet.

Aluminium/Aluminium blister pack of 30 tablets. AUST R 221063.
Not all strengths may be available in Australia.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

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.
Olmesartan medoxomil, a prodrug, is hydrolysed to olmesartan during absorption from the gastrointestinal tract. Olmesartan is a selective AT1 subtype angiotensin II receptor antagonist.

Chemical structure.


Olmesartan medoxomil is described chemically as 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.
Its empirical formula is C29H30N6O6.

CAS number.

144689-63-4.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes