Consumer medicine information

Olmetec

Olmesartan medoxomil

BRAND INFORMATION

Brand name

Olmetec

Active ingredient

Olmesartan medoxomil

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Olmetec.

What is in this leaflet

This leaflet answers some common questions about OLMETEC.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking OLMETEC against the benefits he/she expects it will have for you.

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

Keep this leaflet with your OLMETEC tablets or suspension. You may need to read it again.

What OLMETEC is used for

OLMETEC is used to treat high blood pressure which is sometimes called 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 hypertension (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 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.

How OLMETEC works

OLMETEC 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. OLMETEC blocks the action of angiotensin-II and therefore relaxes your blood vessels. This helps lower your blood pressure.

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

OLMETEC is not addictive.

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

Before you take OLMETEC

When you must not take it

Do not take OLMETEC 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
  • you have an allergy to OLMETEC or any of the ingredients listed at the end of this leaflet
    Symptoms of an allergic reaction to OLMETEC may include skin rash, itchiness, shortness of breath, swelling of the face, lips or tongue, muscle pain or tenderness or joint pain.

Do not take OLMETEC if you are pregnant or breastfeeding. OLMETEC 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 OLMETEC should be discontinued as soon as possible.

Do not take OLMETEC after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If you are not sure whether you should start taking OLMETEC, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to:

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

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

  • kidney problems
  • liver problems
  • heart problems
  • excessive vomiting or diarrhoea recently
  • high levels of potassium in your blood
  • problems with your adrenal glands (small glands above the kidneys).

You must also tell your doctor if you:

  • are following a very low salt diet
  • you are or intend to become pregnant or plan to breastfeed.
  • you are taking potassium supplements, potassium-sparing agents, potassium-containing salt substitutes or other medicines that may increase serum potassium (e.g., trimethoprim-containing products)

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

Taking other medicines

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

Some medicines and OLMETEC may interfere with each other. These include:

  • other medicines used to treat high blood pressure
  • other 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 or potassium-containing salt substitutes
  • other medicines that may increase serum potassium (e.g., 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.

These medicines may be affected by OLMETEC, or may affect how well it works. You may need different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

In general, OLMETEC has been shown not to interfere with other medicines. However, it is important to tell your doctor and pharmacist about any medicines you are taking or plan to take.

Use in children

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

How to take OLMETEC

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

If you have been prescribed OLMETEC suspension, your pharmacist will prepare this for you.

Your doctor or pharmacist will tell you which OLMETEC tablet or how much OLMETEC suspension you will need to take each day. This depends on your condition and whether or not you are taking any other medicines.

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

How much to take

Tablets:
For most adult patients, the usual starting dose of OLMETEC is 20 mg once a day. The dose may need to be increased to OLMETEC 40 mg once a day if necessary.

Suspension:
Follow the instructions given by your doctor or pharmacist.

Do not give OLMETEC suspension to children under 1 year of age.

For children 6-18 years (weighing 35kg or more):
One OLMETEC 20mg tablet once daily, or 10 mL of the 2 mg/mL suspension.

For children 6-18 years (weighing less than 35 kg):
5 mL of the 2 mg/mL suspension.

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

How to take it

Tablets:
Swallow OLMETEC whole with a full glass of water.
Do not chew the tablets.

Suspension:
Shake the bottle and then using either a medicine measure or a dosing syringe give the required volume to your child.

When to take it

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

How long to take it

OLMETEC helps control your condition, but does not cure it. Therefore you must take OLMETEC every day. Continue taking your medicine for as long as your doctor tells you.

If you forget to take it

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

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

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

If you take too much (overdose)

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

Keep telephone numbers for these places handy.

If you take too much OLMETEC, you may feel light-headed, dizzy or you may faint. You may also have a fast heartbeat.

While you are using OLMETEC

Things you must do

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

Make sure you drink enough water during exercise and hot weather when you are taking OLMETEC, especially if you sweat a lot. If you do not drink enough water while taking OLMETEC, 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 have excess vomiting and/or diarrhoea while taking OLMETEC, tell your doctor. 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 OLMETEC, or when your dose is increased, tell your doctor immediately.

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

If you become pregnant while taking OLMETEC, tell your doctor immediately.

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

Have your blood pressure checked when your doctor says, to make sure OLMETEC is working.

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.

Things you must not do

Do not give OLMETEC to anyone else, even if they have the same condition as you.

Do not take OLMETEC to treat any other complaints unless your doctor or pharmacist tells you to.

Do not stop taking OLMETEC, or lower 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.

Be careful driving or operating machinery until you know how OLMETEC affects you. As with other medicines in this class, OLMETEC may cause dizziness, light-headedness or tiredness in some people. Make sure you know how you react to OLMETEC before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed. If this occurs do not drive. If you drink alcohol, dizziness or light-headedness may be worse.

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 has to 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, cereals and fish.
    Also eat less fat and sugar (especially saturated fat) which includes sausages, fatty meats, full cream dairy products, biscuits, cakes, pastries, chocolates, chips and coconut. Monounsaturated and polyunsaturated fats from olive oil, canola oil, avocado and nuts are beneficial in small quantities.
  • 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, maintained over the long term, helps to reduce blood pressure and helps get the heart fitter. Regular exercise also improves your blood cholesterol levels, helps reduce your weight and stress levels, and improves your sleep, mood and ability to concentrate. However, it is important not to overdo it. Walking is good exercise, but try to find a route that is reasonably flat. 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. There are enormous benefits to be gained from giving up smoking. There are many professionals, organisations and strategies to help you quit. Ask your doctor or pharmacist for further information and advice.

Side effects

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

OLMETEC helps most people with high blood pressure, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

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

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

Following is a list of possible side effects. Do not be alarmed by this list. You may not experience any of them.

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

  • feeling light-headed, dizzy or faint
  • cough
  • headache
  • feeling sick (nausea) or vomiting
  • stomach pain
  • diarrhoea
  • an uncomfortable feeling in the stomach
  • unusual tiredness or weakness, fatigue
  • 'flu-like' symptoms
  • runny or blocked nose, or sneezing
  • bronchitis
  • sore throat and discomfort when swallowing (pharyngitis)
  • swelling of the hands, feet or ankles
  • back pain
  • urinary tract infection.

These are common side effects. They are generally mild.

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

  • skin rash or itchiness
  • aching, tender or weak muscles not caused by exercise
  • painful joints
  • fast heart beat
  • 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.
  • symptoms that may indicate high potassium levels in the blood, such as nausea, diarrhoea, muscle weakness, change in heart rhythm.

These may be serious side effects. You may need medical attention. Serious side effects are rare.

If any of the following happen, stop taking OLMETEC and either tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing
  • chest pain.

These are very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are very rare.

Other side effects not listed above may occur in some patients. Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

After using OLMETEC

Storage

Tablets:
Keep your tablets in the box until it is time to take them. If you take the tablets out of the box they will not keep well.

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

Suspension:
Keep the suspension in the bottle until it is time to take it.

Keep the suspension in the refrigerator where the temperature stays between 2 to 8°C.

Do not store OLMETEC or any other medicine in the bathroom or near a sink.

Do not leave it on a windowsill or in the car on hot days. Heat and dampness can destroy some medicines.

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

Disposal

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

Product description

What it looks like

OLMETEC tablets come in three strengths and each has a different appearance:

  • OLMETEC 10 mg - White, circular film-coated tablet with C13 embossed on one side. Blister pack of 30. Not currently available in Australia
  • OLMETEC 20 mg - White, circular film coated tablet with characteristic odour approximately 8.5 mm in diameter, with C14 embossed on one side
  • OLMETEC 40 mg - White, oval film coated tablet with characteristic odour approximately 15 x 7 mm in size, with C15 embossed on one side.

A box of OLMETEC contains 10 or 30 tablets.

OLMETEC suspension is a pale reddish-white suspension.

Ingredients

Active ingredients:

  • OLMETEC 10 mg tablet - 10 mg olmesartan medoxomil per tablet
  • OLMETEC 20 mg tablet - 20 mg olmesartan medoxomil per tablet
  • OLMETEC 40 mg tablet - 40 mg olmesartan medoxomil per tablet.
  • OLMETEC suspension - 2mg/mL olmesartan medoxomil

Other ingredients:

OLMETEC tablets:

  • microcrystalline cellulose
  • low-substituted hydroxypropylcellulose
  • lactose
  • hydroxypropylcellulose
  • magnesium stearate
  • Opadry OY-S-38956 that contains titanium dioxide, talc and hydroxypropylmethylcellulose.

OLMETEC tablets do not contain sucrose, tartrazine or any other azo dyes.

OLMETEC suspension:

  • purified water
  • citric acid
  • flavouring
  • glycerin
  • methylparaben
  • potassium sorbate
  • sodium phosphate
  • sorbitol
  • sucrose
  • calcium sulfate
  • carrageenan
  • dimethicone antifoam emulsion
  • microcrystalline cellulose
  • sodium carboxymethylcellulose
  • sodium phosphate monobasic
  • trisodium phosphate
  • xanthan gum

Supplier

OLMETEC is supplied in Australia by:

Organon Pharma Pty Ltd
Building A, 26 Talavera Road,
Macquarie Park NSW 2113

Australian Registration Numbers

  • OLMETEC 10 mg tablets - AUST R 102134
  • OLMETEC 20 mg tablets - AUST R 102138
  • OLMETEC 40 mg tablets - AUST R 102139

This leaflet was prepared August 2022

® Registered trademark of Daiichi Sankyo Company Ltd

Published by MIMS October 2022

BRAND INFORMATION

Brand name

Olmetec

Active ingredient

Olmesartan medoxomil

Schedule

S4

 

1 Name of Medicine

Olmesartan medoxomil.

2 Qualitative and Quantitative Composition

Each film-coated tablet contains 10 mg olmesartan medoxomil.
Each film-coated tablet contains 20 mg olmesartan medoxomil.
Each film-coated tablet contains 40 mg olmesartan medoxomil.
Olmesartan medoxomil is a white to light yellowish-white powder or crystalline powder. It is practically insoluble in water and sparingly soluble in methanol. Olmetec is available for oral use as film-coated tablets containing 10 mg, 20 mg, or 40 mg olmesartan medoxomil.

List of excipients with known effect.

Lactose (as monohydrate).
For full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

10 mg tablet.

White, circular film-coated tablet with C13 embossed on one side.

20 mg tablet.

White, circular film-coated tablet with C14 embossed on one side.

40 mg tablet.

White, oval film-coated tablet with C15 embossed on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Olmetec is indicated for the treatment of hypertension.

4.2 Dose and Method of Administration

Adults.

Dosage must be individualised. The optimal recommended starting dose of Olmetec 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 Olmetec may be increased to a maximum of 40 mg daily.
Olmetec may be administered with or without food. In order to assist compliance, it is recommended that Olmetec 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. Olmetec 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 insufficiency.

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 Olmetec 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). 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, Olmetec 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).
If a patient becomes volume depleted whilst taking Olmetec, blood pressure and renal function should be closely monitored until the situation resolves.

Hepatic insufficiency.

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 Olmetec 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 Olmetec is based on age and/or weight (see Dosing recommendations in Table 1). If after 2 weeks of therapy further reduction in blood pressure is required, the dose of Olmetec may be increased to a maximum of either 20 mg or 40 mg (see Dosing recommendations 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 insufficiency).
For children who cannot swallow tablets, the equivalent dose may be given as an extemporaneous suspension [see Section 4.2 Dose and Method of Administration, Special populations, Preparation of suspension by compounding pharmacist (for 200 mL of a 2 mg/mL suspension)].
If 10 mg tablets are not available, the extemporaneous suspension may be used.

Preparation of suspension by compounding pharmacist (for 200 mL of a 2 mg/mL suspension).

The suspension is prepared in an amber polyethylene terephthalate (PET) bottle with a child resistant closure. The amber PET bottle should be of a suitable size, e.g. 240 mL*.
* The stability of the suspensions in larger bottles has not been established.
Add 50 mL of purified water to an amber PET bottle containing twenty Olmetec 20 mg tablets and allow it to stand for a minimum of 5 minutes to allow complete disintegration. Shake the container for at least 1 minute and allow the suspension to stand for at least 1 minute. Repeat 1-minute shaking and 1 minute standing steps for four additional times. Add 100 mL of Ora-Sweet* and 50 mL of Ora-Plus* to the suspension and shake well for at least 1 minute.
*Ora-Sweet and Ora-Plus are registered trademarks of Paddock Laboratories, Inc.
Ora-Sweet contains citric acid, flavouring, glycerine, methylparaben, potassium sorbate, sodium phosphate, sorbitol, sucrose, and purified water. Ora-Plus contains calcium sulphate, carrageenan, citric acid, dimethicone antifoam emulsion, methylparaben, microcrystalline cellulose, sodium carboxymethylcellulose, potassium sorbate, sodium phosphate monobasic, trisodium phosphate, xanthan gum, and purified water.
The suspension cannot be prepared using water only and the tablets should not be ground before use. Only 20 mg Olmetec tablets may be used in preparing the suspension. For handling and storage instruction, see Section 6.4 Special Precautions for Storage.

4.3 Contraindications

Olmetec 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).
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.

Hyperkalaemia.

As with other angiotensin receptor antagonists and ACE inhibitors, hyperkalaemia may occur during treatment with Olmetec, especially in the presence of renal impairment and/or heart failure. This is because Olmetec contains olmesartan medoxomil, a drug which inhibits the renin-angiotensin system (RAS) and drugs that inhibit the RAS can cause hyperkalaemia. Concomitant use of Olmetec 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 Olmetec 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 Olmetec is not recommended in such patients.

Ethnic differences.

As with all other angiotensin receptor antagonists, the blood pressure lowering effect of Olmetec 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 Olmetec 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. Olmetec should be immediately discontinued in patients who develop angioedema, and Olmetec 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 hepatic impairment.

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

Use in renal impairment.

When olmesartan medoxomil is used in patients with impaired renal function, periodic monitoring of serum potassium and creatinine levels is recommended. Use of Olmetec 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 Olmetec 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 the elderly.

Of the total number of hypertensive patients receiving Olmetec 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 Olmetec.

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 Olmetec 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 Olmetec and other agents that affect the RAS.
Do not co-administer aliskiren with Olmetec in patients with diabetes (see Section 4.3 Contraindications). Avoid use of aliskiren with Olmetec 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 Olmetec.

Drugs that are affected by Olmetec.

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 Olmetec 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 Olmetec 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, Olmetec 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 Olmetec 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, Olmetec 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 Olmetec 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 birthweight 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 Olmetec tablets 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)

Olmetec 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 Olmetec 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.

Gastrointestinal.

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.

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

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.

Metabolism and nutrition disorders.

Hyperkalaemia.

Musculoskeletal and connective tissue disorders.

Rhabdomyolysis, myalgia, muscle spasm.

Nervous system 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.

Olmetec 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%).
Clinical adverse effects (all causalities) occurring in ≥ 2% of patients aged 6-16 years (Cohorts A and B) and aged 1-5 years (Cohort C) versus placebo. (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 http://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 Olmetec 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 Olmetec tended to increase with time and to increase with dose up to the 40 mg dose (see Table 5). Olmetec 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 Olmetec 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 Olmetec, 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 Olmetec or rebound effect following abrupt withdrawal of olmesartan medoxomil after 1-year of treatment.
The antihypertensive effect of Olmetec 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. Olmetec had an additional blood pressure lowering effect when added to hydrochlorothiazide.

Use in elderly.

The antihypertensive effects of Olmetec 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 Olmetec and if required, titrated to 40 mg after 4 weeks. If after 4 weeks on 40 mg Olmetec target blood pressure was not achieved then hydrochlorothiazide was added. The results obtained for those on Olmetec were similar to those in the losartan group.

Paediatric use.

The antihypertensive effect of Olmetec 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 Olmetec 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, Olmetec reduced both systolic and diastolic blood pressure in a dose-dependent manner. In patients aged 6-16 years the low and high doses of Olmetec 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 Olmetec had smaller increases in their systolic and diastolic blood pressure compared to patients switched to placebo. The difference between placebo and Olmetec 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 Olmetec 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 bodyweight. 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

Olmetec tablets also contain the following inactive ingredients: microcrystalline cellulose, hyprolose, lactose monohydrate, magnesium stearate, and Opadry OY-S-38956 that contains titanium dioxide, purified talc, and hypromellose.
Olmetec extemporaneous suspension contains additional inactive ingredients: purified water, Ora-Sweet (syrup vehicle) and Ora-Plus (suspending vehicle).

6.2 Incompatibilities

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

6.3 Shelf Life

The expiry date can be found on the packaging. In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG).

6.4 Special Precautions for Storage

Tablets.

Store below 25°C.

Extemporaneous suspension.

Store between 2-8°C (Refrigerate; Do not freeze).
The suspension should be refrigerated at 2-8°C (Do not freeze) and can be stored for up to 4 weeks.
Shake the suspension well before each use and return promptly to the refrigerator. An appropriate measuring device (syringe or measuring cup) should be used for the volume to be administered.

6.5 Nature and Contents of Container

10 mg tablet.

Blister pack of 30. Not currently available in Australia.

20 mg tablet.

Blister pack of 30.

40 mg tablet.

Blister pack of 30.

6.6 Special Precautions for Disposal

Any unused suspension must be discarded after 28 days from the date of preparation.
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Olmetec (olmesartan medoxomil), a prodrug, is hydrolyzed to olmesartan during absorption from the gastrointestinal tract. Olmesartan is a selective AT1 subtype angiotensin II receptor antagonist.
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. Its molecular weight is 558.59.

Chemical structure.

Its structural formula is:

CAS number.

144689-63-4.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (S4).

Summary Table of Changes