Consumer medicine information

Sevikar HCT

Olmesartan medoxomil; Amlodipine; Hydrochlorothiazide

BRAND INFORMATION

Brand name

Sevikar HCT

Active ingredient

Olmesartan medoxomil; Amlodipine; Hydrochlorothiazide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Sevikar HCT.

SUMMARY CMI

SEVIKAR HCT®

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 SEVIKAR HCT?

SEVIKAR HCT contains the active ingredients olmesartan medoxomil, amlodipine (as besilate) and hydrochlorothiazide. SEVIKAR HCT is used to treat high blood pressure.

For more information, see Section 1. Why am I using SEVIKAR HCT? in the full CMI.

2. What should I know before I use SEVIKAR HCT?

Do not use if you have ever had an allergic reaction to SEVIKAR HCT 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 SEVIKAR HCT? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with SEVIKAR HCT 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 SEVIKAR HCT?

  • Follow all directions given to you by your doctor or pharmacist carefully. Your doctor or pharmacist will tell you which SEVIKAR HCT tablet you will need to take each day.
  • Swallow SEVIKAR HCT whole with a full glass of water.
  • Take your tablets at the same time each day.

More instructions can be found in Section 4. How do I use SEVIKAR HCT? in the full CMI.

5. What should I know while using SEVIKAR HCT?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using SEVIKAR HCT.
  • If you become pregnant while taking SEVIKAR HCT, tell your doctor immediately.
  • Go to your doctor regularly for a check-up.
Things you should not do
  • Do not stop using this medicine suddenly, or lower the dosage, or take it to treat any other complaints, unless your doctor tells you to.
  • Do not give SEVIKAR HCT to anyone else, even if they have the same condition as you.
Driving or using machines
  • Be careful driving or operating machinery until you know how SEVIKAR HCT affects you.
  • SEVIKAR HCT may cause dizziness, light-headedness or tiredness in some people.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
  • Your doctor may advise you to limit your alcohol intake.
Looking after your medicine
  • Keep your tablets in the box until it is time to take them.
  • Keep your tablets in a cool dry place where the temperature stays below 25°C.

For more information, see Section 5. What should I know while using SEVIKAR HCT? in the full CMI.

6. Are there any side effects?

Common side effects may include dizziness, light-headedness, cough, headache, nausea, vomiting, stomach pain, diarrhoea, tiredness, 'flu-like' symptoms, runny/ blocked nose, sore throat, difficulty swallowing, back pain, blurred vision, sleep or mood disturbances, skin rash/ flushing, swelling of the face or body and urinary infection. Serious side effects may include skin rash, yellowing of the eyes, dry mouth, swelling of the face, lips tongue or throat causing difficulty swallowing or breathing, muscle pain or weakness and chest pain.

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

SEVIKAR HCT®

Active ingredient(s): olmesartan medoxomil, amlodipine (as besilate) and hydrochlorothiazide

Consumer Medicine Information (CMI)

This leaflet provides important information about using SEVIKAR HCT. 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 SEVIKAR HCT.

Where to find information in this leaflet:

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

1. Why am I using SEVIKAR HCT?

SEVIKAR HCT contains the active ingredients olmesartan medoxomil, amlodipine (as besilate) and hydrochlorothiazide.

SEVIKAR HCT 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 SEVIKAR HCT works

SEVIKAR HCT contains olmesartan medoxomil, which 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. SEVIKAR HCT blocks the action of angiotensin-II and therefore relaxes your blood vessels. This helps lower your blood pressure.

SEVIKAR HCT also contains amlodipine besilate, a calcium channel blocker. This reduces the movement of calcium into the cells of the heart and blood vessels. This also helps to lower blood pressure as it relaxes the blood vessels and increases the supply of blood and oxygen to the heart.

SEVIKAR HCT also contains hydrochlorothiazide, a diuretic which reduces the amount of fluid in the body. This also helps to lower blood pressure.

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

SEVIKAR HCT is not addictive.

2. What should I know before I use SEVIKAR HCT?

Warnings

Do not use SEVIKAR HCT if:

  • you are allergic to
    - olmesartan,
    - amlodipine besilate, medicines belonging to a group of chemicals called dihydropyridines used to treat blood pressure and other heart problems,
    - hydrochlorothiazide, a diuretic,
    - or any of the ingredients listed at the end of this leaflet or other sulfonamide-derived drugs.
    Symptoms of an allergic reaction to SEVIKAR HCT may include skin rash, itchiness, shortness of breath, swelling of the face, lips or tongue, muscle pain or tenderness or joint pain.
  • you have serious problems with your kidneys
  • you have serious problems with your liver
  • you have had recent serious heart problems
  • you have low potassium or sodium levels in the blood
  • you have high calcium or uric acid levels in the blood.
  • you have diabetes and are taking a medicine called aliskiren to reduce blood pressure.
  • you are pregnant or breast-feeding
  • the expiry date on the pack has passed or if the packaging is torn or shows signs of tampering

Tell your doctor if:

  • you have allergies to any other medicines or any other substances, such as foods, preservatives or dyes.
  • you have or have had any other medical conditions, especially the following:
    - kidney problems
    - liver problems
    - heart problems
    - diabetes
    - excessive vomiting or diarrhoea recently
    - high levels of potassium in your blood
    - problems with your adrenal glands (small glands above the kidneys)
    - systemic lupus erythematosus, a disease affecting the skin, joints and kidneys
    - gout
  • 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)
  • you have skin cancer or if you develop a new skin lesion during treatment. Treatment with hydrochlorothiazide, particularly long-term use with high doses, may increase the risk of some types of skin and lip cancer (non-melanoma skin cancer). Discuss with your doctor how to protect your skin from sun exposure, and avoid artificial tanning.

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 SEVIKAR HCT if you are pregnant or breastfeeding.

SEVIKAR HCT 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 SEVIKAR HCT should be discontinued as soon as possible.

Use in children

The safety and effectiveness of SEVIKAR HCT in children 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.

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

  • other medicines to treat high blood pressure
  • digitalis glycosides, medicines used to treat heart problems
  • medicines used to treat angina, such as diltiazem
  • antiarrhythmics which treat irregular heartbeats
  • non-steroid anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors, medicines used to relieve pain, swelling and other symptoms of inflammation including arthritis
  • antacids, medicines used to treat heartburn and indigestion
  • simvastatin, a medicine used to help lower cholesterol levels
  • potassium supplements or potassium-containing salt substitutes
  • other medicines that may increase serum potassium (e.g., trimethoprim-containing products)
  • calcium-containing supplements
  • lithium or antidepressant medicines
  • some antibiotics, such as erythromycin or rifampicin
  • some antifungals, such as ketoconazole or itraconazole
  • anti-proteases, medicines used to treat HIV infection such as ritonavir
  • other diuretics, also known as fluid or water tablets
  • insulin and tablets used to treat diabetes
  • medicines which lower your immune system, such as corticosteroids, ciclosporin, tacrolimus and cytotoxic medicines used to treat cancer (including radiation therapy)
  • alcohol
  • laxatives, medicines used to treat constipation
  • medicines used to relieve pain
  • medicines used to treat epilepsy
  • muscle relaxants
  • cholestyramine and colestipol, used to treat high cholesterol
  • St John's Wort
  • grapefruit or grapefruit juice
  • medicines used to treat gout, such as allopurinol
  • medicines used to treat Parkinson's Disease, such as amantadine
  • any medicines that contain aliskiren
  • any medicines that contain colesevelam.

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

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect SEVIKAR HCT.

4. How do I use SEVIKAR HCT?

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

Your doctor or pharmacist will tell you which SEVIKAR HCT tablet 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, ask your doctor or pharmacist for help.

How much to take

  • The dose of SEVIKAR HCT is one tablet to be taken once a day.

How to take SEVIKAR HCT

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

When to take SEVIKAR HCT

  • Take SEVIKAR HCT at about the same time each day, with or without food.

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

How long to take SEVIKAR HCT

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

If you forget to take SEVIKAR HCT

SEVIKAR HCT should be used regularly at the same time each day. 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 take too much SEVIKAR HCT (overdose)

If you think that you have used too much SEVIKAR, 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.

Keep telephone numbers for these places handy.

If you take too much SEVIKAR HCT, you may feel light-headed, dizzy, or you may faint. You may also have nausea, drowsiness, muscle spasm and a fast heartbeat.

Excess fluid may accumulate in your lungs (pulmonary oedema) causing shortness of breath that may develop up to 24-48 hours after intake.

5. What should I know while using SEVIKAR HCT?

Things you should do

  • If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are taking SEVIKAR HCT.
  • Make sure you drink enough water during exercise and hot weather when you are taking SEVIKAR HCT, especially if you sweat a lot.
    If you do not drink enough water while taking SEVIKAR HCT, you may feel 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 SEVIKAR HCT.
    Your blood pressure may suddenly drop.
  • If you are about to have any blood tests tell your doctor that you are taking SEVIKAR HCT.
    SEVIKAR HCT may interfere with the results of some tests.
  • Tell your doctor if photosensitivity reaction occurs during your treatment.
  • Have your blood pressure checked when your doctor says, to make sure SEVIKAR HCT 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.

Call your doctor straight away if:

  • You have excess vomiting and/or diarrhoea while taking SEVIKAR HCT.
    You may lose too much water and salt and your blood pressure may drop too much. You may also have dry mouth, weakness, drowsiness, confusion, muscle pain or cramps and seizures. Tell your doctor immediately if you experience any of these symptoms.
  • You feel light-headed or dizzy after taking your first dose of SEVIKAR HCT, or when your dose is increased.
  • You become pregnant while taking SEVIKAR HCT.
  • You experience acute onset of decreased visual acuity or ocular pain. These could be symptoms of fluid accumulation in the vascular layer of the eye (choroidal effusion) or an increase of pressure in your eye and can happen within hours to weeks of taking SEVIKAR HCT. This can lead to permanent vision loss, if not treated.
  • you experience any fever, severe shortness of breath, breathing faster than normal, difficulty breathing, slightly blue fingertips and lips after taking SEVIKAR HCT. Stop the medication and seek medical attention immediately.

Remind any doctor, dentist or pharmacist you visit that you are using SEVIKAR HCT.

Things you should not do

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

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 (preferably wholegrain), cereals and fish. Also eat less sugar and fat (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.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how SEVIKAR HCT affects you.

As with other medicines in this class, SEVIKAR HCT may cause dizziness, light-headedness or tiredness in some people. Make sure you know how you react to SEVIKAR HCT 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.

Drinking alcohol

Tell your doctor if you drink alcohol.

Your doctor may advise you to limit your alcohol intake.

If you drink alcohol, dizziness or light-headedness may be worse.

Looking after your medicine

  • 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.

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

  • in the bathroom or near a sink, or
  • in the car or on window sills.
  • Heat and dampness can destroy some medicines.

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

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If your doctor tells you to stop taking SEVIKAR HCT or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

SEVIKAR HCT helps most people with high blood pressure, but it may have unwanted side effects in a few people. If you are over 65 years of age you may have an increased chance of getting side effects.

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
Head and nervous system-related:
  • feeling light-headed, dizzy or faint
  • headache
Eye-related:
  • blurred vision
Gastrointestinal-related:
  • diarrhoea
  • feeling sick (nausea) or vomiting
  • stomach pain or discomfort
General conditions:
  • swelling of the face, hands, feet or ankles
  • sore throat and discomfort when swallowing (pharyngitis)
  • back pain
  • unusual tiredness or weakness, fatigue
  • flushing
  • 'flu-like' symptoms
Liver and biliary-related:
  • jaundice
Psychiatric-related:
  • sleep disturbance
  • depression
Respiratory-related:
  • bronchitis
  • Cough
  • Runny or blocked nose, or sneezing
Skin-related:
  • skin rashes or eczema
Urinary system-related:
  • urinary tract infection
These are common side effects and are generally mild. Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • skin rash or itchiness
  • aching, tender or weak muscles not caused by exercise
  • painful joints
  • fast heartbeat
  • shortness of breath or tightness in the chest
  • swelling of the face, 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.
  • symptoms that may indicate water and salt imbalance such as dry mouth, weakness, drowsiness, confusion, muscle pain or cramps and seizures.
  • Hydrochlorothiazide increases sensitivity of the skin to the sun and may increase the risk of some types of skin and lip cancer (non-melanoma skin cancer).
  • Decrease in vision or pain in your eyes due to high pressure (possible signs of fluid accumulation in the vascular layer of the eye (choroidal effusion) or acute angle-closure glaucoma).
Call your doctor as soon as possible, if you notice any of these serious side effects. You may need medical attention.
  • fever, severe shortness of breath, breathing faster than normal, difficulty breathing, slightly blue fingertips and lips.
  • swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing
  • chest pain
Stop taking SEVIKAR HCT and call your doctor immediately, or go straight to the Emergency Department at your nearest hospital if you notice any of these very serious side effects.

Serious side effects are rare.

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

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

Reporting side effects

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

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

7. Product details

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

What SEVIKAR HCT contains

Active ingredient
(main ingredient)
  • SEVIKAR HCT 20/5/12.5 mg contains 20 mg olmesartan medoxomil, 5 mg amlodipine as besilate and 12.5 mg hydrochlorothiazide.
  • SEVIKAR HCT 40/5/12.5 mg contains 40 mg of olmesartan medoxomil, 5 mg amlodipine as besilate and 12.5 mg hydrochlorothiazide.
  • SEVIKAR HCT 40/5/25 mg contains 40 mg of olmesartan medoxomil, 5 mg amlodipine as besilate and 25 mg hydrochlorothiazide.
  • SEVIKAR HCT 40/10/12.5 mg contains 40 mg of olmesartan medoxomil,10 mg amlodipine as besilate and 12.5 mg hydrochlorothiazide.
  • SEVIKAR HCT 40/10/25 mg contains 40 mg of olmesartan medoxomil, 10 mg amlodipine as besilate and 25 mg hydrochlorothiazide.
Other ingredients
(inactive ingredients)
  • microcrystalline cellulose
  • colloidal anhydrous silica
  • pregelatinised maize starch
  • croscarmellose sodium
  • magnesium stearate
  • polyvinyl alcohol
  • macrogol 3350
  • titanium dioxide
  • purified talc
  • and iron oxides (as following):
    - SEVIKAR HCT 20/5/12.5 mg tablet contains iron oxide yellow, red and black.
    - SEVIKAR HCT 40/5/12.5 mg tablet and SEVIKAR HCT 40/5/25 mg tablet contains iron oxide yellow.
    - SEVIKAR HCT 40/10/12.5 mg tablet and SEVIKAR HCT 40/10/25 mg tablet contains iron oxide red and yellow.

SEVIKAR HCT does not contain sucrose, tartrazine or any other azo dyes.

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

What SEVIKAR HCT looks like

SEVIKAR HCT tablets come in five strengths and each has a different appearance:

  • SEVIKAR HCT 20/5/12.5 mg is an orange white round tablet, approximately 8 mm in diameter, with C51 debossed on one side. (AUST R 198998)
  • SEVIKAR HCT 40/5/12.5 mg is a light yellow round tablet, approximately 9.5 mm in diameter, with C53 debossed on one side. (AUST R 199006)
  • SEVIKAR HCT 40/5/25 mg is a light yellow oval tablet, approximately 15 x 7 mm, with C54 debossed on one side. (AUST R 199007)
  • SEVIKAR HCT 40/10/12.5 mg is a round greyish red tablet, approximately 9.5 mm in diameter, with C55 debossed on one side. (AUST R 199005)
  • SEVIKAR HCT 40/10/25 mg is a greyish red oval tablet, approximately 15 x 7 mm, with C57 debossed on one side. (AUST R 199000)

The product is presented in blister packs of 10* or 30 film-coated tablets.

*Not available in Australia

Who distributes SEVIKAR HCT

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

This leaflet was prepared in October 2024.

® Registered trademark of Daiichi Sankyo Company Ltd

Published by MIMS December 2024

BRAND INFORMATION

Brand name

Sevikar HCT

Active ingredient

Olmesartan medoxomil; Amlodipine; Hydrochlorothiazide

Schedule

S4

 

1 Name of Medicine

Olmesartan medoxomil, amlodipine (as besilate) and hydrochlorothiazide.

2 Qualitative and Quantitative Composition

Olmesartan medoxomil is a white or almost white crystalline powder. It is practically insoluble in water and slightly soluble in ethanol (96 per cent), practically insoluble in heptane. The pH of a solution (2% w/v) of olmesartan medoxomil in water is 5.6. The dissociation constant (pKa) is 4.3. The partition coefficient Log P is 1.0 at pH 7.0.
Amlodipine besilate is a white or almost white powder, slightly soluble in water and freely soluble in methanol, sparingly soluble in anhydrous ethanol, slightly soluble in 2-propanol. The pH of solution (1.0% w/v) of amlodipine besilate is in the pH range of 5.0-7.0. The dissociation constant (pKa) is 8.6.
Hydrochlorothiazide is a white, or almost white, crystalline powder. Hydrochlorothiazide is very slightly soluble in water, soluble in acetone, sparingly soluble in alcohol. It dissolves in dilute solutions of alkali hydroxides.
Sevikar HCT 20/5/12.5 mg contains 20 mg olmesartan medoxomil, 5 mg amlodipine as besilate and 12.5 mg hydrochlorothiazide.
Sevikar HCT 40/5/12.5 mg contains 40 mg of olmesartan medoxomil, 5 mg amlodipine as besilate and 12.5 mg hydrochlorothiazide.
Sevikar HCT 40/5/25 mg contains 40 mg of olmesartan medoxomil, 5 mg amlodipine as besilate and 25 mg hydrochlorothiazide.
Sevikar HCT 40/10/12.5 mg contains 40 mg of olmesartan medoxomil, 10 mg amlodipine as besilate and 12.5 mg hydrochlorothiazide.
Sevikar HCT 40/10/25 mg contains 40 mg of olmesartan medoxomil, 10 mg amlodipine as besilate and 25 mg hydrochlorothiazide.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Sevikar HCT 20/5/12.5 mg is a round film-coated tablet, approximately 8 mm in diameter, orange white in colour with C51 debossed on one side.
Sevikar HCT 40/5/12.5 mg is a round film-coated tablet, approximately 9.5 mm in diameter, light yellow in colour with C53 debossed on one side.
Sevikar HCT 40/5/25 mg is an oval film-coated tablet, approximately 15x7 mm, light yellow in colour with C54 debossed on one side.
Sevikar HCT 40/10/12.5 mg is a round film-coated tablet, approximately 9.5 mm in diameter, greyish red in colour with C55 debossed on one side.
Sevikar HCT 40/10/25 mg is an oval film-coated tablet, approximately 15x7 mm, greyish red in colour with C57 debossed on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Sevikar HCT is indicated for the treatment of hypertension, either as replacement for olmesartan medoxomil, amlodipine and hydrochlorothiazide being already taken as separate tablets or as add-on therapy where a patient's blood pressure is not controlled on a dual combination (see Section 4.2 Dose and Method of Administration).
This fixed dose combination is not indicated for initial therapy.

4.2 Dose and Method of Administration

Sevikar HCT is registered in five strengths:
1) Sevikar HCT 20/5/12.5 (olmesartan medoxomil 20 mg, amlodipine as besilate 5 mg and hydrochlorothiazide 12.5 mg);
2) Sevikar HCT 40/5/12.5 (olmesartan medoxomil 40 mg and amlodipine as besilate 5 mg and hydrochlorothiazide 12.5 mg);
3) Sevikar HCT 40/5/25 (olmesartan medoxomil 40 mg and amlodipine as besilate 5 mg and hydrochlorothiazide 25 mg);
4) Sevikar HCT 40/10/12.5 (olmesartan medoxomil 40 mg, amlodipine as besilate 10 mg and hydrochlorothiazide 12.5 mg);
5) Sevikar HCT 40/10/25 (olmesartan medoxomil 40 mg, amlodipine as besilate 10 mg and hydrochlorothiazide 25 mg).
(See Section 6.5 Nature and Contents of Container for marketed strengths.)
The recommended dosage of Sevikar HCT is one tablet daily, with or without food. Treatment should not be initiated with this combination. Treatment should be taken at the same time each day. The tablet should not be chewed. The maximum dose is 40/10/25 mg once daily.

Replacement therapy.

For convenience, patients receiving olmesartan medoxomil, amlodipine and hydrochlorothiazide from separate tablets may be switched to Sevikar HCT tablets containing the same component doses.

Add-on therapy.

For patients whose blood pressure is not adequately controlled on olmesartan and amlodipine or olmesartan and hydrochlorothiazide or amlodipine and hydrochlorothiazide therapy, they may be switched to combination therapy with Sevikar HCT. Titration of the dosage is recommended. For patients whose blood pressure is not adequately controlled on Sevikar HCT 20/5/12.5, then titration to Sevikar HCT 40/5/12.5 is recommended. Subsequently, if the patient's blood pressure is not adequately controlled on Sevikar HCT 40/5/12.5, then titration to the maximum Sevikar HCT 40/10/25 is recommended.
Dosage may be increased after 2 weeks to a maximum dose of 40/10/25 mg once daily, usually by increasing one component at a time but any component can be raised to achieve more rapid control.
Maximum antihypertensive effects are attained within 2 weeks after a change in dose.

Renal insufficiency.

No adjustment of the recommended dose is required for patients with mild (creatinine clearance of 50-80 mL/min) to moderate (creatinine clearance of 30 - < 50 mL/min) impairment of renal function. When Sevikar HCT is used in such patients, periodic monitoring of renal function is advised (see Section 4.4 Special Warnings and Precautions for Use).
The use of Sevikar HCT in patients with severe renal impairment (creatinine clearance < 30 mL/min) is contraindicated (see Section 4.3 Contraindications).

Hepatic insufficiency.

Sevikar HCT should be used with caution in 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). Sevikar HCT should not be used in patients with severe hepatic impairment, cholestasis and biliary obstruction (see Section 4.3 Contraindications). If up-titration of the olmesartan medoxomil component to the maximum dose of 40 mg daily is required, blood pressure should be closely monitored.
In patients with hepatic insufficiency, the starting dose of amlodipine is usually 2.5 mg and this dose is not available in the triple combination.

Intravascular volume depletion.

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

Elderly.

No adjustment of the recommended dose is generally required for elderly patients. In the small, frail or elderly, the starting dose of amlodipine is 2.5 mg and this dose is not available in the triple combination.
Caution, including more frequent monitoring of blood pressure, is recommended in elderly patients, particularly at the maximum dose of Sevikar HCT 40 mg/10 mg/25 mg per day.
Very limited data are available on the use of Sevikar HCT in patients aged 75 years or older. Extreme caution, including more frequent monitoring of blood pressure, is recommended.

Children and adolescents.

Sevikar HCT is not recommended for use in children and adolescents below 18 years of age, due to a lack of data on safety and efficacy.

4.3 Contraindications

Sevikar HCT is contraindicated in:
Patients who are hypersensitive to any component of the tablet, to dihydropyridines, to thiazides or to other sulfonamide-derived drugs.
Pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
Patients with anuria or severe renal impairment (creatinine clearance < 30 mL/min) (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).
Patients with severe hepatic impairment (Child-Pugh score 10-15), cholestasis or biliary obstruction (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).
Patients who are breastfeeding.
Patients with refractory hypokalaemia, hypercalcaemia, hyponatraemia, and symptomatic hyperuricaemia (see Section 4.4 Special Warnings and Precautions for Use, Electrolyte imbalance).
Patients with diabetes who are taking aliskiren (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Due to the component amlodipine, Sevikar HCT is also contraindicated in:
Cardiogenic shock.
Acute myocardial infarction (within the first 4 weeks).
Unstable angina pectoris.

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 Sevikar HCT.

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

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, azotemia, oliguria, or rarely, acute renal failure and/or death.
The possibility of similar effects cannot be excluded with olmesartan medoxomil.

Renovascular hypertension.

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

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 Sevikar HCT in cases where no other etiology is identified.

Hyperkalaemia.

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

Non-melanoma skin cancer.

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

Electrolyte imbalance.

As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.
Careful check should be kept for signs of fluid and electrolyte imbalance. Thiazides, including HCT, can cause fluid or electrolyte imbalance (including hypokalaemia, hyponatraemia, hypochloraemic alkalosis and hypomagnesaemia). It is particularly important to make serum and urine electrolyte determinations when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance include: dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, seizures, confusion, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting (see Section 4.8 Adverse Effects (Undesirable Effects)).
Hypokalaemia may develop with hydrochlorothiazide as with any other potent diuretic, especially with brisk diuresis, after prolonged therapy or when severe cirrhosis is present. Hypokalaemia can sensitise or exaggerate the response of the heart to the toxic effects of digitalis (e.g. increased ventricular irritability). The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or ACTH (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Conversely, due to antagonism at the angiotensin-II receptors (AT1) and ACE inhibitors, hyperkalaemia may occur, especially in the presence of renal impairment and/or heart failure, and diabetes mellitus. This is because Sevikar HCT contains olmesartan medoxomil, a drug that inhibits the renin-angiotensin system (RAS) and drugs that inhibit the RAS can cause hyperkalaemia. Monitor serum electrolytes periodically. Adequate monitoring of serum potassium in patients at risk is recommended. Potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes should be co-administered cautiously with Sevikar HCT (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions) and with frequent monitoring of potassium levels.
There is no evidence that olmesartan medoxomil would reduce or prevent diuretic-induced hyponatraemia.
Diuretic induced hyponatraemia is usually mild and asymptomatic. In a few patients hyponatraemia may become severe and symptomatic. Such patients require immediate attention and appropriate treatment.
Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia.
Dilutional hyponatraemia may occur in oedematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt except in rare instances when the hyponatremia is life threatening. In actual salt depletion, appropriate replacement is the therapy of choice.
Metabolic acidosis may occur. Although a chloride deficit in a particular patient is generally mild and usually does not require specific treatment, except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis.

Angioedema.

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

Acute respiratory toxicity.

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

Metabolic and endocrine effects.

Hyperuricaemia may occur or gout may be precipitated in certain patients receiving thiazide therapy. Thiazide therapy may impair glucose tolerance. Dosage adjustment of antidiabetic agents, including insulin, may be required. Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

Aortic or mitral valve stenosis; obstructive hypertrophic cardiomyopathy.

Due to the amlodipine component of Sevikar HCT, as with all vasodilators, special caution is indicated in patients suffering from aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy. Amlodipine should be used with caution in the presence of a fixed left ventricular outflow obstruction (aortic stenosis).

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 Sevikar HCT is not recommended in such patients.

Photosensitivity.

Cases of photosensitivity reactions have been reported with thiazide diuretics. If photosensitivity reaction occurs during treatment with Sevikar HCT, it is recommended to stop the treatment. If a readministration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.

Increased angina and/or myocardial infarction.

Rarely, patients, particularly those with severe obstructive coronary artery disease, have developed documented increased frequency, duration and/or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.

Congestive heart failure.

As a consequence of the inhibition of the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotaemia and (rarely) with acute renal failure and/or death. Sevikar HCT has not been studied in patients with heart failure.
In general, calcium channel blockers should be used with caution in patients with heart failure. Amlodipine (5-10 mg per day) has been studied in a placebo-controlled trial of 1153 patients with NYHA Class III or IV heart failure on stable doses of ACE inhibitor, digoxin and diuretics. Follow-up was at least 6 months, with a mean of about 14 months. There was no overall adverse effect on survival or cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalisation for worsened heart failure). Amlodipine has been compared to placebo in four 8-12 week studies of patients with NYHA class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsened heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or LVEF.

Beta-blocker withdrawal.

Amlodipine is not a beta-blocker and therefore provides no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be by gradual reduction of the dose of beta-blocker.

Peripheral oedema.

Mild to moderate peripheral oedema was the most common adverse event in the clinical trials with amlodipine. The incidence of peripheral oedema was dose-dependent and ranged in frequency from 3.0 to 10.8% in 5 to 10 mg dose range. Care should be taken to differentiate this peripheral oedema from the effects of increasing left ventricular dysfunction.

Ethnic differences.

As with all other angiotensin receptor antagonists, the blood pressure lowering effect of olmesartan medoxomil can be somewhat less in black patients than in nonblack 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.

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).
Lithium should not be given with thiazide diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity.

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

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

Systemic lupus erythematosus.

Thiazide diuretics (e.g. hydrochlorothiazide) have been reported to cause exacerbation or activation of systemic lupus erythematosus.

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.

General.

Caution should be exercised in patients who have shown prior hypersensitivity to other angiotensin II receptor antagonists. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergy and asthma.

Use in hepatic impairment.

Since amlodipine is extensively metabolised by the liver, exposure to amlodipine is increased in patients with hepatic impairment. In a small number of patients with mild to moderate hepatic impairment given single doses of 5 mg, amlodipine half-life has been prolonged. Worsening of liver function test values may occur.
Minor alterations of fluid and electrolyte balance during thiazide therapy may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease.
Care should be taken when Sevikar HCT is administered in patients with mild to moderate impaired hepatic function or progressive liver disease. Careful monitoring should be performed. A lower starting dose may be required (see Section 4.2 Dose and Method of Administration).
Use of Sevikar HCT in patients with severe hepatic impairment, (Child-Pugh score 10-15), cholestasis and biliary obstruction is contraindicated (see Section 4.3 Contraindications).

Use in renal impairment.

When Sevikar HCT is used in patients with impaired renal function, periodic monitoring of serum potassium and creatinine levels is recommended. Use of Sevikar HCT is not recommended in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see Section 4.3 Contraindications).

Amlodipine.

Amlodipine is extensively metabolised to inactive metabolites with 10% excreted as unchanged drug in the urine. Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment. Amlodipine is not dialysable.

Hydrochlorothiazide.

Thiazide diuretic-associated azotaemia may occur in patients with impaired renal function. There is no experience of the administration of Sevikar HCT in patients with a recent kidney transplant or in patients with end-stage renal impairment (i.e. creatinine clearance < 12 mL/min).
Impaired renal function and/or Azotaemia: When creatinine clearance falls below 30 mL/min thiazide diuretics are ineffective. Azotaemia may be precipitated or increased by hydrochlorothiazide. Cumulative effects of the drug may develop in patients with impaired renal function. If increasing azotaemia and oliguria occur during treatment of severe progressive renal disease, the diuretic should be discontinued.
An adverse event of impaired renal function was reported in 2.1% of subjects receiving Sevikar HCT compared to 0.2% to 1.3% of subjects receiving dual combination therapy.

Use in the elderly.

In general dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant diseases or other drug therapy (see Section 4.2 Dose and Method of Administration).
Blood pressure should be frequently monitored in the elderly.
There are limited data available with this triple combination in those aged ≥ 75 years.

Olmesartan medoxomil.

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.

Amlodipine.

In elderly patients (≥ 65 years) clearance of amlodipine is decreased with a resulting increase in AUC. In clinical trials the incidence of adverse events in elderly patients was approximately 6% higher than that of younger population (< 65 years). Adverse events include oedema, muscle cramps and dizziness.

Paediatric use.

Sevikar HCT is not recommended for use in children and adolescents below 18 years of age, due to a lack of data on safety and efficacy.

Olmesartan medoxomil.

Safety and effectiveness have not been established in children.

Amlodipine.

Safety and effectiveness have not been established in children.

Effects on laboratory tests.

Olmesartan medoxomil.

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

Amlodipine.

In post-marketing experience, hepatic enzyme elevations have been reported.

Hydrochlorothiazide.

Increase in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Sevikar HCT.

No drug interaction studies have been conducted with Sevikar HCT and other drugs; although, studies have been conducted with the individual olmesartan medoxomil, hydrochlorothiazide and amlodipine components of Sevikar HCT, as described below.

Olmesartan medoxomil.

Medicines, 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.

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 Sevikar HCT and other agents that affect the RAS.
Do not co-administer aliskiren with Sevikar HCT in patients with diabetes (see Section 4.3 Contraindications). Avoid use of aliskiren with Sevikar HCT in patients with renal impairment (GFR < 60 mL/min).

Non-steroidal anti-inflammatory drugs (NSAIDs).

NSAIDs (including acetylsalicylic acid at doses > 3 g/day and also COX-2 inhibitors) and angiotensin-II receptor antagonists may act synergistically by decreasing glomerular filtration and worsening renal function. The risk of the concomitant use of NSAIDs and angiotensin II antagonists is the occurrence of acute renal failure. Monitoring of renal function at the beginning of treatment should be recommended as well as regular hydration of the patient. Additionally, the antihypertensive effect of ARBs, including olmesartan, may be attenuated by NSAIDs, including selective COX-2 inhibitors leading to their partial loss of efficacy.

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.

Antacids.

After treatment with antacid (aluminium magnesium hydroxide), a modest reduction in bioavailability of olmesartan was observed.

Pravastatin.

Co-administration of olmesartan medoxomil with pravastatin had no clinically relevant effects on the pharmacokinetics of either component in healthy subjects.

Cytochrome P450 enzymes.

Olmesartan had no clinically relevant inhibitory effects on human cytochrome P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1 and 3A4 in vitro, and had no or minimal inducing effects on rat cytochrome P450 activities. No clinically relevant interactions between olmesartan and drugs metabolised by the above cytochrome P450 enzymes are expected. Olmesartan is not metabolised by cytochrome P450 and has no effect on P450 enzymes. Therefore, interactions with drugs that inhibit, induce or are metabolised by those enzymes are not expected.

Amlodipine.

Amlodipine has been safely administered with thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, long acting nitrates, sublingual nitroglycerine, nonsteroidal anti-inflammatory drugs, antibiotics and oral hypoglycaemic drugs.
Special studies have indicated that the co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers, and that co-administration of cimetidine did not alter the pharmacokinetics of amlodipine; and that co-administration with warfarin did not change the warfarin prothrombin response time. In vitro data from studies with human plasma indicate that amlodipine has no effect on protein binding of the drugs tested (digoxin, phenytoin, warfarin or indomethacin).

Grapefruit juice.

Grapefruit juice is known to inhibit the cytochrome P450 system, thereby affecting the pharmacokinetics of drugs such as calcium channel blockers. Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients resulting in increased blood pressure lowering effects.

CYP3A4 inhibitors.

With concomitant use with the CYP3A4 inhibitor erythromycin in young patients and diltiazem in elderly patients, the plasma concentration of amlodipine was increased. The clinical relevance of this finding is uncertain. It cannot be ruled out that strong inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent than diltiazem. Amlodipine should be used with caution together with CYP3A4 inhibitors.

CYP3A4 inducers.

There are no data available regarding the effect of CYP3A4 inducers on amlodipine. The concomitant use of CYP3A4 inducers (e.g. rifampicin, Hypericum perforatum (St John's wort)) may give a lower plasma concentration of amlodipine. Amlodipine should be used with caution together with CYP3A4 inducers.

Aluminium/ magnesium (antacid).

Co-administration of an aluminium/ magnesium antacid with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.

Sildenafil.

A single 100 mg dose of sildenafil in 16 patients with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.

Atorvastatin.

Co-administration of multiple 10 mg doses of amlodipine with 80 mg of atorvastatin resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.

Simvastatin.

Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.

Ethanol (alcohol).

Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.

Ciclosporin.

In a prospective study in renal transplant patients (N = 11), an average 40% increase in trough ciclosporin levels was observed in the presence of amlodipine. The co-administration of amlodipine with ciclosporin may increase exposure to ciclosporin. As Sevikar HCT contains amlodipine, the monitoring of trough ciclosporin levels during concomitant use is recommended and dose adjustment of ciclosporin should be made as necessary.

Tacrolimus.

The co-administration of amlodipine with tacrolimus may increase exposure of tacrolimus. As Sevikar HCT contains amlodipine, the monitoring of tacrolimus blood levels during concomitant use is recommended and dose adjustment of tacrolimus should be made as necessary.

Hydrochlorothiazide.

Digitalis glycosides.

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

Antidiabetic drugs (oral agents and insulin).

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

Metformin.

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

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

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

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

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

Calcium salts.

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

Amantadine.

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

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

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

Medicinal products affecting potassium levels.

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

Non-steroidal anti-inflammatory drugs (NSAIDs).

In some patients the administration of NSAIDs reduces the diuretic, natriuretic and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when Sevikar HCT tablets and NSAIDs are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

Other drugs.

Alcohol, barbiturates, narcotics or antidepressants.

Potentiation of orthostatic hypotension may occur.

Baclofen, amifostine.

Potentiation of antihypertensive effect may occur.

Cholestyramine and colestipol resins.

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

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

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

Effects of Sevikar HCT on other medicinal products.

Lithium.

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors and angiotensin II antagonists. Therefore, use of olmesartan 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.
Lithium should not be given with thiazide diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity.

Medicinal products affected by serum potassium disturbances.

Periodic monitoring of serum potassium and ECG is recommended when Sevikar HCT is administered with drugs affected by serum potassium disturbances (e.g. digitalis glycosides and antiarrhythmics) and with the following torsades de pointes-inducing medicinal products (including some antiarrhythmics), hypokalaemia being a predisposing factor to torsades de pointes:
Class Ia antiarrhythmics (e.g. quinidine, hydroquinidine, disopyramide);
Class III antiarrhythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide);
Some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
Others (e.g. bepridil, cisapride, diphemanil, erythromycin IV, halofantrin, mizolastine, pentamidine, sparfloxacin, terfenadine, vincamine IV).

Beta-blockers and diazoxide.

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

Pressor amines (e.g. noradrenaline).

The effect of pressor amines may be decreased.

Additional information.

Concomitant administration of olmesartan medoxomil, amlodipine and hydrochlorothiazide had no clinically relevant effects on the pharmacokinetics of either component in healthy subjects.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of olmesartan, amlodipine and hydrochlorothiazide in combination on fertility have not been investigated.

Olmesartan medoxomil.

Fertility of rats was unaffected by administration of olmesartan at dose levels as high as 1000 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.

Amlodipine.

There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of amlodipine up to 10 mg/kg/day (about 10 times the MRHD of 10 mg/day on a mg/m2 basis).

Hydrochlorothiazide.

No animal fertility studies are available for hydrochlorothiazide.
(Category D)
Sevikar HCT can cause foetal harm when administered to a pregnant woman. As a precaution, Sevikar HCT must not be used during the first trimester of pregnancy. The patient should change to an appropriate alternative form of medication before a planned pregnancy. If pregnancy occurs during therapy, Sevikar HCT must be discontinued as soon as possible. There is no experience of the use of Sevikar HCT in pregnant women.
If Sevikar HCT is used during pregnancy, or if the patient becomes pregnant while taking Sevikar HCT, the patient should be apprised of the potential hazard to a foetus. Should exposure to Sevikar HCT have occurred from the second trimester forward, ultrasound examinations of the renal function and of the skull are recommended. Newborns exposed to angiotensin II antagonists in utero must be closely monitored for the occurrence of hypotension, oliguria, and hyperkalaemia.
No animal reproductive toxicity studies have been performed with the combination of olmesartan medoxomil and amlodipine.

Olmesartan medoxomil.

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 Sevikar HCT 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, Sevikar HCT 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.
Olmesartan medoxomil is contraindicated in the second and third trimesters of pregnancy. During the second and third trimesters of pregnancy, substances that act on the renin angiotensin system may cause damage (hypotension, impairment of renal function, oligouria and/or anuria, oligohydramnia, cranial hypoplasia, intrauterine growth retardation) and death in foetuses and neonates. Cases of pulmonary hypoplasia, facial anomalies and contractions of limbs were also reported. Animal experimental studies with olmesartan medoxomil have shown furthermore that renal damage may occur in the late foetal and neonatal phase.
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.

Amlodipine.

Category C. Calcium channel blockers carry the potential to produce foetal hypoxia associated with maternal hypotension. Accordingly they should not be used in pregnant women unless the potential benefit outweighs the risk to the foetus.
Safety of amlodipine in human pregnancy or lactation has not been established.
In animal studies, amlodipine was not teratogenic in rats (18 mg/kg/day) or rabbits (10 mg/kg/day). Amlodipine (10 mg/kg/day as besilate salt, 7 mg/kg/day base), administered orally to rats at or near parturition induced a prolongation of gestation time, an increase in the number of stillbirths and a decreased postnatal survival.

Thiazide diuretics.

Category C. Thiazides, related diuretics and loop diuretics enter the foetal circulation and may cause electrolyte disturbances. Neonatal thrombocytopenia has been reported with thiazides and related diuretics. Loop diuretics like frusemide and bumetanide are probably also associated with this risk. During the latter part of pregnancy products of this type should therefore only be given on sound indications, and then in the lowest effective dose.
The routine use of diuretics in otherwise healthy pregnant women with or without mild oedema is not indicated and exposes mother and foetus to unnecessary hazard. Diuretics do not prevent development of toxaemia of pregnancy and there is no satisfactory evidence that they are useful in the treatment of toxaemia.
Thiazides cross the placental barrier and appear in cord blood.
Use of thiazides when pregnancy is present or suspected requires that the benefits of the drug be weighed against possible hazards to the foetus. These hazards include foetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions which occurred in the adult.
 It is not known whether olmesartan medoxomil is excreted in human milk, but olmesartan is excreted into the milk of lactating rats.
Thiazides and amlodipine appear in human milk. Limited available data from a published clinical lactation study report that amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3-7%, with a maximum of 15%. The effect of amlodipine on infants is unknown.
During breast-feeding, Sevikar HCT is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
There is no available information on the effects of amlodipine on milk production.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. However, it should be borne in mind that dizziness or fatigue may occasionally occur in patients taking antihypertensive therapy.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials experience.

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
Sevikar HCT. In the controlled trials of Sevikar HCT, patients were randomised to (doses in mg): Sevikar HCT (olmesartan medoxomil/amlodipine/hydrochlorothiazide) 20/5/12.5, 40/5/12.5, 40/5/25, 40/10/12.5 or 40/10/25, olmesartan medoxomil/amlodipine 20/5, 40/5 or 40/10, olmesartan medoxomil/hydrochlorothiazide 40/25, or amlodipine/hydrochlorothiazide 10/25. The duration of exposure to any olmesartan medoxomil/amlodipine/hydrochlorothiazide triple-combination therapy was ≥ 26 weeks for 1914 subjects, ≥ 48 weeks for 331 subjects, and ≥ 52 weeks for 7 subjects.
The frequency of adverse reactions was similar between men and women, patients < 65 years of age and patients ≥ 65 years of age, and patients with and without diabetes.
Discontinuations due to adverse events were comparable across all triple combination treatment groups, and to groups of subjects treated with dual combinations. The number of discontinuations due to adverse events, and the most frequent adverse events that occurred in at least 2% of patients treated with Sevikar HCT are presented in Table 1.
Adverse events are listed below by system organ class. Frequencies are defined as: common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).

Cardiac disorders.

Common: palpitations. Uncommon: tachycardia.

Ear and labyrinth disorders.

Uncommon: vertigo.

Gastrointestinal disorders.

Common: nausea, diarrhoea, constipation. Uncommon: vomiting, dyspepsia, dry mouth, upper abdominal pain.

General disorders and administration site conditions.

Common: asthenia. Rare: face oedema.

Immune system disorders.

Rare: drug hypersensitivity.

Investigations.

Common: blood creatinine increased, blood uric acid increased, blood urea increased. Uncommon: blood potassium decreased, gamma glutamyl transferase increased, alanine aminotransferase increased, aspartate aminotransferase increased, increase SGOT, increase SGPT.

Metabolism and nutrition disorders.

Uncommon: hyperkalaemia, hypokalaemia.

Musculoskeletal and connective tissue disorders.

Common: muscle spasm, joint swelling. Uncommon: pain in extremity, back pain, muscular weakness.

Nervous system disorders.

Uncommon: postural dizziness, lethargy, paraesthesia, hypoaesthesia, syncope, presyncope.

Psychiatric disorders.

Uncommon: libido decreased, anxiety.

Renal and urinary disorders.

Common: pollakiuria.

Reproductive system, and breast disorders.

Uncommon: erectile dysfunction.

Respiratory, thoracic and mediastinal disorders.

Uncommon: dyspnoea, cough.

Skin and subcutaneous tissue disorders.

Uncommon: rash. Rare: urticaria.

Vascular disorders.

Common: hypotension. Uncommon: orthostatic hypotension, flushing.

Additional information on the individual components.

Adverse events previously reported with one of the individual components may be potential adverse events with Sevikar HCT, even if not observed in clinical trials with this product.

Olmesartan medoxomil.

Olmesartan medoxomil has been evaluated for safety in more than 3825 patients/ subjects, including more than 3275 patients treated for hypertension in controlled trials. This experience included about 900 patients treated for at least 6 months and more than 525 treated for at least 1 year. Treatment with olmesartan medoxomil was well tolerated, with an incidence of adverse events similar to that seen with placebo. Events were generally mild, transient, and without relationship to the dose of olmesartan medoxomil.
The overall frequency of adverse events was not dose related. Analysis of gender, age, and racial 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. 79/3278) of patients treated with olmesartan medoxomil and 2.7% (i.e. 32/1179) 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 in olmesartan medoxomil treated patients vs. placebo was dizziness (3% vs. 1%).
In double-blind, placebo-controlled monotherapy studies, the overall incidence of treatment emergent adverse events was similar on olmesartan medoxomil and on placebo. In long-term (2 year) treatment, the incidence of withdrawals due to adverse events on olmesartan medoxomil 20 mg once daily was 3%.
The following adverse events have been reported across all clinical trials with olmesartan medoxomil irrespective of causality or incidence relative to placebo. They are listed under body system and ranked under headings of frequency using the conventions described above:

Cardiovascular.

Uncommon: tachycardia. Rare: hypotension.

Central nervous system.

Common: dizziness. Uncommon: vertigo.

Gastrointestinal.

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

General.

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

Musculoskeletal.

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

Myo/ endo/ pericardial and valve disorders.

Uncommon: angina pectoris.

Respiratory system.

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

Skin and appendages.

Uncommon: rash.

Urinary system.

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

Metabolic and nutritional.

Common: increased creatine phosphokinase, hyperglycaemia, hypertriglyceridaemia, hyperuricaemia, blood urea increased. Uncommon: hypercholesterolaemia, hyperlipaemia. Rare: hyperkalaemia.

Liver and biliary.

Common: liver enzyme elevations.

Investigations.

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

Blood and lymphatic system disorders.

Thrombocytopenia.

General disorders and administration site conditions.

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

Gastrointestinal disorders.

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

Hepatobiliary disorders.

Autoimmune hepatitis.

Immune system disorders.

Anaphylactic reactions.

Investigations.

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

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; allergic dermatitis; exanthema.

Renal and urinary disorders.

Acute renal failure.

Vascular disorders.

Flushing.
Further adverse reactions reported in clinical trials or from post-marketing experience with a fixed-dose combination of olmesartan medoxomil and hydrochlorothiazide and not already reported for Sevikar HCT, olmesartan medoxomil monotherapy or hydrochlorothiazide monotherapy or reported in a higher frequency for the dual combination below.

Nervous system disorders.

Disturbances in consciousness (such as loss of consciousness).

Skin and subcutaneous tissue disorders.

Eczema.

Investigations.

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

Amlodipine.

Amlodipine has been evaluated for safety in more than 11,000 patients in clinical trials worldwide. In general, treatment with amlodipine was well-tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with amlodipine were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine (n = 1730) in doses up to 10 mg to placebo (n = 1250), discontinuation of amlodipine due to adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). Amlodipine therapy has not been associated with clinically significant changes in routine laboratory tests. No clinically relevant changes were noted in serum potassium, serum glucose, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen or creatinine or liver function tests.
The most common side effects are headache and oedema. The incidence (%) of side effects which occurred in a dose related manner, are as follows (see Table 2):
Other adverse experiences which were not clearly dose related but which were reported with an incidence greater than 1.0% in placebo controlled clinical trials include the following (see Table 3).
The following events occurred in ≤ 1% but > 0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship:

Autonomic nervous system.

Dry mouth, sweating increased.

Cardiovascular.

Hypotension, angina pectoris, myocardial infarction.

Central and peripheral nervous system.

Hypoesthesia, paraesthesia, tremor, peripheral neuropathy, dysgeusia, syncope, postural dizziness.

Endocrine.

Gynaecomastia.

Gastrointestinal.

Constipation, dyspepsia, dysphagia, diarrhoea, flatulence, vomiting, altered bowel habits, pancreatitis, gingival hyperplasia.

General.

Allergic reactions, asthenia, back pain, hot flushes, malaise, pain, rigors, weight gain, muscle spasm, hyperhidrosis.

Heart rate and rhythm disorders.

Tachycardia.

Metabolic and nutritional.

Anorexia, thirst, hyperglycaemia.

Musculoskeletal system.

Arthralgia, arthrosis, myalgia, ankle swelling, muscle spasm.

Platelet, bleeding and clotting.

Thrombocytopenia.

Psychiatric.

Sexual dysfunction (male and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalisation, mood changes, confusional state, irritability.

Respiratory system.

Dyspnoea, epistaxis.

Skin and appendages.

Angioedema, purpura, alopecia, pruritus, rash, rash erythematous, rash maculopapular, exanthema, hyperhidrosis.

Special senses.

Abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus, visual disturbance (including diplopia and blurred vision), vertigo.

Urinary system.

Micturition frequency, micturition disorder, nocturia.

Vascular (extracardiac).

Vasculitis, postural hypotension, peripheral ischaemia.

White blood cell.

Leucopenia.
These events occurred in less than 1% in placebo controlled trials, but the incidence of these side effects was between 1% and 2% in multiple dose studies.
The following events occurred in ≤ 0.1% of patients: cardiac failure, pulse irregularity, extrasystoles, skin discolouration, urticaria, skin dryness, dermatitis, erythema multiforme, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, coughing, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, Stevens-Johnson syndrome, exfoliative dermatitis, photosensitivity reactions, xerophthalmia and weight decrease.
As with other calcium channel blockers the following adverse events have been rarely reported and cannot be distinguished from the natural history of the underlying disease: myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation) and chest pain.
There have been infrequent, postmarketing reports of hepatitis, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis). Some cases severe enough to require hospitalisation have been reported in association with use of amlodipine. In many instances, causal association is uncertain. There have been postmarketing reports of extrapyramidal disorder in association with use of amlodipine.

Hydrochlorothiazide.

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

Blood and lymphatic system disorders.

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

Cardiac disorders.

Cardiac arrhythmias.

Ear and labyrinth disorders.

Vertigo.

Eye disorders.

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

Gastrointestinal disorders.

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

General disorders and administration site conditions.

Fever.

Hepatobiliary disorders.

Jaundice (intrahepatic cholestatic jaundice), acute cholecystitis.

Immune system disorders.

Anaphylactic reactions.

Infections and infestations.

Sialadenitis.

Investigations.

Blood creatinine increased, blood urea increased.

Metabolism and nutritional disorders.

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

Musculoskeletal and connective tissue disorders.

Muscle spasm, muscular weakness.

Nervous system disorders.

Paresis, headache, light headedness, paraesthesia, dizziness, convulsions.

Psychiatric disorders.

Anorexia, restlessness, confusional state, sleep disturbances, depression, apathy.

Respiratory, thoracic and mediastinal disorders.

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

Skin and subcutaneous tissue disorders.

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

Reproductive system and breast disorders.

Erectile dysfunction.

Renal and urinary disorders.

Renal failure, renal dysfunction, interstitial nephritis.

Vascular disorders.

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

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

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

Reporting suspected adverse effects.

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

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

Symptoms.

There is no experience of overdose in humans with Sevikar HCT. The most likely effects of olmesartan medoxomil overdosage are hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurred.
Amlodipine overdosage can be expected to lead to excessive peripheral vasodilatation with marked hypotension and possibly a reflex tachycardia. Marked and potentially prolonged systemic hypotension up to and including shock with fatal outcome has been reported. Noncardiogenic pulmonary oedema has rarely been reported as a consequence of amlodipine overdose that may manifest with a delayed onset (24-48 hours post-ingestion) and require ventilatory support. Early resuscitative measures (including fluid overload) to maintain perfusion and cardiac output may be precipitating factors (see following section).
Overdosage with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloraemia) and dehydration resulting from excessive diuresis. The most common signs and symptoms of overdosage are nausea and somnolence. Hypokalaemia may result in muscle spasm and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalis glycosides or certain anti-arrhythmic drugs.

Treatment.

In healthy subjects, the administration of activated charcoal immediately or up to 2 hours after ingestion of amlodipine has been shown to reduce substantially the absorption of amlodipine.
Clinically significant hypotension due to an overdose of Sevikar HCT requires active support of the cardiovascular system, including close monitoring of heart and lung function, elevation of the extremities, and attention to circulating fluid volume and urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade.
Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.
No information is available regarding the dialysability of olmesartan or hydrochlorothiazide.
For further advice on the management of an overdose contact the Poisons Information Centre.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Sevikar HCT is a combination of three antihypertensive drugs: olmesartan medoxomil, an angiotensin receptor blocker, amlodipine besilate, a dihydropyridine calcium channel blocker and hydrochlorothiazide, a thiazide diuretic. The combination of these active ingredients has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone or in dual combination.
The olmesartan medoxomil component of Sevikar HCT blocks the vasoconstrictor effects of angiotensin II and the amlodipine component of Sevikar HCT inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle. The hydrochlorothiazide component of Sevikar HCT affects the renal tubular mechanisms of electrolyte reabsorption increasing the excretion of sodium and chloride.
Olmesartan medoxomil. Angiotensin II is formed from angiotensin I in a reaction catalysed 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. The effect of olmesartan on mortality and morbidity is not yet known.
Amlodipine. Experimental data suggests that amlodipine binds to both dihydropyridine and nonhydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine.
Within the physiologic pH range, amlodipine is an ionized compound (pKa = 8.6), and its kinetic interaction with the calcium channel is characterised by a gradual rate of association and dissociation with the binding site, resulting in a gradual onset of effect. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure. Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing.
With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105-114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90-104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/-2 mmHg).
In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.
As with other calcium channel blockers, haemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In haemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.
Hydrochlorothiazide. Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazide diuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. The diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity and increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II and therefore co-administration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with thiazide diuretics. With hydrochlorothiazide, onset of diuresis occurs at about 2 hours and peak effect occurs at about 4 hours post-dose, whilst the action persists for approximately 6-12 hours.
The effectiveness of olmesartan medoxomil/ hydrochlorothiazide combination therapy was maintained over long-term (1-year) treatment. Withdrawal of olmesartan medoxomil therapy, with or without concomitant hydrochlorothiazide therapy, did not result in rebound hypertension. The effects of fixed dose combination of olmesartan medoxomil/ hydrochlorothiazide on mortality and cardiovascular morbidity are currently unknown.

Non-melanoma skin cancer.

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

Clinical trials.

Sevikar HCT.

The antihypertensive efficacy of Sevikar HCT was studied in a double blind, active controlled study [CS8635-A-U301] in hypertensive patients. A total of 2492 patients with hypertension (mean baseline blood pressure 169/101 mmHg) received olmesartan medoxomil/ amlodipine/ hydrochlorothiazide 40/10/25 mg (627 patients), olmesartan medoxomil/ amlodipine 40/10 mg (628 patients), olmesartan medoxomil/ hydrochlorothiazide 40/25 mg (637 patients), or amlodipine/ hydrochlorothiazide 10/25 mg (600 patients).
Each subject was randomised to one of the three dual therapy combinations for two to four weeks. Patients were then randomised to continue on the dual therapy they were receiving or to receive triple therapy. A total of 53% of patients were male, 19% were 65 years or older, 67% were white, 30% were black, and 15% were diabetic.
After 8 weeks of treatment, the triple combination therapy produced greater reductions in both systolic and diastolic blood pressures (p < 0.0001) compared to each of the 3 dual combination therapies.
The seated blood pressure reductions attributable to the addition of a single high dose drug to each high-dose dual drug combination are shown in Table 4.
There were no apparent differences in terms of seated diastolic blood pressure (SeDBP) or seated systolic blood pressure (SeSBP) reductions in black and non-black patients treated with Sevikar HCT.
There were no apparent differences in terms of SeDBP or SeSBP reductions in diabetic and non-diabetic patients treated with Sevikar HCT.
A total of 440 patients participated in the ambulatory blood pressure monitoring portion of the study. Over the 24-hour period, there was a greater reduction in diastolic and systolic ambulatory blood pressure for olmesartan medoxomil/ amlodipine/ hydrochlorothiazide 40/10/25 mg compared to each of the dual combination therapies (see Figure 1 and Figure 2).
In a second double-blind, randomised, parallel-group study [CS8635-A-E302] in 2690 patients (99.9% Caucasian patients), treatment with Sevikar HCT (20 mg/5 mg/12.5 mg, 40 mg/5 mg/12.5 mg, 40 mg/5 mg/25 mg, 40 mg/10 mg/12.5 mg, 40 mg/10 mg/25 mg) resulted in significantly greater reductions in diastolic and systolic blood pressure compared to the corresponding dual combinations, olmesartan medoxomil 20 mg plus amlodipine 5 mg, olmesartan medoxomil 40 mg plus 5 mg amlodipine and olmesartan medoxomil 40 mg plus 10 mg amlodipine, respectively, after 10 weeks of treatment.
The additional blood pressure lowering effect from Sevikar HCT compared to the corresponding dual combinations was between -1.3 and -1.9 mmHg for seated diastolic and between -2.7 and -4.9 mmHg for seated systolic blood pressure.
The proportions of patients reaching blood pressure goal (< 140/90 mmHg for nondiabetic patients and < 130/80 mmHg for diabetic patients) at week 10 ranged from 42.7% to 49.6% for the dual combination treatment groups compared to 52.4% to 58.8% for Sevikar HCT.
In a randomised, double-blind, add-on study [CS8635-A-E303] in 808 patients (99.9% Caucasian patients) not adequately controlled after 8-weeks therapy with olmesartan medoxomil 40 mg plus amlodipine 10 mg dual combination, treatment with Sevikar HCT resulted in numerically additional seated blood pressure reduction of -1.8/-1.0 mmHg when treated with Sevikar HCT 40 mg/10 mg/12.5 mg and a statistically significant additional seated blood pressure reduction of -3.6/-2.8 mmHg when treated with Sevikar HCT 40 mg/10 mg/25 mg compared to the olmesartan medoxomil 40 mg plus amlodipine 10 mg dual combination.
Treatment with Sevikar HCT 40 mg/10 mg/25 mg triple-combination therapy resulted in a statistically significantly greater percentage of subjects reaching their blood pressure goal compared to olmesartan medoxomil 40 mg plus amlodipine 10 mg dual combination therapy (41.3% vs. 24.2%); while the treatment with Sevikar HCT 40 mg/10 mg/12.5 mg triple-combination therapy resulted in a numerically greater percentage of subjects reaching their blood pressure goal compared to olmesartan medoxomil 40 mg plus amlodipine 10 mg dual-combination therapy (29.5% vs. 24.2%) in subjects not adequately controlled on dual-combination therapy.
The antihypertensive effect of Sevikar HCT was similar irrespective of age and gender, and was similar in patients with and without diabetes although the number of patients aged ≥ 75 years and the number of patients with diabetes were limited.
The blood pressure lowering effects of lower dose strengths of Sevikar HCT (olmesartan medoxomil/ amlodipine/ hydrochlorothiazide 20/5/12.5 mg, 40/5/12.5 mg, 40/10/12.5 mg, and 40/5/25 mg) have not been studied.
All of the dose strengths of the triple combination are expected to provide superior blood pressure lowering effects compared to their respective mono and dual combination components. The order of the blood pressure lowering effects among the different dose strengths of Sevikar HCT (olmesartan medoxomil/ amlodipine/ hydrochlorothiazide) is expected to be 20/5/12.5 mg < 40/5/12.5 mg < (40/10/12.5 mg ≈ 40/5/25 mg) < 40/10/25 mg.
There are no trials of Sevikar HCT demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits.

5.2 Pharmacokinetic Properties

Following oral intake of Sevikar HCT, peak plasma concentrations of olmesartan, amlodipine and hydrochlorothiazide are reached at 1.5-2 hours, 6-8 hours and 1.5 to 2 hours, respectively. The rate and extent of absorption of olmesartan medoxomil, amlodipine and hydrochlorothiazide from Sevikar HCT are equivalent to the rate and extent of absorption following intake of the three components as separate tablets. Food does not affect the bioavailability of olmesartan medoxomil and amlodipine from Sevikar HCT.

Olmesartan medoxomil.

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 medoxomil 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 medoxomil 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 co-administered drugs is low (as confirmed by the lack of a clinically significant interaction between olmesartan medoxomil and warfarin). The binding of olmesartan to blood cells is negligible.
In rats, olmesartan crossed the blood-brain barrier poorly, if at all. Olmesartan crossed the placental barrier in rats and was distributed to the foetus. Olmesartan was distributed to milk at low levels in rats.

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. Steady state was reached after the first few doses and no further accumulation was evident within 14 days of repeated dosing. Renal clearance was approximately 0.5-0.7 L/h and was independent of dose.

Amlodipine.

Absorption.

After oral administration of therapeutic doses of amlodipine, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability is estimated as between 64% and 90%. This may reflect significant initial uptake by the liver, followed by a phase of redistribution. This interval is shorter (2-8 hours) in patients with hepatic insufficiency. The bioavailability of amlodipine is not altered by the presence of food.

Distribution.

The volume of distribution is approximately 20 L/kg. The terminal plasma elimination half-life is about 35-50 hours and is consistent with once daily dosing. Steady state plasma levels are reached after 7-8 days of consecutive dosing.

Metabolism.

Amlodipine is extensively metabolised by the liver to inactive metabolites. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.

Excretion.

10% of the parent compound and 60% of metabolites are excreted in the urine.

Hydrochlorothiazide.

Absorption.

Following oral administration of olmesartan medoxomil, amlodipine and hydrochlorothiazide in combination, the median time to peak concentrations of hydrochlorothiazide was 1.5 to 2 hours after dosing.

Distribution.

Hydrochlorothiazide is 68% protein bound in the plasma and its apparent volume of distribution is 0.83-1.14 L/kg.

Metabolism.

Hydrochlorothiazide is not metabolised in man and is excreted almost entirely as unchanged drug in urine.

Excretion.

About 60% of the oral dose is eliminated as unchanged drug within 48 hours. Renal clearance is about 250-300 mL/min. The terminal elimination half-life of hydrochlorothiazide is 10-15 hours.

Pharmacokinetics in special populations.

Elderly. The pharmacokinetic properties of Sevikar HCT in the elderly are similar to those of the individual components.

Olmesartan medoxomil.

In hypertensive patients, the AUC at steady state was increased by approximately 35% in elderly patients (65-75 years old) and by approximately 44% in very elderly patients (≥ 75 years old) compared with the younger age group.

Amlodipine.

In elderly hypertensive patients (mean age 69 years) there was a decrease in clearance of amlodipine from plasma as compared to young volunteers (mean age 36 years) with a resulting increase in the area under the curve (AUC) of about 60%.
Paediatric. No pharmacokinetic data in paediatric patients for Sevikar HCT are available.

Olmesartan medoxomil.

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

Amlodipine.

No pharmacokinetic data for amlodipine in paediatric patients are available.
Gender. Population pharmacokinetic analysis indicated that gender had no effect on the clearance of olmesartan medoxomil and amlodipine. Female patients had approximately 20% smaller clearances of hydrochlorothiazide than male patients.

Olmesartan medoxomil.

Minor differences were observed in the pharmacokinetics of olmesartan medoxomil in women compared to men. AUC and Cmax were 10% to 15% higher in women than in men.
Renal impairment.

Olmesartan medoxomil.

In patients with renal insufficiency, serum concentrations of olmesartan were elevated compared to subjects with normal renal function. After repeated dosing, the AUC was approximately tripled in patients with severe renal impairment (creatinine clearance < 20 mL/min). The pharmacokinetics of olmesartan medoxomil in patients undergoing haemodialysis have not been studied.

Amlodipine.

The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.
Hepatic insufficiency.

Olmesartan medoxomil.

Mean olmesartan AUC after single oral administration to patients with moderate hepatic impairment was increased by about 48% compared with healthy controls (total group), or by about 60% when compared with matched controls only. Olmesartan medoxomil has not been evaluated in patients with severe hepatic impairment.

Amlodipine.

Patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%. There are no adequate studies in patients with liver dysfunction and dosage recommendations have not been established. In a small number of patients with mild to moderate hepatic impairment given single doses of 5 mg, amlodipine half-life has been prolonged. Worsening of liver function test values may occur. Amlodipine therefore should be administered with caution in these patients and careful monitoring should be performed.
Heart failure.

Amlodipine.

Patients with heart failure have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%.

5.3 Preclinical Safety Data

Genotoxicity.

No genotoxicity studies have been conducted with the olmesartan medoxomil/ amlodipine/ hydrochlorothiazide combination.

Olmesartan medoxomil.

Both olmesartan medoxomil and olmesartan tested negative in the in vitro Syrian hamster embryo cell transformation assay and showed no evidence of genetic toxicity in the Ames (bacterial mutagenicity) test. However, both were shown to induce chromosomal aberrations in cultured cells in vitro (Chinese hamster lung) and tested positive for thymidine kinase mutations in the in vitro mouse lymphoma assay. Olmesartan medoxomil tested negative in vivo for mutations in intestinal and kidney cells from the transgenic mouse strain MutaMouse and for clastogenicity in mouse bone marrow (micronucleus test) at oral doses of up to 2000 mg/kg (olmesartan not tested). On balance, the weight-of-evidence indicates that olmesartan medoxomil does not pose a genotoxic risk at clinically relevant doses.

Amlodipine.

Amlodipine did not induce gene mutation in bacteria and mouse lymphoma cells; nor did it induce chromosome aberrations in human lymphocytes or Chinese hamster V79 fibroblast (in vitro) and in mouse bone marrow cells (in vivo).

Hydrochlorothiazide.

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

Carcinogenicity.

There are no carcinogenicity studies with the olmesartan medoxomil/ amlodipine/ hydrochlorothiazide combination.

Olmesartan medoxomil.

Olmesartan was not carcinogenic when administered by dietary administration to rats for up to 2 years. The highest dose tested (2000 mg/kg/day) was, on a mg/m2 basis, about 480 times the maximum recommended human dose (MRHD) of 40 mg/day. 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 1000 mg/kg/day (about 120 times the MRHD), revealed no evidence of a carcinogenic effect of olmesartan.

Amlodipine.

The carcinogenic potential of amlodipine has not been fully elucidated. Amlodipine did not induce any tumours when tested in rats at oral doses up to 2.5 mg/kg. This dose gave rise to plasma levels that are similar to those achieved clinically.
Rats and mice treated with amlodipine maleate in the diet for up to 2 years, at concentrations calculated to provide daily dosage levels of amlodipine 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on mg/m2 basis, similar to the maximum recommended human dose [MRHD] of 10 mg amlodipine/day. For the rat, the highest dose was, on a mg/m2 basis, about two and a half times the MRHD (calculations based on a 60 kg patient).

Hydrochlorothiazide.

Two-year feeding studies in mice and rats uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). There was equivocal evidence for hepatocarcinogenicity in male mice treated with hydrochlorothiazide alone at approximately 600 mg/kg/day.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, colloidal anhydrous silica, pregelatinized maize starch, croscarmellose sodium, and magnesium stearate. The colour coating contains polyvinyl alcohol, macrogol 3350, titanium dioxide, purified talc, and iron oxides.

Sevikar HCT 20/5/12.5 mg tablet.

Opadry II complete film coating system 85F24118 Pink.

Sevikar HCT 40/5/12.5 mg tablet and Sevikar HCT 40/5/25 mg tablet.

Opadry II complete film coating system 85F32331 Yellow.

Sevikar HCT 40/10/12.5 mg tablet and Sevikar HCT 40/10/25 mg tablet.

Opadry II complete film coating system 85F25437 Pink.

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

Store below 25°C.

6.5 Nature and Contents of Container

Sevikar HCT is available in blister packs of 10 and 30 film-coated tablets.
Not all pack sizes may be available.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Olmesartan medoxomil is chemically described as (5-Methyl-2-oxo-1,3-dioxol-4-yl) methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] -1H-imidazole-5-carboxylate. The empirical formula is C29H30N6O6 and its molecular weight is 558.6.
Amlodipine besilate is a racemic mixture and is chemically described as 3-Ethyl 5-methyl (4RS)-2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate benzenesulfonate. The empirical formula is C20H25ClN2O5.C6H6O3S and its molecular weight is 567.1.
Hydrochlorothiazide is described chemically as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. The empirical formula is C7H8ClN3O4S2 and its molecular weight is 297.7.

Chemical structure.

Olmesartan medoxomil has the following structural formula:
Amlodipine besilate has the following structural formula:
Hydrochlorothiazide has the following structural formula:

CAS number.

Olmesartan medoxomil.

Its CAS number is 144689-63-4.

Amlodipine besilate.

The CAS number is 111470-99-6.

Hydrochlorothiazide.

Its CAS no. is 58-93-5.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (Schedule 4).

Summary Table of Changes