Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka 40 mg/5 mg/25 mg film-coated tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
Olmesartan Medoxomil; Amlodipine; Hydrochlorothiazide
Available from:
Krka d.d., Novo mesto
ATC code:
C09DX03
INN (International Name):
Olmesartan Medoxomil; Amlodipine; Hydrochlorothiazide
Dosage:
40/5/25 milligram(s)
Pharmaceutical form:
Film-coated tablet
Therapeutic area:
olmesartan medoxomil, amlodipine and hydrochlorothiazide
Authorization status:
Marketed
Authorization number:
PA1347/096/003
Authorization date:
2020-10-23

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86 mm ± 0,5 mm

102 mm ± 0,5 mm

140 mm ± 0,5 mm

385 mm ± 0,5 mm

655 mm ± 0,8 mm

289 mm ± 0,5 mm

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- Črna U

PL.Olme/Amlo/HCTZ IE first page

Package leaflet: Information for the user

Olmesartan medoxomil/Amlodipine/

Hydrochlorothiazide Krka

20 mg/5 mg/12.5 mg

film-coated tablets

Olmesartan medoxomil/Amlodipine/

Hydrochlorothiazide Krka

40 mg/5 mg/12.5 mg

film-coated tablets

Olmesartan medoxomil/Amlodipine/

Hydrochlorothiazide Krka

40 mg/5 mg/25 mg

film-coated tablets

Olmesartan medoxomil/Amlodipine/

Hydrochlorothiazide Krka

40 mg/10 mg/12.5 mg

film-coated tablets

Olmesartan medoxomil/Amlodipine/

Hydrochlorothiazide Krka

40 mg/10 mg/25 mg

film-coated tablets

olmesartan medoxomil/amlodipine/hydrochlorothiazide

Read all of this leaflet carefully before you start taking this medicine

because it contains important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to

others. It may harm them, even if their signs of illness are the same as

yours.

If you get any side effects, talk to your doctor or pharmacist. This includes

any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka is

and what it is used for

2. What you need to know before you take Olmesartan medoxomil/

Amlodipine/Hydrochlorothiazide Krka

3. How to take Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka

4. Possible side effects

5. How to store Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka

6. Contents of the pack and other information

1. What Olmesartan medoxomil/Amlodipine/

Hydrochlorothiazide Krka is and what it is used for

Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka contains three

active substances called olmesartan medoxomil, amlodipine (as amlodipine

besilate) and hydrochlorothiazide. All three substances help to control high

blood pressure.

Olmesartan medoxomil belongs to a group of medicines called

“angiotensin-II receptor antagonists”, which lowers blood pressure by

relaxing the blood vessels.

Amlodipine belongs to a group of substances called “calcium channel

blockers”. Amlodipine also lowers blood pressure by relaxing blood

vessels.

Hydrochlorothiazide is one of a group of medicines called thiazide

diuretics (“water tablets”). It lowers blood pressure by helping the body to

get rid of extra fluid by making your kidneys produce more urine.

The actions of these substances contribute to decrease your blood

pressure.

Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka is used for the

treatment of high blood pressure:

in adult patients whose blood pressure is not adequately controlled on the

combination of olmesartan medoxomil and amlodipine taken as fixed-dose

combination, or

in patients, who are already taking a fixed-dose combination of olmesartan

medoxomil and hydrochlorothiazide plus the amlodipine as a single tablet

or a fixed-dose combination of olmesartan medoxomil and amlodipine plus

hydrochlorothiazide as a single tablet.

2. What you need to know before you take Olmesartan

medoxomil/Amlodipine/Hydrochlorothiazide Krka

Do not take Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide

Krka if:

you are allergic to olmesartan medoxomil, to amlodipine or a special group

of calcium channel blockers (the dihydropyridines) to hydrochlorothiazide

or to substances similar to hydrochlorothiazide (sulfonamides) or to any of

the other ingredients of this medicine (listed in section 6). If you think you

may be allergic talk to your doctor before taking Olmesartan medoxomil/

Amlodipine/Hydrochlorothiazide Krka.

you have severe kidney problems.

you have diabetes or impaired kidney function and you are treated with a

blood pressure lowering medicine containing aliskiren.

you have low potassium, low sodium, high calcium or high uric acid (with

symptoms of gout or kidney stones) levels in your blood that have not got

better when treated.

you are more than 3 months pregnant. (It is also better to avoid

Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka in early

pregnancy - see section “Pregnancy and breast-feeding”).

you have severe liver problems, if bile secretion is impaired or drainage of

bile from the gall bladder is blocked (e. g. by gallstones), or if you are

jaundiced (yellowing of the skin and eyes).

you have a poor blood supply to your tissues with symptoms such as low

blood pressure, low pulse, fast heartbeat or shock (including cardiogenic

shock, which means shock due to severe heart troubles).

you have very low blood pressure.

the blood flow from your heart is slow or blocked. This may happen if the

blood vessel or valve that takes blood away from your heart becomes

narrow (aortic stenosis).

you have a low heart output after a heart attack (acute myocardial

infarction). Low heart output may make you feel short of breath or have

swelling in your feet and ankles.

Do not take Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka if

any of the above applies to you.

Warnings and precautions

Talk to your doctor or pharmacist before using Olmesartan medoxomil/

Amlodipine/Hydrochlorothiazide Krka.

Tell your doctor if you are taking any of the following medicines used to

treat high blood pressure:

an ACE-inhibitor (for example enalapril, lisinopril, ramipril), in particular if

you have diabetes-related kidney problems,

aliskiren.

Your doctor may check your kidney function, blood pressure, and the

amount of electrolytes (e.g. potassium) in your blood at regular intervals.

See also information under the heading “Do not take Olmesartan

medoxomil/Amlodipine/Hydrochlorothiazide Krka if:”

Tell your doctor if you have any of the following health problems:

Kidney problems or a kidney transplant.

Liver disease.

Heart failure or problems with your heart valves or heart muscle.

Severe vomiting, diarrhoea, treatment with high doses of “water tablets”

(diuretics) or if you are on a low salt diet.

Increased levels of potassium in your blood.

Problems with your adrenal glands (hormone-producing glands on top of

the kidneys).

Diabetes.

Lupus erythematosus (an autoimmune disease).

Allergies or asthma.

Skin reactions such as sunburn or rash after being in the sun or using a

sunbed.

If you have had skin cancer or if you develop an unexpected skin lesion

during the treatment. Treatment with hydrochlorothiazide, particularly long

term use with high doses, may increase the risk of some types of skin and

lip cancer (nonmelanoma skin cancer). Protect your skin from sun

exposure and UV rays while taking Olmesartan medoxomil/Amlodipine/

Hydrochlorothiazide Krka.

Contact your doctor if you experience any of the following symptoms:

diarrhoea that is severe, persistent and causes substantial weight loss.

Your doctor may evaluate your symptoms and decide on how to continue

your blood pressure medication.

decrease in vision or eye 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 Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka. This

can lead to permanent vision impairment, if not treated. If you earlier have

had a penicillin or sulfonamide allergy, you can be at higher risk of

developing this.

As with any medicine, which reduces blood pressure, an excessive drop in

blood pressure in patients with blood flow disturbances of the heart or brain

could lead to a heart attack or stroke. Your doctor will therefore check your

blood pressure carefully.

Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka may cause a

rise in blood fat levels and uric acid levels (the cause of gout – painful

swelling of the joints). Your doctor will probably want to do a blood test from

time to time to check these.

It may change the levels of certain chemicals in your blood called

electrolytes. Your doctor will probably want to do a blood test from time to

time to check these. Signs of electrolyte changes are: thirst, dryness of the

mouth, muscle pain or cramps, tired muscles, low blood pressure

(hypotension), feeling weak, sluggish, tired, sleepy or restless, nausea,

vomiting, less need to pass urine, a rapid heart rate. Tell your doctor if you

notice these symptoms.

If you are due to have tests for parathyroid function you should stop taking

Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka before these

tests are carried out.

You must tell your doctor if you think that you are (or might become)

pregnant. Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka is

not recommended in early pregnancy and must not be taken if you are more

than 3 months pregnant, as it may cause serious harm to your baby if used

at that stage (see section “Pregnancy and breast-feeding”).

Children and adolescents (under 18)

Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka is not

recommended for children and adolescents under the age of 18.

Other medicines and Olmesartan medoxomil/Amlodipine/

Hydrochlorothiazide Krka

Tell your doctor or pharmacist if you are taking, have recently taken or might

take any of the following:

Other blood pressure lowering medicines, as the effect of Olmesartan

medoxomil/Amlodipine/Hydrochlorothiazide Krka can be increased. Your

doctor may need to change your dose and/or to take other precautions: If

you are taking an ACE-inhibitor or aliskiren (see also information under the

headings “Do not take Olmesartan medoxomil/Amlodipine/

Hydrochlorothiazide Krka if:” and “Warnings and precautions”).

Lithium (a medicine used to treat mood swings and some types of

depression), used at the same time as Olmesartan medoxomil/Amlodipine/

Hydrochlorothiazide Krka may increase the toxicity of lithium. If you have

to take lithium your doctor will measure your lithium blood levels.

Diltiazem, verapamil, used for heart rhythm problems and high blood

pressure.

Rifampicin, erythromycin, clarithromycin, tetracyclines or

sparfloxacin, antibiotics used for tuberculosis and other infections.

St. John’s wort (Hypericum perforatum), a herbal remedy for treatment of

depression.

Cisapride, used to increase food movement in the stomach and gut.

Diphemanil, used to treat a slow heartbeat or reduce sweating.

Halofantrine, used for malaria.

Vincamine IV, used to improve circulation to the nervous system.

Amantadine, used for Parkinson’s disease.

Potassium supplements, salt substitutes containing potassium,

“water tablets” (diuretics), heparin (for thinning the blood and prevention

of blood clots), ACE inhibitors (for blood pressure lowering), laxatives,

steroids, adrenocorticotrophic hormone (ACTH), carbenoxolone (a

medicine used to treat mouth and stomach ulcers), penicillin G sodium

(also called benzylpenicillin sodium, an antibiotic), certain pain killers such

as acetylsalicylic acid (“aspirin”) or salicylates. Using these medicines at

the same time as Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide

Krka

may alter the levels of potassium in your blood.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs, medicines used to

relieve pain, swelling and other symptoms of inflammation, including

arthritis), used at the same time as Olmesartan medoxomil/Amlodipine/

Hydrochlorothiazide Krka may increase the risk of kidney failure. The

effect of Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka can

be decreased by NSAIDs. In case of high dosages of salicylate the toxic

effect on central nervous system may be increased.

Sleeping tablets, sedatives and anti-depressant medicines as using

these medicines together with Olmesartan medoxomil/Amlodipine/

Hydrochlorothiazide Krka may cause a sudden drop in blood pressure

when standing up.

Colesevelam hydrochloride, a drug that lowers the level of cholesterol in

your blood, as the effect of Olmesartan medoxomil/Amlodipine/

Hydrochlorothiazide Krka may be decreased. Your doctor may advise you

to take Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka at

least 4 hours before colesevelam hydrochloride.

Certain antacids (indigestion or heartburn remedies) as the effect of

Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka can be

slightly decreased.

Certain muscle relaxing medicines such as baclofen and tubocurarine.

Anticholinergic agents such as atropine and biperiden.

Calcium supplements.

Dantrolene (infusion for severe body temperature abnormalities).

Simvastatin, used to lower levels of cholesterol and fats (triglycerides) in

the blood.

Medicines used to control your body’s immune response (such as

tacrolimus, cyclosporine), enabling your body to accept the transplanted

organ.

Also, tell your doctor or pharmacist if you are taking, have recently

taken or might take any of the following medicines to:

Treat certain mental health problems such as thioridazine,

chlorpromazine, levomepromazine, trifluoperazine, cyamemazine,

sulpiride, amisulpride, pimozide, sultopride, tiapride, droperidol or

haloperidol.

Treat low blood sugar (e. g. diazoxide) or high blood pressure (e. g.

betablockers, methyldopa) as Olmesartan medoxomil/Amlodipine/

Hydrochlorothiazide Krka can affect how these drugs work.

Treat heart rhythm problems such as mizolastine, pentamidine,

terfenadine, dofetilide, ibutilide or erythromycin injections.

Treat HIV/AIDS (e. g. ritonavir, indinavir, nelfinavir).

Treat fungal infections (e. g. ketoconazole, itraconazole, amphotericin).

Treat heart problems such as quinidine, hydroquinidine, disopyramide,

amiodarone, sotalol, bepridil or digitalis.

Treat cancers such as amifostine, cyclophosphamide or methotrexate.

Increase blood pressure and slow heart rate such as noradrenaline.

Treat gout such as probenecid, sulfinpyrazone and allopurinol.

Lower blood fat levels such as colestyramine and colestipol.

Lower blood sugar such as metformin or insulin.

Tell your doctor or pharmacist if you are taking, have recently taken or might

take any other medicines.

Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka with

food and drink

Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka can be taken

with or without food.

Grapefruit juice and grapefruit should not be consumed by people who are

taking Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka. This is

because grapefruit and grapefruit juice can lead to an increase in the blood

levels of the active ingredient amlodipine, which can cause an unpredictable

increase in the blood pressure lowering effect of Olmesartan medoxomil/

Amlodipine/Hydrochlorothiazide Krka.

Take care when drinking alcohol while you are taking Olmesartan

medoxomil/Amlodipine/Hydrochlorothiazide Krka

as some people feel faint

or dizzy. If this happens to you, do not drink any alcohol.

Elderly

If you are over 65 years of age your doctor will regularly check your blood

pressure at any dose increase, to make sure that your blood pressure does

not become too low.

Pregnancy and breast-feeding

Pregnancy

You must tell your doctor if you think that you are (or might become)

pregnant. Your doctor will normally advise you to stop taking Olmesartan

medoxomil/Amlodipine/Hydrochlorothiazide Krka before you become

pregnant or as soon as you know you are pregnant and will advise you to

take another medicine instead of Olmesartan medoxomil/Amlodipine/

Hydrochlorothiazide Krka. Olmesartan medoxomil/Amlodipine/

Hydrochlorothiazide Krka is not recommended during pregnancy and must

not be taken when more than 3 months pregnant as it may cause serious

harm to your baby if used after the third month of pregnancy.

If you become pregnant during therapy with Olmesartan medoxomil/

Amlodipine/Hydrochlorothiazide Krka please inform and see your physician

without delay.

Breast-feeding

Tell your doctor if you are breast-feeding or about to start breast-feeding.

Amlodipine and hydrochlorothiazide have been shown to pass into breast

milk in small amounts. Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide

Krka

is not recommended for mothers, who are breast-feeding, and

your

doctor may choose another treatment for you if you wish to breast-feed.

If you are pregnant or breast-feeding, think you may be pregnant or are

planning to have a baby, ask your doctor or pharmacist for advice before

taking this medicine.

Driving and using machines

You may feel sleepy, sick or dizzy or get a headache while being treated for

your high blood pressure. If this happens do not drive or use machines until

the symptoms wear off. Ask your doctor for advice.

Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka contains

lactose and sodium

If you have been told by your doctor that you have an intolerance to some

sugars, contact your doctor before taking this medicinal product.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is

to say essentially ‘sodium-free’.

3. How to take Olmesartan medoxomil/Amlodipine/

Hydrochlorothiazide Krka

Always take this medicine exactly as your doctor or pharmacist has told you.

Check with your doctor or pharmacist if you are not sure.

The recommended dose of Olmesartan medoxomil/Amlodipine/

Hydrochlorothiazide Krka is one tablet per day.

The tablet can be taken with or without food. Swallow the tablet with some

fluid (such as a glass of water). The tablet should not be chewed. Do not

take the tablet with grapefruit juice.

If possible, take your daily dose at the same time each day, for example at

breakfast time.

If you take more Olmesartan medoxomil/Amlodipine/

Hydrochlorothiazide Krka than you should

If you take more tablets than you should you may experience low blood

pressure with symptoms such as dizziness, fast or slow heart beat.

If you take more tablets than you should or if a child accidentally swallows

some go to your doctor or nearest emergency department immediately and

take your medicine pack or this leaflet with you.

If you forget to take Olmesartan medoxomil/Amlodipine/

Hydrochlorothiazide Krka

If you forget to take a dose take your normal dose the following day as

usual. Do not take a double dose to make up for a forgotten dose.

If you stop taking Olmesartan medoxomil/Amlodipine/

Hydrochlorothiazide Krka

It is important to continue to take Olmesartan medoxomil/Amlodipine/

Hydrochlorothiazide Krka unless your doctor tells you to stop.

If you have any further questions on the use of this medicine, ask your

doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not

everybody gets them. If side effects do occur they are often mild and do not

require treatment to be stopped.

Although not many people may get them, the following two side effects

can be serious:

Allergic reactions with swelling of the face, mouth and/or larynx (voice box)

together with itching and rash may occur during treatment with Olmesartan

medoxomil/Amlodipine/Hydrochlorothiazide Krka. If this happens stop

taking Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka

and contact your doctor immediately.

Severe light-headedness or fainting because Olmesartan medoxomil/

Amlodipine/Hydrochlorothiazide Krka can cause the blood pressure to fall

too low in susceptible individuals. If this happens stop taking Olmesartan

medoxomil/Amlodipine/Hydrochlorothiazide Krka, contact your doctor

immediately and lay down flat.

Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka is a

combination of three active substances. The following information firstly

gives the other side effects reported so far with the combination

olmesartan/amlodipine/hydrochlorothiazide (besides those already

mentioned above) and, secondly, those side effects, which are known for

each of the separate substances or when two substances are given together.

To give you an idea of how many patients might get side effects, they have

been listed as common, uncommon, rare and very rare.

These are the other side effects known about so far with olmesartan/

amlodipine/hydrochlorothiazide:

If these side effects occur they are often mild and you do not need to stop

your treatment.

Common

(may affect less than 1 in 10 people)

Upper respiratory tract infection; sore throat and nose; urinary tract infection;

dizziness; headache; awareness of heartbeat; low blood pressure; nausea;

diarrhoea; constipation; cramps; joint swelling; feeling more of an urge to

pass urine; weakness; ankle swelling; tiredness; abnormal laboratory values.

Uncommon

(may affect less than 1 in 100 people)

Dizziness on standing up; vertigo; fast heartbeat; feeling faint; redness and

warm feeling of the face; cough; dry mouth; muscular weakness; inability to

get or maintain an erection.

These are the side effects, which are known for each of the separate

substances or when two substances are given together:

They may be side effects for Olmesartan medoxomil/Amlodipine/

Hydrochlorothiazide Krka, even if they have not been seen so far with

Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka.

Very common

(may affect more than 1 in 10 people)

Oedema (fluid retention)

Common

(may affect less than 1 in 10 people)

Bronchitis; stomach and gut infection; vomiting; increased blood sugar;

sugar in urine; confusion; feeling sleepy; visual disturbance (including double

vision and blurred vision); runny or stuffy nose; sore throat; difficult

breathing; cough; abdominal pain; heartburn; stomach discomfort; flatulence;

pain in the joints or bones; back pain; skeletal pain; blood in the urine; flu-like

symptoms; chest pain; pain.

Uncommon

(may affect less than 1 in 100 people)

Reduced number of a type of blood cells known as platelets, which can

result in bruising easily or a prolonged bleeding time; anaphylactic reactions;

abnormally reduced appetite (anorexia); problems sleeping; irritability; mood

changes including feeling anxious; feeling “down” or depressed; shiver;

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sleep disturbances; distorted sense of taste; loss of consciousness; reduced

sense of touch; tingling sensations; worsening of shortsightedness; ringing in

the ears (tinnitus); angina (pain or uncomfortable feeling in the chest, known

as angina pectoris); irregular heart beat; rash; loss of hair; allergic

inflammation of the skin; redness of skin; purplish spots or patches on the

skin due to small haemorrhages (purpura); discolouration of the skin; red

itchy bumps (hives); increased sweating; itching; eruption of the skin; skin

reactions to light such as sunburn or rash; muscle pain; problems to pass

urine; feeling urge to pass urine at night; breast enlargement in men;

decreased sexual desire; swelling of the face; feeling unwell; weight

increase or decrease; exhaustion.

Rare

(may affect less than 1 in 1,000 people)

Swollen and sore salivary glands; reduced number of white cells in the

blood, which could increase the risk of infections; low red blood cell count

(anaemia); bone marrow damage; restlessness; feeling uninterested

(apathy); fits (convulsions); objects you look at appearing yellow; dry eyes;

blood clots (thrombosis, embolism); fluid accumulation in the lungs;

pneumonia; inflammation of blood vessels and small blood vessels in the

skin; inflammation of the pancreas; yellowing of the skin and eyes; acute

inflammation of the gall bladder; symptoms of lupus erythematosus such as

rash, joint pains and cold hands and fingers; severe skin reactions including

intense skin rash, hives, reddening of the skin over your whole body, severe

itching, blistering, peeling and swelling of the skin, inflammation of mucous

membranes (Stevens Johnson Syndrome, toxic epidermal necrolysis),

sometimes life-threatening; impaired movement; acute kidney failure;

non-infectious kidney inflammation; poor kidney function; fever.

Very Rare

(may affect less than 1 in 10,000 people)

High muscle tension; numbness of hands or feet; heart attack; inflammation

of the stomach; thickening of the gums; blockage in the gut; inflammation of

the liver.

Not Known

(frequency cannot be estimated from the available data)

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). Trembling, rigid posture, mask-like face,

slow movements and a shuffling, unbalanced walk.

Skin and lip cancer (Non-melanoma skin cancer).

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes

any possible side effects not listed in this leaflet. You can also report side

effects directly via the national reporting system listed in

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

E-mail: medsafety@hpra.ie

By reporting side effects you can help provide more information on the

safety of this medicine.

5. How to store Olmesartan medoxomil/Amlodipine/

Hydrochlorothiazide Krka

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the

packaging after EXP. The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask

your pharmacist how to throw away medicines you no longer use. These

measures will help protect the environment.

6. Contents of the pack and other information

What Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka

contains

The active substances are olmesartan medoxomil, amlodipine and

hydrochlorothiazide.

20 mg/5 mg/12.5 mg:

Each film-coated tablet contains 20 mg olmesartan medoxomil, 5 mg

amlodipine (as amlodipine besilate) and 12.5 mg hydrochlorothiazide.

40 mg/5 mg/12.5 mg:

Each film-coated tablet contains 40 mg olmesartan medoxomil, 5 mg

amlodipine (as amlodipine besilate) and 12.5 mg hydrochlorothiazide.

40 mg/5 mg/25 mg:

Each film-coated tablet contains 40 mg olmesartan medoxomil, 5 mg

amlodipine (as amlodipine besilate) and 25 mg hydrochlorothiazide.

40 mg/10 mg/12.5 mg:

Each film-coated tablet contains 40 mg olmesartan medoxomil, 10 mg

amlodipine (as amlodipine besilate) and 12.5 mg hydrochlorothiazide.

40 mg/10 mg/25 mg:

Each film-coated tablet contains 40 mg olmesartan medoxomil, 10 mg

amlodipine (as amlodipine besilate) and 25 mg hydrochlorothiazide.

The other ingredients (excipients) are pregelatinised starch, silicified

microcrystalline cellulose (microcrystalline cellulose and colloidal

anhydrous silica), lactose monohydrate, croscarmellose sodium,

copovidone and magnesium stearate in the tablet core and poly(vinyl

alcohol), macrogol 3350, titanium dioxide (E171), talc, red iron oxide

(E172) – only for 40 mg/5 mg/25 mg, 40 mg/10 mg/12.5 mg,

40 mg/10 mg/25 mg, yellow iron oxide (E172) – only for

40 mg/5 mg/12.5 mg, 40 mg/5 mg/25 mg and black iron oxide (E172) only

for 40 mg/10 mg/25 mg in film coating. See section 2 “Olmesartan

medoxomil/Amlodipine/Hydrochlorothiazide Krka contains lactose and

sodium”.

What Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka

looks like and contents of the pack

20 mg/5 mg/12.5 mg:

Film-coated tablets (tablets) are white or almost white, round, biconvex with

bevelled edges.

Tablet dimensions: diameter 8.5 mm ± 0.5 mm.

40 mg/5 mg/12.5 mg:

Film-coated tablets (tablets) are pale brownish-yellow to pale brown-yellow,

biconvex, capsule-shaped, engraved with a mark C1 on one side of the

tablet.

Tablet dimensions: 15 mm ± 1 mm x 8 mm ± 1 mm.

40 mg/5 mg/25 mg:

Film-coated tablets (tablets) are pale pinkish-orange, biconvex,

capsule-shaped, engraved with a mark C2 on one side of the tablet.

Tablet dimensions: 15 mm ± 1 mm x 8 mm ± 1 mm.

40 mg/10 mg/12.5 mg:

Film-coated tablets (tablets) are pale pink, biconvex, capsule-shaped,

engraved with a mark C3 on one side of the tablet.

Tablet dimensions: 15 mm ± 1 mm x 8 mm ± 1 mm.

40 mg/10 mg/25 mg:

Film-coated tablets (tablets) are pale greyish-violet to pale grey-violet,

biconvex, capsule-shaped, scored on both sides of the tablet. The tablet can

be divided into equal doses.

Tablet dimensions: 15 mm ± 1 mm x 8 mm ± 1 mm.

Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka is available in

boxes containing:

14, 28, 30, 56, 60, 84, 90 and 98 film-coated tablets in blisters.

14, 28, 56 and 98 film-coated tablets in blisters, calendar packs.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

This medicinal product is authorised in the Member States of the EEA

under the following names:

Denmark

Olmesartan/Amlodipin/Hydrochlorthiazid Krka

Belgium

Olmesartan/Amlodipine/HCTZ Krka

Germany

OlmeAmlo HCT

Estonia, Lithuanina,

Latvia, Romania,

Slovenia

Olsitri

Greece

Pollaplo HCT

Spain

Olmesartán/Amlodipino/Hidroclorotiazida Krka

Ireland

Olmesartan medoxomil/Amlodipine/

Hydrochlorothiazide Krka

Portugal

Amlodipina + Olmesartan medoxomilo +

Hidroclorotiazida Krka

This leaflet was last revised in

'DIII

iKRKk

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka 40 mg/5 mg/25 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 40 mg olmesartan medoxomil, 5 mg amlodipine (as amlodipine besilate) and 25 mg

hydrochlorothiazide.

Excipient(s) with known effect:

Each film-coated tablet contains 14.54 mg lactose (as lactose monohydrate).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet (tablet)

Pale pinkish-orange, biconvex, capsule-shaped, film-coated tablets, engraved with a mark C2 on one side of the tablet.

Tablet dimensions: 15 mm ± 1 mm x 8 mm ± 1 mm.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Treatment of essential hypertension.

Add-on therapy

Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka is indicated in adult patients whose blood pressure is not

adequately controlled on the combination of olmesartan medoxomil and amlodipine taken as dual-component formulation.

Substitution therapy

Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka is indicated as substitution therapy in adult patients whose

blood pressure is adequately controlled on the combination of olmesartan medoxomil, amlodipine and hydrochlorothiazide,

taken as a dual-component (olmesartan medoxomil and amlodipine or olmesartan medoxomil and hydrochlorothiazide) and a

single-component formulation (hydrochlorothiazide or amlodipine).

4.2 Posology and method of administration

Posology

Adults

The recommended dose of Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka is 1 tablet per day.

Add-on therapy

Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka 40 mg/5 mg/25 mg may be administered in patients whose

blood pressure is not adequately controlled on Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka 40 mg/5

mg/12.5 mg.

A step-wise titration of the dosage of the individual components is recommended before changing to the triple-component

combination. When clinically appropriate, direct change from dual-component combination to the triple-component

combination may be considered.

Substitution therapy

Patients controlled on stable doses of olmesartan medoxomil, amlodipine and hydrochlorothiazide taken at the same time as a

dual-component (olmesartan medoxomil and amlodipine or olmesartan medoxomil and hydrochlorothiazide) and a

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single-component formulation (hydrochlorothiazide or amlodipine) may be switched to Olmesartan

medoxomil/Amlodipine/Hydrochlorothiazide Krka containing the same component doses.

The maximum recommended dose of Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka is 40 mg/10 mg/25 mg

per day.

Elderly (age 65 years or over)

Caution, including more frequent monitoring of blood pressure, is recommended in elderly people, particularly at the

maximum dose of Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka 40 mg/10 mg/25 mg per day.

An increase of the dosage should take place with care in elderly people (see sections 4.4 and 5.2).

Very limited data are available on the use of olmesartan/amlodipine/HCTZ in patients aged 75 years or older. Extreme caution,

including more frequent monitoring of blood pressure, is recommended.

Renal impairment

The maximum dose in patients with mild to moderate renal impairment (creatinine clearance of 30 – 60 mL/min) is Olmesartan

medoxomil/Amlodipine/Hydrochlorothiazide Krka 20 mg/5 mg/12.5 mg, owing to limited experience of the 40 mg olmesartan

medoxomil dosage in this patient group.

Monitoring of serum concentrations of potassium and creatinine is advised in patients with moderate renal impairment.

The use of Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka in patients with severe renal impairment (creatinine

clearance < 30 mL/min) is contraindicated (see sections 4.3, 4.4 and 5.2).

Hepatic impairment

Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka should be used with caution in patients with mild hepatic

impairment (see sections 4.4 and 5.2).

In patients with moderate hepatic impairment the maximum dose should not exceed Olmesartan

medoxomil/Amlodipine/Hydrochlorothiazide Krka 20 mg/5 mg/12.5 mg once daily. Close monitoring of blood pressure and

renal function is advised in patients with hepatic impairment.

As with all calcium antagonists, amlodipine's half-life is prolonged in patients with impaired liver function and dosage

recommendations have not been established. Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka should therefore

be administered with caution in these patients. The pharmacokinetics of amlodipine have not been studied in severe hepatic

impairment. Amlodipine should be initiated at the lowest dose and titrated slowly in patients with impaired liver function.

Use of Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka is contraindicated in patients with severe hepatic

impairment (see sections 4.3 and 5.2), cholestasis or biliary obstruction (see section 4.3).

Paediatric population

Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka is not recommended for use in patients aged below 18 years

due to a lack of data on safety and efficacy.

Method of administration:

The tablet should be swallowed with a sufficient amount of fluid (e. g. one glass of water). The tablet should not be chewed

and should be taken at the same time each day.

Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka can be taken with or without food.

4.3 Contraindications

Hypersensitivity to the active substances, to dihydropyridine derivates or to sulfonamide-derived substances (since

hydrochlorothiazide is a sulfonamide-derived drug) or to any of the excipients listed in section 6.1.

Severe renal impairment (see sections 4.4 and 5.2).

Refractory hypokalaemia, hypercalcaemia, hyponatraemia and symptomatic hyperuricaemia.

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Severe hepatic insufficiency, cholestasis and biliary obstructive disorders (see section 5.2).

2nd and 3rd trimester of pregnancy (see sections 4.4 and 4.6).

The concomitant use of Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka with aliskiren-containing products is

contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m

) (see sections 4.5 and 5.1).

Due to the amlodipine component, Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka is contraindicated in

patients with:

- Shock (including cardiogenic shock).

- Severe hypotension

- Obstruction of the outflow tract of the left ventricle (e.g. high grade aortic stenosis).

- Haemodynamically unstable heart failure after acute myocardial infarction.

4.4 Special warnings and precautions for use

Patients with hypovolaemia or sodium depletion:

Symptomatic hypotension may occur in patients who are volume and/or sodium depleted as a result of vigorous diuretic

therapy, dietary salt restriction, diarrhoea or vomiting, especially after the first dose. Correction of this condition prior to

administration of Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka or close medical supervision at the start of the

treatment is recommended.

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

In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone

system (e. g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment

with medicinal products that affect this system has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute

renal failure.

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.

Renal impairment and kidney transplantation:

When Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka is used in patients with impaired renal function, periodic

monitoring of serum concentrations of potassium and creatinine is recommended.

Use of Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka is not recommended in patients with severe renal

impairment (creatinine clearance < 30 mL/min) (see sections 4.2, 4.3 and 5.2).

Thiazide diuretic-associated azotaemia may occur in patients with impaired renal function.

If progressive renal impairment becomes evident, careful reappraisal of therapy is necessary, with consideration given to

discontinuing diuretic therapy.

There is no experience of the administration of olmesartan/amlodipine/HCTZ in patients with a recent kidney transplant or in

patients with end-stage renal impairment (i. e. creatinine clearance < 12 mL/min).

Dual blockade of the renin-angiotensin-aldosterone system (RAAS):

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of

hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the

combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections

4.5 and 5.1).

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to

frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

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Hepatic impairment:

Exposure to amlodipine and olmesartan medoxomil is increased in patients with hepatic impairment (see section 5.2).

Furthermore, 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 Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka is administered in patients with mild

to moderate hepatic impairment.

In patients with moderate hepatic impairment, the dose of olmesartan medoxomil should not exceed 20 mg (see section 4.2).

In patients with impaired hepatic function, amlodipine should be initiated at the lower end of the dosing range and caution

should be used, both on initial treatment and when increasing the dose.

Use of Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka is contraindicated in patients with severe hepatic

impairment, cholestasis or biliary obstruction (see section 4.3).

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy:

Due to the amlodipine component of Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka, as with other vasodilators,

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

Primary aldosteronism:

Patients with primary aldosteronism generally will not respond to anti-hypertensive medicinal products acting through

inhibition of the renin-angiotensin system. Therefore, the use of Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka

is not recommended in such patients.

Metabolic and endocrine effects:

Thiazide therapy may impair glucose tolerance. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic

agents may be required (see section 4.5). Latent diabetes mellitus may become manifest during thiazide therapy.

Increases in cholesterol and triglyceride levels are undesirable effects known to be associated with thiazide diuretic therapy.

Hyperuricaemia may occur or frank gout may be precipitated in some patients receiving thiazide therapy.

Electrolyte imbalance:

As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate

intervals.

Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (including hypokalaemia, hyponatraemia and

hypochloraemic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of the mouth, thirst, weakness, lethargy,

drowsiness, restlessness, muscle pain or cramps, muscle fatigue, hypotension, oliguria, tachycardia, and gastrointestinal

disturbances such as nausea or vomiting (see section 4.8).

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).

Conversely, due to antagonism at the angiotensin-II receptors (AT

) through the olmesartan medoxomil component of

Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka hyperkalaemia may occur, especially in the presence of renal

impairment and/or heart failure, and diabetes mellitus. Close monitoring of serum potassium in patients at risk is

recommended. Potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes and other

medicinal products that may increase serum potassium levels (e. g. heparin) should be co-administered cautiously with

Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka (see section 4.5) and with frequent monitoring of potassium

levels.

There is no evidence that olmesartan medoxomil would reduce or prevent diuretic-induced hyponatraemia. Chloride deficit is

generally mild and usually does not require treatment.

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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.

Lithium:

As with other angiotensin II receptor antagonists, the coadministration of Olmesartan

medoxomil/Amlodipine/Hydrochlorothiazide Krka and lithium is not recommended (see section 4.5).

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 angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been

associated with oliguria and/or progressive azotaemia and (rarely) with acute renal failure and/or death.

Patients with heart failure should be treated with caution. In a long-term, placebo controlled study of amlodipine in patients

with severe heart failure (NYHA III and IV), the reported incidence of pulmonary oedema was higher in the amlodipine group

than in the placebo group (see section 5.1). Calcium channel blockers, including amlodipine, should be used with caution in

patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

Sprue-like enteropathy:

In very rare cases severe, chronic diarrhoea with substantial weight loss has been reported in patients taking olmesartan few

months to years after drug initiation, possibly caused by a localized delayed hypersensitivity reaction. Intestinal biopsies of

patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, and in

the absence of other apparent etiologies, olmesartan treatment should be immediately discontinued and should not be

restarted. If diarrhoea does not improve during the week after the discontinuation, further specialist (e.g. a gastro-enterologist)

advice should be considered.

Choroidal effusion, Acute Myopia and Secondary Angle-Closure Glaucoma

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in choroidal effusion with visual field defect,

transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain

and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent

vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical

treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute

angle-closure glaucoma may include a history of sulfonamide or penicillin allergy (see section 4.8).

Pregnancy:

Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued angiotensin II receptor

antagonists therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive

treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with

angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started

(see sections 4.3 and 4.6).

Paediatric population:

Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka is not indicated in children and adolescents under the age of 18

years.

Elderly:

In the elderly, increase of the dosage should take place with care (see section 5.2).

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Photosensitivity:

Cases of photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If photosensitivity reaction

occurs during treatment with Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka, it is recommended to stop the

treatment. If re-administration of the diuretic is deemed necessary, it is recommended to protect the areas exposed to the sun

or to artificial UVA.

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 (see also section 4.8).

Other:

As with any antihypertensive agent, excessive blood pressure reduction in patients with ischaemic heart disease or ischaemic

cerebrovascular disease could result in a myocardial infarction or stroke.

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma,

but are more likely in patients with such a history.

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

As with all other angiotensin II receptor antagonists, the blood pressure lowering effect of olmesartan is somewhat less in black

patients than in non-black patients, however, this effect was not seen in one of the three clinical trials with

olmesartan/amlodipine/HCTZ that included black patients (30 %), see also section 5.1.

Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka contains lactose. Patients with rare hereditary problems of

galactose intolerance, the total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5 Interaction with other medicinal products and other forms of interactions

Potential interactions related to the Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka combination:

Concomitant use not recommended

Lithium:

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of

lithium with angiotensin converting enzyme inhibitors and, rarely, with angiotensin II receptor antagonists. In addition, renal

clearance of lithium is reduced by thiazides and consequently the risk of lithium toxicity may be increased. Therefore use of

Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka and lithium in combination is not recommended (see section

4.4). If use of the combination proves necessary, careful monitoring of serum lithium levels is recommended.

Concomitant use requiring caution

Baclofen:

Potentiation of antihypertensive effect may occur.

Non-steroidal anti-inflammatory medicinal products:

NSAIDs (i.e. acetylsalicylic acid (> 3 g/day), COX-2 inhibitors and non-selective NSAIDs) may reduce the antihypertensive effect

of thiazide diuretics and angiotensin II receptor antagonists.

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In some patients with compromised renal function (e. g. dehydrated patients or elderly people with compromised renal

function) the co-administration of angiotensin II receptor antagonists and agents that inhibit cyclooxygenase may result in

further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, the

combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and

consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically

thereafter.

Concomitant use to be taken into account

Amifostine:

Potentiation of antihypertensive effect may occur.

Other antihypertensive agents:

The blood pressure lowering effect of Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka can be increased by

concomitant use of other antihypertensive medicinal products.

Alcohol, barbiturates, narcotics or antidepressants:

Potentiation of orthostatic hypotension may occur.

Potential interactions related to olmesartan medoxomil:

Concomitant use not recommended

ACE-inhibitors, angiotensin II receptor blockers or aliskiren:

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use

of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as

hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single

RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

Medicinal products affecting potassium levels:

Concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other

medicinal products that may increase serum potassium levels (e. g. heparin, ACE inhibitors) may lead to increases in serum

potassium (see section 4.4). If medicinal products that affect potassium are to be prescribed in combination with Olmesartan

medoxomil/Amlodipine/Hydrochlorothiazide Krka, monitoring of serum potassium is advised.

Additional information

Bile acid sequestering agent colesevelam:

Concurrent administration of the bile acid sequestering agent colesevelam hydrochloride reduces the systemic exposure and

peak plasma concentration of olmesartan and reduces t1/2. Administration of olmesartan medoxomil at least 4 hours prior to

colesevelam hydrochloride decreased the drug interaction effect. Administering olmesartan medoxomil at least 4 hours before

the colesevelam hydrochloride dose should be considered (see section 5.2).

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

observed.

Olmesartan medoxomil had no significant effect on the pharmacokinetics or pharmacodynamics of warfarin or the

pharmacokinetics of digoxin.

Coadministration of olmesartan medoxomil with pravastatin had no clinically relevant effects on the pharmacokinetics of either

component in healthy subjects.

Olmesartan had no clinically relevant inhibitory effects on human cytochrome P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1

and 3A4 in vitro, and had no or minimal inducing effects on rat cytochrome P450 activities. No clinically relevant interactions

between olmesartan and medicinal products metabolised by the above cytochrome P450 enzymes are expected.

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Potential interactions related to amlodipine

Concomitant use requiring caution

Effects of other medicinal products on amlodipine

CYP3A4 inhibitors:

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides

like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure. The

clinical translation of these pharmacokinetic variations may be more pronounced in the elderly. There is an increased risk of

hypotension. Close observation of patients is recommended and dose adjustment may thus be required.

CYP3A4 inducers:

Upon co-administration of known inducers of the CYP3A4, the plasma concentration of amlodipine may vary. Therefore, blood

pressure should be monitored and dose regulation considered both during and after concomitant medication particularly with

strong CYP3A4 inducers (e.g. rifampicin, hypericum perforatum).

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.

Dantrolene (infusion): In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with

hyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalaemia, it is recommended

that the co-administration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant

hyperthermia and in the management of malignant hyperthermia.

Effects of amlodipine on other medicinal products

The blood pressure-lowering effect of amlodipine adds to the blood pressure-lowering effects of other antihypertensive agents.

In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin or warfarin.

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.

Tacrolimus: There is a risk of increased tacrolimus blood levels when co-administered with amlodipine. In order to avoid

toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood

levels and dose adjustment of tacrolimus when appropriate.

Cyclosporine: In a prospective study in renal transplant patients, an average 40% increase in trough cyclosporine levels was

observed when used concomitantly with amlodipine. The co-administration of Olmesartan

medoxomil/Amlodipine/Hydrochlorothiazide Krka with cyclosporine may increase exposure to cyclosporine. Monitor trough

cyclosporine levels during concomitant use and cyclosporine dose reductions should be made as necessary.

Potential interactions related to hydrochlorothiazide:

Concomitant use not recommended

Medicinal products affecting potassium levels:

The potassium-depleting effect of hydrochlorothiazide (see section 4.4) may be potentiated by the coadministration of other

medicinal products associated with potassium loss and hypokalaemia (e. g. other kaliuretic diuretics, laxatives, corticosteroids,

ACTH, amphotericin, carbenoxolone, penicillin G sodium or salicylic acid derivatives). Such concomitant use is therefore not

recommended.

Concomitant use requiring caution

Calcium salts:

Thiazide diuretics may increase serum calcium owing to decreased excretion. If calcium supplements must be prescribed,

serum calcium should be monitored and calcium dosage adjusted accordingly.

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Cholestyramine and colestipol resins:

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

Digitalis glycosides:

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

Medicinal products affected by serum potassium disturbances:

Periodic monitoring of serum potassium and ECG is recommended when Olmesartan

medoxomil/Amlodipine/Hydrochlorothiazide Krka is administered with medicinal products affected by serum potassium

disturbances (e. g. digitalis glycosides and antiarrhythmics) and with the following torsades de pointes (ventricular

tachycardia)-inducing medicinal products (including some antiarrhythmics), hypokalaemia being a predisposing factor to

torsades de pointes (ventricular tachycardia):

- 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, mizolastin, pentamidine, sparfloxacin, terfenadine,

vincamine IV).

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

The effect of nondepolarizing skeletal muscle relaxants may be potentiated by hydrochlorothiazide.

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

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

Antidiabetic medicinal products (oral agents and insulin):

The treatment with a thiazide may influence the glucose tolerance. Dosage adjustment of the antidiabetic medicinal product

may be required (see section 4.4).

Metformin:

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

to hydrochlorothiazide.

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.

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

Dosage adjustment of uricosuric medicinal products may be necessary since hydrochlorothiazide may raise the level of serum

uric acid. Increase in dosage of probenecid or sulfinpyrazone may be necessary. Coadministration of a thiazide may increase

the incidence of hypersensitivity reactions to allopurinol.

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 medicinal products and potentiate their myelosuppressive effects.

Salicylates:

In case of high dosages of salicylates hydrochlorothiazide may enhance the toxic effect of the salicylates on the central nervous

system.

Methyldopa:

There have been isolated reports of haemolytic anaemia occurring with concomitant use of hydrochlorothiazide and

methyldopa.

Health Products Regulatory Authority

13 November 2020

CRN00C0LX

Page 10 of 25

Cyclosporine:

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

Tetracyclines:

Concomitant administration of tetracyclines and thiazides increases the risk of tetracycline-induced increase in urea. This

interaction is probably not applicable to doxycycline.

4.6 Fertility, pregnancy and lactation

Pregnancy

The use of Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka is contra-indicated during the 2nd and 3rd trimester

of pregnancy (see sections 4.3 and 4.4). Given the effects of the individual components in this combination product on

pregnancy, the use of Olmesartan medoxomil/Amlodipine/Hydrochlorothiazide Krka is not recommended during the first

trimester of pregnancy (see section 4.4).

Olmesartan medoxomil

The use of angiotensin II receptor antagonists is not recommended during the first trimester of pregnancy (see section 4.4).

The use of angiotensin II receptor antagonists is contra-indicated during the 2nd and 3rd trimester of pregnancy (see sections

4.3 and 4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of

pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled

epidemiological data on the risk with angiotensin II receptor antagonists, similar risks may exist for this class of drugs. Unless

continued angiotensin receptor blocker therapy is considered essential, patients planning pregnancy should be changed to

alternative anti-hypertensive treatments, which have an established safety profile for use in pregnancy. When pregnancy is

diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative

therapy should be started.

Exposure to angiotensin II receptor antagonists therapy during the 2nd and 3rd trimesters is known to induce human

fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure,

hypotension, hyperkalaemia) (see also section 5.3).

Should exposure to angiotensin II receptor antagonists have occurred from the 2nd trimester of pregnancy, ultrasound check

of renal function and skull is recommended.

Infants, whose mothers have taken angiotensin II receptor antagonists should be closely observed for hypotension (see

also sections 4.3 and 4.4).

Hydrochlorothiazide

There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are

insufficient.

Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use

during the 2nd and 3rd trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like

icterus, disturbance of electrolyte balance and thrombocytopenia.

Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or pre-eclampsia due to the risk of

decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease.

Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other

treatment could be used.

Amlodipine

Data on a limited number of exposed pregnancies do not indicate that amlodipine or other calcium receptor antagonists have

a harmful effect on the health of the fetus. However, there may be a risk of prolonged delivery.

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