Amlodipine/Valsartan/Hydrochlorothiazide Rowex 5 mg/160 mg/12.5 mg Film-coated tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
Amlodipine besilate; Valsartan; Hydrochlorothiazide
Available from:
Rowex Ltd
ATC code:
C09DX; C09DX01
INN (International Name):
Amlodipine besilate; Valsartan; Hydrochlorothiazide
Dosage:
5/160/12.5 milligram(s)
Pharmaceutical form:
Film-coated tablet
Therapeutic area:
Angiotensin II antagonists, other combinations; valsartan, amlodipine and hydrochlorothiazide
Authorization status:
Not marketed
Authorization number:
PA0711/291/001
Authorization date:
2019-08-19

Package leaflet: Information for the user

Amlodipine/Valsartan/Hydrochlorothiazide Rowex 5 mg/160 mg/12.5 mg Film-coated tablets

Amlodipine/Valsartan/Hydrochlorothiazide Rowex 10 mg/160 mg/12.5 mg Film-coated tablets

Amlodipine/Valsartan/Hydrochlorothiazide Rowex 5 mg/160 mg/25 mg Film-coated tablets

Amlodipine/Valsartan/Hydrochlorothiazide Rowex 10 mg/160 mg/25 mg Film-coated tablets

Amlodipine/Valsartan/Hydrochlorothiazide Rowex 10 mg/320 mg/25 mg Film-coated tablets

amlodipine/valsartan/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

What Amlodipine/Valsartan/Hydrochlorothiazide Rowex is and what it is used for

What you need to know before you take Amlodipine/Valsartan/Hydrochlorothiazide Rowex

How to take Amlodipine/Valsartan/Hydrochlorothiazide Rowex

Possible side effects

How to store Amlodipine/Valsartan/Hydrochlorothiazide Rowex

Contents of the pack and other information

1.

What Amlodipine/Valsartan/Hydrochlorothiazide Rowex is and what it is used for

Amlodipine/Valsartan/Hydrochlorothiazide Rowex tablets contain three substances called amlodipine,

valsartan and hydrochlorothiazide. All of these substances help to control high blood pressure.

Amlodipine belongs to a group of substances called “calcium channel blockers”. Amlodipine stops

calcium from moving into the blood vessel wall, which stops the blood vessels from tightening.

Valsartan belongs to a group of substances called “angiotensin-II receptor antagonists”. Angiotensin

II is produced by the body and makes the blood vessels tighten, thus increasing the blood pressure.

Valsartan works by blocking the effect of angiotensin II.

Hydrochlorothiazide

belongs

group

substances

called

“thiazide

diuretics”.

Hydrochlorothiazide increases urine output, which also lowers blood pressure.

As a result of all three mechanisms, the blood vessels relax and blood pressure is lowered.

Amlodipine/Valsartan/Hydrochlorothiazide Rowex is used to treat high blood pressure in adult patients

whose blood pressure is already controlled while taking amlodipine, valsartan and hydrochlorothiazide

and who may benefit from taking one tablet containing all three substances.

2.

What you need to know before you take Amlodipine/Valsartan/Hydrochlorothiazide Rowex

Do not take Amlodipine/Valsartan/Hydrochlorothiazide Rowex

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

Amlodipine/Valsartan/Hydrochlorothiazide Rowex in early pregnancy – see Pregnancy section).

allergic

amlodipine

other

calcium

channel

blockers,

valsartan,

hydrochlorothiazide, sulphonamide-derived medicines (medicines used to treat chest or urinary

infections), or any of the other ingredients of this medicine (listed in section 6)

If you think you may be allergic, do not take Amlodipine/Valsartan/Hydrochlorothiazide Rowex

and talk to your doctor.

if you have liver disease, destruction of the small bile ducts within the liver (biliary cirrhosis) leading

to the build up of bile in the liver (cholestasis)

if you have severe kidney problems or if you are having dialysis

if you are unable to produce urine (anuria)

if the level of potassium or sodium in your blood is too low despite treatment to increase the

potassium or sodium levels in your blood

if the level of calcium in your blood is too high despite treatment to reduce the calcium levels in

your blood

if you have gout (uric acid crystals in the joints)

if you have severe low blood pressure (hypotension)

if you have narrowing of the aortic valve (aortic stenosis) or cardiogenic shock (a condition where

your heart is unable to supply enough blood to the body)

if you suffer from heart failure after a heart attack

if you have diabetes or impaired kidney function and you are treated with a blood pressure lowering

medicine containing aliskiren.

If any of the above applies to you, do not take Amlodipine/Valsartan/Hydrochlorothiazide Rowex

and talk to your doctor.

Warnings and precautions

Talk to your doctor or pharmacist before taking Amlodipine/Valsartan/Hydrochlorothiazide Rowex

if you have a low level of potassium or magnesium in your blood (with or without symptoms such

as muscle weakness, muscle spasms, abnormal heart rhythm)

if you have a low level of sodium in your blood (with or without symptoms such as tiredness,

confusion, muscle twitching, convulsions)

if you have a high level of calcium in your blood (with or without symptoms such as nausea,

vomiting, constipation, stomach pain, frequent urination, thirst, muscle weakness and twitching)

if you have kidney problems, have had a kidney transplant or if you had been told that you have a

narrowing of your kidney arteries

if you have liver problems

if you have or have had heart failure or coronary artery disease, particularly if you are prescribed

the maximum dose of Amlodipine/Valsartan/Hydrochlorothiazide Rowex (10 mg/320 mg/25 mg)

if you have experienced a heart attack. Follow your doctor’s instructions for the starting dose

carefully. Your doctor may also check your kidney function.

if your doctor has told you that you have a narrowing of the valves in your heart (called “aortic or

mitral stenosis”) or that the thickness of your heart muscle is abnormally increased (called

“obstructive hypertrophic cardiomyopathy”)

if you suffer from aldosteronism. This is a disease in which the adrenal glands make too much of

the hormone aldosterone. If this applies to you, the use of

Amlodipine/Valsartan/Hydrochlorothiazide Rowex is not recommended.

if you suffer from a disease called systemic lupus erythematosus (also called “lupus” or “SLE”)

if you have diabetes (high level of sugar in your blood)

if you have high levels of cholesterol or triglycerides in your blood

if you experience skin reactions such as rash after sun exposure

if you had an allergic reaction to other high blood pressure medicines or diuretics (a type of

medicine also known as “water tablets”), especially if you suffer from asthma and allergies

if you have been sick (vomiting or diarrhoea)

if you have experienced swelling, particularly of the face and throat, while taking other medicines

(including angiotensin converting enzyme inhibitors). If you get these symptoms, stop taking

Amlodipine/Valsartan/Hydrochlorothiazide Rowex and contact your doctor straight away. You

should never take Amlodipine/Valsartan/Hydrochlorothiazide Rowex again.

if you experience dizziness and/or fainting during treatment with

Amlodipine/Valsartan/Hydrochlorothiazide Rowex, tell your doctor as soon as possible

if you experience a decrease in vision or eye pain. These could be symptoms of an increase of

pressure in your eye and can happen within hours to a week of taking

Amlodipine/Valsartan/Hydrochlorothiazide Rowex. This can lead to permanent vision

impairment, if not treated.

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.

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 (non-melanoma skin cancer). Protect your skin from sun

exposure and UV rays while taking Amlodipine/Valsartan/Hydrochlorothiazide Rowex.

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 Amlodipine/Valsartan/Hydrochlorothiazide

Rowex”.

If any of these apply to you, talk to your doctor.

Children and adolescents

The use of Amlodipine/Valsartan/Hydrochlorothiazide Rowex in children and adolescents under

18 years of age is not recommended.

Elderly people (age 65 years and older)

Amlodipine/Valsartan/Hydrochlorothiazide Rowex can be used by people aged 65 years and over at

the same dose as for other adults and in the same way as they have already taken the three substances

called amlodipine, valsartan and hydrochlorothiazide. Elderly patients, particularly those taking the

maximum dose of Amlodipine/Valsartan/Hydrochlorothiazide Rowex (10 mg/320 mg/25 mg), should

have their blood pressure checked regularly.

Other medicines and Amlodipine/Valsartan/Hydrochlorothiazide Rowex

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

medicines. Your doctor may need to change your dose and/or to take other precautions. In some cases

you may have to stop using one of the medicines. This is especially important if you are using any of

the medicines listed below:

Do not take together with:

lithium (a medicine used to treat some types of depression)

medicines or substances that increase the amount of potassium in your blood. These include

potassium supplements or salt substitutes containing potassium, potassium-sparing medicines and

heparin

ACE inhibitors or aliskiren (see also information under the headings “Do not take

Amlodipine/Valsartan/Hydrochlorothiazide Rowex” and “Warnings and precautions”).

Caution should be used with:

alcohol, sleeping pills and anaesthetics (medicines allowing patients to undergo surgery and other

procedures)

amantadine (anti-Parkinson therapy, also used to treat or prevent certain illnesses caused by

viruses)

anticholinergic agents (medicines used to treat a variety of disorders such as gastrointestinal

cramps, urinary bladder spasm, asthma, motion sickness, muscular spasms, Parkinson's disease

and as an aid to anaesthesia)

anticonvulsant medicines and mood-stabilising medicines used to treat epilepsy and bipolar

disorder (e.g. carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone)

cholestyramine, colestipol or other resins (substances used mainly to treat high levels of lipids in

the blood)

simvastatin (a medicine used to control high cholesterol levels)

ciclosporin (a medicine used in transplantation to prevent organ rejection or for other conditions,

e.g. rheumatoid arthritis or atopic dermatitis)

cytotoxic medicines (used to treat cancer), such as methotrexate or cyclophosphamide

digoxin or other digitalis glycosides (medicines used to treat heart problems)

verapamil, diltiazem (heart medicines)

iodine contrast media (agents used for imaging examinations)

medicines for the treatment of diabetes (oral agents such as metformin or insulins)

medicines for the treatment of gout, such as allopurinol

medicines that may increase blood sugar levels (beta blockers, diazoxide)

medicines that may induce “torsades de pointes” (irregular heartbeat), such as antiarrhythmics

(medicines used to treat heart problems) and some antipsychotics

medicines that may reduce the amount of sodium in your blood, such as antidepressants,

antipsychotics, antiepileptics

medicines that may reduce the amount of potassium in your blood, such as diuretics (water

tablets), corticosteroids, laxatives, amphotericin or penicillin G

medicines to increase blood pressure such as adrenaline or noradrenaline

medicines used for HIV/AIDS (e.g. ritonavir, indinavir, nelfinavir)

medicines used to treat fungal infections (e.g. ketoconazole, itraconazole)

medicines used for oesophageal ulceration and inflammation (carbenoxolone)

medicines used to relieve pain or inflammation, especially non-steroidal anti-inflammatory agents

(NSAIDs), including selective cyclooxygenase-2 inhibitors (Cox-2 inhibitors)

muscle relaxants (medicines to relax the muscles which are used during operations)

nitroglycerin and other nitrates, or other substances called “vasodilators”

other medicines to treat high blood pressure, including methyldopa

rifampicin (used, for example, to treat tuberculosis), erythromycin, clarithromycin (antibiotics)

St. John’s wort

dantrolene (infusion for severe body temperature abnormalities)

vitamin D and calcium salts.

Amlodipine/Valsartan/Hydrochlorothiazide Rowex with food, drink and alcohol

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

Amlodipine/Valsartan/Hydrochlorothiazide Rowex. This is because grapefruit and grapefruit juice can

lead to an increase in the blood levels of the active substance amlodipine, which can cause an

unpredictable increase in the blood pressure lowering effect of

Amlodipine/Valsartan/Hydrochlorothiazide Rowex. Talk to your doctor before drinking alcohol.

Alcohol may make your blood pressure fall too much and/or increase the possibility of dizziness or

fainting.

Pregnancy and breast-feeding

Pregnancy

You must tell your doctor if you think you are (or might become) pregnant. Your doctor will

normally advise you to stop taking Amlodipine/Valsartan/Hydrochlorothiazide Rowex before you

become pregnant or as soon as you know you are pregnant and will advise you to take another

medicine instead of Amlodipine/Valsartan/Hydrochlorothiazide Rowex.

Amlodipine/Valsartan/Hydrochlorothiazide Rowex is not recommended in early 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.

Breast-feeding

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

Amlodipine/Valsartan/Hydrochlorothiazide Rowex is not recommended for mothers who are breast-

feeding, and your doctor may choose another treatment for you if you wish to breast-feed, especially if

your baby is a newborn, or was born prematurely.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

This medicine may make you feel dizzy, drowsy, nauseous or have a headache. If you experience

these symptoms, do not drive or use tools or machines.

3.

How to take Amlodipine/Valsartan/Hydrochlorothiazide Rowex

Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not

sure. This will help you get the best results and lower the risk of side effects.

The usual dose of Amlodipine/Valsartan/Hydrochlorothiazide Rowex is one tablet per day.

It is best to take the tablet at the same time each day. Morning is the best time.

Swallow the tablet whole with a glass of water.

You can take Amlodipine/Valsartan/Hydrochlorothiazide Rowex with or without food. Do not

take Amlodipine/Valsartan/Hydrochlorothiazide Rowex with grapefruit or grapefruit juice.

Depending on how you respond to the treatment, your doctor may suggest a higher or lower dose.

Do not exceed the prescribed dose.

If you take more Amlodipine/Valsartan/Hydrochlorothiazide Rowex than you should

If you have accidentally taken too many Amlodipine/Valsartan/Hydrochlorothiazide Rowex tablets,

talk to a doctor immediately. You may require medical attention.

If you forget to take Amlodipine/Valsartan/Hydrochlorothiazide Rowex

If you forget to take a dose of this medicine, take it as soon as you remember and then take the next

dose at its usual time. If it is almost time for your next dose you should simply take the next tablet at

the usual time. Do not take a double dose (two tablets at once) to make up for a forgotten tablet.

If you stop taking Amlodipine/Valsartan/Hydrochlorothiazide Rowex

Stopping your treatment with Amlodipine/Valsartan/Hydrochlorothiazide Rowex may cause your

disease to get worse. Do not stop taking your medicine unless your doctor tells you to.

Always take this medicine, even if you are feeling well

People who have high blood pressure often do not notice any signs of the problem. Many feel normal.

It is very important that you take this medicine exactly as your doctor tells you to get the best results

and reduce the risk of side effects. Keep your appointments with the doctor even if you are feeling

well.

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.

As for any combination containing three active substances, side effects associated with each individual

component cannot be excluded. The side effects reported with

Amlodipine/Valsartan/Hydrochlorothiazide Rowex or one of its three active substances (amlodipine,

valsartan and hydrochlorothiazide) are listed below and may occur with the use of

Amlodipine/Valsartan/Hydrochlorothiazide Rowex.

Some side effects can be serious and need immediate medical attention.

Consult a doctor immediately if you experience any of the following serious side effects after

taking this medicine:

Common (may affect up to 1 in 10 people):

dizziness

low blood pressure (feeling of faintness, light-headedness, sudden loss of consciousness).

Uncommon (may affect up to 1 in 100 people):

severely decreased urine output (decreased kidney function).

Rare (may affect up to 1 in 1,000 people):

spontaneous bleeding

irregular heartbeat

liver disorder.

Very rare (may affect up to 1 in 10,000 people):

sudden wheeziness, chest pain, shortness of breath or difficulty breathing

swelling of eyelids, face or lips

swelling of the tongue and throat which causes great difficulty breathing

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 the mucous

membranes (Stevens-Johnson syndrome, toxic epidermal necrolysis) or other allergic reactions

heart attack

inflamed pancreas, which may cause severe abdominal and back pain accompanied with feeling of

being very unwell

weakness, bruising, fever and frequent infections

stiffness.

Other side effects may include:

Very common (may affect more than 1 in 10 people):

low level of potassium in the blood

increase of lipids in the blood.

Common (may affect up to 1 in 10 people):

sleepiness

palpitations (awareness of your heartbeat)

flushing

ankle swelling (oedema)

abdominal pain

stomach discomfort after meal

tiredness

headache

frequent urination

high level of uric acid in the blood

low level of magnesium in the blood

low level of sodium in the blood

dizziness, fainting on standing up

reduced appetite

nausea and vomiting

itchy rash and other types of rash

inability to achieve or maintain an erection.

Uncommon (may affect up to 1 in 100 people):

fast heartbeat

spinning sensation

vision disorder

stomach discomfort

chest pain

increase of urea nitrogen, creatinine and uric acid in the blood

high level of calcium, fat or sodium in the blood

decrease of potassium in the blood

breath odour

diarrhoea

dry mouth

weight increase

loss of appetite

disturbed sense of taste

back pain

joint swelling

muscle cramps/weakness/pain

pain in extremity

inability to either stand or walk in a normal manner

weakness

abnormal coordination

dizziness on standing up or after exercising

lack of energy

sleep disturbances

tingling or numbness

neuropathy

sudden, temporary loss of consciousness

low blood pressure on standing up

cough

breathlessness

throat irritation

excessive sweating

itching

swelling, reddening and pain along a vein

skin reddening

trembling

mood changes

anxiety

depression

sleeplessness

taste abnormalities

fainting

loss of pain sensation

visual disturbances

visual impairment

ringing in the ears

sneezing/runny nose caused by inflammation of the lining of the nose (rhinitis)

altered bowel habits

indigestion

hair loss

itchy skin

skin discolouration

disorder in passing urine

increased need to urinate at night

increased number of times of passing urine

discomfort or enlargement of the breasts in men

pain

feeling unwell

weight decrease.

Rare (may affect up to 1 in 1,000 people):

low level of blood platelets (sometimes with bleeding or bruising underneath the skin)

sugar in the urine

high level of sugar in the blood

worsening of the diabetic metabolic state

abdominal discomfort

constipation

liver disorders which can occur together with yellow skin and eyes, or dark-coloured urine

(haemolytic anaemia)

increased sensitivity of skin to sun

purple skin patches

kidney disorders

confusion.

Very rare (may affect up to 1 in 10,000 people):

decreased number of white blood cells

decrease in blood platelets which may result in unusual brusing or easy bleeding (red blood cell

damage)

swelling of the gums

abdominal bloating (gastritis)

inflammation of the liver (hepatitis)

yellowing of the skin (jaundice)

liver enzyme increase which may have an effect on some medical tests

increased muscle tension

inflammation of blood vessels often with skin rash

sensitivity to light

disorders combining rigidity, tremor and/or movement disorders

fever, sore throat or mouth ulcers, more frequent infections (lack or low level of white blood cells)

pale

skin,

tiredness,

breathlessness,

dark-coloured

urine

(haemolytic

anaemia,

abnormal

breakdown of red blood cells either in the blood vessels or elsewhere in the body)

confusion, tiredness, muscle twitching and spasm, rapid breathing (hypochloraemic alkalosis)

severe upper stomach ache (inflammation of the pancreas)

difficulty

breathing

with

fever,

coughing,

wheezing,

breathlessness

(respiratory

distress,

pulmonary oedema, pneumonitis)

facial rash, joint pain, muscle disorder, fever (lupus erythematosus)

inflammation of blood vessels with symptoms such as rash, purplish-red spots, fever (vasculitis)

severe skin disease that causes rash, red skin, blistering of the lips, eyes or mouth, skin peeling,

fever (toxic epidermal necrolysis).

Not known (frequency cannot be estimated from the available data):

changes in blood tests for kidney function, increase of potassium in your blood, low level of red

blood cells

abnormal red blood cell test

low level of a certain type of white blood cell and blood platelet

increase of creatinine in the blood

abnormal liver function test

severely decreased urine output

inflammation of blood vessels

weakness, bruising and frequent infections (aplastic anaemia)

decrease in vision or pain in your eyes due to high pressure (possible signs of acute angle-closure

glaucoma)

breathlessness

severely decreased urine output (possible signs of renal disorder or renal failure)

severe skin disease that causes rash, red skin, blistering of the lips, eyes or mouth, skin peeling,

fever (erythema multiforme)

muscle spasm

fever (pyrexia)

blistering skin (sign of a condition called dermatitis bullous)

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 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 Amlodipine/Valsartan/Hydrochlorothiazide Rowex

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 carton and blister after EXP. The

expiry date refers to the last day of that month.

Do not store above 30

Store in the original package in order to protect from moisture.

Do not use any Amlodipine/Valsartan/Hydrochlorothiazide Rowex pack that is damaged or shows signs

of tampering.

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 Amlodipine/Valsartan/Hydrochlorothiazide Rowex contains

Amlodipine/Valsartan/Hydrochlorothiazide Rowex 5 mg/160 mg/12.5 mg Film-coated tablets

The active substances of Amlodipine/Valsartan/Hydrochlorothiazide Rowex are amlodipine (as

amlodipine besylate), valsartan and hydrochlorothiazide. Each film-coated tablet contains 5 mg

amlodipine (as amlodipine besylate), 160 mg valsartan and 12.5 mg hydrochlorothiazide.

The other ingredients are cellulose microcrystalline; crospovidone (type A); silica, colloidal

anhydrous; magnesium stearate; hypromellose (type 2910); macrogol 4000; talc; titanium dioxide

(E171).

Amlodipine/Valsartan/Hydrochlorothiazide Rowex 10 mg/160 mg/12.5 mg Film-coated tablets

The active substances of Amlodipine/Valsartan/Hydrochlorothiazide Rowex are amlodipine (as

amlodipine besylate), valsartan and hydrochlorothiazide. Each film-coated tablet contains 10 mg

amlodipine (as amlodipine besylate), 160 mg valsartan, and 12.5 mg hydrochlorothiazide.

The other ingredients are cellulose microcrystalline; crospovidone (type A); silica, colloidal

anhydrous; magnesium stearate; hypromellose (type 2910); macrogol 4000; talc; titanium dioxide

(E171); yellow iron oxide (E172); red iron oxide (E172).

Amlodipine/Valsartan/Hydrochlorothiazide Rowex 5 mg/160 mg/25 mg Film-coated tablets

The active substances of Amlodipine/Valsartan/Hydrochlorothiazide Rowex are amlodipine (as

amlodipine besylate), valsartan and hydrochlorothiazide. Each film-coated tablet contains 5 mg

amlodipine (as amlodipine besylate), 160 mg valsartan and 25 mg hydrochlorothiazide.

The other ingredients are cellulose microcrystalline; crospovidone (type A); silica, colloidal

anhydrous; magnesium stearate; hypromellose (type 2910); macrogol 4000; talc; titanium dioxide

(E171); yellow iron oxide (E172).

Amlodipine/Valsartan/Hydrochlorothiazide Rowex 10 mg/160 mg/25 mg Film-coated tablets

The active substances of Amlodipine/Valsartan/Hydrochlorothiazide Rowex are amlodipine (as

amlodipine besylate), valsartan and hydrochlorothiazide. Each film-coated tablet contains 10 mg

amlodipine (as amlodipine besylate), 160 mg valsartan, and 25 mg hydrochlorothiazide.

The other ingredients are cellulose microcrystalline; crospovidone (type A); silica, colloidal

anhydrous; magnesium stearate; hypromellose (type 2910); macrogol 4000; talc; yellow iron oxide

(E172).

Amlodipine/Valsartan/Hydrochlorothiazide Rowex 10 mg/320 mg/25 mg Film-coated tablets

The active substances of Amlodipine/Valsartan/Hydrochlorothiazide Rowex are amlodipine (as

amlodipine besylate), valsartan and hydrochlorothiazide. Each film-coated tablet contains 10 mg

amlodipine (as amlodipine besylate), 320 mg valsartan, and 25 mg hydrochlorothiazide.

The other ingredients are cellulose microcrystalline; crospovidone (type A); silica, colloidal

anhydrous; magnesium stearate; hypromellose (type 2910); macrogol 4000; talc; yellow iron oxide

(E172).

What Amlodipine/Valsartan/Hydrochlorothiazide Rowex looks like and contents of the pack

Amlodipine/Valsartan/Hydrochlorothiazide Rowex 5 mg/160 mg/12.5 mg Film-coated tablets

Amlodipine/Valsartan/Hydrochlorothiazide Rowex 5 mg/160 mg/12.5 mg Film-coated tablets are

white, oval tablets with “NVR” on one side and “VCL” on the other side.

Length: approx. 15 mm

Width: approx. 5.9 mm

Amlodipine/Valsartan/Hydrochlorothiazide Rowex 10 mg/160 mg/12.5 mg Film-coated tablets

Amlodipine/Valsartan/Hydrochlorothiazide Rowex 10 mg/160 mg/12.5 mg Film-coated tablets are

pale yellow, oval tablets with “NVR” on one side and “VDL” on the other side.

Length: approx. 15 mm

Width: approx. 5.9 mm

Amlodipine/Valsartan/Hydrochlorothiazide Rowex 5 mg/160 mg/25 mg Film-coated tablets

Amlodipine/Valsartan/Hydrochlorothiazide Rowex 5 mg/160 mg/25 mg Film-coated tablets are

yellow, oval tablets with “NVR” on one side and “VEL” on the other side.

Length: approx. 15 mm

Width: approx. 5.9 mm

Amlodipine/Valsartan/Hydrochlorothiazide Rowex 10 mg/160 mg/25 mg Film-coated tablets

Amlodipine/Valsartan/Hydrochlorothiazide Rowex 10 mg/160 mg/25 mg Film-coated tablets are

brown-yellow, oval tablets with “NVR” on one side and “VHL” on the other side.

Length: approx. 15 mm

Width: approx. 5.9 mm

Amlodipine/Valsartan/Hydrochlorothiazide Rowex 10 mg/320 mg/25 mg Film-coated tablets

Amlodipine/Valsartan/Hydrochlorothiazide Rowex 10 mg/320 mg/25 mg Film-coated tablets are

brown-yellow, oval tablets with “NVR” on one side and “VFL” on the other side.

Length: approx. 19 mm

Width: approx. 7.5 mm

Amlodipine/Valsartan/Hydrochlorothiazide Rowex is available in PVC/PVDC-Alu blister or unit dose

blister packs.

Amlodipine/Valsartan/Hydrochlorothiazide Rowex is available in blister packs containing 14, 28,

28x1, 30, 56, 56x1, 60, 90, 98, 98x1, 100, 280 or 280x1 film-coated tablets, in multipacks of 280

tablets (comprising 4 cartons, each containing 70x1 tablets, or 20 cartons, each containing 14 tablets).

Not all pack sizes may be available in your country.

Marketing Authorisation Holder and Manufacturers

Marketing Authorisation Holder

Rowex Ltd., Bantry, Co. Cork, Ireland.

Manufacturers

Salutas Pharma GmbH, Otto-von Guericke -Allee 1, 39179 Barleben, Sachsen-Anhalt, Germany.

Novartis Farmacéutica SA, Ronda de Santa Maria, 158, 08210 Barberà del Vallès (Barcelona), Spain.

Novartis Pharma GmbH, Roonstrasse 25, 90429 Nürnberg, Bayern, Germany.

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

names:

Austria

Amlodipin/ Valsartan/ HCT Sandoz 5 mg/ 160 mg/ 12,5 mg - Filmtabletten

Amlodipin/ Valsartan/ HCT Sandoz 10 mg/160 mg/12,5 mg – Filmtabletten

Amlodipin/ Valsartan/ HCT Sandoz 5 mg/160 mg/25 mg - Filmtabletten

Amlodipin/ Valsartan/ HCT Sandoz HCT 10 mg/160 mg/25 mg –

Filmtabletten

Amlodipin/ Valsartan/ HCT Sandoz 10 mg/320 mg/25 mg – Filmtabletten

Belgium

Amlodipin/Valsartan/HCT Sandoz 5mg/160mg/12,5mg filmomhulde

tabletten

Amlodipin/Valsartan/HCT Sandoz 10mg/160mg/12,5mg filmomhulde

tabletten

Amlodipin/Valsartan/HCT Sandoz 5mg/160mg/25mg filmomhulde

tabletten

Amlodipin/Valsartan/HCT Sandoz 10mg/160mg/25mg filmomhulde

tabletten

Amlodipin/Valsartan/HCT Sandoz 10mg/320mg/25mg filmomhulde

tabletten

Croatia

Amlodipin/valsartan/hidroklorotiazid Sandoz 5 mg/160 mg/12,5 mg filmom

obložene tablete

Amlodipin/valsartan/hidroklorotiazid Sandoz 10 mg/160 mg/12,5 mg

filmom obložene tablete

Amlodipin/valsartan/hidroklorotiazid Sandoz 5 mg/160 mg/25 mg filmom

obložene tablete

Amlodipin/valsartan/hidroklorotiazid Sandoz 10 mg/160 mg/25 mg filmom

obložene tablete

Amlodipin/valsartan/hidroklorotiazid Sandoz 10 mg/320 mg/25 mg filmom

obložene tablete

Finland

Amlodipin/Valsartan/Hydrochlorothiazide Sandoz 5 mg/160 mg/

12,5 mg tabletti, kalvopäällysteinen

Amlodipin/Valsartan/Hydrochlorothiazide Sandoz 10 mg/160 mg/

12,5 mg tabletti, kalvopäällysteinen

Amlodipin/Valsartan/Hydrochlorothiazide Sandoz 5 mg/160 mg/

25 mg tabletti, kalvopäällysteinen

Amlodipin/Valsartan/Hydrochlorothiazide Sandoz 10 mg/160 mg/

25 mg tabletti, kalvopäällysteinen

Amlodipin/Valsartan/Hydrochlorothiazide Sandoz 10 mg/320 mg/

25 mg tabletti, kalvopäällysteinen

Germany

Amlodipin/Valsartan/HCT - 1 A Pharma 5 mg/160 mg/12,5 mg

Filmtabletten

Amlodipin/Valsartan/HCT - 1 A Pharma 10 mg/160 mg/12,5 mg

Filmtabletten

Amlodipin/Valsartan/HCT - 1 A Pharma 5 mg/160 mg/25 mg Filmtabletten

Amlodipin/Valsartan/HCT - 1 A Pharma 10 mg/160 mg/25 mg

Filmtabletten

Amlodipin/Valsartan/HCT - 1 A Pharma 10 mg/320 mg/25 mg

Filmtabletten

Greece

Amlodipine+Valsartan+Hydrochlorothiazide/Sandoz (5+160+12,5) mg

επικαλυμμένα με λεπτό υμένιο δισκία

Amlodipine+Valsartan+Hydrochlorothiazide/Sandoz (10+160+12,5) mg

επικαλυμμένα με λεπτό υμένιο δισκία

Amlodipine+Valsartan+Hydrochlorothiazide/Sandoz (5+160+25) mg

επικαλυμμένα με λεπτό υμένιο δισκία

Amlodipine+Valsartan+Hydrochlorothiazide/Sandoz (10+160+25) mg

επικαλυμμένα με λεπτό υμένιο δισκία

Amlodipine+Valsartan+Hydrochlorothiazide/Sandoz (10+320+25) mg

επικαλυμμένα με λεπτό υμένιο δισκία

Hungary

Amlodipin/Valsartan/HCT Sandoz 5 mg/160 mg/12,5 mg filmtabletta

Amlodipin/Valsartan/HCT Sandoz 10 mg/160 mg/12,5 mg filmtabletta

Amlodipin/Valsartan/HCT Sandoz 5 mg/160 mg/25 mg filmtabletta

Amlodipin/Valsartan/HCT Sandoz 10 mg/160 mg/25 mg filmtabletta

Amlodipin/Valsartan/HCT Sandoz 10 mg/320 mg/25 mg filmtabletta

Ireland

Amlodipine/Valsartan/ Hydrochlorothiazide Rowex 5 mg/160 mg/12.5 mg

Film-coated tablets

Amlodipine/Valsartan/ Hydrochlorothiazide Rowex 10 mg/160 mg/12.5 mg

Film-coated tablets

Amlodipine/Valsartan/ Hydrochlorothiazide Rowex 5 mg/160 mg/25 mg

Film-coated tablets

Amlodipine/Valsartan/ Hydrochlorothiazide Rowex 10 mg/160 mg/25 mg

Film-coated tablets

Amlodipine/Valsartan/ Hydrochlorothiazide Rowex 10 mg/320/25 mg Film-

coated tablets

Lithuania

Amlodipine/Valsartan/ Hydrochlorothiazide Sandoz 5 mg/160 mg/12,5 mg

plėvele dengtos tabletės

Amlodipine/Valsartan/ Hydrochlorothiazide Sandoz 10 mg/160 mg/12,5 mg

plėvele dengtos tabletės

Amlodipine/Valsartan/ Hydrochlorothiazide Sandoz 5 mg/160 mg/ 25 mg

plėvele dengtos tabletės

Amlodipine/Valsartan/ Hydrochlorothiazide Sandoz 10 mg/160 mg/25 mg

plėvele dengtos tabletės

Amlodipine/Valsartan/ Hydrochlorothiazide Sandoz 10 mg/320 mg/25 mg

plėvele dengtos tabletės

Spain

Amlodipino/Valsartán/Hidroclorotiazida Sandoz 5 mg/160 mg/12,5 mg

comprimidos recubiertos con película EFG

Amlodipino/Valsartán/Hidroclorotiazida Sandoz 10 mg/160 mg/12,5 mg

comprimidos recubiertos con película EFG

Amlodipino/Valsartán/Hidroclorotiazida Sandoz 5 mg/160 mg/25 mg

comprimidos recubiertos con película EFG

Amlodipino/Valsartán/Hidroclorotiazida Sandoz 10 mg/160 mg/25 mg

comprimidos recubiertos con película EFG

Amlodipino/Valsartán/Hidroclorotiazida Sandoz 10 mg/320 mg/25 mg

comprimidos recubiertos con película EFG

The Netherlands

Amlodipine besilaat/Valsartan/HCT Sandoz 5 mg/160 mg/12.5 mg

filmomhulde tabletten

Amlodipine besilaat/Valsartan/HCT Sandoz 10 mg/160 mg/12.5 mg

filmomhulde tabletten

Amlodipine besilaat/Valsartan/HCT Sandoz 5 mg/160 mg/25 mg

filmomhulde tabletten

Amlodipine besilaat/Valsartan/HCT Sandoz 10 mg/160 mg/25 mg

filmomhulde tabletten

Amlodipine besilaat/Valsartan/HCT Sandoz 10 mg/320 mg/25 mg

filmomhulde tabletten

This leaflet was last revised in 09/2019.

Health Products Regulatory Authority

20 August 2019

CRN008LMV

Page 1 of 20

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Amlodipine/Valsartan/Hydrochlorothiazide Rowex 5 mg/160 mg/12.5 mg Film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 5 mg of amlodipine (as amlodipine besylate), 160 mg of valsartan and 12.5 mg of

hydrochlorothiazide.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet

White, ovaloid, biconvex tablets with bevelled edge, debossed "NVR" on one side and "VCL" on the other side.

Length: approx. 15 mm

Width: approx. 5.9 mm

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Treatment of essential hypertension as substitution therapy in adult patients whose blood pressure is adequately controlled on

the combination of amlodipine, valsartan and hydrochlorothiazide (HCT), taken either as three single-component formulations

or as a dual-component and a single-component formulation.

4.2 Posology and method of administration

The recommended dose of Amlodipine/Valsartan/Hydrochlorothiazide Rowex is one tablet per day, to be taken preferably in

the morning.

Before switching to Amlodipine/Valsartan/Hydrochlorothiazide Rowex patients should be controlled on stable doses of the

monocomponents taken at the same time. The dose of Amlodipine/Valsartan/Hydrochlorothiazide Rowex should be based on

the doses of the individual components of the combination at the time of switching.

The maximum recommended dose of Amlodipine/Valsartan/Hydrochlorothiazide Rowex is 10 mg/320 mg/25 mg.

Special populations

Renal impairment

Due to the hydrochlorothiazide component, Amlodipine/Valsartan/Hydrochlorothiazide Rowex is contraindicated for use in

patients

with

anuria

(see

section

4.3)

patients

with

severe

renal

impairment

(glomerular

filtration

rate

(GFR)

<30 ml/min/1.73 m

) (see sections 4.3, 4.4 and 5.2).

No adjustment of the initial dose is required for patients with mild to moderate renal impairment (see sections 4.4 and 5.2).

Hepatic impairment

Due to the valsartan component, Amlodipine/Valsartan/Hydrochlorothiazide Rowex is contraindicated in patients with severe

hepatic impairment (see section 4.3). In patients with mild to moderate hepatic impairment without cholestasis, the maximum

recommended dose is 80 mg valsartan and therefore Amlodipine/Valsartan/Hydrochlorothiazide Rowex is not suitable in this

group of patients (see sections 4.3, 4.4 and 5.2). Amlodipine dose recommendations have not been established in patients with

mild to moderate hepatic impairment. When switching eligible hypertensive patients (see section 4.1) with hepatic impairment

to Amlodipine/Valsartan/Hydrochlorothiazide Rowex, the lowest available dose of the amlodipine component should be used.

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Heart failure and coronary artery disease

There is limited experience with the use of amlodipine/valsartan/HCT, particulary at the maximum dose, in patients with heart

failure and coronary artery disease. Caution is advised in patients with heart failure and coronary artery disease, particularly at

the maximum dose of amlodipine/valsartan/HCT, 10 mg/320 mg/25 mg.

Elderly (age 65 years or over)

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

maximum dose of amlodipine/valsartan/HCT, 10 mg/320 mg/25 mg, since available data in this patient population are limited.

When switching eligible elderly hypertensive patients (see section 4.1) to Amlodipine/Valsartan/Hydrochlorothiazide Rowex,

the lowest available dose of the amlodipine component should be used.

Paediatric population

There is no relevant use of Amlodipine/Valsartan/Hydrochlorothiazide Rowex in the paediatric population (patients below age

18 years) for the indication of essential hypertension.

Method of administration

Oral use.

Amlodipine/Valsartan/Hydrochlorothiazide Rowex can be taken with or without food.

The tablets should be swallowed whole with some water, at the same time of the day and preferably in the morning.

4.3 Contraindications

-Hypersensitivity to the active substances, to other sulphonamide derivatives, to dihydropyridine derivatives, or to any of the

excipients listed in section 6.1.

-Second and third trimesters of pregnancy (see sections 4.4 and 4.6).

-Hepatic impairment, biliary cirrhosis or cholestasis.

-Severe renal impairment (GFR <30 ml/min/1.73 m

), anuria and patients undergoing dialysis.

-Concomitant use of Amlodipine/Valsartan/Hydrochlorothiazide Rowex with aliskiren-containing products in patients with

diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m

) (see sections 4.5 and 5.1).

-Refractory hypokalaemia, hyponatraemia, hypercalcaemia, and symptomatic hyperuricaemia.

-Severe hypotension.

-Shock (including cardiogenic shock).

-Obstruction of the outflow tract of the left ventricle (e.g. hypertrophic obstructive cardiomyopathy and high grade aortic

stenosis).

-Haemodynamically unstable heart failure after acute myocardial infarction.

4.4 Special warnings and precautions for use

The safety and efficacy of amlodipine in hypertensive crisis have not been established.

Sodium- and/or volume-depleted patients

Excessive hypotension, including orthostatic hypotension, was seen in 1.7% of patients treated with the maximum dose of

amlodipine/valsartan/HCT

(10 mg/320 mg/25 mg)

compared

1.8%

valsartan/hydrochlorothiazide

(320 mg/25 mg)

patients, 0.4% of amlodipine/valsartan (10 mg/320 mg) patients, and 0.2% of hydrochlorothiazide/amlodipine (25 mg/10 mg)

patients in a controlled trial in patients with moderate to severe uncomplicated hypertension.

sodium-depleted

and/or

volume-depleted

patients,

such

those

receiving

high

doses

diuretics,

symptomatic

hypotension may occur after initiation of treatment with amlodipine/valsartan/HCT. Amlodipine/Valsartan/Hydrochlorothiazide

Rowex should be used only after correction of any pre-existing sodium and/or volume depletion.

If excessive hypotension occurs with Amlodipine/Valsartan/Hydrochlorothiazide Rowex, the patient should be placed in the

supine position and, if necessary, given an intravenous infusion of normal sodium chloride solution. Treatment can be

continued once blood pressure has been stabilised.

Serum electrolyte changes

Amlodipine/valsartan/hydrochlorothiazide

In the controlled trial of amlodipine/valsartan/HCT the counteracting effects of valsartan 320 mg and hydrochlorothiazide

25 mg on serum potassium approximately balanced each other in many patients. In other patients, one or the other effect may

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Page 3 of 20

be dominant. Periodic determinations of serum electrolytes to detect possible electrolyte imbalance should be performed at

appropriate intervals.

Periodic determination of serum electrolytes and potassium in particular should be performed at appropriate intervals to

detect possible electrolyte imbalance, especially in patients with other risk factors such as impaired renal function, treatment

with other medicinal products or history of prior electrolyte imbalances.

Valsartan

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

medicinal products that may increase potassium levels (heparin, etc.) is not recommended. Monitoring of potassium should be

undertaken as appropriate.

Hydrochlorothiazide

Treatment with Amlodipine/Valsartan/Hydrochlorothiazide Rowex should only start after correction of hypokalaemia and any

coexisting hypomagnesaemia. Thiazide diuretics can precipitate new onset hypokalaemia or exacerbate pre-existing

hypokalaemia. Thiazide diuretics should be administered with caution in patients with conditions involving enhanced

potassium loss, for example salt‑losing nephropathies and prerenal (cardiogenic) impairment of kidney function. If

hypokalaemia develops during hydrochlorothiazide therapy, Amlodipine/Valsartan/Hydrochlorothiazide Rowex should be

discontinued until stable correction of the potassium balance.

Thiazide diuretics can precipitate new onset hyponatraemia and hypochloroaemic alkalosis or exacerbate pre-existing

hyponatraemia. Hyponatraemia, accompanied by neurological symptoms (nausea, progressive disorientation, apathy) has been

observed. Treatment with hydrochlorothiazide should only be started after correction of pre-existing hyponatraemia. In case

severe or rapid hyponatraemia develops during Amlodipine/Valsartan/Hydrochlorothiazide Rowex therapy, the treatment

should be discontinued until normalisation of natraemia.

All patients receiving thiazide diuretics should be periodically monitored for imbalances in electrolytes, particularly potassium,

sodium and magnesium.

Renal impairment

Thiazide

diuretics

precipitate

azotaemia

patients

with

chronic

kidney

disease.

When

Amlodipine/Valsartan/Hydrochlorothiazide Rowex is used in patients with renal impairment periodic monitoring of serum

electrolytes

(including

potassium),

creatinine

uric

acid

serum

levels

recommended.

Amlodipine/Valsartan/Hydrochlorothiazide Rowex is contraindicated in patients with severe renal impairment, anuria or

undergoing dialysis (see section 4.3).

No dose adjustment of Amlodipine/Valsartan/Hydrochlorothiazide Rowex is required for patients with mild to moderate renal

impairment (GFR ≥30 ml/min/1.73 m

Renal artery stenosis

Amlodipine/Valsartan/Hydrochlorothiazide Rowex should be used with caution to treat hypertension in patients with unilateral

or bilateral renal artery stenosis or stenosis to a solitary kidney since blood urea and serum creatinine may increase in such

patients.

Kidney transplantation

To date there is no experience of the safe use of amlodipine/valsartan/HCT in patients who have had a recent kidney

transplantation.

Hepatic impairment

Valsartan is mostly eliminated unchanged via the bile. The half-life of amlodipine is prolonged and AUC values are higher in

patients with impaired liver function; dose recommendations have not been established. In patients with mild to moderate

hepatic impairment without cholestasis, the maximum recommended dose is 80 mg valsartan, and therefore,

Amlodipine/Valsartan/Hydrochlorothiazide Rowex is not suitable in this group of patients (see sections 4.2, 4.3 and 5.2).

Angioedema

Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx,

and/or

tongue,

been

reported

patients

treated

with

valsartan.

Some

these

patients

previously

experienced

angioedema with other medicinal products including ACE inhibitors. Amlodipine/Valsartan/Hydrochlorothiazide Rowex should

be discontinued immediately in patients who develop angioedema and should not be re-administered.

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Heart failure and coronary artery disease/post-myocardial infarction

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. Similar outcomes have been

reported

with

valsartan.

Evaluation

patients

with

heart

failure

post-myocardial

infarction

should

always

include

assessment of renal function.

In a long-term, placebo-controlled study (PRAISE-2) of amlodipine in patients with NYHA (New York Heart Association

Classification) III and IV heart failure of non-ischaemic aetiology, amlodipine was associated with increased reports of

pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo.

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.

Caution

advised

patients

with

heart

failure

coronary

artery

disease,

particularly

maximum

dose

amlodipine/valsartan/HCT, 10 mg/320 mg/25 mg, since available data in these patient populations is limited.

Aortic and mitral valve stenosis

As with all other vasodilators, special caution is indicated in patients with mitral stenosis or significant aortic stenosis that is not

high grade.

Pregnancy

Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRA therapy is

considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an

established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped

immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Primary hyperaldosteronism

Patients with primary hyperaldosteronism should not be treated with the angiotensin II antagonist valsartan as their

renin-angiotensin system is not activated. Therefore, Amlodipine/Valsartan/Hydrochlorothiazide Rowex is not recommended in

this population.

Systemic lupus erythematosus

Thiazide diuretics, including hydrochlorothiazide, have been reported to exacerbate or activate systemic lupus erythematosus.

Other metabolic disturbances

Thiazide diuretics, including hydrochlorothiazide, may alter glucose tolerance and raise serum levels of cholesterol, triglycerides

and uric acid. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic agents may be required.

hydrochlorothiazide

component,

Amlodipine/Valsartan/Hydrochlorothiazide

Rowex

contraindicated

symptomatic hyperuricaemia. Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid

and may cause or exacerbate hyperuricaemia as well as precipitate gout in susceptible patients.

Thiazides reduce urinary calcium excretion and may cause intermittant and slight elevation of serum calcium in the absence of

known disorders of calcium metabolism. Amlodipine/Valsartan/Hydrochlorothiazide Rowex is contraindicated in patients with

hypercalcaemia

should

only

used

after

correction

pre-existing

hypercalcaemia.

Amlodipine/Valsartan/Hydrochlorothiazide Rowex should be discontinued if hypercalcaemia develops during treatment. Serum

levels of calcium should be periodically monitored during treatment with thiazides. Marked hypercalcaemia may be evidence of

hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

Photosensitivity

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

occurs during treatment with Amlodipine/Valsartan/Hydrochlorothiazide Rowex, 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.

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Page 5 of 20

Acute angle-closure glaucoma

Hydrochlorothiazide, a sulphonamide, has been associated with an idiosyncratic reaction resulting in 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 a week of treatment 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 treatment 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.

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.

Elderly (age 65 years or over)

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

maximum dose of amlodipine/valsartan/HCT, 10 mg/320 mg/25 mg, since available data in this patient population are limited.

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

There is evidence that the concomitant use of ACE inhibitors, ARBs 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, ARBs 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 ARBs should not be used

concomitantly in patients with diabetic nephropathy.

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 (HCT) exposure has been observed in two epidemiological studies based on

the Danish National Cancer Registry. Photosensitizing actions of HCT could act as a possible mechanism for NMSC.

Patients taking HCT 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

HCT may also need to be reconsidered in patients who have experienced previous NMSC (see also section 4.8).

4.5 Interaction with other medicinal products and other forms of interactions

No formal interaction studies with other medicinal products have been performed with amlodipine/valsartan/HCT. Thus, only

information on interactions with other medicinal products that are known for the individual active substances is provided in

this section.

However, it is important to take into account that amlodipine/valsartan/HCT may increase the hypotensive effect of other

antihypertensive agents.

Concomitant use not recommended

Active substance(s)

Known interactions with the following agents

Effect of the interaction with other

medicinal products

Valsartan and

Lithium

Reversible increases in serum lithium

concentrations and toxicity have been

reported during concomitant administration

of lithium with ACE inhibitors, angiotensin II

receptor antagonists including valsartan or

thiazides. Since renal clearance of lithium is

reduced by thiazides, the risk of lithium

toxicity may presumably be increased further

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20 August 2019

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Page 6 of 20

with

Amlodipine/Valsartan/Hydrochlorothiazide

Rowex. Therefore careful monitoring of

serum lithium concentrations is

recommended during concomitant use.

Valsartan

Potassium-sparing diuretics, potassium supplements,

salt substitutes containing potassium and other

substances that may increase potassium levels

If a medicinal product that affects potassium

levels is considered necessary in

combination with valsartan, frequent

monitoring of potassium plasma levels is

advised.

Amlodipine

Grapefruit or grapefruit juice

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.

Caution required with concomitant use

Active substance(s)

Known

interactions

with the

following

agents

Effect of the interaction with other medicinal products

Amlodipine

CYP3A4

inhibitors

(i.e.

ketoconazole,

itraconazole,

ritonavir)

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. Clinical monitoring and dose adjustment may thus be required.

CYP3A4

inducers

(anticonvulsant

agents [e.g.

carbamazepine,

phenobarbital,

phenytoin,

fosphenytoin,

primidone],

rifampicin,

Hypericum

perforatum [St.

John's wort])

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).

Simvastatin

Co-administration of multiple doses of 10 mg amlodipine with 80 mg simvastatin

resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone.

It is recommended to limit the dose of simvastatin to 20 mg daily in patients on

amlodipine.

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.

Valsartan and HCT

Non-steroidal

anti-inflammat

ory drugs

(NSAIDs),

including

selective

cyclooxygenase-2

inhibitors

NSAIDS can attenuate the antihypertensive effect of both angiotensin II antagonists

and hydrochlorothiazide when administered simultaneously. Furthermore,

concomitant use of Amlodipine/Valsartan/Hydrochlorothiazide Rowex and NSAIDs

may lead to worsening of renal function and an increase in serum potassium.

Therefore, monitoring of renal function at the beginning of the treatment is

recommended, as well as adequate hydration of the patient.

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(COX-2

inhibitors),

acetylsalicylic

acid (>3 g/day),

and

non-selective

NSAIDs

Valsartan

Inhibitors of the

uptake

transporter

(rifampicin,

ciclosporin) or

efflux

transporter

(ritonavir)

The results of an in vitro study with human liver tissue indicate that valsartan is a

substrate of the hepatic uptake transporter OATP1B1 and of the hepatic efflux

transporter MRP2. Co-administration of inhibitors of the uptake transporter

(rifampicin, ciclosporin) or efflux transporter (ritonavir) may increase the systemic

exposure to valsartan.

Alcohol,

barbiturates or

narcotics

Concomitant administration of thiazide diuretics with substances that also have a

blood pressure lowering effect (e.g. by reducing sympathetic central nervous system

activity or direct vasodilatation) may potentiate orthostatic hypotension.

Amantadine

Thiazides, including hydrochlorothiazide, may increase the risk of adverse reactions

caused by amantadine.

Anticholinergic

agents and

other medicinal

products

affecting gastric

motility

The bioavailability of thiazide-type diuretics may be increased by anticholinergic

agents (e.g. atropine, biperiden), apparently due to a decrease in gastrointestinal

motility and the stomach emptying rate. Conversely, it is anticipated that prokinetic

substances such as cisapride may decrease the bioavailability of thiazide-type

diuretics.

Antidiabetic

agents (e.g.

insulin and oral

antidiabetic

agents)

Thiazides may alter glucose tolerance.Dose adjustment of the antidiabetic medicinal

product may be necessary.

-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

Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta

blockers may increase the risk of hyperglycaemia. Thiazide diuretics, including

hydrochlorothiazide, may enhance the hyperglycaemic effect of diazoxide.

Ciclosporin

Concomitant treatment with ciclosporin may increase the risk of hyperuricaemia and

gout-type complications.

Cytotoxic

agents

Thiazides, including hydrochlorothiazide, may reduce the renal excretion of cytotoxic

agents (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive

effects.

Digitalis

glycosides

Thiazide-induced hypokalaemia or hypomagnesaemia may occur as undesirable

effects, favouring the onset of digitalis-induced cardiac arrhythmias.

Iodine

contrasting

agents

In case of diuretic-induced dehydration, there is an increased risk of acute renal

failure, especially with high doses of iodine products. Patients should be re-hydrated

before the administration.

Ion exchange

resins

Absorption of thiazide diuretics, including hydrochlorothiazide, is decreased by

cholestyramine or colestipol. This could result in sub-therapeutic effects of thiazide

diuretics. However, staggering the dosage of hydrochlorothiazide and resin such that

hydrochlorothiazide is administered at least 4 hours before or 4‑6 hours after the

administration of resins would potentially minimise the interaction.

Medicinal

products

affecting serum

potassium level

The hypokalaemic effect of hydrochlorothiazide may be increased by concomitant

administration of kaliuretic diuretics, corticosteroids, laxatives, adrenocorticotropic

hormone (ACTH), amphotericin, carbenoxolone, penicillin G and salicylic acid

derivatives or antiarrhythmics. If these medicinal products are to be prescribed with

the amlodipine /valsartan /hydrochlorothiazide combination, monitoring of

potassium plasma levels is advised.

Medicinal

products

The hyponatraemic effect of diuretics may be intensified by concomitant

administration of medicinal products such as antidepressants, antipsychotics,

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affecting serum

sodium level

antiepileptics, etc. Caution is indicated in long-term administration of these medicinal

products.

Medicinal

products that

could induce

torsades de

pointes

Due to the risk of hypokalaemia, hydrochlorothiazide should be administered with

caution when associated with medicinal products that could induce torsades de

pointes, in particular Class Ia and Class III antiarrhythmics and some antipsychotics.

Medicinal

products used in

the treatment of

gout

(probenecid,

sulfinpyrazone

and allopurinol)

Dose adjustment of uricosuric medicinal products may be necessary as

hydrochlorothiazide may raise the level of serum uric acid. Increase of dose of

probenecid or sulfinpyrazone may be necessary.

Co-administration of thiazide diuretics, including hydrochlorothiazide, may increase

the incidence of hypersensitivity reactions to allopurinol.

Methyldopa

There have been isolated reports of haemolytic anaemia occurring with concomitant

use of hydrochlorothiazide and methyldopa.

Non-depolarising

skeletal muscle

relaxants (e.g.

tubocurarine)

Thiazides, including hydrochlorothiazide, potentiate the action of curare derivatives.

Other

anti-hypertensive

medicinal

products

Thiazides potentiate the antihypertensive action of other antihypertensive medicinal

products (e.g. guanethidine, methyldopa, beta‑blockers, vasodilators, calcium

channel blockers, ACE inhibitors, ARBs and Direct Renin Inhibitors [DRIs]).

Pressor amines

(e.g.

noradrenaline,

adrenaline)

Hydrochlorothiazide may reduce the response to pressor amines such as

noradrenaline. The clinical significance of this effect is uncertain and not sufficient to

preclude their use.

Vitamin D and

calcium salts

Administration of thiazide diuretics, including hydrochlorothiazide, with vitamin D or

with calcium salts may potentiate the rise in serum calcium. Concomitant use of

thiazide type diuretics may lead to hypercalcaemia in patients pre-disposed for

hypercalcaemia (e.g. hyperparathyroidism, malignancy or vitamin-D-mediated

conditions) by increasing tubular calcium reabsorption.

Dual blockade of the RAAS with ARBs, ACE inhibitors or aliskiren

Clinical trial data have shown that dual blockade of the RAAS through the combined use of ACE inhibitors, ARBs 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).

4.6 Fertility, pregnancy and lactation

Pregnancy

Amlodipine

The safety of amlodipine in human pregnancy has not been established. In animal studies, reproductive toxicity was observed

at high doses (see section 5.3). Use in pregnancy is only recommended when there is no safer alternative and when the disease

itself carries greater risk for the mother and foetus.

Valsartan

The use of Angiotensin II Receptor Antagonists (AIIRAs) is not recommended during the first trimester of pregnancy (see

section 4.4). The use of AIIRAs is contraindicated during the second and third trimesters 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 (AIIRAs), similar risks may exist for this class of

medicinal products. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to

alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is

diagnosed, treatment with AIIRAs should be stopped immediately, and if appropriate, alternative therapy should be started.

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Exposure to AIIRAs therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal

function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see

section 5.3).

Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull

is recommended.

Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see 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 second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects

like icterus, disturbance of electrolyte balance and thrombocytopenia.

Amlodipine/valsartan/hydrochlorothiazide

There is no experience on the use of amlodipine/valsartan/HCT in pregnant women. Based on the existing data with the

components, the use of Amlodipine/Valsartan/Hydrochlorothiazide Rowex is not recommended during first trimester and

contra-indicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).

Breast-feeding

No information is available regarding the use of valsartan during breast-feeding. 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. Hydrochlorothiazide is excreted in human milk in small

amounts.

Thiazides

high

doses

causing

intense

diuresis

inhibit

milk

production.

Amlodipine/Valsartan/Hydrochlorothiazide

Rowex

during

breast-feeding

recommended.

Amlodipine/Valsartan/Hydrochlorothiazide Rowex is used during breast-feeding, doses should be kept as low as possible.

Alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a

newborn or preterm infant.

Fertility

There are no clinical studies on fertility with amlodipine/valsartan/HCT.

Valsartan

Valsartan had no adverse reactions on the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day.

This dose is 6 times the maximum recommended human dose on a mg/m

basis (calculations assume an oral dose of

320 mg/day and a 60-kg patient).

Amlodipine

Reversible biochemical changes in the head of spermatozoa have been reported in some patients treated by calcium channel

blockers. Clinical data are insufficient regarding the potential effect of amlodipine on fertility. In one rat study, adverse

reactions were found on male fertility (see section 5.3).

4.7 Effects on ability to drive and use machines

Patients taking Amlodipine/Valsartan/Hydrochlorothiazide Rowex and driving vehicles or using machines should take into

account that dizziness or weariness may occasionally occur.

Amlodipine

have

mild

moderate

influence

ability

drive

machines.

patients

taking

Amlodipine/Valsartan/Hydrochlorothiazide Rowex suffer from dizziness, headache, fatigue or nausea the ability to react may

be impaired.

4.8 Undesirable effects

The safety profile of amlodipine/valsartan/HCT presented below is based on clinical studies performed with

amlodipine/valsartan/HCT and the known safety profile of the individual components amlodipine, valsartan and

hydrochlorothiazide.

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Summary of the safety profile

The safety of amlodipine/valsartan/HCT has been evaluated at its maximum dose of 10 mg/320 mg/25 mg in one controlled

short-term (8 weeks) clinical study with 2,271 patients, 582 of whom received valsartan in combination with amlodipine and

hydrochlorothiazide. Adverse reactions were generally mild and transient in nature and only infrequently required

discontinuation of therapy. In this active controlled clinical trial, the most common reasons for discontinuation of therapy with

amlodipine/valsartan/HCT were dizziness and hypotension (0.7%).

In the 8-week controlled clinical study, no significant new or unexpected adverse reactions were observed with triple therapy

treatment compared to the known effects of the monotherapy or dual therapy components.

In the 8-week controlled clinical study, changes in laboratory parameters observed with the combination of

amlodipine/valsartan/HCT were minor and consistent with the pharmacological mechanism of action of the monotherapy

agents. The presence of valsartan in the triple combination attenuated the hypokalaemic effect of hydrochlorothiazide.

Tabulated list of adverse reactions

The following adverse reactions, listed by MedDRA System Organ Class and frequency, concern amlodipine/valsartan/HCT and

amlodipine, valsartan and HCT individually.

Very common: ≥1/10; 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, not known (cannot be estimated from the available data).

MedDRA

System Organ

Class

Adverse reactions

Frequency

Amlodipine/valsartan/

HCT

Amlodipine

Valsartan

HCT

Neoplasms

benign,

malignant and

unspecified (incl

cysts and

polyps)

Non-melanoma skin cancer (Basal

cell carcinoma and Squamous cell

carcinoma)

Not known

Blood and

lymphatic

system

disorders

Agranulocytosis, bone marrow

failure

Very rare

Haemoglobin and haematocrit

decreased

Not known

Haemolytic anaemia

Very rare

Leukopenia

Very rare

Very rare

Neutropenia

Not known

Thrombocytopenia, sometimes with

purpura

Very rare

Not known

Rare

Aplastic anaemia

Not known

Immune system

disorders

Hypersensitivity

Very rare

Not known

Very rare

Metabolism and

nutrition

disorders

Anorexia

Uncommon

Hypercalcaemia

Uncommon

Rare

Hyperglycaemia

Very rare

Rare

Hyperlipidaemia

Uncommon

Hyperuricaemia

Uncommon

Common

Hypochloraemic alkalosis

Very rare

Hypokalaemia

Common

Very common

Hypomagnesaemia

Common

Hyponatraemia

Uncommon

Common

Worsening of diabetic metabolic

Rare

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state

Psychiatric

disorders

Depression

Uncommon

Rare

Insomnia/sleep disorders

Uncommon

Uncommon

Rare

Mood swings

Uncommon

Confusion

Rare

Nervous system

disorders

Coordination abnormal

Uncommon

Dizziness

Common

Common

Rare

Dizziness postural, dizziness

exertional

Uncommon

Dysgeusia

Uncommon

Uncommon

Extrapyramidal syndrome

Not known

Headache

Common

Common

Rare

Hypertonia

Very rare

Lethargy

Uncommon

Paraesthesia

Uncommon

Uncommon

Rare

Peripheral neuropathy, neuropathy

Uncommon

Very rare

Somnolence

Uncommon

Common

Syncope

Uncommon

Uncommon

Tremor

Uncommon

Hypoesthesia

Uncommon

Eye disorders

Acute angle-closure glaucoma

Not known

Visual disturbance

Uncommon

Visual impairment

Uncommon

Uncommon

Rare

Ear and

labyrinth

disorders

Tinnitus

Uncommon

Vertigo

Uncommon

Uncommon

Cardiac

disorders

Palpitations

Common

Tachycardia

Uncommon

Arrhythmias (including bradycardia,

ventricular tachycardia, and atrial

fibrillation)

Very rare

Rare

Myocardial infarction

Very rare

Vascular

disorders

Flushing

Common

Hypotension

Common

Uncommon

Orthostatic hypotension

Uncommon

Common

Phlebitis, thrombophlebitis

Uncommon

Vasculitis

Very rare

Not known

Respiratory,

thoracic and

mediastinal

disorders

Cough

Uncommon

Very rare

Uncommon

Dyspnoea

Uncommon

Uncommon

Respiratory distress, pulmonary

oedema, pneumonitis

Very rare

Rhinitis

Uncommon

Throat irritation

Uncommon

Gastrointestinal

disorders

Abdominal discomfort, abdominal

pain upper

Uncommon

Common

Uncommon

Rare

Breath odour

Uncommon

Change of bowel habit

Uncommon

Constipation

Rare

Decreased appetite

Common

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Diarrhoea

Uncommon

Uncommon

Rare

Dry mouth

Uncommon

Uncommon

Dyspepsia

Common

Uncommon

Gastritis

Very rare

Gingival hyperplasia

Very rare

Nausea

Uncommon

Common

Common

Pancreatitis

Very rare

Very rare

Vomiting

Uncommon

Uncommon

Common

Hepatobiliary

disorders

Liver function test abnormal,

including blood bilirubin increase

Very rare**

Not known

Hepatitis

Very rare

Intrahepatic cholestasis, jaundice

Very rare

Rare

Skin and

subcutaneous

tissue disorders

Alopecia

Uncommon

Angioedema

Very rare

Not known

Dermatitis bullous

Not known

Cutaneous lupus

erythematosus-like reactions,

reactivation of cutaneous lupus

erythematosus

Very rare

Erythema multiforme

Very rare

Not known

Exanthema

Uncommon

Hyperhidrosis

Uncommon

Uncommon

Photosensitivity reaction*

Very rare

Rare

Pruritus

Uncommon

Uncommon

Not known

Purpura

Uncommon

Rare

Rash

Uncommon

Not known

Common

Skin discoloration

Uncommon

Urticaria and other forms of rash

Very rare

Common

Vasculitis necrotising and toxic

epidermal necrolysis

Not known

Very rare

Exfoliative dermatitis

Very rare

Stevens-Johnson syndrome

Very rare

Quincke oedema

Very rare

Musculoskeletal

and connective

tissue disorders

Arthralgia

Uncommon

Back pain

Uncommon

Uncommon

Joint swelling

Uncommon

Muscle spasm

Uncommon

Uncommon

Not known

Muscular weakness

Uncommon

Myalgia

Uncommon

Uncommon

Not known

Pain in extremity

Uncommon

Ankle swelling

Common

Renal and

urinary

disorders

Blood creatinine increased

Uncommon

Not known

Micturition disorder

Uncommon

Nocturia

Uncommon

Pollakiuria

Common

Uncommon

Renal dysfunction

Not known

Acute renal failure

Uncommon

Not known

Renal failure and impairment

Not known

Rare

Reproductive

system and

breast disorders

Impotence

Uncommon

Uncommon

Common

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Gynaecomastia

Uncommon

General

disorders and

administration

site conditions

Abasia, gait disturbance

Uncommon

Asthenia

Uncommon

Uncommon

Not known

Discomfort, malaise

Uncommon

Uncommon

Fatigue

Common

Common

Uncommon

Non cardiac chest pain

Uncommon

Uncommon

Oedema

Common

Common

Pain

Uncommon

Pyrexia

Not known

Investigations

Lipids increased

Very common

Blood urea nitrogen increased

Uncommon

Blood uric acid increased

Uncommon

Glycosuria

Rare

Blood potassium decreased

Uncommon

Blood potassium increased

Not known

Weight increase

Uncommon

Uncommon

Weight decrease

Uncommon

* See section 4.4 Photosensitivity

** Mostly consistent with cholestasis

Description of selected adverse reactions

Non-melanoma skin cancer: based on available data from epidemiological studies, cumulative dose-dependent association

between HCT and NMSC has been observed (see also sections 4.4 and 5.1).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517.

Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

4.9 Overdose

Symptoms

There is no experience of overdose with amlodipine/valsartan/HCT. The major symptom of overdose with valsartan is possibly

pronounced hypotension with dizziness. Overdose with amlodipine may result in excessive peripheral vasodilation and,

possibly, reflex tachycardia. Marked and potentially prolonged systemic hypotension, including shock with fatal outcome, have

been reported with amlodipine.

Treatment

Amlodipine/Valsartan/Hydrochlorothiazide

Clinically

significant

hypotension

Amlodipine/Valsartan/Hydrochlorothiazide

Rowex

overdose

calls

active

cardiovascular support, including frequent monitoring of cardiac and respiratory function, elevation of 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.

Amlodipine

If ingestion is recent, induction of vomiting or gastric lavage may be considered. Administration of activated charcoal to

healthy volunteers immediately or up to two hours after ingestion of amlodipine has been shown to significantly decrease

amlodipine absorption.

Amlodipine is unlikely to be removed by haemodialysis.

Valsartan

Valsartan is unlikely to be removed by haemodialysis.

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Hydrochlorothiazide

Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloraemia) and hypovolaemia

resulting

from

excessive

diuresis.

most

common

signs

symptoms

overdose

nausea

somnolence.

Hypokalaemia may result in muscle spasms and or accentuate arrhythmia associated with the concomitant use of digitalis

glycosides or certain anti‑arrhythmic medicinal products.

The degree to which hydrochlorothiazide is removed by haemodialysis has not been established.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Agents acting on the renin-angiotensin system, angiotensin II antagonists, other combinations,

ATC code:C09DX01.

Mechanism of action

Amlodipine/Valsartan/Hydrochlorothiazide

Rowex

combines

three

antihypertensive

compounds

with

complementary

mechanisms to control blood pressure in patients with essential hypertension: amlodipine belongs to the calcium antagonist

class and valsartan to the angiotensin II antagonist class of medicinal products and hydrochlorothiazide belongs to the thiazide

diuretics class of medicinal products. The combination of these substances has an additive antihypertensive effect.

Amlodipine/Valsartan/Hydrochlorothiazide

Clinical efficacy and safety

Amlodipine/valsartan/HCT was studied in a double-blind, active controlled study in hypertensive patients. A total of

2,271 patients with moderate to severe hypertension (mean baseline systolic/diastolic blood pressure was 170/107 mmHg)

received treatments of amlodipine/valsartan/hydrochlorothiazide,10 mg/320 mg/25 mg, valsartan/hydrochlorothiazide

320 mg/25 mg, amlodipine/valsartan 10 mg/320 mg, or hydrochlorothiazide/amlodipine 25 mg/10 mg. At study initiation

patients were assigned lower doses of their treatment combination and were titrated to their full treatment dose by week 2.

week 8,

mean

reductions

systolic/diastolic

blood

pressure

were

39.7/24.7 mmHg

with

amlodipine/valsartan/hydrochlorothiazide,

32.0/19.7 mmHg

with

valsartan/hydrochlorothiazide,

33.5/21.5 mmHg

with

amlodipine/valsartan,

31.5/19.5 mmHg

with

amlodipine/hydrochlorothiazide.

triple

combination

therapy

statistically superior to each of the three dual combination treatments in reduction of diastolic and systolic blood pressures.

The reductions in systolic/diastolic blood pressure with amlodipine/valsartan/HCT were 7.6/5.0 mmHg greater than with

valsartan/hydrochlorothiazide, 6.2/3.3 mmHg greater than with amlodipine/valsartan, and 8.2/5.3 mmHg greater than with

amlodipine/hydrochlorothiazide. The full blood pressure lowering effect was achieved 2 weeks after being on their maximal

dose

amlodipine/valsartan/HCT.

Statistically

greater

proportions

patients

achieved

blood

pressure

control

(<140/90 mmHg) with amlodipine/valsartan/HCT (71%) compared to each of the three dual combination therapies (45‑54%)

(p<0.0001).

In a subgroup of 283 patients focusing on ambulatory blood pressure monitoring, clinically and statistically superior reductions

24-hour

systolic

diastolic

blood

pressures

were

observed

with

triple

combination

compared

valsartan/hydrochlorothiazide, valsartan/amlodipine, and hydrochlorothiazide/amlodipine.

Amlodipine

Mechanism of action

The amlodipine component of Amlodipine/Valsartan/Hydrochlorothiazide Rowex inhibits the transmembrane entry of calcium

ions into cardiac and vascular smooth muscle. The mechanism of the antihypertensive action of amlodipine is due to a direct

relaxant effect on vascular smooth muscle, causing reductions in peripheral vascular resistance and in blood pressure.

Pharmacodynamic effects

Experimental data suggest that amlodipine binds to both dihydropyridine and non-dihydropyridine 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.

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.

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Plasma concentrations correlate with effect in both young and elderly patients.

In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular

resistance and increases 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 humans, even when co-administered with beta blockers to humans.

Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or humans. In clinical

studies in which amlodipine was administered in combination with beta blockers to patients with either hypertension or angina,

no adverse events on electrocardiographic parameters were observed.

Amlodipine has been studied in patients with chronic stable angina, vasospastic angina and angiographically documented

coronary artery disease.

Clinical efficacy and safety

Use in patients with hypertension

A randomised double-blind morbidity-mortality study called the Antihypertensive and Lipid-Lowering treatment to prevent

Heart Attack Trial (ALLHAT) was performed to compare newer therapies: amlodipine 2.5‑10 mg/day (calcium channel blocker)

or lisinopril 10‑40 mg/day (ACE-inhibitor) as first-line therapies to that of the thiazide-diuretic, chlorthalidone 12.5‑25 mg/day

in mild to moderate hypertension.

A total of 33,357 hypertensive patients aged 55 or older were randomised and followed for a mean of 4.9 years. The patients

had at least one additional coronary heart disease risk factor, including: previous myocardial infarction or stroke (>6 months

prior to enrollment) or documentation of other atherosclerotic cardiovascular disease (overall 51.5%), type 2 diabetes (36.1%),

high density lipoprotein - cholesterol <35 mg/dl or <0.906 mmol/l (11.6%), left ventricular hypertrophy diagnosed by

electrocardiogram or echocardiography (20.9%), current cigarette smoking (21.9%).

The primary endpoint was a composite of fatal coronary heart disease or non-fatal myocardial infarction. There was no

significant difference in the primary endpoint between amlodipine-based therapy and chlorthalidone-based therapy: risk ratio

(RR) 0.98 95% CI (0.90‑1.07) p=0.65. Among secondary endpoints, the incidence of heart failure (component of a composite

combined cardiovascular endpoint) was significantly higher in the amlodipine group as compared to the chlorthalidone group

(10.2% versus 7.7%, RR 1.38, 95% CI [1.25‑1.52] p<0.001). However, there was no significant difference in all-cause mortality

between amlodipine-based therapy and chlorthalidone-based therapy RR 0.96 95% CI [0.89‑1.02] p=0.20.

Valsartan

Mechanism of action

Valsartan is an orally active, potent and specific angiotensin II receptor antagonist. It acts selectively on the receptor subtype

, which is responsible for the known actions of angiotensin II.

Clinical efficacy and safety

Administration of valsartan to patients with hypertension results in a drop in blood pressure without affecting pulse rate.

In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs within 2 hours, and the

peak drop in blood pressure is achieved within 4‑6 hours. The antihypertensive effect persists over 24 hours after

administration. During repeated administration, the maximum reduction in blood pressure with any dose is generally attained

within 2‑4 weeks.

Hydrochlorothiazide

Mechanism of action

The site of action of thiazide diuretics is primarily in the renal distal convoluted tubule. It has been shown that there is a

high-affinity receptor in the renal cortex as the primary binding site for the thiazide diuretic action and inhibition of NaCl

transport in the distal convoluted tubule. The mode of action of thiazides is through inhibition of the Na

symporter perhaps

by competing for the Cl

site, thereby affecting electrolyte reabsorption mechanisms: directly increasing sodium and chloride

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excretion to an approximately equal extent, and indirectly, by this diuretic action, reducing plasma volume, with consequent

increases in plasma renin activity, aldosterone secretion and urinary potassium loss, and a decrease in serum potassium.

Non-melanoma skin cancer

Based on available data from epidemiological studies, cumulative dose-dependent association between HCT and NMSC has

been observed. One study included a population comprised of 71,533 cases of BCC and of 8,629 cases of SCC matched to

1,430,833 and 172,462 population controls, respectively. High HCT 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 HCT: 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) (see also section 4.4).

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with

Amlodipine/Valsartan/Hydrochlorothiazide Rowex in all subsets of the paediatric population in essential hypertension (see

section 4.2 for information on paediatric use).

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

Two large randomised, controlled trials (ONTARGET [ONgoing Telmisartan Alone and in combination with Ramipril Global

Endpoint Trial] and VA NEPHRON-D [The Veterans Affairs Nephropathy in Diabetes]) have examined the use of the

combination of an ACE inhibitor with an ARB.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes

mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus

and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an

increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given

their similar pharmacodynamic properties, these results are also relevant for other ACE inhibitors and ARBs.

ACE inhibitors and ARBs should therefore not be used concomitantly in patients with diabetic nephropathy (see section 4.4).

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test

the benefit of adding aliskiren to a standard therapy of an ACE inhibitor or an ARB in patients with type 2 diabetes mellitus and

chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse

outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo

group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were

more frequently reported in the aliskiren group than in the placebo group.

5.2 Pharmacokinetic properties

Linearity

Amlodipine, valsartan and hydrochlorothiazide exhibit linear pharmacokinetics.

Amlodipine/valsartan/hydrochlorothiazide

Following oral administration of amlodipine/valsartan/HCT in normal healthy adults, peak plasma concentrations of amlodipine,

valsartan and hydrochlorothiazide are reached in 6‑8 hours, 3 hours, and 2 hours, respectively. The rate and extent of

absorption of amlodipine, valsartan and hydrochlorothiazide from amlodipine/valsartan/HCT are the same as when

administered as individual dosage forms.

Amlodipine

Absorption

After oral administration of therapeutic doses of amlodipine alone, peak plasma concentrations of amlodipine are reached in

6‑12 hours. Absolute bioavailability has been calculated as between 64% and 80%. Amlodipine bioavailability is unaffected by

food ingestion.

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Distribution

Volume of distribution is approximately 21 l/kg. In vitro studies with amlodipine have shown that approximately 97.5% of

circulating active substance is bound to plasma proteins.

Biotransformation

Amlodipine is extensively (approximately 90%) metabolised in the liver to inactive metabolites.

Elimination

Amlodipine elimination from plasma is biphasic, with a terminal elimination half-life of approximately 30 to 50 hours.

Steady-state plasma levels are reached after continuous administration for 7‑8 days. Ten per cent of original amlodipine and

60% of amlodipine metabolites are excreted in urine.

Valsartan

Absorption

Following oral administration of valsartan alone, peak plasma concentrations of valsartan are reached in 2‑4 hours. Mean

absolute bioavailability is 23%. Food decreases exposure (as measured by AUC) to valsartan by about 40% and peak plasma

concentration (C

) by about 50%, although from about 8 h post dosing plasma valsartan concentrations are similar for the

fed and fasted groups. This reduction in AUC is not, however, accompanied by a clinically significant reduction in the

therapeutic effect, and valsartan can therefore be given either with or without food.

Distribution

The steady-state volume of distribution of valsartan after intravenous administration is about 17 litres, indicating that valsartan

does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (94‑97%), mainly serum albumin.

Biotransformation

Valsartan is not transformed to a high extent as only about 20% of dose is recovered as metabolites. A hydroxy metabolite has

been identified in plasma at low concentrations (less than 10% of the valsartan AUC). This metabolite is pharmacologically

inactive.

Elimination

Valsartan shows multiexponential decay kinetics (t

½α

<1 h and t

½ß

about 9 h). Valsartan is primarily eliminated in faeces (about

83% of dose) and urine (about 13% of dose), mainly as unchanged active substance. Following intravenous administration,

plasma clearance of valsartan is about 2 l/h and its renal clearance is 0.62 l/h (about 30% of total clearance). The half-life of

valsartan is 6 hours.

Hydrochlorothiazide

Absorption

The absorption of hydrochlorothiazide, after an oral dose, is rapid (T

about 2 hours). The increase in mean AUC is linear and

dose proportional in the therapeutic range.

The effect of food on hydrochlorothiazide absorption, if any, has little clinical significance. Absolute bioavailability of

hydrochlorothiazide is 70% after oral administration.

Distribution

The apparent volume of distribution is 4‑8 l/kg. Circulating hydrochlorothiazide is bound to serum proteins (40‑70%), mainly

serum albumin. Hydrochlorothiazide also accumulates in erythrocytes at approximately 3 times the level in plasma.

Biotransformation

Hydrochlorothiazide is eliminated predominantly as unchanged compound.

Elimination

Hydrochlorothiazide is eliminated from plasma with a half-life averaging 6 to 15 hours in the terminal elimination phase. There

is no change in the kinetics of hydrochlorothiazide on repeated dosing, and accumulation is minimal when dosed once daily.

More than 95% of the absorbed dose is being excreted as unchanged compound in the urine. The renal clearance is composed

of passive filtration and active secretion into the renal tubule.

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Special populations

Paediatric patients (age below 18 years)

No pharmacokinetic data are available in the paediatric population.

Elderly (age 65 years or over)

Time to peak plasma amlodipine concentrations is similar in young and elderly patients. In elderly patients, amlodipine

clearance tends to decline, causing increases in the area under the curve (AUC) and elimination half-life. Mean systemic AUC of

valsartan is higher by 70% in the elderly than in the young, therefore caution is required when increasing the dosage.

Systemic exposure to valsartan is slightly elevated in the elderly as compared to the young, but this has not been shown to

have any clinical significance.

Limited data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly

subjects compared to young healthy volunteers.

Since the three components are equally well tolerated in younger and elderly patients, normal dose regimens are

recommended (see section 4.2).

Renal impairment

The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. As expected for a compound where

renal clearance accounts for only 30% of total plasma clearance, no correlation was seen between renal function and systemic

exposure to valsartan.

Patients with mild to moderate renal impairment may therefore receive the usual initial dose (see sections 4.2 and 4.4).

In the presence of renal impairment, mean peak plasma levels and AUC values of hydrochlorothiazide are increased and the

urinary excretion rate is reduced. In patients with mild to moderate renal impairment, a 3-fold increase in hydrochlorothiazide

AUC has been observed. In patients with severe renal impairment an 8-fold increase in AUC has been observed.

Amlodipine/Valsartan/Hydrochlorothiazide Rowex is contraindicated in patients with severe renal impairment, anuria or

undergoing dialysis (see section 4.3).

Hepatic impairment

Very limited clinical data are available regarding amlodipine administration in patients with hepatic impairment. Patients with

hepatic impairment have decreased clearance of amlodipine with resulting increase of approximately 40–60% in AUC. On

average, in patients with mild to moderate chronic liver disease, exposure (measured by AUC values) to valsartan is twice that

found

healthy

volunteers

(matched

age,

weight).

valsartan

component,

Amlodipine/Valsartan/Hydrochlorothiazide Rowex is contraindicated in patients with hepatic impairment (see sections 4.2 and

4.3).

5.3 Preclinical safety data

Amlodipine/Valsartan/Hydrochlorothiazide

In a variety of preclinical safety studies conducted in several animal species with amlodipine, valsartan, hydrochlorothiazide,

valsartan/hydrochlorothiazide,

amlodipine/valsartan

amlodipine/valsartan/hydrochlorothiazide

(Amlodipine/Valsartan/Hydrochlorothiazide Rowex), there was no evidence of systemic or target organ toxicity that would

adversely affect the development of Amlodipine/Valsartan/Hydrochlorothiazide Rowex for clinical use in humans.

Preclinical safety studies of up to 13 weeks in duration were conducted with amlodipine/valsartan/hydrochlorothiazide in rats.

The combination resulted in expected reduction of red blood cell mass (erythrocytes, haemoglobin, haematocrit, and

reticulocytes), increase in serum urea, increase in serum creatinine, increase in serum potassium, juxtaglomerular (JG)

hyperplasia in the kidney and focal erosions in the glandular stomach in rats. All these changes were reversible after a 4-week

recovery period and were considered to be exaggerated pharmacological effects.

The amlodipine/valsartan/hydrochlorothiazide combination was not tested for genotoxicity or carcinogenicity as there was no

evidence of any interaction between these substances, which have been on the market for a long time. However, amlodipine,

valsartan and hydrochlorothiazide have been tested individually for genotoxicity and carcinogenicity with negative results.

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Amlodipine

Reproductive toxicology

Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of labour and decreased pup

survival at dosages approximately 50 times greater than the maximum recommended dosage for humans based on mg/kg.

Impairment of fertility

There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females 14 days prior to mating) at

doses up to 10 mg/kg/day (8 times* the maximum recommended human dose of 10 mg on a mg/m

basis). In another rat

study in which male rats were treated with amlodipine besilate for 30 days at a dose comparable with the human dose based

on mg/kg, decreased plasma follicle-stimulating hormone and testosterone were found as well as decreases in sperm density

and in the number of mature spermatids and Sertoli cells.

Carcinogenesis, mutagenesis

Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to provide daily dosage levels of

0.5, 1.25, and 2.5 mg/kg/day showed no evidence of carcinogenicity. The highest dose (for mice, similar to, and for rats twice*

the maximum recommended clinical dose of 10 mg on a mg/m

basis) was close to the maximum tolerated dose for mice but

not for rats.

Mutagenicity studies revealed no active substance related effects at either the gene or chromosome levels.

* Based on patient weight of 50 kg

Valsartan

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose

toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.

In rats, maternally toxic doses (600 mg/kg/day) during the last days of gestation and lactation led to lower survival, lower

weight gain and delayed development (pinna detachment and ear-canal opening) in the offspring (see section 4.6). These

doses in rats (600 mg/kg/day) are approximately 18 times the maximum recommended human dose on a mg/m

basis

(calculations assume an oral dose of 320 mg/day and a 60-kg patient).

In non-clinical safety studies, high doses of valsartan (200 to 600 mg/kg body weight) caused in rats a reduction of red blood

cell parameters (erythrocytes, haemoglobin, haematocrit) and evidence of changes in renal haemodynamics (slightly raised

blood urea nitrogen, and renal tubular hyperplasia and basophilia in males). These doses in rats (200 and 600 mg/kg/day) are

approximately 6 and 18 times the maximum recommended human dose on a mg/m

basis (calculations assume an oral dose of

320 mg/day and a 60-kg patient).

In marmosets at comparable doses, the changes were similar though more severe, particularly in the kidney where the changes

developed to a nephropathy including raised blood urea nitrogen and creatinine.

Hypertrophy of the renal juxtaglomerular cells was also seen in both species. All changes were considered to be caused by the

pharmacological action of valsartan which produces prolonged hypotension, particularly in marmosets. For therapeutic doses

of valsartan in humans, the hypertrophy of the renal juxtaglomerular cells does not seem to have any relevance.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Cellulose microcrystalline

Crospovidone (type A)

Silica, colloidal anhydrous

Magnesium stearate

Coating

Hypromellose (type 2910)

Titanium dioxide (E171)

Macrogol 4000

Talc

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6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

Do not store above 30°C.

6.5 Nature and contents of container

PVC/PVDC-Alu blisters.

Pack sizes: 14, 28, 30, 56, 60, 90, 98 or 100 film-coated tablets.

Multipacks of 280 tablets, comprising 20 cartons, each containing 14 tablets.

PVC/PVDC-Alu perforated unit dose blisters:

Pack sizes: 28x1, 56x1, 98x1 or 280x1 film-coated tablets

Multipacks of 280 tablets, comprising 4 cartons, each containing 70x1 tablets.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Rowex Ltd

Newtown

Bantry

Co. Cork

Ireland

8 MARKETING AUTHORISATION NUMBER

PA0711/291/001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 19

August 2019

10 DATE OF REVISION OF THE TEXT

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