Benetor Plus 20 mg/12.5 mg film-coated tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

Buy It Now

Active ingredient:
Olmesartan medoxomil; Hydrochlorothiazide
Available from:
Daiichi Sankyo Ireland Ltd
ATC code:
C09DA; C09DA08
INN (International Name):
Olmesartan medoxomil; Hydrochlorothiazide
Dosage:
20 mg/12.5 milligram(s)
Pharmaceutical form:
Film-coated tablet
Prescription type:
Product subject to prescription which may be renewed (B)
Therapeutic area:
Angiotensin II antagonists and diuretics; olmesartan medoxomil and diuretics
Authorization status:
Marketed
Authorization number:
PA1595/002/001
Authorization date:
2005-05-12

Page 1 of 10

Package Leaflet: Information for the user

Benetor Plus 20 mg/12.5 mg

Benetor Plus 20 mg/25 mg

Film-coated tablets

olmesartan medoxomil/hydrochlorothiazide

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

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

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

This medicine has been prescribed for you only. Do not pass it on to others. It may harm

them, even if their signs of illness are the same as yours.

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

effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Benetor Plus is and what it is used for

2. What you need to know before you take Benetor Plus

3. How to take Benetor Plus

4. Possible side effects

5. How to store Benetor Plus

6. Contents of the pack and other information

1.

What Benetor Plus is and what it is used for

Benetor Plus contains two active substances, olmesartan medoxomil and hydrochlorothiazide,

that are used to treat high blood pressure (hypertension):

Olmesartan

medoxomil

group

medicines

called

angiotensin

II-receptor

antagonists. It lowers blood pressure by relaxing the blood vessels.

Hydrochlorothiazide is one of a group of medicines called thiazide diuretics (“water tablets”).

It lowers blood pressure by helping the body to get rid of extra fluid by making your kidneys

produce more urine.

You will only be given Benetor Plus if Benetor (olmesartan medoxomil) alone has not adequately

controlled your blood pressure. When given together, the two active substances in Benetor Plus

help to lower blood pressure more than if either of them were given alone.

You may already be taking medicines to treat your high blood pressure, but your doctor may want

you to take Benetor Plus to lower it more.

Page 2 of 10

High blood pressure can be controlled with medicines such as Benetor Plus tablets. Your doctor

has probably also recommended that you make some changes in your lifestyle to help lower your

blood pressure (for example losing weight, giving up smoking, reducing the amount of alcohol

you drink and reducing the amount of salt in your diet). Your doctor may also have urged you to

take regular exercise, such as walking or swimming. It is important to follow this advice from

your doctor.

2.

What you need to know before you take Benetor Plus

Do not take Benetor Plus:

if you are allergic to olmesartan medoxomil or hydrochlorothiazide, or any of the other

ingredients of this medicine (listed in section 6) or substances similar to hydrochlorothiazide

(sulfonamides)

if you are more than 3 months pregnant (It is also better to avoid Benetor Plus in early

pregnancy – see pregnancy section)

if you have severe kidney problems

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

lowering medicine containing aliskiren

if you suffer from low potassium, low sodium, high calcium or high uric acid levels in the

blood (with symptoms of gout or kidney stones) that do not get better when treated

if you suffer from severe liver problems or yellowing of the skin and eyes (jaundice) or

problems with drainage of the bile from the gallbladder (biliary obstruction e.g. gallstones)

If you think any of these apply to you, or you are unsure, do not take the tablets. Talk to your

doctor first and follow the advice given.

Warnings and precautions

Talk to your doctor before using Benetor Plus.

Before you take the tablets,

tell your doctor

if you are taking any of the following medicines

used to treat high blood pressure:

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

diabetes-related kidney problems.

aliskiren

Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g.

potassium) in your blood at regular intervals.

See also information under the heading “Do not take Benetor Plus”.

Before you take the tablets,

tell your doctor

if you have any of the following health problems:

Mild to moderate kidney problems or if you have had a recent kidney transplant

Liver diseases

Heart failure or problems with your heart valves or heart muscles

Vomiting (being sick) or diarrhoea which is severe or it goes on for several days

Page 3 of 10

Treatment with high doses of water tablets (diuretics) or if you are on a low salt diet

Problems with your adrenal glands (e.g. primary aldosteronism)

Diabetes

Lupus erythematosus (an autoimmune disease)

Allergies or asthma

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 Benetor Plus.

Contact your doctor

if you experience any of the following symptoms:

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

evaluate your symptoms and decide on how to continue your blood pressure medication.

decrease in vision or eye pain. These could be symptoms of fluid accumulation in the

vascular layer of the eye (choroidal effusion) or an increase of pressure in your eye and can

happen within hours to weeks of taking Benetor Plus. This can lead to permanent vision

impairment, if not treated.

Your doctor may want to see you more often and do some tests if you have any of these

conditions.

Benetor Plus may cause a rise in blood fat levels and uric acid levels (the cause of gout – painful

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

check these.

It may change the levels of certain chemicals in your blood called electrolytes. Your doctor will

probably want to do a blood test from time to time to check these. Signs of electrolyte changes

are: thirst, dryness of the mouth, muscle pain or cramps, tired muscles, low blood pressure

(hypotension), feeling weak, sluggish, tired, sleepy or restless, nausea, vomiting, less need to pass

urine, a rapid heart rate.

Tell your doctor if you notice these symptoms.

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

patients with blood flow disturbances of the heart or brain could lead to a heart attack or stroke.

Your doctor will therefore check your blood pressure carefully.

If you are due to have tests for parathyroid function, you should stop taking Benetor Plus before

these tests are carried out.

If you are a sports person, this medicine could change the results of an anti-dope test to make it

positive.

You must tell your doctor if you think that you are (or might become) pregnant. Benetor Plus is

not recommended in early pregnancy, and must not be taken if you are more than 3 months

pregnant, as it may cause serious harm to your baby if used at that stage (see pregnancy section).

Children and adolescents

Benetor Plus is not recommended for children and adolescents under the age of 18.

Page 4 of 10

Other medicines and Benetor Plus

Tell your doctor or pharmacist if you are using, have recently used or might use any other

medicines.

In particular, tell your doctor or pharmacist about any of the following:

Other blood pressure lowering medicines (anti-hypertensives), as the effect of Benetor Plus

can be increased.

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

If you are taking an ACE-inhibitor or aliskiren (see also information under the headings “Do

not take Benetor Plus” and “Warnings and precautions”).

Medicines which may alter the levels of potassium in your blood if used at the same time as

Benetor Plus. These include:

potassium supplements (as well as salt substitutes containing potassium)

water tablets (diuretics)

heparin (for thinning the blood)

laxatives

steroids

adrenocorticotrophic hormone (ACTH)

carbenoxolone (a medicine used to treat mouth and stomach ulcers)

penicillin G sodium (also called benzylpenicillin sodium, an antibiotic)

certain pain killers such as aspirin or salicylates

Lithium (a medicine used to treat mood swings and some types of depression) used at the

same time as Benetor Plus may increase the toxicity of lithium. If you have to take lithium,

your doctor will measure your lithium blood levels.

Non-steroidal

anti-inflammatory

(NSAIDs)

medicines

(medicines

used

relieve

pain,

swelling and other symptoms of inflammation, including arthritis) used at the same time as

Benetor Plus may increase the risk of kidney failure and the effect of Benetor Plus can be

decreased by NSAIDs.

Sleeping tablets, sedatives and anti-depressant medicines, as using these medicines together

with Benetor Plus may cause a sudden drop in blood pressure when standing up.

Certain medicines such as baclofen and tubocurarine, used to relax muscles.

Amifostine and some other drugs used to treat cancers, such as cyclophosphamide or

methotrexate.

Colestyramine and colestipol, medicines for lowering blood fat levels.

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

effect of Benetor Plus may be decreased. Your doctor may advise you to take Benetor Plus at

least 4 hours before colesevelam hydrochloride.

Anticholinergic agents, such as atropine and biperiden.

Drugs

such

thioridazine,

chlorpromazine,

levomepromazine,

trifluoperazine,

cyamemazine,

sulpiride,

amisulpride,

pimozide,

sultopride,

tiapride,

droperidol

haloperidol, used to treat certain psychiatric disorders.

Certain medicines such as quinidine, hydroquinidine, disopyramide, amiodarone, sotalol or

digitalis, used to treat heart problems.

Medicines such as mizolastine, pentamidine, terfenadine, dofetilide, ibutilide or erythromycin

injections, which may change the heart rhythm.

Oral anti-diabetic medicines, such as metformin, or insulin, used to lower blood sugar.

Beta-blockers and diazoxide, medicines used to treat high blood pressure or low blood sugar,

respectively, as Benetor Plus can enhance their blood-sugar-increasing effect.

Page 5 of 10

Methyldopa, a medicine used to treat high blood pressure.

Medicines such as noradrenaline, used to increase blood pressure and slow heart rate.

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

Medicines such as probenecid, sulfinpyrazone and allopurinol, used to treat gout.

Calcium supplements.

Amantadine, an anti-viral drug.

Ciclosporin, a medicine used to stop rejection of organ transplants.

Certain antibiotics called tetracyclines or sparfloxacin.

Amphotericin, a medicine used to treat fungal infections.

Certain antacids, used to treat too much stomach acid, such as aluminium magnesium

hydroxide, as the effect of Benetor Plus can be slightly decreased.

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

Halofantrine, used for malaria.

Benetor Plus with food and drink

Benetor Plus can be taken with or without food.

Take care when drinking alcohol while you are taking Benetor Plus, as some people feel faint or

dizzy. If this happens to you, do not drink any alcohol, including wine, beer or alcopops.

Black patients

As with other similar drugs the blood pressure lowering effect of Benetor Plus is somewhat less

in black patients.

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 Benetor Plus before you become pregnant or as soon as you

know you are pregnant and will advise you to take another medicine instead of Benetor Plus.

Benetor Plus is not recommended during pregnancy, and must not be taken when more than 3

months pregnant, as it may cause serious harm to your baby if it is used after the third month of

pregnancy.

Breast-feeding

Tell your doctor if you are breast-feeding or about to start breast-feeding. Benetor Plus is not

recommended for mothers who are breast-feeding, and your doctor may choose another treatment

for you if you wish to breast-feed.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby,

ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines

You may feel sleepy or dizzy while being treated for your high blood pressure. If this happens, do

not drive or use machines until the symptoms wear off. Ask your doctor for advice.

Page 6 of 10

Benetor Plus contains lactose

This medicine contains lactose (a type of sugar). If you have been told by your doctor that you

have an intolerance to some sugars, contact your doctor before taking this medicine.

3.

How to take Benetor Plus

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

pharmacist if you are not sure.

The recommended dose

is one Benetor Plus 20 mg/12.5 mg tablet a day. However, if your blood

pressure is not controlled, your doctor may decide to change your dose to one Benetor Plus 20

mg/25 mg tablet a day.

Swallow the tablet with water. If possible, you should take your dose

at the same time each day

for example at breakfast time. It is important to continue to take Benetor Plus until your doctor

tells you to stop.

If you take more Benetor Plus than you should

If you take more tablets than you should, or if a child accidentally swallows one or more, go to

your doctor or nearest accident and emergency department immediately and take your medicine

pack with you.

If you forget to take Benetor Plus

If you forget to take a dose, take your normal dose on the following day as usual. Do

not

take a

double dose to make up for a forgotten dose.

If you stop taking Benetor Plus

It is important to continue to take Benetor Plus unless your doctor tells you to stop.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

However, the following two side effects can be serious:

Allergic reactions that may affect the whole body, with swelling of the face, mouth and/or

voice box (larynx) together with itching and rash may occur rarely.

If this happens, stop

taking Benetor Plus and contact your doctor immediately.

Benetor Plus can cause the blood pressure to fall too low in susceptible individuals or as the

result of an allergic reaction. Light-headedness or fainting may occur uncommonly.

If this

happens, stop taking Benetor Plus, contact your doctor immediately and lie down flat.

Page 7 of 10

Benetor Plus is a combination of two active substances and the following information firstly gives

the other side effects reported so far with the combination Benetor Plus (besides those already

mentioned above) and, secondly, those which are known about for the separate active substances.

These are the other side effects known about so far with Benetor Plus:

If these side effects occur, they are often mild and

you do not need to stop your treatment.

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

Dizziness, weakness, headache, tiredness, chest pain, swelling of ankles, feet, legs, hands or arms.

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

Fluttering of the heartbeat (palpitations), rash, eczema, vertigo, cough, indigestion, abdominal

pain, nausea, vomiting, diarrhoea, muscle cramps and muscular pain, pain in joints, arms and

legs, back pain, erection difficulties in men, blood in urine.

Some changes in blood test results have also been seen uncommonly and include:

Rise in blood fat levels, rise in blood urea or uric acid, rise in creatinine, rise or decrease in blood

potassium levels, rise in blood calcium levels, rise in blood sugar, increase in levels of liver

function. Your doctor will know about these from a blood test and will tell you if you need to do

anything.

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

Feeling unwell, disturbances in consciousness, skin lumps (wheals), acute kidney failure.

Some changes in blood test results have also been seen in rare cases and include:

Rise in blood urea nitrogen, decrease in haemoglobin and haematocrit values. Your doctor will

know about these from a blood test and will tell you if you need to do anything.

Further side effects reported with use of olmesartan medoxomil or hydrochlorothiazide

alone, but not with Benetor Plus or in a higher frequency:

Olmesartan medoxomil:

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

Bronchitis, cough, runny or stuffy nose, sore throat, abdominal pain, indigestion, diarrhoea,

nausea, gastroenteritis, pain in the joints or bones, back pain, blood in urine, urinary tract

infection, flu-like symptoms, pain.

Some changes in blood test results have also been seen commonly and include:

Rise in blood fat levels, rise in blood urea or uric acid, increase in levels of liver and muscle

function.

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

Quick allergic reactions that may affect the whole body and may cause breathing problems as

well as a rapid fall of blood pressure that may even lead to fainting (anaphylactic reactions),

swelling of the face, angina (pain or uncomfortable feeling in the chest; known as angina

pectoris), feeling unwell, allergic skin rash, itching, exanthema (skin eruption), skin lumps

(wheals).

Page 8 of 10

Some changes in blood test results have also been seen uncommonly and include:

Reduced numbers of a type of blood cell, known as platelets (thrombocytopenia).

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

Impaired kidney function, lack of energy.

Some changes in blood test results have also been seen rarely and include:

Increase in blood potassium.

Hydrochlorothiazide:

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

Changes in blood results including: Increase in blood fat and uric acid levels.

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

Feeling confused, abdominal pain, stomach upset, bloated feeling, diarrhoea, nausea, vomiting,

constipation, excretion of glucose into the urine.

Some changes in blood results have also been seen and include:

Increase

blood

creatinine,

urea,

calcium

sugar

levels,

decrease

blood

chloride,

potassium, magnesium and sodium levels. Increase of serum amylase (hyperamylasaemia).

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

Decreased

loss

appetite,

severe

difficulty

breathing,

anaphylactic

skin

reactions

(hypersensitivity reactions), worsening of pre-existing myopia, erythema, skin reactions to light,

itching, purplish spots or patches on the skin due to small haemorrhages (purpura), skin lumps

(wheals).

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

Swollen and sore salivary glands, decreased number of white blood cells, decreased number of

blood

platelets,

anaemia, bone

marrow damage,

restlessness,

feeling

‘down’

or depressed,

problems sleeping, feeling un-interested (apathy), tingling and numbness, fits (convulsions),

objects you look at appearing yellow, blurred vision, dry eyes, irregular heartbeat, inflammation

of the blood vessels, blood clots (thrombosis or embolism), inflammation of the lung, fluid

accumulation in the lungs, inflammation of the pancreas, jaundice, infection in the gall bladder,

symptoms of lupus erythematosus such as rash, joint pains and cold hands and fingers, allergic

skin reactions, peeling and blistering of the skin, non-infectious inflammation of the kidney

(interstitial nephritis), fever, muscle weakness (sometimes causing impaired movement).

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

Electrolyte

disturbance

leading

abnormally

depleted

level

chloride

blood

(hypochloraemic alkalosis), blockage in the gut (paralytic ileus).

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

Decrease in vision or eye pain (possible signs of fluid accumulation in the vascular layer of the

eye (choroidal effusion) or

acute angle-closure glaucoma).

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.

Page 9 of 10

You can also report side effects directly via HPRA Pharmacovigilance Website: www.hpra.ie

By reporting side effects you can help provide more information on the safety of this medicine.

5.

How to store Benetor Plus

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

This medicinal product does not require any special storage conditions.

Do not use this medicine after the expiry date which is stated on the carton and on the blister strip

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

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 Benetor Plus contains

The active substances are:

Benetor Plus 20 mg/12.5 mg: Each film-coated tablet contains 20 mg olmesartan medoxomil and

12.5 mg hydrochlorothiazide.

Benetor Plus 20 mg/25 mg: Each film-coated tablet contains 20 mg olmesartan medoxomil and

25 mg hydrochlorothiazide.

The other ingredients are:

Microcrystalline cellulose, lactose monohydrate*, low substituted hyprolose, hyprolose,

magnesium stearate, titanium dioxide (E 171), talc, hypromellose, iron (III) oxides (E 172).

* See ‘

Benetor Plus contains lactose

’ section above

What Benetor Plus looks like and contents of the pack

Benetor Plus 20 mg/12.5 mg film-coated tablets of 8.5 mm are reddish-yellow, round with "C22"

on one side.

Benetor Plus 20 mg/25 mg film-coated tablets of 8.5 mm are pinkish, round with "C24" on one

side.

They are available in packs of 14, 28, 30, 56, 84, 90, 98 and 10 x 28 film-coated tablets and in

packs with perforated unit dose blisters of 10, 50 and 500 film-coated tablets.

Not all pack sizes may be marketed.

Page 10 of 10

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

Daiichi Sankyo Ireland Limited

Riverside One

Sir John Rogerson’s Quay

Dublin 2

Ireland

Manufacturer:

DAIICHI SANKYO EUROPE GmbH

Luitpoldstrasse 1

85276 Pfaffenhofen

Germany

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

names:

Austria:

Olmetec Plus

Belgium:

Olmetec Plus

Denmark:

Olmetec Plus

Germany:

Olmetec Plus

Greece:

Olmetec Plus

Finland:

Olmetec Plus

France:

Co Olmetec

Iceland:

Olmetec Plus

Ireland:

Benetor Plus

Italy:

Olmegan

Luxembourg:

Olmetec Plus

The Netherlands:

Olmetec HCTZ

Norway:

Olmetec Comp

Portugal:

Olmetec Plus

Spain:

Olmetec Plus

Olmetec Plus

This leaflet was last revised in June 2020.

Health Products Regulatory Authority

03 September 2020

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Page 1 of 18

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Benetor Plus 20 mg/12.5 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 20 mg olmesartan medoxomil and 12.5 mg hydrochlorothiazide

Excipient(s) with known effect

Benetor Plus 20 mg/12.5 mg film-coated tablets: Each film-coated tablet contains 110.7 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablets.

Reddish-yellow, round, film-coated tablets of 8.5 mm with C22 debossed on one side.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Treatment of essential hypertension.

Benetor Plus fixed dose combination is indicated in adult patients whose blood pressure is not adequately controlled on

olmesartan medoxomil alone.

4.2 Posology and method of administration

Posology

Adults

Benetor Plus is not for use as initial therapy, but in patients whose blood pressure is not adequately controlled by 20 mg

olmesartan medoxomil alone. Benetor Plus is administered once daily, with or without food.

When clinically appropriate, direct change from monotherapy with 20 mg olmesartan medoxomil to the fixed combination may

be considered, taking into account that theantihypertensive effect of olmesartan medoxomil is maximal by about 8 weeks after

initiating therapy (see section 5.1 ). Dose titration of the individual components is recommended:

20 mg olmesartan medoxomil/12.5 mg hydrochlorothiazide may be administered in patients whose blood pressure is not

adequately controlled by the optimal monotherapy olmesartan medoxomil 20 mg alone.

20 mg olmesartan medoxomil/ 25 mg hydrochlorothiazide may be administered in patients whose blood pressure is not

adequately controlled by 20 mg olmesartan medoxomil/ 12.5 mg hydrochlorothiazide.

Elderly people (age 65 years or over)

In elderly people the same dosage of the combination is recommended as for adults.

Renal impairment

When Benetor Plus is used in patients with mild to moderate renal impairment (creatinine clearance of 30 – 60 mL/min)

periodic monitoring of renal function is advised (see section 4.4). BenetorPlus is contraindicated in patients with severe renal

impairment (creatinine clearance < 30 mL/min) (see section 4.3).

Hepatic impairment

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Page 2 of 18

Benetor Plus should be used with caution in patients with mild to moderate hepatic impairment (see sections 4.4, 5.2). In

patients with moderate hepatic impairment, an initial dose of 10 mg olmesartan medoxomil once daily is recommended and

the maximum dose should not exceed 20 mg once daily. Close monitoring of blood pressure and renal function is advised in

hepatically-impaired patients who are receiving diuretics and/or other antihypertensive agents. There is no experience of

olmesartan medoxomil in patients with severe hepatic impairment.

Benetor Plus should not be used in patients with severe hepatic impairment (see sections 4.3, 5.2), cholestasis and biliary

obstruction (see section 4.3).

Paediatric population

The safety and efficacy of Benetor Plus in children and adolescents below 18 years has not been established. No data are

available.

Method of administration

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

should be taken at the same time each day.

4.3 Contraindications

Hypersensitivity to the active substances, to any of the excipients listed in section 6.1 or to other sulfonamide-derived

substances (since hydrochlorothiazide is a sulfonamide-derived medicinal product).

Severe renal impairment (creatinine clearance < 30 mL/min).

Refractory hypokalaemia, hypercalcaemia, hyponatraemia and symptomatic hyperuricaemia.

Severe hepatic impairment, cholestasis and biliary obstructive disorders.

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

The concomitant use of Benetor Plus with aliskiren-containing products is contraindicated in patients with diabetes mellitus or

renal impairment (GFR < 60 mL/min/1.73 m

) (see sections 4.5 and 5.1).

4.4 Special warnings and precautions for use

Intravascular volume depletion:

Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by

vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the

administration of Benetor Plus.

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

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

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

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

renal failure.

Renovascular hypertension:

There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or

stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the

renin-angiotensin-aldosterone system.

Renal impairment and kidney transplantation:

Benetor Plus should not be used in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see section 4.3).

No dosage adjustment is necessary in patients with mild to moderate renal impairment (creatinine clearance is ≥ 30 mL/min,

< 60 mL/min). However, in such patients Benetor Plus should be administered with caution and periodic monitoring of serum

potassium, creatinine and uric acid levels is recommended. Thiazide diuretic-associated azotaemia may occur in patients with

impaired renal function. If progressive renal impairment becomes evident, careful reappraisal of therapy is necessary, with

consideration given to discontinuing diuretic therapy. There is no experience of the administration of Benetor Plus in patients

with a recent kidney transplantation.

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

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

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

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Page 3 of 18

combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5

and 5.1).

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

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

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

Hepatic impairment:

There is currently no experience of olmesartan medoxomil in patients with severe hepatic impairment. Furthermore, minor

alterations of fluid and electrolyte balance during thiazide therapy may precipitate hepatic coma in patients with impaired

hepatic function or progressive liver disease. Therefore care should be taken in patients with mild to moderate hepatic

impairment (see section 4.2). Use of Benetor Plus in patients with severe hepatic impairment, cholestasis and biliary obstruction

is contraindicated (see sections 4.3, 5.2).

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy:

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

hypertrophic cardiomyopathy.

Primary aldosteronism:

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

inhibition of the renin-angiotensin system. Therefore, the use of Benetor Plus is not recommended in such patients.

Metabolic and endocrine effects:

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

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

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

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

Electrolyte imbalance:

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

intervals.

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

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

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

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

The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who

are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or ACTH

(see section 4.5).

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

) through the olmesartan medoxomil component of Benetor

Plus hyperkalaemia may occur, especially in the presence of renal impairment and/or heart failure, and diabetes mellitus.

Adequate monitoring of serum potassium in patients at risk is recommended. Potassium-sparing diuretics, potassium

supplements or potassium-containing salt substitutes and other medicinal products that may increase serum potassium levels

(e.g. heparin) should be co-administered cautiously with Benetor Plus (see section 4.5).

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

generally mild and usually does not require treatment.

Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of serum calcium in the

absence of known disorders of calcium metabolism. Hypercalcaemia may be evidence of hidden hyperparathyroidism.

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

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Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia.

Dilutional hyponatraemia may occur in oedematous patients in hot weather.

Lithium:

As with other medicinal products containing angiotensin II receptor antagonists and thiazide in combination, the

coadministration of Benetor Plus and lithium is not recommended (see section 4.5).

Sprue-like enteropathy:

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

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

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

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

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

advice should be considered.

Choroidal Effusion, Acute Myopia and Secondary Angle-Closure Glaucoma:

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

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

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

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

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

acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Non-melanoma skin cancer:

An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with

increasing cumulative dose of hydrochlorothiazide (HCTZ) exposure has been observed in two epidemiological studies based

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

Patients taking HCTZ should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and

promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and,

in case of exposure, adequate protection should be advised to the patients in order to minimize the risk of skin cancer.

Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. The use of

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

Ethnic differences:

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

less in black patients than in non-black patients, possibly because of a higher prevalence of low-renin status in the black

hypertensive population.

Anti-doping test:

Hydrochlorothiazide contained in this medicinal product could produce a positive analytic result in an anti-doping test.

Pregnancy:

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

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

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

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

(see sections 4.3 and 4.6)

Other:

In general arteriosclerosis, in patients with ischaemic heart disease or ischaemic cerebrovascular disease, there is always a risk

that excessive blood pressure decrease could result in a myocardial infarction or stroke.

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

but are more likely in patients with such a history.

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

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp-lactase

deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interaction with other medicinal products and other forms of interactions

Potential interactions related to both olmesartan medoxomil and hydrochlorothiazide:

Concomitant use not recommended

Lithium:

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

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

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

Benetor Plus and lithium in combination is not recommended (see section 4.4). If use of the combination proves necessary,

careful monitoring of serum lithium levels is recommended.

Concomitant use requiring caution

Baclofen:

Potentiation of antihypertensive effect may occur.

Non-steroidal anti-inflammatory medicinal products:

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

of thiazide diuretics and angiotensin II receptor antagonists.

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

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

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

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

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

thereafter.

Concomitant use to be taken into account

Amifostine:

Potentiation of antihypertensive effect may occur.

Other antihypertensive agents:

The blood pressure lowering effect of Benetor Plus can be increased by concomitant use of other antihypertensive medicinal

products.

Alcohol, barbiturates, narcotics or antidepressants:

Potentiation of orthostatic hypotension may occur.

Potential interactions related to olmesartan medoxomil:

Concomitant use not recommended

ACE-inhibitors, angiotensin II receptor blockers or aliskiren:

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

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

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

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

Medicinal products affecting potassium levels:

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Based on experience with the use of other medicinal products that affect the renin-angiotensin system, concomitant use of

potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that

may increase serum potassium levels (e.g. heparin, ACE inhibitors) may lead to increases in serum potassium (see section 4.4). If

medicinal products which affect potassium levels are to be prescribed in combination with Benetor Plus, monitoring of

potassium plasma levels is advised.

Bile acid sequestering agent colesevelam:

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

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

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

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

Additional information

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

observed.

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

pharmacokinetics of digoxin.

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

component in healthy subjects.

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

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

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

Potential interactions related to hydrochlorothiazide:

Concomitant use not recommended

Medicinal products affecting potassium levels:

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

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

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

recommended.

Concomitant use requiring caution

Calcium salts:

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

serum calcium levels should be monitored and calcium dosage adjusted accordingly.

Cholestyramine and colestipol resins:

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

Digitalis glycosides:

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

Medicinal products affected by serum potassium disturbances:

Periodic monitoring of serum potassium and ECG is recommended when Benetor Plus is administered with medicinal products

affected by serum potassium disturbances (e.g. digitalis glycosides and antiarrhythmics) and with the following torsades de

pointes (ventricular tachycardia)-inducing medicinal products (including some antiarrhythmics), hypokalaemia being a

predisposing factor to torsades de pointes (ventricular tachycardia):

- Class Ia antiarrythmics (e.g. quinidine, hydroquinidine, disopyramide).

- Class III antiarrythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide).

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- Some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride,

amisulpride, tiapride, pimozide, haloperidol, droperidol).

- Others (e.g. bepridil, cisapride, diphemanil, erythromycin IV, halofantrin, mizolastin, pentamidine, sparfloxacin, terfenadine,

vincamine IV).

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

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

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

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

Antidiabetic medicinal products (oral agents and insulin):

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

may be required (see section 4.4).

Metformin:

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

to hydrochlorothiazide.

Beta-blockers and diazoxide:

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

Pressor amines (e.g. noradrenaline):

The effect of pressor amines may be decreased.

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

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

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

the incidence of hypersensitivity reactions to allopurinol.

Amantadine:

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

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

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

Salicylates:

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

system.

Methyldopa:

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

methyldopa.

Cyclosporine:

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

Tetracyclines:

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

interaction is probably not applicable to doxycycline.

4.6 Fertility, pregnancy and lactation

Pregnancy (see section 4.3)

Given the effects of the individual components in this combination product on pregnancy, the use of Benetor Plus is not

recommended during the first trimester of pregnancy (see section 4.4). The use of Benetor Plus is contra-indicated during the

2nd and 3rd trimester of pregnancy (see sections 4.3 and 4.4).

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Olmesartan medoxomil:

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

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

4.3 and 4.4).

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

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

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

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

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

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

therapy should be started.

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

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

hypotension, hyperkalaemia). (See also 5.3 Preclinical safety data.)

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

of renal function and skull is recommended.

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

sections 4.3 and 4.4).

Hydrochlorothiazide:

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

insufficient.

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

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

icterus, disturbance of electrolyte balance and thrombocytopenia.

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

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

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

treatment could be used.

Breast-feeding

Olmesartan medoxomil:

Because no information is available regarding the use of Benetor Plus during breast-feeding, Benetor Plus is not recommended

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

a newborn or preterm infant.

Hydrochlorothiazide:

Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit

the milk production.

The use of Benetor Plus during breast-feeding is not recommended. If Benetor Plus is used during breast-feeding, doses

should be kept as low as possible.

4.7 Effects on ability to drive and use machines

Benetor Plus has minor or moderate influence on the ability to drive and use machines. Dizziness or fatigue may occasionally

occur in patients taking antihypertensive therapy, which may impair the ability to react.

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4.8 Undesirable effects

The most commonly reported adverse reactions during treatment with Benetor Plus are headache (2.9%), dizziness (1.9%) and

fatigue (1.0%).

Hydrochlorothiazide may cause or exacerbate volume depletion which may lead to electrolyte imbalance (see section 4.4).

In clinical trials involving 1155 patients treated with olmesartan medoxomil/ hydrochlorothiazide combinations at dosages of

20/12.5 mg or 20/25 mg and 466 patients treated with placebo for periods of up to 21 months, the overall frequency of

adverse reactions on olmesartan medoxomil/hydrochlorothiazide combination therapy was similar to that on placebo.

Discontinuations due to adverse reactions were also similar for olmesartan medoxomil/hydrochlorothiazide 20/12.5 mg -

20/25 mg (2%) and placebo (3%). The frequency of adverse reactions on olmesartan medoxomil/ hydrochlorothiazide overall

relative to placebo appeared to be unrelated to age (< 65 years versus ≥ 65 years), gender or race although the frequency of

dizziness was somewhat increased in patients aged ≥ 75 years.

In addition, the safety of Benetor Plus as a high dose combination was investigated in clinical trials in 3709 patients receiving

olmesartan medoxomil in combination with hydrochlorothiazide in the dose strengths 40 mg/12.5 mg and 40 mg/25 mg.

Adverse reactions from Benetor Plus in clinical trials, post-authorisation safety studies and spontaneous reporting are

summarised in the below table as well as adverse reactions from the individual components olmesartan medoxomil and

hydrochlorothiazide based on the known safety profile of these substances.

The following terminologies have been used in order to classify the occurrence of adverse reactions: 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

Benetor Plus

Olmesartan

HCTZ

Infections and infestations

Sialadenitis

Rare

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

Aplastic anaemia

Rare

Bone marrow depression

Rare

Haemolytic anaemia

Rare

Leukopenia

Rare

Neutropenia/

Agranulocytosis

Rare

Thrombocytopenia

Uncommon

Rare

Immune system disorders

Anaphylactic reactions

Uncommon

Uncommon

Metabolism and nutrition disorders

Anorexia

Uncommon

Glykosuria

Common

Hypercalcaemia

Common

Hypercholesterolaemia

Uncommon

Very common

Hyperglycaemia

Common

Hyperkalaemia

Rare

Hypertriglyceridaemia

Uncommon

Common

Very common

Hyperuricaemia

Uncommon

Common

Very common

Hypochloraemia

Common

Hypochloraemic

alcalosis

Very rare

Hypokaliaemia

Common

Hypomagnesaemia

Common

Hyponatriaemia

Common

Hyperamylasaemia

Common

Psychiatric disorders

Apathy

Rare

Depression

Rare

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Restlessness

Rare

Sleep disturbances

Rare

Nervous system disorders

Confusional state

Common

Convulsions

Rare

Disturbances in

consciousness (such as

loss of consciousness)

Rare

Dizziness/light-headedn

Common

Common

Common

Headache

Common

Common

Rare

Loss of appetite

Uncommon

Paraesthesia

Rare

Postural dizziness

Uncommon

Somnolence

Uncommon

Syncope

Uncommon

Eye disorders

Lacrimation decreased

Rare

Transient blurred vision

Rare

Worsening of

pre-existing myopia

Uncommon

Acute myopia, acute

angle-closure glaucoma

Not known

Choroidal effusion

Not known

Xanthopsia

Rare

Ear and labyrinth disorders

Vertigo

Uncommon

Uncommon

Rare

Cardiac disorders

Angina pectoris

Uncommon

Cardiac arrhythmias

Rare

Palpitations

Uncommon

Vascular disorders ​ ​

Embolism

Rare

Hypotension

Uncommon

Rare

Necrotising angiitis

(vasculitis, cutaneous

vasculitis)

Rare

Orthostatic hypotension

Uncommon

Uncommon

Thrombosis

Rare

Respiratory, thoracic and mediastinal disorders

Bronchitis

Common

Cough

Uncommon

Common

Dyspnoea

Rare

Interstitial pneumonia

Rare

Pharyngitis

Common

Pulmonary oedema

Rare

Respiratory distress

Uncommon

Rhinitis

Common

Gastrointestinal disorders

Abdominal pain

Uncommon

Common

Common

Constipation

Common

Diarrhoea

Uncommon

Common

Common

Dyspepsia

Uncommon

Common

Gastric irritation

Common

Gastroenteritis

Common

Meteorism

Common

Nausea

Uncommon

Common

Common

Pancreatitis

Rare

Paralytic ileus

Very rare

Vomiting

Uncommon

Uncommon

Common

Sprue-like enteropathy

(see section 4.4)

Very rare

Hepato-biliary disorders ​

Acute cholecystitis

Rare

Jaundice (intrahepatic

Rare

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