Bifril Plus 30 mg/12.5 mg film-coated tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

Buy It Now

Active ingredient:
ZOFENOPRIL CALCIUM; Hydrochlorothiazide
Available from:
Menarini International Operations Luxembourg S.A.
ATC code:
C09BA; C09BA15
INN (International Name):
ZOFENOPRIL CALCIUM; Hydrochlorothiazide
Dosage:
30 mg/12.5 milligram(s)
Pharmaceutical form:
Film-coated tablet
Prescription type:
Product subject to prescription which may be renewed (B)
Therapeutic area:
ACE inhibitors and diuretics; zofenopril and diuretics
Authorization status:
Not marketed
Authorization number:
PA0865/013/001
Authorization date:
2005-05-13

Package leaflet: Information for the user

Bifril Plus 30 mg /12.5 mg film-coated tablets

(zofenopril calcium / 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. 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 Bifril Plus is and what it is used for

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

3. How to take Bifril Plus

4. Possible side effects

5. How to store Bifril Plus

6. Content of the pack and other information

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

Bifril Plus contains zofenopril calcium 30 mg and hydrochlorothiazide 12.5 mg as the active ingredients.

Zofenopril calcium is a cardiovascular drug which belongs to a group of blood pressure lowering

medicines called angiotensin converting enzyme (ACE) inhibitors.

Hydrochlorothiazide is a diuretic, that acts by increasing the amount of urine you produce.

Bifril Plus is used to treat mild to moderate high blood pressure (hypertension), when this is not adequately

controlled by taking zofenopril alone.

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

Do not take Bifril Plus if you:

are more than 3 months pregnant (It is also better to avoid Bifril Plus in early pregnancy - see

“pregnancy section”).

are allergic to zofenopril calcium or to hydrochlorothiazide or to any of the other ingredients of this

medicine (listed in section 6)

allergic

other

sulphonamide-derived

substances

(like

hydrochlorothiazide,

which

sulphonamide-derived drug)

have had any previous allergic reaction to any other ACE inhibitor such as captopril or enalapril

have a history of severe swelling and itching around the face, nose and throat (angioneurotic oedema)

associated with previous ACE inhibitor therapy, or if you suffer from hereditary/idiopathic angioneurotic

oedema (rapid swelling of the skin, tissues, digestive tract and other organs)

have taken or are currently taking sacubitril/valsartan, a medicine used to treat a type of long-term

(chronic) heart failure in adults, as the risk of angioedema (rapid swelling under the skin in an area such

as the throat) is increased

suffer from severe liver or kidney problems

suffer from narrowing of the arteries to the kidneys

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

containing aliskiren

Warnings and precautions

Talk to your doctor before taking Bifril Plus.

Tell your doctor if you:

have liver or kidney problems

have high blood pressure that is caused by a kidney problem or by narrowing of the artery leading to the

kidney (renovascular hypertension)

have recently had a kidney transplant

are undergoing dialysis

are on LDL apheresis (a procedure similar to kidney dialysis that clears your blood of harmful

cholesterol)

have abnormally high levels of the hormone aldosterone in your blood (primary aldosteronism) or

decreased levels of the hormone aldosterone in your blood (hypoaldosteronism)

have a narrowing of the heart valve (aortic stenosis) or thickening of the heart walls (hypertrophic

cardiomyopathy)

suffer or have suffered from psoriasis (skin disease characterised by scaly pink patches)

are receiving desensitization treatment (‘allergy injections’) for insect stings

have lupus erythematosus (a disorder of the immune system, your body’s defence system)

if you tend to have low blood potassium, and especially if you suffer from prolonged QT syndrome (a

kind of ECG abnormality) or you are taking digitalis (to help your heart pump)

have diabetes

if you have angina or disorders affecting the brain, since low blood pressure can lead to a heart attack or

stroke.

are taking any of the following medicines used to treat high blood pressure:

an “angiotensin II receptor blocker” (ARBs) (also known as sartans - for example valsartan,

telmisartan, irbesartan, etc.), in particular if you have diabetes-related kidney problems.

aliskiren

are taking any of the following medicines, the risk of angioedema (rapid swelling under the skin in area

such as the throat) may be increased:

racecadotril, (a medicine used to treat diarrhoea)

medicines used to prevent organ transplant rejection and for cancer (e.g., temsirolimus, sirolimus,

everolimus)

vildagliptin, (a medicine used to treat diabetes).

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 Bifril Plus.

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 Bifril Plus’’

The hydrochlorothiazide in Bifril Plus may cause your skin to be oversensitive to sunlight or artificial UV

light. Stop taking Bifril Plus and tell your doctor if you get a rash, itchy spots or sensitive skin during

treatment (see also section 4).

Anti-dope test: Bifril Plus could cause a positive anti-dope test.

Your blood pressure may get too low with Bifril Plus, especially after the first dose (this is more likely if

you have also been taking diuretics, are dehydrated or a low-salt diet, or if you have sickness or diarrhea). If

this happens, tell your doctor immediately and then lie down on your back (see also section 4).

If you are having an operation, tell your anaesthetist that you are taking Bifril Plus before being

anaesthetised. This will help him/her to control your blood pressure and heart rate during the procedure.

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

Do not give this medicine to children and adolescents under the age of 18 years because it is unlikely to be

safe.

Other medicines and Bifril Plus

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

In particular, tell your doctor if you are taking:

potassium supplements (including salt substitutes), potassium-sparing diuretics and other medicines that

can increase the amount of potassium in your blood (e.g. trimethoprim and co-trimoxazole for infections

caused by bacteria; cyclosporin, an immunosuppressant medicine used to prevent organ transplant

rejection; and heparin used to thin blood to prevent clots)

other medicines that affect the levels of blood chemicals (AdrenoCorticoTropic Hormone - ACTH - used

to stimulate the production of some hormones by the body, amphotericin B injections, carbenoxolone,

stimulant laxatives)

lithium (used to treat mood disorders)

anaesthetics

narcotic drugs (such as morphine)

antipsychotic drugs (used to treat schizophrenia and similar illnesses)

antidepressants of the tricyclic type, e.g. amitriptyline and clomipramine

barbiturates (used to treat anxiety, insomnia, and seizure disorders)

other high blood pressure medicines and vasodilators (including, beta-blockers alpha-blockers and

diuretics, such as hydrochlorothiazide, furosemide, torasemide).

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

If you are taking an angiotensin II receptor blocker (ARB) or aliskiren (see also information under the

headings ’Do not take Bifril Plus’ and ’Warnings and precautions’)

nitroglycerine and other nitrates used for chest pain (angina)

antacids including cimetidine (used to treat heartburn and stomach ulcers)

cyclosporin (used after organ transplants) and other immunosuppressant drugs (medicines that suppress

your body’s immune defences)

medicines for gout (e.g. probenecid, sulfinpyrazone and allopurinol)

insulin or oral anti-diabetic medicines

cytostatic agents (used to treat cancer or diseases which affect the body’s immune defences)

corticosteroids (powerful anti-inflammatory drugs)

procainamide (used to control an irregular heart beat)

nonsteroidal anti-inflammatory drugs (NSAIDs, such as aspirin or ibuprofen)

sympathomimetic drugs (medicines that act on the nervous system, including some used to treat asthma

or hay fever and pressor amines, e.g. adrenalin)

calcium salts

digitalis (used to help the heart pump)

cholestyramine and colestipol resins (used to lower cholesterol)

medicines used to relax muscles (e.g. tubocurarine)

amantadine (an antiviral medicine).

racecadotril (a medicine used to treat diarrhoea), medicines used to prevent organ transplant rejection

and for cancer (e.g. temsirolimus, sirolimus, everolimus) and vildagliptin (a medicine used to treat

diabetes). The risk of angioedema may be increased.

Bifril Plus with food, drink and alcohol

Bifril Plus can be taken with food or on an empty stomach, but always with some water.

Alcohol increases the hypotensive (lowering of blood pressure) effect of Bifril Plus; ask your doctor for

further advice on drinking alcohol whilst on this medication.

Pregnancy and breast-feeding

Pregnancy

If you are pregnant, you think you may be pregnant or are planning to have a baby, ask your doctor for

advice before taking this medicine. Your doctor will normally advise you to stop taking Bifril Plus before

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

instead of Bifril Plus.

Bifril Plus 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

If you are breast-feeding or about to start breast-feeding ask your doctor for advice before taking this

medicine. Bifril 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, especially if your baby is newborn, or was born

prematurely.

Driving and using machines

This medicine may cause dizziness or tiredness. If this happens to you, do not drive or operate machinery.

Bifril Plus contains lactose

This product contains lactose. If you know you have an intolerance to some sugars, contact your doctor

before taking this medicine.

3.

How to take Bifril Plus

Always take Bifril Plus exactly as your doctor has told you. Check with your doctor if you are not sure.

The recommended dose of Bifril Plus is one tablet per day.

Bifril Plus may be taken with food or on an empty stomach. The tablet is best taken with some water.

The score line is only there to help you break the tablet if you have difficulty swallowing it whole.

If you are over 65 and suffer from an impaired kidney function, Bifril Plus may not be suitable for you (see

also section 2 ’Warnings and precautions’)

Use in children and adolescents

This medicine is not recommended for use in children and adolescents under the age of 18 years.

If you take more Bifril Plus than you should

If you accidentally take too many tablets, contact your doctor or nearest hospital immediately (taking any

remaining tablets, the carton or this leaflet with you if possible).

The most frequent symptoms and signs of an overdose are low blood pressure with fainting (hypotension),

very slow heart beat (bradycardia), changes in blood chemicals (electrolytes), kidney dysfunction, excessive

urination with consequent dehydration, nausea and somnolence, muscle spasms, heart rhythm disturbances

(especially if you are also taking digitalis or medicines for heart rhythm problems).

If you forget to take Bifril Plus

If you miss a dose, take the next dose as soon as you remember. However if your next dose is nearly due,

skip the forgotten dose and take the next scheduled normal dose at the usual time. Do not take a double dose

to make up for a forgotten tablet.

If you stop taking Bifril Plus

Always consult your doctor before stopping Bifril Plus treatment.

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

4. Possible side effects

Like all medicines, Bifril Plus can cause side effects, although not everybody gets them.

The following side effects have been reported in clinical trials with Bifril Plus:

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

dizziness

headache

cough.

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

rapid-onset swelling, especially of the lips, cheeks, eyelids, tongue, palate, voice box (larynx), with

possible sudden difficulty breathing (angioneurotic edema). If you have any of these, it means that

you have a serious allergy for Bifril Plus. You may require urgent medical intervention, or you may

need to be hospitalized

infection

bronchitis

sore throat

increase in blood cholesterol and/or other lipids, increased blood glucose, potassium, uric acid,

creatinine and liver enzymes

decrease in blood potassium

insomnia

somnolence, fainting, muscle tightness (hypertonia)

angina, heart attack, atrial fibrillation, palpitations

flushing, low blood pressure, high blood pressure

nausea, indigestion, gastritis, inflammation of the gums, dry mouth, stomach pain

skin disease characterised by scaly pink patches (psoriasis), acne, dry skin, itching, hives

back pain

increased urine (polyuria)

general weakness (asthenia), flu like symptoms, peripheral swelling (usually around the ankles)

impotence

The following side effects were not reported in clinical trials with Bifril Plus, but they have been reported

with zofenopril calcium and/or other ACE inhibitors, so they may also occur with the use of Bifril Plus:

Tiredness (fatigue). Severe low blood pressure at the start of treatment or when the dosage is

increased, with dizziness, impaired vision, fainting; low blood pressure on standing.

Chest pain, muscle aches and/or cramps.

Impaired consciousness, sudden dizziness, suddenly impaired vision or weakness and/or loss of

sense of touch on one side of the body (transient ischaemic attack or stroke).

Reduced kidney function, changes in the amount of daily urine, presence of proteins in the urine

(proteinuria).

Vomiting, diarrhoea, constipation.

Allergic

skin

reaction

with

peeling,

redness,

loosening

blistering

of the

skin

(toxic

epidermal necrolysis), worsening of psoriasis, hair loss (alopecia).

Increased sweating.

Mood changes, depression, sleep disorders.

Altered skin sensations such as burning, prickling, or tingling (paraesthesia).

Disorders of balance, confusion, ringing in the ears (tinnitus), taste disturbances, blurred vision.

Difficulty in breathing, narrowing of the airways in the lung (bronchospasm), sinusitis, runny or

stuffy nose (rhinitis), inflammation of the tongue (glossitis).

Yellowing of the skin (jaundice), inflammation of the liver or pancreas (hepatitis, pancreatitis),

bowel obstruction (ileus).

Changes in blood tests, such as red blood cell, white blood cell or platelet count or a reduction

in all kinds of blood cells (pancytopenia): Contact your doctor if you find that you bruise

easily or develop an unexplained sore throat or fever.

Increased blood levels of bilirubin, increased blood urea.

Anaemia due to rupture of red blood cells (haemolytic anaemia), which may occur if you suffer

from G6PD (glucose-6-phosphate dehydrogenase) deficiency.

The following side effects were not reported in clinical trials with Bifril Plus, but they have been reported

with hydrochlorothiazide, so they may also occur with the use of Bifril Plus:

Impaired production of new blood cells by the bone marrow (bone marrow failure).

Fever, whole-body allergic reaction (anaphylactic reaction).

Altered levels of body fluids (dehydration) and blood chemicals (electrolytes), gout, diabetes,

metabolic alkalosis.

Apathy, nervousness, restlessness.

Convulsions, depressed level of consciousness, coma, paresis.

Yellow vision (xanthopsia), worsening of myopia, decreased lacrimation.

Vertigo (spinning sensation).

Heart rhythm disturbances (arrhythmias), changes in the electrocardiogram.

Formation of blood clots in veins (thrombosis) and embolism, circulatory collapse (shock).

Respiratory distress, lung inflammation (pneumonitis), formation of fibrous tissue in the lungs

(interstitial lung disease), fluid accumulation in the lung (pulmonary oedema).

Thirst, lack of appetite (anorexia), absence of bowel movements (ileus paralytic), excessive gas

in the stomach, inflammation of the glands that produce saliva (sialoadenitis), increased blood

amylase

pancreatic

enzyme,

hyperamylasaemia),

inflammation

gall

bladder

(cholecystitis).

Purple spots/blotches on the skin (purpura), increased sensitivity of your skin to sunlight, rash

(especially

facial)

and/or

patchy

redness

that

cause

scarring

(cutaneous

lupus

erythematosus), inflammation of blood vessels with consequent death of tissue (vasculitis

necrotising).

Acute kidney failure (with reduced urine production and build-up of fluid and wastes in your

body), inflammation of the connective tissue within the kidneys (interstitial nephritis), sugar in

the urine.

Frequency ‘not known’: 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 Bifril Plus

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

Do not store above 30

Do not use this medicine after the expiry date which is stated on the box and blister pack after ‘EXP’. The

expiry date refers to the last day of that month

Always keep the tablets in their original packaging.

Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines you

no longer use. These measures will help protect the environment.

6 . Content of the pack and other information

What Bifril Plus contains

The active substances are zofenopril calcium 30 mg and hydrochlorothiazide 12.5 mg.

The other ingredients are the following:

Tablet Core: Microcrystalline cellulose, lactose monohydrate, maize starch, hypromellose, silica

colloidal anhydrous, magnesium stearate

Film Coat: Opadry Pink 02B24436 (hypromellose, titanium dioxide (E 171), macrogol 400, iron

oxide red (E 172), macrogol 6000

(see section 2 ‘Bifril Plus contains lactose’).

What Bifril Plus looks like and contents of the pack

Bifril Plus 30mg/12.5 mg tablets are pastel-red, round, slightly bi-convex film-coated tablets with a score

line on one side. The score line is to facilitate breaking for ease of swallowing and not to divide into equal

doses. The tablets are available in packs of 14, 28, 30, 50, 56, 90 or 100 tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Menarini International Operations Luxembourg S.A.

1, Avenue de la Gare L-1611, Luxembourg.

Manufacturer

A. MENARINI Manufacturing Logistics and Services Srl

Campo di Pile, L'Aquila, Italy.

Menarini –Von Heyden GmbH

Leipziger Strasse 7-13,

01097 – Dresden (Germany).

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

Austria: Bifril Plus

Belgium: Zopranol Plus

France: Coteoula

Greece: Zopranol-Plus

Ireland: Bifril Plus

Italy: Zoprazide

Iceland: Bifril Comp

Luxembourg: Zopranol Plus

Portugal: Zopranol Plus

The Netherlands: Zopranol HCTZ

United Kingdom: Zofenico

This leaflet was last revised in 07/2019.

Health Products Regulatory Authority

10 November 2019

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Bifril Plus 30 mg/12.5 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 28.7 mg of zofenopril as 30 mg of zofenopril calcium and 12.5 mg of hydrochlorothiazide.

Excipients with known effect:

Each film-coated tablet contains 56.20 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

Pastel-red, round, slightly bi-convex tablets of 9 mm with a score line on one side.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Treatment of mild to moderate essential hypertension.

This fixed dose combination is indicated in patients whose blood pressure is not adequately controlled on zofenopril alone.

4.2 Posology and method of administration

Posology

Adults

Dose titration with the individual components (i.e. zofenopril and hydrochlorothiazide) is recommended before changing to

the fixed dose combination.

When clinically appropriate direct change from monotherapy to the fixed combination may be considered.

Patients without volume or salt depletion

The usual effective dose is one tablet once daily.

Patients suspected of volume or salt depletion

The use of Bifril Plusis not recommended.

Elderly (over 65 years)

In the elderly with normal creatinine clearance no dose adjustment is necessary.

In the elderly with reduced creatinine clearance (less than 45 mL/min) the use of Bifril Plusis not recommended.

Creatinine clearance may be estimated from serum creatinine by the following

Cockroft-Gault formula:

[(140-age) * weight (Kg)]

CrCl (mL/min) = _______________________________________

72 *serum Cr (mg/dL)

The above method provides creatinine clearance in males. For females the value obtained should be multiplied by 0.85.

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Paediatric population

The safety and efficacy of Bifril Plusin children and adolescents below 18 years has not been established.

Therefore, its use is not recommended.

Renal impairment and dialysis

In hypertensive patients with mild impairment (creatinine clearance > 45 mL/min) the same dose level and once-daily regimen

of Bifril Pluscan be employed as for patients with normal renal function.

In patients with moderate to severe impairment (creatinine clearance < 45 mL/min) its use is not recommended (see section

4.4).

In patients with severe renal impairment (creatinine clearance <30 ml/min) Bifril Plus is contraindicated (see section 4.3).

In hypertensive patients maintained on dialysis the use of Bifril Plusis not recommended.

Hepatic impairment

In hypertensive patients with mild to moderate hepatic impairment, where the 30 mg dose of zofenopril alone has been

achieved, the same dose regimen can be employed as for patients with normal hepatic function.

In hypertensive patients with severe liver impairment Bifril Plusis contra-indicated.

Method of administration

Bifril Plus should be used once daily, with or without food.

To ease swallowing, tablets may be broken in two parts and swallowed one half after the other, at the prescribed time of

administration.

4.3 Contraindications

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

Hypersensitivity to zofenopril or any other ACE inhibitor.

Hypersensitivity to hydrochlorothiazide or other sulphonamide-derived substances.

Hypersensitivity to any of the excipients listed in section 6.1

History of angioneurotic oedema associated with previous ACE inhibitor therapy.

Concomitant use with sacubitril/valsartan therapy. Bifril Plus must not be initiated earlier than 36 hours after the last dose of

sacubitril/valsartan (see also sections 4.4 and 4.5).

Hereditary/idiopathic angioneurotic oedema.

Severe hepatic impairment.

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

Bilateral renal artery stenosis or unilateral renal artery stenosis in cases of a solitary single kidney.

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

renal impairment (GFR < 60 ml/min/1.73 m2) (see Sections 4.5 and 5.1).

4.4 Special warnings and precautions for use

ZOFENOPRIL

Hypotension:

As with other ACE inhibitors and diuretics, Bifril Plus may cause a profound fall in blood pressure especially after the first dose,

although symptomatic hypotension is seen rarely in uncomplicated hypertensive patients.

It is more likely to occur in patients who have been volume and electrolyte depleted by diuretic therapy, dietary salt restriction,

dialysis, diarrhoea or vomiting, or who have severe renin-dependent hypertension (see section 4.5 and section 4.8).

In patients with heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. This

is more likely to occur in those patients with more severe degrees of heart failure, as reflected by the use of high doses of loop

diuretics, hyponatraemia or functional renal impairment.

In patients at increased risk of symptomatic hypotension, treatment should be started under close medical supervision

preferably in the hospital, with low doses and careful dose titration. If possible, diuretic treatment should be discontinued

temporarily when therapy with Bifril Plus is initiated.

Such considerations apply also to patients with angina pectoris or cerebrovascular disease in whom an excessive fall in blood

pressure could result in myocardial infarction or cerebrovascular accident.

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If hypotension develops, the patient should be placed in a supine position. Volume repletion with intravenous normal saline

may be required. The occurrence of hypotension after the initial dose does not preclude subsequent careful dose titration with

each component of the medicinalproduct after effective management.

Patients with 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 ACE inhibitors. Treatment with diuretics may be a

contributory factor. Loss of renal function may occur with only mild changes in serum creatinine even in patients with unilateral

renal artery stenosis.

In these patients, therapy should be initiated under close medical supervision with low dose, careful titration and monitoring of

renal function.

Patients with renal insufficiency:

Close monitoring of renal function during therapy should be performed as deemed appropriate. Renal failure has been

reported in association with ACE inhibitors, mainly in patients with severe heart failure or underlying renal disease, including

renal artery stenosis. Some patients, with no apparent pre-existing renal disease have developed increases in blood urea and

creatinine concentrations, particularly when a diuretic is given concomitantly. Dosage reduction of the individual components

may be required. It is recommended that the renal function be monitored closely during the first few weeks of therapy.

Patients who are dialysed:

Patients who are dialysed using high-flux polyacrylonitrile membranes (e.g. AN 69) and treated with ACE inhibitors are likely to

experience anaphylactoid reactions such as facial swelling, flushing, hypotension and dyspnoea within a few minutes of

commencing haemodialysis. It is recommended to use an alternative membrane or an alternative antihypertensive medicinal

product.

The efficacy and safety of zofenopril in myocardial infarction patients undergoing haemodialysis has not been established.

Therefore, it should not be used in these patients.

Patients on LDL apheresis:

Patients treated with an ACE inhibitor undergoing LDL apheresis with dextran sulphate may experience anaphylactoid reactions

similar to those seen in patients undergoing haemodialysis with high-flux membranes (see above). It is recommended that an

agent from another class of antihypertensiveproducts is used in these patients.

Anaphylactic reactions during desensitisation or after insect bites:

Rarely, patients receiving ACE inhibitors during desensitisation treatment (e.g. hymenoptera venom) or after insect bites have

experienced life-threatening anaphylactoid reactions. In the same patients, these reactions have been avoided when ACE

inhibitors were temporarily withheld but they have reappeared upon inadvertent re-administration of the medicinal product.

Therefore, caution should be used in patients treated with ACE inhibitors undergoing such desensitisation procedures.

Kidney transplantation:

There is no experience regarding the administration of Bifril Plus in patients with a recent kidney transplantation. Its use in

transplant recipients is therefore not recommended.

Primary aldosteronism:

Patients with primary aldosteronism generally will not respond to antihypertensive products acting through inhibition of the

renin-angiotensin system. Therefore the use of zofenopril is not recommended.

Hypersensitivity/Angioedema:

Angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx may occur in patients treated with

ACE inhibitors which occurs most frequently during the first weeks of treatment. However in rare cases severe angioedema may

develop after long-term treatment with an angiotensin converting enzyme inhibitor. Treatment with ACE inhibitors should

promptly be discontinued and replaced by an agent belonging to another class of antihypertensive products.

Angioedema involving the tongue, glottis or larynx may be fatal. Emergency therapy should be given including, but not

necessarily limited to, immediate subcutaneous adrenaline solution 1:1000 (0.3 to 0.5 ml) or slow intravenous adrenaline 1

mg/ml (which should be diluted as instructed) with close monitoring of ECG and blood pressure. The patient should be

hospitalised and observed for at least 12 to 24 hours and should not be discharged until complete resolution of symptoms has

occurred.

Even in such instances where swelling of only the tongue is involved, without respiratory distress, patients may require

observation since treatment with antihistamines and corticosteroids may not be sufficient.

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Angiotensin converting enzyme inhibitors cause a higher rate of angioedema in black patients than in non-black patients.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while

receiving an ACE inhibitor (see 4.3 Contraindications).

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to the increased risk of angioedema.

Treatment with sacubitril/valsartan must not be initiated earlier than 36 hours after the last dose of Bifril Plus. Treatment with

Bifril Plus must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.5).

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin

may lead to an increased risk of angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment)

(see section 4.5). Caution should be used when starting racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus)

and vildagliptin in a patient already taking any ACE inhibitor.

Cough:

During treatment with ACE-inhibitors a dry and non-productive cough may occur which disappears after discontinuation of

therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.

Hepatic failure:

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant

hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors

who develop jaundice or marked elevations of hepatic enzymesshould discontinue the ACE inhibitor and receive appropriate

medical follow-up.

Serum potassium:

ACE inhibitors can cause hyperkalaemia because they inhibit the release of aldosterone. The effect is usually not significant in

patients with normal renal function. However, in patients with impaired renal function and/or in patients taking potassium

supplements (including salt substitutes), potassium-sparing diuretics, heparin, trimethoprim or co-trimoxazole also known as

trimethoprim/sulfamethoxazole and especially aldosterone antagonists or angiotensin receptor blockers, hyperkalaemia can

occur.

Potassium-sparing diuretics and angiotensin-receptor blockers should be used with caution in patients receiving ACE inhibitors,

and serum potassium and renal function should be monitored (see section 4.5).

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

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

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

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

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

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

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

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

Surgery/Anaesthesia:

ACE inhibitors may cause hypotension or even hypotensive shock in patients undergoing major surgery or during anaesthesia,

since they may block angiotensin II formation secondary to compensatory renin release. If it is not possible to withhold the ACE

inhibitor, intravascular and plasma volumes should be carefully monitored.

Aortic and mitral valve stenosis/Hypertrophic cardiomyopathy:

ACE inhibitors should be used with caution in patients with mitral valve stenosis and left ventricular outflow tract obstruction

and avoided in cases of cardiogenic shock and haemodynamically significant obstruction.

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Neutropenia/Agranulocytosis:

Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors. The risk

of neutropenia appears to be dose- and type-related and is dependent on patient's clinical status. It is rarely seen in

uncomplicated patients but may occur in patients with some degree of renal impairment especially when it is associated with

collagen vascular disease e.g. systemic lupus erythematosus, scleroderma and therapy with immunosuppressive agents,

treatment with allopurinol or procainamide, or a combination of these complicating factors. Some of these patients developed

serious infections which in a few instances did not respond to intensive antibiotic therapy.

If zofenopril is used in such patients, it is advised that white blood cell count and differential counts should be performed prior

to therapy, every 2 weeks during the first 3 months of zofenopril therapy, and periodically thereafter. During treatment all

patients should be instructed to report any sign of infection (e.g. sore throat, fever) when a differential white blood cell count

should be performed. Zofenopril and other concomitant medication (see section 4.5) should be withdrawn if neutropenia

(neutrophils less than 1000/mm3) is detected or suspected. It is reversible after discontinuation of the ACE inhibitor.

Psoriasis:

ACE inhibitors should be used with caution in patients with psoriasis.

Proteinuria:

Proteinuria may occur particularly in patients with existing renal function impairment or on relatively high doses of ACE

inhibitors. Patients with prior renal disease should have urinary protein estimation (dip-stick on first morning urine) prior to

treatment, and periodically thereafter.

Diabetic patients:

The glycaemia levels should be closely monitored in diabetic patientspreviously treated with oral antidiabeticproductsor insulin,

during the first month of treatment with an ACE inhibitor (see section 4.5).

Lithium:

The combination of Lithium and Bifril Plus is generally not recommended (see section 4.5).

Ethnic differences:

As with other angiotensin converting enzyme inhibitors, zofenopril may be less effective in lowering blood pressure in black

people than in non-blacks.

Angiotensin converting enzyme inhibitors cause a higher rate of angioedema in black patients than in non-black patients.

Pregnancy:

ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor 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 ACE inhibitors should be stopped immediately, and,

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

HYDROCHLOROTHIAZIDE

Renal impairment:

In patients with renal disease, thiazides may increase azotaemia. Cumulative effects of this active substance may develop in

patients with impaired renal function. If progressive renal impairment becomes evident, as indicated by a rising non-protein

nitrogen, careful reappraisal of therapy is necessary, with consideration given to discontinuing diuretic therapy.

Hepatic impairment:

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor

alterations of fluid and electrolyte balance may precipitate hepatic coma.

Metabolic and endocrine effects:

Thiazide therapy may impair glucose tolerance. 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 have been associated with thiazide diuretic therapy. Thiazide therapy may

precipitate hyperuricaemia and/or gout in certain patients.

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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 (hypokalaemia, hyponatraemia, and

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

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

disturbances such as nausea or vomiting.

Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with zofenopril may reduce

diuretic-induced hypokalaemia. 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).

Dilutional hyponatraemia may occur in oedematous patients in hot weather. Chloride deficit is generally mild and usually does

not require treatment.

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

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

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

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

Lupus erythematosus:

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

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).

Anti-doping test:

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

Other:

Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.

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

occurs during treatment, it is recommended to stop the treatment. If re-administration of the diuretic is deemed necessary, it is

recommended to protect the areas exposed to the sun or artificial UVA

ZOFENOPRIL/HYDROCHLOROTHIAZIDE COMBINATION

In addition to the warnings related to the monocomponents, the following should be observed:

Pregnancy:

Bifril Plus is not recommended during the first trimester of pregnancy (see section 4.6).

Patients with renal insufficiency:

Considering the effect of zofenopril and hydrochlorothiazide in patients with impaired renal function, Bifril Plus should not be

administered to patients with moderate to severe renal insufficiency (creatinine clearance < 45 ml/min).

Risk of hypokalaemia:

The combination of an ACE inhibitor with a thiazide diuretic does not rule out the occurrence of hypokalaemia. Regular

monitoring of serum potassium should be performed.

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Galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption:

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

glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interactions

ZOFENOPRIL

Medicines increasing the risk of angioedema

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated as this increases the risk of angioedema (see

section 4.3 and 4.4).

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin

may lead to an increased risk for angioedema (see section 4.4).

Concomitant use not recommended

Potassium sparing diuretics, potassium supplementspotassium-containing salt substitutes or other agents that increase serum

potassium

Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with

zofenopril. Potassium sparing diuretics (e.g. spironolactone, triamterene, or amiloride), potassium supplements, or

potassium-containing salt substitutes may lead to significant increases in serum potassium. Care should also be taken when

zofenopril is co-administered with other agents that increase serum potassium, such as trimethoprim and cotrimoxazole

(trimethoprim/sulfamethoxazole) as trimethoprim is known to act as a potassium-sparing diuretic like amiloride. Therefore, the

combination of zofenopril with the above-mentioned drugs is not recommended. If concomitant use is indicated, they should

be used with caution and with frequent monitoring of serum potassium.

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).

Concomitant use requiring caution

Diuretics (thiazide or loop diuretics)

Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with

zofenopril (see 4.4). The hypotensive effects can be reduced by discontinuation of the diuretic, by increasing volume or salt

intake or by initiating therapy with a low dose of zofenopril.

Anaesthetics medicinal products

ACE inhibitors may enhance the hypotensive effects of certain anaesthetic medicinal products.

Narcotics/Tricyclic antidepressants/Antipsychotics/Barbiturates:

Postural hypotension may occur.

Other antihypertensive substances (e.g. Beta-blockers, alpha-blockers, calcium antagonists)

There may be additive hypotensive effect or potentiation. Treatment with nitroglycerine and other nitrates, or other

vasodilators, should be used with caution.

Cimetidine

May enhance the risk of hypotensive effect.

Cyclosporin

Hyperkalaemia may occur during concomitant use of ACE inhibitors with cyclosporin

Monitoring of serum potassium is recommended.

Heparin

Hyperkalaemia may occur during concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium is

recommended.

Allopurinol, procainamide, systemic corticosteroids, cytostatic or immunosuppressive agents

Increased risk of hypersensitivity reactions when ACE inhibitors are used concurrently. Data from other ACE inhibitors indicate

an increased risk of leukopenia when used concurrently.

Antidiabetics

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Rarely ACE inhibitors can potentiate the blood glucose-reducing effects of insulin and oral antidiabetics like sulphonylurea, in

diabetics. In such cases it may be necessary to reduce the dose of the antidiabetic during simultaneous treatment with ACE

inhibitors.

Haemodialysis with high-flux dialysis membranes

Increased risk of anaphylactoid reactions when ACE inhibitors are used concurrently.

Sympathomimetics

May reduce the antihypertensive effects of ACE inhibitors; patients should be carefully monitored to confirm that the desired

effect is being obtained.

Antacids

Reduce the bioavailability of ACE inhibitors.

Food

May reduce the rate but not the extent of absorption of zofenopril.

Gold

Nitritoid reactions (symptoms of vasodilatation including flushing, nausea, dizziness and hypotension, which can be very

severe) following injectable gold (for example, sodium aurothiomalate) have been reported more frequently in patients

receiving ACE inhibitor therapy.

Additional information

CYP enzymes

Direct clinical data on the interaction of zofenopril with other active substances which are metabolised by CYP enzymes are not

available. However, in vitro metabolic studies with zofenopril demonstrated no potential interaction with active substances that

are metabolised by CYP enzymes.

HYDROCHLOROTHIAZIDE

Concomitant use requiring caution

Cholestyramine and colestipol resins

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

cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastro-intestinal tract by

up to 85% and 43%, respectively.

Sulphonamide diuretics should be taken at least one hour before or four to six hours after these medications.

Corticosteroids, ACTH, amphotericin B (parenteral), carbenoxolone, stimulant laxatives

There may be intensified electrolyte depletion, particularly hypokalaemia when administered concomitantly with

hydrochlorothiazide.

Calcium salts

Increased serum calcium levels due to decreased excretion may occur when administered concurrently with thiazide diuretics.

Cardiac glycosides

Thiazide induced hypokalaemia or hypomagnesaemia favours the occurrence of digitalis induced cardiac arrhythmia.

Medicinal products associated with torsade de pointes

Because of the risk of hypokalaemia, caution should be used when hydrochlorothiazide is coadministered with medicinal

productsassociated with torsade de pointes, e.g. some antiarrhythmics, some antipsychotics, and other medicinal

productsknown to induce torsade de pointes.

Pressor amines (e.g. adrenaline)

Possible decreased response to pressor amines, but not sufficient to preclude their use with hydrochlorothiazide.

Skeletal muscle relaxants, non-depolarising (e.g. tubocurarine)

Possible increasedresponsiveness to the muscle relaxant when used with hydrochlorothiazide.

Amantadine

Thiazide may increase the risk of undesirable effects caused by amantadine.

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

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

acid. Increase of dosage of probenecid or sulfinpyrazone may be necessary. Co-administration of thiazide diuretics may

increase the incidence of hypersensitivity reactions to allopurinol.

Additional information

Laboratory test interactions:because of their effects on calcium metabolism, thiazides may interfere with tests for parathyroid

function.

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ZOFENOPRIL/HYDROCHLOROTHIAZIDE COMBINATION

In addition to the interactions related to the monocomponents, the following should be observed:

Concomitant use not recommended

Lithium

Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and enhance the already increased risk of lithium

toxicity with ACE inhibitors.

Therefore, Bifril Plus is not recommended in association with lithium and careful monitoring of serum lithium levels should be

performed if the combination proves necessary.

Clinical Chemistry

Thiazides may decrease serum PBI (Protein Bound Iodine) levels without signs of thyroid disturbance.

Concomitant use requiring caution

Non-Steroidal Anti-Inflammatory medicinal product (including ASA ³ 3g/day)

The administration of non-steroidal anti-inflammatory agents may reduce the antihypertensive effect of ACE inhibitors and

diuretics. Furthermore, it has been described that NSAIDS and ACE inhibitors exert an additive effect on the increase in serum

potassium whereas renal function may decrease. These effects are in principle reversible, and occur especially in patients with

impaired renal function. Rarely, acute renal failure may occur, particularly in patients with compromised renal function such as

the elderly or dehydrated.

Alcohol

Enhances the hypotensive effect of ACE and hydrochlorothiazide.

Trimethoprim

Concomitant administration of ACE-inhibitors and thiazides with trimethoprim increases the risk of hypercalaemia.

4.6 Fertility, pregnancy and lactation

Pregnancy

Zofenopril and hydrochlorothiazide

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

recommended during the first trimester of pregnancy (see section 4.4). The use of Bifril Plus is contra-indicated during the 2nd

and 3rd trimester of pregnancy (see section 4.3 and 4.4)

Zofenopril

The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE

inhibitors 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. Unless continued ACE inhibitor

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 ACE inhibitors

should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to ACE inhibitor 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 ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of

renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors 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.

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.

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Breast-feeding

Because no information is available regarding the use of Bifril Plus during breastfeeding, Bifril Plus is not recommended and

alternative treatments with better established safety profiles during breastfeeding 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 Bifril Plus during breast feeding is not recommended. If Bifril Plus is used during breast feeding,

doses should be kept as low as possible.

4.7 Effects on ability to drive and use machines

No studies on the effect on the ability to drive and use machines have been performed. When driving vehicles or operating

machines it should be remembered that occasionally drowsiness, dizziness or weariness may occur.

4.8 Undesirable effects

In controlled clinical trials involving 597 patients randomised to receive zofenopril plus hydrochlorothiazide, no adverse

reactions peculiar to this combination product have been observed. Adverse reactions have been limited to those that were

reported previously with zofenopril calcium or hydrochlorothiazide. The incidence of undesirable effects showed no correlation

with gender or age of the patients.

Tabulated list of adverse reactions

The table below shows all the adverse reactions that have been reported during clinical trials as at least probably-possibly

related to treatment with zofenopril/hydrochlorothiazide 30/12.5 mg. They are listed by body-system and ranked under

headings of frequency using the following convention: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon

(≥ 1/1,000, ≤1/100); rare (≥ 1/10,000, ≤1/1,000); very rare (≤1/10,000).

MedDRA

System Organ Class

Adverse reactions

Frequency

Infections and infestations

Infection

Uncommon

Bronchitis

Uncommon

Pharyngitis

Uncommon

Metabolism and nutrition disorders

Hypercholesterolaemia

Uncommon

Hyperglycaemia

Uncommon

Hyperlipidaemia

Uncommon

Hypokalaemia,

Uncommon

Hyperkalaemia

Uncommon

Hyperuricaemia

Uncommon

Nervous system disorders

Dizziness

Common

Headache

Common

Somnolence

Uncommon

Syncope

Uncommon

Hypertonia

Uncommon

Psychiatric disorders

Insomnia

Uncommon

Cardiac disorders

Angina pectoris

Uncommon

Atrial fibrillation,

Uncommon

Myocardial infarction

Uncommon

Palpitations

Uncommon

Vascular disorders

Flushing

Uncommon

Hypotension

Uncommon

Hypertension

Uncommon

Respiratory, thoracic and mediastinal disorders

Cough

Common

Dyspnoea

Uncommon

Gastrointestinal disorders

Nausea

Uncommon

Dyspepsia

Uncommon

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Gastritis

Uncommon

Gingivitis

Uncommon

Dry mouth

Uncommon

Abdominal pain

Uncommon

Skin and subcutaneous tissue disorders

Angioedema

Uncommon

Psoriasis

Uncommon

Acne

Uncommon

Dry skin

Uncommon

Pruritus

Uncommon

Urticaria

Uncommon

Musculoskeletal and connective tissue disorders

Back pain

Uncommon

Renal and urinary disorders

Polyuria

Uncommon

General disorders and administration site conditions

Asthenia

Uncommon

Influenza like illness

Uncommon

Oedema peripheral

Uncommon

Reproductive system and breast disorders

Erectile dysfunction

Uncommon

Investigations

Creatinine increase

Uncommon

Liver Function test abnormal

Uncommon

Additional information on individual component

Adverse reactions known to occur with each component given as monotherapy may occur during treatment with Bifril Plus:

ZOFENOPRIL

The most common undesirable effects typical of ACE inhibitors occurred in clinical trials in patients treated with zofenopril

were the following:

MedDRA

System Organ Class

Adverse reactions

Frequency

Nervous system disorders ​

Dizziness

Common

Headache

Common

Respiratory, thoracic and mediastinal disorders

Cough

Common

Gastrointestinal disorders ​

Nausea

Common

Vomiting

Common

Skin and subcutaneous tissue disorders

Rash

Uncommon

Angioedema

Rare

Musculoskeletal and connective tissue disorders

Muscle cramp

Uncommon

General disorders and administration site conditions

Fatigue

Common

Asthenia

Uncommon

The following adverse reactions have been observed associated with ACE inhibitors therapy:

Blood and lymphatic system disorders

In a few patients agranulocytosis and pancytopenia may occur.

There are reports of haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency.

Endocrine disorders

Not known, inappropriate antidiuretic hormone secretion

Metabolism and nutrition disorders

Very rare hypoglycaemia.

Psychiatric disorders

Rarely, depression, mood altered, sleep disorders, confusional state.

Nervous system disorders

Occasionally paraesthesia, dysgeusia, balance disorder.

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Eye disorders

Rarely, vision blurred.

Ear and labyrinth disorders

Rarely, tinnitus.

Cardiac disorders

Individual cases of tachycardia, palpitations, arrhythmias, angina pectoris, myocardial infarction have been reported for ACE

inhibitors in association with hypotension.

Vascular Disorders

Severe hypotension has occurred after initiation or increase of therapy. This occurs especially in certain risk groups (see Special

warnings and precautions for use). In association with hypotension, symptoms like dizziness, feeling of weakness, impaired

vision, rarely with disturbance of consciousness (syncope).

Rarely flushing occurs.

Respiratory, thoracic and mediastinal disorders

Rarely dyspnoea, sinusitis, rhinitis, glossitis, bronchitis and bronchospasm have been reported. ACE inhibitors have been

associated with the onset of angioneurotic oedema in a small subset of patients involving the face and oropharyngeal tissues.

In isolated cases angioneurotic oedema involving the upper airways has caused fatal airway obstruction.

Gastro-intestinal disorders

Occasionally, abdominal pain, diarrhoea, constipation and dry mouth can occur.

Individual cases of pancreatitis and ileus have been described in association with ACE inhibitors.

Very rare small bowel angioedema.

Hepatobiliary disorders

Individual cases of cholestatic jaundice and hepatitis have been described in association with ACE inhibitors.

Skinand subcutaneous tissue disorders

Occasionally allergic and hypersensitivity reactions can occur like pruritus, urticaria, erythema multiforme, Stevens-Johnson

syndrome, toxic epidermic necrolysis, psoriasis-like efflorescences, alopecia.

This can be accompanied by fever, myalgia, arthralgia, eosinophilia and/or increased ANA- titers.

Rarely hyperhidrosis occurs.

Musculoskeletal and connective tissue disorders

Occasionally, myalgia can occur.

Renal and urinary disorders

Renal insufficiency may occur or be intensified. Acute renal failure has been reported (see Special warnings and precautions for

use).

Rarely micturition disorders occur.

Reproductive system and breast disorders

Rarely, erectile dysfunction.

General disorders and administration site conditions

Very rarely oedema peripheral and chest pain.

Investigations

Increases in blood urea and creatinine, reversible on discontinuation may occur, especially in the presence of renal insufficiency,

severe heart failure and renovascular hypertension.

In a few patients, decreases in haemoglobin, haematocrit, platelets and white-cell count have been reported.

Increases in serum levels of hepatic enzymes and bilirubin have also been reported

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HYDROCHLOROTHIAZIDE

The adverse events reported that have been reported with the use of hydrochlorothiazide alone include the following:

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

Frequency 'not known': Non-melanoma skin cancer (Basal cell carcinoma and Squamous cell carcinoma)

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

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

Blood and lymphatic system disorders

Leukopenia, neutropenia, agranulocytosis, thrombocytopenia, aplastic anaemia, haemolytic anaemia, bone marrow failure.

Immune system disorders

Anaphylactic reaction.

Metabolism and nutrition disorders

Anorexia, dehydration, gout, diabetes mellitus, metabolic alkalosis, hyperuricaemia, electrolyte imbalance (including

hyponatraemia, hypokalaemia, hypomagnesaemia, hypochloraemia, hypercalcaemia), hyperglycaemia, hyperamylasaemia.

Psychiatric disorders

Apathy, confusional state, depression, nervousness, restlessness, sleep disorder.

Nervous system disorders

Convulsions, depressed level of consciousness, coma, headache, dizziness, paraesthesia, paresis.

Eye disorders

Xanthopsia, blurred vision, myopia (aggravated), lacrimation decreased.

Ear and labyrinth disorders

Vertigo.

Cardiac disorders

Cardiac arrhythmias, palpitations.

Vascular disorders

Orthostatic hypotension, thrombosis, embolism, shock.

Respiratory thoracic and mediastinal disorders

Pneumonitis, interstitial lung disease, pulmonary oedema.

Gastrointestinal disorders

Dry mouth, nausea, vomiting, stomach discomfort, diarrhoea, constipation, abdominal pain, ileus paralytic, flatulence,

sialoadenitis, pancreatitis.

Hepato-biliary disorders

Jaundice cholestatic, cholecystitis.

Skin and subcutaneous tissue disorders

Pruritus, purpura, urticaria, photosensitivity reactions, rash, cutaneous lupus erythematosus, vasculitis necrotising, toxic

epidermal necrolysis.

Musculoskeletal and connective tissue disorders

Muscle spasm, myalgia.

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Renal and urinary disorders

Renal impairment, renal failure acute, nephritis interstitial, glycosuria.

Reproductive system and breast disorders

Erectile dysfunction.

General disorders and administration site conditions

Asthenia, pyrexia, fatigue, thirst.

Investigations

Electrocardiogram change, blood cholesterol increased, blood triglycerides increased.

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 of overdosage are severe hypotension, shock, stupor, bradycardia, electrolyte disturbances and renal failure.

Treatment is symptomatic and supportive. After ingestion of an overdose, the patients should be kept under close supervision,

preferably in an intensive care unit. Serum electrolytes and creatinine should be monitored frequently. Therapeutic measures

depend on the nature and severity of the symptoms. If the ingestion is recent, measures to prevent absorption such as gastric

lavage and administration of adsorbents and sodium sulphate may be implemented. If hypotension occurs, the patient should

be placed in shock position and the judicious use of volume expanders and/or treatment with angiotensin II considered.

Bradycardia or extensive vagal reactions should be treated by administering atropine. The use of a pacemaker may be

considered. ACE inhibitors may be removed from the circulation by hemodialysis. The use of high-flux polyacrylonitrile

membranes should be avoided.

Overdosage with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypoclroraemia) and dehydration

resulting from excessive diuresis. The most common signs and symptoms of overdosage are nausea and somnolence.

Hypokalaemia may result in muscle spasm and/or accentuate cardiac arrhythmias associated with the concomitant use of

digitalis glycosides or certain anti-arrhythmic medicinal products.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: ACE-inhibitors and diuretics

ATC code: C09B A 15

ZOFENOPRIL/HYDROCHLOROTHIAZIDE COMBINATION

Bifril Plus is a fixed dose combination product containing zofenopril, an inhibitor of angiotensin converting enzyme (ACE) and

Hydrochlorthiazide, a thiazide diuretic. Both components have complementary modes of action and exert an additive

antihypertensive effect.

Zofenopril is a sulfhydryl ACE inhibitor able to block the enzyme that catalyses the conversion of angiotensin I to the

vasoconstrictor peptide angiotensin II, which leads to decreased vasopressor activity and to reduced aldosterone secretion.

This latter decrease may result in an increase in serum potassium concentration, along with sodium and fluid loss. The

cessation of the negative feedback of angiotensin II on the renin secretion results in an increase of the plasma renin activity.

The mechanism through which zofenopril lowers blood pressure is believed to be primarily suppression of the

renin-angiotensin-aldosterone system. ACE is identical to kininase II, an enzyme that degrades bradykinin, a potent

vasodilatatory peptide, that seems to play a role in the therapeutic effect of ACE inhibitors.

Hydrochlorothiazide is a diuretic and antihypertensive agent. It affects the distal renal tubular mechanism of electrolyte

reabsorption. Hydrochlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis

may be accompanied by some loss of potassium and bicarbonate. Presumably through blockade of the

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renin-angiotensin-aldosterone system, co-administration of zofenopril tends to reverse the potassium lost associated with

these diuretics. With hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.

Other information:

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

Endpoint Trial), VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes) have examined the use of combination of an

ACE-inhibitor with an angiotensin II receptor blocker.

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 angiotensin II

receptor blockers.

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

nephropathy.

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 angiotensin II receptor blocker 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. CV 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.

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

between HCTZ and NMSC has been observed. One study included a population comprised of 71,533 cases of BCC and of 8,629

cases of SCC matched to 1,430,833 and 172,462 population controls, respectively. High HCTZ use (≥50,000 mg cumulative) was

associated with an adjusted OR of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clear cumulative

dose response relationship was observed for both BCC and SCC. Another study showed a possible association between lip

cancer (SCC) and exposure to HCTZ: 633 cases of lip-cancer were matched with 63,067 population controls, using a risk-set

sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR 2.1 (95% CI: 1.7-2.6)

increasing to OR 3.9 (3.0-4.9) for high use (~25,000 mg) and OR 7.7 (5.7-10.5) for the highest cumulative dose (~100,000 mg)

(see also section 4.4).

5.2 Pharmacokinetic properties

Concomitant administration of zofenopril and hydrochlorothiazide has little or no effect on the bioavailability of either active

substance. The combination tablet is bioequivalent to concomitant administration of the separate entities.

ZOFENOPRIL

Zofenopril is a prodrug, since the active inhibitor is the free sulfhydryl compound, zofenoprilat, resulting from thio-ester

hydrolysis.

Absorption:

Zofenopril is rapidly and completely absorbed by the oral route and undergoes nearly complete conversion to zofenoprilat,

which reaches peak blood levels after 1.5 h following an oral dose of zofenopril. Single dose kinetics are linear over a

dose-range of 10-80 mg of zofenopril and no accumulation occurs after the administration of 15-60 mg of zofenopril for 3

weeks. The presence of food in the gastrointestinal tract reduces the rate but not the extent of absorption and the AUCs of

zofenoprilat are nearly identical in the fasted or fed state.

Distribution:

Approximately 88% of the circulating radioactivity measured ex-vivo following a radiolabelled dose of zofenopril is bound to

plasma protein and the steady state volume of distribution is 96 litres.

Biotransformation:

Eight metabolites, accounting for 76% of the urinary radioactivity, were identified in human urine following a radiolabelled

dose of zofenopril. The main metabolite is zofenoprilat (22%), which is the metabolized through several pathways, including

glucoronide conjugation (17%), cyclization and glucoronide conjugation (13%), cysteine conjugation (9%) and S-methylation of

the thiol group (8%).

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Elimination:

Radiolabelled zofenoprilat administered intravenously is eliminated in urine (76%) and faeces (16%) while following an oral

dose of radiolabelled zofenopril, 69% and 26% of the radioactivity is recovered in urine and faeces respectively, indicating a

dual route of elimination (kidney and liver). Half-life of zofenoprilat is 5.5 h and its total body clearance is 1300 ml/min

following oral zofenopril.

Pharmacokinetics in special populations

Pharmacokinetics in the elderly

In the elderly, no dose adjustment is required when the renal function is normal.

Pharmacokinetics in renal dysfunction

Based on comparison of key pharmacokinetic parameters of zofenoprilat measured after oral administration of radiolabelled

zofenopril, patients with mild renal impairment (creatinine clearance >45 and <90 ml/min) eliminate zofenopril from the body

at the same rate as normal subjects (creatinine clearance > 90 ml/min).

In patients with moderate to severe renal impairment (7- 44 ml/min), the rate of elimination is reduced to about 50% of normal.

In patients with end stage renal disease on haemodialysis and peritoneal dialysis, the rate of elimination is reduced to 25% of

normal.

Pharmacokinetics in hepatic dysfunction

In patients with mild to moderate hepatic dysfunction given single doses of radiolabelled zofenopril, the Cmax and Tmax

values for zofenoprilat were similar to those in normal subjects. However, AUC values in cirrhotic patients were about twice

those obtained for normal subjects, indicating that the initial dose of zofenopril for patients with mild to moderate hepatic

dysfunction should be half of that for patients with normal hepatic function.

There are no pharmacokinetic data of zofenopril and zofenoprilat in patients with severe hepatic dysfunction, therefore

zofenopril is contraindicated in these patients.

HYDROCHLOROTHIAZIDE

Absorption:

Hydrochlorothiazide is well absorbed (65 to 75 %) following oral administration. Plasma concentrations are linearly related to

the administered dose. The absorption of hydrochlorothiazide is dependent on intestinal transit time, being increased when

the intestinal transit time is slow for example when given with food. When plasma levels have been followed for at least 24

hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours and peak plasma levels were observed

within 1 and 5 h after dosing.

Distribution:

The thiazides are widely distributed in body fluids and are extensively (92 %) bound to plasma proteins, particularly so to

albumin, the substituted molecules being the most highly bound. This results in a lower renal clearance than the earlier

compounds and in a more prolonged duration of action. No relationship has been demonstrated between hydrochlorothiazide

plasma levels and the degree of reduction of blood pressure.

Elimination:

Hydrochlorothiazide is eliminated primarily by renal pathway. Most of thiazide is excreted in the urine unchanged and more

than 95 % of hydrochlorothiazide appears unchanged in the urine within 3-6 hours after an oral dose. In patients with renal

disease, plasma concentrations of hydrochlorothiazide are increased and elimination half-life is prolonged.

Hydrochlorothiazide crosses the placental but not the blood-brain barrier.

5.3 Preclinical safety data

The fixed combination zofenopril/hydrochlorothiazide revealed no special risks for human use, based on acute toxicity,

repeated dose toxicity and genotoxicity studies.

Reproductive toxicity of the combination has been studied in rats and rabbits and zofenopril and HCTZ did not show to be

teratogenic. However in pregnant rats and rabbits the combination markedly increased the maternal toxicity induced by

zofenopril alone.

Carcinogenicity studies were not performed with the combination zofenopril/ hydrochlorothiazide.

Carcinogenicity studies conducted in mice and rats with zofenopril alone revealed no evidence of carcinogenicity.

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Preclinical data of HCTZ reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated

dose toxicity, genotoxicity and carcinogenic potential.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet Core

Microcrystalline cellulose

Lactose, monohydrate

Maize Starch

Hypromellose

Silica, colloidal anhydrous

Magnesium stearate

Film Coat:

Opadry Pink 02B24436:

Hypromellose

Titanium dioxide (E 171)

Macrogol 400

Iron oxide Red (E 172)

Macrogol 6000

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 30° C.

6.5 Nature and contents of container

PVDC coated PVC/Aluminium blisters.

14, 28, 30, 56, 50, 90 or 100 film coated tablets/pack

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Menarini International Operations Luxembourg S.A.

1, Avenue de la Gare

1611 Luxembourg

Luxembourg

8 MARKETING AUTHORISATION NUMBER

PA0865/013/001

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9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 13 May 2005

Date of last renewal: 3 February 2009

10 DATE OF REVISION OF THE TEXT

November 2019

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