BIFRIL 60 mg film-coated tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
ZOFENOPRIL CALCIUM
Available from:
Menarini International Operations Luxembourg S.A.
ATC code:
C09AA; C09AA15
INN (International Name):
ZOFENOPRIL CALCIUM
Dosage:
60 milligram(s)
Pharmaceutical form:
Film-coated tablet
Prescription type:
Product subject to prescription which may be renewed (B)
Therapeutic area:
ACE inhibitors, plain; zofenopril
Authorization status:
Not marketed
Authorization number:
PA0865/004/004
Authorization date:
1999-03-04

Package leaflet: Information for the user

Bifril 30mg 7.5mg 15mg 60mg

film-coated tablets

(zofenopril calcium)

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 is and what it is used for

2. What you need to know before you take Bifril

3. How to take Bifril

4. Possible side effects

5. How to store Bifril

6. Contents of the pack and other information

1. What Bifril is and what it is used for

Bifril contains zofenopril calcium 30 mg 7.5 mg 15 mg 60 mg which belongs to a group of blood

pressure lowering medicines called angiotensin converting enzyme (ACE) inhibitors.

Bifril is used to treat the following conditions:

high blood pressure (hypertension).

heart attack (acute myocardial infarction) in people who may or may not show signs and symptoms

of heart failure, and who have not received treatment that helps dissolve blood clots (thrombolytic

therapy).

2. What you need to know before you take Bifril

Do not take Bifril if you:

are allergic to zofenopril calcium or any of the other ingredients of this medicine (listed in

section 6)

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

edema) 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 problems

suffer from narrowing of the arteries to the kidneys

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

pregnancy section.)

are a woman of child-bearing age unless using effective contraception.

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.

Tell your doctor if you:

have

high blood pressure

liver

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)

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.

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 areas 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

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”

Your

blood pressure may get too low

with Bifril, especially after the first dose (this is more likely if

you are also taking diuretics, are dehydrated or on a low-salt diet). If this happens, tell your doctor

immediately

and then lie down on your back.

If you are having an

operation, tell your

anaesthetist

that you are taking Bifril before being

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

In addition if you suffer from

heart attack

(acute myocardial infarction) and you:

have low blood pressure (< 100mmHg) or are in a state of circulatory shock (as a result of your

heart problem) – Bifril is not recommended for you

are over 75 years of age – Bifril should be used with special care.

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

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:

Formatted: Not Highlight

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, a medicine used to thin blood to prevent

clots)

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” 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 defence)

allopurinol (used to treat gout)

insulin or oral anti-diabetic medicines

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

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).

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 with food, drink and alcohol

Bifril can be taken with food or on an empty stomach, but the tablet is best taken with water. Alcohol

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

advice on drinking alcohol whilst on this medication.

Pregnancy and breast-feeding

Pregnancy

If you are pregnant, if 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 before

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

medicine instead of Bifril.

Bifril 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 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

Formatted: Not Highlight

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

machinery.

Bifril contains lactose

This product contains

lactose.

If you know you have an intolerance to some sugars, contact your doctor

before taking this medicine.

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

‘sodium-free’.

3.

How to take Bifril

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

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

for 30 mg, 15 mg, 60 mg only

The tablet can be divided into equal doses.

Treatment of high blood pressure

(hypertension)

The normal starting dose of Bifril is 15mg, once a day. Your doctor will gradually adjust the dosage

(usually at four weeks intervals) to find the dose that suits you best. Long-term antihypertensive effects

are usually obtained with 30mg of Bifril, once a day. The maximum dose is 60mg per day, taken in a

single or two divided doses.

If you are dehydrated, have a salt deficiency or are taking diuretics (water pills), it may be necessary to

start your treatment with 7.5mg of Bifril.

Liver or kidney problems

If you have mild to moderate liver impairment or moderate to severe kidney impairment, your doctor

will start your treatment with half the therapeutic dose of Bifril (15mg). If you are receiving dialysis,

one-quarter of the usual therapeutic dose (7.5mg) is needed at the start of your treatment.

Heart attack

(acute myocardial infarction)

Bifril treatment should begin within the first 24 hours after the onset of symptoms.

You will receive Bifril tablets twice a day in the morning and evening, as follows:

7.5mg twice a day, on the first and second day of treatment

15mg twice a day, on the third and fourth day of treatment

From the fifth day onwards, the dose should be increased to 30mg, twice a day

Your doctor may adjust your dose or the maximum dose you receive on the basis of your blood

pressure measurements

Treatment will then be continued for a further six weeks, or longer, if symptoms of heart failure

persist.

If you take more Bifril than you should

If you accidentally take too many tablets, contact your doctor or nearest Accident & Emergency

department immediately (taking any remaining tablets, the carton or this leaflet with you if possible).

most

frequent

symptoms

signs

overdose

blood

pressure

with

fainting

(hypotension), very slow heart beat (bradycardia), changes in blood chemicals (electrolytes) and kidney

dysfunction.

If you forget to take Bifril

If you miss a dose, take the next dose as soon as you remember. However if a long delay has occurred

(e.g. several hours) so that the next due dose is near, 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

Always consult your doctor before stopping Bifril treatment, whether you are taking it for high blood

pressure or following a heart attack.

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 can cause side effects, although not everybody gets them.

Most side effects associated with ACE inhibitors are reversible and disappear after treatment is finished.

Common side effects

(may affect up to 1 in 10 people):

fatigue (tiredness)

nausea and/or vomiting

dizziness

headache

cough.

Uncommon side effects

(may affect up to 1 in 100 people):

general weakness

muscle cramps

skin rash.

Rare side effects

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

rapid swelling and itching, especially around the face, mouth and throat, with possible difficulty

in breathing.

In addition to the side effects reported with Bifril, the following have generally been reported with

ACE

inhibitors

Severe low blood pressure at the start of treatment or when the dosage is increased, with

dizziness, impaired vision, fainting (syncope)

Increased or irregular heartbeat, palpitations and chest pain (heart attack or angina pectoris)

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)

Peripheral oedema (accumulation of water in the limbs), low blood pressure on standing, chest

pain, muscle aches and/or cramps

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

(proteinuria), impotence

Abdominal pain, diarrhoea, constipation, dry mouth

Allergic reactions like skin rash, hives (urticaria), itching, peeling, redness, loosening and

blistering of the skin (toxic epidermal necrolysis), worsening of psoriasis (a skin disease

characterised by scaly pink patches), hair loss (alopecia)

Increased sweating and flushing

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), bronchitis

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 liver enzymes (transaminases) and bilirubin, increased blood urea and

creatinine

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

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

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

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 box and blister pack

after ‘EXP’.

The expiry date refers to the last day of that month

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. Contents of the pack and other information

What Bifril contains

active substance

is zofenopril calcium 30mg 7.5mg 15mg 60 mg. The

other ingredients

microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, colloidal

anhydrous silica, hypromellose, titanium dioxide (E171), macrogol 400, and macrogol 6000 (see section

2 Bifril contains lactose’).

What Bifril looks like and contents of the pack

Bifril 30 is available as white, oblong film-coated tablets in packs of 7, 14, 15, 28, 30, 50, 56, 90 or 100

film-coated tablets and in packs with perforated unit dose blisters of 50 and 56 film-coated tablets.

Bifril 7.5 is available as white, round film-coated tablets with convex faces in packs of 12, 14, 15, 28,

30, 48, 50, 56, 90 or 100 film-coated tablets and in packs with perforated unit dose blisters of 50 and 56

film-coated tablets.

Bifril 15 is available as white, oblong film-coated tablets in packs of 12, 14, 15, 28, 30, 50, 56, 90 or

100 film-coated tablets and in packs with perforated unit dose blisters of 50 and 56 film-coated tablets.

Bifril 60 is available as white, oblong film-coated tablets in packs of 14, 15, 28, 30, 50, 56, 90 or 100

film-coated tablets and in packs with perforated unit dose blisters of 50 and 56 film-coated 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

Belgium: Zopranol

France: Teoula

Greece: Zofepril

Ireland: Bifril

Italy: Zofepril

Iceland: Bifril

Luxembourg: Zopranol

Portugal: Zopranol

The Netherlands: Zopranol

United Kingdom: Bifril

This leaflet was last revised in 06/2019.

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

BIFRIL 60 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each BIFRIL 60 mg tablet contains 60 mg of zofenopril calcium as 57.3 mg of zofenopril.

Excipients with known effect:

Each BIFRIL 60 mg film-coated tablet contains 138.8 mg of lactose monohydrate

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet

White oblong film coated tablets with a breakline. The tablet can be divided into equal doses.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Hypertension

BIFRIL is indicated for the treatment of mild to moderate essential hypertension.

Acute Myocardial Infarction

BIFRIL is indicated for the treatment initiated within the first 24 hours of patients with acute myocardial infarction with or

without signs and symptoms of heart failure, who are haemodynamically stable and have not received thrombolytic therapy.

4.2 Posology and method of administration

Posology

Hypertension

Adults

The need for dosage titration should be determined by measurement of blood pressure just before the next dose. The dose

should be increased at an interval of four weeks.

Patients without volume or salt depletion:

Treatment should be started with 15 mg once daily and titrated upwards to achieve optimal blood pressure control.

The usual effective dose is 30 mg once daily.

The maximum dose is 60 mg per day administered in a single or two divided doses.

In case of inadequate response, other antihypertensive agents such as diuretics may be added (see Sections 4.3, 4.4, 4.5 and

5.1).

Patients suspected of volumeor salt depletion

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First-dose hypotension may occur in high risk patients (see Special warnings and precautions for use). Initiation of therapy

with ACE inhibitors requires correction of salt and/or volume deficiencies, discontinuation of an existing diuretic therapy for

two to three days before ACE inhibition and a starting dose of 15 mg daily. If this is not possible, the initial dose should be 7.5

mg daily.

Patients at high risk for severe acute hypotension should be monitored closely preferably in hospital, for as long as the

maximal effect is expected after administration of the first dose and whenever the dose of ACE inhibitor and/or diuretic is

increased. This also applies to patients with angina pectoris or cerebrovascular disease in whom excessive hypotension could

result in a myocardial infarction or cerebrovascular accident.

Renal impairment and dialysis

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

regimen for BIFRIL can be employed as for patients with normal renal function. Patients with moderate to severe impairment

(creatinine clearance < 45 ml/min.) should be given one-half the therapeutic dose of BIFRIL; the once-daily dosage regimen

does not require modification.

The starting dose and the dosage regimen of BIFRIL for hypertensive patients maintained on dialysis should be one-quarter the

dose used for patients with normal renal function.

Recent clinical observations have shown a high incidence of anaphylactoid-like reactions in patients on ACE inhibitors during

haemodialysis with high-flux dialysis membranes or during LDL apheresis (see section 4.4 «Special warnings and precaution

for use»).

Elderly (over 65 years)

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

In the elderly with reduced creatinine clearance (less than 45 ml/min) half of the daily dose is recommended.

Creatinine clearance may be estimated from serum creatinine by the following formula:

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

Hepatic impairment

In hypertensive patients with mild to moderate hepatic impairment, the starting dose of BIFRIL is half of the dose for patients

with normal hepatic function.

In hypertensive patients with severe liver impairment BIFRIL is contraindicated

Paediatric population

The safety and efficacy of BIFRIL in children and adolescents below 18 years has not been established. Therefore its use is not

recommended.

Acute myocardial infarction

Adults

Treatment with BIFRIL should begin within 24 hours after the onset of symptoms of acute myocardial infarction and continued

for six weeks.

The posology should be as follows:

and 2

day: 7.5 mg every 12 hours

and 4

day: 15 mg every 12 hours

from 5

day and onwards: 30 mg every 12 hours

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In the event of low systolic blood pressure ( ≥

120mmHg) at the start of treatment or during the first three days following

myocardial infarction, the daily dose should not be increased. In the event of hypotension (≥100mmHg), the treatment can be

continued with the dose that was previously tolerated. In the event of severe hypotension (systolic blood pressure lower than

90mmHg in two consecutive measurement at least one hour apart), BIFRIL should be discontinued.

After 6 weeks treatment patients must be re-evaluated and the treatment should be discontinued in patients without signs of

left ventricular dysfunction or cardiac failure. If these signs are present, treatment might be continued long term.

Patients should also receive, as appropriate, the standard treatment such as nitrates, aspirin or b-blockers.

Elderly (over 65 years)BIFRIL should be used with caution in myocardial infarction patients who are more than 75 years of age.

Renal impairment and dialysis

The efficacy and safety of BIFRIL in myocardial infarction patients with renal impairment or who are undergoing dialysis has not

been established. Therefore, BIFRIL should not be used in these patients.

Hepatic impairment

The efficacy and safety of BIFRIL in myocardial infarction patients with hepatic impairment has not been established. Therefore,

it should not be used in these patients.

Method of administration

BIFRIL can be taken before, during or after meals. Dosage must be titrated according to the therapeutic response of the patient.

4.3 Contraindications

Hypersensitivity to zofenopril calcium, any other ACE inhibitor or 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 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.

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

Women of child-bearing potential unless protected by effective contraception.

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

The concomitant use of BIFRIL 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

Hypotension:

As with other ACE inhibitors, BIFRIL 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 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 appearance of hypotension after the initial dose does not preclude subsequent careful dose titration

with drug after effective management.

In some patients with heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may

occur with BIFRIL. This effect is anticipated and is not usually a reason to discontinue treatment. If hypotension becomes

symptomatic, a reduction of dose or discontinuation of BIFRIL may be necessary.

Hypotension in acute myocardial infarction:

Treatment with BIFRIL must not be initiated in acute myocardial infarction patients if there is a risk of additional serious

heamodynamic depression following treatment with a vasodilator. These are patients with a systolic blood pressure of

<100mmHg or with cardiogenic shock. Treatment with BIFRIL in acute myocardial infarction patients may lead to severe

hypotension. In the case of persistent hypotension (systolic blood pressure <90mmHg for more than one hour), BIFRIL should

be discontinued. In patients with severe heart failure following an acute myocardial infarction BIFRIL should only be

administered if the patient is haemodynamically stable.

Myocardial infarction patients with impaired hepatic function:

The efficacy and safety of BIFRIL in myocardial infarction patients with hepatic impairment has not been established. Therefore,

it should not be used in these patients

Elderly:

BIFRIL should be used with caution in myocardial infarction patients ≥75 years of age

Patients with renovascular hypertension:

There is an increased risk of severe hypotension and renal insufficiency when patients with renovascular hypertension and

pre-existing bilateral renal artery stenosis or stenosis of the artery to a solitary 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. If considered absolutely necessary, treatment with BIFRIL should

be started in hospital under close medical supervision with low doses and careful dose titration. Diuretic treatment should be

discontinued temporarily when therapy with BIFRIL is initiated and renal function be closely monitored during the first few

weeks of therapy.

Patients with renal insufficiency:

BIFRIL should be used with caution in patients with renal insufficiency as they require reduced doses. 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 ACE inhibitor and/or discontinuation of the

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

The efficacy and safety of BIFRIL in myocardial infarction patients with renal impairment has not been established. Therefore, in

presence of renal impairment (serum creatinine ≥ 2.1 mg/dl and proteinuria ≥500 mg/day) and myocardial infarction BIFRIL

should not be used.

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 BIFRIL 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 dextrane 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 antihypertensive drugs is used in these patients.

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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 in patients with a recent kidney transplantation.

Primary aldosteronism:

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

renin-angiotensin system. Therefore the use of this product 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 drugs.

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.

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 Contraindication).

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. Treatment with Bifril

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 for 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 an ACE inhibitor.

Cough:

During treatment with BIFRIL a dry and non-productive cough may occur which disappears after discontinuation of BIFRIL. 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 enzymes

should 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).

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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 obstruction in the outflow of the left

ventricule.

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 patients previously treated with oral antidiabetic products

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

Lithium:

The combination of Lithium and BIFRIL 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:

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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).

Other:

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

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 supplements, potassium-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,

amiloride),

potassium

supplements,

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.

Lithium

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

lithium with ACE inhibitors. 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 is not recommended in association with lithium and careful monitoring of serum lithium levels should be

performed if the concomitant use proves necessary.

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.

Anaesthetic medicinal products

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

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Narcotic drugs/Tricyclic antidepressants/Antipsychotics/Barbiturates

Postural hypotension may occur.

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

There

additive

hypotensive

effect

potentiation.

Treatment

with

nitroglycerine

other

nitrates,

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, cytostatic or immunosuppressive agents, systemic corticosteroids or procainamide

Increased risk of hypersensitivity reactions when ACE inhibitors are used concurrently. Concomitant administration with ACE

inhibitors may lead to an increased risk of leukopenia.

Antidiabetics

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.

To be taken into account with concomitant use

Non-Steroidal Anti-inflammatory medicinal products (including ASA ≥ 3g/day)

The administration of non-steroidal anti-inflammatory agents may reduce the antihypertensive effect of an ACE inhibitor.

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

whereas

renal

function

decrease.

These

effects

principle

reversible,

occur

especially

patients

with

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

such as the elderly or dehydrated.

Antacids

Reduce the bioavailability of ACE inhibitors.

Sympathomimetics

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

effect is being obtained.

Food

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

Additional information

Direct clinical data on the interaction of zofenopril with other drugs which are metabolised by CYP enzymes are not available.

However, in vitro metabolic studies with zofenopril demonstrated no potential interaction with drug that are metabolised by

CYP enzymes.

4.6 Fertility, pregnancy and lactation

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Pregnancy

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 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. 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).

Breast-feeding

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

alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a

newborn or preterm infant.

4.7 Effects on ability to drive and use machines

There are no studies on the effect of BIFRIL on the ability to drive. When driving vehicles or operating machines it should be

remembered that occasionally drowsiness, dizziness or weariness may occur.

4.8 Undesirable effects

Tabulated list of adverse reactions

The table below shows all the adverse reactions that have been reported during clinical practice in patients treated with BIFRIL.

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

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.

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

Metabolism and nutrition disorders

Very rare hypoglycaemia

Endocrine disorders

Not known, inappropriate antidiuretic hormone secretion.

Psychiatric disorders

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

Nervous system disorders

Occasionally paraesthesia, dysgeusia, balance disorder.

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.

Skin and 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.

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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.

Reporting of suspected adverse reactions:

Reporting

suspected

adverse

reactions

after

authorisation

medicinal

product

important.

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.

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: ACE inhibitor, ATC code: C09AA15.

The beneficial effects of BIFRIL in hypertension and acute myocardial infarction

appear to result primarily from the suppression

of the plasma renin-angiotensin aldosterone system. Inhibition of ACE (Ki 0.4 nM in rabbit lung for arginine salt of

zofenoprilat) results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to reduced

aldosterone secretion. Although the latter decrease is small, small increases in serum potassium concentrations may occur,

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 plasma ACE activity is suppressed by 53.4% and 74.4% at 24 hours after administration

of single oral doses of 30 mg and 60 mg zofenopril calcium respectively.

Inhibition of ACE results in an increased activity of circulating and local kallikrein-kinin-system, which contributes to peripheral

vasodilatation by activating the prostaglandin system. It is possible that this mechanism is involved in the hypotensive effect of

zofenopril calcium and is responsible for certain side effects.

In patients with hypertension, administration of BIFRIL results in a reduction of supine and standing blood pressure to about

the same extent, with no compensatory increase of the heart rate. Mean systemic vascular resistance tends to decline after

BIFRIL administration.

Achievement of optimal blood pressure reduction may require several weeks of therapy in some patients. The antihypertensive

effects are maintained during long term therapy.

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Abrupt withdrawal of therapy has not been associated with a rapid increase in blood pressure.

Currently there are no data

regarding the effects of BIFRIL on morbidity and mortality in hypertensive patients.

Although antihypertensive effects have been found in all races studied, black hypertensive patients (usually a low-renin

hypertensive population) has a smaller average response to ACE inhibitor monotherapy than non-black patients. This

difference disappears when a diuretic is added.

The clinical effect resulting from the early use of BIFRIL following myocardial infarction may be linked to many factors such as

the reduction in plasma levels of angiotensin II (in this way limiting the process of ventricular remodelling which can negatively

influence the quod vitam prognosis of the infarction patient), and the increase in plasma/tissue concentrations of vasodilator

substances (prostaglandins-kinin system)

A randomised, placebo-controlled clinical trial of zofenopril was performed in 1,556 patients with anterior myocardial infarction

who had not received thrombolytic therapy. Treatment was begun within 24 hours and continued for 6 weeks. The incidence

of the primary combined endpoint (severe heart failure and/or death at 6 weeks) was reduced in zofenopril-treated patients

(zofenopril 7.1%, placebo 10.6%). At one year, the survival rate was improved in the BIFRILgroup.

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.

5.2 Pharmacokinetic properties

Zofenopril calcium is a prodrug, since the active inhibitor is the free sulfhydryl compound, zofenoprilat, resulting from

thio-ester hydrolysis.

Absorption:

Zofenopril calcium 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 BIFRIL. Single dose kinetics are linear over a

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

calcium 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 calcium 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 calcium. The main metabolite is zofenoprilat (22%), which is then metabolized through several pathways,

including glucuronide conjugation (17%), cyclization and glucuronide conjugation (13%), cysteine conjugation (9%) and

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S-methylation of the thiol group (8%). Half-life of zofenoprilat is 5.5 h and its total body clearance is 1300 ml/min following

oral zofenopril calcium.

Elimination:

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

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

indicating a dual route of elimination (kidney and liver).

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 calcium, 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. This indicates that these patients should be given half the usual starting dose of BIFRIL.

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

normal. This indicates that these patients should be given a quarter of the usual starting dose of BIFRIL.

Pharmacokinetics in hepatic dysfunction:

In patients with mild to moderate hepatic dysfunction given single doses of radiolabelled zofenopril calcium, 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 BIFRIL 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.

5.3 Preclinical safety data

In repeat oral dose toxicity studies conducted in three mammalian species most of the treatment related effects where those

usually reported for ACE inhibitors. These changes included a decrease in erythrocytic parameters, an increase in serum urea

nitrogen, a decrease in heart weight and hyperplasia of the juxta-glomerular cells which occurred at dose levels much higher

than the maximum recommended human dose. In a repeat dose oral toxicity study in the dog, species-specific

immunologically-mediated blood dyscrasias occurred at high dose levels.

No significant changes in cytochrome P450 enzyme activities have been observed in a 1 year repeated oral toxicity study in the

monkey.

In reproductive toxicity studies, zofenopril caused a dose related reduction in growth rate in offspring and also nephrotoxicity

and reduced postnatal viability at dose levels of 90 and 270 mg/kg in the F1 generation. Treatment with zofenopril during

pregnancy caused foetal and developmental toxicity in offspring in the rat and also embryo- and feto-toxicity in the rabbit but

only at maternally toxic dose levels.

Genotoxicity studies showed that zofenopril was not mutagenic or clastogenic.

Carcinogenicity studies conducted in mice and rats revealed no evidence of carcinogenicity. An increased incidence of

testicular atrophy occurred only in the mouse study, the clinical significance of which is unknown.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

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Core:

Microcrystalline cellulose

Lactose monohydrate

Croscarmellose sodium

Magnesium stearate

Colloidal anhydrous silica

Coat:

Hypromellose

Titanium dioxide (E171)

Macrogol 400

Macrogol 6000

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

No special precautions for storage

6.5 Nature and contents of container

Blister PVDC /PVC/aluminium or Aclar/Aluminium, packs of:

14, 15, 28, 30, 50, 50 unit doses, 56, 56 unit doses, 90 or 100 film coated tablets

(Not all pack sizes may be marketed.)

6.6 Special precautions for disposal and other handling

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

PA0865/004/004

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 04 March 1999

Date of last renewal: 30 July 2008

10 DATE OF REVISION OF THE TEXT

July 2019

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