Zestril 20mg tablets

United Kingdom - English - eMC (Electronic Medicines Compendium)

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Active ingredient:
Lisinopril
Available from:
CST Pharma Ltd
ATC code:
C09AA03
INN (International Name):
Lisinopril
Dosage:
20mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 02050501; GTIN: 5055946806730

Package leaflet: Information for the patient

Zestril

®

20mg Tablets

(lisinopril)

Your medicine is known as the above but will be referred to as

Zestril throughout the remainder of this leaflet.

This product is available in multiple strengths and all strengths will

be referred to throughout this leaflet.

Read all of this leaflet carefully before you start taking this

medicine because it contains important information for you.

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

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

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

on to others. It may harm them, even if their signs of illness are

the same as yours.

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

includes any possible side effects not listed in this leaflet. See

section 4.

What is in this leaflet:

What Zestril is and what it is used for

What you need to know before you take Zestril

How to take Zestril

Possible side effects

How to store Zestril

Contents of the pack and other information

1.

What Zestril is and what it is used for

Zestril contains a medicine called lisinopril. This belongs to a group

of medicines called ACE inhibitors.

Zestril can be used for the following conditions:

To treat high blood pressure (hypertension).

To treat heart failure.

If you have recently had a heart attack (myocardial infarction).

To treat kidney problems caused by Type II diabetes in people

with high blood pressure.

Zestril works by making your blood vessels widen.

This helps to lower your blood pressure. It also makes it easier for

your heart to pump blood to all parts of your body.

2.

What you need to know before you take Zestril

Do not take Zestril:

if you are allergic to lisinopril or any of the other ingredients of

this medicine (listed in section 6).

if you have ever had an allergic reaction to another ACE inhibitor

medicine. The allergic reaction may have caused swelling of the

hands, feet, ankles, face, lips, tongue or throat. It may also have

made it difficult to swallow or breathe (angioedema).

if you 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.

if a member of your family has had severe allergic reactions

(angioedema) to an ACE inhibitor or you have had severe

allergic reactions (angioedema) without a known cause.

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

Zestril in early pregnancy - see Pregnancy section).

if you have diabetes or impaired kidney function and you are

treated with a blood pressure lowering medicine containing

aliskiren.

If you are not sure if any of these apply to you, talk to your doctor or

pharmacist before taking Zestril.

If you develop a dry cough which is persistent for a long time after

starting treatment with Zestril, talk to your doctor.

Warnings and precautions

Talk to your doctor or pharmacist before taking Zestril:

if you have a narrowing (stenosis) of the aorta (an artery in your

heart) or a narrowing of the heart valves (mitral valves).

if you have a narrowing (stenosis) of the kidney artery.

if you have an increase in the thickness of the heart muscle

(known as hypertrophic cardiomyopathy).

if you have problems with your blood vessels (collagen vascular

disease).

if you have low blood pressure. You may notice this as feeling

dizzy or light-headed, especially when standing up.

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

if you have liver problems.

if you have diabetes.

if you are taking any of the following medicines, the risk of

angioedema (rapid swelling under the skin in area such as the

throat) is increased:

temsirolimus, sirolimus, everolimus and other medicines

belonging to the class of mTOR inhibitors (used to avoid

rejection of transplanted organs and for cancer).

Racecadotril, a medicine used to treat diarrhoea;

Vildagliptin, a medicine used to treat diabetes.

if you 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), in

particular if you have diabetes-related kidney problems

aliskiren.

Your doctor may check your kidney function, blood pressure and

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

regular intervals. See also information under the heading “Do not

take Zestril”.

if you have recently had diarrhoea or vomiting (being sick).

if your doctor has told you to control the amount of salt in your

diet.

if you have high levels of cholesterol and you are having a

treatment called ‘LDL apheresis’.

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

pregnant. Zestril 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).

if you are of black origin as Zestril may be less effective. You

may also more readily get the side effect ‘angioedema’ (a

severe allergic reaction).

If you are not sure if any of these apply to you, talk to your doctor or

pharmacist before taking Zestril.

Treatment for allergies such as insect stings

Tell your doctor if you are having or are going to have treatment to

lower the effects of an allergy such as insect stings (desensitisation

treatment). If you take Zestril while you are having this treatment, it

may cause a severe allergic reaction.

Operations

If you are going to have an operation (including dental surgery) tell

your doctor or dentist that you are taking Zestril. This is because you

can get low blood pressure (hypotension) if you are given certain

local or general anaesthetics while you are taking Zestril.

Children and adolescents

Zestril has been studied in children. For more information, talk to

your doctor. Zestril is not recommended in children under 6 years of

age or in any child with severe kidney problems.

Other medicines and Zestril

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

or might take any other medicines. This is because Zestril can affect

the way some medicines work and some medicines can have an

effect on Zestril. Your doctor may need to change your dose and/or

to take other precautions.

In particular, tell your doctor or pharmacist if you are taking any of

the following medicines:

Other medicines to help lower your blood pressure.

An angiotensin II receptor blocker (ARB) or aliskiren, (see also

information under the headings “Do not take Zestril” and

“Warnings and precautions”).

Water tablets (diuretic medicines).

Beta-blocker medicines, such as atenolol and propranolol.

Nitrate medicines (for heart problems).

Non-steroidal anti-inflammatory drugs (NSAIDs) used to treat

pain and arthritis.

Aspirin (Acetylsalicylic acid), if you are taking more than 3 grams

each day.

Medicines for depression and for mental problems, including

lithium.

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; ciclosporin, an immunosuppressant medicine used to

prevent organ transplant rejection; and heparin, a medicine used

to thin blood to prevent clots).

Insulin or medicines that you take by mouth for diabetes.

Medicines used to treat asthma.

Medicines to treat nose or sinus congestion or other cold

remedies (including those you can buy in the pharmacy).

Medicines to suppress the body’s immune response

(immunosuppressants).

Allopurinol (for gout).

Procainamide (for heart beat problems).

Medicines that contain gold, such as sodium aurothiomalate,

which may be given to you as an injection.

The following medicines may increase the risk of angioedema (signs

of angioedema include swelling of the face, lips, tongue and/or throat

with difficulty in swallowing or breathing):

Medicines to break up blood clots (tissue plasminogen

activator), usually given in hospital.

Medicines which are most often used to avoid rejection of

transplanted organs (temsirolimus, everolimus and other

medicines belonging to the class of mTOR inhibitors). See

section 2 “Warnings and precautions”.

Racecadotril used to treat diarrhoea.

Vildagliptin, a medicine used to treat diabetes.

Pregnancy and breast-feeding

Pregnancy:

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

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

before you become pregnant or as soon as you know you are

pregnant and will advise you to take another medicine instead of

Zestril. Zestril is not recommended in early pregnancy, and must not

be taken when more than 3 months pregnant, as it may cause

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

Breast-feeding:

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

breast-feeding. Zestril 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

Some people feel dizzy or tired when taking this medicine. If this

happens to you, do not drive or use any tools or machines.

You must wait to see how your medicine affects you before

trying these activities.

3.

How to take Zestril

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

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

Once you have started taking Zestril your doctor may take blood

tests. Your doctor may then adjust your dose so you take the right

amount of medicine for you.

SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Zestril 20mg tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains lisinopril dihydrate equivalent to 20 mg anhydrous lisinopril.

For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

20mg tablets: round, brownish-red, uncoated, biconvex tablet with “

20” on

one side and plain on the other side. Diameter 8mm.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Hypertension

Treatment of hypertension

Heart failure

Treatment of symptomatic heart failure

Acute myocardial infarction

Short-term (6 weeks) treatment of haemodynamically stable patients within

24 hours of an acute myocardial infarction

Renal complications of diabetes mellitus

Treatment of renal disease in hypertensive patients with Type 2 diabetes

mellitus and incipient nephropathy (see section 5.1)

4.2

Posology and method of administration

Zestril should be administered orally in a single daily dose. As with all

other medication taken once daily, Zestril should be taken at approximately

the same time each day. The absorption of Zestril tablets is not affected by

food.

The dose should be individualised according to patient profile and blood

pressure response (see section 4.4).

Hypertension

Zestril may be used as monotherapy or in combination with other classes of

antihypertensive therapy (see sections 4.3, 4.4, 4.5 and 5.1).

Starting dose

In patients with hypertension the usual recommended starting dose is

10 mg. Patients with a strongly activated renin-angiotensin-aldosterone

system (in particular, renovascular hypertension, salt and /or volume

depletion, cardiac decompensation, or severe hypertension) may experience

an excessive blood pressure fall following the initial dose. A starting dose

of 2.5-5 mg is recommended in such patients and the initiation of treatment

should take place under medical supervision. A lower starting dose is

required in the presence of renal impairment (see Table 1 below).

Maintenance dose

The usual effective maintenance dosage is 20 mg administered in a single

daily dose. In general, if the desired therapeutic effect cannot be achieved in

a period of 2 to 4 weeks on a certain dose level, the dose can be further

increased. The maximum dose used in long-term, controlled clinical trials

was 80 mg/day.

Diuretic-treated patients

Symptomatic hypotension may occur following initiation of therapy with

Zestril. This is more likely in patients who are being treated currently with

diuretics. Caution is recommended therefore, since these patients may be

volume and/or salt depleted. If possible, the diuretic should be discontinued

2 to 3 days before beginning therapy with Zestril. In hypertensive patients

in whom the diuretic cannot be discontinued, therapy with Zestril should be

initiated with a 5 mg dose. Renal function and serum potassium should be

monitored. The subsequent dosage of Zestril should be adjusted according

to blood pressure response. If required, diuretic therapy may be resumed

(see section 4.4 and section 4.5).

Dosage adjustment in renal impairment

Dosage in patients with renal impairment should be based on creatinine

clearance as outlined in Table 1 below.

Table 1 Dosage adjustment in renal impairment

Creatinine Clearance (ml/min)

Starting Dose (mg/day)

Less than 10 ml/min (including patients on

dialysis)

2.5 mg*

10-30 ml/min

2.5-5 mg

31-80 ml/min

5-10 mg

* Dosage and/or frequency of administration should be adjusted depending on the blood

pressure response.

The dosage may be titrated upward until blood pressure is controlled or to a

maximum of 40 mg daily.

Use in hypertensive paediatric patients aged 6–16 years

The recommended initial dose is 2.5 mg once daily in patients 20 to <50 kg,

and 5 mg once daily in patients

50 kg. The dosage should be individually

adjusted to a maximum of 20 mg daily in patients weighing 20 to <50 kg,

and 40 mg in patients

50 kg. Doses above 0.61 mg/kg (or in excess of

40 mg) have not been studied in paediatric patients (see section 5.1).

In children with decreased renal function, a lower starting dose or increased

dosing interval should be considered.

Heart failure

In patients with symptomatic heart failure, Zestril should be used as

adjunctive therapy to diuretics and, where appropriate, digitalis or beta-

blockers. Zestril may be initiated at a starting dose of 2.5 mg once a day,

which should be administered under medical supervision to determine the

initial effect on the blood pressure. The dose of Zestril should be increased:

By increments of no greater than 10 mg

At intervals of no less than 2 weeks

To the highest dose tolerated by the patient up to a maximum of 35 mg

once daily.

Dose adjustment should be based on the clinical response of individual

patients.

Patients at high risk of symptomatic hypotension, e.g. patients with salt

depletion with or without hyponatraemia, patients with hypovolaemia or

patients who have been receiving vigorous diuretic therapy should have

these conditions corrected, if possible, prior to therapy with Zestril. Renal

function and serum potassium should be monitored (see section 4.4).

Posology in Acute myocardial infarction

Patients should receive, as appropriate, the standard recommended

treatments such as thrombolytics, aspirin, and beta-blockers. Intravenous or

transdermal glyceryl trinitrate may be used together with Zestril.

Starting dose (first 3 days after infarction)

Treatment with Zestril may be started within 24 hours of the onset of

symptoms. Treatment should not be started if systolic blood pressure is

lower than 100 mm Hg. The first dose of Zestril is 5 mg given orally,

followed by 5 mg after 24 hours, 10 mg after 48 hours and then 10 mg once

daily. Patients with a low systolic blood pressure (120 mm Hg or less) when

treatment is started or during the first 3 days after the infarction should be

given a lower dose - 2.5 mg orally (see section 4.4).

In cases of renal impairment (creatinine clearance <80 ml/min), the initial

Zestril dosage should be adjusted according to the patient’s creatinine

clearance (see Table 1).

Maintenance dose

The maintenance dose is 10 mg once daily. If hypotension occurs (systolic

blood pressure less than or equal to 100 mm Hg) a daily maintenance dose

of 5 mg may be given with temporary reductions to 2.5 mg if needed. If

prolonged hypotension occurs (systolic blood pressure less than 90 mm Hg

for more than 1 hour) Zestril should be withdrawn.

Treatment should continue for 6 weeks and then the patient should be re-

evaluated. Patients who develop symptoms of heart failure should continue

with Zestril (see section 4.2).

Renal complications of diabetes mellitus

In hypertensive patients with type 2 diabetes mellitus and incipient

nephropathy, the dose is 10 mg Zestril once daily which can be increased to

20 mg once daily, if necessary, to achieve a sitting diastolic blood pressure

below 90 mm Hg.

In cases of renal impairment (creatinine clearance <80 ml/min), the initial

Zestril dosage should be adjusted according to the patient’s creatinine

clearance (see Table 1).

Paediatric population

There is limited efficacy and safety experience in hypertensive children

>6 years old, but no experience in other indications (see section 5.1). Zestril

is not recommended in children in other indications than hypertension.

Zestril is not recommended in children below the age of 6, or in children

with severe renal impairment (GFR < 30 ml/min/1.73 m

) (see section 5.2).

Elderly

In clinical studies, there was no age-related change in the efficacy or safety

profile of the drug. When advanced age is associated with decrease in renal

function, however, the guidelines set out in Table 1 should be used to

determine the starting dose of Zestril. Thereafter, the dosage should be

adjusted according to the blood pressure response.

Use in kidney transplant patients

There is no experience regarding the administration of Zestril in patients

with recent kidney transplantation. Treatment with Zestril is therefore not

recommended.

4.3

Contraindications

Hypersensitivity to Zestril, to any of the excipients listed in section 6.1 or any

other angiotensin converting enzyme (ACE) inhibitor.

History of angioedema associated with previous ACE inhibitor therapy.

Concomitant use of Zestril with sacubitril/valsartan therapy. Zestril must not be

initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see

sections 4.4 and 4.5).

Hereditary or idiopathic angioedema.

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

The concomitant use of Zestril with aliskiren-containing products is

contraindicated in patients with diabetes mellitus or renal impairment

(GFR < 60 ml/min/1.73 m

) (see sections 4.5 and 5.1).

4.4

Special warnings and precautions for use

Symptomatic hypotension

Symptomatic hypotension is seen rarely in uncomplicated hypertensive

patients. In hypertensive patients receiving Zestril, hypotension is more

likely to occur if the patient has been volume-depleted, e.g. by diuretic

therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or has

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 most 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,

initiation of therapy and dose adjustment should be closely monitored.

Similar considerations apply to patients with ischaemic heart or

cerebrovascular disease in whom an excessive fall in blood pressure could

result in a myocardial infarction or cerebrovascular accident.

If hypotension occurs, the patient should be placed in the supine position

and, if necessary, should receive an intravenous infusion of normal saline.

A transient hypotensive response is not a contraindication to further doses,

which can be given usually without difficulty once the blood pressure has

increased after volume expansion.

In some patients with heart failure who have normal or low blood pressure,

additional lowering of systemic blood pressure may occur with Zestril. This

effect is anticipated and is not usually a reason to discontinue treatment. If

hypotension becomes symptomatic, a reduction of dose or discontinuation

of Zestril may be necessary.

Hypotension in acute myocardial infarction

Treatment with Zestril must not be initiated in acute myocardial infarction

patients who are at risk of further serious haemodynamic deterioration after

treatment with a vasodilator. These are patients with systolic blood pressure

of 100 mm Hg or lower, or those in cardiogenic shock. During the first

3 days following the infarction, the dose should be reduced if the systolic

blood pressure is 120 mm Hg or lower. Maintenance doses should be

reduced to 5 mg or temporarily to 2.5 mg if systolic blood pressure is

100 mm Hg or lower. If hypotension persists (systolic blood pressure less

than 90 mm Hg for more than 1 hour) then Zestril should be withdrawn.

Aortic and mitral valve stenosis / hypertrophic cardiomyopathy

As with other ACE inhibitors, Zestril should be given with caution to

patients with mitral valve stenosis and obstruction in the outflow of the left

ventricle such as aortic stenosis or hypertrophic cardiomyopathy.

Renal function impairment

In cases of renal impairment (creatinine clearance <80 ml/min), the initial

Zestril dosage should be adjusted according to the patient’s creatinine

clearance (see Table 1 in section 4.2), and then as a function of the patient’s

response to treatment. Routine monitoring of potassium and creatinine is

part of normal medical practice for these patients.

In patients with heart failure, hypotension following the initiation of

therapy with ACE inhibitors may lead to some further impairment in renal

function. Acute renal failure, usually reversible, has been reported in this

situation.

In some patients with bilateral renal artery stenosis or with a stenosis of the

artery to a solitary kidney, who have been treated with angiotensin-

converting enzyme inhibitors, increases in blood urea and serum creatinine,

usually reversible upon discontinuation of therapy, have been seen. This is

especially likely in patients with renal insufficiency. If renovascular

hypertension is also present there is an increased risk of severe hypotension

and renal insufficiency. In these patients, treatment should be started under

close medical supervision with low doses and careful dose titration. Since

treatment with diuretics may be a contributory factor to the above, they

should be discontinued and renal function should be monitored during the

first weeks of Zestril therapy.

Some hypertensive patients with no apparent pre-existing renal vascular

disease have developed increases in blood urea and serum creatinine,

usually minor and transient, especially when Zestril has been given

concomitantly with a diuretic. This is more likely to occur in patients with

pre-existing renal impairment. Dosage reduction and/or discontinuation of

the diuretic and/or Zestril may be required.

In acute myocardial infarction, treatment with Zestril should not be initiated

in patients with evidence of renal dysfunction, defined as serum creatinine

concentration exceeding 177 micromol/l and/or proteinuria exceeding

500 mg/24 h. If renal dysfunction develops during treatment with Zestril

(serum creatinine concentration exceeding 265 micromol/l or a doubling

from the pre-treatment value) then the physician should consider

withdrawal of Zestril.

Hypersensitivity/Angioedema

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has

been reported rarely in patients treated with angiotensin-converting enzyme

inhibitors, including Zestril. This may occur at any time during therapy. In

such cases, Zestril should be discontinued promptly and appropriate

treatment and monitoring should be instituted to ensure complete resolution

of symptoms prior to dismissing the patients. Even in those instances where

swelling of only the tongue is involved, without respiratory distress,

patients may require prolonged observation since treatment with

antihistamines and corticosteroids may not be sufficient.

Very rarely, fatalities have been reported due to angioedema associated

with laryngeal oedema or tongue oedema. Patients with involvement of the

tongue, glottis or larynx, are likely to experience airway obstruction,

especially those with a history of airway surgery. In such cases emergency

therapy should be administered promptly. This may include the

administration of adrenaline and/or the maintenance of a patent airway. The

patient should be under close medical supervision until complete and

sustained resolution of symptoms has occurred.

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 section 4.3).

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 Zestril. Treatment with Zestril 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 an

ACE inhibitor.

Anaphylactoid reactions in haemodialysis patients

Anaphylactoid reactions have been reported in patients dialysed with high

flux membranes (e.g. AN 69) and treated concomitantly with an ACE

inhibitor. In these patients, consideration should be given to using a

different type of dialysis membrane or different class of antihypertensive

agent.

Anaphylactoid reactions during low-density lipoproteins (LDL)

apheresis

Rarely, patients receiving ACE inhibitors during low-density lipoproteins

(LDL) apheresis with dextran sulphate have experienced life-threatening

anaphylactoid reactions. These reactions were avoided by temporarily

withholding ACE inhibitor therapy prior to each apheresis.

Desensitisation

Patients receiving ACE inhibitors during desensitisation treatment (e.g.

hymenoptera venom) have sustained 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.

Hepatic failure

Very rarely, ACE inhibitors have been associated with a syndrome that

starts with cholestatic jaundice and progresses to fulminant necrosis and

(sometimes) death. The mechanism of this syndrome is not understood.

Patients receiving Zestril who develop jaundice or marked elevations of

hepatic enzymes should discontinue Zestril and receive appropriate medical

follow-up.

Neutropenia/Agranulocytosis

Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been

reported in patients receiving ACE inhibitors. In patients with normal renal

function and no other complicating factors, neutropenia occurs rarely.

Neutropenia and agranulocytosis are reversible after discontinuation of the

ACE inhibitor. Zestril should be used with extreme caution in patients with

collagen vascular disease, immunosuppressant therapy, treatment with

allopurinol or procainamide, or a combination of these complicating

factors, especially if there is pre-existing impaired renal function. Some of

these patients developed serious infections, which in a few instances did not

respond to intensive antibiotic therapy. If Zestril is used in such patients,

periodic monitoring of white blood cell counts is advised and patients

should be instructed to report any sign of infection.

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

There is evidence that the concomitant use of ACE inhibitors, angiotensin II

receptor blockers or aliskiren increases the risk of hypotension,

hyperkalaemia and decreased renal function (including acute renal failure).

Dual blockade of RAAS through the combined use of ACE inhibitors,

angiotensin II receptor blockers or aliskiren is therefore not recommended

(see sections 4.5 and 5.1).

If dual blockade therapy is considered absolutely necessary, this should

only occur under specialist supervision and subject to frequent close

monitoring of renal function, electrolytes and blood pressure.

ACE inhibitors and angiotensin II receptor blockers should not be used

concomitantly in patients with diabetic nephropathy.

Race

ACE inhibitors cause a higher rate of angioedema in black patients than in

non-black patients.

As with other ACE inhibitors, Zestril may be less effective in lowering

blood pressure in black patients than in non-blacks, possibly because of a

higher prevalence of low-renin states in the black hypertensive population.

Cough

Cough has been reported with the use of ACE inhibitors. Characteristically,

the cough is non-productive, persistent and resolves after discontinuation of

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

differential diagnosis of cough.

Surgery/Anaesthesia

In patients undergoing major surgery or during anaesthesia with agents that

produce hypotension, Zestril may block angiotensin II formation secondary

to compensatory renin release. If hypotension occurs and is considered to

be due to this mechanism, it can be corrected by volume expansion.

Hyperkalaemia

ACE inhibitors can cause hyperkalemia 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, diabetes

mellitus and/or in patients taking potassium supplements (including salt

substitutes), potassium-sparing diuretics (e.g. spironolactone, triamterene or

amiloride), other drugs associated with increase in serum potassium (e.g.

heparin, trimethoprim or co-trimoxazole also known as

trimethoprim/sulfamethoxazole) and especially aldosterone antagonists or

angiotensin-receptor blockers, hyperkalemia 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).

Diabetic patients

In diabetic patients treated with oral antidiabetic agents or insulin,

glycaemic control should be closely monitored during the first month of

treatment with an ACE inhibitor (see 4.5 Interaction with other medicinal

products and other forms of interaction).

Lithium

The combination of lithium and Zestril is generally not recommended (see

section 4.5).

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 anti-hypertensive 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).

4.5

Interaction with other medicinal products and other forms of interaction

Antihypertensive agents

When Zestril is combined with other antihypertensive agents (e.g. glyceryl

trinitrate and other nitrates, or other vasodilators), additive falls in blood

pressure may occur.

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).

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 treatment of ACE inhibitors with mammalian target of

rapamycin (mTOR) inhibitors (e.g. temsirolimus, sirolimus, everolimus) or

neutral endopeptidase (NEP) inhibitors (e.g. racecadotril), vildagliptin or

tissue plasminogen activator may increase the risk of angioedema (see

section 4.4).

Diuretics

When a diuretic is added to the therapy of a patient receiving Zestril the

antihypertensive effect is usually additive.

Patients already on diuretics and especially those in whom diuretic therapy

was recently instituted, may occasionally experience an excessive reduction

of blood pressure when Zestril is added. The possibility of symptomatic

hypotension with Zestril can be minimised by discontinuing the diuretic

prior to initiation of treatment with Zestril (see section 4.4 and section 4.2).

Potassium supplements, potassium-sparing diuretics or potassium-

containing salt substitutes and other drugs that may increase serum

potassium levels

Although serum potassium usually remains within normal limits,

hyperkalaemia may occur in some patients treated with Zestril. Use of

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

potassium supplements or potassium-containing salt substitutes, particularly

in patients with impaired renal function, may lead to a significant increase

in serum potassium. Care should also be taken when Zestril is co-

administered with other agents that increase serum potassium, such as

trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole) as

trimethoprim is known to act as a potassium-sparing diuretic like amiloride.

Therefore, the combination of Zestril 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.

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