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LISINOPRIL 5.0 MG TABLETS

Active substance(s): LISINOPRIL DIHYDRATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Lisinopril 5mg Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
One tablet contains: 5.44mg lisinopril dihydrate, equivalent to 5mg lisinopril
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Tablet
The tablets are round, convex, slightly red and with a score notch on one side,
diameter 5.5mm.
The tablet can be divided into equal halves.

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
Posology
Lisinopril should be administered orally in a single daily dose. As with all other
medication taken once daily, lisinopril should be taken at approximately the same
time each day. The absorption of lisinopril is not affected by food.
The dose should be individualised according to patient profile and blood pressure
response (see section 4.4).
Hypertension
Lisinopril 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 lisinopril.
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 lisinopril. In hypertensive patients in whom the diuretic cannot be discontinued,
therapy with lisinopril should be initiated with a 5 mg dose. Renal function and serum
potassium should be monitored. The subsequent dosage of lisinopril 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
2.5
mg*
dialysis)
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, lisinopril should be used as adjunctive
therapy to diuretics and, where appropriate, digitalis or beta-blockers. Lisinopril 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 lisinopril 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 lisinopril. Renal function and serum potassium should
be monitored (see section 4.4).
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 lisinopril
Starting dose (first 3 days after infarction):
Treatment with lisinopril may be started within 24 hours of the onset of symptoms.
Treatment should not be started if systolic blood pressure is lower than 100 mmHg.
The first dose of lisinopril 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 mmHg 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 lisinopril
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 mmHg) 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 mmHg for more than 1 hour) lisinopril 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 lisinopril (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 lisinopril once daily which can be increased to 20 mg once daily, if
necessary, to achieve a sitting diastolic blood pressure below 90 mmHg.
In cases of renal impairment (creatinine clearance < 80 ml/min), the initial lisinopril
dosage should be adjusted according to the patient's creatinine clearance (see Table
1).
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
lisinopril. 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 lisinopril in patients with
recent kidney transplantation. Treatment with lisinopril is therefore not
recommended.

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). Lisinopril is not
recommended in children in other indications than hypertension.
Lisinopril is not recommended in children below the age of 6, or in children with
severe renal impairment (GFR< 30ml/min/1.73 m2) (see section 5.2).
Method of administration
For oral administration.

4.3

Contraindications
Hypersensitivity to lisinopril, to any of the excipients listed in section 6.1or any
other angiotensin converting enzyme (ACE) inhibitor.
History of angioedema associated with previous ACE inhibitor therapy
Hereditary or idiopathic angioedema.
Second and third trimesters of pregnancy (see section 4.4 and 4.6).

The concomitant use of lisinopril with aliskiren-containing products is
contraindicated in patients with diabetes mellitus or renal impairment (GFR <
60 ml/min/1.73m2) (see sections 4.5 and 5.1).
4.4

Special warnings and precautions for use
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.
Symptomatic Hypotension
Symptomatic hypotension is seen rarely in uncomplicated hypertensive patients. In
hypertensive patients receiving lisinopril, 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 lisinopril. This effect is
anticipated and is not usually a reason to discontinue treatment. If hypotension
becomes symptomatic, a reduction of dose or discontinuation of lisinopril may be
necessary.
Hypotension in Acute Myocardial Infarction
Treatment with lisinopril 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 mmHg 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 mmHg or lower. Maintenance
doses should be reduced to 5 mg or temporarily to 2.5 mg if systolic blood pressure is
100 mmHg or lower. If hypotension persists (systolic blood pressure less than
90 mmHg for more than 1 hour) then lisinopril should be withdrawn.
Aortic and mitral valve stenosis / hypertrophic cardiomyopathy
As with other ACE inhibitors, lisinopril 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 lisinopril
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
lisinopril 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 lisinopril 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 lisinopril may be required.
In acute myocardial infarction, treatment with lisinopril 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 lisinopril (serum creatinine concentration
exceeding 265 micromol/l or a doubling from the pre-treatment value) then the
physician should consider withdrawal of lisinopril.
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 lisinopril. This may occur at any time during therapy. In such cases,
lisinopril 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 patient
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 mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) Patients taking concomitant mTOR inhibitors (e.g. sirolimus, everolimus,
temsirolimus) therapy may be at increased risk for angioedema (e.g. swelling of the
airways or tongue, with or without respiratory impairment) (see section 4.5).
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 or hepatitis and progresses to fulminant necrosis and (sometimes)
death. The mechanism of this syndrome is not understood. Patients receiving
lisinopril who develop jaundice or marked elevations of hepatic enzymes should
discontinue lisinopril 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. Lisinopril 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 lisinopril 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.
Race
Angiotensin converting enzyme inhibitors cause a higher rate of angioedema in black
patients than in non-black patients. As with other ACE inhibitors, lisinopril 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, lisinopril 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
Elevations in serum potassium have been observed in some patients treated with ACE
inhibitors, including lisinopril. Patients at risk for the development of hyperkalaemia
include those with renal insufficiency, diabetes mellitus, hypoaldosteronism or those
using concomitant potassium-sparing diuretics, potassium supplements or potassiumcontaining salt substitutes, or those patients taking other drugs associated with
increases in serum potassium (e.g. heparin, co-trimoxazole also known as
trimethoprim/sulfamethoxazole). If concomitant use of the above-mentioned agents is
deemed appropriate, regular monitoring of serum potassium is recommended (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 lisinopril is generally not recommended (see section
4.5).
Pregnancy and lactation
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).
Use of lisinopril is not recommended during breast-feeding.

4.5

Interaction with other medicinal products and other forms of interaction
Lisinopril can interact with the following drugs or group of drugs:
Diuretics
When a diuretic is added to the therapy of a patient receiving lisinopril 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 lisinopril is added. The possibility of symptomatic hypotension with
lisinopril can be minimised by discontinuing the diuretic prior to initiation of
treatment with lisinopril (see section 4.4 and section 4.2).
Potassium supplements, potassium-sparing diuretics or potassium-containing salt
substitutes
Although in clinical trials, serum potassium usually remained within normal limits,
hyperkalaemia did occur in some patients. Risk factors for the development of
hyperkalaemia include renal insufficiency, diabetes mellitus, and concomitant use of
potassium-sparing diuretics (e.g., spironolactone, triamterene or amiloride),
potassium supplements or potassium-containing salt substitutes. The use of potassium
supplements, potassium-sparing diuretics or potassium-containing salt substitutes,
particularly in patients with impaired renal function, may lead to a significant
increase in serum potassium.
If lisinopril is given with a potassium-losing diuretic, diuretic-induced hypokalaemia
maybe ameliorated.
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 lithium toxicity with ACE inhibitors. Use of lisinopril with lithium is not
recommended, but if the combination proves necessary, careful monitoring of serum
lithium levels should be performed (see section 4.4).
Non steroidal anti-inflammatory drugs (NSAIDs) including acetylsalicylic acid
≥ 3g/day
When ACE-inhibitors are administered simultaneously with non-steroidal antiinflammatory drugs (i.e. acetylsalicylic acid at anti-inflammatory dosage regimens,
COX-2 inhibitors and non-selective NSAIDs), attenuation of the antihypertensive
effect may occur. Concomitant use of ACE inhibitors and NSAIDs may lead to an
increased risk of worsening of renal function, including possible acute renal failure,
and an increase in serum potassium, especially in patients with poor pre-existing renal
function. These effects are usually reversible. The combination should be
administered with caution, especially in the elderly. Patients should be adequately
hydrated and consideration should be given to monitoring renal function after
initiation of concomitant therapy, and periodically thereafter.
Other antihypertensive agents
When lisinopril 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-aldosteronesystem (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 (se sections 4.3, 4.4 and
5.1).
Tricyclic antidepressants / Antipsychotics /Anaesthetics
Concomitant use of certain anaesthetic medicinal products, tricyclic antidepressants,
antipsychotics or muscle relaxants with ACE inhibitors may result in further
reduction of blood pressure (see section 4.4).
Sympathomimetics
Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.
Antidiabetics
Epidemiological studies have suggested that concomitant administration of ACE
inhibitors and antidiabetic medicines (insulins, oral hypoglycaemic agents) may cause
an increased blood glucose lowering effect with risk of hypoglycaemia. This
phenomenon appeared to be more likely to occur during the first weeks of combined
treatment and in patients with renal impairment.
Acetylsalicylic acid, thrombolytics, beta-blockers, nitrates
Lisinopril may be used concomitantly with acetylsalicylic acid (at cardiologic doses),
thrombolytics, betablockers and/or nitrates.
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.
mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus)
Patients taking concomitant mTOR inhibitors therapy may be at increased risk for
angioedema (see section 4.4).
Co-trimoxazole (trimethoprim/sulfamethoxazole)
Patients taking concomitant co-trimoxazole (trimethoprim/sulfamethoxazole) may be
at increased risk for hyperkalaemia (see section 4.4).
Tissue Plasminogen Activators
Concomitant treatment with tissue plasminogen activators may increase the risk of
angioedema.

4.6

Fertility, pregnancy and lactation
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 also section 5.3).
Should exposure to ACE inhibitors have occurred from the second trimester of
pregnancy, an ultrasound check of renal function and the skull is recommended.
Infants whose mothers have taken ACE inhibitors should be closely observed for
hypotension, (see sections 4.3 and 4.4), oliguria and hyperkalaemia. Lisinopril, which
crosses the placenta, has been removed from the neonatal circulation by peritoneal
dialysis with some clinical benefit, and theoretically may be removed by exchange
transfusion.
Breast-feeding
It is not known whether lisinopril is excreted into human breast milk. Lisinopril is
excreted into the milk of lactating rats. The use of lisinopril is not recommended in
women who are breast-feeding.
Because no information is available regarding the use of Lisinopril during breastfeeding, Lisinopril is not recommended and alternative treatments with better
established safety profiles during breast-feeding are preferable, especially while
nursing a newborn or preterm infant.

4.7

Effects on ability to drive and use machines
When driving vehicles or operating machines it should be taken into account that
occasionally dizziness, tiredness or confusion may occur.

4.8

Undesirable effects
Safety data from clinical studies suggest that lisinopril is generally well tolerated in
hypertensive paediatric patients, and that the safety profile in this age group is
comparable to that seen in adults.

The following undesirable effects have been observed and reported during treatment
with lisinopril and other ACE inhibitors with the following frequencies: 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), Not known (cannot be estimated
from the available date) including isolated reports.
Within each frequency grouping, undesirable effects are presented in order of
decreasing seriousness.
Blood and lymphatic system disorders:
Rare: decreases in haemoglobin, decreases in haematocrit.
Very rare: bone marrow depression, anaemia, thrombocytopenia, leucopenia,
neutropenia, agranulocytosis (see section 4.4), haemolytic anaemia,
lymphadenopathy, autoimmune disease.
Endocrine disorders
Rare: syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Metabolism and nutrition disorders
Very rare: hypoglycaemia.
Nervous system and psychiatric disorders:
Common: dizziness, headache.
Uncommon: mood alterations, paraesthesia, vertigo, taste disturbance, sleep
disturbances, hallucinations.
Rare: mental confusion, olfactory disturbance.
Frequency not known: depressive symptoms, syncope.
Cardiac and vascular disorders:
Common: orthostatic effects (including hypotension).
Uncommon: myocardial infarction or cerebrovascular accident, possibly secondary to
excessive hypotension in high risk patients (see section 4.4), palpitations, tachycardia.
Raynaud's phenomenon.
Respiratory, thoracic and mediastinal disorders:
Common: cough.
Uncommon: rhinitis.
Very rare: bronchospasm, sinusitis. Allergic alveolitis/eosinophilic pneumonia.
Gastrointestinal disorders:

Common: diarrhoea, vomiting.
Uncommon: nausea, abdominal pain and indigestion.
Rare: dry mouth.
Very rare: pancreatitis, intestinal angioedema, hepatitis- either hepatocellular or
cholestatic, jaundice and hepatic failure (see section 4.4).
Skin and subcutaneous tissue disorders:
Uncommon: rash, pruritus,
Rare: urticaria, alopecia, psoriasis, hypersensitivity/angioneurotic oedema:
angioneurotic oedema of the face, extremities, lips, tongue, glottis, and/or larynx (see
section 4.4).
Very rare: diaphoresis, pemphigus, toxic epidermal necrolysis, Stevens-Johnson
Syndrome, erythema multiforme, cutaneous pseudolymphoma.
A symptom complex has been reported which may include one or more of the
following: fever, vasculitis, myalgia, arthralgia/arthritis, a positive antinuclear
antibodies (ANA), elevated red blood cell sedimentation rate (ESR), eosinophilia and
leucocytosis, rash, photosensitivity or other dermatological manifestations may occur.
Renal and urinary disorders:
Common: renal dysfunction.
Rare: uraemia, acute renal failure.
Very rare: oliguria/anuria.
Reproductive system and breast disorders:
Uncommon: impotence rare: gynaecomastia.
General disorders and administration site conditions:
Uncommon: fatigue, asthenia.
Investigations:
Uncommon: increases in blood urea, increases in serum creatinine, increases in liver
enzymes, hyperkalaemia.
Rare: increases in serum bilirubin, hyponatraemia.
Safety data from clinical studies suggest that lisinopril is generally well tolerated in
hypertensive paediatric patients, and that the safety profile in this age group is
comparable to that seen in adults.
Reporting of suspected adverse reactions:

Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

4.9

Overdose
Limited data are available for overdose in humans. Symptoms associated with
overdosage of ACE inhibitors may include hypotension, circulatory shock, electrolyte
disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia,
dizziness, anxiety and cough. The recommended treatment of overdose is intravenous
infusion of normal saline solution. If hypotension occurs, the patient should be placed
in the shock position. If available, treatment with angiotensin II infusion and/or
intravenous catecholamines may also be considered. If ingestion is recent, take
measures aimed at eliminating lisinopril (e.g., emesis, gastric lavage, administration
of absorbents and sodium sulphate). lisinopril may be removed from the general
circulation by haemodialysis (see 4.4 special warning and precautions for use).
Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum
electrolytes and creatinine concentrations should be monitored frequently.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Angiotensin converting enzyme inhibitors, ATC code:
C09A A03
Mechanism of action
Lisinopril is a peptidyl dipeptidase inhibitor. It inhibits the angiotensin converting
enzyme (ACE) that catalyses the conversion of angiotensin I to the vasoconstrictor
peptide, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the
adrenal cortex. Inhibition of ACE results in decreased concentrations of angiotensin II
which results in decreased vasopressor activity and reduced aldosterone secretion.
The latter decrease may result in an increase in serum potassium concentration.
Pharmacodynamic effects
Whilst the mechanism through which lisinopril lowers blood pressure is believed to
be primarily suppression of the renin-angiotensin-aldosterone system, lisinopril is
antihypertensive even in patients with low renin hypertension. ACE is identical to
kininase II, an enzyme that degrades bradykinin. Whether increased levels of
bradykinin, a potent vasodilatory peptide, play a role in the therapeutic effects of
lisinopril remains to be elucidated.

Clinical efficacy and safety
The effect of lisinopril on mortality and morbidity in heart failure has been studied by
comparing a high dose (32.5 mg or 35 mg once daily) with a low dose (2.5 mg or
5 mg once daily). In a study of 3,164 patients, with a median follow up period of 46
months for surviving patients, high dose lisinopril produced a 12% risk reduction in
the combined endpoint of all-cause mortality and all-cause hospitalisation (p = 0.002)
and an 8% risk reduction in all-cause mortality and cardiovascular hospitalisation
(p = 0.036) compared with low dose. Risk reductions for all-cause mortality (8%;
p = 0.128) and cardiovascular mortality (10%; p = 0.073) were observed. In a posthoc analysis, the number of hospitalisations for heart failure was reduced by 24%
(p = 0.002) in patients treated with high-dose lisinopril compared with low dose.
Symptomatic benefits were similar in patients treated with high and low doses of
lisinopril.
The results of the study showed that the overall adverse event profiles for patients
treated with high or low dose lisinopril were similar in both nature and number.
Predictable events resulting from ACE inhibition, such as hypotension or altered renal
function, were manageable and rarely led to treatment withdrawal. Cough was less
frequent in patients treated with high dose lisinopril compared with low dose.
In the GISSI-3 trial, which used a 2x2 factorial design to compare the effects of
lisinopril and glyceryl trinitrate given alone or in combination for 6 weeks versus
control in 19,394, patients who were administered the treatment within 24 hours of an
acute myocardial infarction, lisinopril produced a statistically significant risk
reduction in mortality of 11% versus control (2p = 0.03). The risk reduction with
glyceryl trinitrate was not significant but the combination of lisinopril and glyceryl
trinitrate produced a significant risk reduction in mortality of 17% versus control
(2p = 0.02). In the sub-groups of elderly (age > 70 years) and females, pre-defined as
patients at high risk of mortality, significant benefit was observed for a combined
endpoint of mortality and cardiac function. The combined endpoint for all patients, as
well as the high-risk sub-groups, at 6 months also showed significant benefit for those
treated with lisinopril or lisinopril plus glyceryl trinitrate for 6 weeks, indicating a
prevention effect for lisinopril. As would be expected from any vasodilator treatment,
increased incidences of hypotension and renal dysfunction were associated with
lisinopril treatment but these were not associated with a proportional increase in
mortality.
In a double-blind, randomised, multicentre trial which compared lisinopril with a
calcium channel blocker in 335 hypertensive type 2 diabetes mellitus subjects with
incipient nephropathy characterised by microalbuminuria, lisinopril 10 mg to 20 mg
administered once daily for 12 months, reduced systolic/diastolic blood pressure by
13/10 mmHg and urinary albumin excretion rate by 40%. When compared with the
calcium channel blocker, which produced a similar reduction in blood pressure, those
treated with lisinopril showed a significantly greater reduction in urinary albumin
excretion rate, providing evidence that the ACE inhibitory action of lisinopril reduced
microalbuminuria by a direct mechanism on renal tissues in addition to its blood
pressure lowering effect.
Lisinopril treatment does not affect glycaemic control as shown by a lack of
significant effect on levels of glycated haemoglobin (HbA1c).
Renin-angiotensin system (RAS)-acting agents
Two large randomised, controlled trials (ONTARGET (Ongoing Telmisartan Alone
and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D

(The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the
combination of an ACE-inhibitor with an 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 endorgan 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. Cardiovascular death and stroke were both numerically more frequent in
the aliskiren group than in the placebo group and adverse events and serious adverse
events of interest (hyperkalaemia, hypotension and renal dysfunction) were more
frequently reported in the aliskiren group than in the placebo group.
Paediatric population
In a clinical study involving 115 paediatric patients with hypertension, aged
6-16 years, patients who weighed less than 50 kg received either 0.625 mg, 2.5 mg or
20 mg of lisinopril once a day, and patients who weighed 50 kg or more received
either 1.25 mg, 5 mg or 40 mg of lisinopril once a day. At the end of 2 weeks,
lisinopril administered once daily lowered trough blood pressure in a dose-dependent
manner with a consistent antihypertensive efficacy demonstrated at doses greater than
1.25 mg.
This effect was confirmed in a withdrawal phase, where the diastolic pressure rose by
about 9 mmHg more in patients randomized to placebo than it did in patients who
were randomized to remain on the middle and high doses of lisinopril. The dosedependent antihypertensive effect of lisinopril was consistent across several
demographic subgroups: age, Tanner stage, gender, and race.

5.2

Pharmacokinetic properties
Lisinopril is an orally active non-sulphydryl-containing ACE inhibitor.
Absorption
Following oral administration of lisinopril, peak serum concentrations occur within
about 7 hours, although there was a trend to a small delay in time taken to reach peak
serum concentrations in acute myocardial infarction patients. Based on urinary

recovery, the mean extent of absorption of lisinopril is approximately 25% with
interpatient variability of 6-60% over the dose range studied (5-80 mg).
The absolute bioavailability is reduced approximately 16% in patients with heart
failure. Lisinopril absorption is not affected by the presence of food.
Distribution
Lisinopril does not appear to be bound to serum proteins other than to circulating
angiotensin converting enzyme (ACE). Studies in rats indicate that lisinopril crosses
the blood-brain barrier poorly.
Elimination
Lisinopril does not undergo metabolism and is excreted entirely unchanged into the
urine On multiple dosing lisinopril has an effective half-life of accumulation of 12.6
hours. The clearance of lisinopril in healthy subjects is approximately 50 ml/min.
Declining serum concentrations exhibit a prolonged terminal phase, which does not
contribute to drug accumulation. This terminal phase probably represents saturable
binding to ACE and is not proportional to dose.
Hepatic impairment
Impairment of hepatic function in cirrhotic patients resulted in a decrease in lisinopril
absorption (about 30% as determined by urinary recovery) but an increase in
exposure (approximately 50%) compared to healthy subjects due to decreased
clearance.
Renal impairment
Impaired renal function decreases elimination of lisinopril, which is excreted via the
kidneys, but this decrease becomes clinically important only when the glomerular
filtration rate is below 30 ml/min. In mild to moderate renal impairment (creatinine
clearance 30-80 ml/min) mean AUC was increased by 13% only, while a 4.5- fold
increase in mean AUC was observed in severe renal impairment (creatinine clearance
5-30 ml/min).
Lisinopril can be removed by dialysis. During 4 hours of haemodialysis, plasma
lisinopril concentrations decreased on average by 60%, with a dialysis clearance
between 40 and 55 ml/min.
Heart failure
Patients with heart failure have a greater exposure of lisinopril when compared to
healthy subjects (an increase in AUC on average of 125%), but based on the urinary
recovery of lisinopril, there is reduced
absorption of approximately 16% compared to healthy subjects.
Elderly
Older patients have higher blood levels and higher values for the area under the
plasma concentration time curve (increased approximately 60%) compared with
younger subjects .

Paediatrics
The pharmacokinetic profile of lisinopril was studied in 29 paediatric hypertensive
patients, aged between 6 and 16 years, with a GFR above 30 ml/min/1.73m2. After
doses of 0.1 to 0.2 mg/kg, steady state peak plasma concentrations of lisinopril
occurred within 6 hours, and the extent of absorption based on urinary recovery was
about 28%. These values are similar to those obtained previously in adults. AUC and
Cmax values in children in this study were consistent with those observed in
adults.

5.3

Preclinical safety data
Preclinical data reveal no special hazard for humans based on conventional studies of
general pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic
potential. Angiotensin converting enzyme inhibitors, as a class, have been shown to
induce adverse effects on the late foetal development, resulting in foetal death and
congenital effects, in particular affecting the skull. Foetotoxicity, intrauterine growth
retardation and patent ductus arteriosus have also been reported. These developmental
anomalies are thought to be partly due to a direct action of ACE inhibitors on the
foetal renin-angiotensin system and partly due to ischaemia resulting from maternal
hypotension and decreases in foetal-placental blood flow and oxygen/nutrients
delivery to the foetus.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Calcium hydrogen phosphate dihydrate
Croscarmellose sodium
Maize starch
Mannitol
Magnesium stearate
Ferric oxide red

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
4 years

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions’.

6.5

Nature and contents of container
Polyvinylchloride/aluminium blisters packed in cardboard boxes containing 10, 14,
28, 30, 30x1, 50, 56, 60, 98 and 100 tablets
Not all pack sizes may be marketed.

6.6

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

7

MARKETING AUTHORISATION HOLDER
Crescent Pharma Limited
Units 3 and 4 Quidhampton Business Units
Polhampton Lane
Overton
Basingstoke
Hamshire
RG25 3 ED

8

MARKETING AUTHORISATION NUMBER(S)
PL 20416/0352

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
04/11/2013

10

DATE OF REVISION OF THE TEXT
04/08/2017

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