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.
 

4.2 Posology and method of administration
Lisino should be administered orally in a single daily dose. As with all other medication taken once
daily, Lisino should be taken at approximately the same time each day. The absorption of Lisino
tablets is not affected by food.
The dose should be individualised according to patient profile and blood pressure response.
Hypertension
Lisino may be used as monotherapy or in combination with other classes of antihypertensive
therapy.

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.
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 Lisino. 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 Lisino. In hypertensive patients in whom
the diuretic cannot be discontinued, therapy with Lisino should be initiated with a 5 mg dose.
Renal function and serum potassium should be monitored. The subsequent dosage of Lisino should
be adjusted according to blood pressure response. If required, diuretic therapy may be resumed.
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.
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, Lisino should be used as adjunctive therapy to diuretics
and, where appropriate, digitalis or beta-blockers. Lisino 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 Lisino 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 Lisino. Renal
function and serum potassium should be monitored.
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 Lisino.
Starting dose (first 3 days after infarction)
Treatment with Lisino 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 Lisino 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 Lisino dosage should be
adjusted according to the patient's creatinine clearance .
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) Lisino 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 Lisino.
Renal complications of diabetes mellitus
In hypertensive patients with type 2 diabetes mellitus and incipient nephropathy, the dose is 10 mg
Lisino 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 Lisino dosage should be
adjusted according to the patient's creatinine clearance .
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). Lisino is not recommended in children in other
indications than hypertension.
Lisino is not recommended in children below the age of 6, or in children with severe renal
impairment (GFR < 30ml/min/1.73m2).
Older people
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 Lisino. 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 Lisino in patients with recent kidney
transplantation. Treatment with Lisino is therefore not recommended

Symptomatic hypotension
Symptomatic hypotension is seen rarely in uncomplicated hypertensive patients. In hypertensive
patients receiving Lisino, hypotension is more likely to occur if the patient has been volumedepleted,
e.g. by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or has
severe renin-dependent hypertension . 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 Lisino. This effect is anticipated and is not usually a
reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or
discontinuation of Lisino may be necessary.
Hypotension in acute myocardial infarction
Treatment with Lisino 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 Lisino should be withdrawn.
Aortic and mitral valve stenosis / hypertrophic cardiomyopathy
As with other ACE inhibitors, Lisino 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 Lisino dosage should
be adjusted according to the patient's creatinine clearance , 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 Lisino 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 Lisino
has been given concomitantly with a diuretic. This is more likely to occur in patients with preexisting
renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or Lisino
may be required.
In acute myocardial infarction, treatment with Lisino 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 Lisino (serum creatinine concentration exceeding 265 micromol/l or a doubling
from the pre-treatment value) then the physician should consider withdrawal of Lisino.
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 Lisino. This may occur
at any time during therapy. In such cases, Lisino 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.
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 readministration
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 Lisino who develop jaundice or marked elevations
of hepatic enzymes should discontinue Lisino 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. Lisino 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 Lisino 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 .
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
Angiotensin-converting enzyme inhibitors cause a higher rate of angioedema in black patients
than in non-black patients.
As with other ACE inhibitors, Lisino 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 nonproductive,
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,
Lisino 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 Lisino. Patients at risk for the development of hyperkalaemia include those with renal
insufficiency, diabetes mellitus, or those using concomitant potassium-sparing diuretics,
potassium supplements or potassium-containing salt substitutes, or those patients taking other
drugs associated with increases in serum potassium (e.g. heparin). If concomitant use of the
above-mentioned agents is deemed appropriate, regular monitoring of serum potassium is
recommended.
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
Lithium
The combination of lithium and Lisino is generally not recommended.
Pregnancy
ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy
is considered essential, patients planning pregnancy should be changed to alternative antihypertensive
treatments which have an established safety profile for use in pregnancy. When
pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if
appropriate, alternative therapy should be started.
Use of lisinopril is not recommended during breast-feeding.

Dual blockade of the rennin-angiotensin-aldosterone system (RAAS):
Combination therapy of ACEI and ARB drugs may cause an increased risk of hyperkalemia,
worsening of kidney function and hypotension. Therefore, this combination should not be used,
especially in patients with renal impairment.

Antihypertensive agents
When Lisino 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 RAASacting
agent .
Diuretics
When a diuretic is added to the therapy of a patient receiving Lisino 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
Lisino is added. The possibility of symptomatic hypotension with Lisino can be minimised by
discontinuing the diuretic prior to initiation of treatment with Lisino.
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 potassiumcontaining
salt substitutes, particularly in patients with impaired renal function, may lead to a
significant increase in serum potassium. If Lisino is given with a potassium-losing diuretic,
diuretic-induced hypokalaemia may be 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 Lisino with lithium is not recommended, but if the combination proves
necessary, careful monitoring of serum lithium levels should be performed .
Non-steroidal anti-inflammatory medicinal products (NSAIDs) including acetylsalicylic acid
≥ 3 g/day
When ACE-inhibitors are administered simultaneously with non-steroidal anti-inflammatory 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 ACEinhibitors
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.
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.
Tricyclic antidepressants / Antipsychotics / Anaesthetics
Concomitant use of certain anaesthetic medicinal products, tricyclic antidepressants and
antipsychotics with ACE inhibitors may result in further reduction of blood pressure.
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.
Tissue Plasminogen Activators
Concomitant treatment with tissue plasminogen activators may increase the risk of angioedema.
Acetylsalicylic acid, thrombolytics, beta-blockers, nitrates
Lisino may be used concomitantly with acetylsalicylic acid (at cardiologic doses), thrombolytics,
beta-blockers and/or nitrates.

Pregnancy
The use of ACE inhibitors is not recommended during the first trimester of pregnancy. The use of
ACE inhibitors is contra-indicated during the second and third trimester of pregnancy.
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 inhibitors 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.
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).
Should exposure to ACE inhibitors 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.
Breastfeeding
Because no information is available regarding the use of Lisino during breast-feeding, Lisino is not
recommended and alternative treatments with better established safety profiles during breastfeeding
are preferable, especially while nursing a newborn or preterm infant.

When driving vehicles or operating machines it should be taken into account that occasionally
dizziness or tiredness may occur

The following undesirable effects have been observed and reported during treatment with Lisino
and other ACE inhibitors with the following frequencies: Very common (≥ 1/10), common (≥
1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (<
1/10,000), not known (cannot be estimated from the available data).
Blood and the lymphatic system disorders
rare: decreases in haemoglobin, decreases in haematocrit
very rare:
bone marrow depression, anaemia, thrombocytopenia, leucopenia,
neutropenia, agranulocytosis , haemolytic anaemia, lymphadenopathy,
autoimmune disease.
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 , 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.
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
very rare:
sweating, 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, 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.
Endocrine disorders
rare: syndrome of inappropriate antidiuretic hormone secretion (SIADH).
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.
To report any side effects please contact National Pharmacovigilance and Drug Safety
Center (NPC) details below:
The National Pharmacovigilance and Drug Safety Centre (NPC)
• Fax: +966-11-205-7662
• Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
• Toll free phone: 8002490000
• E-mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc

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 Lisino (e.g. emesis, gastric lavage, administration of
Jamjoom Pharmaceuticals Company
Jeddah, Kingdom of Saudi Arabia
Product : Lisino 10 mg Tablets Regional administrative Information
absorbents and sodium sulphate). Lisino may be removed from the general circulation by
haemodialysis (see section 4.4). Pacemaker therapy is indicated for therapy-resistant bradycardia.
Vital signs, serum electrolytes and creatinine concentrations should be monitored frequently.

Pharmacotherapeutic group: Angiotensin-converting enzyme inhibitors, ATC code: C09A A03.
Mechanism of Action
Lisino 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 Lisino 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
3164 patients, with a median follow-up period of 46 months for surviving patients, high dose
Lisino 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 post-hoc analysis, the
number of hospitalisations for heart failure was reduced by 24% (p=0.002) in patients treated with
high-dose Lisino compared with low dose. Symptomatic benefits were similar in patients treated
with high and low doses of Lisino.

The results of the study showed that the overall adverse event profiles for patients treated with high
or low dose Lisino 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 Lisino compared
with low dose.
In the GISSI-3 trial, which used a 2x2 factorial design to compare the effects of Lisino 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, Lisino
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 Lisino 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 Lisino or Lisino plus glyceryl
trinitrate for 6 weeks, indicating a prevention effect for Lisino. As would be expected from any
vasodilator treatment, increased incidences of hypotension and renal dysfunction were associated
with Lisino treatment but these were not associated with a proportional increase in mortality.
In a double-blind, randomised, multicentre trial which compared Lisino with a calcium channel
blocker in 335 hypertensive Type 2 diabetes mellitus subjects with incipient nephropathy
characterised by microalbuminuria, Lisino 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 Lisino showed a significantly greater reduction in urinary
albumin excretion rate, providing evidence that the ACE inhibitory action of Lisino 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 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. 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 Lisino once a day, and
patients who weighed 50 kg or more received either 1.25 mg, 5 mg or 40 mg of Lisino once a day.
At the end of 2 weeks, Lisino administered once daily lowered trough blood pressure in a dosedependent
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 mm
Hg more in patients randomised to placebo than it did in patients who were randomised to remain

on the middle and high doses of Lisino. The dose-dependent antihypertensive effect of Lisino was
consistent across several demographic subgroups: age, Tanner stage, gender, and race.

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 angiotensinconverting
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.
Paediatric population
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.
Older people
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.

Preclinical data reveal no special hazard for humans based on conventional studies of general
pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. Angiotensinconverting
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.

Dibasic Calcium Phosphate Dihydrate
Mannitol
Pregelatinised Starch – 1500
Maize Starch
Dried Maize Starch
Colloidal Silicon Dioxide - Aerosil 200
Magnesium Stearate

Not applicable.

Do not store above 30°C

Lisino 10 mg Tablets are packed in Aluminum - PVC / PVDC blister of 10 Tablets each.

No special requirements.