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PARLIPRIMA 20MG/5MG TABLETS

Active substance(s): AMLODIPINE BESILATE / LISINOPRIL DIHYDRATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Parliprima 20 mg/5 mg tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 20 mg lisinopril (as dihydrate) and 5 mg amlodipine (as besilate).
For the full list of excipients, see section 6.1

3.

PHARMACEUTICAL FORM

Tablet.
White or off-white, round, biconvex tablet with engraving on one side: “CF2”, other side is
without engraving, diameter 11 mm.
4.1

Therapeutic indications
Treatment of essential hypertension in adults.

4.2

Parliprima is indicated as substitution therapy of adult patients with blood pressure
adequately controlled with lisinopril and amlodipine given concurrently at the same
dose level.
Posology and method of administration

Posology
The recommended dose is one tablet daily. The maximum daily dose is one tablet. In general,
fixed dose combination preparations are not suitable for initial therapy.
Parliprima is indicated only for patients in whom the optimal maintenance dose of lisinopril
and amlodipine has been titrated to 20 mg and 5 mg, respectively.
If dose adjustment becomes necessary, dose titration with the individual components can be
considered.
Patients with renal impairment
To find the optimal starting dose and maintenance dose of patients with renal impairment, the
patients should be individually titrated using the individual components of lisinopril and
amlodipine.
Renal function, serum potassium and sodium levels should be monitored during therapy with
Parliprima. In the case of renal function deterioration, the use of Parliprima should be
discontinued and replaced by the therapy with individual components adequately adjusted.
Amlodipine is not dialyzable.
Patients with hepatic impairment

Dosage recommendations have not been established in patients with mild to moderate hepatic
impairment; therefore dose selection should be cautious and should start at the lower end of
the dosing range (see sections 4.4 and 5.2). To find the optimal starting dose and maintenance
dose of patients with hepatic impairment, the patients should be individually titrated using the
free combination of lisinopril and amlodipine.
The pharmacokinetics of amlodipine have not been studied in severe hepatic impairment.
Amlodipine should be initiated at the lowest dose and titrated slowly in patients with severe
hepatic impairment.
Paediatric population (<18 years)
The safety and efficacy of Parliprima in children aged below 18 years have not been
established.
Elderly (>65 years)
Elderly patients should be treated with caution.
In clinical studies, there was no age-related change in the efficacy or safety profile of
amlodipine or lisinopril. To find the optimal maintenance dose of elderly patients they should
be individually titrated using the free combination of lisinopril and amlodipine.
Method of administration
For oral administration
Since food does not affect the absorption of the preparation, Parliprima may be taken
irrespective of meals, i.e. before, during or after meals.
4.3

Contraindications

Related to lisinopril:
Hypersensitivity to lisinopril or to any other angiotensin converting enzyme (ACE)
inhibitor.
A history of angioedema relating to previous ACE inhibitor therapy.
Hereditary or idiopathic angioedema.
2nd and 3rd trimesters of pregnancy (see sections 4.4 and 4.6).
The concomitant use of Parliprima with aliskiren-containing products is contraindicated
in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see
sections 4.5 and 5.1).
Related to amlodipine:
Hypersensitivity to amlodipine or to any other dihydropyridine derivative.
Severe hypotension.
Shock (including cardiogenic shock).
Obstruction of the outflow tract of the left ventricle (e.g., high grade aortic stenosis).
Haemodynamically unstable heart failure after acute myocardial infarction.
Related to Parliprima:
All of the above detailed contraindications related to the individual monocomponents are also
relating to the fixed combination Parliprima.
Hypersensitivity to any of the excipients listed in section 6.1.
4.4

Special warnings and precautions for use

All of the warnings regarding the individual monocomponents detailed below are also relating
to the fixed combination Parliprima.

Related to lisinopril:
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 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, 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 hour. 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 ACE 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 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).
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 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.
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 ACEinhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see
section 4.5 and 5.1).
If dual blockade therapy is considered absolutely necessary, this should only occur under
specialist supervision and subject to frequent close monitoring of renal function, electrolytes
and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in
patients with diabetic nephropathy.
Race
Angiotensin converting enzyme inhibitors cause a high 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 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,
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, or those using concomitant potassiumsparing 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 level 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 section
4.5).
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.
Related to amlodipine:
The safety and efficacy of amlodipine in hypertensive crisis have not been established.
Patients with cardiac failure
Patients with heart failure should be treated with caution. In a long-term, placebo controlled
study in patients with severe heart failure (NYHA class III and IV) the reported incidence of
pulmonary oedema was higher in the amlodipine treated group than in the placebo group (see
section 5.1).
Calcium channel blockers, including amlodipine, should be used with caution in patients with
congestive heart failure, as they may increase the risk of future cardiovascular events and
mortality.
Use in patients with impaired hepatic function
The half-life of amlodipine is prolonged and AUC values are higher in patients with impaired
liver function and dosage recommendations have not been established. Amlodipine should
therefore be initiated at the lower end of the dosing range and caution should be used, both on
initial treatment and when increasing the dose. Slow dose titration and careful monitoring
may be required in patients with severe hepatic impairment.
Use in elderly patients
In the elderly increase of the dosage should take place with care (see sections 4.2 and 5.2).
Use in renal failure
Amlodipine may be used in such patients at normal doses. Changes in amlodipine plasma
concentrations are not correlated with the degree of renal impairment. Amlodipine is not
dialyzable.
4.5

Interaction with other medicinal products and other forms of interaction

Interactions linked to lisinopril
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
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).
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 potassiumcontaining 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 potassiumlosing 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 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 ≥3 g/day
Chronic administration of NSAIDs may reduce the antihypertensive effect of an ACE
inhibitor. NSAIDs and ACE inhibitors exert an additive effect on the increase in serum
potassium and may result in a deterioration of renal function. These effects are usually
reversible. Rarely, acute renal failure may occur, especially in patients with compromised
renal function such as the elderly or dehydrated.
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.
Other antihypertensive agents
Concomitant use of these agents may increase the hypotensive effect of lisinopril.
Concomitant use with glyceryl trinitrate and other nitrates, or other vasodilators, may further
reduce blood pressure.
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 (see
section 4.4).
Sympathomimetics
Sympathomimetics may reduce the antihypertensive effect 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, beta-blockers and/or nitrates.
Interactions linked to amlodipine
Effects of other medicinal products on amlodipine
CYP3A4 inhibitors
Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease
inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or
diltiazem) may give rise to significant increase in amlodipine exposure. The clinical
translation of these PK variations may be more pronounced in the elderly. Clinical monitoring
and dose adjustment may thus be required.
CYP3A4 inducers
There is no data available regarding the effect of CYP3A4 inducers on amlodipine. The
concomitant use of CYP3A4 inducers (e.g., rifampicin, St. John's wort [Hypericum
perforatum]) may give a lower plasma concentration of amlodipine. Amlodipine should be
used with caution together with CYP3A4 inducers.
Administration of amlodipine with grapefruit or grapefruit juice is not recommended as
bioavailability may be increased in some patients resulting in increased blood pressure
lowering effects.
Dantrolene (infusion): In animals, lethal ventricular fibrillation and cardiovascular collapse
are observed in association with hyperkalemia after administration of verapamil and
intravenous dantrolene. Due to risk of hyperkalemia, it is recommended that the coadministration of calcium channel blockers such as amlodipine be avoided in patients
susceptible to malignant hyperthermia and in the management of malignant hyperthermia.
Effects of amlodipine on other medicinal products
The blood pressure lowering effects of amlodipine adds to the blood pressure-lowering effects
of other medicinal products with antihypertensive properties.
In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin,
digoxin, warfarin or cyclosporine.
Simvastatin
Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted
in a 77% increase in exposure to simvastatin compared to simvastatin alone. Limit the dose of
simvastatin in patients on amlodipine to 20 mg daily.
4.6

Fertility, pregnancy and lactation

Pregnancy
The use of Parliprima is not recommended during the first trimester of pregnancy and is
contraindicated during the second and third trimesters of pregnancy.

No experience is available with the use of lisinopril and amlodipine in pregnant women from
adequately controlled clinical studies. However, the use of both active substances during
pregnancy is either not recommended or contraindicated (for substance-specific details, see
below).
When pregnancy is diagnosed, treatment with Parliprima should be stopped immediately
and, if appropriate, alternative therapy should be started (see section 4.4).
Parliprima should not be initiated during pregnancy. Unless continued Parliprima therapy is
considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments with an established safety profile for use in pregnancy.
Linked to lisinopril
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 in the second and third trimesters
(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 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.
ACE inhibitors therapy exposure during the second and third trimesters is known to induce
human foetotoxicity (decreased renal function, oligohydramnios, skull ossification
retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section
5.3). Should exposure to ACE inhibitor have occurred from the second trimester of
pregnancy, ultrasound check of renal function and skull is recommended. Infants whose
mothers have taken ACE inhibitors should be closely observed for hypotension (see sections
4.3 and 4.4).
Linked to amlodipine
The safety of amlodipine in human pregnancy has not been established.
In animal studies, reproductive toxicity was observed at high doses (see section 5.3).
Use in pregnancy is only recommended when there is no safer alternative and when the
disease itself carries greater risk for the mother and fetus.
Breastfeeding
Because no information is available regarding the use of lisinopril and amlodipine during
breast-feeding, this medicinal product is not recommended and alternative treatments with
better established safety profiles during breast-feeding are preferable, especially while breastfeeding a newborn or preterm infant.
Fertility
No experience is available with the effect of lisinopril and amlodipine on fertility from
adequately controlled clinical studies.
Linked to amlodipine

Reversible biochemical changes in the head of spermatozoa have been reported in some
patients treated by calcium channel blockers. Clinical data are insufficient regarding the
potential effect of amlodipine on fertility. In one rat study, adverse effects were found on
male fertility (see section 5.3).
4.7 Effects on ability to drive and use machines
Linked to lisinopril
When driving vehicles or operating machines it should be taken into account that occasionally
dizziness or tiredness may occur.
Linked to amlodipine
Amlodipine can have minor or moderate influence on the ability to drive and use machines. If
patients suffering from dizziness, headache, fatigue or nausea the ability to react may be
impaired. Caution is recommended especially at the start of treatment.
According to the above Parliprima may influence the ability to drive and operate machines
(particularly during the initial period of treatment).
4.8

Undesirable effects

During a controlled clinical study (n=195), the incidence of adverse reactions was not higher
in subjects receiving both active substances concomitantly than in patients on monotherapy.
Adverse reactions were consistent with those reported previously with amlodipine and/or
lisinopril. Adverse reactions were usually mild, transient and rarely warranted the
discontinuation of treatment. The most common adverse reactions with the combination were
headache (8%), cough (5%), and dizziness (3%).
Frequencies are defined as follows: 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). Within each frequency grouping,
undesirable effects are presented in order of decreasing seriousness.
The following adverse drug reactions (ADRs) have been reported during the treatment with
lisinopril and amlodipine independently:
System Organ Class

Frequency

Blood and lymphatic
system disorders

Very rare

Immune system
disorders
Endocrine disorders

Very rare
rare

ADRs with lisinopril
Bone marrow
depression,
Agranulocytosis (see
section 4.4),
Leucopenia,
Neutropenia,
Thrombocytopenia,
Haemolytic anaemia,
Anaemia,
Lymphadenopathy
Autoimmune disorder
Inappropriate
antidiuretic hormone
secretion (SIADH)

ADRs with
amlodipine
Thrombocytopenia,
Leucopenia

Allergic reaction

System Organ Class
Metabolism and
nutrition disorders
Psychiatric disorders

Nervous system
disorders

Frequency

ADRs with lisinopril

Very rare

Hypoglycaemia

Uncommon

Mood changes,
Sleep disturbance

Rare

Mental confusion

Not known

Depression

Common

Dizziness, Headache

Uncommon

Vertigo, Paraesthesia,
Dysgeusia

Very rare

Not known

ADRs with
amlodipine
Hyperglycaemia
Insomnia, Mood
changes (including
anxiety),
Depression
Confusion
Somnolence,
Dizziness,
Headache
(especially at the
beginning of
treatment)
Syncope, Tremor,
Dysgeusia,
Hypoaesthesia,
Paraesthesia
Hypertonia,
Peripheral
neuropathy

Syncope

Eye disorders

Uncommon

Ear and labyrinth
disorders
Cardiac disorders

Uncommon

Visual disturbances
(including diplopia)
Tinnitus

Common

Palpitations

Uncommon

Very rare

Vascular disorders

Common
Uncommon

Myocardial infarction,
possibly secondary to
excessive hypotension
in high risk patients
(see section 4.4),
Tachycardia,
Palpitations
Myocardial
infarction,
Arrhythmias
(including
bradycardia,
ventricular
tachycardia, atrial
fibrillation)
Flushing

Orthostatic
hypotension
Cerebrovascular
Hypotension
accident, possibly
secondary to excessive
hypotension in high
risk patients (see

System Organ Class

Frequency

ADRs with lisinopril

ADRs with
amlodipine

section 4.4), Raynaud’s
phenomenon
Very rare
Respiratory, thoracic
and mediastinal
disorders

Gastrointestinal
disorders

Vasculitis

Common

Cough

Uncommon

Rhinitis

Dyspnoea, Rhinitis

Very rare

Bronchospasm,
Alveolitis
allergic/Eosinophilic
pneumonia, Sinusitis
Diarrhoea, Vomiting

Cough

Common
Uncommon

Abdominal pain,
Nausea, Indigestion

Rare

Dry mouth

Very rare

Pancreatitis, Intestinal
angioedema

Hepatobiliary disorders Very rare

Hepatic failure,
Hepatitis, Cholestatic
jaundice, (see section
4.4)
Rash, Pruritus,

Skin and subcutaneous
tissue disorders

Uncommon

Rare

Very rare

Musculoskeletal and

Common

Psoriasis, Urticaria,
Alopecia,
Hypersensitivity/angio
edema of the face,
extremities, lips,
tongue, glottis and/or
larynx (see section 4.4)
Toxic epidermal
necrolysis, StevensJohnson Syndrome,
Erythema multiforme,
Pemphigus,
Hyperhidrosis,
Cutaneous
pseudolymphoma*

Abdominal pain,
Nausea
Vomiting,
Dyspepsia, Altered
bowel habit
(including diarrhoea
and constipation),
Dry mouth
Pancreatitis,
Gastritis, Gingival
hyperplasia
Hepatitis, Jaundice,

Alopecia, Purpura,
Skin discolouration,
Hyperhidrosis,
Pruritus, Rash,
Exanthema

Angioedema,
Exfoliative
dermatitis, StevensJohnson syndrome,
Erythema
multiforme,
Quincke’s oedema,
Photosensitivity,
Urticaria
Ankle oedema

System Organ Class

Frequency

connective tissue
disorders

Uncommon

Renal and urinary
disorders

Common

Micturition disorder,
Nocturia, Increased
urinary frequency

Very rare

Acute renal failure,
Uraemia
Oliguria/Anuria

Uncommon

Impotence

Rare

Gynaecomastia

Common

Impotence,
Gynaecomastia
Oedema, Fatigue

General disorders and
administration site
conditions

Uncommon

Fatigue, Asthenia

Investigations

Uncommon

Blood urea increased,
Serum creatinine
increased,
Hyperkalaemia,
Hepatic enzymes
increased
Haemoglobin
decreased, Haematocrit
decreased, Serum
bilirubin increased,
Hyponatraemia

Rare

ADRs with
amlodipine
Arthralgia, Myalgia,
Muscle cramps,
Back pain

Renal dysfunction

Uncommon

Rare

Reproductive system
and breast disorders

ADRs with lisinopril

Very rare

Chest pain, Pain,
Malaise, Asthenia
Weight increase,
Weight decrease

Hepatic enzymes
increased**

* 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.
** Mostly consistent with cholestasis.
Exceptional cases of extrapyramidal syndrome have been also reported with the use of
amlodipine.
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 Yellow Card
Scheme at www.mhra.gov.uk/yellowcard.
4.9

Overdose

No data are available on human overdosage with Parliprima.
Linked to lisinopril 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.
Linked to amlodipine overdose
In humans experience with intentional overdose is limited.
Symptoms:
Available data suggest that gross overdosage could result in excessive peripheral
vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic
hypotension up to and including shock with fatal outcome have been reported.
Treatment:
Clinically significant hypotension due to amlodipine overdosage calls for active
cardiovascular support including frequent monitoring of cardiac and respiratory function,
elevation of extremities and attention to circulating fluid volume and urine output.
A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that
there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in
reversing the effects of calcium channel blockade.
Gastric lavage may be worthwhile in some cases. In healthy volunteers the use of charcoal up
to 2 hours after administration of amlodipine 10 mg has been shown to reduce the absorption
rate of amlodipine.
Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.
Overdose with Parliprima can result in excessive peripheral vasodilatation with marked
hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation,
tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. Symptomatic treatment
(placing the patient in a supine position, monitoring – and when necessary, support – of
cardiac and respiratory function, blood pressure, fluid and electrolyte balance, and creatinine
concentrations) is recommended. In case of serious hypotension, the lower extremities should
be elevated, and when intravenous administration of fluid does not elicit sufficient response,
supportive treatment added-on with administration of peripheral vasopressor agents may be
necessary, unless contraindicated. If available, treatment with angiotensin II infusion may also
be considered. Intravenous administration of calcium gluconate may be beneficial in reversing
the effects of calcium channel blockade.
Since amlodipine is slowly absorbed, gastric lavage can be useful in some cases.
Lisinopril can be removed from the systemic circulation by haemodialysis. The use of highflux polyacrylonitrile membranes should be avoided during dialysis.
5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: ACE inhibitors and calcium channel blockers, ATC code:
C09BB03

Parliprima is a fixed dose combination containing the active substances lisinopril and
amlodipine.
Lisinopril
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.
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.
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 3164 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 allcause 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 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, predefined 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 patients with Type 2 diabetes mellitus subjects with and
incipient nephropathy characterized 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-per-cent. 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).
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 dose-dependent
antihypertensive effect of lisinopril was consistent across several demographic subgroups:
age, Tanner stage, gender, and race.
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.
Amlodipine
Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel
blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into
cardiac and vascular smooth muscle.
The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect
on vascular smooth muscle.

In patients with hypertension, once daily dosing provides clinically significant reductions of
blood pressure in both the supine and standing positions throughout the 24 hour interval. Due
to the slow onset of action, acute hypotension is not a feature of amlodipine administration.
Amlodipine has not been associated with any adverse metabolic effects or changes in plasma
lipids and is suitable for use in patients with asthma bronchiale, diabetes mellitus, and gout.
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)
A randomized, double-blind, morbidity-mortality study called the Antihypertensive and
Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was performed to
compare newer drug therapies: amlodipine 2.5-10 mg/day (calcium channel blocker) or
lisinopril 10-40 mg/d ay (ACE-inhibitor) as first-line therapies to that of the thiazide-diuretic,
chlorthalidone 12.5-25 mg/day in mild to moderate hypertension.
A total of 33,357 hypertensive patients aged 55 or older were randomized and followed for a
mean of 4.9 years. The patients had at least one additional CHD (coronary heart disease) risk
factor, including: previous myocardial infarction or stroke (> 6 months prior to enrolment) or
documentation of other atherosclerotic CVD (cardiovascular disease) (overall 51.5%), type 2
diabetes (36.1%), HDL-C < 35 mg/dl (11.6%), left ventricular hypertrophy diagnosed by
electrocardiogram or echocardiography (20.9%), current cigarette smoking (21.9%).
The primary endpoint was a composite of fatal CHD or non-fatal myocardial infarction. There
was no significant difference in the primary endpoint between amlodipine-based therapy and
chlorthalidone-based therapy: RR 0.98 95% CI [0.90-1.07] p=0.65. However, there was no
significant difference in all-cause mortality between amlodipine-based therapy and
chlorthalidone-based therapy: RR 0.96 95% CI [0.89-1.02] p=0.20.
Paediatric population
In a study involving 268 children aged 6-17 years with predominantly secondary
hypertension, comparison of a 2.5 mg dose and 5.0 mg dose of amlodipine with placebo,
showed that both doses reduced systolic blood pressure significantly more than placebo. The
difference between the two doses was not statistically significant.
The long-term effects of amlodipine on growth, puberty and general development have not
been studied. The long-term efficacy of amlodipine on therapy in childhood to reduce
cardiovascular morbidity and mortality in adulthood has also not been established.
5.2

Pharmacokinetic properties

Lisinopril
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 inter-patient variability of
6 60% over the dose range studied (5 80 mg). The absolute bioavailability is reduced
approximately 16% in patients with heart failure. The absorption of lisinopril is not affected by
the presence of food.
Distribution and protein binding
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 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 in healthy subjects. 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.
Pharmacokinetic features in special populations
Hepatic impairment
Impairment of hepatic function in cirrhotic patients resulted in a decrease in lisinopril
absorption (approximately 30% as determined by urinary recovery), but an increase in
exposure (approximately 50%) compared to healthy subjects due to decreased clearence.
Renal impairment
Impaired renal function decreases the elimination of lisinopril, which is excreted via the
kidneys, but this decrease becomes clinically relevant only when the glomerular filtration rate
is below 30 ml/min. In mild to moderate renal impairment (creatinine clearance 30 to 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 between 5 and 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 a reduced absorption of approximately 16% compared to healthy 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.
Elderly
Older patients have higher blood levels and higher values for the area under the plasma
concentration-time curve (increased approximately 60-per-cent) compared with younger
subjects.
Amlodipine
Absorption
After oral administration amlodipine is well absorbed, producing peak plasma concentrations
between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64
and 80%. The bioavailability of amlodipine is not affected by food intake.
Distribution and plasma protein binding The volume of distribution is approximately 21 l/kg.
In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to
plasma proteins.
Biotransformation and elimination
The terminal plasma elimination half-life is about 35-50 hours and is consistent with once
daily dosing. Amlodipine is extensively metabolized by the liver to inactive metabolites with
10% of the parent compound and 60% of metabolites excreted in the urine.

Pharmacokinetic features in special populations
Use in hepatic impairment
Very limited clinical data are available regarding amlodipine administration in patients with
hepatic impairment. Patients with hepatic insufficiency have decreased clearance of
amlodipine resulting in a longer half-life and an increase in AUC of approximately 40-60%.
Elderly
The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger
subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and
elimination half-life in elderly patients.
Increases in AUC and elimination half-life in patients with congestive heart failure were as
expected for the patient age group studied.
Paediatric population
A population PK study has been conducted in 74 hypertensive children aged from 12 months
to 17 years (with 34 patients aged 6 to 12 years and 28 patients aged 13 to 17 years) receiving
amlodipine between 1.25 and 20 mg given either once or twice daily. In children 6 to 12 years
and in adolescents 13-17 years of age the typical oral clearance (CL/F) was 22.5 and 27.4 l/h
respectively in males and 16.4 and 21.3 l/h respectively in females. Large variability in
exposure between individuals was observed. Data reported in children below 6 years is
limited.
Fixed dose combination
No pharmacokinetic interactions have been described between the active substances of
Parliprima. Pharmacokinetic parameters (AUC, Cmax, tmax, half-life) were not different from
those observed after administration of the individual components separately.
The gastrointestinal absorption of Parliprima is not influenced by food.
5.3

Preclinical safety data

Non-clinical studies have not been conducted with the combination lisinopril-amlodipine.
Lisinopril
Preclinical data reveal no special hazard for humans based on conventional studies of general
pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential.
ACE inhibitors, as a class, have been shown to induce adverse effects on late fetal development,
resulting in fetal 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.
Amlodipine
Reproductive toxicology
Reproductive studies in rats and mice have shown delayed date of delivery, prolonged
duration of labour and decreased pup survival at dosages approximately 50 times greater than
the maximum recommended dosage for humans based on mg/kg.
Carcinogenesis, mutagenesis
Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to
provide daily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day, showed no evidence of

carcinogenicity. The highest dose (for mice similar to, and for rats twice* the maximum
recommended clinical dose of 10 mg/day on a mg/m2 basis) was close to the maximum
tolerated dose for mice but not for rats.
Mutagenicity studies revealed no drug related effects at either the gene or chromosome level.
Impairment of fertility
There was no effect on the fertility of rats treated with amlodipine (males for 64 days and
females 14 days prior to mating) at doses up to 10 mg/kg/day (8 times* the maximum
recommended human dose of 10 mg/day on a mg/m2 basis). In another rat study in which
male rats were treated with amlodipine besilate for 30 days at a dose comparable with the
human dose based on mg/kg, decreased plasma follicle-stimulating hormone and testosterone
were found as well as decreases in sperm density and in the number of mature spermatids and
Sertoli cells.
* Based on patient weight of 50 kg.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Cellulose, microcrystalline
Sodium starch glycolate (type A)
Magnesium stearate

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
2 years

6.4

Special precautions for storage
Store below 25°C.
Store in the original package in order to protect from light and moisture.

6.5

Nature and contents of container

28, 30, 50, 56, 90, 98 or 100 tablets in white, PVC/PE/PVDC/Aluminium blisters in a
carton.
Not all pack sizes may be marketed.
6.6

Special precautions for disposal and other handling

No special requirements for disposal.
Any unused medicinal product or waste material should be disposed of in accordance with
local requirements.

7

MARKETING AUTHORISATION HOLDER
Gedeon Richter Plc.
Gyömrői út 19-21,
H-1103 Budapest
Hungary

8

MARKETING AUTHORISATION NUMBER(S)
PL 04854/0109

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
19/01/2012

10

DATE OF REVISION OF THE TEXT
18/12/2014

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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