ACERYCAL 5MG/5MG TABLETS

Main information

  • Trade name:
  • ACERYCAL 5MG/5MG TABLETS
  • Available from:
  • Les Laboratoires Servier
  • Dosage:
  • 5/5 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine type:
  • Human

Documents

Localization

  • Available in:
  • ACERYCAL 5MG/5MG TABLETS
    Ireland
  • Language:
  • English

Other information

Status

  • Source:
  • IMB
  • Authorization date:
  • 13-06-2008
  • Last update:
  • 23-04-2015

Summary of Product characteristics


Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Acerycal 5mg/5mg tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One tablet contains 3.395 mg perindopril equivalent to 5 mg perindopril arginine and 6.935 mg amlodipine besilate

equivalent to 5 mg amlodipine

Excipient : lactose monohydrate.

For a full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Tablet.

White, rod-shaped tablet engraved with 5/5 on one face and on the other face.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Acerycal is indicated as substitution therapy for treatment of essential hypertension and/or stable coronary artery

disease, in patients already controlled with perindopril and amlodipine given concurrently at the same dose level.

4.2 Posology and method of administration

Oral route.

One tablet per day as a single dose, preferably to be taken in the morning and before a meal.

The fixed dose combination is not suitable for initial therapy.

If a change of posology is required, the dose of Acerycal could be modified or individual titration with free

combination may be considered.

Patients with renal impairment and elderly (see sections 4.4 and 5.2)

Elimination of perindoprilat is decreased in the elderly and in patients with renal failure. Therefore, the usual medical

follow-up will include frequent monitoring of creatinine and potassium.

Acerycal can be administered in patients with Clcr 60ml/min, and is not suitable for patients with Clcr < 60ml/min.

In these patients, an individual dose titration with the monocomponents is recommended.

Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment.

Patients with hepatic impairment: see sections 4.4 and 5.2

A dosage regimen for patients with hepatic impairment has not been established. Therefore, Acerycal should be

administered with caution.

Children and adolescents

Acerycal should not be used in children and adolescents as the efficacy and tolerability of perindopril and amlodipine,

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4.3 Contraindications

Linked to perindopril:

- Hypersensitivity to perindopril or to any other ACE inhibitor,

- History of angioedema associated with previous ACE inhibitor therapy,

- Hereditary or idiopathic angioedema,

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

Linked to amlodipine:

- Severe hypotension,

- Hypersensitivity to amlodipine or to any other dihydropyridines,

- Shock, including cardiogenic shock,

- Obstruction of the outflow-tract of the left ventricle (e.g. high grade aortic stenosis),

- Unstable angina pectoris (excluding Prinzmetal's angina),

- Heart failure after acute myocardial infarction (during the first 28 days).

Linked to Acerycal:

All contraindications related to each monocomponent, as listed above, should apply also to the fixed combination of

Acerycal.

- Hypersensitivity to any of the excipients.

4.4 Special warnings and precautions for use

All warnings related to each monocomponent, as listed below, should apply also to the fixed combination of Acerycal.

Linked to perindopril

Special warnings

Hypersensitivity/Angioedema:

Angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx has been reported rarely in

patients treated with ACE inhibitors, including perindopril (see section 4.8). This may occur at any time during therapy.

In such cases, Acerycal should promptly be discontinued and appropriate monitoring should be initiated and continued

until complete resolution of symptoms has occurred. In those instances where swelling was confined to the face and

lips the condition generally resolved without treatment, although antihistamines have been useful in relieving

symptoms.

Angioedema associated with laryngeal oedema may be fatal. Where there is involvement of the tongue, glottis or

larynx, likely to cause airway obstruction, 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.

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).

Intestinal angioedema has been reported rarely in patients treated with ACE inhibitors. These patients presented with

abdominal pain (with or without nausea or vomiting); in some cases there was no prior facial angioedema and C-1

esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan, or

ultrasound or at surgery and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be

included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain (see section 4.8).

Anaphylactoid reactions during low-density lipoproteins (LDL) apheresis:

Rarely, patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis with dextran sulphate have

experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE

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Anaphylactoid reactions during desensitisation:

Patients receiving ACE inhibitors during desensitisation treatment (e.g. hymenoptera venom) have experienced

anaphylactoid reactions. In the same patients, these reactions have been avoided when the ACE inhibitors were

temporarily withheld, but they reappeared upon inadvertent rechallenge.

Neutropenia/Agranulocytosis/Thrombocytopenia/Anaemia:

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. Perindopril 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 perindopril 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 (e.g. sore throat, fever).

Pregnancy:

ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitors is considered essential,

patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established

safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped

immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Precautions for use

Hypotension:

ACE inhibitors may cause a fall in blood pressure. Symptomatic hypotension is seen rarely in uncomplicated

hypertensive patients and is more likely to occur in patients who have been volume-depleted e.g. by diuretic therapy,

dietary salt restriction, dialysis, diarrhoea or vomiting, or who have severe renin-dependent hypertension (see sections

4.5 and 4.8). In patients at high risk of symptomatic hypotension, blood pressure, renal function and serum potassium

should be monitored closely during treatment with Acerycal.

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 sodium chloride 9 mg/ml (0.9%) solution. 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.

Aortic and mitral valve stenosis / hypertrophic cardiomyopathy:

As with other ACE inhibitors, perindopril 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 impairement:

In cases of renal impairment (creatinine clearance < 60 ml/min) an individual dose titration with the monocomponents

is recommended (see section 4.2).

Routine monitoring of potassium and creatinine are part of normal medical practice for patients with renal impairment

(see section 4.8).

In some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, who have been treated

with ACE 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. 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 perindopril has been given concomitantly with a diuretic. This is more likely to occur in

patients with pre-existing renal impairment.

Hepatic failure:

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to

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Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue

the ACE inhibitor and receive appropriate medical follow-up (see section 4.8).

Race:

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

As with other ACE inhibitors, perindopril may be less effective in lowering blood pressure in black people than in non-

blacks, possibly because of a higher prevalence of low-renin states in the black hypertensive population.

Cough:

Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent and

resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential

diagnosis of cough.

Surgery/Anaesthesia:

In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, Acerycal may block

angiotensin II formation secondary to compensatory renin release. The treatment should be discontinued one day prior

to the surgery. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume

expansion.

Hyperkaliemia:

Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including perindopril.

Risk factors for the development of hyperkalemia include those with renal insufficiency, worsening of renal function,

age (> 70 years), diabetes mellitus, intercurrent events, in particular dehydratation, acute cardiac decompensation,

metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene, or

amiloride), potassium supplements or potassium-containing salt substitutes; or those patients taking other drugs

associated with increases in serum potassium (e.g. heparin). 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. Hyperkalemia can cause serious, sometimes fatal arrhythmias. If concomitant

use of perindopril and any of the above mentioned agents is deemed appropriate, they should be used with caution and

with frequent monitoring of serum potassium (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).

Linked to amlodipine:

Precautions for use

Patients with impaired hepatic function:

As with all calcium antagonists, amlodipine's half-life is prolonged in patients with impaired liver function. The drug

should therefore be administered with caution in these patients and with a close monitoring of the hepatic enzymes.

Patients with heart failure:

Patients with cardiac failure should be treated with caution.

In a long-term, placebo controlled study (PRAISE-2) of amlodipine in patients with NYHA III and IV heart failure of

nonischaemic aetiology, amlodipine was associated with increased reports of pulmonary oedema despite no significant

difference in the incidence of worsening heart failure as compared to placebo (see section 5.1).

Linked to Acerycal

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Precautions for use

Excipients:

Due to the presence of lactose, patients with rare hereditary problems of galactose intolerance, glucose-galactose

malabsorption, or the Lapp lactase deficiency should not take this medicinal product.

Interactions

The concomitant use of Acerycal with lithium, potassium-sparing diuretics or potassium supplements, or dantrolene is

not recommended (see section 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

Linked to perindopril

Concomitant use not recommended:

Potassium sparing diuretics, potassium supplements or potassium-containing salt substitutes:

Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated

with perindopril. Potassium sparing diuretics (e.g. spironolactone, triamterene, or amiloride), potassium supplements,

or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore the

combination of perindopril with the above-mentioned drugs is not recommended (see section 4.4). If concomitant use is

indicated because of demonstrated hypokalaemia they should be used with caution and with frequent monitoring of

serum potassium.

Lithium:

Reversible increases in serum lithium concentrations and toxicity (severe neurotoxicity) have been reported during

concurrent use of ACE inhibitors. The combination of perindopril with lithium is not recommended. If the combination

proves necessary, careful monitoring of serum lithium levels is recommended (see section 4.4).

Estramustine:

Risk of increased adverse effects such as angioneurotic oedema (angioedema).

Concomitant use which requires special care:

Non-steroidal anti-inflammatory medicinal products (NSAIDs) including aspirin 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 ACE-inhibitors and NSAIDs may lead to an increased risk of

worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in

patients with poor pre-existing renal function. 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.

Antidiabetic agents (insulin, hypoglycaemic sulphonamides):

The use of angiotensin converting enzyme inhibitors may increase the hypoglycaemic effect in diabetics receiving

treatment with insulin or with hypoglycaemic sulphonamides. The onset of hypoglycaemic episodes is very rare (there

is probably an improvement in glucose tolerance with a resulting reduction in insulin requirements).

Concomitant use which requires special care:

Diuretics:

Patients on diuretics, and especially those who are volume and/or salt depleted, may experience excessive reduction in

blood pressure after initiation of therapy with an ACE inhibitor. The possibility of hypotensive effects can be reduced

by discontinuation of the diuretic, by increasing volume or salt intake prior to initiating therapy with low and

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Sympathomimetics:

Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.

Gold:

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in

patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including

perindopril.

Linked to amlodipine

Concomitant use not recommended:

Dantrolene (infusion): In animals, lethal ventricular fibrillations are observed after administration of verapamil and

dantrolene I.V. By extrapolation, the combination of amlodipine and dantrolene should be avoided.

Concomitant use which requires special care:

CYP3A4 inducers (rifampicine, Hypericum perforatum, anticonvulsant agents i.e carbamazepine, phenobarbital,

phenytoine, fosphenytoine, primidone): co-administration may lead to reduced plasma concentration of amlodipine due

to an increase of the hepatic metabolism of amlodipine by these inducers. Caution should be exercised in combination

of amlodipine with CYP3A4 inducers and posology of amlodipine could be adapted if needed.

CYP3A4 inhibitors (itraconazole, ketoconazole): co-administration may increase the plasma concentration of

amlodipine and consequently its adverse effects. Caution should be exercised when combining amlodipine with

itraconazole or ketoconazole and posology of amlodipine should be adjusted if needed.

Concomitant use to be taken into consideration:

Beta-blockers used in heart failure (bisoprolol, carvedilol, metoprolol):

Risk of hypotension, heart weakness in patients with cardiac heart failure, be it latent or uncontrolled (addition of

negative inotrope effect). Furthermore, the beta-blocker may minimize the sympathic reflex in case of excessive

heamodynamic repercussion.

Others combinations:

In monotherapy, amlodipine has been safely administered with thiazide diuretics, beta blockers, ACE inhibitors, long-

acting nitrates, sublingual nitroglycerin, digoxin, warfarin, atorvastatin, sildenafil, anti-acid medicines (aluminium

hydroxide gel, magnesium hydroxide, simeticone), cimetidine, non-steroidal anti-inflammatory medicines, antibiotics

and oral hypoglycaemic medicines.

Indeed, specific studies conducted with some drugs have shown no influence on amlodipine:

- co-administration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.

- when sildenafil and amlodipine were used in combination, each one independently exerted its own blood pressure

lowering effect.

- grapefruit juice: co-administration of 240ml of grapefruit juice with a single oral dose of 10mg amlodipine in 20

healthy volunteers had no significant effect on the pharmacokinetics of amlodipine.

Moreover, specific studies conducted with some drugs have shown that amlodipine has no influence on their

pharmacokinetics parameters:

- atorvastatin: co-administration of multiple doses of 10mg amlodipine with 80mg of atorvastatin resulted in no

significant change in the steady-state pharmacokinetics parameters of atorvastatin.

- digoxin: co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal

clearance in normal volunteers.

- warfarin: in healthy male volunteers, the co-administration of amlodipine did not significantly alter the effect of

warfarin on prothrombin response time. Co-administration of amlodipine with warfarin did not change the warfarin

prothrombin response time.

- ciclosporin: Pharmacokinetic studies with ciclosporin have demonstrated that amlodipine does not significantly

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Concomitant use which requires special care:

Baclofen. Potentiation of antihypertensive effect. Monitoring of blood pressure and renal function, and dose adaptation

of the antihypertensive if necessary.

Concomitant use to be taken into consideration:

. Antihypertensive agents (such as beta-blockers) and vasodilatators:

Concomitant use of these agents may increase the hypotensive effects of perindopril and amlodipine. Concomitant

use with nitroglycerine and other nitrates or other vasodilatators, may further reduce blood pressure and therefore

should be considered with caution.

. Corticosteroids, tetracosactide: reduction in antihypertensive effect (salt and water retention due to corticosteroids).

. Alpha-blockers (prazosin, alfuzosin, doxazosin, tamsulosin, terazosin): increased antihypertensive effect and

increased risk of orthostatic hypotension.

. Amifostine: may potentiate the antihypertensive effect of amlodipine.

. Tricyclic antidepressants/antipsychotics/anaesthetics: increased antihypertensive effect and increased risk of

orthostatic hypotension.

4.6 Fertility, pregnancy and lactation

Given the effects of the individual components in this combination product on pregnancy and lactation:

Acerycal is not recommended during the first trimester of pregnancy. Acerycal is contraindicated during the second and

third trimesters of pregnancy.

Acerycal is not recommended during lactation. A decision should therefore be made whether to discontinue nursing or

to discontinue Acerycal taking account the importance of this therapy for the mother.

Pregnancy:

Linked to perindopril

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first

trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued

ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative

antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is

diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy

should be started.

Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity

(decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure,

hypotension, hyperkalaemia) (see section 5.3).

Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal

function and skull is recommended.

Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see sections 4.3 and

4.4).

Linked to amlodipine

Data on a limited number of exposed pregnancies do not indicate that amlodipine and other calcium receptor

antagonists have a harmful effect on the health of the foetus. However, there may be a risk of prolonged delivery.

The use of ACE inhibitors is not recommended during the first trimester of pregnancy

(see section 4.4). The use of ACE inhibitors is contraindicated during the second and

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Lactation:

Linked to perindopril

Because no information is available regarding the use of perindopril during breastfeeding, perindopril is not

recommended and alternative treatments with better established safety profiles during breast-feeding are preferable,

especially while nursing a newborn or preterm infant.

Linked to amlodipine

It is not known whether amlodipine is excreted in breast milk. Similar calcium channel blockers of the dihydropyridine

type are excreted in breast milk.

Therefore, as a precaution, lactation is not recommended during the treatment with amlodipine.

Fertility :

Reversible biochemical changes in the head of spermatozoa which can impair fecundation have been reported in some

patients treated by calcium channel blockers.

4.7 Effects on ability to drive and use machines

No studies on the effects of Acerycal on the ability to drive and use machines have been performed. When driving

vehicles or operating machines it should be taken into account that occasionally dizziness or weariness may occur.

4.8 Undesirable effects

The following undesirable effects have been observed during treatment with perindopril or amlodipine given separately

and ranked under the MedDRA classification by body system and under the following frequency :

Very common ( 1/10) ; common ( 1/100 to <1/10) ; uncommon ( 1/1000 to <1/100) ; rare ( 1/10000 to <1/1000) ;

very rare (<1/10000) ; not known (cannot be estimated from the available data).

MedDRA

System Organ

Class Undesirable Effects Frequency

Amlodipine Perindopril

Blood and the

lynphatic System

Disorders Leucopenia/neutropenia (see section 4.4) Very rare Very rare

Agranulocytosis or pancytopenia (see section 4.4) - Very rare

Thrombocytopenia (see section 4.4) Very rare Very rare

Haemolytic anaemia in patients with a congenital deficiency of G-6PDH

(see section 4.4) - Very rare

Decrease in haemoglobine and haematocrit - Very rare

Immune System

Disorders Allergic reaction: Urticaria Very rare Uncommon

Metabolism and

Nutrition

Disorders Hyperglycaemia Very rare -

Weight gain Uncommon -

Weight decrease Uncommon -

Hypoglycaemia (see sections 4.4 and 4.5) - Not known

Psychiatric

disorders Insomnia Uncommon -

Mood changes Uncommon Uncommon

Sleep disturbances - Uncommon

Nervous System

disorders Somnolence Common -

Dizziness Common Common

Headache Common Common

Tremor Uncommon -

Hypoesthaesia

Paresthaesia Uncommon

Uncommon -

Common

Hypertonia Very rare -

Peripheral neuropathy Very rare -

Vertigo - Common

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Eye Disorders Visual disturbances Uncommon Common

Ear and labyrinth

disorders Tinnitus Uncommon Common

Cardiac Disorders Palpitations Common -

Syncope Uncommon -

Angina pain

Angina pectoris Rare

- -

Very rare

Myocardial infarction, possibly secondary to excessive hypotension in

high risk patients (see section 4.4) Very rare Very rare

Arrythmia (including bradycardia, ventricular tachycardia and atrial

fibrillation) Very rare Very rare

Vascular

Disorders Flushing Common -

Hypotension (and effects related to hypotension) Uncommon Common

Stroke possibly secondary to excessive hypotension in high-risk patients

(see section 4.4) - Very rare

Vasculitis Very Rare Not known

Respiratory,

Thoracic and

Mediastinal

Disorders Dyspnoea Uncommon Common

Rhinitis Uncommon Very rare

Cough Very rare Common

Bronchospasm - Uncommon

Eosinophilic pneumonia - Very rare

Gastro-intestinal

Disorders Gingival hyperplasia Very rare -

Abdominal pain, nausea Common Common

Vomiting Uncommon Common

Dyspepsia Uncommon Common

Altered bowel habits Uncommon -

Dry mouth Uncommon Uncommon

Dysgeusia - Common

Taste perversion Uncommon -

Diarrheoa , constipation - Common

Pancreatitis Very rare Very rare

Gastritis Very rare -

Hepato-biliary

Disorders Hepatitis, cholestatic jaundice

Hepatitis etheir cytolitic or cholestatic (see section 4.4) Very rare

- -

Very rare

Skin and

Subcutaneous

Tissue Disorders Quincke’s oedema

Angioedema of face, extremities, lips, mucous membranes, tongue, glottis

and/or larynx (see section 4.4) Very rare

- -

Uncommon

Erythema multiform Very rare Very rare

Alopecia Uncommon -

Purpura Uncommon -

Skin discoloration Uncommon -

Increased sweating

Sweating Uncommon

- -

Uncommon

Prurit Uncommon Common

Rash Uncommon Common

Stevens-Johnson Syndrome Very rare -

Musculoskeletal

And Connective

Tissue Disorders Arthralgia, myalgia Uncommon -

Muscle cramps Uncommon Common

Back pain Uncommon -

Renal and

Urinary Disorders Micturition disorder, nocturia, increased urinary frequency Uncommon -

Renal impairment - Uncommon

Acute renal failure - Very rare

Reproductive

System and Breast

Disorders Impotence Uncommon Uncommon

Gynaecomastia Uncommon -

General Disorders

and

Administration

Site Condition Oedema, peripheral oedema Common -

Fatigue Common -

Chest pain Uncommon -

Asthenia Uncommon Common

Pain Uncommon -

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Additional information linked to amlodipine

Exceptional cases of extrapyramidal syndrome have been reported with calcium channel blockers.

4.9 Overdose

There is no information on overdosage with Acerycal in humans.

For amlodipine, experience with intentional overdose in humans is limited. Large overdosage could result in excessive

peripheral vasodilatation with subsequent marked and probably prolonged systemic hypotension. Any hypotension due

to amlodipine overdosage calls for a monitoring in cardiologic intensive care unit. 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.

Amlodipine is not dialyzable.

For perindopril, limited data are available for overdosage in humans. Symptoms associated with the 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 overdosage 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. Perindopril can be removed from the systemic circulation by haemodialysis

(see section 4.4). Pacemaker therapy is indicated for treatment-resistant bradycardia. Vital signs, serum electrolytes and

creatinine concentrations should be monitored continuously.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: perindopil and amlodipine, ATC code: C09BB04

Perindopril:

Perindopril is an inhibitor of the enzyme that converts angiotensin I into angiotensin II (Angiotensin Converting

Enzyme ACE). The converting enzyme, or kinase, is an exopeptidase that allows conversion of angiotensin I into the

vasoconstrictor angiotensin II as well as causing the degradation of the vasodilator bradykinin into an inactive

heptapeptide. Inhibition of ACE results in a reduction of angiotensin II in the plasma, which leads to increased plasma

renin activity (by inhibition of the negative feedback of renin release) and reduced secretion of aldosterone. Since ACE

inactivates bradykinin, inhibition of ACE also results in an increased activity of circulating and local kallikrein-kinin

systems (and thus also activation of the prostaglandin system). It is possible that this mechanism contributes to the

blood pressure-lowering action of ACE inhibitors and is partially responsible for certain of their side effects (e.g.

cough).

Perindopril acts through its active metabolite, perindoprilat. The other metabolites show no inhibition of ACE activity

in vitro.

Hypertension:

Perindopril is active in all grades of hypertension : mild, moderate, severe ; a reduction in systolic and diastolic blood

pressures in both supine and standing positions is observed.

Perindopril reduces peripheral vascular resistance, leading to blood pressure reduction. As a consequence, peripheral

Investigations Hepatic enzymes elevations: ALT, AST (mostly consistent with

cholestasis) Very rare -

Serum bilirubin and liver enzymes elevation - Rare

Increases in blood urea and serum creatinine, hyperkalaemia (see section

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Renal blood flow increases as a rule, while the glomerular filtration rate (GFR) is usually unchanged.

The antihypertensive activity is maximal between 4 and 6 hours after a single dose and is sustained for at least 24

hours: trough effects are about 87-100 % of peak effects.

The decrease in blood pressure occurs rapidly. In responding patients, normalisation is achieved within a month and

persists without the occurrence of tachyphylaxis.

Discontinuation of treatment does not lead to a rebound effect.

Perindopril reduces left ventricular hypertrophy.

In man, perindopril has been confirmed to demonstrate vasodilatory properties. It improves large artery elasticity and

decreases the media:lumen ratio of small arteries.

Patients with stable coronary artery disease:

The EUROPA study was a multicentre, international, randomised, double-blind, placebo-controlled clinical trial lasting

4 years.

Twelve thousand two hundred and eighteen (12218) patients aged over 18 were randomised to 8 mg perindopril tert-

butylamine (equivalent to 10 mg perindopril arginine) (n=6110) or placebo (n=6108).

The trial population had evidence of coronary artery disease with no evidence of clinical signs of heart failure. Overall,

90% of the patients had a previous myocardial infarction and/or a previous coronary revascularisation. Most of the

patients received the study medication on top of conventional therapy including platelet inhibitors, lipid lowering

agents and beta-blockers.

The main efficacy criterion was the composite of cardiovascular mortality, non fatal myocardial infarction and/or

cardiac arrest with successful resuscitation. The treatment with 8 mg perindopril tert-butylamine (equivalent to 10 mg

perindopril arginine) once daily resulted in a significant absolute reduction in the primary endpoint of 1.9% (relative

risk reduction of 20%, 95%CI [9.4; 28.6] – p<0.001).

In patients with a history of myocardial infarction and/or revascularisation, an absolute reduction of 2.2%

corresponding to a RRR of 22.4% (95%CI [12.0; 31.6] – p<0.001) in the primary endpoint was observed by

comparison to placebo.

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. The precise mechanism by which amlodipine relieves angina has not been fully determined but amlodipine

reduces total ischaemic burden by the following two actions :

- Amlodipine dilates peripheral arterioles and thus, reduces the total peripheral resistance (afterload) against which the

heart works. Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption

and oxygen requirements.

- The mechanism of action of amlodipine also probably involves dilatation of the main coronary arteries and coronary

arterioles, both in normal and ischaemic regions. This dilatation increases myocardial oxygen delivery in patients

with coronary artery spasm (Prinzmetal's or variant angina).

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.

In patients with angina, once daily administration of amlodipine increases total exercise time, time to angina onset, and

time to 1mm ST segment depression, and decreases both angina attack frequency and glyceryl trinitrate tablet

consumption.

Amlodipine has not been associated with any adverse metabolic effects or changes in plasma lipids and is suitable for

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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/d

(calcium channel blocker) or lisinopril 10-40 mg/d (ACE-inhibitor) as first-line therapies to that of the thiazide-diuretic,

chlorthalidone 12.5-25 mg/d 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 risk factor, including: previous myocardial infarction or stroke > 6 months

prior to enrollment or documentation of other atherosclerotic CVD (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). Among secondary endpoints, the incidence of heart failure (component of a composite

combined cardiovascular endpoint) was significantly higher in the amlodipine group as compared to the chlorthalidone

group (10.2% vs 7.7%, RR 1.38, (95% CI [1.25-1.52] p<0.001)). 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).

5.2 Pharmacokinetic properties

The rate and extent of absorption of perindopril and amlodipine from Acerycal are not significantly different,

respectively, from the rate and extent of absorption of perindopril and amlodipine from individual tablet formulations.

Perindopril:

After oral administration, the absorption of perindopril is rapid and the peak concentration is achieved within 1 hour.

The plasma half-life of perindopril is equal to 1 hour.

Perindopril is a prodrug. Twenty seven percent of the administered perindopril dose reaches the bloodstream as the

active metabolite perindoprilat. In addition to active perindoprilat, perindopril yields five metabolites, all inactive. The

peak plasma concentration of perindoprilat is achieved within 3 to 4 hours.

As ingestion of food decreases conversion to perindoprilat, hence bioavailability, perindopril arginine should be

administered orally in a single daily dose in the morning before a meal.

It has been demonstrated a linear relationship between the dose of perindopril and its plasma exposure.

The volume of distribution is approximately 0.2 l/kg for unbound perindoprilat. Protein binding of perindoprilat to

plasma proteins is 20%, principally to angiotensin converting enzyme, but is concentration-dependent. Perindoprilat is

eliminated in the urine and the terminal half-life of the unbound fraction is approximately 17 hours, resulting in steady-

state within 4 days.

Elimination of perindoprilat is decreased in the elderly, and also in patients with heart or renal failure (see section 4.2).

Therefore, the usual medical follow-up will include frequent monitoring of creatinine and potassium.

Dialysis clearance of perindoprilat is equal to 70 ml/min.

Perindopril kinetics are modified in patients with cirrhosis: hepatic clearance of the parent molecule is reduced by half.

However, the quantity of perindoprilat formed is not reduced and therefore no dosage adjustment is required (see

sections 4.2 and 4.4).

Amlodipine:

After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6-12 hours

post dose. Absolute bioavailability has been estimated to be between 64 and 80%. The volume of distribution is

approximately 21 l/kg. Its bioavailability is not influenced by food. In vitro studies have shown that approximately

97.5% of circulating amlodipine is bound to plasma proteins.

The terminal plasma elimination half-life is about 35-50 hours and is consistent with once daily dosing. Amlodipine is

extensively metabolised by the liver to inactive metabolites. About 60% of the administered dose is excreted in the

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Use in the 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. The recommended dosage regimen for the elderly is the same, although increasing the dose should

take place with caution.

Use in patients with renal failure: see section 4.2.

Use in patients with impaired hepatic function: As with all calcium antagonists, amlodipine's half-life is prolonged in

patients with impaired liver function.

5.3 Preclinical safety data

Perindopril:

In the chronic oral toxicity studies (rats and monkeys), the target organ is the kidney, with reversible damage.

No mutagenicity has been observed in in vitro or in vivo studies.

Reproduction toxicology studies (rats, mice, rabbits and monkeys) showed no sign of embryotoxicity or teratogenicity.

However, angiotensin converting enzyme inhibitors, as a class, have been shown to induce adverse effects on late fetal

development, resulting in fetal death and congenital effects in rodents and rabbits: renal lesions and an increase in peri-

and postnatal mortality have been observed.

No carcinogenicity has been observed in long term studies in rats and mice.

Amlodipine:

Toxicological studies in animal reveal no special hazards for humans regarding safety pharmacology, genotoxicity,

carcinogenicity, fertility and studies with repeated dosing. Reproductive toxicology studies in rats showed a prolonged

duration of pregnancy and an increase in peri and postnatal mortality.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate

Cellulose, microcrystalline (E460)

Silica, colloidal anhydrous (E551)

Magnesium stearate (E470B)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Keep the container tightly closed in order to protect from moisture. Store in the original package.

6.5 Nature and contents of container

5, 7, 10, 14, 20, 28, 30 or 50 tablets in polypropylene container equipped with a low density polyethylene flow reducer

and a low density polyethylene stopper containing a desiccant gel.

Box of 1 container of 5, 7, 10, 14, 20, 28, 30 or 50 tablets.

Box of 2 containers of 28, 30 or 50 tablets.

Box of 3 containers of 30 tablets.

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Box of 10 containers of 50 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Les Laboratoires Servier

22, rue Garnier

92200 Neuilly-sur-Seine

France

8 MARKETING AUTHORISATION NUMBER

PA 568/018/001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of First Authorisation: 13th June 2008

10 DATE OF REVISION OF THE TEXT

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There are no safety alerts related to this product.

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