Servier Laboratories Ireland Ltd

ACERYCAL 5mg/5mg tablets

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.

Tablet.

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

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.

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, alone or in combination, have not been established in children and adolescents.

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.

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 inhibitor therapy prior to each apheresis.

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 beenavoided 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 fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. 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

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

Precautions for use

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).

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 to be taken into consideration:

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 progressive doses of perindopril.

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 alter the pharmacokinetics of ciclosporin.

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.

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. Animal studies have not shown teratogenic effect (see section 5.3).

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.

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.

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).

Additional information linked to amlodipine

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

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. Periondopril 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.

Pharmacotherapeutic group: ACE inhibitors and calcium channel blockers, 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 blood flow increases, with no effect on heart rate.

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 use in patients with asthma, diabetes, and gout.

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).

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 urine, 10% as unchanged amlodipine.

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.

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.

Lactose monohydrate

Cellulose, microcrystalline (E460)

Silica, colloidal anhydrous (E551)

Magnesium stearate (E470B)

Not applicable.

3 years

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

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.

Box of 4 containers of 30 tablets.

Box of 10 containers of 50 tablets.

Not all pack sizes may be marketed.

No special requirements.

Les Laboratoires Servier

22, rue Garnier

92200 Neuilly-sur-Seine

France

PA 568/18/01-02-03-04

Date of first authorisation: 13th June 2008

June 2010