Vidonorm 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.

Posology

One tablet per day as a single dose.

The fixed dose combination is not suitable for initial therapy.

If the change of the dosage is required, it should be carried out by individual titration using the mono component products.

Patients with renal impairment and older people (see sections 4.4 and 5.2).

Elimination of perindoprilat is decreased in older people and in patients with renal failure. Therefore, the usual medical follow-up will include frequent monitoring of creatinine and potassium.

Vidonorm 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. Amlodipine is not dialysable.

Patients with hepatic impairment: see sections 4.4 and 5.2.

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

Paediatric population

Vidonorm should not be used in children and adolescents as the efficacy and tolerability of perindopril alone or in combination with amlodipine have not been established in children and adolescents.

Method of administration

Oral route. Preferably to be taken in the morning and before a meal.

Linked to perindopril:   -              Hypersensitivity to perindopril or to any other ACEinhibitor, -              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), -              Concomitant use of Vidonorm with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.4, 4.5 and 5.1). Linked to amlodipine:   -              Hypersensitivity to amlodipine or to any otherdihydropyridines, -              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. Linked to Vidonorm:   All contraindications related to each monocomponent, as listed above, should apply also to the fixed combination of Vidonorm. -              Hypersensitivity to any of the excipients listed in section 6.1.

 

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

 

Linked to perindopril

 

Stable coronary artery disease:

If an episode of unstable angina pectoris (major or not) occurs during the first month of perindopril treatment, a careful appraisal of the benefit/risk should be performed before treatment continuation.

 

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 with symptomatic 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 (see sections 4.2 and 4.8). 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.

In some patients with congestive heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with perindopril.

This effect is anticipated and is usually not a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or discontinuation of perindopril may be necessary.

 

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 impairment:

In cases of renal impairment (creatinine clearance < 60 ml/min) the initial perindopril dosage should be adjusted according to the patient's creatinine clearance (see section 4.2) and then as a function of the patient's response to treatment. Routine monitoring of potassium and creatinine are part of normal medical practice for these patients (see section 4.8).

 

In patients with symptomatic 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 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. 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 perindopril 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 perindopril 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 perindopril may be required.

 

Haemodialysis patients:

Anaphylactoid reactions have been reported in patients dialysed with high flux membranes, 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.

 

Kidney transplantation:

 

There is no experience regarding the administration of perindopril in patients with a recent kidney transplantation.

 

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, perindopril 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.

 

Concomitant use of mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus)

Patients taking concomitant mTOR inhibitor (e.g. sirolimus, everolimus, temsirolimus) therapy may be at increased risk for angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see section 4.5).

 

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

Rarely, patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.

 

Anaphylactic 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.

 

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).

 

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).

 

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, perindopril 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.

 

Hyperkalaemia:

Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including perindopril. Risk factors for the development of hyperkalaemia include those with renal insufficiency, worsening of renal function, age (> 70 years), diabetes mellitus, intercurrent events, in particular dehydration, 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. Hyperkalaemia can cause serious, sometimes fatal arrhythmias. If concomitant use 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).

 

Lithium:

The combination of lithium and perindopril is generally not recommended (see section 4.5).

 

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

The combination of perindopril and potassium-sparing drugs, potassium supplements or potassium- containing salt substitutes is generally not recommended (see section 4.5).

 

Dual blockade of the renin-angiotensin-aldosterone system (RAAS):

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).

 

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

 

Pregnancy:

ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative 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).

 

Linked to amlodipine:

 

The safety and efficacy of amlodipine in hypertensive crisis has 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.

 

Hepatic impairment

The half life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function; 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.

 

Elderly

In the elderly increase of the dosage should take place with care (see sections 4.2 and 5.2).

 

Renal impairment

Amlodipine may be used in such patients at normal doses. Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment. Amlodipine is not dialysable.

 

Linked to Vidonorm

 

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

 

Precautions for use

 

Interactions

The concomitant use of Vidonorm with lithium, potassium-sparing diuretics or potassium supplements, or dantrolene is not recommended (see section 4.5).

Linked to perindopril

 

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).

 

Racecadotril

 

ACE inhibitors (e.g. perindopril) are known to cause angioedema. This risk may be elevated when used concomitantly with racecadotril (a drug used against acute diarrhoea).

 

mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus)

Patients taking concomitant mTOR inhibitor therapy may be at increased risk for angioedema (see section 4.4).

 

Drugs inducing hyperkalaemia

Some drugs or therapeutic classes may increase the occurrence of hyperkalaemia: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensin-II receptors antagonists, NSAIDs, heparins, immunosuppressant agents such as ciclosporin or tacrolimus, trimethoprim. The combination of these drugs increases the risk of hyperkalaemia.

 

Concomitant use not recommended (see section 4.4):

 

Estramustine:

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

 

Potassium-sparing diuretics (e.g. triamterene, amiloride), potassium salts:

Hyperkalaemia (potentially lethal), especially in conjunction with renal impairment (additive hyperkalaemic effects).

The combination of perindopril with the above-mentioned drugs is not recommended (see section 4.4). If concomitant use is nonetheless indicated, they should be used with caution and with frequent monitoring of serum potassium. For use of spironolactone in heart failure, see below.

 

Lithium:

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Use of perindopril with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed (see section 4.4).

 

Concomitant use which requires special care:

 

Antidiabetic agents (insulins, oral hypoglycaemic agents):

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.

 

Baclofen:

Increased antihypertensive effect. Monitor blood pressure and adapt antihypertensive dosage if necessary.

 

Non-potassium-sparing 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.

 

In arterial hypertension, when prior diuretic therapy can have caused salt/volume depletion, either the diuretic must be discontinued before initiating the ACE inhibitor, in which case a non-potassium- sparing diuretic can be thereafter reintroduced or the ACE inhibitor must be initiated with a low dosage and progressively increased.

 

In diuretic-treated congestive heart failure, the ACE inhibitor should be initiated at a very low dosage, possibly after reducing the dosage of the associated non-potassium-sparing diuretic.

 

In all cases, renal function (creatinine levels) must be monitored during the first few weeks of ACE inhibitor therapy.

 

Potassium-sparing diuretics (eplerenone, spironolactone):

With eplerenone or spironolactone at doses between 12.5 mg to 50 mg by day and with low doses of ACE inhibitors:

In the treatment of class II-IV heart failure (NYHA) with an ejection fraction < 40%, and previously treated with ACE inhibitors and loop diuretics, risk of hyperkalaemia, potentially lethal, especially in case of non-observance of the prescription recommendations on this combination.

Before initiating the combination, check the absence of hyperkalaemia and renal impairment. A close monitoring of the kalaemia and creatinaemia is recommended in the first month of the treatment once a week at the beginning and, monthly thereafter.

 

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.

 

Concomitant use which requires some care:

 

Antihypertensive agents and vasodilators:

Concomitant use of these agents may increase the hypotensive effects of perindopril. Concomitant use with nitroglycerin and other nitrates, or other vasodilators, may further reduce blood pressure.

 

Gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin):

Increased risk of angioedema, due to dipeptidyl peptidase IV (DPP-IV) decreased activity by the gliptin, in patients co-treated with an ACE inhibitor.

 

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 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

 

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 resulting in an increased risk of hypotension. The clinical translation of these PK variations may be more pronounced in the elderly. Clinical monitoring of patients is recommended and dose adjustment may thus be required. Clarithromycin is an inhibitor of CYP3A4. There is an increased risk of hypotension in patients receiving clarithromycin with

 

amlodipine. Close observation of patients is recommended when amlodipine is co administered with clarithromycin.

 

CYP3A4 inducers:

There is no data available regarding the effect of CYP3A4 inducers on amlodipine. The concomitant use of CYP3A4 inducers (e.g., rifampicin, 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 co-administration 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 or warfarin.

 

Tacrolimus:

There is a risk of increased tacrolimus blood levels when co-administered with amlodipine but the pharmacokinetic mechanism of this interaction is not fully understood. In order to avoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.

 

Cyclosporine:

No drug interaction studies have been conducted with cyclosporine and amlodipine in healthy volunteers or other populations with the exception of renal transplant patients, where variable trough concentration increases (average 0% - 40%) of cyclosporine were observed. Consideration should be given for monitoring cyclosporine levels in renal transplant patients on amlodipine, and cyclosporine dose reductions should be made as necessary.

 

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.

 

Linked to Vidonorm

 

Concomitant use which requires special care:

 

Baclofen:

Potentiation of antihypertensive effect. Monitoring of blood pressure and renal function, and dose adjustment of the antihypertensive if necessary.

 

Concomitant use to be taken into consideration:

 

Antihypertensive agents (such as beta-blockers) and vasodilators:

Concomitant use of these agents may increase the hypotensive effects of perindopril and amlodipine. Concomitant use with nitroglycerine and other nitrates or other vasodilators, 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:

 

Vidonorm is not recommended during the first trimester of pregnancy. When a pregnancy is planned or confirmed, the switch to an alternative treatment should be initiated as soon as possible.

Vidonorm is contraindicated during the second and third trimesters of pregnancy.

 

Vidonorm is not recommended during lactation. A decision should therefore be made whether to discontinue nursing or to discontinue Vidonorm taking account the importance of this therapy for the mother.

 

Pregnancy:

 

Linked to perindopril

 

The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).

 

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.

 

Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see 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 foetus.

 

Breastfeeding:

 

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.

 

A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with amlodipine should be made taking into account the benefit of breast-feeding to the child and the benefit of amlodipine therapy to the mother.

 

Fertility:

 

Linked to perindopril

 

There was no effect on reproductive performance or fertility.

 

Linked to amlodipin

 

Reversible biochemical changes in the head of spermatozoa have been reported in some patients treated with 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).

 

No studies on the effects of Vidonorm 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 low blood pressure, headache, nausea, 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 (≥1/1,000 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).

 

System organ class	Frequency	Adverse reactions
		Amlodipine	Perindopril
Blood and lymphatic system disorders	Uncommon		Eosinophilia**
	Very rare	Leukocytopenia, Thrombocytopenia	Agranulocytosis or pancytopenia, Haemoglobin decreased and haematocrit decreased, Leucopenia/neutropenia, Haemolytic anaemia in patients with a congenital deficiency of

 

			G-6PDH (see section 4.4), Thrombocytopenia
Immune system disorders	Very rare	Allergic reactions
Metabolism and nutrition disorders	Uncommon		Hypoglycaemia (see sections 4.4 and 4.5)**, Hyperkalaemia, reversible on discontinuation (see section 4.4)**, Hyponatraemia**
	Very rare	Hyperglycaemia
Psychiatric disorders	Uncommon	Depression, Mood changes (including anxiety), Insomnia	Mood disturbances, Sleep disorder
	Rare	Confusion
Nervous system disorders	Common	Somnolence, Dizziness, Headache (especially at the beginning of the treatment)	Dizziness, Headache, Paraesthesia, Vertigo
	Uncommon	Tremor, Dysgeusia, Syncope, Hypoaesthesia, Paraesthesia	Somnolence**, Syncope**
	Very rare	Hypertonia, peripheral neuropathy	Confusion
	Not known	Extrapyramidal disorder
Eye disorders	Common	Visual disturbance (including diplopia)	Visual disturbances
Ear and labyrinth disorders	Common		Tinnitus
	Uncommon	Tinnitus
Cardiac disorders	Common	Palpitations
	Uncommon	Arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation)	Palpitations**, Tachycardia**
	Very rare	Myocardial infarction	Angina pectoris (see section 4.4), Arrhythmia, Myocardial infarction, possibly secondary to excessive hypotension in high risk patients (see section 4.4)
Vascular disorders	Common	Flushing	Hypotension (and effects related to hypotension)
	Uncommon	Hypotension	Vasculitis**
	Very rare	Vasculitis	Stroke possibly secondary to excessive hypotension in high- risk patients (see section 4.4)
Respiratory,	Common	Dyspnoea	Cough,

 

thoracic and mediastinal disorders			Dyspnoea
	Uncommon	Cough, Rhinitis	Bronchospasm
	Very rare		Eosinophilic pneumonia, Rhinitis
Gastrointestinal disorders	Common	Abdominal pain, Nausea, Dyspepsia, Altered bowel habits (including diarrhoea and constipation)	Abdominal pain, Constipation, Diarrhoea, Dysgeusia, Dyspepsia, Nausea, Vomiting
	Uncommon	Vomiting, Dry mouth	Dry mouth
	Very rare	Pancreatitis, Gastritis, Gingival hyperplasia	Pancreatitis
Hepatobiliary disorders	Very rare	Hepatitis, Jaundice, Hepatic enzyme increased*	Hepatitis either cytolytic or cholestatic (see section 4.4)
Skin and subcutaneous tissue disorders	Common		Pruritus, Rash
	Uncommon	Alopecia, Purpura, Skin discolouration, Hyperhidrosis, Pruritus, Rash, Exanthema, Urticaria	Urticaria (see section 4.4), Angioedema of face, extremities, lips, mucous membranes, tongue, glottis and/or larynx (see section 4.4), Photosensitivity reactions**, Pemphigoid**, Hyperhidrosis,
	Rare		Psoriasis aggravation
	Very rare	Angioedema, Erythema multiforme, Exfoliative dermatitis, Stevens-Johnson syndrome, Quincke oedema, Photosensitivity	Erythema multiforme
Musculoskeletal and connective tissue disorders	Common	Ankle swelling, Muscle cramps	Muscle cramps
	Uncommon	Arthralgia, Myalgia, Back pain	Arthralgia**, Myalgia**
Renal and urinary disorders	Uncommon	Micturition disorder, Nocturia, Increased urinary frequency	Renal insufficiency
	Very rare		Acute renal failure
Reproductive system and breast disorders	Uncommon	Impotence, Gynaecomastia	Erectile dysfunction
General disorders and administration	Very common	Oedema

 

site conditions	Common	Fatigue, Asthenia	Asthenia
	Uncommon	Chest pain, Pain, Malaise	Chest pain**, Malaise**, Oedema peripheral**, Pyrexia**
Investigations	Uncommon	Weight increased, Weight decreased	Blood urea increased**, Blood creatinine increased**
	Rare		Blood bilirubin increased, Hepatic enzyme increased
Injury, poisoning and procedural complications	Uncommon		Fall**

 

Linked to perindopril

 

** Frequency calculated from clinical trials for adverse events detected from spontaneous report

 

Linked to amlodipine

 

*  Mostly consistent with cholestasis

 

Clinical trials with perindopril:

During the randomised period of the EUROPA study, only serious adverse events were collected. Few patients experienced serious adverse events: 16 (0.3%) of the 6122 perindopril patients and 12 (0.2%) of the 6107 placebo patients. In perindopril-treated patients, hypotension was observed in 6 patients, angioedema in 3 patients and sudden cardiac arrest in 1 patient. More patients withdrew for cough, hypotension or other intolerance on perindopril than on placebo, 6.0% (n=366) versus 2.1% (n=129) respectively.

 

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.

 

•  Saudi Arabia:

The National Pharmacovigilance and Drug Safety Centre (NPC) ·  Fax: +966-11-205-7662 ·  Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340. ·  Toll free phone: 8002490000 ·  E-mail: npc.drug@sfda.gov.sa ·  Website: www.sfda.gov.sa/npc

 

o    Other GCC States:

Please contact the relevant competent authority.

 

There is no information on overdosage with Vidonorm in humans.

 

Linked to perindopril

 

Limited data are available for overdose in humans. Symptoms associated with the overdose 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 sodium chloride 9 mg/ml (0.9%) 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 may 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.

 

Linked to amlodipine

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.

 

Pharmacotherapeutic group: ACE inhibitors and calcium channel blockers, ATC code: C09BB04

 

Linked to 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.

 

Clinical efficacy and safety 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.

 

An adjunctive therapy with a thiazide diuretic produces an additive-type of synergy. The combination of an ACE inhibitor and a thiazide also decreases the risk of hypokalaemia induced by the diuretic treatment.

 

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 (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 tertbutylamine 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.

 

Paediatric population:

 

The safety and efficacy of perindopril in children and adolescents aged below 18 years have not been established (see section 4.2).

In an open, non-comparative clinical study in 62 hypertensive children aged from 2 to 15 years with a glomerular filtration rate >30 ml/min/1.73 m², patients received perindopril with an average dose of

0.07 mg/kg. The dose was individualised according to the patient profile and blood pressure response up to a maximum dose of 0.135 mg/kg/day.

59 patients completed the period of three months, and 36 patients completed the extension period of the study, i.e. were followed at least 24 months (mean study duration: 44 months).

Systolic and diastolic blood pressure remained stable from the inclusion to the last assessment in patients previously treated by other antihypertensive treatments, and decreased in naïve patients. More than 75% of children had systolic and diastolic blood pressure below the 95th percentile at their last assessment.

The  safety  was  consistent  with   the   known   safety   profile   of   perindopril. Dual blockade of the renin-angiotensin-aldosterone system (RAAS) clinical trial data:

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.”

 

Linked to 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.

 

Use in patients with coronary artery disease (CAD):

 

The effectiveness of amlodipine in preventing clinical events in patients with coronary artery disease (CAD) has been evaluated in an independent, multi-center, randomized, double- blind, placebo- controlled study of 1997 patients; Comparison of Amlodipine vs. Enalapril to Limit Occurrences of Thrombosis (CAMELOT). Of these patients, 663 were treated with amlodipine 5- 10 mg, 673 patients were treated with enalapril 10-20 mg, and 655 patients were treated with placebo, in addition to standard care of statins, beta-blockers, diuretics and aspirin, for 2 years.

The key efficacy results are presented in Table 1. The results indicate that amlodipine treatment was associated with fewer hospitalizations for angina and revascularization procedures in patients with CAD.

 

Table 1. Incidence of significant clinical outcomes for CAMELOT
Cardiovascular event rates, No. (%)				Amlopidine vs. Placebo
Outcomes	Amlopidine	Placebo	Enalapril	Hazard Ratio (95% CI)	P Value
Primary Endpoint
Adverse cardiovascular events	110 (16.6)	151 (23.1)	136 (20.2)	0.69 (0.54- 0.88)	.003
Individual Components
Coronary revascularization	78 (11.8)	103 (15.7)	95 (14.1)	0.73 (0.54- 0.98)	.03
Hospitalization for angina	51 (7.7)	84 (12.8)	86 (12.8)	0.58 (0.41- 0.82)	.002
Nonfatal MI	14 (2.1)	19 (2.9)	11 (1.6)	0.73 (0.37- 1.46)	.37
Stroke or TIA	6 (0.9)	12 (1.8)	8 (1.2)	0.50 (0.19- 1.32)	.15
Cardiovascular death	5 (0.8)	2 (0.3)	5 (0.7)	2.46 (0.48- 12.7)	.27
Hospitalization for CHF	3 (0.5)	5 (0.8)	4 (0.6)	0.59 (0.14- 2.47)	.46
Resuscitated cardiac arrest	0	4 (0.6)	1 (0.1)	NA	.04
New-onset peripheral vascular disease	5 (0.8)	2 (0.3)	8 (1.2)	2.6 (0.50- 13.4)	.24

Abbreviations: CHF, congestive heart failure; CI, confidence interval; MI, myocardial infarction;

 

TIA, transient ischemic attack.

 

Use in patients with heart failure:

Haemodynamic studies and exercise based controlled clinical trials in NYHA Class II-IV heart failure patients have shown that amlodipine did not lead to clinical deterioration as measured by exercise tolerance, left ventricular ejection fraction and clinical symptomatology.

A placebo controlled study (PRAISE) designed to evaluate patients in NYHA Class III-IV heart failure receiving digoxin, diuretics and angiotensin-converting enzyme (ACE) inhibitors has shown that amlodipine did not lead to an increase in risk of mortality or combined mortality and morbidity in patients with heart failure.

In a follow-up, long-term, placebo controlled study (PRAISE-2) of amlodipine in patients with NYHA III and IV heart failure without clinical symptoms or objective findings suggestive of underlying ischaemic disease, on stable doses of ACE inhibitors, digitalis, and diuretics, amlodipine had no effect on total or cardiovascular mortality. In this same population amlodipine was associated with increased reports of pulmonary oedema.

 

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/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).

 

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. See section 4.2.

 

The rate and extent of absorption of perindopril and amlodipine from Vidonorm are not significantly different, respectively, from the rate and extent of absorption of perindopril and amlodipine from individual tablet formulations.

 

Linked to perindopril:

 

Absorption

After oral administration, the absorption of perindopril is rapid and the peak concentration is achieved within 1 hour. The plasma halflife 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 tert- butylamine 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. Distribution

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.

 

Elimination

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.

 

Special population

Elimination of perindoprilat is decreased in the elderly, and also in patients with heart or renal failure (see section 4.2). Dosage adjustment in renal insufficiency is desirable depending on the degree of impairment (creatinine clearance).

 

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).

 

Linked to amlodipine:

 

Absorption, distribution, plasma protein binding:

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. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.

The bioavailability of amlodipine is not affected by food intake. Biotransformation

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 with 10% of the parent compound and 60% of metabolites excreted in the urine.

 

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 older and younger subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half-life

 

in older 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 1 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/hr respectively in males and 16.4 and 21.3 l/hr respectively in females. Large variability in exposure between individuals was observed. Data reported in children below 6 years is limited. See section 4.2.

 

Linked to 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. Fertility was not impaired either in male or in female rats.

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

 

Linked to 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.

 

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 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.

 

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 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 the chromosome levels.

 

*Based on patient weight of 50 kg

Cellulose, microcrystalline, Polacrilin potassium,

Silica, hydrophobic colloidal, Magnesium stearate.

Not applicable.

 

3 years

This medicinal product does not require any special temperature storage conditions. Store in the original package in order to protect from light and moisture.

 

30 tablets are in PA/Aluminium/PVC // Aluminium blister and carton box

 

No special requirements.

 

Any unused medicinal product or waste material should be disposed of in accordance with local requirements