Apo-Perindopril/Amlodipine Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES ............................................................................................. 2

TABLE OF CONTENTS ............................................................................................................... 2

PART I: HEALTH PROFESSIONAL INFORMATION ....................................................................... 4

1 INDICATIONS .................................................................................................................... 4

1.1 Pediatrics (<18 years of age) ....................................................................................... 4

1.2 Geriatrics (> 65 years of age) ...................................................................................... 4

2 CONTRAINDICATIONS ....................................................................................................... 4

3 SERIOUS WARNINGS AND PRECAUTIONS BOX .................................................................. 5

4 DOSAGE AND ADMINISTRATION ....................................................................................... 5

4.1 Dosing Considerations ................................................................................................ 5

4.2 Recommended Dose and Dosage Adjustment ........................................................... 6

4.4 Administration ............................................................................................................ 6

4.5 Missed Dose ............................................................................................................... 6

5 OVERDOSAGE ................................................................................................................... 7

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING....................................... 7

7 WARNINGS AND PRECAUTIONS ........................................................................................ 8

7.1 Special Populations ................................................................................................... 15

7.1.1 Pregnant Women ..................................................................................................... 15

7.1.2 Breast-feeding .......................................................................................................... 15

7.1.3 Pediatrics .................................................................................................................. 15

7.1.4 Geriatrics .................................................................................................................. 16

7.1.5 Diabetic patients ...................................................................................................... 16

8 ADVERSE REACTIONS ...................................................................................................... 16

8.1 Adverse Reaction Overview ...................................................................................... 16

8.2 Clinical Trial Adverse Reactions ................................................................................ 16

8.3 Less Common Clinical Trial Adverse Reactions ......................................................... 18

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ................................................................................................................. 19

8.5 Post-Market Adverse Reactions ............................................................................... 19

9 DRUG INTERACTIONS ...................................................................................................... 20

9.3 Drug-Behavioural Interactions .................................................................................. 20

9.4 Drug-Drug Interactions ............................................................................................. 20

9.5 Drug-Food Interactions ............................................................................................. 27

9.6 Drug-Herb Interactions ............................................................................................. 27

9.7 Drug-Laboratory Test Interactions ............................................................................ 27

10 CLINICAL PHARMACOLOGY ............................................................................................. 27

10.1 Mechanism of Action ................................................................................................ 27

10.2 Pharmacodynamics .................................................................................................. 28

10.3 Pharmacokinetics ..................................................................................................... 29

11 STORAGE, STABILITY AND DISPOSAL ............................................................................... 32

12 SPECIAL HANDLING INSTRUCTIONS ................................................................................ 32

PART II: SCIENTIFIC INFORMATION ........................................................................................ 33

13 PHARMACEUTICAL INFORMATION ................................................................................. 33

14 CLINICAL TRIALS .............................................................................................................. 35

14.1 Clinical Trials by Indication ....................................................................................... 35

14.2 Comparative Bioavailability Studies.......................................................................... 40

15 MICROBIOLOGY .............................................................................................................. 42

16 NON-CLINICAL TOXICOLOGY ........................................................................................... 42

17 SUPPORTING PRODUCT MONOGRAPHS.......................................................................... 51

PATIENT MEDICATION INFORMATION ................................................................................... 52

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

APO-PERINDOPRIL/AMLODIPINE (perindopril arginine and amlodipine) is indicated for:

• The treatment of mild to moderate essential hypertension in patients for whom combination therapy is appropriate.
• APO-PERINDOPRIL/AMLODIPINE 3.5 mg/2.5 mg is indicated for initial therapy in patients with mild to moderate essential hypertension.
• APO-PERINDOPRIL/AMLODIPINE is not indicated for switching therapy from the individual drugs currently on the market (perindopril as erbumine or arginine salt, amlodipine) (see 4 DOSAGE AND ADMINISTRATION section).

1.1 Pediatrics (<18 years of age)

APO-PERINDOPRIL/AMLODIPINE is not indicated in pediatric patients <18 years of age. The efficacy and safety have not been studied in this population.

1.2 Geriatrics (> 65 years of age)

APO-PERINDOPRIL/AMLODIPINE is not indicated for the initiation of treatment in elderly patients. There is no sufficient clinical experience to justify the use in the elderly (> 65 years).

2 CONTRAINDICATIONS

APO-PERINDOPRIL/AMLODIPINE (perindopril arginine and amlodipine) is contraindicated in:

• Patients who are hypersensitive to the active ingredients of this drug, to any ingredient in the formulation or component of the container, to any other angiotensin converting enzyme inhibitor (ACE-inhibitor), or to any other dihydropyridine derivatives. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING
• Patients with renal impairment (creatinine clearance < 60 mL/min) (see 7 WARNINGS AND PRECAUTIONS, Renal).
• Patients with a history of hereditary/idiopathic angioedema, or angioedema related to previous treatment with an ACE-inhibitor (see 7 WARNINGS AND PRECAUTIONS, Immune).
• Women who are pregnant, intend to become pregnant, or of childbearing potential who are not using adequate contraception. (see 7 WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women).
• Nursing women (see 7 WARNINGS AND PRECAUTIONS, Special Populations, Breast-feeding).
• Patients with mitral valve stenosis and left ventricular outflow tract obstruction (e.g. aortic stenosis, hypertrophic cardiomyopathy).
• Patients with heart failure.
• Combination with sacubitril/valsartan due to an increased risk of angioedema. APO-PERINDOPRIL/AMLODIPINE must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan.
• Combination with aliskiren-containing drugs in patients with diabetes mellitus (type 1 or 2) or moderate to severe renal impairment (GFR < 60 mL/min/1.73 m²) (see 7 WARNINGS AND PRECAUTIONS, Dual Blockade of the Renin-Angiotensin System (RAS) and Renal and 9 DRUG INTERACTIONS, Dual Blockade of the Renin-Angiotensin System (RAS) with ACE inhibitors, ARBs or aliskiren-containing drugs).
• Patients with extracorporeal treatments leading to contact of blood with negatively charged surfaces (see 9 DRUG INTERACTIONS).
• Patients with bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney (see 7 WARNINGS AND PRECAUTIONS, Renal).

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

APO-PERINDOPRIL/AMLODIPINE is a combination product containing perindopril as an arginine salt (perindopril arginine) and amlodipine expressed as free base (amlodipine besylate) and is available in three fixed-dose perindopril arginine/amlodipine combinations of 3.5 mg / 2.5 mg, 7 mg / 5 mg, and 14 mg / 10 mg.

Dosages of the perindopril arginine in APO-PERINDOPRIL/AMLODIPINE are not marketed individually.

Patients cannot be titrated with the individual drugs currently on the market prior to the initiation of APO-PERINDOPRIL/AMLODIPINE, since dosages of perindopril arginine in APO-PERINDOPRIL/AMLODIPINE are not equivalent to those marketed individually (perindopril as erbumine or arginine salt).

4.2 Recommended Dose and Dosage Adjustment

The recommended starting dose of APO-PERINDOPRIL/AMLODIPINE is 3.5 mg / 2.5 mg once daily in hypertensive patients for whom combination therapy is appropriate.

After 4 weeks of treatment, the dose may be increased to 7 mg / 5 mg once daily in adult patients whose blood pressure is not at appropriate target.

If necessary, titration to 14 mg / 10 mg once daily may be considered in adult patients insufficiently controlled after 4 weeks of treatment with 7 mg / 5 mg.

Pediatrics (<18 years of age):

Health Canada has not authorized an indication for pediatric use.

Elderly (> 65 years of age):

APO-PERINDOPRIL/AMLODIPINE is not indicated for the initiation of treatment in elderly patients (> 65 years of age).

Hepatic Impairment:

APO-PERINDOPRIL/AMLODIPINE is not recommended in patients with hepatic impairment (see 7 WARNINGS AND PRECAUTIONS).

Renal Impairment:

APO-PERINDOPRIL/AMLODIPINE is contraindicated in patients with renal impairment (creatinine clearance <60 mL/min) (see 2 CONTRAINDICATIONS).

Use with Diuretics: In patients who are currently being treated with a diuretic, symptomatic hypotension can occur following the initial dose of APO-PERINDOPRIL/AMLODIPINE. Consider reducing the dose of diuretic prior to starting APO-PERINDOPRIL/AMLODIPINE (see 9 DRUG INTERACTIONS, Drug-Drug Interactions).

4.4 Administration

APO-PERINDOPRIL/AMLODIPINE should be taken as a single dose, preferably in the morning and before a meal.

4.5 Missed Dose

If a dose is missed, a double dose should not be taken, but just carry on with the next dose at the normal time.

5 OVERDOSAGE

There is no experience of overdose with perindopril arginine and amlodipine.

For perindopril, limited data are available for overdosage in humans. The most likely clinical manifestation would be symptoms attributable to severe hypotension.

The recommended treatment of overdosage is intravenous infusion of normal saline solution. If available, treatment with angiotensin II infusion and/or intravenous catecholamines may also be considered. Perindopril can be removed from the systemic circulation by haemodialysis (see 10 CLINICAL PHARMACOLOGY – Special Populations, Renal insufficiency). Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously.

For amlodipine, experience with overdosage in humans is limited.

Symptoms: available data suggest that overdosage could result in excessive peripheral vasodilatation with marked and probably prolonged hypotension and possibly reflex tachycardia. Shock and fatal outcome have been reported.

Non-cardiogenic pulmonary oedema has rarely been reported as a consequence of amlodipine overdose that may manifest with a delayed onset (24 to 48 hours post-ingestion) and require ventilatory support. Early resuscitative measures (including fluid overload) to maintain perfusion and cardiac output may be precipitating factors.

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. Since amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1– Dosage Forms, Strengths, Composition and Packaging

Dosage forms

APO-PERINDOPRIL/AMLODIPINE 3.5 mg / 2.5 mg tablets: white to off-white colored, round shaped, biconvex uncoated tablets engraved “3.5” on one side and “A2.5” on the other side.

APO-PERINDOPRIL/AMLODIPINE 7 mg / 5 mg tablets: white to off-white colored, round shaped biconvex uncoated tablets engraved “APO” on one side and “7 over 5” on the other side.

APO-PERINDOPRIL/AMLODIPINE 14 mg / 10 mg tablets: white to off-white colored, round shaped biconvex uncoated tablets engraved “APO” on one side and “14 over 10” on the other side.

Composition

One tablet of APO-PERINDOPRIL/AMLODIPINE 3.5 mg / 2.5 mg contains 3.5 mg perindopril arginine and 2.5 mg amlodipine.

One tablet of APO-PERINDOPRIL/AMLODIPINE 7 mg / 5 mg contains 7 mg perindopril arginine and to 5 mg amlodipine.

One tablet of APO-PERINDOPRIL/AMLODIPINE 14 mg / 10 mg contains 14 mg perindopril arginine and 10 mg amlodipine.

Packaging

APO-PERINDOPRIL/AMLODIPINE 3.5 mg / 2.5 mg tablets & APO-PERINDOPRIL/AMLODIPINE 7 mg / 5 mg tablets are available in blister packages of 100’s (10x10) and bottles containing 30, 100, and 500 tablets.

APO-PERINDOPRIL/AMLODIPINE 14 mg / 10 mg tablets are available in blister packages of 100’s (10x10) and bottles containing 30, 100, and 500 tablets.

7 WARNINGS AND PRECAUTIONS

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

Cardiovascular

Aortic and mitral valve stenosis / hypertrophic cardiomyopathy

APO-PERINDOPRIL/AMLODIPINE is contraindicated in patients with mitral valve stenosis and obstruction in the outflow tract of the left ventricle such as aortic stenosis or hypertrophic cardiomyopathy.

Dual blockade of the Renin-Angiotensin System (RAS)

There is evidence that co-administration of angiotensin converting enzyme (ACE) inhibitors, such as the perindopril component of APO-PERINDOPRIL/AMLODIPINE, or of angiotensin receptor antagonists (ARBs) with aliskiren increases the risk of hypotension, syncope, stroke, hyperkalemia and deterioration of renal function, including renal failure, in patients with diabetes mellitus (type 1 or type 2) and/or moderate to severe renal impairment (GFR < 60 mL/min/1.73 m²). Therefore, the use of APO-PERINDOPRIL/AMLODIPINE in combination with aliskiren-containing drugs is contraindicated in these patients (see 2 CONTRAINDICATIONS).

Further, co-administration of ACE inhibitors, including the perindopril component of APO-PERINDOPRIL/AMLODIPINE, with other agents blocking the RAS, such as ARBs or aliskiren-containing drugs, is generally not recommended in other patients, since such treatment has been associated with an increased incidence of severe hypotension, renal failure, and hyperkalemia (see 9 DRUG INTERACTIONS).

Hypotension

APO-PERINDOPRIL/AMLODIPINE can cause symptomatic hypotension. 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, diarrhea or vomiting), or who have severe renin-dependent hypertension. In patients at high risk of symptomatic hypotension, blood pressure, renal function and serum potassium should be monitored closely during treatment with APO-PERINDOPRIL/AMLODIPINE.

Similar considerations apply to patients with ischemic 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.

Peripheral Oedema

Mild to moderate peripheral oedema was the most common adverse event in the clinical trials with amlodipine. The incidence of peripheral oedema was dose-dependent and ranged in frequency from 3.0 to 10.8% in 5 to 10 mg dose range. Peripheral oedema is also one of the most frequently occurring adverse drug reactions that resulted in discontinuation of perindopril arginine and amlodipine. Care should be taken to differentiate this peripheral oedema from the effects of increasing left ventricular dysfunction.

Patients with Heart Failure

Patients with heart failure were excluded from the clinical trials for perindopril arginine and amlodipine. APO-PERINDOPRIL/AMLODIPINE should not be used in patients with congestive heart failure.

Hypertensive Crisis

The safety and efficacy of perindopril arginine and amlodipine in hypertensive crisis has not been established.

Increased Angina and/or Myocardial Infarction

Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of APO-PERINDOPRIL/AMLODIPINE, particularly in patients with severe obstructive coronary artery disease.

Primary aldosteronism

Patients with primary aldosteronism generally will not respond to anti-hypertensive drugs acting through inhibition of the RAS. Therefore, the use of APO-PERINDOPRIL/AMLODIPINE is not recommended in these patients.

Driving and Operating Machinery

Perindopril and amlodipine can have minor or moderate influence on the ability to drive and use machines. If patients suffer from dizziness, headache, fatigue, weariness or nausea, the ability to react may be impaired. Caution is recommended with APO-PERINDOPRIL/AMLODIPINE especially at the start of treatment.

Endocrine and Metabolism

Hyperkalemia

Monitor serum potassium periodically in patients receiving APO-PERINDOPRIL/AMLODIPINE.

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 dehydration, acute cardiac decompensation, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene, or amiloride, alone or in combination), potassium supplements or potassium-containing salt substitutes; or those patients taking other drugs associated with increases in serum potassium (e.g. heparin, other ACE inhibitors, ARBs, cyclooxygenase-2 (COX-2) inhibitors and non-selective non-steroidal anti-inflammatory drugs (NSAIDs), immunosuppressant agents such as cyclosporine or tacrolimus, trimethoprim and fixed dose combination with sulfamethoxazole).

APO-PERINDOPRIL/AMLODIPINE is not recommended for concomitant use with potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes, particularly in patients with impaired renal function (see 9 DRUG INTERACTIONS, Drug-Drug Interactions).

Hyperkalemia (serum potassium >5.5 mEq/L) can cause serious, sometimes fatal arrhythmias. If concomitant use of APO-PERINDOPRIL/AMLODIPINE and any of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium.

Hematologic

Neutropenia/Agranulocytosis/Thrombocytopenia/Anaemia

Neutropenia/agranulocytosis, thrombocytopenia and anemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia occurs rarely. APO-PERINDOPRIL/AMLODIPINE 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 APO-PERINDOPRIL/AMLODIPINE 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) to their physician (see 7 WARNINGS AND PRECAUTIONS - Monitoring and Laboratory Tests section).

Hepatic/Biliary/Pancreatic

Patients with Impaired Liver Function

Increases in serum transaminase and/or bilirubin levels, cholestatic jaundice and cases of hepatocellular injury with or without cholestasis have occurred during ACE inhibitor therapy, even in patients with no pre-existing liver disease. Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death.

In a small number of patients with mild to moderate hepatic impairment given single dose of 5 mg, amlodipine half-life has been prolonged.

APO-PERINDOPRIL/AMLODIPINE is not recommended in patients with impaired liver.

Immune

Angioedema – Head, and Neck or Extremities

Angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx has been reported in patients treated with ACE inhibitors, including perindopril. This may be life-threatening and occur at any time during therapy. In such cases, APO-PERINDOPRIL/AMLODIPINE 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 and may be fatal, emergency therapy should be administered promptly. This may include the administration of epinephrine (e.g., 0.3 to 0.5 mL of subcutaneous epinephrine solution 1:1000) 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 APO-PERINDOPRIL/AMLODIPINE (see 2 CONTRAINDICATIONS).

Concomitant use of mTOR inhibitors, DPP-IV inhibitors and NEP inhibitors

Patients taking a concomitant mTOR inhibitor (e.g. sirolimus, everolimus, temsirolimus), DPP-IV inhibitor (e.g. sitagliptin, linagliptin, saxagliptin) or neutral endopeptidase (NEP) inhibitor may be at increased risk for angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment). Caution should be used when initiating ACE inhibitor therapy in patients already taking a mTOR, DPP-IV or NEP inhibitor or vice versa (see 9 DRUG INTERACTIONS).

Intestinal Angioedema

Intestinal angioedema has been reported 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 history of facial angioedema and C-1 esterase levels were normal.

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.

Anaphylactoid Reactions during Low-Density Lipoproteins (LDL) Apheresis

Rarely, patients receiving ACE inhibitors during 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 been avoided when the ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.

Anaphylactoid Reactions during Membrane Exposure (hemodialysis patients)

Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes (e.g. polyacrylonitrile [PAN]) and treated concomitantly with an ACE inhibitor. Dialysis should be stopped immediately if symptoms such as nausea, abdominal cramps, burning, angioedema, shortness of breath and severe hypotension occur. Symptoms are not relieved by antihistamines. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agents.

Nitritoid Reactions – Gold

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting, and symptomatic hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including perindopril arginine and amlodipine (see 9 DRUG INTERACTIONS).

Monitoring and Laboratory Tests

Hematological monitoring

It is recommended that the white blood cell count be monitored to permit detection of a possible leukopenia.

Renal function monitoring

Use of APO-PERINDOPRIL/AMLODIPINE should include appropriate assessment of renal function, particularly in the first few weeks of treatment after initiation of therapy, or up titration. Potassium and creatinine should be monitored periodically thereafter.

Serum Electrolyte monitoring

It is recommended that serum potassium and serum sodium be monitored regularly. More frequent monitoring of serum potassium is necessary in patients with impaired renal function.

Peri-Operative Considerations

Surgery/anesthesia

In patients undergoing major surgery or during anesthesia with agents that produce hypotension, perindopril may block angiotensin II formation secondary to compensatory renin release. APO-PERINDOPRIL/AMLODIPINE 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.

Race

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

ACE inhibitors are generally 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.

Renal

Impaired Renal Function

APO-PERINDOPRIL/AMLODIPINE is contraindicated in patients with renal impairment (creatinine clearance < 60 mL/min) (see 2 CONTRAINDICATIONS).

As a consequence of inhibiting the renin-angiotensin-aldosterone system (RAAS), changes in renal function may be anticipated in susceptible individuals treated with APO-PERINDOPRIL/AMLODIPINE. Potassium and creatinine should be monitored in patients treated with APO-PERINDOPRIL/AMLODIPINE.

The use of ACE inhibitors, including perindopril which is a component of APO-PERINDOPRIL/AMLODIPINE, or ARBs with aliskiren-containing drugs is contraindicated in patients with moderate to severe renal impairment (GFR < 60 mL/min/1.73 m²) (See 2 CONTRAINDICATIONS and 9 DRUG INTERACTIONS, Dual Blockade of the Renin-Angiotensin-System (RAS) with ARBs, ACE inhibitors, or aliskiren-containing drugs).

Hypertensive Patients with Renal Artery Stenosis

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 nitrogen (BUN) 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 BUN 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.

Renovascular hypertension

There is an increased risk of hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with ACE inhibitors (see 2 CONTRAINDICATIONS). Treatment with diuretics may be a contributory factor. Loss of renal function may occur with only minor changes in serum creatinine even in patients with unilateral renal artery stenosis.

Kidney transplantation

Since there is no experience regarding the administration of perindopril arginine and amlodipine in patients with a recent kidney transplantation, treatment with APO-PERINDOPRIL/AMLODIPINE is therefore not recommended.

Reproductive Health: Female and Male Potential

Sexual Function/Reproduction

Reversible biochemical changes in the head of spermatozoa have been reported in some patients treated by calcium channel blockers. Clinical data are insufficient regarding the potential effect of amlodipine on fertility. In one rat study, adverse effects were found on male fertility (see 16 NON-CLINICAL TOXICOLOGY, Reproductive and developmental toxicity).

Respiratory

Cough

Cough has been reported with the use of perindopril arginine and amlodipine. Characteristically, the cough is dry, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.

Skin

Dermatological reactions characterised by maculo-papular pruritic rashes and sometimes photosensitivity has been reported with another ACE inhibitor. Rare and sometimes severe skin reactions (lichenoid eruptions, psoriasis, pemphigus like rash, rosacea, Stevens-Johnson syndrome, etc) have occurred.

Patients who develop a cutaneous reaction with one ACE inhibitor might not when switched to another drug of the same class, but there are reports of cross-reactivity.

Stevens-Johnson syndrome occurred in ≤ 0.1% of patients in clinical trials with amlodipine.

7.1 Special Populations

7.1.1 Pregnant Women

ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. APO-PERINDOPRIL/AMLODIPINE is contraindicated during pregnancy.

Patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is detected, treatment with APO-PERINDOPRIL/AMLODIPINE should be stopped immediately, and an alternative therapy should be started.

7.1.2 Breast-feeding

The presence of ACE inhibitor in human milk has been reported. Amlodipine is excreted in human milk. The minimum proportion of the maternal dose received by the infant has been estimated to be between 3 and 15% and this might vary according to breastmilk composition. The effect of amlodipine on infants is unknown. The use of APO-PERINDOPRIL/AMLODIPINE is contraindicated during breastfeeding (see 2 CONTRAINDICATIONS).

7.1.3 Pediatrics (< 18 years of age)

The safety and effectiveness of perindopril arginine and amlodipine in patients below the age of 18 have not been established. Therefore, use in this age group is not recommended.

7.1.4 Geriatrics (> 65 years of age)

APO-PERINDOPRIL/AMLODIPINE is not indicated for the initiation of treatment in the elderly (> 65 years) patients. Greater sensitivity of some older individuals cannot be ruled out.

7.1.5 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 APO-PERINDOPRIL/AMLODIPINE (see 9 DRUG INTERACTIONS, Drug-Drug Interactions).

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

The following adverse reactions were the most frequently reported during clinical trials: cough, dizziness, headache, and oedema.

The most serious adverse reactions reported during clinical trials were: hypotension, lip swelling, and renal failure acute.

The adverse drug reactions most frequently resulting in clinical intervention (discontinuation of perindopril arginine and amlodipine) were due to cough, erythema, fatigue, and peripheral oedema.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

CL2-005 study

The most frequent adverse events during the 8-week placebo-controlled study CL2-005 are presented in Table 2.

Table 2 - Most Frequently Reported Emergent Adverse Events (≥ 1%)

Aml: Amlodipine; Per: Perindopril

PATH study

The most frequent emergent adverse events (EAEs) during the 6-week active controlled PATH study are presented in Table 3.

Table 3 - Most Frequently Reported Emergent Adverse events (≥ 1%)

Aml: Amlodipine; EAE: Emergent Adverse Event; PERa: Perindopril arginine; PERe: Perindopril erbumine

8.3 Less Common Clinical Trial Adverse Reactions (<1%)

The following adverse drug reactions occurred in patients treated with perindopril arginine and amlodipine in randomized, double-blind controlled trials (<1% but >0.1%):

Blood and lymphatic system disorders: leukopenia, thrombocytopenia

Cardiac disorders: angina pectoris, atrial fibrillation, chest pain, myocardial infarction, sinus tachycardia

Gastrointestinal disorders: constipation, diarrhea, dry mouth, vomiting

General disorders and administration site conditions: asthenia

Immune system disorders: angioedema, dermatitis allergic, pruritus allergic

Investigations: creatinine renal clearance decreased, gamma-glutamyltransferase increased

Musculoskeletal and connective tissue disorders: arthralgia, muscle spasms, myalgia

Nervous system disorders: cerebrovascular accident, ischemic stroke, syncope, transient ischemic attack

Psychiatric disorders: insomnia, depression

Reproductive system and breast disorders: erectile dysfunction

Skin and subcutaneous tissue disorders: hyperhidrosis

Vascular disorders: hot flush, hypotension, orthostatic hypotension

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

The following were observed in patients treated with perindopril:

• Abnormal liver function test
• Hyperkalemia
• Increases in blood creatinine, BUN, serum cholesterol and plasma glucose.
• Decreases in hematocrit and hemoglobin.

8.5 Post-Market Adverse Reactions

The most commonly reported adverse reactions with perindopril and amlodipine given separately are: abdominal pain, change of bowel habits, dysgeusia, dyspepsia, dyspnea, exanthema, joint swelling (ankle swelling), palpitations, paraesthesia, prurit, somnolence, tinnitus, vertigo, visual impairment (including diplopia).

The other adverse drug reactions previously reported during clinical trials and/or post-marketing experience with one of the individual components of perindopril arginine and amlodipine are listed below since they may occur with the fixed-dose combination:

Blood and lymphatic system disorders: agranulocytosis or pancytopenia, eosinophilia, leukopenia/neutropenia, haemolytic anaemia enzyme specific in patients with a congenital deficiency of G-6PDH

Cardiac disorders: arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), tachycardia

Endocrine disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Gastrointestinal disorders: gastritis, gingival hyperplasia, pancreatitis

General disorders and administration site conditions: chest pain, malaise, pain, pyrexia

Hepato-biliary disorders: hepatitis, hepatitis either cytolytic or cholestatic, jaundice

Immune system disorders: hypersensitivity

Infections and infestations: rhinitis

Injury, poisoning and procedural complications: fall

Investigations: blood bilirubin increased, blood urea increased, hepatic enzyme increased, weight decreased, weight increased

Metabolism and nutrition disorders: hyperglycaemia, hypoglycaemia, hyponatraemia

Nervous system disorders: cerebrovascular accident possibly secondary to excessive hypotension in high-risk patients, extrapyramidal disorder (extrapyramidal syndrome), hypoaesthesia, hypertonia, neuropathy peripheral, tremor

Psychiatric disorders: confusional state, mood altered (including anxiety), sleep disorder, depression

Renal and urinary disorders: micturition disorder, nocturia, renal failure, anuria/oliguria

Reproductive system and breast disorders: gynaecomastia

Respiratory, thoracic and mediastinal disorders: bronchospasm, eosinophilic pneumonia

Skin and subcutaneous tissue disorders: alopecia, angioedema of face, extremities, lips, mucous membranes, tongue, glottis and/or larynx, erythema multiforme, exfoliative dermatitis, pemphigoid, photosensitivity reaction, psoriasis aggravation, purpura, Quincke’s oedema, skin discolouration, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticarial

Vascular disorders: Raynaud’s phenomenon, vasculitis, flushing

9 DRUG INTERACTIONS

9.3 Drug-Behavioural Interactions

Lifestyle interactions have not been established.

9.4 Drug-Drug Interactions

Table 4 - Established or Potential Concomitant Drug-Drug Interactions

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical.

9.5 Drug-Food Interactions

Administration of APO-PERINDOPRIL/AMLODIPINE with grapefruit or grapefruit juice is not recommended as amlodipine bioavailability may be increased in some patients resulting in increased blood pressure lowering effects.

9.6 Drug-Herb Interactions

The concomitant use of CYP3A4 inducers such as St. John’s wort (hypericum perforatum) may give a lower plasma concentration of amlodipine. Consider dose regulation both during and after concomitant medication particularly with strong CYP3A4 inducers. APO-PERINDOPRIL/AMLODIPINE should be used with caution together with CYP3A4 inducers.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory products/methods have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

APO-PERINDOPRIL/AMLODIPINE combines two compounds: amlodipine belonging to the dihydropyridine calcium antagonist (calcium channel blocker) class and perindopril belonging to the angiotensin converting enzyme (ACE) inhibitor class of medicines.

Perindopril

Following oral administration, perindopril is rapidly hydrolysed to perindoprilat, its principal active metabolite. ACE catalyzes the conversion of angiotensin I to the vasoconstrictor substance angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex.

Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and decreased aldosterone secretion. The latter change may result in a small increase in serum potassium (see 7 WARNINGS AND PRECAUTIONS - Endocrine and Metabolism).

Decreased levels of angiotensin II and the accompanying lack of negative feedback on renin secretion leads to increased plasma renin activity.

ACE is identical to kininase II, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of perindopril arginine and amlodipine remains to be elucidated.

The mechanism through which perindopril lowers blood pressure appears to be primarily suppression of the renin-angiotensin-aldosterone system (RAAS).

Amlodipine

Amlodipine is a calcium ion influx inhibitor (calcium entry blocker or calcium ion antagonist). Amlodipine is a member of the dihydropyridine class of calcium antagonists. The therapeutic effect of this group of drugs is believed to be related to their specific cellular action of selectively inhibiting transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells.

Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound, and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

10.2 Pharmacodynamics

Perindopril

In most patients with mild to moderate essential hypertension, administration of 4 to 8 mg daily of perindopril erbumine (equivalent to 5 to 10 mg/day perindopril arginine) results in a reduction of both supine and standing blood pressure with little or no effect on heart rate. Antihypertensive activity commences within 1 hour with peak effects usually achieved by 4 to 6 hours after dosing. At recommended doses given once daily, antihypertensive effects persist over 24 hours. The blood pressure reductions observed at trough plasma concentration were 75 to 100% of peak effects.

Amlodipine

Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. With chronic once daily oral administration (5 and 10 mg once daily), antihypertensive effectiveness is maintained throughout the 24 hours dose interval with minimal peak to trough differences in plasma concentration.

Negative inotropic effects have not been observed when amlodipine was administered at the recommended doses to man but has been demonstrated in animal models. Hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in angina patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume.

Amlodipine does not change sinoatrial (SA) nodal function or atrioventricular (AV) conduction in intact animals or humans. In clinical studies in which amlodipine was administered in combination with β-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed.

10.3 Pharmacokinetics

The rate and extent of absorption of perindopril and amlodipine from perindopril arginine and amlodipine tablets are not significantly different from the rate and extent of absorption of perindopril and amlodipine from individual tablet formulations.

Table 5 - Summary of Perindopril/Perindoprilat and Amlodipine’s Pharmacokinetic Parameters (Geometric Mean (CV%)) Following Single Administration of Perindopril Arginine and Amlodipine (14 mg/10 mg) in Healthy Volunteers (PKH-05985-009)

* : median and range

Perindopril

Absorption

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

About 25% of the administered perindopril dose reaches the bloodstream as the active metabolite perindoprilat. The peak plasma concentration of perindoprilat is in about 4 hours after oral administration of perindopril.

As ingestion of food decreases the extent of biotransformation of perindopril to perindoprilat, hence bioavailability, perindopril arginine should be administered orally in a single daily dose in the morning before a meal.

Distribution

The volume of distribution is approximately 0.5 L/kg for unbound perindoprilat. Plasma protein binding of perindoprilat is 10 to 35%, principally to angiotensin converting enzyme, but is concentration dependent.

Metabolism

Perindopril is extensively metabolised following oral administration, with only 4 to 12% of the dose recovered unchanged in the urine. In addition to active perindoprilat, perindopril yields five other metabolites (perindopril glucuronide, perindoprilat glucuronide, a perindopril lactam, and two perindoprilat lactams), all inactive.

The two main circulating metabolites of perindopril are perindoprilat and perindoprilat glucuronide.

Elimination

The terminal plasma half-life of perindopril is 1.2 hour. Perindoprilat is eliminated in the urine and the terminal half-life of the unbound fraction is approximately 17 hours, resulting in steady-state within 3 to 4 days.

Amlodipine

Absorption

After oral administration of therapeutic doses, absorption of amlodipine occurs gradually with peak plasma concentration reached between 6 to 12 hours. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of amlodipine is not affected by food intake.

Distribution

The volume of distribution is approximately 21 L/kg. Ex vivo studies have shown that approximately 93% of circulating amlodipine is bound to plasma proteins.

Metabolism

Amlodipine is extensively (about 90%) metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of the metabolites excreted in the urine.

Elimination

The terminal plasma elimination half-life is about 35 to 50 hours. Steady state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.

Special Populations and Conditions

• Pediatrics (<18 years of age) No pharmacokinetic data are available in the pediatric population.
• Geriatrics (>65 years of age) Elimination of perindoprilat is decreased in the elderly. In elderly patients, amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half-life.
• Sex The effectiveness of perindopril arginine and amlodipine was not influenced by gender.
• Genetic Polymorphism Pharmacokinetics differences due to genetic polymorphism have not been studied.
• Ethnic Origin The blood pressure lowering effects of ACE inhibitors generally are lower in black persons than Caucasian patients. The cardiovascular benefits of ACE inhibitors, in terms of risk reduction in coronary artery disease, have not been extensively studied in blacks.

• Hepatic Insufficiency APO-PERINDOPRIL/AMLODIPINE is not recommended in patients with impaired liver function (see 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic).

  The bioavailability of perindoprilat is increased in patients with impaired hepatic function. Plasma concentrations in patients with hepatic impairment were about 50% higher than those observed in healthy subjects or hypertensive patients with normal liver function.

  Following single oral administration of 5 mg of amlodipine, patients with chronic mild to moderate hepatic insufficiency showed about 40% increase in AUC of amlodipine as compared to normal volunteers. The terminal elimination half-life of amlodipine was prolonged from 34 hours in young normal subjects to 56 hours in the elderly patients with hepatic insufficiency.

• Renal Insufficiency In patients with renal insufficiency, perindoprilat AUC increases with decreasing renal function. At creatinine clearances of 30 to 80 mL/min, AUC is about double that of 100 mL/min. When creatinine clearance drops below 30 mL/min, AUC increases more markedly.

  Therefore, APO-PERINDOPRIL/AMLODIPINE is contraindicated in patients with renal impairment (creatinine clearance < 60 mL/min) (see 2 CONTRAINDICATIONS, 7 WARNINGS and PRECAUTIONS - Renal).

  Perindopril and perindoprilat are dialyzable.

  The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Plasma concentrations of amlodipine in the patients with moderate to severe renal failure were higher than in the normal subjects. Amlodipine is not dialyzable.

11 STORAGE, STABILITY AND DISPOSAL

Store between 15°C to 30°C. Protect from light and moisture.

12 SPECIAL HANDLING INSTRUCTIONS

Not Applicable.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

APO-PERINDOPRIL/AMLODIPINE is a combination of perindopril arginine and amlodipine besylate.

Drug Substance

Perindopril

	pKa1 = 3.17± 0.20; pKa = 5.67 ± 0.39.

Amlodipine

Proper name:	Amlodipine besylate
Chemical name:	1. (±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridine dicarboxylic acid 3-ethyl 5-methyl ester, benzenesulfonic acid salt. 2. (±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5- methoxycarbonyl- 6-methyl1, 4-dihydropyridine,benzenesulfonic acid salt; 3. 3,5-pyridinecarboxylic acid, 2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-, 3-ethyl 5-methyl ester, (±)-, monobenzenesulfonate; 4. 3-ethyl 5-methyl(±)-2-[(2-aminoethoxy)methyl]-4-(o-chlorophenyl) 1,4-dihydro-6-methnyl-3,5-pyridinedicarboxylate, Monobenzenesulfonate. 5. 3-ethyl 5-methyl (4RS)-2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl)-6-methnyl-1,4-dihydropyridine-3,5-dicarboxylate benzenesulfonate.
Molecular formula and molecular mass:	C20H25ClN2O5.C6H5SO3H 567.1 g/mol
Structural formula:
Physicochemical properties:	Amlodipine besylate is a white or almost white powder. Amlodipine besylate is soluble in water. M.P.= 202°C. The pKa = 8.6

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

Study CL2-005

In this 8-week randomized, double-blind, placebo-controlled, parallel group factorial study, a total of 1581 patients with mild to moderate uncomplicated essential hypertension (i.e. not at high cardiovascular risk and without target organ damages, 95 mmHg ≤ supine diastolic blood pressure (DBP) < 110 mmHg and 150 mmHg ≤ supine systolic blood pressure (SBP) <180 mmHg, mean baseline SBP/ DBP was 161/101 mmHg) received treatment with perindopril arginine 3.5 mg/amlodipine 2.5 mg, perindopril arginine 3.5 mg, perindopril arginine 5 mg, amlodipine 2.5 mg, amlodipine 5 mg, or placebo. The mean age of the population was 52 years with most patients (86.7%) <65 years, 47% were male, mean BMI was 26.8 kg/m², 98.6% were Caucasian, and 1.1% were Black. The mean time since diagnosis of hypertension was 4 years and 8 months. There were 965 (39%) patients who did not receive treatment for hypertension prior to the selection. No patients included had a history of diabetes.

Table 6 - Summary of Patient Demographics and Trial Design for Study CL2-005

AML: Amlodipine; F: Female; M: Male; PERa: Perindopril arginine; SD: Standard deviation

PATH Study

The highest strength of perindopril arginine/amlodipine (14 mg/10 mg) was studied in a randomised, double-blind, active controlled trial in hypertensive patients (mean seated DBP ≥ 95 and ≤ 115 mmHg, mean seated SBP< 180 mmHg, and the mean baseline SBP/DBP was 158/101 mmHg).

A total of 837 U.S. hypertensive patients received treatments of perindopril arginine 14 mg/amlodipine 10 mg (n=271), perindopril erbumine 16 mg (n=274, corresponding to 20 mg of perindopril arginine), or amlodipine 10 mg (n=275) once daily for 6 weeks. The mean age of the population was 51 years with most of the patients (92.8%) having <65 years, 51% of patients were male, and 34% were Black. Overall, 20% of the population had type 2 diabetes. The population was largely obese with the mean BMI equal to 33.1 kg/m². There were 270 (32%) patients who did not receive treatment for hypertension prior to selection. Patients with renal insufficiency were not allowed to take part in this study.

Table 7 - Summary of Patient Demographics and Trial Design for PATH Study

AML: Amlodipine; F: Female; M: Male; PERa: Perindopril arginine; PERe: Perindopril erbumine; SD: Standard deviation

Study CL2-005

Perindopril 3.5 mg/amlodipine 2.5 mg was superior to placebo on reducing SBP/DBP (estimate of the difference of the change from baseline to last post-baseline value was -7.2/-4.1 mmHg, p<0.001 for both). The controlled rate (SBP<140 mmHg and DBP<90 mmHg) by perindopril 3.5 mg/amlodipine 2.5 mg was superior to placebo (43.5% versus 26.6%, p<0.001).

Perindopril 3.5 mg/amlodipine 2.5 mg was superior to perindopril 3.5 mg and amlodipine 2.5 mg administered separately on reducing SBP/DBP (estimate of the difference of SBP/DBP reduction between treatments was -5.0/-3.6 mmHg and -5.2/-3.0 mmHg as compared to perindopril 3.5 mg and amlodipine 2.5 mg, respectively, p<0.001 for all comparisons).

See results summarized in Tables 8 & 9.

Table 8 - Study CL2-005 - SBP - Superiority of Perindopril 3.5 mg/Amlodipine 2.5 mg as Compared to Placebo, Perindopril 3.5 mg, and Amlodipine 2.5 mg

Table 9 - Study CL2-005 - DBP - Superiority of Perindopril 3.5 mg/Amlodipine 2.5 mg as Compared to Placebo, Perindopril 3.5 mg, and Amlodipine 2.5 mg

Superiority tests of Per 3.5/Aml 2.5 as compared to reference treatment (Placebo, Per 3.5, Aml 2.5); One-sided type I error rate: 0.025

(1) Estimate of the difference between baseline and centre adjusted treatment group means: Per 3.5/Aml 2.5 minus reference treatment

(2) 95% Confidence interval of the estimate

(3) General linear model with baseline as covariate and centre as random factor

* For patients with a last post-baseline value not under treatment but with a post-baseline value under treatment, the last post-baseline value under treatment was taken into account

Aml: Amlodipine; CI: Confidence interval; DBP: Diastolic blood pressure; Per: Perindopril; SD: Standard deviation

Perindopril 3.5 mg/amlodipine 2.5 mg was non inferior to perindopril 5 mg and amlodipine 5 mg administered separately on reducing SBP/DBP: estimate of the difference of SBP/DBP reduction between treatments was -2.8/-2.6 mmHg, in comparison to perindopril 5 mg (p<0.001 for both) and -0.3/-0.8 mmHg in comparison to amlodipine 5 mg (p≤0.003 for all). See results summarized in Tables 10 & 11.

Perindopril 3.5 mg/amlodipine 2.5 mg presented a better controlled rate than perindopril 5 mg (43.5% versus 33.3%, p=0.018, 95% CI÷ [1.8; 18.5]) and a trend toward a better controlled rate than amlodipine 5 mg (43.5% versus 37.9%, p=0.202, 95% CI÷ [-3.0; 14.1]).

Table 10 - Study CL2-005 - SBP - Non inferiority of Perindopril 3.5 mg/Amlodipine 2.5 mg as Compared to Perindopril 5 mg and- Amlodipine 5 mg

Aml: Amlodipine; CI: Confidence interval; Per: Perindopril; SBP: Systolic blood pressure; SD: Standard deviation

Table 11 - Study CL2-005 - DBP - Non inferiority of Perindopril 3.5 mg/Amlodipine 2.5 mg as Compared to Perindopril 5 mg and Amlodipine 5 mg

Non-inferiority tests of Per 3.5/Aml 2.5 as compared to reference treatment (Per 5, Aml 5); Non-inferiority limit: 2 mmHg for DBP -3 mmHg for SBP; One-sided type I error rate: 0.025

(1) Estimate of the difference between baseline and centre adjusted treatment group means: Per 3.5/Aml 2.5 minus reference treatment

(2) 95% Confidence interval of the estimate

(3) General linear model with baseline as covariate and centre as random factor

* For patients with a last post-baseline value not under treatment but with a post-baseline value under treatment, the last post-baseline value under treatment was taken into account

Aml: Amlodipine; CI: Confidence interval; DBP: Diastolic blood pressure; Per: Perindopril; SD: Standard deviation

There were 1297 patients (among the 1581 randomized patients from the CL2-005 study) who participated in the sub-study on ambulatory blood pressure monitoring (ABPM). Results of the ABPM sub-study were consistent with those of the main study. The SBP and DBP lowering effect of the perindopril 3.5 mg/amlodipine 2.5 mg combination was statistically significantly greater over the 24- hour period than that of placebo, Perindopril 3.5 mg, Perindopril 5 mg, Amlodipine 2.5 mg and similar to Amlodipine 5 mg.

Figure 1 displayed below illustrates the efficacy of the Perindopril 3.5 mg / Amlodipine 2.5 mg fixed dose combination over placebo during the overall 24-h period at week 8.

Figure 1 – Study CL2-005 – ABPM - Hourly Means of SBP/DBP (mmHg) at Week 8 (N=1073)

PATH Study

Treatment with the fixed dose combination perindopril arginine 14 mg/amlodipine 10 mg produced mean blood pressure reductions of 22.8/15.4 mmHg SBP/DBP, compared to 18.8/12.9 mmHg for amlodipine 10 mg, and 12.7/9.1 mmHg for perindopril erbumine16 mg (corresponding to perindopril arginine 20 mg). Treatment with perindopril arginine 14 mg/amlodipine 10 mg resulted in significantly and clinically greater SBP (-4.0 mmHg vs amlodipine 10 and -10.1 mmHg vs perindopril erbumine 16 mg) and DBP (-2.5 mmHg vs amlodipine 10 and -6.3 mmHg vs perindopril erbumine 16 mg) reductions (p<0.001 and p< 0.01 respectively) and significantly higher control rates (51%) (defined as SBP/DBP < 140/90 mmHg for non-diabetics and < 130/80 mmHg for diabetics) compared to amlodipine 10 mg (37%, p=0.001) and perindopril erbumine16 mg (26%, p<0.001).

See results summarized in Tables 12, 13.

Table 12 - PATH Study-Change from Baseline in Systolic Blood Pressure (mmHg)

Table 13 - PATH Study-Change from Baseline in Diastolic Blood Pressure (mmHg)

Aml: Amlodipine; CI: Confidence interval; LS: Least square; PERa: Perindopril arginine; PERe: Perindopril erbumine; DBP: Diastolic blood pressure; SD: Standard deviation; SE: Standard error

14.2 Comparative Bioavailability Studies

A randomized, single-dose, blinded, 2-way crossover comparative bioavailability study was conducted under fasting conditions on healthy Asian male volunteers 20 to 42 years of age (n=22). The rate and extent of absorption of perindopril and amlodipine was measured and compared following a single oral dose (1 x 14 / 10 mg tablet) of APO-PERINDOPRIL/AMLODIPINE (Perindopril arginine & Amlodipine Besylate) 14 / 10 mg tablet (Apotex Inc.) and VIACORAM^® (Perindopril arginine & Amlodipine besylate) 14 / 10 mg Tablet (Servier Canada Inc.). The results from measured data in 20 subjects are summarized in the following tables.

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA: PERINDOPRIL DATA

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA: AMLODIPINE DATA

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

Perindopril arginine

The toxicological evaluation of perindopril arginine is based on the overall toxicology profile of the erbumine salt of perindopril. No carcinogenicity, reproductive and developmental toxicity studies have been conducted with perindopril arginine.

General Toxicology:

Chronic Toxicity Studies

Repeated oral gavage administration of the arginine salt of perindopril for 4 weeks in Wistar rats and Beagle dogs did not elicit unexpected toxicity in comparison with the known effects of the erbumine salt.

Carcinogenicity:

No evidence of carcinogenicity was observed in the two 104-week studies in B₆C₃F₁ mice and Fischer 344 rats treated with perindopril erbumine at dosages ≤6 times the maximum recommended human dose (MRHD).

Genotoxicity:

The genotoxic potential of perindopril arginine was investigated in a series of in vitro and in vivo tests tabulated below.

In vitro

In vivo

No mutagenic or clastogenic potential was found in the Ames test, in the mouse lymphoma assay, in the chromosomal aberration test or in the bone marrow micronucleus assay ≤ 2000 mg perindopril free acid/kg. Chromosomal aberrations were found after prolonged (20 hours) treatment of human lymphocytes with 1294 mcg perindopril free acid/mL, but the test was considered inappropriate since the accurate assessment of toxicity was not possible. The absence of clastogenic effect in vitro after more prolonged exposure (24 hours) to higher concentrations (≤ 3685 mcg perindopril free acid/mL) in the mouse lymphoma assay, combined with the absence of clastogenic potential in vivo after one administration ≤ 2000 mg perindopril free acid/kg, supported the overall non genotoxicity potential of perindopril arginine salt.

Reproductive and Developmental Toxicology:

Fertility Studies

Studies were performed by administrating perindopril erbumine by the oral route. In the table below, the reported doses or concentrations of perindopril are expressed in terms of perindopril erbumine salt.

PR (n) = nth day of pregnancy; G = generation; D = day

Teratogenicity Studies

Studies were performed by administrating perindopril erbumine by the oral route. The following doses or concentrations are expressed in terms of perindopril erbumine salt.

PR (n) = nth day of pregnancy

No teratogenic effects of perindopril were seen in studies of pregnant rats, mice, rabbits and cynomolgus monkeys.

Amlodipine

Carcinogenicity:

There was no evidence of a carcinogenic effect when amlodipine was administered in the diet for ≤24 months to rats and at doses of ≤2.5 mg/kg/day in mice.

Perindopril arginine/Amlodipine combination

General Toxicology:

The safety profile of the perindopril/amlodipine combination was assessed in Wistar rats (n=10/sex/group) by daily gavage for 13 weeks at 3.75 mg/2 mg, 7.5 mg/4 mg, 15 mg/8 mg, 15 mg/0 mg or 0 mg/8 mg per kg. No mortality occurred in this study. At the end of the study, a lower mean bodyweight was noted for the males given amlodipine at 8 mg/kg either alone (-10% versus control, p<0.01) or in combination with perindopril at 15 mg/kg (-7% versus control, not significant).

Lower mean ratios of heart weight to body weight were seen for the males given perindopril either in combination with amlodipine at 3.75 mg/2 mg, 7.5 mg/4 mg and 15 mg/8 mg per kg dosages (-9%, -11% and -12% versus control, respectively, p<0.01 for all) or alone at 15 mg/kg (-14% versus control, p<0.01). For the females, lower mean ratios of heart weight to body weight were seen only for those given perindopril alone at 15 mg/kg (-8% versus control, p<0.05).

These isolated abnormalities are considered of minor toxicological importance, given that the high safety margin dose around 12 up to 50 times MRHD.

Neither new target organ toxicity nor relevant additive effects were identified with the combination of perindopril/amlodipine. The No Observed Adverse Effect Level (NOAEL) was set at 7.5 mg/4 mg per kg of perindopril arginine/amlodipine.

DETAILED PHARMACOLOGY

Perindopril arginine and amlodipine have complementary mechanisms of action which could account for potential synergistic pharmacological effects. Perindopril inhibits the renin angiotensin system, amlodipine induces a peripheral arterial dilation leading to a plasma renin activity increase. Perindopril inhibits the secretion of aldosterone and inhibits reabsorption of sodium on the proximal renal tubule.

Perindopril

In Vitro Studies:

Perindopril was shown to be an inhibitor of angiotensin converting enzyme (ACE) in both plasma and tissue. Perindoprilat, the diacid form of perindopril, exhibited greater inhibition of ACE activity than perindopril (IC₅₀ = 2 x 10^-9M and 800 x 10^-9M respectively).

In Vivo Studies:

The mechanism of action of perindopril was previously established with the market authorization of COVERSYL^® (perindopril erbumine). Perindopril erbumine at dose of 4 mg daily is equivalent to 5 mg/day perindopril arginine.

Following oral dosing of perindopril to normotensive (0.03 to 1 mg/kg) or hypertensive (0.3 to 3 mg/kg) rats, plasma ACE inhibition was assessed in vivo by the decrease in pressor response to intravenous angiotensin I. Orally administered to conscious dogs, perindopril produced a dose-dependent reduction (34% at 0.1 mg/kg, 60% at 0.3 mg/kg and 92% at 1 mg/kg) of angiotensin I (150 ng/kg IV) pressor response but had no effect on angiotensin II (100 ng/kg IV) response. In normotensive rats, plasma ACE was maximally inhibited (≥ 90%) by perindopril (1,

4 or 8 mg/kg p.o.) 1 hour following administration, then returned to control levels 24 hours later.

After 4 weeks of oral treatment (10 mg/kg) in stroke-prone spontaneously hypertensive rats, converting enzyme inhibition was mostly demonstrated in kidney (96%), aorta (64%), heart (52%), lung (36%) and brain (26%).

In human subjects, perindopril at single oral doses of 4 to 8 mg/day produced 80% inhibition of plasma ACE activity between 2 and 8 hours post-dose, with 40 to 60% inhibition persisting at 24 hours post-dose. Multiple oral doses of perindopril over 7 days (4 to 8 mg/day) confirmed the inhibitory effect on plasma ACE and showed that it produces corresponding decreases in angiotensin II with significant increases in plasma renin activity.

Amlodipine

Cardiovascular Activity - In Vivo:

In anesthetized dogs, amlodipine (i.v. 25 to 1600 mcg/kg) was a potent coronary and peripheral vasodilator; ED₅₀ values were 103 and 212 mcg/kg for reductions of coronary and systemic vascular resistances, respectively. The reductions in vascular resistance were associated with corresponding increases in cardiac output, coronary flow, heart rate and myocardial contractility. Amlodipine possessed slow onset of action, minimal effect on blood pressure, and a long duration of action. Amlodipine caused slight, transient negative inotropic responses only at the highest dose, in excess of that required to cause maximal vasodilatation. The drug did not adversely affect atrial ventricular conduction, as assessed by PR interval.

Oral administration of amlodipine (0.5 to 2.0 mg/kg) to conscious dogs produced dose-related reductions in systemic vascular resistance (max. of 78%) and reflexly-induced increases in heart rate, cardiac output and myocardial contractility; maximum effects were achieved much later (3 to 5 hours) than after parenteral administration (5 to 30 min) which may explain the dose-related modest blood pressure reductions (max. change of 25%) observed by the oral route.

Antihypertensive Efficacy - In Vivo:

Amlodipine produced dose-related reductions in blood pressure of spontaneously hypertensive rats (SHR) after oral administration. The antihypertensive effect was maintained for ≥ 6 h after each one of the 3 doses used (1, 3, and 10 mg/kg). In young SHR the development of hypertension was attenuated by 60% over a 12-week period when amlodipine was added to the diet to provide the dose of 8 mg/kg/day. In mature SHR receiving amlodipine for 8 weeks, a marked antihypertensive effect was evident by day 2 and attained a maximum by day 5. This effect was maintained for the remaining treatment period with no change in heart rate. In addition, treated animals showed a small, but statistically significant, reduction in ventricular weight and marked elevation in plasma renin activity.

In conscious renal-hypertensive dogs, oral administration of single doses of amlodipine (0.25, 0.5 and 1.0 mg/kg) produced dose-related reductions in blood pressures with maximum effects occurring at 5 hours post-dose. These responses were accompanied by dose-related increases in heart rate.

The slow onset and long-lasting antihypertensive effects of amlodipine were confirmed in conscious renal-hypertensive dogs in which blood pressure was recorded continuously for 24 hours.

In conscious renal-hypertensive dogs, orally administered amlodipine (0.025, 0.05 and 0.25 mg/kg/day) for 10 to 14 days produced progressive reductions in the daily, resting, pre-dose blood pressure which stabilized after 4 or 5 days. The minimum blood pressures achieved each day were approximately equivalent and tolerance did not develop. Heart rate was inconsistently affected.

For more detailed pharmacology on amlodipine, please refer to the Product Monograph for NORVASC.

17 SUPPORTING PRODUCT MONOGRAPHS

1. 1. VIACORAM^® (perindopril arginine and amlodipine (as amlodipine besylate) tablets, 3.5 mg /2.5 mg, 7 mg/5 mg, 14 mg/10 mg), submission control 275866, Product Monograph, Servier Canada Inc. (OCT 24, 2023)