Mylan-Perindopril Arginine Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

MYLAN-PERINDOPRIL ARGININE (perindopril arginine) is indicated for:

• Hypertension

  • The treatment of mild to moderate essential hypertension. It may be used alone or in association with other drugs, particularly thiazide diuretics.

The safety and efficacy of perindopril arginine in renovascular hypertension have not been established and therefore, its use in this condition is not recommended.

The safety and efficacy of concurrent use of perindopril arginine with antihypertensive agents, other than amlodipine and thiazide diuretics, have not been established.

• Congestive Heart Failure

  • The treatment of mild to moderate congestive heart failure, generally as adjunctive therapy to diuretics, and where appropriate a digitalis glycoside.

    • Treatment should be initiated under close medical supervision. The safety and efficacy of perindopril arginine have not been demonstrated for New York Heart Association Category IV patients.

• Hypertensive and/or post-MI patients with stable coronary artery disease.

  • The reduction of cardiovascular risk in patients with hypertension or post-myocardial infarction and stable coronary disease.

Perindopril erbumine has been demonstrated to reduce the risk of cardiovascular death, non-fatal myocardial infarction, and cardiac arrest in mild or moderately hypertensive patients with stable coronary artery disease, or in patients with a previous (>3 months ago) myocardial infarction and stable coronary artery disease, including patients with previous revascularization when administered as an add-on to conventional treatment such as platelet inhibitors, beta blockers, lipid-lowering agents, nitrates, calcium channel blockers or diuretics.

See DOSAGE AND ADMINISTRATION.

Geriatrics (>65 years of age)

Although clinical experience has not identified significant differences in response between the elderly (>65 years) and younger patients, greater sensitivity of some older individuals cannot be ruled out.

Pediatrics

The safety and effectiveness of perindopril arginine in children have not been established. Its use in this age group, therefore, is not recommended.

CONTRAINDICATIONS

MYLAN-PERINDOPRIL ARGININE (perindopril arginine) is contraindicated in:

• Patients who are hypersensitive to this drug or to any ingredient in the formulation. For a complete listing (see DOSAGE FORMS, COMPOSITION AND PACKAGING).
• Patients with a history of hereditary/idiopathic angioedema, or angioedema related to previous treatment with an angiotensin converting enzyme inhibitor (see WARNINGS and PRECAUTIONS, General).
• Women who are pregnant, intend to become pregnant, or of childbearing potential who are not using adequate contraception (see WARNINGS and PRECAUTIONS, Special Populations, Pregnant Women).
• Nursing women (see WARNINGS AND PRECAUTIONS, Special Populations, Nursing Women).
• Patients with hereditary problems of galactose intolerance, glucose-galactose malabsorption, or the Lapp lactase deficiency as MYLAN-PERINDOPRIL ARGININE contains lactose (see WARNINGS AND PRECAUTIONS, Sensitivity/ Resistance).
• Combination with sacubitril/ valsartan due to an increased risk of angioedema.
• Combination with angiotension converting enzyme (ACE) inhibitors, including perindopril arginine, with aliskiren-containing drugs in patients with diabetes mellitus (type 1 or 2) or moderate to severe renal impairment (GFR <60ml/min/1.73m²) (see WARNINGS AND PRECAUTIONS, Dual Blockade of the Renin-Angiotensin System (RAS) and Renal, and 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 DRUG INTERACTIONS),
• Patients with bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney (see WARNINGS AND PRECAUTIONS, Renal).

WARNINGS AND PRECAUTIONS

General

Driving a vehicle or performing other hazardous tasks

Perindopril 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 MYLAN-PERINDOPRIL ARGININE especially at the start of treatment.

Head and neck angioedema

Life-threatening angioedema has been reported with ACE inhibitors. The overall incidence is approximately 0.1-0.2%. The aetiology is thought to be non-immunogenic and may be related to accentuated bradykinin activity. Usually, the angioedema is non-pitting edema of the skin mucous membrane and subcutaneous tissue.

Angioedema involving the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with ACE inhibitors, including perindopril erbumine. Angioedema associated with laryngeal involvement may be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, MYLAN-PERINDOPRIL ARGININE should be discontinued immediately, the patient treated appropriately in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment, although antihistamines may be useful in relieving symptoms. Where there is involvement of the tongue, glottis or larynx, angioedema may be fatal due to airway obstruction, appropriate therapy (including but not limited to 0.3 to 0.5 ml of subcutaneous epinephrine solution 1:1000 and oxygen) should be administered promptly (see ADVERSE REACTIONS).

Treatment of progressive angioedema should be aggressive. Failing a rapid response to medical therapy, mechanical methods to secure an airway should be used before massive edema complicates oral or nasal intubation.

Patients who respond to medical treatment should be observed carefully for a possible rebound phenomenon.

The onset of angioedema associated with use of ACE inhibitors may be delayed for weeks or months.

Patients may have multiple episodes of angioedema with long symptom-free intervals. Angioedema may occur with or without urticaria.

The incidence of angioedema during ACE inhibitor therapy has been reported to be higher in black than in non-black patients.

There are reports that switching a patient to another ACE inhibitor could be followed by a recurrence of angioedema. Because of the potential severity of this rare event, another ACE inhibitor should not be used in patients with a history of angioedema (see CONTRAINDICATIONS).

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see 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) or neutral endopeptidase (NEP) inhibitor may be at increased risk for angioedema. Caution should be used when initiating ACE inhibitor therapy in patients already taking an mTOR, DPP-IV or NEP inhibitor or vice versa (see 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.

Cardiovascular

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

Perindopril erbumine can cause symptomatic hypotension. Perindopril erbumine has been associated with hypotension in 0.3% of uncomplicated hypertensive patients in U.S. placebo-controlled trials. Symptoms related to orthostatic hypotension were reported in another 0.8% of patients. It is more likely to occur after the first or second dose or when the dose is increased and in patients who are volume depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhoea, or vomiting or with impaired renal function. Volume and/or salt depletion should be corrected before initiation of therapy with perindopril arginine (see DOSAGE AND ADMINISTRATION). In patients with ischemic heart or cerebrovascular disease and/or severe congestive heart failure, with or without associated renal insufficiency, ACE inhibitors may cause an excessive fall in blood pressure which could result in syncope, a myocardial infarction, neurological deficits, oliguria and/or progressive azotemia and, rarely, in acute renal failure and/or death (see ADVERSE REACTIONS).

In all high-risk patients it is advisable to initiate treatment with perindopril arginine 2.5 mg.

Because of the potential fall in blood pressure in these patients, therapy with perindopril arginine should be started under very close medical supervision. Such patients should be followed closely for the first two weeks of treatment and whenever the dose of perindopril arginine and/or diuretic is increased.

In controlled studies versus placebo and other ACE inhibitors, the first administration of 2 mg of perindopril erbumine in patients with mild-moderate heart failure was not associated with any significant reduction in blood pressure as compared to placebo (see ACTIONS AND CLINICAL PHARMACOLOGY - Pharmacodynamics).

If hypotension occurs, the patient should be placed in a supine position and, if necessary, receive an intravenous infusion of 0.9% sodium chloride. A transient hypotensive response is not a contraindication to further doses which usually can be given without difficulty once the blood pressure has increased after volume expansion. However, lower doses of perindopril arginine and/or reduced concomitant diuretic therapy should be considered.

Aortic Stenosis/Hyperthrophic Cardiomyopathy

As with other ACE inhibitors, perindopril arginine 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. There is concern on theoretical grounds that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators including ACE inhibitors because they do not develop as much afterload reduction. Vasodilators may tend to drop diastolic pressure, and hence coronary pressure, without producing the concomitant reduction in myocardial oxygen demand that normally accompanies vasodilation.

Dual blockade of the Renin-Angiotensin System (RAS)

There is evidence that co-administration of angiotensin converting enzyme (ACE) inhibitors, such as perindopril arginine, 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/1.73m²). Therefore, the use of perindopril arginine in combination with aliskiren-containing drugs is contraindicated in these patients (see CONTRAINDICATIONS).

Further, co-administration of ACE inhibitors, including perindopril arginine, 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.

Primary aldosteronism

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

Hematologic

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 such as systemic lupus erythematosus or scleroderma, and those on multiple drug therapy with agents known to be nephrotoxic or myelosuppressive (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 (see WARNINGS AND PRECAUTIONS - Monitoring and Laboratory Tests). Patients should be instructed to report any sign of infection.

Hepatic

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.

Immune

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.

Anaphylactoid Reactions during LDL Apheresis

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

Anaphylactoid Reactions during Desensitization

There have been isolated reports of patients experiencing sustained, life-threatening anaphylactoid reactions while receiving ACE inhibitors during desensitization treatment with hymenoptera (bees, wasps) venom. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld for at least 24 hours, but they reappeared upon inadvertent rechallenge.

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 (see DRUG

INTERACTIONS).

Peri-Operative Considerations

ACE inhibitors may augment the hypotensive effects of anaesthetics and analgesics. In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, perindopril arginine will block the angiotensin II formation that could otherwise occur 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.

Renal

Impaired Renal Function

As a consequence of inhibiting the renin-angiotensin-aldosterone system (RAAS), changes in renal function may be anticipated in susceptible individuals.

In cases of renal impairment (creatinine clearance <60 ml/min) the initial perindopril dosage should be adjusted according to the patient’s creatinine clearance and then as a function of the patient’s response to treatment. Routine monitoring of potassium and creatinine are part of normal medical practice for these patients (see WARNINGS AND PRECAUTIONS – Monitoring and Laboratory Tests).

The use of ACE inhibitors, including perindopril arginine, or ARBs with aliskiren-containing drugs is contraindicated in patients with moderate to severe renal impairment (GFR < 60 ml/min/1.73m2). (See CONTRAINDICATIONS and DRUG INTERACTIONS, Dual Blockade of the ReninAngiotensin-System (RAS) with ARBs, ACE inhibitors, or aliskiren-containing drugs).

Hypertensive Patients with Congestive Heart Failure

In patients with severe congestive heart failure, where renal function may depend on the activity of the RAAS, treatment with ACE inhibitors, including perindopril arginine, may be associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death.

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.

Hypertensive Patients with Renal Artery Stenosis

In clinical trials in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine were observed in 20% of patients. Experience with ACE inhibitors suggests that these increases are usually reversible upon discontinuation of the drug. In such patients, renal function should be monitored during the first few weeks of therapy. ACE inhibitors should be avoided in patients with known or suspected renal artery stenosis. When an ACE inhibitor is given to a patient with stenosis of the renal artery supplying a solitary kidney, or bilateral artery stenosis, acute renal insufficiency may occur. ACE inhibition may also cause a decrease in renal function in patients with stenosis of the artery supplying a transplanted kidney. It is believed that renal artery stenosis reduces the pressure in the afferent glomerular arteriole, and transglomerular hydrostatic pressure is then maintained by angiotensin II- induced constriction of the efferent arteriole. When an ACE inhibitor is given, the efferent arteriole relaxes, glomerular filtration falls, and renal failure may result. The thrombotic occlusion of a stenosed renal artery can be precipitated by ACE inhibitors (see WARNINGS AND PRECAUTIONS - Monitoring and Laboratory Tests).

Some hypertensive patients without apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient. These increases are more likely to occur in patients treated concomitantly with a diuretic and in patients with pre-existing renal impairment. Reduction of dosages of perindopril arginine, the diuretic or both may be required. In some cases, discontinuation of either or both drugs may be necessary. Evaluation of hypertensive patients should always include an assessment of renal function (see DOSAGE AND ADMINISTRATION). If deterioration in renal function has occurred after treatment with one ACE inhibitor, then it is likely to be precipitated by another and in these patients usage of another class of antihypertensive agent would be preferable. Patients with unilateral renal artery disease present a special problem as deterioration of function may not be apparent from measurement of blood urea and serum creatinine.

Proteinuria

Some ACE inhibitors have been associated with the occurrence (up to 0.7%) of proteinuria (<1 gram / 24 hours) and/or decline in renal function in patients with one or more of the following characteristics: old age, pre-existing renal disease, concomitant treatment with potassium-sparing diuretics or high doses of other diuretics, limited cardiac reserve, or treatment with a non-steroidal anti-inflammatory drug.

Perindoprilat, the active form of perindopril, is dialysable with a clearance of 70 ml/min (see DOSAGE AND ADMINISTRATION).

Hyperkalemia and agents increasing serum potassium

In clinical trials, hyperkalemia (serum potassium >5.5 mEq/L) occurred in approximately 2.2% of the hypertensive patients compared to 1.4% in placebo (see ADVERSE REACTIONS). In most cases, these were isolated values which resolved despite continued therapy. In controlled studies, no patient discontinued therapy due to hyperkalemia.

Risk factors for development of hyperkalemia may include renal impairment, worsening of renal function, diabetes mellitus, elderly patients, intercurrent events, in particular dehydration, acute cardiac decompensation, metabolic acidosis and the concomitant use of potassium-sparing diuretic (e.g. spironolactone, eplerenone, triamterene, or amiloride), potassium supplements, potassium-containing salt substitutes or any drugs associated with increase in serum potassium (e.g. aliskiren, NSAIDs, heparin, cyclosporine, tacrolimus, trimethoprim and fixed dose combination with sulfamethoxazole, angiotensin receptor blockers) which should be used cautiously, if at all, with perindopril arginine (see DRUG INTERACTIONS, Drug-Drug Interactions). The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes particularly in patients with impaired renal function may lead to a significant increase in serum potassium. Hyperkalemia can cause serious, sometimes fatal arrhythmias. In some patients hyponatremia may co-exist with hyperkalemia (see WARNINGS AND PRECAUTIONS - Monitoring and Laboratory Tests). If concomitant use of the above mentioned agents is deemed appropriate, regular monitoring of serum potassium and urea is recommended.

Renovascular hypertension

There is an increased risk of hypotension and renal insufficiency when patient with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with ACE inhibitors (see 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.

Respiratory

Cough

A dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose of perindopril erbumine has been reported. Such possibility should be considered as part of the differential diagnosis of the cough.

The cough is often worse when lying down or at night, and has been reported more frequently in women (who account for 2/3 of the reported cases). Patients who cough may have increased bronchial reactivity compared with those who do not. The observed higher frequency of this side-effect in non-smokers may be due to a higher level of tolerance of smokers to cough.

The cough is most likely due to stimulation of the pulmonary cough reflex by kinins (bradykinin) and/or prostaglandins, which accumulate because of ACE inhibition. Once a patient has developed intolerable cough, an attempt may be made to switch the patient to another ACE inhibitor; the reaction may recur but this is not invariably the case. A change to another class of drugs may be required in severe cases.

Sensitivity/ Resistance

Due to the presence of lactose, patients with hereditary problems of galactose intolerance, glucose-galactose malabsorption or the Lapp lactase deficiency should not take MYLAN-PERINDOPRIL ARGININE.

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.

Special Populations

Pregnant Women

ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected, perindopril arginine should be discontinued as soon as possible (see CONTRAINDICATIONS).

The use of ACE inhibitors is contraindicated during the second and third trimesters of pregnancy, because it has been associated with fetal and neonatal injury including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death.

Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function, associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.

Prematurity, and patent ductus arteriosus and other structural cardiac malformations, as well as neurologic malformations, have also been reported following exposure in the first trimester of pregnancy.

Infants with a history of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function; however, limited experience with those procedures has not been associated with significant clinical benefit.

Perindoprilat, the active form of perindopril, can be removed from the body by hemodialysis (see ACTIONS AND CLINICAL PHARMACOLOGY - Pharmacokinetics and Metabolism, Special populations and conditions – Renal insufficiency).

Animal data

See Part II - Scientific information – TOXICOLOGY, Teratogenicity studies.

Nursing Women

The presence of concentrations of ACE inhibitor have been reported in human milk. Use of ACE inhibitors is contraindicated during breast-feeding (see CONTRAINDICATIONS).

Pediatrics

The safety and effectiveness of perindopril arginine in children have not been established. Its use in this age group, therefore, is not recommended.

Geriatrics (>65 years of age)

Although clinical experience has not identified significant differences in response between the elderly (> 65 years) and younger patients, greater sensitivity of some older individuals cannot be ruled out.

Renal insufficiency is commonly observed in elderly people. Care should therefore be taken when prescribing perindopril arginine to elderly patients. The initial dose of perindopril arginine in the elderly should always be 2.5 mg daily and patients should be monitored closely during the initial stages of treatment (see DOSAGE AND ADMINISTRATION).

In a study of 91 elderly patients with a mean age of 71.9 years, a 6% increase in serum potassium occurred in the first month of treatment and subsequently remained stable. There was no change in the group in blood urea, creatinine or creatinine clearance.

Particular care should be taken in elderly patients with congestive heart failure who have renal and/or hepatic insufficiency.

Diabetic patients

In diabetic patients treated with oral antidiabetic agents or insulin, glycemic control should be closely monitored during the first month of treatment with an ACE inhibitor.

Patients with Impaired Liver Function

Hepatitis (hepatocellular and/or cholestatic), elevations of liver enzymes and/or serum bilirubin have occurred during therapy with ACE inhibitors, in patients with or without pre-existing liver abnormalities. In most cases, the changes were reversed upon discontinuation of the drug.

Elevations of liver enzymes and/or serum bilirubin have been reported with perindopril erbumine (see ADVERSE REACTIONS). Should the patient receiving perindopril arginine experience any unexplained symptoms, particularly during the first weeks or months of treatment, it is recommended that a full set of liver function tests and any other necessary investigation be carried out. Discontinuation of perindopril arginine should be considered when appropriate.

Perindopril arginine should be used with particular caution in patients with pre-existing liver abnormalities. In such patients, baseline liver function tests should be obtained before administration of the drug and close monitoring of response and metabolic effects should apply.

Monitoring and Laboratory Tests

Hematological Monitoring

Periodic monitoring of white blood cell counts is advised in patients with collagen vascular disease such as systemic lupus erythematosus or scleroderma, and those on multiple drug therapy with agents known to be nephrotoxic or myelosuppressive (immunosuppressant therapy, treatment with allopurinol or procainamide), or a combination of these complicating factors, especially if there is pre-existing impaired renal function.

Renal Function Monitoring

Routine monitoring of potassium and creatinine is part of normal medical practice for renal impairment patients (creatinine clearance <60 ml/min). Particularly careful monitoring is required in hypertensive patients with renal artery stenosis. In such patients, renal function should be monitored during the first few weeks of therapy.

Electrolyte Monitoring

If concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, drugs associated with increase in serum potassium, or other RAAS inhibitors is deemed appropriate, regular monitoring of serum potassium and urea is recommended.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

The most frequent adverse reactions observed with perindopril are: cough, dizziness, headache, asthenia, gastro-intestinal disorders (abdominal pain, nausea, and dyspepsia).

The most serious adverse reactions are: hypersensitivity reaction (angioedema), renal dysfunction (in high risk patients), pancreatitis, blood disorders (pancytopenia, agranulocytosis, and thrombocytopenia).

During the long-term safety assessment in heart failure patients, the severe adverse events occurring with the highest frequency were angina pectoris and orthostatic hypotension.

The most severe drug reactions from post-marketing experience were pancreatitis and blood disorders (pancytopenia, agranulocytosis, and thrombocytopenia).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

• Hypertension

Perindopril erbumine was evaluated for safety in approximately 3,400 patients with hypertension (1,216 patients in controlled clinical trials including 181 elderly patients). Perindopril erbumine was evaluated for long-term safety in approximately 1,000 patients that were treated for ≥1 year.

During clinical trials, the most severe adverse drug reactions occurring in hypertensive patients treated with perindopril were angioneurotic oedema and renal insufficiency.

In an open-labelled European study of about 47,000 patients with essential hypertension, seen in everyday medical practice, and treated for 1 year with perindopril erbumine, with or without multiple other medications, the most frequently observed adverse events were: cough (9.7%), digestive symptoms (2.0%), fatigue (1.8%), headache (1.4%) and dizziness (1.4%). In this study, in total, 5.1% of patients withdrew due to adverse events, 3.2% due to cough.

In placebo-controlled U.S. trials, 1,012 patients received either perindopril monotherapy (n=630), perindopril/HCT (n=159) or placebo (n=230). Table 1 presents adverse reactions that occurred in ≥1% of the patients treated with perindopril monotherapy or placebo.

The incidence of premature discontinuation of therapy due to adverse events in the placebo-controlled U.S clinical trials was 6.5% in patients treated with perindopril and 6.7% in patients treated with placebo. The most common causes of premature discontinuation were cough, headache, asthenia and dizziness; cough was the reason for withdrawal in 1.3% and 0.4% of patients treated with perindopril and placebo, respectively. While dizziness was not reported more frequently in the perindopril group (8.2%) than in the placebo group (8.5%), it was clearly increased with dose, suggesting a causal relationship with perindopril.

Other reported adverse events (reported in ≥1% patients), regardless of causality, include: back pain (6.8%), rhinitis, sinusitis (each 5.2%), pain in lower extremities (5.1%), pharyngitis (3.7%), viral infection (3.3%), urinary tract infection (3.2%), pain in upper extremities (2.9%), nausea (2.7%), abdominal pain (2.5%), accidental injury, hypertonia, paresthesia (each 2.4%), non- specific chest-pain, abnormal ECG (each 2.2%), dyspepsia (2.1%), vomiting (1.9%), fever, seasonal allergy (each 1.8%), ALT increase (1.6%), generalized myalgia, neck pain, tinnitus (each 1.4%), joint pain, somnolence (each 1.1%), flatulence, arthritis, palpitations (each 1.0%).

Myocardial infarction and cerebrovascular accident occurred possibly secondary to excessive hypotension in high-risk patients (see WARNINGS and PRECAUTIONS – Cardiovascular).

Withdrawals

In total 56 of 1,275 patients studied (4.4%) stopped treatment because of adverse reactions. In a specific study of 632 patients, 36 (5.7%) patients withdrew because of adverse events. A plausible or probable relationship with perindopril erbumine treatment were considered to exist in 19 (3%) cases.

Adverse drug reactions that most commonly result in premature discontinuation of therapy were cough (0.5%), headache (0.5%), dizziness (0.5%) and asthenia (0.4%).

• Congestive Heart Failure

In heart failure trials, safety was evaluated in 167 patients treated with perindopril in 3-month placebo-controlled trials and long-term safety was assessed in 513 patients treated for ≥6months, 352 of which were followed for at least 1 year. Table 2 presents adverse drug reactions that occurred in ≥1% of the 167 patients treated with perindopril during the double-blind period lasting 3 months, as compared to the same adverse events occurring in the 170 patients receiving a placebo. Discontinuation of therapy due to adverse events was required in 5.4% of the 167 patients with perindopril, as compared to 4.7% of the 170 patients who received a placebo.

• Hypertensive and/or Post-MI Patients with Stable Coronary Artery Disease

Perindopril was evaluated for safety in the EUROPA trial. This was a double-blind, placebo-controlled study in 12,218 patients with stable coronary artery disease (CAD), the majority of which had hypertension and/or had survived a previous heart attack. The overall rate of discontinuation was 22.8% (1391 / 6110 patients) and 20.7% (1266 / 6108 patients) in the perindopril and placebo groups, respectively.

The most common reasons for discontinuation that were more frequent on perindopril erbumine than placebo were cough (2.7%), drug intolerance (2.4%), hypotension (1.0%) and kidney failure (0.3%).

Serious Adverse Events in EUROPA trial

There were no significant differences in the numbers of deaths between the perindopril (n=375) and control (n=420) groups. However, 10 patients died during the open run-in period of the study, of whom 7 from cardiovascular causes, including stroke. A total of 795 patients (out of 12,230; 6.5%) died during the study, 464 of the 795 (58%) died from a cardiovascular cause.

During the randomized period of the EUROPA study, only serious adverse events were collected. Few patients experienced serious adverse events: 16 (0.3%) of the 6,122 perindopril patients and 12 (0.2%) of the 6,107 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 (6.0%, n=366) than on placebo (2.1%, n=129).

On the other hand, atrial cardioversion occurred significantly more frequently in the perindopril group (0.5%, n=42) than in the control group (0.3%, n=17).

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

Adverse events, irrespective of causal relationship to the drug, which occurred in <1.0% of hypertensive and heart failure patients treated with perindopril erbumine in clinical trials, are listed as follows:

Potential Adverse Events Reported with ACE Inhibitors

Other medically important adverse events reported with other available ACE inhibitors include cardiac arrest, eosinophilic pneumonitis, neutropenia/agranulocytosis, pancytopenia, anemia (including hemolytic and aplastic), thrombocytopenia, acute renal failure, nephritis, hepatic failure, jaundice (hepatocellular or cholestatic), symptomatic hyponatremia, bullous pemphigus, acute pancreatitis, exfoliative dermatitis and a syndrome which may include: arthralgia/arthritis, vasculitis, serositis, myalgia, fever, rash or other dermatologic manifestations, a positive ANA, leukocytosis, eosinophilia or an elevated ESR. Many of these adverse events have also been reported for perindopril.

Taste disturbances (dysgeusia)

Taste disturbances were reported to be common (prevalence up to 12.5%) with high doses of another ACE inhibitor.

Taste disturbance with ACE inhibitors have been described as suppression of taste or a metallic sensation in the mouth. Any dysgeusia usually occurs in the first weeks of treatment and may disappear in most cases within 1-3 months.

Abnormal Hematologic and Clinical Chemistry Findings

Serum Electrolytes

In clinical trials, hyperkalemia (serum potassium >5.5 mEq/L) occurred in approximately 2.2% of the hypertensive patients treated with perindopril compared to 1.4% in placebo-treated patients. Hyperkalemia may occur especially in the presence of renal insufficiency, severe heart failure and renovascular hypertension (see WARNINGS AND PRECAUTIONS – Renal).

Blood Urea Nitrogen/ Serum Creatinine

Elevations of BUN (>40 mg/dl) or serum creatinine (>2.5 mg/dl) were observed in 0.2% and 0.3% of patients, respectively, treated with perindopril erbumine monotherapy. Decreases in serum sodium and increases in serum creatinine occurred more frequently in patients on concomitant diuretics than in those treated with perindopril erbumine alone. Increases in blood urea, plasma creatinine, and hematuria were observed and may occur especially in the presence of renal insufficiency.

Hematology

Small decreases in hemoglobin and hematocrit occurred in hypertensive patients treated with perindopril erbumine, but were rarely of clinical importance. In controlled clinical trials, no patient was discontinued from therapy due to the development of anemia.

Liver Function

Elevations of liver enzymes (ALT: 1.6% perindopril erbumine vs 0.9% placebo, AST: 0.5% perindopril erbumine vs 0.4% placebo) were observed in U.S. placebo-controlled clinical trials. Elevations in serum bilirubin were observed (see WARNINGS AND PRECAUTIONS – Special population).

Other

Elevations in serum cholesterol and plasma glucose were observed.

Post-Market Adverse Drug Reactions

The most frequent adverse events occurring in post-marketing experience were cough, gastro-intestinal symptoms (abdominal pain, nausea, and dyspepsia), asthenia, fatigue, dizziness and headache.

Post-marketing experience with all ACE inhibitors suggests that exposure in utero may be associated with hypotension and decreased renal perfusion in the fetus. ACE inhibitors have also been associated with fetal death in utero. No ACE inhibitor should be used in pregnancy.

DRUG INTERACTIONS

Overview

Drug-Drug Interactions

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

Drug-Food Interactions

The presence of food in the gastrointestinal tract does not affect the rate or extent of perindopril absorption. However, the extent of biotransformation of perindopril to perindoprilat is reduced, resulting in a decrease of perindoprilat bioavailability by 35%. Therefore it is recommended that perindopril arginine be taken before a meal.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory products/methods have not been established.

Drug-Lifestyle Interactions

Lifestyle interactions have not been established.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Dosage of MYLAN-PERINDOPRIL ARGININE must be individualized and adjustment is required in the elderly, and in case of renal impairment.

Recommended Dose and Dosage Adjustment

• Hypertension

Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation and salt restriction. The dosage of other antihypertensive agents being used with MYLAN-PERINDOPRIL ARGININE may need to be adjusted. The presence of food in the gastrointestinal tract reduces the bioavailability of perindoprilat.

Monotherapy

The recommended initial dose of MYLAN-PERINDOPRIL ARGININE, in patients not on diuretics, is 5 mg once daily. Dosage should be adjusted according to blood pressure response, generally at intervals of at least 2 weeks. The usual maintenance dose is 5 to 10 mg daily administered in a single daily dose. No additional blood pressure lowering effects were achieved with doses greater than 10 mg daily.

In some patients treated once daily, the antihypertensive effect may diminish towards the end of the dosing interval. This can be evaluated by measuring blood pressure just prior to dosing to determine whether satisfactory control is maintained for 24 hours. If it is not, either twice daily administration with the same total daily dose, or an increase in dose should be considered. If blood pressure is not controlled with MYLAN-PERINDOPRIL ARGININE alone, a diuretic may be added. After the addition of a diuretic, it may be possible to reduce the dose of MYLAN-PERINDOPRIL ARGININE.

Concomitant Diuretic Therapy

Symptomatic hypotension occasionally may occur following the initial dose of MYLAN-PERINDOPRIL ARGININE and is more likely in patients who are currently being treated with a diuretic. The diuretic should, if possible, be discontinued for two or three days before beginning therapy with MYLAN-PERINDOPRIL ARGININE to reduce the likelihood of hypotension (see WARNINGS AND PRECAUTIONS). If the diuretic cannot be discontinued, an initial dose of 2.5 mg MYLAN-PERINDOPRIL ARGININE should be used with careful medical supervision for several hours and until blood pressure has stabilized. The dosage of MYLAN-PERINDOPRIL ARGININE should subsequently be titrated to the optimal response.

The Elderly

In the elderly, treatment should begin with a 2.5 mg dose in the morning. If necessary, after one month of treatment this dose can be increased to 5 mg daily and then to 10 mg depending on renal function given in one or two divided doses.

• Congestive Heart Failure

MYLAN-PERINDOPRIL ARGININE is generally used in conjunction with a diuretic and, where appropriate, a digitalis glycoside in patients with congestive heart failure. Therapy should be initiated under close medical supervision. Blood pressure and renal function should be monitored, both before and during treatment with perindopril because severe hypotension and, more rarely, consequent renal failure have been reported (see WARNINGS AND PRECAUTIONS).

Initiation of therapy requires consideration of recent diuretic therapy and the possibility of severe salt/ volume depletion. If possible, the dose of diuretic should be reduced before beginning treatment. Serum potassium should also be monitored (see DRUG INTERACTIONS, Drug- Drug Interactions).

The recommended initial dose is 2.5 mg once daily taken in the morning under close medical supervision. The dose may, in most instances, be increased to 5 mg once daily (once blood pressure acceptability has been demonstrated). The usual effective dose in clinical trials was

4 mg/day of perindopril erbumine administered as a single dose. Dose titration may be performed over a 2- to 4-week period.

The Elderly

No special dosage recommendation is required for elderly patients with congestive heart failure.

• Hypertensive and/or Post-MI Patients with Stable C Artery Disease

In patients with hypertension and stable coronary artery disease or in post-myocardial infarction patients with coronary artery disease, MYLAN-PERINDOPRIL ARGININE should be given at an initial dose of 5 mg once daily for 2 weeks, and then increased as tolerated, to a maintenance dose of 10 mg once daily, preferably to be taken early in the morning. In these patients, MYLAN-PERINDOPRIL ARGININE should be administered as add-on to the conventional treatment, such as platelet inhibitors, beta blockers, lipid-lowering agents, nitrates, calcium channel blockers or diuretics.

The Elderly

In elderly patients (>70 years), MYLAN-PERINDOPRIL ARGININE should be given as a 2.5 mg dose once daily in the first week, followed by 5 mg once daily in the second week and 10 mg once daily for maintenance dose if tolerated.

Renal Impairment

In case of renal impairment, the dosage of MYLAN-PERINDOPRIL ARGININE must be adjusted based on creatinine clearance. The following dosages are recommended:

In these patients, normal medical follow up includes periodic assessment of potassium and creatinine levels.

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.

Administration

It is recommended that MYLAN-PERINDOPRIL ARGININE be taken once daily in the morning before a meal.

OVERDOSAGE

Limited data are available regarding overdosage of perindopril arginine in humans. The most likely clinical manifestation would be symptoms attributable to severe hypotension. In the case of overdosage, gastric washout and intravenous infusion of a normal saline solution are recommended.

However, of the two cases reported in the perindopril clinical trials, one (dosage unknown) required ventilation assistance and the other developed hypothermia, circulatory arrest, and subsequently died, following ingestion of up to 180 mg of perindopril erbumine. Thus, intervention in perindopril arginine overdosage may require vigorous support.

Perindopril arginine can be removed by hemodialysis, with clearances of about 52 ml/min for perindopril and 67 ml/min for perindoprilat, the active metabolite (see ACTIONS AND CLINICAL PHARMACOLOGY – Special Populations and Conditions – Renal insufficiency).

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Perindopril arginine is a non-sulphydryl angiotensin converting enzyme (ACE) inhibitor, which is used in the treatment of hypertension and mild to moderate congestive heart failure.

Following oral administration, perindopril arginine is rapidly hydrolysed to perindoprilat, its principal active metabolite.

Angiotensin-converting enzyme catalyses the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE activity leads to decreased levels of angiotensin II, thereby resulting in decreased vasoconstriction and decreased aldosterone secretion. The latter change may result in a small increase in serum potassium (see WARNINGS AND PRECAUTIONS – Hyperkalemia and agents increasing serum potassium). Decreased levels of angiotensin II and the accompanying lack of negative feedback on renal renin secretion results in increases in plasma renin activity.

ACE is identical to kininase II. Thus, perindopril arginine administration may interfere with the degradation of the vasodepressor peptide bradykinin. It is not known whether this effect contributes to the therapeutic activity of perindopril arginine.

The mechanism through which perindopril arginine lowers blood pressure appears to result primarily from suppression of the RAAS.

Pharmacodynamics

In most patients with mild to moderate essential hypertension, administration of 4 to 8 mg daily of perindopril erbumine results in a reduction of both supine and standing blood pressure with little or no effect on heart rate. Antihypertensive activity commences within one 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 75-100% of peak effects. When once and twice daily dosing were compared, the twice daily regimen was slightly superior, but by no more than about 0.5 to 1.0 mmHg. Abrupt withdrawal of perindopril erbumine has not been associated with a rapid increase in blood pressure. In studies carried out in patients with mild to moderate essential hypertension, the reduction in blood pressure was accompanied by a reduction in peripheral resistance with no change in glomerular filtration rate. When perindopril erbumine is given together with thiazide like diuretics, the antihypertensive effects are synergistic.

In uncontrolled studies in patients with insulin-dependent diabetes, perindopril erbumine did not appear to affect glycemic control. In long term use in this population, no effect on urinary protein excretion was seen.

Administration of perindopril erbumine to patients with congestive heart failure reduces cardiac work by a decrease in preload and afterload. Clinical trials have demonstrated that perindopril decreases left and right ventricular filling pressures, reduces total peripheral vascular resistance, increases cardiac output with an improved cardiac index, and increases muscular regional blood flow. The exercise tolerance of these patients is improved and is associated with an improvement of clinical symptomatology. At the recommended doses, the hemodynamic effects are maintained throughout the 24-hour dosing interval in most patients.

In controlled studies versus placebo and other ACE inhibitors, the first administration of 2 mg of perindopril erbumine in patients with mild-moderate heart failure was not associated with any significant reduction in blood pressure as compared to placebo.

The efficacy of perindopril erbumine in reduction of cardiovascular risk in hypertension or post-myocardial infarction was based on one mortality/morbidity study (EUROPA trial, see CLINICAL TRIALS).

Pharmacokinetics

Perindopril arginine is a non-sulphydryl angiotensin converting enzyme (ACE) inhibitor. Following oral administration, perindopril arginine is rapidly hydrolysed to perindoprilat, its active metabolite. The clearance of perindoprilat and other metabolites is primarily by the renal pathway.

ND: Not determined

Absorption

After oral administration of perindopril erbumine, perindopril is rapidly absorbed with peak plasma concentrations occurring at about one hour, with a bioavailability of 24%. Following absorption, perindopril is converted into perindoprilat, its active metabolite, with a mean bioavailability of 25%.

The peak plasma concentration of perindoprilat is reached in about 4 hours after oral administration of perindopril erbumine.

The presence of food in the gastrointestinal tract does not affect the rate or extent of perindopril absorption after oral administration of perindopril erbumine. However, the extent of biotransformation of perindopril to perindoprilat is reduced, resulting in a decrease of perindoprilat bioavailability by 35%. Therefore it is recommended that perindopril erbumine is taken before a meal.

Distribution

Plasma protein binding of perindoprilat is low (10 to 35%), the binding is concentration dependent due to the saturable binding of perindoprilat to the circulating angiotensin-converting enzyme. The volume of distribution is approximately 0.5 L/kg for unbound perindoprilat.

Metabolism

Perindopril is extensively metabolised following oral administration, with only 4 to 12% of the dose recovered unchanged in the urine. Six metabolites have been identified. They include perindoprilat, the active form, and five others that do not possess appreciable therapeutic activity (perindopril glucuronide, perindoprilat glucuronide, a perindopril lactam, and two perindoprilat lactams).

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

Two different pathways identified and quantified for perindoprilat formation are the pre-systemic

(first pass effect) and systemic hydrolysis of perindopril. Perindopril is indeed sensitive to a pre- systemic first-pass effect, accounting for 63% of the perindoprilat formation. The systemic hydrolysis of perindopril into perindoprilat accounts for the remaining 37% left.

Excretion

The clearance of perindoprilat and other metabolites is primarily by the renal pathway. The systemic clearance of perindopril (367 ml/min) can be split into 39% leading to perindoprilat formation and 61% to renal excretion or other biotransformations.

The terminal plasma half-life of perindopril is very short (1.2h), thus leading to no accumulation with a once daily oral dosing regimen. The terminal plasma half-life of unbound perindoprilat is about 17 hours, resulting in a steady-state within 3 days.

Special Populations and Conditions

Pediatrics

The safety and effectiveness of perindopril arginine in children have not been established. Its use in this age group, therefore, is not recommended.

Geriatrics

In a pharmacokinetic study with single dose administration, mean peak plasma concentrations of perindoprilat were significantly higher in elderly healthy volunteers (32.5 ng/ml) than in younger volunteers (13.5 ng/ml) due to both higher bioavailability and reduced renal clearance in this group.

Single and multiple dose pharmacokinetics of perindopril were evaluated in a study of elderly hypertensive patients (72 to 91 years of age), C_max and AUC were found to be approximately two-fold higher than in healthy younger subjects. The higher concentrations of perindoprilat observed in these patients were reflected in greater ACE inhibition (see WARNINGS and PRECAUTIONS - Geriatrics and DOSAGE AND ADMINISTRATION - Dosage adjustment).

Gender

The effectiveness of perindopril erbumine was not influenced by gender.

Race

The blood pressure lowering effects of angiotensin converting enzyme (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

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.

Renal Insufficiency

In patients with renal insufficiency, perindoprilat AUC increases with decreasing renal function. At creatinine clearances of 30-80 ml/min, AUC is about double that of 100 ml/min. When creatinine clearance drops below 30 ml/min, AUC increases more markedly. Therefore the dosage of perindopril should be adjusted in patients with a creatinine clearance below 30 ml/min.

Perindopril, and its active metabolite perindoprilat, are dialysable. In a limited number of patients studied, perindopril hemodialysis clearance ranged from 41.7 to 76.7 ml/min (mean 52.0 ml/min). Perindoprilat hemodialysis clearance ranged from 37.4 to 91.0 ml/min (mean 67.2 ml/min).

Heart Failure

Patients with heart failure have reduced perindoprilat clearance, which may result in a dose interval AUC that is increased up to 40% which should lead to an initial reduction of perindopril dosage.

Genetic Polymorphism

Pharmacokinetics differences due to genetic polymorphism have not been studied.

STORAGE AND STABILITY

Store at controlled room temperature (15-30°C).

SPECIAL HANDLING INSTRUCTIONS

No special requirements.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Dosage form:

MYLAN-PERINDOPRIL ARGININE (perindopril arginine) tablets:

• 2.5 mg: Each white to off-white, film-coated, round, biconvex tablet debossed with M on one side of the tablet and PA over 1 on the other side contains: perindopril arginine 2.5 mg.
• 5 mg: Each green film-coated, capsule shaped, side-notched, biconvex tablet debossed with M on one side of the tablet and PA2 on the other side contains: perindopril arginine 5 mg.
• 10 mg: Each green film-coated, round, biconvex tablet debossed with M on one side of the tablet and PA3 on the other side contains: perindopril arginine 10 mg.

Composition

2.5 mg, 5 mg and 10 mg tablets

Active principle: Perindopril arginine

Excipients:

2.5 mg: lactose monohydrate, magnesium stearate, maltodextrin, polyvinyl alcohol, povidone, silica, sodium starch glycolate, soya lecithin, talc, titanium dioxide and xanthan gum.

5 mg and 10 mg: FD&C blue #1, iron oxide yellow, lactose monohydrate, magnesium stearate, maltodextrin, polyvinyl alcohol, povidone, quinoline yellow aluminium lake, silica, sodium starch glycolate, soya lecithin, talc, titanium dioxide and xanthan gum.

Packaging

Each dosage strength is available in bottles of 30, 100 and 500 tablets.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name:	Perindopril arginine
Chemical name:	(2S, 3aS, 7aS)-1-[(2S)-2-{[(2S)-1-(ethoxy-1-oxopentan-2-yl]amino}propanoyl]octahydro-1H-indole-2-carboxylic acid L-Arginine
Molecular formula and molecular mass:	C19H32N2O5.C6H14N4O2 542.67 g/mol
Structural formula:

CLINICAL TRIALS

Comparative Bioavailability Studies

A double blinded, balanced, randomized, two-treatment, two-period, two-sequence, single-dose, crossover, comparative bioavailability study of Mylan-Perindopril Arginine (perindopril arginine) 10 mg tablets (Mylan Pharmaceuticals ULC) and ^PrCOVERSYL^® (perindopril erbumine) 8 mg tablets (Servier Canada Inc.) was conducted with twenty-two (22) healthy adult Asian male subjects under fasting conditions. A summary of the bioavailability data is presented in the table below.

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

* Mylan-Perindopril Arginine (perindopril arginine) 10 mg tablets (Mylan Pharmaceuticals ULC).

^{† Pr} Coversyl^® (perindopril erbumine) 8 mg tablets by Servier Canada Inc., Canada, were purchased in Canada.

^§ Expressed as the median (range) only.

^€ Expressed as the arithmetic mean (CV%) only.

Perindopril erbumine was first approved in France in 1988 and has been approved worldwide in 106 countries including European countries, USA and Japan. The efficacy and the safety of perindopril have also been established in a broad range of special patient populations.

Hypertension

Study demographics and trial design

The efficacy of perindopril erbumine in mild to moderate essential hypertension was demonstrated in two multicenter, double-blind, placebo-controlled U.S. studies (protocols PB and PC).

Efficacy results

The efficacy results from the two multicenter, double-blind, placebo-controlled U.S. studies (protocols PB and PC) evaluating the use of perindopril erbumine in patients with mild to moderate essential hypertension is presented in Table 6. In study PB, the blood pressure (BP) results are provided both at trough (measurements taken prior to dosing) and at peak (measurements taken 6 hrs post- dosing), while in study PC, only the trough (measurements taken prior to dosing) measurements of BP were collected. For both studies, the BP measurements were taken in the supine position.

Table 6 - Efficacy results for primary endpoints of pivotal placebo-controlled US clinical trials in mild to moderate essential hypertension

1. 1. Statistically significant difference between perindopril and placebo (p≤0.05)

NM Not measured – Blood pressure measurements at peak were not taken in Study PC.

OD Once-a-day

BID Twice-a-day

Congestive Heart Failure

Study demographics and trial design

The efficacy of perindopril erbumine in Congestive Heart Failure was based on two pivotal studies (NP00032 and NP05251) in the form of multicentre, randomized, double- blind placebo controlled studies in addition to the usual background therapy.

Table 7 - Summary of patient demographics for clinical trials in the indication of Congestive Heart Failure

Efficacy results

The first pivotal trial (Report NP 32) was a phase III, multicentre, double-blind placebo controlled study. The aim of this trial was to assess the efficacy and the safety of perindopril erbumine (2-4 mg) once a day for 3 months, in 125 outpatients with chronic congestive heart failure (CHF) receiving baseline diuretic treatment with or without digitalis. Sixty-one (61) patients were randomly assigned to the perindopril group and 64 to the placebo group.

The main efficacy criterion was the number of patients with success on global efficacy assessment. Success was defined as the combination of the following items: improvement in overall HF severity score between Visit 0 (day 1) and visit 3 (day 90); increase in exercise test duration ≥10% between Visit 0 and Visit 3; stability or decrease in diuretic and/or digitalis dosing-regimen; no parenteral administration of diuretics or nitrates, no study premature discontinuation for the following reasons: patients death, adverse reaction, poor study drug compliance, patient lost to follow-up. Incomplete combinations of these items were considered as failures. The secondary efficacy criteria were Visit 3/Visit 0 evolutions in NYHA functional classes, overall HF severity scores, exercise test durations, cardiothoracic ratios (C/T) on chest X ray.

Concerning the efficacy results of the main criterion, the numbers (and percentages) of patients with success were 56% (34 out of 61) and 31% (20 out of 64) in perindopril and placebo groups respectively. This difference was statistically significant (p=0.006).

The safety assessment was obtained from numbers of patients with adverse events (AE) leading to study discontinuation, numbers of patients experiencing one or more AE (spontaneous and post-questioning complaints, except those already present on baseline records) and numbers of patients with clinically significant changes from baseline laboratory results.

This 3-month double-blind placebo controlled study showed that perindopril erbumine (2-4 mg per os once a day) resulted in an improvement of clinical signs and symptoms in patients with chronic mild to moderate congestive heart failure receiving baseline diuretic and digitalis therapy. The clinical improvement was confirmed by an increase in exercise test duration and was associated with a good clinical and laboratory safety profile.

Table 8 - Efficacy results for primary and secondary endpoints of studies in the indication of Congestive Heart Failure

The second pivotal trial (Report NP 5251) was also a phase III study. This trial entitled “Study of perindopril in chronic congestive heart failure. A six month multicenter double-blind study of perindopril versus placebo”. The aim of this study was to assess the efficacy and the safety of perindopril erbumine, 2-4 mg once a day for 6 months, in 212 outpatients with congestive heart failure (CHF) receiving baseline diuretic treatment with or without digitalis.

One hundred and six (106) patients were randomly assigned in the perindopril group and 106 to the placebo group.

The main efficacy criterion was the evolution of exercise test durations. The secondary efficacy criteria were: the evolution of overall HF severity scores and NYHA functional classes; the evolution of cardiothoracic ratios (C/T) on chest X ray; the evolution of left ventricular ejection fraction (LVEF), cardiac output (CO), maximal O₂ consumption (VO₂ max) and anaerobic threshold; the number of patients with success on global efficacy assessment.

The improvement of exercise test durations was more favourable in the perindopril group compared to the placebo group but the difference did not reach statistical significance; increases in durations were respectively 84.4 (126.4 SD) and 55.0 (148.5 SD) seconds (p=0.21) according to PP analysis. The p value was 0.15 as per ITT analysis.

The safety assessment was obtained from numbers of patients with adverse events (AE) leading to study discontinuation, numbers of patients experiencing one or more AE (spontaneous complaints, except those already present on baseline records) and numbers of patients with clinically significant changes from baseline laboratory results.

This 6-month double-blind placebo controlled study carried out in 212 patients showed that perindopril erbumine (2-4 mg per os once a day) resulted in an improvement of clinical signs and symptoms in patients with chronic congestive heart failure receiving baseline diuretic or diuretic and digitalis therapy. This improvement was clearly demonstrated and statistically significant in more severe patients.

Hypertensive and/or Post-MI Patients with Stable Coronary Artery Disease

Study demographics and trial design

The efficacy of perindopril erbumine in Reduction of cardiovascular risk in hypertension or post-myocardial infarction was based on one mortality/morbidity study (EUROPA trial, NP15314) which was a multi-centre, randomized, double-blind placebo controlled study looking at perindopril erbumine in addition to conventional therapy such as platelet inhibitors, β-blockers, lipid lowering agents, nitrates, calcium channel blockers or diuretics.

Table 9 - Summary of patient demographics for clinical trials in the indication of Reduction of the cardiovascular risk in hypertension or post-myocardial infarction

The EURopean trial on reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) study was conducted in 12,218 patients (98% Caucasian) who had evidence of stable coronary artery disease without clinical heart failure. Patients had evidence of coronary artery disease documented by previous myocardial infarction more than 3 months before screening, coronary revascularisation more than 6 months before screening, angiographic evidence of stenosis (≥70% stenosis in ≥1 major coronary arteries), or a positive stress test in men with a history of chest pain. After a run-in period of 4 weeks during which all patients received perindopril 2 mg to 8 mg, the patients were randomly assigned to perindopril 8 mg once daily (n=6,110) or matching placebo (n=6,108), in addition to conventional therapy. The mean follow-up was 4.2 years.

The study examined the long-term effects of perindopril on time to first event of cardiovascular mortality, nonfatal myocardial infarction, or resuscitated cardiac arrest in patients with hypertension and/or previous myocardial infarction having stable coronary artery disease. Hypertension was defined as BP ≥140/90 mmHg, or being treated for hypertension, at baseline.

The mean age of patients was 60 years; 85% were male. The majority of patients were hypertensive (58%), had suffered a previous myocardial infarction (65%), or both. 92% were taking platelet inhibitors, 63% were taking β-blockers, 56% were taking lipid-lowering therapy,

43% were on nitrates, 31% were on calcium channel blockers, and 9% on diuretics.

Efficacy results

The EUROPA study showed that perindopril significantly reduced the relative risk for the primary endpoint events (ARR= -1.9%, Table 10). This beneficial effect is largely attributable to a reduction in the risk of nonfatal myocardial infarction. This beneficial effect of perindopril on the primary outcome, evident after about one year, became statistically significant after 3 years of treatment (Figure 1). Systolic and diastolic blood pressure reduction was 4.9 ± 16.3 mmHg and 2.4 ± 8.7 mmHg more in the perindopril group compared to the placebo group throughout the study (Figure 2).

Table 10 - Primary Endpoint and Relative Risk Reduction

RRR: relative risk reduction; MI: myocardial infarction; CI = confidence interval

There were no significant differences in numbers of deaths between the groups (375 in the perindopril group and 420 deaths in the control group). However, ten patients died during the open run-in period of the study, of whom 7 from cardiovascular causes, including stroke. A total of 795 patients (out of 12,230; 6.5%) died during the study, 464 of the 795 died (58%) from a cardiovascular cause.

The outcome was similar across all predefined subgroups by age, underlying disease or concomitant medication (Figure 3).

Figure 1 - Time to First Occurrence of Primary Endpoint

Figure 2 - Systolic and Diastolic Blood Pressure for the perindopril and placebo Treatment Arms (Double-blind treatment period)

Figure 3 - Effect of Treatment with perindopril in Predefined Subgroups

DETAILED PHARMACOLOGY

Mechanism of action

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). The active diacids of perindopril (perindoprilat) and ramipril (ramiprilat) proved to possess a similar inhibitory potency against rat plasma converting enzyme (IC₅₀ = 2 to 3 x 10^-9M). Both diacids were more active than enalaprilat or captopril (IC₅₀ = 1 to 6 x 10^-8M).

In Vivo Studies

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.) one 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%). Perindopril orally administered at 1 mg/kg to sodium replete spontaneous hypertensive rats was shown to be more potent than enalapril (1 mg/kg) both in terms of intensity (91% of inhibition versus 64%, 4 hours after dosing) and duration of action (68% of inhibition versus 12%, 12 hours after dosing).

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.

TOXICOLOGY

Acute toxicity studies

No mortality occurred during the oral studies in the rat and mouse.

Signs of toxicity observed in animals treated intravenously were as follows:

• Convulsive symptoms and severe dyspnoea in mice
• Considerable hypermobility in rats
• Death, by respiratory arrest, occurring within minutes of the injection.

In the dog treated orally with increasing doses of perindopril erbumine, vomiting, reduction in activity, salivation and tachycardia were observed without mortality.

Chronic Toxicity Studies

S-: Low sodium diet N: Normal sodium diet S+: High sodium diet

Carcinogenicity

No evidence of carcinogenicity has been observed during the 104-week study in the B₆ C₃ F₁ mouse treated with oral doses of 0.75, 2 and 7.5 mg/kg/day perindopril erbumine.

No evidence of carcinogenicity has been observed during the 104-week study in the Fischer 344 rat treated with oral doses of 0.75, 2 and 7.5 mg/kg/day perindopril erbumine.

At least one ACE inhibitor has caused an increase in the incidence of oxyphilic renal tubular cells and oncocytomas in rats. The potential of ACE inhibitors to cause this effect in man is unknown. Moreover, the progression of oxyphilic cells to oncocytomas is rare in humans and when it does occur, it is considered to be benign.

Genotoxicity

Perindopril erbumine was not shown to induce genic mutation (AMES test and mouse lymphoma test) nor chromosomal mutation (in vivo and in vitro clastogenicity tests and micronuleus test) in prokaryotes and eukaryotes, nor primary change of yeast DNA (gene conversion test).

Reproductive and Developmental Toxicity

Fertility Studies

Studies were performed by administrating perindopril erbumine by the oral route. Pivotal studies are tabulated hereafter.

PR (n) = Days of pregnancy; G = Generation; D = Day

Teratogenicity Studies

PR (n) = nth day of pregnancy

No teratogenic effects of perindopril were seen in studies of pregnant rats, mice, rabbits and cynomolgus monkeys. On a mg/m² basis, the doses used in these studies were 6 times (in mice),

670 times (in rats), 50 times (in rabbits) and 17 times (in monkeys) the maximum recommended human dose (assuming a 50 kg adult). On a mg/kg basis, these multiples are 60 times (in mice),

3,750 times (in rats), 150 times (in rabbits) and 50 times (in monkeys) the maximum recommended human dose.

Post-Natal Studies

PC (n) = Days post-coitum; PP (n) = Days post-partum; PR (n) = Days of pregnancy; G = Generation

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