Taro-Quinapril Product Monograph

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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 ...................................................................5

4.3 Administration .................................................................................................................7

4.4 Missed Dose.....................................................................................................................7

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

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING .............................................8

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

7.1 Special Populations ........................................................................................................ 13

7.1.1 Pregnant Women ...................................................................................................... 13

7.1.2 Breast-feeding ........................................................................................................... 14

7.1.3 Pediatrics (<18 years of age) ...................................................................................... 14

7.1.4 Geriatrics (>65 years of age) ...................................................................................... 14

1. 8.

   ADVERSE REACTIONS ........................................................................................................... 15

   8.1 Adverse Reaction Overview ............................................................................................ 15

   8.2 Clinical Trial Adverse Reactions ....................................................................................... 15

   8.3 Less Common Clinical Trial Adverse Reactions ................................................................. 17

   8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data .................................................................................................................................... 18

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

2. 9.

   DRUG INTERACTIONS ........................................................................................................... 19

   9.1 Serious drug interactions ................................................................................................ 19

   9.3 Drug-Behavioural Interactions ........................................................................................ 19

   9.4 Drug-Drug Interactions ................................................................................................... 19

   9.5 Drug-Food Interactions ................................................................................................... 26

   9.6 Drug-Herb Interactions ................................................................................................... 26

   9.7 Drug-Laboratory Test Interactions .................................................................................. 26

10 CLINICAL PHARMACOLOGY ................................................................................................. 26

10.1 Mechanism of Action .................................................................................................... 26

10.2 Pharmacodynamics ...................................................................................................... 27

10.3 Pharmacokinetics ......................................................................................................... 28

11 STORAGE, STABILITY AND DISPOSAL ................................................................................... 29

PART II: SCIENTIFIC INFORMATION .......................................................................................... 30

13 PHARMACEUTICAL INFORMATION ...................................................................................... 30

1. 14.

   CLINICAL TRIALS ................................................................................................................. 31

   14.1 Trial Design and Study Demographics............................................................................ 31

   14.2 Study Results................................................................................................................ 31

   14.3 Comparative Bioavailability Studies............................................................................... 31

15 MICROBIOLOGY .................................................................................................................. 31

16 NON-CLINICAL TOXICOLOGY................................................................................................ 31

17 SUPPORTING PRODUCT MONOGRAPHS .............................................................................. 39

PATIENT MEDICATION INFORMATION ..................................................................................... 40

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

TARO-QUINAPRIL (Quinapril Tablets) is indicated for:

• Hypertension: treatment of essential hypertension. It is usually administered in association with other drugs, particularly thiazide diuretics.
• Congestive Heart Failure: treatment of congestive heart failure as adjunctive therapy when added to diuretics and/or digitalis glycosides.

The safety and efficacy of Quinapril Tablets in renovascular hypertension has not been established; therefore, use in this condition is not recommended.

Treatment with TARO-QUINAPRIL should be initiated under close medical supervision.

1.1 Pediatrics (<18 years of age)

Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics (> 65 years of age)

Of the total number of subjects in clinical studies of Quinapril Tablets, 21% were ≥65 years old. (There was no distinction between patients >65 or >75 years.) No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience did not identify differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

2 CONTRAINDICATIONS

TARO-QUINAPRIL is contraindicated in:

• Patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
• Patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme (ACE) inhibitor (see 7 WARNINGS AND PRECAUTIONS, Immune, Head and Neck Angioedema).
• Combination with sacubitril/valsartan due to increased risk of angioedema. TARO-QUINAPRIL must not be initiated until at least 36 hours have elapsed following discontinuation of sacubitril/valsartan therapy. If treatment with TARO-QUINAPRIL is stopped, sacubitril/valsartan therapy must not be initiated until 36 hours after the last dose of TARO-QUINAPRIL.
• Women who are pregnant, intend to become pregnant, or of childbearing potential who are not using adequate contraception (see 7 WARNINGS AND PRECAUTIONS, 7.1 Special Populations, 7.1.1 Pregnant Women and 8 ADVERSE REACTIONS).
• Nursing women (see 7 WARNINGS AND PRECAUTIONS, 7.1 Special Populations, 7.1.2 Breast-feeding).

• Combination with aliskiren-containing medicines in patients with:

  • diabetes mellitus (type 1 or type 2),
  • moderate to severe kidney insufficiency (GFR < 60 mL/min/1.73 m²),
  • hyperkalemia (> 5mMol/L) or
  • congestive heart failure who are hypotensive (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular, Dual blockade of the Renin-Angiotensin System (RAS)and Renal, Renal Impairment, and 9 DRUG INTERACTIONS, 9.4 Drug-Drug Interactions, Aliskiren-containing medicines and Angiotensin receptor blockers (ARBs)).

• Combination with angiotensin receptor blockers (ARBs) in patients with:

  • diabetes mellitus (type 1 or type 2) with end organ damage,
  • moderate to severe kidney insufficiency (GFR < 60 mL/min/1.73m²),
  • hyperkalemia (> 5mMol/L) or
  • congestive heart failure who are hypotensive (see DRUG INTERACTIONS, Angiotensin receptor blockers (ARBs).

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

Dosage of TARO-QUINAPRIL must be individualized.

4.2 Recommended Dose and Dosage Adjustment

Hypertension

Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure (BP) elevation and salt restriction. The dosage of other antihypertensive agents being used with TARO-QUINAPRIL may need to be adjusted.

Monotherapy:

The recommended initial dose of TARO-QUINAPRIL in patients not on diuretics is 10 mg once daily. An initial dose of 20 mg once daily can be considered for patients without advanced age, renal impairment, or concomitant heart failure and who are not volume depleted (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension). Dosage should be adjusted according to BP response, generally at intervals of 2-4 weeks. A dose of 40 mg daily should not be exceeded.

In some patients treated once daily, the antihypertensive effect may diminish towards the end of the dosing interval. This can be evaluated by measuring BP just prior to dosing to determine whether satisfactory control is being maintained for 24 hours. If it is not, either 2x daily administration with the same total daily dose, or an increase in dose should be considered. If BP is not controlled with TARO-QUINAPRIL alone, a diuretic may be added. After the addition of a diuretic, it may be possible to reduce the dose of TARO-QUINAPRIL.

Concomitant Diuretic Therapy:

Symptomatic hypotension occasionally may occur following the initial dose of TARO-QUINAPRIL and is more likely in patients who are currently being treated with a diuretic. The diuretic should, if possible, be discontinued for 2-3 days before beginning therapy with TARO-QUINAPRIL to reduce the likelihood of hypotension depleted (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension). If the diuretic cannot be discontinued, an initial dose of 5 mg TARO-QUINAPRIL should be used with careful medical supervision for several hours and until BP has stabilized. The dosage of TARO-QUINAPRIL should subsequently be titrated (as described above) to the optimal response.

Dosing Adjustment in Renal Impairment:

For use in hemodialysis patients, see 7 WARNINGS AND PRECAUTIONS, Immune, Anaphylactoid Reactions during Membrane Exposure. Quinapril should be administered on days when dialysis is not performed.

Starting doses should be reduced according to the following guidelines:

Patients should subsequently have dosage titrated (as described above) to the optimal response.

Dosage in the Elderly (>65 years):

The recommended initial dosage of TARO-QUINAPRIL is 10 mg once daily (depending on renal function), followed by titration (as described above) to the optimal response.

Congestive Heart Failure

TARO-QUINAPRIL is indicated as adjunctive therapy to diuretics, and/or cardiac glycosides. Therapy should be initiated under close medical supervision. BP and renal function should be monitored, both before and during treatment with TARO-QUINAPRIL, because severe hypotension and, more rarely, consequent renal failure have been reported (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension).

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, to reduce the likelihood of hypotension. Serum potassium should also be monitored (see 7 WARNINGS AND PRECAUTIONS and 9 DRUG INTERACTIONS).

The recommended starting dose is 5 mg once daily, to be administered under close medical supervision to determine the initial effect on BP. After the initial dose, the patient should be observed for ≥2 hours, or until the pressure has stabilized for ≥1 additional hour (See 7 WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension). This dose may improve symptoms of heart failure, but increases in exercise duration have generally required higher doses. Therefore, if the initial dosage of TARO-QUINAPRIL is well tolerated or after effective management of symptomatic hypotension following initiation of therapy, the dose should then be increased gradually to 10 mg once daily, then 20 mg once daily, and to 40 mg per day given in 2 equally divided doses, depending on the patient's response. The maximum daily dose is 40 mg.

The dose titration may be done at weekly intervals, as indicated by the presence of residual signs or symptoms of heart failure.

Renal Impairment or Hyponatremia:

Kinetic data indicate that Quinapril Tablets elimination is dependent on the level of renal function. The recommended initial dose of TARO-QUINAPRIL is 5 mg in patients with a creatinine clearance of 30-60 mL/min and 2.5 mg in patients with a creatinine clearance of 10-30 mL/min. There is insufficient data for dosage recommendation in patients with a creatinine clearance <10 mL/min. If the initial dose is well tolerated, TARO-QUINAPRIL may be administered the following day as a 2x daily regimen. In the absence of excessive hypotension or significant deterioration of renal function, the dose may be increased at weekly intervals based on clinical and hemodynamic response (See 7 WARNINGS AND PRECAUTIONS and 8 ADVERSE REACTIONS).

4.3 Administration

See 4 DOSAGE AND ADMINISTRATION, 4.2 Recommended Dose and Dosage Adjustment

4.4 Missed Dose

A patient missing a dose should take it as soon as they remember to. If it is almost time for the next dose, the missed dose should be skipped. The patient should be cautioned against taking two doses concomitantly to “make up” for the missed dose.

5 OVERDOSAGE

No data are available regarding overdosage with Quinapril Tablets. The most likely clinical manifestation would be symptoms attributable to severe hypotension, which should be normally treated by intravenous volume expansion with 0.9% sodium chloride. Hemodialysis and peritoneal dialysis have little effect on the elimination of quinapril and quinaprilat.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

TARO-QUINAPRIL 5 mg: white to off-white, round, convex faced, film coated tablets debossed with ‘18’ on one side and break line on the other side.

TARO-QUINAPRIL 10 mg: white to off-white, round, convex faced, film coated tablets debossed with ‘RX549’ on one side and plain on the other side.

TARO-QUINAPRIL 20 mg: white to off-white, round, convex faced, film coated tablets debossed with ‘RX550’ on one side and plain on the other side.

TARO-QUINAPRIL 40 mg: white to off-white, round, convex faced, film coated tablets debossed with ‘RX551’ on one side and plain on the other side.

All strengths are available in HDPE Bottles of 30s, 100s, 500s and 1000s.

7 WARNINGS AND PRECAUTIONS

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

Cardiovascular

Dual blockade of the Renin-Angiotensin System (RAS)

Dual blockade of the Renin-Angiotensin System (RAS): There is evidence that co-administration of angiotensin converting enzyme (ACE) inhibitors, such as TARO-QUINAPRIL, or of angiotensin receptor antagonists (ARBs) with aliskiren increases the risk of hypotension, syncope, stroke, hyperkalemia and deterioration of renal function, including acute renal failure, in patients with diabetes mellitus (type 1 or type 2) and/or moderate to severe kidney insufficiency (GFR < 60 mL/min/1.73 m²). Therefore, the use of TARO-QUINAPRIL in combination with aliskiren-containing drugs is contraindicated in these patients (see 2 CONTRAINDICATIONS).

Further, co-administration of ACE inhibitors, including TARO-QUINAPRIL, 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. Administration should be limited to individually defined cases with close monitoring of renal function and blood potassium levels (see 2 CONTRAINDICATIONS).

Hypotension

Symptomatic hypotension has occurred after administration of Quinapril Tablets, usually after the first or second dose or when the dose was increased. It is more likely to occur in patients who are volume depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. In patients with ischemic heart or cerebrovascular disease, an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident (See 8 ADVERSE REACTIONS). Because of the potential fall in blood pressure in these patients, therapy with TARO-QUINAPRIL should be started under close medical supervision (see 4 DOSAGE AND ADMINISTRATION). Such patients should be followed closely for the first weeks of treatment and whenever the dose of TARO-QUINAPRIL is increased. In patients with severe congestive heart failure, with or without associated renal insufficiency, excessive hypotension has been observed and may be associated with oliguria and/or progressive azotemia, and rarely with acute failure and/or death.

If hypotension occurs, the patient should be placed in 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 TARO-QUINAPRIL and/or reduced concomitant diuretic therapy should be considered.

Valvular Stenosis

There is concern on theoretical grounds that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators because they do not develop as much afterload reduction.

Driving and Operating Machinery

The ability to engage in activities such as operating machinery or operating a motor vehicle may be impaired, especially when initiating quinapril therapy.

Exercise caution when driving or operating a vehicle or potentially dangerous machinery.

Endocrine and Metabolism

Hyperkalemia

Elevated serum potassium (>5.7 mMol/L) was observed in approximately 2% of patients receiving Quinapril Tablets. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was a cause of discontinuation of therapy in <0.1% of hypertensive patients. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of agents to treat hypokalemia, potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs known to raise serum potassium levels. Because of the risk of hyperkalemia it is advised that combination therapy be initiated with caution and the patient’s serum potassium levels be closely monitored (see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Test, Hyperkalemia, 8 ADVERSE

REACTIONS, and 9 DRUG INTERACTIONS, 9.4 Drug-Drug Interactions, Agents Increasing Serum Potassium, Trimethoprim-containing products).

Hyponatraemia and SIADH

Syndrome of Inappropriate Anti-diuretic Hormone (SIADH) and subsequent hyponatraemia has been observed in some patients treated with other ACE inhibitors. It is recommended that serum sodium levels be monitored regularly in the elderly and in other patients at risk of hyponatraemia.

Hypoglycemia and Diabetes

ACE inhibitors may reduce insulin resistance and may lead to hypoglycemia in diabetic patients on insulin or oral hypoglycemic agents; closer monitoring of diabetic patients may be required.

Hematologic

Neutropenia/Agranulocytosis

Agranulocytosis and bone marrow depression have been caused by ACE inhibitors. Agranulocytosis did occur during Quinapril Tablets treatment in 1 patient with a history of neutropenia during previous captopril therapy. Periodic monitoring of white blood cell counts should be considered, especially in patients with collagen vascular disease and/or renal disease.

Hepatic/Biliary/Pancreatic

Patients with Impaired Liver Function

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

Elevations of liver enzymes and/or serum bilirubin have been reported for Quinapril Tablets (see 8 ADVERSE REACTIONS). Should the patient receiving TARO-QUINAPRIL 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 TARO-QUINAPRIL should be considered when appropriate.

There are no adequate studies in patients with cirrhosis and/or liver dysfunction. TARO-QUINAPRIL 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.

TARO-QUINAPRIL, when combined with a diuretic should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. The metabolism of quinapril to quinaprilat is normally dependent upon hepatic esterase. Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired de-esterification of quinapril.

Immune

Hypersensitivity to ACE inhibitor

Head and Neck Angioedema

Head and neck angioedema has been reported in patients treated with Quinapril Tablets. Angioedema associated with laryngeal involvement may be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, TARO-QUINAPRIL 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, likely to cause airway obstruction, appropriate therapy (including but not limited to 0.3 to 0.5 mL of subcutaneous epinephrine solution 1:1000) should be administered promptly (see 8 ADVERSE REACTIONS).

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

Patients taking a concomitant mTOR inhibitor (e.g. temsirolimus), DPP-4 inhibitor (e.g. sitagliptin) or neutral endopeptidase (NEP) inhibitor may be at increased risk for angioedema. Caution should be used when either initiating ACE inhibitor therapy in patients already taking a mTOR, DPP-4 inhibitor or NEP inhibitor or vice versa (see 9 DRUG INTERACTIONS).

Patients with a history of angioedema related or unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see 2 CONTRAINDICATIONS).

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. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Anaphylactoid Reactions during Membrane Exposure

Anaphylactoid reactions have been reported in patients dialysed 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 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 desensitizing 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 have reappeared upon inadvertent rechallenge to an ACE inhibitor.

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 Quinapril Tablets (see 9 DRUG INTERACTIONS).

Monitoring and Laboratory Tests

Hematology:

Periodic monitoring of white blood cell counts should be considered, especially in patients with collagen vascular disease and/or renal disease (see 7 WARNINGS AND PRECAUTIONS, Hematologic, Neutropenic/Agranulocytisis).

Hyperkalemia:

Patients with renal insufficiency, diabetes mellitus or concomitantly taking agents to treat hypokalemia may be at increased risk of developing hyperkalemia. Serum potassium should be monitored regularly (see 2 CONTRAINDICATIONS, 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Hyperkalemia).

Hyponatraemia: (see 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Hyponatraemia and SIADH). It is recommended that serum sodium levels be monitored regularly in the elderly and in other patients at risk of hyponatraemia.

Creatinine and Blood Urea Nitrogen: Increases (>1.25x the upper limit of normal) in serum creatinine and blood urea nitrogen (BUN) were observed in 2% each of patients treated with Quinapril Tablets alone. Increases were more likely to occur in patients receiving concomitant diuretic therapy than in those on Quinapril Tablets alone (see 7 WARNINGS AND PRECAUTIONS, Renal, Renal Impairment). These increases often reversed on continued therapy. In controlled studies of heart failure, increases in BUN and serum creatinine were observed in 11% and 8%, respectively, of patients treated with Quinapril Tablets. Most often, these patients were receiving diuretics with or without digitalis. Use of TARO-QUINAPRIL Tablets should include appropriate assessment of renal function.

Hepatic: Elevations of liver enzymes and/or serum bilirubin have occurred in patients receiving Quinapril Tablets. If a patient receiving TARO-QUINAPRIL experience any unexplained symptoms, particularly during the first weeks or months of treatment, a full set of liver function tests and any other investigation should be carried out. Discontinuation of TARO-QUINAPRIL should be considered when appropriate. In patients with pre-existing liver abnormalities, baseline liver function tests should be obtained before administration of the drug and response and metabolic effects should be closely monitored (see 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, Patients with Impaired Liver Function).

Peri-Operative Considerations

Surgery/Anaesthesia

In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, Quinapril Tablets will block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

Renal

Renal Impairment

The use of ACE inhibitors, including TARO-QUINAPRIL, with ARBs or aliskiren-containing drugs is contraindicated in patients with moderate to severe kidney insufficiency (GFR < 60 mL/min/1.73m²) (see 2 CONTRAINDICATIONS and 9 DRUG INTERACTIONS, 9.4 Drug-Drug Interactions, Aliskiren-containing medicines and Angiotensin receptor blockers (ARBs)).

As a consequence of inhibiting the renin-angiotensin-aldosterone system (RAAS), changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the RAAS, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk (see 4 DOSAGE AND ADMINISTRATION and 8 ADVERSE REACTIONS).

Use of TARO-QUINAPRIL should include appropriate assessment of renal (see 4 DOSAGE AND ADMINISTRATION and 8 ADVERSE REACTIONS).

Respiratory

Cough

Cough has been reported with the use of ACE inhibitors, including quinapril. Characteristically, the cough is dry and persistent and usually disappears only after withdrawal or lowering of the dose of TARO-QUINAPRIL. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of the cough.

Skin

Psoriasis and Aggravation of Psoriasis

Psoriasis or aggravation of psoriasis have been reported in patients receiving ACE inhibitors. Quinapril should be used with caution in patients, especially those with a medical history or family history of psoriasis. Consider discontinuation of quinapril if clinically significant psoriasis or psoriasis aggravation occurs.

7.1 Special Populations

7.1.1 Pregnant Women

Quinapril is contraindicated in pregnancy (see 2 CONTRAINDICATIONS and 8 ADVERSE REACTIONS). ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, TARO-QUINAPRIL should be discontinued as soon as possible.

The use of ACE inhibitors during the second and third trimesters of pregnancy 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; oligohydramnios in this setting has been 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.

If oligohydramnios is observed, a non-stress test (NST), and/or a biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. If concerns regarding fetal well-being still persist, a contraction stress testing (CST) should be considered. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Animal Data: No fetotoxic or teratogenic effects were observed in rats at doses as high as 300 mg/kg/day (180x the maximum daily human dose), despite maternal toxicity at 150 mg/kg/day. Offspring body weights were reduced in rats treated late in gestation and during lactation with doses of ≥25 mg/kg/day. Quinapril hydrochloride was not teratogenic in rabbits; however, maternal and embryo toxicity were seen in some rabbits at 1 mg/kg/day.

No adverse effects on fertility or reproduction were observed in rats at dose levels ≤100 mg/kg/day (60x the maximum daily human dose) (see 16 NON-CLINICAL TOXICOLOGY, Table 5).

7.1.2 Breast-feeding

The presence of concentrations of ACE inhibitor has been reported in human milk. The use of TARO-QUINAPRIL is contraindicated during breast-feeding (see 2 CONTRAINDICATIONS).

7.1.3 Pediatrics (<18 years of age)

No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4 Geriatrics (>65 years of age)

Of the total number of subjects in clinical studies of Quinapril Tablets, 21% were ≥65 years old. (There was no distinction between patients >65 or >75 years.) No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see 4 DOSAGE AND ADMINISTRATION and 8 ADVERSE REACTIONS).

Elderly patients exhibited increased area under the plasma concentration time curve and peak levels for quinaprilat compared to values observed in younger patients; this appeared to relate to decreased renal function rather than to age itself.

8. ADVERSE REACTIONS

8.1 Adverse Reaction Overview

This information is not available for this drug product.

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.

Hypertension

Quinapril Tablets monotherapy was evaluated for safety in 2005 hypertensive patients, including 313 elderly patients, enrolled in placebo-controlled clinical trials. There was no increase in the incidence of adverse events (AEs) in elderly patients given the same daily dosages. Quinapril Tablets was evaluated for long-term safety in >1100 patients treated for≥1 year. AEs were usually mild and transient in nature.

The most serious AE was angioedema (0.1%). Renal insufficiency (1 case), agranulocytosis (1 case) and mild azotemia (2 cases in CHF patients) have been reported. Myocardial infarction and cerebrovascular accident occurred, possibly secondary to excessive hypotension in high risk patients (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension).

The most frequent AEs in controlled clinical trials were headache (8.1%), dizziness (4.1%), cough (3.2%), fatigue (3.2%), rhinitis (3.2%), nausea and/or vomiting (2.3%), and abdominal pain (2.0%).

Discontinuation of therapy because of AEs was required in 4.7% of patients treated with Quinapril Tablets in placebo-controlled trials.

Congestive Heart Failure (CHF)

Out of the 1108 patients with CHF, 605 (55%) experience ≥1 AE. In controlled clinical trials, 525 of these patients were evaluated for safety. The frequencies of AEs were similar for both sexes as well as for younger (< 65 years) and older (> 65 years) patients.

The most serious non-fatal AEs/reactions were angioedema (0.1%), chest pain of unknown origin (0.8%), angina pectoris (0.4%), hypotension (0.1%) and impaired renal function (see 7 WARNINGS AND PRECAUTIONS, Renal, Renal Impairment). Myocardial infarct and cerebrovascular accident occurred (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension). Rare cases of eosinophilic pneumonitis have been reported. Hepatitis or hepatic failure have rarely been observed with other ACE inhibitors.

The most frequent AEs in controlled clinical trials were dizziness (11.2%), cough (7.6%), chest pain (6.5%), dyspnea (5.5%), fatigue (5.1%), and nausea/vomiting (5.0%).

Discontinuation due to AEs in controlled clinical trials was required for 41 (8.0%) patients. Hypotension (0.8%) and cough (0.8%) were the most common reasons for withdrawal.

AEs occurring in ≥0.5% of 2005 hypertensive patients treated with Quinapril Tablets monotherapy and in 525 patients with CHF treated with Quinapril Tablets as adjunctive therapy, in controlled clinical trials, are presented in the table below:

¹Quinapril Tablets monotherapy

²Quinapril Tablets as adjunctive therapy to diuretic and/or digitalis.

8.3 Less Common Clinical Trial Adverse Reactions

AEs occurring in <0.5% of patients with hypertension or CHF include:

Clinical adverse experiences probably, possibly, or definitely related, or of uncertain relationship to therapy occurring in 0.5% to < 1.0% of the patients treated with quinapril (with or without concomitant diuretic) in controlled or uncontrolled clinical trials and less frequent events seen in clinical trials or post-marketing experience (indicated by a *) included:

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

Clinical Trial Findings

This information is not available for this drug product.

8.5 Post-Market Adverse Reactions

Blood and lymphatic system disorders: Thrombocytopenia, hemolytic anemia

Cardiovascular disorders: Postural hypotension, syncope

General disorders and administration site conditions: Anaphylactoid reaction; photosensitivity reaction

Skin and subcutaneous tissue disorders: Alopecia, exfoliative dermatitis, pemphigus

See 8 ADVERSE REACTIONS, 8.3 Less Common Clinical Trial Adverse Reactions

9. DRUG INTERACTIONS

9.1 Serious drug interactions

9.3 Drug-Behavioural Interactions

Alcohol use should be avoided when taking TARO-QUINAPRIL as it can cause orthostatic hypotension

9.4 Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 3 - Established or Potential Drug-Drug Interactions

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

9.5 Drug-Food Interactions

The rate and extent of quinapril absorption are diminished moderately (approximately 25-30%) when Quinapril Tablets are administered during a high-fat meal (see 4 DOSAGE AND ADMINISTRATION). However, no effect on quinapril absorption occurs when taken during a regular meal.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

TARO-QUINAPRIL is a nonpeptide, nonsulphydryl inhibitor of angiotensin converting enzyme (ACE), which is used in the treatment of hypertension.

ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor angiotensin II. After absorption, quinapril is rapidly de-esterified to quinaprilat (quinapril diacid), its principal active metabolite. Its primary mode of action is to inhibit circulating and tissue ACE, thereby decreasing vasopressor activity and aldosterone secretion. Although the decrease in aldosterone is small, it results in a small increase in serum K⁺ (see 7 WARNINGS AND PRECAUTIONS). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. Although Quinapril Tablets had antihypertensive activity in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to ACE inhibitor monotherapy than non-black patients.

ACE is identical to kininase II. Thus, quinapril may interfere with the degradation of bradykinin, a potent peptide vasodilator. However, it is not known whether this system contributes to the therapeutic effects of TARO-QUINAPRIL.

In animal studies, the antihypertensive effect of quinapril outlasts its inhibitory effect on circulating ACE. Tissue ACE inhibition more closely correlates with the duration of antihypertensive effects and this may be related to enzyme binding characteristics.

In Vitro Studies:

Quinapril was shown to be an inhibitor of angiotensin converting enzyme (ACE) in both plasma and tissue. In assays utilizing human plasma as sources of ACE, the diacid form of quinapril (quinaprilat) exhibited greater inhibition of ACE activity than quinapril (6.4 x 10^-10M and 8.4 x 10^-8M, respectively). In rabbit and rat aortic strips, quinapril (10^-7M, 10^-5M) specifically suppressed the contractile responses elicited by angiotensin I (50% contraction at approximately 10^-7M and 10^-6M angiotensin I, respectively), but had no effect on contractions induced by angiotensin II and potassium chloride.

In Vivo Studies:

Following oral dosing of quinapril, captopril or enalapril (0.1-3 mg/kg) to conscious normotensive rats, plasma ACE inhibition was assessed in vivo by the decrease in pressor response to intravenous (IV) angiotensin I, angiotensin II, norepinephrine and bradykinin. Quinapril produced a dose-dependent reduction (44% at 0.1 mg/kg, 81% at 0.3 mg/kg) of angiotensin I (0.32 mcg/kg IV) pressor response and potentiated the response to bradykinin (154% after 0.3 mg/kg quinapril), but had no effect on angiotensin II and norepinephrine responses. Quinapril was equipotent to captopril and enalapril, but had a longer duration of action than captopril. In the conscious dog, oral administration of quinapril (0.1-3 mg/kg) resulted in plasma ACE inhibition comparable to that of enalapril and captopril.

In human subjects, quinapril at single oral doses of 10-20 mg/day produced 95-100% inhibition of plasma ACE activity at 0.5 hour postdose, with >80% inhibition persisting at 24 hours postdose. Multiple oral doses of quinapril to humans for 12-weeks (20-80 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. Once or 2x daily dosing did not alter the results.

10.2 Pharmacodynamics

Hypertension

Administration of 10-40 mg of Quinapril Tablets to patients with essential hypertension results in a reduction of both sitting and standing BP with minimal effect on heart rate. Antihypertensive activity commences within 1 hour with peak effects usually achieved by 2-4 hours after dosing. Achievement of maximum BP lowering effects may require 2 weeks of therapy in some patients.

At the recommended doses, antihypertensive effects are maintained throughout the 24-hour dosing interval in most patients. While the dose response relationship is relatively flat, a dose of 40 mg was somewhat more effective at trough than 10-20 mg, and 2x daily dosing tended to give a somewhat lower BP than 1x daily dosing with the same total daily dose. The antihypertensive effect of Quinapril Tablets was maintained during long-term therapy with no evidence of loss of effectiveness.

Hemodynamic assessments in patients with essential hypertension indicate that BP reduction produced by quinapril is accompanied by a reduction in total peripheral resistance and renal vascular resistance with little or no change in heart rate and cardiac index. There was an increase in renal blood flow which was not significant. Little or no change in glomerular filtration rate (GFR) or filtration fraction was observed.

Quinapril has been shown to reduce microalbuminuria in patients with essential hypertension independently of changes in systemic BP.

When Quinapril Tablets is given together with thiazide-type diuretics, the antihypertensive effects are approximately additive.

Congestive heart failure

Administration of Quinapril Tablets to patients with congestive heart failure (CHF) reduces peripheral vascular resistance, systolic and diastolic BP, pulmonary capillary wedge pressure, and increases cardiac output. The onset of effects was observed within 1 hour and maximal effects occurred at 1.25-4 hours after administration of Quinapril Tablets. Peak hemodynamic effects correlated well with peak plasma levels of quinaprilat (1-4 hours after administration).

Exercise tolerance was improved with Quinapril Tablets therapy.

The effect of Quinapril Tablets on survival in patients with heart failure has not been evaluated.

10.3 Pharmacokinetics

Absorption:

Following oral administration of Quinapril Tablets, peak plasma concentrations of quinapril occur within 1 hour. Based on the recovery of quinapril and its metabolites in urine, the extent of absorption is ≥60%.

Distribution:

Approximately 97% of either quinapril or quinaprilat circulating in plasma is bound to proteins.

Metabolism:

Following absorption, quinapril is de-esterified to its major active metabolite, quinaprilat (quinapril diacid) a potent ACE inhibitor, and to minor inactive metabolites. Quinapril has an apparent half-life in plasma of approximately 1 hour. Peak plasma quinaprilat concentrations occur approximately 2 hours after an oral dose of Quinapril Tablets.

Elimination:

Quinaprilat is eliminated primarily by renal excretion and has an effective accumulation half-life of approximately 3 hours. Quinaprilat has an elimination half-life in plasma of approximately 2 hours with a prolonged terminal phase of 25 hours.

Pharmacokinetic studies in patients with end-stage renal disease on chronic hemodialysis or continuous ambulatory peritoneal dialysis indicate that dialysis has little effect on the elimination of quinapril and quinaprilat.

The disposition of quinapril and quinaprilat in patients with renal insufficiency is similar to that in patients with normal renal function until creatinine clearance is ≤60 mL/min. With creatinine clearance <60 mL/min, peak and trough quinaprilat concentrations increase, apparent half-life increases, and time to steady state may be delayed. The elimination of quinaprilat may be reduced in elderly patients (>65 years) and in those with heart failure; this reduction is attributable to decrease in renal function (see 4 DOSAGE AND ADMINISTRATION). Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired de-esterification of quinapril.

The rate and extent of quinapril absorption are diminished moderately (approximately 25-30%) when Quinapril Tablets are administered during a high-fat meal. However, no effect on quinapril absorption occurs when taken during a regular meal.

Studies in rats indicate that quinapril and its metabolites do not cross the blood-brain barrier.

Special Populations and Conditions

• Geriatrics Therapeutic effects appear to be the same for elderly (>65 years of age) and younger adult patients given the same daily dosages, with no increase in AEs in elderly patients.
• Ethnic Origin The antihypertensive effect of ACE inhibitors is generally lower in black than in non-black patients

11 STORAGE, STABILITY AND DISPOSAL

Store at controlled room temperature, 15-30°C. Protect from moisture. Dispense in well-closed containers.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Quinapril Hydrochloride

Chemical name: (3S)-2-[(2S)-2-[[(1S)-1-(Ethoxycarbonyl)-3- phenylpropyl]amino]-propanoyl]-1,2,3,4- tetraydroisoquinoline-3-carboxylic acid hydrochloride

Molecular formula and Molecular mass: C₂₅H₃₀N₂O₅.HCl 475.0 g/mol

Structural formula:

Description: Quinapril hydrochloride is a white or almost white or slightly pink powder.

Solubility: At 25^⁰C, Quinapril Hydrochloride is freely soluble in methanol and water, soluble in 0.1mol/L hydrochloric acid, sparingly soluble in chloroform, slightly soluble in acetonitrile, very slightly soluble in ethyl acetate, practically insoluble in cyclohexane, ether and acetone. Quinapril hydrochloride is freely soluble in pH 0-14 solution.

pH : 2.3-2.8

Melting Range: Quinapril hydrochloride melts at about 110^⁰C.

14. CLINICAL TRIALS

14.1 Trial Design and Study Demographics

This information is not available for this drug product.

14.2 Study Results

This information is not available for this drug product.

14.3 Comparative Bioavailability Studies

A randomized, two-way, single-dose, crossover comparative bioavailability study of TARO-QUINAPRIL 40 mg tablets (Sun Pharma Canada Inc.) and Accupril^® 40 mg tablets (Pfizer Canada Inc.) was conducted in healthy, adult, male and female subjects under fasting conditions. Comparative bioavailability data from 24 subjects that were included in the statistical analysis are presented in the following table:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

¹ TARO-QUINAPRIL (quinapril as quinapril hydrochloride) tablets, 40 mg (Sun Pharma Canada Inc.)

² Accupril^® (quinapril as quinapril hydrochloride) tablets, 40 mg (Pfizer Canada Inc.)

³ Expressed as the arithmetic mean (CV %) only.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

Quinapril showed a low order of acute toxicity. Clinical signs of toxicity in both mice and rats were depression or hypoactivity, prostration and ataxia. Peak mortality occurred within 24 hours in oral studies and within 15 minutes in IV studies. Asymptomatic oral dose levels were 500 mg/kg in mice and 1000 mg/kg in rats.

In the dog study, escalating oral doses of 50-400 mg/kg were given over 13-consecutive days. Vomiting occurred after doses of ≥150 mg/kg. BPs decreased with increasing dose. At 400 mg/kg, the female had elevated creatinine and blood urea nitrogen (BUN) levels, decreased sodium and chloride levels, and granular casts in the urine. Gastric erosions and ulcers were seen in both animals and renal tubular dilatation was noted in the female.

The results of quinapril toxicity from chronic, reproductive, genetic, and carcinogenicity studies are given in Tables 4-7, respectively. Table 8 summarizes the results of toxicity studies with quinaprilat, the major active metabolite of quinapril.

¹ 52 weeks treatment plus 4 weeks without treatment for some animals

² UC = Untreated Control; VC = Vehicle Control; BUN = blood urea nitrogen; JGA = juxtaglomerular apparatus.

¹ UC = Untreated Control; VC = Vehicle Control

¹ UC = Untreated Control; VC= Vehicle Control; JGA = juxtaglomerular apparatus; RBC = red blood cell count

C. Genotoxicity Studies:

¹ VC = Vehicle Control; MLD = median lethal dose; JGA = juxtaglomerular apparatus

17 SUPPORTING PRODUCT MONOGRAPHS

1. 1. Accupril® (Quinapril Tablets, 5 mg, 10 mg, 20 mg and 40 mg), submission control 266170, Product Monograph, Pfizer Canada ULC. (December 15, 2022).