Apo-Quinapril/HCTZ Product Monograph

RECENT MAJOR LABEL CHANGES

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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 ................................................................................................. 6

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

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 .................................................................................................... 18

7.1.1 Pregnant Women ....................................................................................................... 18

7.1.2 Breast-feeding ............................................................................................................ 19

7.1.3 Pediatrics ................................................................................................................... 19

7.1.4 Geriatrics .................................................................................................................... 19

8 ADVERSE REACTIONS .................................................................................................. 19

8.1 Adverse Reaction Overview ....................................................................................... 20

8.2 Clinical Trial Adverse Reactions ................................................................................. 20

8.3 Less Common Clinical Trial Adverse Reactions .......................................................... 21

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ................................................................................................................ 23

8.5 Post-Market Adverse Reactions ................................................................................. 23

9 DRUG INTERACTIONS .................................................................................................. 23

9.1 Serious drug interactions ........................................................................................... 23

9.2 Drug-Behavioural Interactions ................................................................................... 24

9.3 Drug-Drug Interactions .............................................................................................. 24

9.4 Drug-Food Interactions .............................................................................................. 33

9.5 Drug-Herb Interactions .............................................................................................. 34

9.6 Drug-Laboratory Test Interactions ............................................................................. 34

10 CLINICAL PHARMACOLOGY ......................................................................................... 34

10.1 Mechanism of Action ................................................................................................. 34

10.2 Pharmacodynamics .................................................................................................... 34

10.3 Pharmacokinetics ....................................................................................................... 36

11 STORAGE, STABILITY AND DISPOSAL ........................................................................... 38

PART II: SCIENTIFIC INFORMATION ...................................................................................... 39

13 PHARMACEUTICAL INFORMATION .............................................................................. 39

14 CLINICAL TRIALS .......................................................................................................... 41

14.1 Trial Design and Study Demographics ....................................................................... 41

14.3 Comparative Bioavailability Studies ........................................................................... 41

15 MICROBIOLOGY .......................................................................................................... 44

16 NON-CLINICAL TOXICOLOGY ....................................................................................... 44

17 SUPPORTING PRODUCT MONOGRAPHS ...................................................................... 50

PATIENT MEDICATION INFORMATION ................................................................................. 51

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

APO-QUINAPRIL/HCTZ (quinapril hydrochloride and hydrochlorothiazide) is indicated for the treatment of essential hypertension in patients for whom combination therapy is appropriate.

APO-QUINAPRIL/HCTZ is not indicated for initial therapy. Patients in whom quinapril and hydrochlorothiazide are initiated simultaneously can develop symptomatic hypotension (see 7 WARNINGS AND PRECAUTIONS, Cardiovascular, - Hypotension and 9 DRUG INTERACTIONS).

Patients should be titrated on the individual drugs. If the fixed combination represents the dosage determined by this titration, the use of APO-QUINAPRIL/HCTZ may be more convenient in the management of patients. If during maintenance therapy dosage adjustment is necessary, it is advisable to use individual drugs.

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)

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 adverse events in elderly patients.

2 CONTRAINDICATIONS

APO-QUINAPRIL/HCTZ 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, General, Angioedema).

• Combination with sacubitril/valsartan due to increased risk of angioedema. APO-QUINAPRIL/HCTZ must not be initiated until at least 36 hours have elapsed following discontinuation of sacubitril/valsartan therapy. If treatment with APO-QUINAPRIL/HCTZ is stopped, sacubitril/valsartan therapy must not be initiated until 36 hours after the last

  • -QUINAPRIL/HCTZ.
• Patients hypersensitive to other sulfonamide-derived drugs because of the hydrochlorothiazide component.
• Patients with anuria.
• 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 (> 5 mMol/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, 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)
  • congestive heart failure who are hypotensive (see 9 DRUG INTERACTIONS, Angiotensin receptor blockers (ARBs)).
• Patients with the rare hereditary condition of galactose intolerance, glucose-galactose malabsorption or Lapp lactase deficiency as APO-QUINAPRIL/HCTZ contains lactose (see 7 WARNINGS AND PRECAUTIONS, Sensitivity/Resistance).

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

Dosage of APO-QUINAPRIL/HCTZ must be individualized. The fixed combination is not for initial therapy. The dose of APO-QUINAPRIL/HCTZ (quinapril hydrochloride and hydrochlorothiazide) should be determined by titration of the individual components.

Once the patient has been successfully titrated with the individual components as described below, APO-QUINAPRIL/HCTZ may be substituted if the titrated doses and dosing schedule can be achieved by the fixed combination (see 1 INDICATIONS and 7 WARNINGS AND PRECAUTIONS). In some patients, a twice daily administration may be required.

Patients do not generally require hydrochlorothiazide (HCTZ) in excess of 50 mg daily, particularly when combined with other antihypertensive agents.

4.2 Recommended Dose and Dosage Adjustment

Quinapril Monotherapy: The recommended initial dose of 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 blood pressure (BP) response, generally at intervals of 2 to 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 quinapril alone, a diuretic may be added. After the addition of a diuretic, it may be possible to reduce the dose of quinapril.

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

If a diagnosis of acute respiratory distress syndrome (ARDS) is suspected, APO-QUINAPRIL/HCTZ should be withdrawn and appropriate treatment given.

Dosage Adjustment in Renal Impairment: For use in hemodialysis patients, see 7 WARNINGS

AND PRECAUTIONS and 8 ADVERSE REACTIONS, 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 as described under Monotherapy.

When concomitant diuretic therapy is required in patients with severe renal impairment, a loop diuretic rather than a thiazide is preferred for use with quinapril. Therefore, for patients with severe renal dysfunction, APO-QUINAPRIL/HCTZ is not recommended.

Dosage in the Elderly: The recommended initial dosage of quinapril is 10 mg once daily (depending on renal function), followed by titration to the optimal response as described above under Monotherapy.

4.3 Administration

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

4.4 Missed Dose

If a dose of this medication has been missed, it should be taken as soon as possible. However, 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 hydrochloride and hydrochlorothiazide or quinapril. 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.

The most common signs and symptoms observed for HCTZ monotherapy overdosage are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 2 – Dosage Forms, Strengths, Composition and Packaging

APO-QUINAPRIL/HCTZ (quinapril hydrochloride and hydrochlorothiazide) is available as fixed combination tablets in 3 strengths of quinapril hydrochloride with hydrochlorothiazide:

APO-QUINAPRIL/HCTZ 10/12.5 mg: Contains 10 mg of quinapril (as quinapril hydrochloride) and 12.5 mg of hydrochlorothiazide - Pink colored, scored, oval shaped, biconvex, film-coated tablets debossed with ‘D’ on scored side and ‘18’ on other side.

APO-QUINAPRIL/HCTZ 20/12.5 mg: Contains 20 mg of quinapril (as quinapril hydrochloride) and 12.5 mg of hydrochlorothiazide - Pink colored, triangular, biconvex, film-coated tablets debossed with ‘D’ and ‘19’ on either sides of a scoreline on one side and plain on the other side.

APO-QUINAPRIL/HCTZ 20/25 mg: Contains 20 mg of quinapril (as quinapril hydrochloride) and 25 mg of hydrochlorothiazide - Pink colored, round shaped, biconvex, film-coated tablets debossed with ‘D’ on one side and ‘20’ on other side.

Packaging: Blister Pack of 28 (2 X 14) tablets and HDPE bottles of 90 tablets.

7 WARNINGS AND PRECAUTIONS

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

Carcinogenesis and Mutagenesis

Non-melanoma skin cancer

An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin] after hydrochlorothiazide therapy was reported in some epidemiological studies. The risk may be higher with increasing cumulative use (see 8 ADVERSE REACTIONS, 8.5 Post-Market Adverse Reactions). The photosensitizing action of hydrochlorothiazide may be a possible mechanism for NMSC (see 16 NON-CLINICAL TOXICOLOGY, Carcinogenicity, Hydrochlorothiazide).

Patients taking hydrochlorothiazide should be informed of the potential risk of NMSC. They should be advised to regularly check their skin for new lesions as well as changes to existing ones, and to promptly report any suspicious skin lesions. Patients should also be advised to limit exposure to sunlight, to avoid the use of indoor tanning equipment, and to use adequate protection (e.g. a broad spectrum sunscreen with a SPF of 30 or higher, clothing, and a hat) when exposed to sunlight or UV light to minimize the risk of skin cancer.

Alternatives to hydrochlorothiazide may be considered for patients who are at a particularly high risk for NMSC (e.g., light coloured skin, known personal or family history of skin cancer, ongoing immunosuppressive therapy, etc.) (see 8 ADVERSE REACTIONS, 8.5 Post-Market Adverse Reactions).

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 quinapril hydrochloride and hydrochlorothiazide, 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 APO-QUINAPRIL/HCTZ in combination with aliskiren-containing drugs is contraindicated in these patients (see 2 CONTRAINDICATIONS).

Further, co-administration of ACE inhibitors, including APO-QUINAPRIL/HCTZ, 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, acute 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, 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 APO-QUINAPRIL/HCTZ should be started under close medical supervision. Such patients should be followed closely for the first weeks of treatment and whenever the dose of APO-QUINAPRIL/HCTZ 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 renal 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. If symptoms persist, the dosage should be reduced, or the drug discontinued.

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.

Endocrine and Metabolism

Initial and periodic determination of serum electrolytes should be performed at appropriate intervals to detect possible electrolyte imbalance.

Hyperkalemia/Hypokalemia

Quinapril: Elevated serum potassium (>5.7 mMol/L) was observed in approximately 2% of patients receiving quinapril. 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 (see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests, Serum Electrolytes, 8 ADVERSE REACTIONS, and 9 DRUG INTERACTIONS, Agents Increasing Serum Potassium, Trimethoprim -containing products). The addition of a potassium-sparing diuretic to APO-QUINAPRIL/HCTZ, which contains a diuretic, is not recommended.

Hydrochlorothiazide: Treatment with thiazide diuretics has been associated with hypokalemia. Hypokalemia can also sensitize or exaggerate the response of the heart to the toxic effects of digitalis. The risk of hypokalemia is greatest in patients with cirrhosis of the liver, in patients experiencing a brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes, and in patients receiving concomitant therapy with corticosteroids or ACTH or with other drugs known to increase the risk of hypokalemia induced by thiazide diuretics (e.g. aminoglycoside antibiotics, cisplatin, foscarnet, amphotericin B and loop diuretics (furosemide)).

Quinapril/Hydrochlorothiazide: The opposite effects of hydrochlorothiazide and quinapril on serum potassium may approximately balance each other in many patients so that no net effect will be seen. In other patients, one or the other effect may be dominant.

Other electrolytes imbalances

Hydrochlorothiazide: In addition to hypokalemia, treatment with thiazide diuretics has also been associated with hyponatremia and hypochloremic alkalosis. These disturbances have sometimes been manifest as one or more of the following: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, nausea, confusion, seizures and vomiting.

Chloride deficits secondary to thiazide therapy are generally mild and require specific treatment only under extraordinary circumstances (e.g. in liver disease or renal disease). Dilutional hyponatremia may occur in edematous patients, especially in hot weather; appropriate therapy is water restriction rather than administration of salt, except when the hyponatremia is life threatening. In actual salt depletion, replacement of salt is the therapy of choice.

Thiazides may decrease calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hypoparathyroidism. In a few patients on prolonged thiazide therapy, pathological changes in the parathyroid gland have been observed, with hypercalcemia and hypophosphatemia. More serious complications of hyperparathyroidism (renal lithiasis, bone resorption, and peptic ulceration) have not been seen. Thiazides should be discontinued before performing tests for parathyroid function.

Thiazides increase the urinary excretion of magnesium, and hypomagnesaemia may result.

Hypoglycemia/Hyperglycemia and Diabetes

Quinapril: 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.

Hydrochlorothiazide: Thiazide-induced hyperglycemia may compromise blood sugar control. Depletion of serum potassium augments glucose intolerance. Monitor glycemic control, supplement potassium, if necessary, to maintain appropriate serum potassium levels, and adjust diabetes medications as required (see 9 DRUG INTERACTIONS, Antidiabetic agents (e.g. insulin, oral hypoglycemic agents, sitagliptin)).

Overt diabetes may be precipitated in susceptible individuals.

Other metabolic parameters

Hyperuricemia may occur, or acute hyperuricemia may be precipitated, in certain patients receiving thiazide therapy.

Increase in cholesterol, triglyceride and glucose levels may be associated with thiazide diuretic therapy.

Thiazides may decrease serum PBI levels without signs of thyroid disturbance.

Hematologic

Neutropenia/Agranulocytosis

Agranulocytosis and bone marrow depression have been caused by ACE inhibitors. Agranulocytosis did occur during quinapril treatment in one 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

Impairment of Liver Function

APO-QUINAPRIL/HCTZ 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. Also, since the metabolism of quinapril to quinaprilat is normally dependent upon hepatic esterase, patients with impaired liver function could develop markedly elevated plasma levels of quinapril.

Elevations of liver enzymes and/or serum bilirubin have been reported for quinapril hydrochloride and hydrochlorothiazide (see 8 ADVERSE REACTIONS). There are no adequate studies in patients with cirrhosis and/or liver dysfunction. APO-QUINAPRIL/HCTZ should be used with particular caution in patients with pre-existing liver abnormalities. A full set of liver function tests and any other necessary investigations should be obtained in these patients before administration of the drug and close monitoring of response and metabolic effects should apply. Discontinuation of APO-QUINAPRIL/HCTZ should be considered when appropriate.

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.

Immune

Hypersensitivity to ACE inhibitor

Angioedema

Angioedema has been reported in patients treated with ACE inhibitors, including quinapril. Angioedema associated with laryngeal involvement may be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with APO-QUINAPRIL/HCTZ (quinapril hydrochloride and hydrochlorothiazide) 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 inhibitor, DPP-4 inhibitor or NEP inhibitor or vice versa (see 9 DRUG INTERACTIONS).

Concomitant use of sacubitril/valsartan

A potential increased risk of angioedema has been reported with concomitant use of sacubitril/valsartan and ACE inhibitors. (see 2 CONTRAINDICATIONS; 9.3 Drug-Drug Interactions). APO-QUINAPRIL/HCTZ must not be initiated until at least 36 hours have elapsed following discontinuation of sacubitril/valsartan therapy. If treatment with APO-QUINAPRIL/HCTZ is stopped, sacubitril/valsartan therapy must not be initiated until 36 hours after the last dose of APO-QUINAPRIL/HCTZ.

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).

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 agent.

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 hydrochloride and hydrochlorothiazide (see 9 DRUG INTERACTIONS).

Hypersensitivity to Hydrochlorothiazide

Sensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma.

Systemic Lupus Erythematosus

Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.

Monitoring and Laboratory Tests

Serum Electrolytes: Variations of serum electrolytes levels have been observed with quinapril hydrochloride and hydrochlorothiazide. Initial and periodic determination of serum electrolytes should be performed at appropriate intervals to detect possible electrolyte imbalance (See 2 CONTRAINDICATIONS and 7 WARNINGS AND PRECAUTIONS).

Creatinine and Blood Nitrogen: Increases (>1.25x ULN) in serum creatinine and blood urea nitrogen (BUN) were observed in 3% and 4% respectively, of patients treated with quinapril hydrochloride and hydrochlorothiazide (see 7 WARNINGS AND PRECAUTIONS and 4 DOSAGE AND ADMINISTRATION).

Hepatic: Elevations of liver enzymes and/or serum bilirubin have occurred in patients receiving quinapril hydrochloride and hydrochlorothiazide. If a patient receiving APO-QUINAPRIL/HCTZ 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 APO-QUINAPRIL/HCTZ should be considered when appropriate. In patients with pre -existing liver abnormalities, baseline liver function tests should be obtained before administration of the drug. The response and metabolic effects should be closely monitored (see 7 WARNINGS AND PRECAUTIONS).

Glucose: Elevations in glucose values have occurred. Monitor glycemic control, supplement potassium, if necessary, to maintain appropriate serum potassium levels, and adjust diabetes medications as required (see 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Hypoglycemia/Hyperglycemia and Diabetes and 9 DRUG INTERACTIONS, Antidiabetic agents (e.g. insulin, oral hypoglycemic agents, sitagliptin)).

Triglyceride: Elevations in triglyceride values have occurred (see 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Other metabolic parameters).

Serum Uric Acid: Elevations in serum uric acid values have occurred (see 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Other metabolic parameters).

Hematology: Possibly clinically important increases and decreases in hematology parameters have occurred. 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, Neutropenia/Agranulocytosis).

Other laboratory test values with clinically important deviations during controlled and uncontrolled trials included: Magnesium, Cholesterol, PBI, Parathyroid Function Tests and Calcium (see 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Other electrolytes imbalances and Other metabolic parameters).

Ophthalmologic

Choroidal Effusion, Acute Myopia and Secondary Angle -Closure Glaucoma related to Hydrochlorothiazide

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in choroidal effusion, acute transient myopia and/or acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity, blurred vision or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss.

The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle -closure glaucoma may include a history of sulfonamide or penicillin allergy.

Peri-Operative Considerations

Surgery/Anaesthesia

In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, ACE inhibitors 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

Azotemia

Azotemia may be precipitated or increased by hydrochlorothiazide. Cumulative effects of the drug may develop in patients with impaired renal function. If increasing azotemia and oliguria occur, APO-QUINAPRIL/HCTZ should be discontinued.

Renal Impairment

The use of ACE inhibitors, including APO-QUINAPRIL/HCTZ, with ARBs or aliskiren-containing drugs is contraindicated in patients with moderate to severe kidney insufficiency (GFR < 60 mL/min/1.73 m²) (see 2 CONTRAINDICATIONS and 9 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 8 ADVERSE REACTIONS and 4 DOSAGE AND ADMINISTRATION).

Use of APO-QUINAPRIL/HCTZ should be followed by the appropriate assessment of renal function (see 8 ADVERSE REACTIONS and 4 DOSAGE AND ADMINISTRATION).

Thiazides may not be appropriate diuretics for use in patients with renal impairment and are ineffective at creatinine clearance values of ≤30 mL/min (i.e. moderate or severe renal insufficiency) (see 8 ADVERSE REACTIONS and 4 DOSAGE AND ADMINISTRATION).

Reproductive Health: Female and Male Potential

• Fertility

See 7 WARNINGS AND PRECAUTIONS, 7.1 Special Populations, 7.1.1 Pregnant Women and 16 NON-CLINICAL TOXICOLOGY

• Teratogenic Risk

See 7 WARNINGS AND PRECAUTIONS, 7.1 Special Populations, 7.1.1 Pregnant Women and 16 NON-CLINICAL TOXICOLOGY

Respiratory

Cough

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

Acute Respiratory Distress Syndrome (ARDS)

Severe cases of acute respiratory toxicity, including ARDS have been reported after taking hydrochlorothiazide. Pulmonary oedema typically develops within minutes to hours after hydrochlorothiazide intake. At the onset, symptoms include dyspnea, fever, pulmonary deterioration and hypotension. If diagnosis of ARDS is suspected, APO-QUINAPRIL/HCTZ should be withdrawn and appropriate treatment given. Hydrochlorothiazide should not be administered to patients who previously experienced ARDS following hydrochlorothiazide intake.

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 APO-QUINAPRIL/HCTZ (see 2 CONTRAINDICATIONS).

Skin

Psoriasis and Aggravation of Psoriasis

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

Photosensitivity

Photosensitivity reactions have been reported with the use of thiazide diuretics.

If photosensitivity reactions occur during treatment with hydrochlorothiazide-containing drugs, treatment should be stopped.

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, APO-QUINAPRIL/HCTZ 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 neurological 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 test (CST) should be considered. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Thiazides cross the placental barrier and appear in cord blood. Although studies in humans have not been done, effects to the fetus may include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions which have occurred in the adult.

Animal Data: No fetotoxic or teratogenic effects were observed in rats at quinapril doses as high as 300 mg/kg/day (180x 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 doses as low as 0.5 mg/kg/day and 1 mg/kg/day, respectively.

No adverse effects on fertility or reproduction were observed in rats at quinapril dose levels ≤100 mg/kg/day (60x maximum daily human dose).

7.1.2 Breast-feeding

The presence of concentrations of ACE inhibitor has been reported in human milk. Thiazides also appear in human milk. The use of APO-QUINAPRIL/HCTZ is contraindicated during breast-feeding (see 2 CONTRAINDICATIONS).

7.1.3 Pediatrics

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

7.1.4 Geriatrics

Quinapril: 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 adverse events in elderly patients.

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.

Quinapril hydrochloride and hydrochlorothiazide was evaluated for safety in 1571 patients with essential hypertension, including 943 patients in controlled studies (see Table 3), 345 patients in placebo-controlled trials, and 517 patients who were treated with quinapril hydrochloride and hydrochlorothiazide for ≥1 year. Adverse reactions were limited to those reported previously with quinapril or hydrochlorothiazide (HCTZ) when used separately for the treatment of hypertension.

Serious or clinically significant adverse reactions observed in <0.2% of patients treated with quinapril and HCTZ were: hematemesis, gout, syncope and angioedema. Therapy was discontinued in 2.1% of patients due to an adverse event (AE). Headache (0.5%) and dizziness (0.3%) were the most frequent reasons for withdrawal.

The most frequent adverse experiences in controlled trials were headache (6.7%), dizziness (4.8%), cough (3.2%) and fatigue (2.9%). The cough is characteristically non- productive, persistent and resolves after discontinuation of therapy (see 7 WARNINGS AND PRECAUTIONS, Respiratory, Cough).

Table 3 - Adverse Events in ≥1% of Quinapril/Hydrochlorothiazide Patients in Controlled Clinical Studies.

8.3 Less Common Clinical Trial Adverse Reactions

Clinical AEs regardless of relationship to therapy, occurring in ≥0.5% to <1.0% of patients treated with quinapril plus HCTZ in controlled and uncontrolled trials and less frequent clinically significant events seen in clinical trials or in post marketing experience included:

Rare AEs, not listed above, which have been reported with either HCTZ, quinapril, or the combination include:

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

Non-melanoma skin cancer:

Some pharmacoepidemiologic studies have suggested a higher risk of squamous cell carcinoma and basal cell carcinoma of the skin with increasing use of hydrochlorothiazide. A systematic review and meta-analysis undertaken by Health Canada suggested, with important uncertainty, that the use of hydrochlorothiazide for several years (>3 years) could lead to:

• 122 additional cases (95% CI, from 112 to 133 additional cases) of squamous cell carcinoma per 1000 treated patients compared with non-use of hydrochlorothiazide (meta-analysis of 3 observational studies).
• 31 additional cases (95% CI, from 24 to 37 additional cases) of basal cell carcinoma per 1000 treated patients compared with non-use of hydrochlorothiazide (meta-analysis of 2 observational studies).

Eye disorders:

Choroidal effusion, acute myopia, acute angle-closure glaucoma (frequency unknown).

Respiratory

Acute respiratory distress syndrome (ARDS) has been reported in very rare instances (see 7 WARNINGS AND PRECAUTIONS, Respiratory).

9 DRUG INTERACTIONS

9.1 Serious drug interactions

9.2 Drug-Behavioural Interactions

Alcohol use should be avoided when taking APO-QUINAPRIL/ HCTZ as it can cause orthostatic hypotension.

9.3 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 4 - Established or Potential Drug-Drug Interactions

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

9.4 Drug-Food Interactions

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

9.5 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.6 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

APO-Quinapril/HCTZ is a fixed-combination tablet which combines the antihypertensive actions of an angiotension-converting enzyme (ACE) inhibitor, quinapril hydrochloride and a diuretic, hydrochlorothiazide (HCTZ). In clinical studies, administration of this combination produced greater reductions in blood pressure (BP) than the single agents given alone.

Quinapril:

In human subjects, quinapril at single oral doses of 10 to 20 mg/day produced 95 to 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 to 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.

Hydrochlorothiazide

Electrolyte and water excretion starts approximately 2 hours after administration, reaches its peak after 3 to 6 hours and lasts from 6 to 12 hours.

The onset of the antihypertensive effect requires several days and administration for 2 to 4 weeks is necessary for optimal therapeutic effect.

10.2 Pharmacodynamics

Quinapril:

Quinapril is a nonpeptide, nonsulphydryl ACE inhibitor. 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.

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 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.

Administration of 10 to 40 mg of quinapril 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 to 4 hours after dosing. Achievement of maximum BP lowering effects may require 2 to 4 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 to 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 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.

Hydrochlorothiazide:

HCTZ acts directly on the kidney to increase excretion of sodium and chloride, and an accompanying volume of water. HCTZ also increases the excretion of potassium and bicarbonate and decreases calcium excretion.

As a result of its diuretic effect, HCTZ increases plasma renin activity, increases aldosterone secretion, decreases serum potassium, and increases urinary potassium loss. Administration of quinapril inhibits the renin-angiotensin-aldosterone axis and tends to attenuate the potassium decrease associated with HCTZ.

The mechanism underlying the antihypertensive activity of diuretics is unknown. During chronic administration peripheral vascular resistance is reduced; however, this may be secondary to changes in sodium balance.

Quinapril/Hydrochlorothiazide:

When quinapril and HCTZ are given together, the antihypertensive effects are approximately additive.

10.3 Pharmacokinetics

Quinapril:

Absorption:

Following oral administration of quinapril, 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.

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.

The rate and extent of quinapril absorption are diminished moderately (approximately 25 to 30%) when 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.

Hydrochlorothiazide:

Absorption:

After oral administration of HCTZ, diuresis begins within 2 hours, peaks in about 4 hours, and lasts about 6 to 12 hours; the extent of absorption is approximately 50 to 80%.

Distribution

Approximately 40% of hydrochlorothiazide is bound to plasma proteins.

Metabolism

Hydrochlorothiazide undergoes negligible hepatic metabolism and has not been shown to induce or inhibit any CYP450 isoenzymes.

Elimination:

HCTZ is excreted unchanged by the kidney. When plasma levels have been followed for ≥24 hours, the plasma half-life has been observed to vary between 4 to 15 hours. At least 61% of the oral dose is eliminated unchanged within 24 hours. HCTZ crosses the placental but not the blood-brain barrier.

Quinapril/Hydrochlorothiazide:

Concomitant administration of quinapril and HCTZ has little or no effect on the bioavailability or the pharmacokinetics of either drug.

Special Populations and Conditions

• Geriatrics

  Quinapril: 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

  Quinapril: The antihypertensive effect of ACE inhibitors is generally lower in black than in non- black patients.

• Renal Insufficiency:

  Quinapril: 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.

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

11 STORAGE, STABILITY AND DISPOSAL

Protect from moisture, keep container tightly closed and store between 15°C and 30°C.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Quinapril Hydrochloride and Hydrochlorothiazide.

Quinapril Hydrochloride

Chemical Name: (3S)-2-[(2S)-2-[[(1S)-1-(Ethoxycarbonyl)-3-phenylpropyl] amino] propanoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid hydrochloride

(Or)

3-Isoquinolinecarboxylic acid, 2-[2-[[1-(ethoxycarbonyl)-3- phenylpropyl] amino]-1-oxopropyl]-1,2,3,4-tetrahydro-, monohydrochloride,[3S -[2[R*(R*)],3R *]].

Molecular Formula: C₂₅H₃₀N₂O₅.HCl

Molecular Mass: 474.98 g/mol

Molecular Structure:

Physicochemical properties:

Description: White or almost white or slightly pink, hydroscopic powder.

Dissociation Constants: 7.4

Solubility: Freely soluble in water and in ethanol (96 percent), very slightly soluble in acetone.

Hydrochlorothiazide

Chemical Name: 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7- sulfonamide 1,1-dioxide

Molecular Formula: C₇H₈ClN₃O₄S₂

Molecular Mass: 297.7 g/mol

Molecular Structure:

Physicochemical properties:

Description: A white or almost white, crystalline powder.

Dissociation Constants: 7.9

Melting Point: 274°C

Solubility:

Partition Coefficient (log P): -0.268

14 CLINICAL TRIALS

14.1 Trial Design and Study Demographics

Two controlled studies evaluated the efficacy and safety of quinapril and HCTZ combination therapy compared with each drug given as monotherapy in patients with essential hypertension. The combination therapy caused a statistically significant greater fall in diastolic blood pressure (DBP) than each drug given as monotherapy. In a placebo controlled study, when quinapril hydrochloride (10 mg, 40 mg) and HCTZ (12.5 mg, 25 mg) were administered alone or in combination, mean reductions in DBP (at trough) produced by quinapril monotherapy ranged from 7.3 to 10.3 mmHg, by HCTZ monotherapy from 7.2 to 11.4 mmHg, and by combination therapy from 8.2 to 14.9 mmHg. Placebo produced a mean reduction in DBP of 2.2 mmHg.

14.3 Comparative Bioavailability Studies

A randomized, two-treatment, two-sequence, two-period, crossover, single 1 x 20/25 mg dose bioequivalence study of APO-QUINAPRIL/HCTZ (Quinapril Hydrochloride and Hydrochlorothiazide Tablets) 20 mg/25 mg (Apotex Inc.) versus ACCURETIC^® (Quinapril Hydrochloride and Hydrochlorothiazide) 20 mg/25 mg tablets (Pfizer Canada Inc.) was conducted in 36 healthy Asian male subjects from 19 to 44 years of age under fasting conditions. A summary of the bioavailability data from 33 subjects who completed the study is presented in the following tables.

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

^* APO-QUINAPRIL/HCTZ (Quinapril Hydrochloride and Hydrochlorothiazide Tablets) 20 mg/25 mg (Apotex Inc.).

^† ACCURETIC (Quinapril Hydrochloride and Hydrochlorothiazide) 20 mg/25 mg tablets (Pfizer Canada Inc.) were purchased from Canada.

^§ Expressed as the median (range) only.

^$ Expressed as arithmetic mean (% CV) only.

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILTY DATA

^* APO-QUINAPRIL/HCTZ (Quinapril Hydrochloride and Hydrochlorothiazide Tablets) 20 mg/25 mg (Apotex Inc.).

^† ACCURETIC (Quinapril Hydrochloride and Hydrochlorothiazide) 20 mg/25 mg tablets (Pfizer Canada Inc.) were purchased from Canada.

^§ Expressed as the median (range) only.

^$ Expressed as arithmetic mean (% CV) only.

A randomized, two-treatment, two-sequence, two-period, crossover, single 1 x 20/12.5 mg dose bioequivalence study of APO-QUINAPRIL/HCTZ (quinapril Hydrochloride and Hydrochlorothiazide Tablets) 20 mg/ 12.5 mg (Apotex Inc.) versus ACCURETIC® (Quinapril

Hydrochloride and Hydrochlorothiazide) 20 mg/12.5 mg tablets (Pfizer Canada Inc.) was conducted in 36 healthy Asian male subjects from 21 to 45 years of age under fasting conditions. A summary of the bioavailability data from 35 subjects who completed the study is presented in the following tables.

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

^* APO-QUINAPRIL/HCTZ (Quinapril Hydrochloride and Hydrochlorothiazide Tablets) 20/12.5 mg (Apotex Inc.)

^† Accuretic^® (Quinapril Hydrochloride and Hydrochlorothiazide) 20/12.5 mg tablets (Pfizer Canada Inc.) were purchased in Canada.

^§ Expressed as the median (range) only.

^$ Expressed as arithmetic mean (%CV) only.

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

^* APO-QUINAPRIL/HCTZ (Quinapril Hydrochloride and Hydrochlorothiazide Tablets) 20/12.5 mg (Apotex Inc.)

^† Accuretic^® (Quinapril Hydrochloride and Hydrochlorothiazide) 20/12.5 mg tablets (Pfizer Canada Inc.) were purchased from Canada.

^§ Expressed as the median (range) only.

^$ Expressed as arithmetic mean (%CV) only.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

The results of quinapril toxicity from chronic, carcinogenicity, genotoxicity, reproductive studies are given in Tables, 5 to 8 respectively.

Table 9 summarizes the results of toxicity studies with quinaprilat, the major active metabolite of quinapril.

Quinapril Hydrochloride and Hydrochlorothiazide

The 14-day Median Lethal Dose (MLD) in mice was 1068/667 mg/kg quinapril/ HCTZ; in rats it was 4640/2896 mg/kg. For quinapril alone, the oral MLD ranged from 1440 to 2150 mg/kg for mice, and from 3531 to 4280 mg/kg in rats. In dogs, no drug-related clinical signs of toxicity were observed at doses of 125 to 250x the maximum human dose of quinapril given in combination with HCTZ, and 60 to 120x the maximum human dose of HCTZ in combination (100/60 mg/kg in males, 200/120 mg/kg in females).

Hydrochlorothiazide

According to the experimental data available, hydrochlorothiazide revealed inconsistent evidence of carcinogenic activity in rats and mice, with conflicting evidence of hepatic adenoma in male mice at the highest dose and adrenal pheochromocytoma in one rat study but not in another. Current evidence is inadequate to draw a clear conclusion for a carcinogenic effect of hydrochlorothiazide in animals.

The mutagenic potential was assessed in a series of in vitro and in vivo test systems. While some positive results were obtained in vitro, all in vivo studies provided negative results.

Hydrochlorothiazide enhanced the UVA-induced formation of pyrimidine dimers in vitro and in the skin of mice following oral treatment. It is therefore concluded that although there is no relevant mutagenic potential in vivo, hydrochlorothiazide could enhance the genotoxic effects of UVA light. This mechanism of photosensitization could be associated with a higher risk for non-melanoma skin cancer.

17 SUPPORTING PRODUCT MONOGRAPHS

1. 1. ACCURETIC® (Quinapril (as hydrochloride) and Hydrochlorothiazide Tablets, 10/12.5 mg, 20/12.5 mg and 20/25 mg), submission control 265148, Product Monograph, ®Parke, Davis & Company LLC, (December 13, 2022).