PMS-Ramipril-HCTZ (Pharmascience, 10.0 mg / 12.5 mg, 10.0 mg / 25.0 mg) Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

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

TABLE OF CONTENTS

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

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

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

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

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

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

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

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

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

4.4 Administration .................................................................................................................. 7

4.5 Missed Dose ...................................................................................................................... 7

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

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

7 WARNINGS AND PRECAUTIONS ........................................................................................... 9

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 ............................................................................................ 19

8.2 Clinical Trial Adverse Reactions ...................................................................................... 19

8.3 Less Common Clinical Trial Adverse Reactions ............................................................... 20

8.4 Abnormal Hematologic and Clinical Chemistry Findings ................................................ 21

8.5 Post-Market Adverse Reactions ...................................................................................... 21

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

9.3 Drug-Behavioural Interactions ........................................................................................ 23

9.4 Drug-Drug Interactions ................................................................................................... 23

9.5 Drug-Food Interactions ................................................................................................... 32

9.6 Drug-Herb Interactions ................................................................................................... 32

9.7 Drug-Laboratory Test Interactions .................................................................................. 32

10 CLINICAL PHARMACOLOGY ................................................................................................ 32

10.1 Mechanism of Action ...................................................................................................... 32

10.2 Pharmacodynamics ......................................................................................................... 32

10.3 Pharmacokinetics ............................................................................................................ 33

11 STORAGE, STABILITY AND DISPOSAL .................................................................................. 36

12 SPECIAL HANDLING INSTRUCTIONS .................................................................................... 36

PART II : SCIENTIFIC INFORMATION ......................................................................................... 37

13 PHARMACEUTICAL INFORMATION ..................................................................................... 37

14 CLINICAL TRIALS ................................................................................................................ 39

14.1 Clinical Trials by Indication.............................................................................................. 39

14.3 Comparative Bioavailability Studies ............................................................................... 45

15 MICROBIOLOGY ................................................................................................................. 46

16 NON-CLINICAL TOXICOLOGY .............................................................................................. 47

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

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

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

pms-RAMIPRIL-HCTZ (ramipril/hydrochlorothiazide) is indicated for the treatment of essential hypertension in patients for whom this combination therapy is appropriate.

pms-RAMIPRIL-HCTZ is not indicated for initial therapy (see 4 DOSAGE AND ADMINISTRATION). Patients in whom ramipril and diuretic are initiated simultaneously can develop symptomatic hypotension.

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

Pediatrics

Pediatrics (< 18 years of age): The safety and effectiveness of ramipril and hydrochlorothiazide in pediatric patients have not been established. Therefore, pms-RAMIPRIL-HCTZ is not indicated in this patient population.

Geriatrics

Geriatrics (> 65 years of age): There is limited clinical experience with ramipril and hydrochlorothiazide in the elderly (> 65 years) (see 7.1.4 Geriatrics).

2 CONTRAINDICATIONS

• Patients who are hypersensitive to this drug, any other angiotensin converting enzyme inhibitor (ACE inhibitor), other thiazide diuretics, sulfonamides or any ingredient in the formulation or component of the container. For a complete listing of ingredients, see 6 DOSAGE FORMS, COMPOSITION AND PACKAGING.
• Patients who have a history of hereditary/idiopathic angioedema with or without treatment with an ACE inhibitor (see 7 WARNINGS AND PRECAUTIONS, Immune, Angioedema)
• Pregnant and nursing women (see 7.1.1 Pregnant Women and 7.1.2 Breast-feeding).
• Patients with hemodynamically relevant bilateral renal artery stenosis, or unilateral in the single kidney (see 7 WARNINGS AND PRECAUTIONS, Renal, Renal impairment)
• Patients with hypotensive states or hemodynamically unstable states
• Concomitant use with sacubitril/valsartan due to an increased risk of angioedema. Do not initiate pms-RAMIPRIL-HCTZ until at least 36 hours have elapsed following the last dose of sacubitril/valsartan. In the case of a switch from pms-RAMIPRIL-HCTZ to sacubitril/valsartan, do not start sacubitril/valsartan until at least 36 hours have elapsed following the last dose of pms-RAMIPRIL-HCTZ.

• Combination with aliskiren-containing drugs in patients with:

  • diabetes mellitus (type 1 or type 2)
  • moderate to severe renal impairment (GFR < 60 ml/min/1.73m²)
  • hyperkalemia(> 5 mMol/L)
  • congestive heart failure who are hypotensive (see 7 WARNINGS ANDPRECAUTIONS, Dual Blockade of the Renin-Angiotensin System (RAS) and Renal, and 9 DRUG INTERACTIONS, Dual Blockade of the Renin-Angiotensin-System (RAS))

• Combination with angiotensin II receptor antagonists (ARBs) in patients with:

  • diabetes 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 7 WARNINGS ANDPRECAUTIONS, Dual Blockade of the Renin-Angiotensin System (RAS) and 9 DRUG INTERACTIONS, Dual Blockade of the Renin-Angiotensin-System (RAS))
• Combination with extracorporeal treatments leading to contact of blood with negatively charged surfaces since such use may lead to anaphylactoid reactions. Such extracorporeal treatments include dialysis or hemofiltration with certain high-flux (e.g., polyacrylonitril) membranes and low-density lipoprotein apheresis with dextran sulfate (see 7 WARNINGS AND PRECAUTIONS, Immune).
• Patients with anuria
• Patients with severe renal impairment (creatinine clearance <30 ml/min/1.73m²)
• Patients on dialysis
• Patients with severe hepatic impairment
• Patients with clinically relevant electrolyte disturbances (e.g., hypokalemia, hyponatremia or hypercalcemia)

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• Dosage should be individualized.
• pms-RAMIPRIL-HCTZ (ramipril/hydrochlorothiazide) is not for initial therapy.
• The dose of pms-RAMIPRIL-HCTZ should be determined by the titration of the individual components.
• Special attention for dialysis patients.

4.2 Recommended Dose and Dosage Adjustment

Once the patient has been successfully titrated with the individual components as described below, pms-RAMIPRIL-HCTZ may be substituted if the titrated dose and dosing schedule can be achieved by the fixed combination (see 1 INDICATIONS, and 7 WARNINGS AND PRECAUTIONS).

Usual dosage: 2.5 mg ramipril and 12.5 mg hydrochlorothiazide daily. Generally, it is recommended that the daily dose be administered in the morning as a single dose.

Due to the risk of angioedema when used concomitantly with sacubitril/valsartan, pms-RAMIPRIL-HCTZ must not be started until 36 hours has passed following the last dose of sacubitril/valsartan (see 2 CONTRAINDICATIONS).

Titration will be based on physician’s judgment according to severity of hypertension and other associated risk factors.

Maximum daily dose: 10 mg ramipril and 50 mg hydrochlorothiazide.

Dosage in elderly patients

Initial doses should be lower and subsequent dose titration should be more gradual because of greater chance of undesirable effects especially in very old and frail patients (see 7 WARNINGS AND PRECAUTIONS).

Dosage in patients with impaired renal function

Moderate renal impairment (creatinine clearance 30- 60 ml/min/1.73 m²): In patients with moderate renal impairment, treatment is started with ramipril alone at a daily dose of 1.25 mg. After gradually increasing the dose of ramipril, medication with the combination preparation is started at a daily dose of 2.5 mg ramipril /12.5 mg hydrochlorothiazide (not available from Pharmascience Inc.). Maximum permitted daily dose: 5 mg ramipril/ 25 mg hydrochlorothiazide (not available from Pharmascience Inc.). pms-RAMIPRIL-HCTZ 10 mg/12.5 mg and pms-RAMIPRIL-HCTZ 10 mg/25 mg MUST NOT be used in these patients.

pms-RAMIPRIL-HCTZ is contraindicated in patients with severe renal impairment (creatinine clearance<30 ml/min/1.73 m²) and in dialysis patients (see 2 CONTRAINDICATIONS).

Dosage in patients with impaired hepatic function

Mild or moderate hepatic impairment: In patients with mild to moderate hepatic impairment, treatment with pms-RAMIPRIL-HCTZ must be initiated only under close medical supervision and the maximum daily dose is 2.5 mg of ramipril/12.5 mg hydrochlorothiazide (not available from Pharmascience Inc.). pms-RAMIPRIL-HCTZ 10 mg/12.5 mg and 10 mg/25 mg MUST NOT be used in these patients.

pms-RAMIPRIL-HCTZ is contraindicated in patients with severe hepatic impairment (see 2 CONTRAINDICATIONS).

Dosing in patients pre-treated with diuretics

In patients pre-treated with a diuretic, consideration must be given to discontinuing the diuretic≥2- 3 days (depending on the duration of action of the diuretic) before starting treatment with pms-RAMIPRIL-HCTZ or at least to reducing the diuretic dose. Should discontinuation not be possible, it is recommended that treatment be initiated with the smallest possible dosage of ramipril (1.25 mg daily) in a free combination. It is recommended that, subsequently, a changeover be made to an initial daily dose of ≤2.5 mg ramipril /12.5 mg hydrochlorothiazide (not available from Pharmascience Inc.).

4.4 Administration

pms-RAMIPRIL-HCTZ tablets should be swallowed with sufficient amounts of liquid (approximately ½ glass). The tablets must not be chewed or crushed.

Generally, it is recommended that the daily dose be administered in the morning as a single dose. No substantial food effect is to be expected with pms-RAMIPRIL-HCTZ.

4.5 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, skip the missed dose and go back to the regular dosing schedule. Do not double doses.

5 OVERDOSAGE

Overdosage may cause persistent diuresis, excessive peripheral vasodilatation (with marked hypotension, electrolyte disturbances, cardiac arrhythmias, impairment of consciousness up to and including coma and cerebral convulsions), bradycardia, renal failure, paresis and paralytic ileus.

In patients with obstruction of urinary outflow (e.g., from prostatic hyperplasia), sudden diuresis may induce acute urinary retention with overdistension of the bladder.

Management

Treatment is symptomatic and supportive. Primary detoxification by, for example, administration of adsorbants may be considered. In the event of hypotension, administration of α ₁-adrenergic agonists (e.g., norepinephrine, dopamine) or angiotensin II (angiotensinamide), must be considered in addition to volume and salt substitution.

In attempting to eliminate ramipril, or ramiprilat, there is limited/no experience available concerning the efficacy of forced diuresis, altering urine pH, hemofiltration or dialysis. If dialysis or hemofiltration is nevertheless contemplated, consider risks of anaphylactoid reactions with high flux membrane (see 7 WARNINGS AND PRECAUTIONS, Immune, Anaphylactoid Reactions to ACE Inhibitors during membrane exposure).

Removal of thiazide diuretics by dialysis is negligible.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1: Dosage Forms, Strengths, Composition and Packaging

Table 2: Tablet Description

Both pms-RAMIPRIL-HCTZ (10 mg /12.5 mg, 10 mg/ 25 mg) combination tablets are packaged in cartons of 30 tablets.

Both pms-RAMIPRIL-HCTZ (10 mg /12.5 mg, 10 mg/ 25 mg) combination tablets are also available in plastic bottles of 100 tablets.

7 WARNINGS AND PRECAUTIONS

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX

General

Cough

A dry, persistent cough, which usually disappears only after withdrawal or lowering the dose of ramipril and hydrochlorothiazide tablets, has been reported. This is likely related to ramipril, the ACE inhibitor component of ramipril and hydrochlorothiazide tablets. Such a possibility should be considered as part of the differential diagnosis of cough (see 8.2 Clinical Trial Adverse Reactions).

Dual blockade of the Renin-Angiotensin System (RAS)

There is evidence that co-administration of ACE inhibitors, such as the ramipril component in ramipril and hydrochlorothiazide tablets, or of ARBs with aliskiren increases the risk of hypotension, syncope, stroke, hyperkalemia and deterioration of renal function, including renal failure, in patients with diabetes mellitus (type 1 or type 2) and/or moderate to severe renal impairment (GFR < 60 ml/min/1.73m²).

Therefore, the use of pms-RAMIPRIL-HCTZ in combination with aliskiren-containing drugs is contraindicated in these patients (see 2 CONTRAINDICATIONS).

The use of pms-RAMIPRIL-HCTZ in combination with an ARB is contraindicated in patients with diabetic nephropathy (see 2 CONTRAINDICATIONS).

Further, co-administration of ACE inhibitors, including the ramipril component of pms-RAMIPRIL-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, renal failure, and hyperkalemia (see 9 DRUG INTERACTIONS).

Carcinogenicity and Mutagenicity

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. The certainty of the evidence was assessed by Health Canada (see 8.5 Post Market Adverse Reactions). The photosensitizing action of hydrochlorothiazide may be a possible mechanism for NMSC (see 16 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 8.5 Post Market Adverse Reactions).

Cardiovascular

Aortic 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.

Hypotension

Symptomatic hypotension has occurred after administration of ramipril, 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, vomiting or in other situations in which a significant activation of the RAS is to be anticipated such as in patients with severe, and particularly malignant hypertension, in patients with hemodynamically relevant left-ventricular outflow impediment (e.g., stenosis of the aortic valve) or in patients with hemodynamically relevant renal artery stenosis. All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting, or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with their physician.

Generally, it is recommended that dehydration, hypovolaemia or salt depletion be corrected before initiating treatment (in patients with heart failure, however, such corrective action must be carefully weighed against the risk of volume overload). When these conditions have become clinically relevant, treatment with ramipril must only be started or continued if appropriate steps are taken concurrently to prevent an excessive fall in blood pressure and deterioration of renal function.

In patients with ischemic heart disease or cerebrovascular disease, an excessive fall in blood pressure (BP) could result in a myocardial infarction or cerebrovascular accident (see 8.5 Post-Market Adverse Reactions, Cardiovascular). Because of the potential fall in BP in these patients, therapy with pms-RAMIPRIL-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 pms-RAMIPRIL-HCTZ is increased. In patients with severe congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension and has been 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 a supine position and, if necessary, receive an intravenous infusion of 0.9% sodium chloride. A transient hypotensive response may not be a contraindication to further doses which usually can be given without difficulty once BP has increased after volume expansion in hypertensive patients. However, lower doses of pms-RAMIPRIL-HCTZ should be considered. In patients receiving treatment following acute myocardial infarction, consideration should be given to discontinuation of pms-RAMIPRIL-HCTZ (see 8.5 Post- Market Adverse Reactions, Cardiovascular).

pms-RAMIPRIL-HCTZ may lower the state of patient alertness and/or reactivity, particularly at the start of treatment. Patients should be cautioned to report light-headedness, especially during the first few days of pms-RAMIPRIL-HCTZ therapy. If actual syncope occurs, the patients should be told to discontinue the drug and consult with their physician.

Driving a vehicle or performing other hazardous tasks

Some adverse effects (e.g., some symptoms of a reduction in blood pressure such as light- headedness, dizziness, syncope) may impair the patient's ability to concentrate and react and, therefore, constitute a risk in situations where these abilities are of particular importance (e.g., operating a vehicle or machinery).

Hematologic

Neutropenia/Agranulocytosis

Agranulocytosis and bone marrow depression have been caused by ACE inhibitors. Several cases of agranulocytosis, neutropenia or leukopenia have been reported in which a causal relationship to ramipril cannot be excluded (see 8.5 Post-Market Adverse Reactions). Current experience with the drug shows the incidence to be rare.

Hematological reactions to ACE inhibitors are more likely to occur in patients with impaired renal function and in those with concomitant collagen disease (e.g., lupus erythematosus or scleroderma) or in those treated with other drugs that may cause changes of the blood picture. Periodic monitoring of white blood cell counts should be considered (see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests, Hematological Monitoring).

Patients should be told to report promptly to their physician any indication of infection (e.g., sore throat, fever) as this may be a sign of neutropenia (see 8.5 Post-Market Adverse Reactions).

Hepatic/Biliary

Hepatitis (hepatocellular and/or cholestatic), elevations of liver enzymes and/or serum bilirubin have occurred during therapy with ACE inhibitors in patients with or without pre -existing liver abnormalities (see 8.5 Post-Market Adverse Reactions). In most cases the changes were reversed on discontinuation of the drug. Should the patient receiving pms-RAMIPRIL-HCTZ 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 investigations be carried out. Discontinuation of pms-RAMIPRIL-HCTZ should be considered when appropriate.

Rarely, ACE inhibitors, including ramipril, have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

Patients should be advised to return to their physician if they experience any symptoms possibly related to liver dysfunction. This would include "viral-like symptoms" in the first weeks to months of therapy (such as fever, malaise, muscle pain, rash or adenopathy which are possible indicators of hypersensitivity reactions), or if abdominal pain, nausea or vomiting, loss of appetite, jaundice, itching or any other unexplained symptoms occur during therapy (see 8.5 Post-Market Adverse Reactions).

Thiazides should be used with caution in patients with mild to moderate impairment of hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. pms-RAMIPRIL-HCTZ should not be used in patients with severe impairment of hepatic function (see 2 CONTRAINDICATIONS).

There are no adequate studies in patients with cirrhosis and/or liver dysfunction. In patients with impaired liver function, response to the treatment with ramipril may be either increased or reduced. In addition, in patients in whom severe liver cirrhosis with oedema and ascites is present, the RAS may be significantly activated. pms-RAMIPRIL-HCTZ 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 (see 10 CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Insufficiency).

Immune

Angioedema-Head and Neck

Angioedema has been reported in patients treated with ACE inhibitors including Ramipril. Life threatening angioedema has been reported in patients treated with ACE inhibitors including ramipril. The overall incidence is approximately 0.1 – 0.2%. Angioedema involving the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with ACE inhibitors. Angioedema associated with laryngeal involvement may be fatal. If laryngeal stridor or angioedema of the face, extremities, lips, tongue, or glottis occurs, pms-RAMIPRIL-HCTZ 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 tongue, glottis, or larynx, likely to cause airway obstruction, appropriate therapy (including, but not limited to 0.3 - 0.5 ml of subcutaneous epinephrine solution 1:1000) should be administered promptly.

Angioedema, including laryngeal edema, may occur especially following the first dose of pms-RAMIPRIL-HCTZ. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema, such as swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing. They should immediately stop taking pms-RAMIPRIL-HCTZ and consult with their physician.

An increased incidence of angioedema was observed in patients taking ACE inhibitors and mTOR inhibitors (mammalian target of rapamycin inhibitors) (see 9 DRUG INTERACTIONS).

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

Patients taking a concomitant mTOR inhibitor (e.g., sirolimus, everolimus, temsirolimus), DPP-IV inhibitor (e.g., sitagliptin) or neutral endopeptidase (NEP) inhibitor may be at increased risk for angioedema. Caution should be used when initiating ACE inhibitor therapy in patients already taking a mTOR, DPP-IV 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).

Angioedema – Intestinal

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, facial angioedema also occurred. The intestinal angioedema symptoms resolved after stopping the ACE inhibitor (see 8.5 Post-Market Adverse Reactions, Immune)

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

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

Anaphylactoid Reactions to ACE Inhibitors during membrane exposure

Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes [e.g., polyacrylonitrile (PAN)] and treated concomitantly with an ACE inhibitor. Therefore, the use of pms-RAMIPRIL-HCTZ in patients dialyzed with high-flux membranes is contraindicated (see 2 CONTRAINDICATIONS). 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. If such treatment is required, a different type of dialysis membrane or a different class of antihypertensives is recommended.

Anaphylactoid Reactions to ACE Inhibitors 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. Therefore, the use of pms-RAMIPRIL-HCTZ in patients receiving low density lipoprotein apheresis with dextran sulfate is contraindicated (see 2 CONTRAINDICATIONS). If such treatment is required, consideration should be given to using a different type of apheresis or a different class of antihypertensive agents.

Anaphylactoid Reactions to ACE Inhibitors during desensitization

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

Hypersensitivity to Thiazide Diuretics

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

The possibility of exacerbation or activation of systemic lupus erythematosus has been reported in patients treated with hydrochlorothiazide.

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 ramipril and hydrochlorothiazide tablets (see 9 DRUG INTERACTIONS).

Metabolism

Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypokalemia, hyponatremia, and hypochloremic alkalosis).

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

Thiazides may decrease serum PBI (protein-bound iodine) levels without signs of thyroid disturbance.

Thiazides have been shown to increase excretion of magnesium; this may result in hypomagnesemia.

Thiazides may decrease urinary 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 hyperparathyroidism. Thiazides should be discontinued before carrying out tests of parathyroid function.

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

Dosage adjustments of insulin or oral hypoglycemic agents may be required. Latent diabetes mellitus may become manifest during thiazide therapy.

Administration of ACE inhibitors in patients with diabetes may potentiate the blood glucose lowering effect of oral hypoglycemic agents or insulin (see 9.4 Drug-Drug Interactions).

Elevated serum potassium (>5.7 mEq/L) was observed in approximately 1% of hypertensive patients in clinical trials treated with the ACE inhibitor ramipril. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was not a cause of discontinuation of therapy in any hypertensive patient. Risk factors for the development of hyperkalemia may include renal insufficiency, diabetes mellitus, and the concomitant use of agents to treat hypokalemia or other drugs associated with increases in serum potassium (see 9.4 Drug-Drug Interactions, Agents increasing serum potassium).

Patients should be told not to use salt substitutes containing potassium, potassium supplements or potassium sparing diuretics without consulting their physician.

Monitoring and Laboratory Tests

Hematology monitoring

It is recommended that the white blood cell count be monitored to permit detection of a possible leukopenia due to the ACE inhibitor component of pms-RAMIPRIL-HCTZ, ramipril. More frequent monitoring is advised in the initial phase of treatment and in patients:

• with impaired renal function,
• those with concomitant collagen disease (e.g., lupus erythematosus or scleroderma) or
• those treated with other drugs that can cause changes in the blood picture (see 7 WARNINGS AND PRECAUTIONS, Hematologic, Neutropenia/Agranulocytosis and; 9.4 Drug-Drug Interactions, Allopurinol, Immunosuppressants, Corticosteroids, Procainamide, Cytostatics and other substances that may change the blood picture).

Metabolism monitoring

Appropriate monitoring of electrolytes and blood sugar is required.

It is recommended that serum sodium, potassium, calcium, uric acid and blood glucose be monitored regularly. More frequent monitoring of serum potassium is necessary in patients with impaired renal function.

Renal function monitoring

Use of pms-RAMIPRIL-HCTZ should include appropriate assessment of renal function, particularly in the initial weeks of treatment.

Particularly careful monitoring is required in patients with:

• heart failure
• renovascular disease (atherosclerotic renal artery stenosis (AS-RAS) and fibromuscular dysplasia(FMD))
• impairment of renal function
• kidney transplant
• elderly patients

Ophthalmologic

Choroidal Effusion, Acute Myopia and Secondary Angle-Closure Glaucoma

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 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/Anesthesia

In patients undergoing surgery or anesthesia with agents producing hypotension, ramipril and hydrochlorothiazide tablets may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it may be corrected by volume repletion.

Thiazides may increase the responsiveness to tubocurarine.

Patients planning to undergo surgery and/or anesthesia should be told to inform their physician that they are taking an ACE inhibitor.

Renal

Renal impairment

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; therefore, use of pms-RAMIPRIL-HCTZ should include appropriate assessment of renal function.

The use of ACE inhibitors – including the ramipril component of pms-RAMIPRIL-HCTZ – or ARBs with aliskiren-containing drugs is contraindicated in patients with diabetes mellitus (type 1 or 2), moderate to severe renal impairment (GFR < 60 ml/min/1.73m²), hyperkalemia(> 5 mMol/L) or congestive heart failure who are hypotensive (see 2 CONTRAINDICATIONS and 9.5 Drug-Drug Interactions, Dual Blockade of the Renin-Angiotensin-System (RAS)).

Concomitant use of ACE inhibitors – including the ramipril component of pms-RAMIPRIL-HCTZ, with ARBs is contraindicated in patients with diabetes with end organ damage due to risk of hyperkalemia, moderate to severe kidney insufficiency (GFR< 60 mL/min/1.73m²), hyperkalemia(> 5mMol/L) or congestive heart failure who are hypotensive (see 2 CONTRAINDICATIONS; and 9 DRUG INTERACTIONS, Dual Blockade of the Renin-Angiotensin-System (RAS)).

pms-RAMIPRIL-HCTZ should be used with caution in patients with renal insufficiency as they may require reduced or less frequent doses (see 4 DOSAGE AND ADMINISTRATION). Close monitoring of renal function during therapy should be performed as deemed appropriate in patients with renal insufficiency (see 7 WARNINGS ANDPRECAUTIONS, Monitoring and Laboratory Tests, Renal Function Monitoring).

Thiazides may not be appropriate diuretics for use in patients with renal impairment and are ineffective at GFR values ≤30 mL/min per 1.73 m² body surface area (i.e., severe insufficiency).

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 during treatment of severe progressive renal disease the diuretic should be discontinued.

Respiratory

Acute Respiratory Distress

Severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after taking hydrochlorothiazide. Pulmonary oedema typically develops within minutes to hours after hydrochlorothiazide intake. At the onset, symptoms can include dyspnoea, fever, pulmonary deterioration and hypotension. If diagnosis of ARDS is suspected, ALTACE HCT should be withdrawn and appropriate treatment should be given. ALTACE HCT must not be administered to patients who previously experienced ARDS following intake of hydrochlorothiazide or another thiazide diuretic.

Skin

Photosensitivity

Photosensitivity reactions have been reported with the use of thiazide diuretics. If the photosensitivity reactions occur during treatment with hydrochlorothiazide drugs, treatment should be stopped.

7.1 Special Populations

7.1.1 Pregnant Women

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, pms-RAMIPRIL-HCTZ should be discontinued as soon as possible, and, if appropriate, alternative therapy should be started. Patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy.

The use of ACE inhibitors is contraindicated during pregnancy.

Prematurity, 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.

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.

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 BP 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. It is not known if ramipril or ramiprilat can be removed from the body by hemodialysis.

Since the use of ramipril and hydrochlorothiazide tablets during pregnancy can cause injury and even death of the developing fetus, patients should be advised to report promptly to their physician if they become pregnant.

Animal Data

No teratogenic effects of ramipril were seen in studies of pregnant rats, rabbits, and cynomolgus monkeys at doses 2500x, 6.25x and 1250x, respectively, the maximum human dose. In rats, the highest dose (1000 mg/kg) caused reduced food intake in the dams, with consequent reduced birth weights of the pups and weight development during the lactation period. In rabbits, maternal effects were mortalities (≥100 mg/kg) and reduced body weight. In monkeys, maternal effects were mortalities (≥50 mg/kg), vomiting, and reduced weight gain.

7.1.2 Breast-feeding

The presence of concentrations of ACE inhibitor and thiazides have been reported in human milk. The use of pms-RAMIPRIL-HCTZ is contraindicated during breastfeeding.

7.1.3 Pediatrics

Pediatrics (<18 years of age): The safety and effectiveness of ramipril and hydrochlorothiazide tablets in children have not been established. Therefore, pms-RAMIPRIL-HCTZ is not indicated in this patient population.

7.1.4 Geriatrics

Geriatrics (>65 years of age): Because of decreased cardiovascular reserve, greater sensitivity in older patients (> 65 years) may be expected. Evaluation of renal function at beginning of treatment is recommended.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

The most frequent adverse drug reactions observed with ramipril and hydrochlorothiazide tablets (ramipril/hydrochlorothiazide) were: headache (3.9%), dizziness (2.2%) and bronchitis (2.1%). The common serious adverse event (AE) pooled from the different clinical trials was tachycardia (0.2%).

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.

Table 3: Adverse Events occurring ≥ 1% in patients taking ramipril and hydrochlorothiazide (HCT) in controlled clinical trials

Adverse Events

*: Patients taking ramipril and hydrochlorothiazide tablets or ramipril + hydrochlorothiazide in combination.

8.3 Less Common Clinical Trial Adverse Reactions

Cardiac disorders: angina pectoris, palpitation, peripheral edema, tachycardia.

Ear and labyrinth disorders: hearing loss, tinnitus

Eye disorders: conjunctivitis, visual disturbances (including blurred vision).

Gastrointestinal disorders: abdominal pain (sometimes with enzyme changes suggesting pancreatitis), aphthous stomatitis, constipation, dry mouth, dyspepsia, dysphagia, gastroenteritis, gastritis, gastrointestinal pain, gingivitis, increased salivation, nausea, upper abdominal pain

General disorders and administration site conditions: chest pain, fever, shock

Hepatobiliary disorders: increased hepatic enzymes and/or conjugated bilirubin, cholestatic or cytolytic hepatitis. Calculous cholecystitis (due to hydrochlorothiazide)

Immune system disorders: allergic reactions

Metabolism and nutrition disorders: anorexia, decreased appetite, excessive thirst, gout, hyperglycemia, hyperuricemia, hypokalemia, weight gain (related to ramipril).

Musculoskeletal and connective tissue disorders: arthralgia, arthritis, myalgia.

Nervous system disorders: burning sensation (mainly to the skin of face or extremities), disorders of balance, neuropathy, paresthesia, polyneuritis, taste loss, tremor, vertigo.

Psychiatric disorders: anxiety, apathy, depression, insomnia, nervousness, sleep disorder, somnolence.

Renal and urinary disorders: abnormal kidney function, increase in urinary output (in connection with an improvement in cardiac performance), renal failure.

Reproductive system and breast disorders: impotence

Respiratory, thoracic and mediastinal disorders: dyspnea, sinusitis.

Skin and subcutaneous tissue disorders: alopecia, angioedema, erythroderma, maculopapular rash, maculopapular exanthema, pruritus, psoriasis, purpura, rash, sweating.

Non-melanoma skin cancer

Some pharmacoepidemiological studies have suggested a higher risk of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) of the skin with increasing use of hydrochlorothiazide.

Noting substantial uncertainty, a systematic review and meta-analysis undertaken by Health Canada suggested 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 SCC 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 BCC per 1000 treated patients compared with non-use of hydrochlorothiazide (meta-analysis of 2 observational studies).

Vascular disorders: hot flushes, hypotension, postural hypotension, syncope

8.4 Abnormal Hematologic and Clinical Chemistry Findings

Hematologic: decrease in red blood cell count, hemoglobin or hematocrit, leucocytosis.

Hydrochlorothiazide

Renal function test: increased serum concentrations of uric acid.

Cholesterol: increase in serum cholesterol and triglycerides.

Glucose: lower tolerance to glucose. In patients with diabetes mellitus, this may lead to a deterioration of the metabolic control.

8.5 Post-Market Adverse Reactions

Blood and lymphatic system disorders: Agranulocytosis, bone marrow depression, eosinophilia, hemolytic anemia, reduction in the white blood cell or blood platelet count, neutropenia, pancytopenia. Hemoconcentration in the context of fluid depletion (see 7 WARNINGS AND PRECAUTIONS, Hematologic; and 9 DRUG INTERACTIONS).

Cardiac disorders: angina pectoris, cardiac arrhythmias, myocardial infarction, myocardial ischemia, palpitations, peripheral oedema, tachycardia.

Endocrine disorders: Syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Ear and labyrinth disorders: disturbed hearing, tinnitus.

Eye disorders: decreased lacrimation, visual disturbances, xanthopsia due to hydrochlorothiazide, choroidal effusion, acute myopia, acute angle-closure glaucoma (frequency not known).

Gastrointestinal disorders: abdominal discomfort, constipation, diarrhea, digestive disturbances, dryness of the mouth, gastric pain (including gastritic-like gastric pain), glossitis, inflammatory reactions of the oral cavity and gastrointestinal tract, diarrhea, increased levels of pancreatic enzymes, intestinal angioedema, nausea, pancreatitis (cases of fatal outcome have been very exceptionally reported), vomiting. Sialoadenitis due to hydrochlorothiazide.

General disorders and administration site conditions: asthenia, fatigue, fever, weakness.

Hepatobiliary disorders: cholestatic jaundice, hepatocellular damage, increases in serum levels of hepatic enzymes and/or bilirubin, liver damage (including acute liver failure).

Immune system disorders: anaphylactic or anaphylactoid reactions to ramipril or any of the other ingredients are rare (see 7 WARNINGS AND PRECAUTIONS, Immune). Anaphylactic reactions to hydrochlorothiazide are possible. The likelihood and the severity of anaphylactoid reactions to insect venoma are increased under ACE inhibition. Increased antinuclear antibodies.

Metabolism and nutrition disorders: decline in serum sodium concentration; decrease in potassium concentration due to hydrochlorothiazide, dehydration, development or aggravation of a metabolic alkalosis, glycosuria (due to hydrochlorothiazide); hypochloremia, hypomagnesemia, hypercalcemia, increase in the concentration of serum potassium due to ramipril. General signs of disturbances in the electrolyte balance: confusion, drowsiness, headache, increased fluid excretion and muscle cramps.

Musculoskeletal and connective tissue disorders: arthralgia, muscle cramps, myalgia. Muscular weakness, musculoskeletal stiffness, tetany due to hydrochlorothiazide.

Nervous system disorders: cerebral ischemia (including ischaemic stroke and transient ischaemic attack), disorders of balance, dizziness, headache, impaired psychomotor skills (impaired reactions), light-headedness, paresthesia, smell, taste disturbances and tremor.

Psychiatric disorders: attention disturbances, confusion, depressed mood, feeling of anxiety, nervousness, restlessness, somnolence.

Renal and urinary disorders: increase in serum urea and serum creatinine and impairment of renal function, progression to acute renal failure, interstitial nephritis and pre -existing proteinuria may deteriorate (though ACE inhibitors usually reduce proteinuria).

Respiratory, thoracic and mediastinal disorders: bronchitis, bronchospasm (including aggravated asthma), dry (non-productive) tickling cough, dyspnea, nasal congestion, sinusitis.

Alveolitis allergic (pneumonitis), non-cardiogenic pulmonary oedema due to hydrochlorothiazide.

Acute respiratory distress syndrome (ARDS) due to hydrochlorothiazide.

Reproductive system and breast disorders: gynaecomastia, reduced libido, transient erectile impotence.

Skin and subcutaneous tissue disorders: alopecia, cutaneous or mucosal reactions such as rash, pruritus or urticaria, erythema multiforme, exacerbation of psoriasis, exfoliative dermatitis, maculopapular rash, pemphigoid or lichenoid exanthema or enanthema, pemphigus, photosensitivity, psoriasiform, Stevens-Johnson syndrome, sweating, systemic lupus erythematosus, toxic epidermal necrolysis.

Angioedema. Very exceptionally, the airway obstruction resulting from angioedema may have a fatal outcome.

System Organ Class: Neoplasms benign, malignant and unspecified (including cysts and polyps):

Non-melanoma skin and lip cancer (Basal cell carcinoma and Squamous cell carcinoma)

*Non-melanoma skin and lip cancer: Based on available data from two epidemiological studies based on Danish National cancer registries, cumulative dose-dependent association between HCTZ and non-melanoma skin and lip cancer (Basal cell carcinoma and Squamous cell carcinoma) has been observed (see 7 WARNINGS AND PRECAUTIONS, Non-melanoma skin cancer; and 10.2 Pharmacodynamics).

Vascular disorders: disturbed orthostatic regulation, exacerbation of perfusion disturbances due to vascular stenosis, hypotension, precipitation or intensification of Raynaud’s phenomenon, syncope, thrombosis (in the context of severe fluid depletion), vascular stenosis, vasculitis.

9 DRUG INTERACTIONS

9.3 Drug-Behavioural Interactions

Consumption of alcohol while using pms-RAMIPRIL-HCTZ may potentiate the risk of orthostatic hypotension (see 9.4 Drug-Drug Interactions).

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 4: Established or Potential Drug-Drug Interactions

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

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Tests for Parathyroid Function

Hydrochlorothiazide stimulates renal calcium reabsorption and may cause hypercalcemia. This must be considered when carrying out tests for parathyroid function.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Ramipril and hydrochlorothiazide tablets have antihypertensive and diuretic effects. Ramipril and hydrochlorothiazide are used singly or together for antihypertensive therapy. The antihypertensive effects of both substances are complementary.

The blood-pressure-lowering effects of both components together are greater than the effect of either monotherapy. In patients treated with ramipril and a thiazide diuretic there was essentially no change in serum potassium (see 7 WARNINGS AND PRECAUTIONS, Metabolism).

10.2 Pharmacodynamics

Ramipril

Administration of ramipril causes a marked reduction in peripheral arterial resistance. Administration of ramipril to patients with hypertension leads to a reduction in supine and standing blood pressure (BP) without a compensatory rise in heart rate.

In most patients, the onset of the antihypertensive effect of a single dose becomes apparent 1- 2 hours after oral administration. The peak effect of a single dose is usually reached 3- 6 hours after oral administration. The antihypertensive effect of a single dose usually lasts for 24 hours.

Abrupt discontinuation of ramipril does not produce a rapid and excessive rebound increase in BP.

Hydrochlorothiazide

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

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

10.3 Pharmacokinetics

Table 5: Summary of pharmacokinetic parameters after single doses of 5/25 mg ramipril and hydrochlorothiazide tablets, 5 mg ramipril, 25 mg hydrochlorothiazide (HCT) or 5 mg ramipril + 25 mg HCT from study HOE9829/1502

No significant pharmacokinetic interaction has been observed between ramipril and hydrochlorothiazide administered as a fixed combination formulation of ramipril/ hydrochlorothiazide tablets (ramipril/hydrochlorothiazide 5 mg/ 25 mg tablet Aventis Pharma Canada Inc.) under fasting conditions, on the basis of ramipril and hydrochlorothiazide parameters (C_max and AUC).

Ramipril

Absorption

Ramipril is rapidly absorbed after oral administration. As measured by the recovery of radioactivity in the urine, which represents only one of the elimination routes, absorption of ramipril is ≥56%. Administration of ramipril at the same time as food has no relevant effect on absorption.

Distribution

As a result of this activation/metabolization of the prodrug, approximately 20% of orally administered ramipril is bioavailable.

The bioavailability of ramiprilat after oral administration of 2.5 and 5 mg ramipril is approximately 45% compared with its availability after intravenous administration of the same doses.

Peak plasma concentrations of ramipril are reached within 1 hour after oral administration. Peak plasma concentrations of ramiprilat are reached 2- 4 hours after oral administration of ramipril.

The protein-binding of ramipril and ramiprilat is approximately 73% and 56%, respectively.

Metabolism

The prodrug ramipril undergoes an extensive hepatic first pass metabolism (hydrolysis), which is essential for the formation of the sole active metabolite ramiprilat. In addition to this activation into ramiprilat, ramipril is glucuronized and transformed into ramipril diketopiperazine (ester). Ramiprilat is glucuronized as well and transformed into ramiprilat diketopiperazine(acid).

When high doses (10 mg) of ramipril are administered, impairment of hepatic function retards the activation of ramipril into ramiprilat, resulting in increased ramipril plasma levels.

Excretion

Following oral administration of 10 mg of radioactive labelled ramipril, approximately 40% of total radioactivity is excreted in faeces and approximately 60% in urine.

The elimination half-life of ramipril is approximately 1 hour.

Approximately 80- 90% of the metabolites in urine and bile have been identified as ramiprilat or ramiprilat metabolites. Ramipril glucuronide and ramipril diketopiperazine represented approximately 10- 20% of the total amount, whereas unmetabolized ramipril accounted for approximately 2%.

Plasma concentrations of ramiprilat decline in a polyphasic manner. The initial distribution and elimination phase has a half-life of approximately 3 hours. It is followed by an intermediate phase (half-life approximately 15 hours) and a terminal phase with very low plasma ramiprilat concentrations and a half-life of approximately 4- 5 days.

Despite this long terminal phase, a single daily dose of 2.5 mg ramipril or more yields steady state plasma concentrations of ramiprilat after approximately 4 days. The "effective" half-life, which is relevant for dosage, is 13- 17 hours under multiple-dose conditions.

Renal excretion of ramiprilat is reduced in patients with impaired renal function, and renal ramiprilat clearance is proportionally related to creatinine clearance. This results in elevated plasma concentrations of ramiprilat, which decrease more slowly than in persons with normal renal function (see 7 WARNINGS AND PRECAUTIONS, Renal).

Hydrochlorothiazide

Absorption

The bioavailability of hydrochlorothiazide after oral administration is approximately 70%.

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.

Excretion

Hydrochlorothiazide is excreted almost entirely (>95%) by renal route in unchanged form. After oral administration of a single dose, 50-70% is excreted within 24 hours.

The elimination half-life is 5- 6 hours. In renal insufficiency excretion is reduced and the half-life prolonged. Renal clearance of hydrochlorothiazide correlates closely with creatinine clearance.

Special Populations and Conditions

Geriatrics (> 65 years of age)

In healthy subjects aged 65- 76 years, ramipril and ramiprilat kinetics are similar to those in healthy young subjects.

Race

The average response to ACE inhibitor monotherapy was lower in black hypertensive patients (usually a low-renin hypertensive population) than in non-black patients.

Cardiovascular Insufficiency

The clearance of hydrochlorothiazide may be decreased in patients with congestive heart failure.

Hepatic Insufficiency

No relevant changes in the pharmacokinetics of hydrochlorothiazide have been noted in liver cirrhosis.

In patients with impaired liver function, plasma ramipril levels increased about 3-fold, although peak concentrations of ramiprilat in these patients were not different from those seen in patients with normal hepatic function.

Hydrochlorothiazide should not be administered in hepatic coma or pre-coma. It should be used only with caution in patients with progressive hepatic disease (see 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary).

Renal Insufficiency

Renal excretion of ramipril, ramiprilat, and its metabolite is reduced in patients with impaired renal function, and renal ramiprilat clearance is proportionally related to creatinine clearance. This results in elevated plasma concentrations of ramiprilat, which decreases more slowly than in persons with normal renal function.

In patients with creatinine clearance < 40 mL/min/1.73m², increases in C_max and AUC of ramipril and ramiprilat compared to normal subjects were observed following multiple dosing with 5 mg ramipril (see 4 DOSAGE AND ADMINISTRATION, Dosage in patients with impaired renal function) .

The clearance of hydrochlorothiazide is decreased in renal failure.

Hydrochlorothiazide must be present at the site of action in the renal tubule in sufficient concentration in order to achieve its therapeutic effect. Hydrochlorothiazide reaches its site of action almost exclusively by secretion into the tubular fluid via the organic acid cotransporter. In mild renal insufficiency, higher doses are required to achieve sufficient concentrations of drug at the site of action due to decreased tubular secretion in renal failure. However, hydrochlorothiazide becomes ineffective once creatinine clearance <30- 50 mL/min.

11 STORAGE, STABILITY AND DISPOSAL

Store pms-RAMIPRIL-HCTZ (ramipril/hydrochlorothiazide) between 15℃ - 30℃. Protect from heat and humidity.

12 SPECIAL HANDLING INSTRUCTIONS

There are no special handling instructions for pms-RAMIPRIL-HCTZ.

PART II : SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Ramipril

Chemical name: 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]- L-alanyl] -(1S,3S,5S)-2-azabicyclo- [3.3.0] octane-3-carboxylicacid

USP Chemical name: Cyclopenta[b]pyrrole-2-carboxylic acid, 1-[2-[[1-(ethoxycarbonyl)-3- phenylpropyl]amino]-1-oxopropyl]octahydro-, [2S- [1[R*(R*)],2 a,3a ,6a ]]-.(2S,3aS,6aS)-1-[(S)-N-[(S)-1-Carboxy-3- phenylpropyl]alanyl]octahydrocyclopenta[b]pyrrole-2-carboxylicacid, 1- ethyl ester

Molecular formula and molecular mass: C23H32N2O5 416.52 g/mol

Structural formula:

CH₂CH₂C NH COOC₂H₅ H C H C CH₃ O N H H HOOC

Physicochemical properties:

Description: A white to off-white crystalline powder

Melting point: 105℃ to 112℃

Solubility: Slightly soluble in water, and freely soluble in ethanol and methanol.

Drug Substance

Proper name: Hydrochlorothiazide

Chemical name: 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1- dioxide.

Molecular formula and molecular mass: C7H8ClN3O4S2 297.72 g/mol

Structural formula:

Physicochemical properties:

Description: A white or almost white, crystalline powder

Solubility: Very slightly soluble in water, soluble in acetone, sparingly soluble in alcohol. It dissolves in dilute solutions of alkali hydroxides.

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

The Treatment of Essential Hypertension in Patients for Whom this Combination

Therapy is Appropriate

Table 6: Summary of patient demographics for clinical trials in specific indication

R = Ramipril, H = Hydrochlorothiazide, od = once daily, bid = twice daily

All populations included in the 7 phase II/III safety studies were similar, male and female patients suffering from mild to moderate hypertension (WHO stage I or II hypertension).

A subgroup analysis was performed with data derived from studies 1, 2, 3, and 4 in order to assess the efficacy and/or safety of the combination of ramipril/hydrochlorothiazide in different risk groups, which included elderly, diabetic, renally insufficient, and patients with concomitant medications (non-steroidal anti-inflammatory drugs, nitrates, digitalis, and antigout agents). A total of 1180 patients participated in studies 1- 4.

R= Ramipril

H= Hydrochlorothiazide (HCT)

14.3 Comparative Bioavailability Studies

• A blind, randomized, two-way crossover bioequivalence study was performed in normal healthy male volunteers (n = 24) under fasting conditions on Ramipril/Hydrochlorothiazide tablets using Pharmascience Inc. pms-RAMIPRIL-HCTZ 10 mg/25 mg tablets versus the reference product, ALTACE HCT^® 10 mg/25 mg Tablets, by Sanofi Aventis Canada Inc. The pharmacokinetic data calculated for the pms-RAMIPRIL-HCTZ 10 mg/25 mg tablets and ALTACE HCT^® 10 mg/25 mg tablets formulation are tabulated below:

  • SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

    RAMIPRIL

^*pms-RAMIPRIL-HCTZ, Pharmascience Inc., Montréal, Canada

^†ALTACE HCT^®, Sanofi Aventis Canada Inc., Laval, Québec, Canada

^§ Expressed as the median (range)

^€ Expressed as the arithmetic mean (CV %)

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

HYDROCHLOROTHIAZIDE

^*pms-RAMIPRIL-HCTZ, Pharmascience Inc., Montréal, Canada

^†ALTACE HCT^®, Sanofi Aventis Canada Inc., Laval, Québec, Canada

^§ Expressed as the median (range)

^€ Expressed as the arithmetic mean (CV %)

In addition, a drug interaction study was conducted demonstrating comparable bioavailability between the clinically proven 5 mg ramipril/25 mg hydrochlorothiazide combination tablet and the Canadian reference tablets of 5 mg ramipril and 25 mg hydrochlorothiazide, taken concomitantly.

These results demonstrate that the bioavailability of ramipril and hydrochlorothiazide tablets is comparable to the bioavailability of the Canadian reference ramipril and hydrochlorothiazide tablets, taken concomitantly.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

Acute toxicity

Ramipril

As it has an LD₅₀ >10,000 mg/kg body weight in mice and rats and >1000 mg/kg body weight in beagle hounds, oral administration of ramipril has been found to be devoid of acute toxicity.

Ramipril + Hydrochlorothiazide

The oral LD₅₀ in rats and mice is >10,000 mg/kg body weight, i.e., the combination ramipril + hydrochlorothiazide (1:5) is totally devoid of acute toxicity. This is consistent with the results of acute toxicity testing of the single components.

Chronic toxicity

Ramipril

Studies involving chronic administration have been conducted in rats, dogs and monkeys. In rats, daily doses of the order on 40 mg/kg body weight lead to shifts in plasma electrolytes and to anaemia. At daily doses of ≥3.2 mg/kg body weight, there was some evidence of changes in renal morphology (distal tubular atrophy). However, these effects can be explained in pharmacodynamic terms and are characteristic of the substance class. Daily doses of 2 mg/kg body weight have been tolerated by rats without toxic effects. Tubular atrophy is encountered in rats, but not in dogs and monkeys.

As an expression of the pharmacodynamic activity of ramipril (a sign of increased renin production as a reaction to reduced angiotensin II formation), pronounced enlargement of the juxtaglomerular apparatus has been noted in the dog and monkey - especially at daily doses of

≥250 mg/kg body weight. Indications of plasma electrolyte shifts and changes in blood picture have also been found in the dog and monkey. Dogs and monkeys tolerated daily doses of

2.5 mg/kg body weight and 8 mg/kg body weight, respectively, without harmful effects.

Ramipril + Hydrochlorothiazide

With the exception of disturbances in electrolyte balance, studies conducted in rats and monkeys yielded no conspicuous findings.

Reproduction toxicology

Ramipril

Reproduction toxicology studies in the rat, rabbit and monkey did not disclose any teratogenic properties.

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

The administration of ramipril to female rats during the fetal period and lactation produced irreversible renal damage (dilatation of the renal pelvis) in the offspring at doses of ≥50 mg/kg body weight.

Ramipril + Hydrochlorothiazide

Rats

In studies on embryotoxicity, the combination was administered to rats in daily doses of 1- 2400 mg/kg body weight during the sensitive phase of organogenesis. Hydrochlorothiazide has been studied in a similar way alone at daily doses of 125-2000 mg/kg body weight; these doses corresponded to the proportions of hydrochlorothiazide contained in the 3 highest doses of the combination.

The studies in rats showed that dams tolerated the combination administered at dose levels of

≤10 mg/kg body weight without complications. Doses of ≥150 mg/kg body weight showed toxic effects on dams and led to reduced food intake and weight development. Heart and liver weights were reduced. Clinical symptoms of toxicity and deaths occurred at dose levels of 2400 mg/kg body weight.

At dose levels of ≥150 mg/kg body weight, urine excretion increased, and after 2400 mg/kg body weight kidney weights were slightly increased. These effects are attributable to the pharmacodynamic action of hydrochlorothiazide.

A dose of 1 mg/kg body weight does not impair the development of the embryo. Doses of

≥10 mg/kg body weight led to a slight retardation in development of the fetus, which manifested itself in delayed skeletal ossification and, at dose levels of ≥150 mg/kg body weight, in reduced body weight and reduced body length. Placenta weight was also reduced.

Morphological investigations conducted in fetuses revealed increased occurrences of dilatation of the renal pelvis and the ureter as well as waved and thickened ribs at dose levels of ≥150 mg/kg body weight and, at levels of ≥600 mg/kg body weight, bent and shortened scapula and bones of the limbs.

The studies with hydrochlorothiazide alone confirm that the retardation of fetal growth is attributable to the diuretic. The other findings point to a joint effect of the 2 single components in the combination.

The study in rats revealed that the combination is somewhat more toxic than either of the single components, but without any signs of a teratogenic effect of the combination or of hydrochlorothiazide.

Other studies were conducted in rats to determine the peri- and postnatal toxicity of the combination; doses of 10 and 60 mg/kg body weight daily were given orally during the last third of pregnancy and during the 3 weeks of lactation. At doses of 10 mg/kg body weight, the drug neither had an adverse effect on the dams' general condition, the course of pregnancy or parturition, nor did it lead to a disturbance of intrauterine and postnatal development of the progeny.

After administration of 60 mg/kg body weight, the dams reduced food intake slightly, and the pups showed slightly reduced weights at birth and during the first week thereafter. In the subsequent period, the postnatal development of the pups turned up no conspicuous findings. The incidence of dilatation of the renal pelvis (such as has been noted following higher doses of ramipril) was not increased.

Rabbits

In studies on embryotoxicity, the combination was administered to rabbits in daily doses of 0.96 –6.00 mg/kg body weight during the sensitive phase of organogenesis.

A further group received hydrochlorothiazide (2 mg/kg; corresponding to the amount in the

• 2.40 mg/kg ramipril +hydrochlorothiazide dose group).

Administration of the combination in rabbits at dose levels of 0.96 mg/kg body weight led to a slight reduction in food intake and stagnation in body weight. However, it had no adverse effect on the intrauterine development in the progeny.

Following administration at dose levels of ≥2.40 mg/kg body weight, the dams reduced their intake of food and water and lost weight; furthermore, deaths and spontaneous abortions occurred at these dose levels and living fetuses showed slightly retarded growth at birth. No signs of external anomalies or of anomalies affecting internal organs and skeleton of the fetuses were detected which could be attributed to administration of the combination.

Hydrochlorothiazide alone administered at daily doses of 2 mg/kg body weight was tolerated by the dams and their fetuses.

From this study, it can be concluded that the combination is slightly more toxic for the damns than either component alone and that this combination did not provoke teratogenic changes.

Studies on possible impairment of fertility and reproductive capability were not conducted with the combination, since no toxic effect was to be expected on the basis of results in the single components.

Immunotoxicology

Ramipril

Toxicology studies have yielded no indication that ramipril possesses any immunotoxic effects.

Mutagenicity

Ramipril

Extensive mutagenicity testing using several test systems has yielded no indication that ramipril possesses mutagenic or genotoxic properties.

Ramipril + Hydrochlorothiazide

Mutagenicity studies were not conducted with the combination since the results of tests with each component alone have shown no evidence of any such risk.

Carcinogenicity

Ramipril

Long-term studies in rat and mouse have yielded no indication of any tumorigenic effect.

Renal tubules with oxyphilic cells and tubules with oxyphilic cellular hyperplasia in rats are regarded as response to functional alterations and morphological changes, and not as a neoplastic or pre-neoplastic response.

Ramipril + Hydrochlorothiazide

Carcinogenicity studies were not conducted with the combination since the results of tests with each component alone have shown no evidence of any such risk.

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 pheocytochroma 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

^PrALTACE HCT^® (Ramipril and Hydrochlorothiazide Tablets, 2.5/12.5 mg, 5/12.5 mg, 10/12.5 mg, 5/25 mg, 10/25 mg), submission Control No.: 265837, Product Monograph, Bausch Health, Canada Inc., January 6, 2023.