ENALAPRIL MALEATE/HCTZ

5 Missed dose 05/2023 7 WARNINGS AND PRECAUTIONS 05/2023 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 ................................................................................................................... 1 Pediatrics ........................................................................................................................

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

4 3 SERIOUS WARNINGS AND PRECAUTIONS BOX .................................................................. 5 4 DOSAGE AND ADMINISTRATION ....................................................................................... 1 Dosing Considerations.....................................................................................................

2 Recommended Dose and Dosage Adjustment ................................................................ 4 Administration ................................................................................................................

5 Missed Dose .................................................................................................................... 7 5 OVERDOSAGE ...................................................................................................................

7

). Therefore, exercise caution when driving or operating a vehicle or potentially dangerous machinery. Ear/Nose/Throat Cough:A dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose of Enalapril Maleate / Hydrochlorothiazide has been reported.

Such possibility should be considered as part of the differential diagnosis of the cough. Endocrine and Metabolism Initial and periodic determination of serum electrolytes should be performed at appropriate intervals to detect possible electrolyte imbalance.

Metabolism:

Hyperuricemia may occur or acute gout may be precipitated in certain patients receiving thiazide therapy. Thiazides may decrease serum protein-bound iodine (PBI) 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 for parathyroid function. Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

Hematologic Neutropenia/Agranulocytosis:

Agranulocytosis and bone marrow depression have been caused by angiotensin converting enzyme inhibitors. Current experience with the drug shows the incidence to be rare. Periodic monitoring of white blood cell counts should be considered, especially in patients with collagen vascular disease and renal disease.

Hepatic/Biliary/Pancreatic Patients with Impaired Liver Function:

Hepatitis, jaundice (hepatocellular and/or cholestatic), elevations of liver enzymes and/or serum bilirubin have occurred during therapy with enalapril in patients with or without pre-existing liver abnormalities (see 8 ADVERSE REACTIONS).

In most cases the changes were reversed on discontinuation of the drug. Should the patient receiving ENALAPRIL MALEATE / HCTZ experience any unexplained symptoms (see PATIENT MEDICATION INFORMATION), particularly during the first weeks or months of treatment, it is recommended that a full set of liver function tests and any other ENALAPRIL MALEATE / HCTZ (enalapril maleate and hydrochlorothiazide tablets) Page 1 of 61 necessary investigation be carried out.

Discontinuation of ENALAPRIL MALEATE / HCTZ should be considered when appropriate. There are no adequate studies in patients with cirrhosis and/or liver dysfunction. ENALAPRIL MALEATE / 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. Thiazides 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.

4 DRUG- DRUG INTERACTIONS). Ophthalmologic Choroidal effusion, Acute Myopia and Secondary Angle-Closure Glaucoma: Hydrochlorothiazide, a sulphonamide, can cause an idiosyncratic reaction, resulting in choroidal effusion, acute transient myopia and /or secondary 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 sulphonamide or penicillin allergy.

Peri-Operative Considerations Surgery/Anesthesia:

In patients undergoing major surgery or during anesthesia with agents that produce hypotension, enalapril blocks 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.

Thiazides may increase the responsiveness to tubocurarine.

Renal Renal Impairment:

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, 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. 73m2). 4 DRUG-DRUG INTERACTIONS). Use of ENALAPRIL MALEATE / HCTZ should include appropriate assessment of renal function. Thiazides may not be appropriate diuretics for use in patients with renal impairment and are ineffective at creatinine […]

05/2023 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 ................................................................................................................... 1 Pediatrics ........................................................................................................................

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

4 3 SERIOUS WARNINGS AND PRECAUTIONS BOX .................................................................. 5 4 DOSAGE AND ADMINISTRATION ....................................................................................... 1 Dosing Considerations.....................................................................................................

2 Recommended Dose and Dosage Adjustment ................................................................ 4 Administration ................................................................................................................

5 Missed Dose .................................................................................................................... 7 5 OVERDOSAGE ...................................................................................................................

7 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING....................................... 7 7 WARNINGS AND PRECAUTIONS ........................................................................................ 1 Special Populations .......................................................................................................

2 Breast-feeding .......................................................................................................... 3 Pediatrics ..................................................................................................................

4 Geriatrics .................................................................................................................. 14 8 ADVERSE REACTIONS ......................................................................................................

1 Adverse Reaction Overview .......................................................................................... 2 Clinical Trial Adverse Reactions .....................................................................................

3 Less Common Clinical Trial Adverse Reactions ............................................................. 4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data...............................................................................................................................

5 Post-Market Adverse Reactions .................................................................................... 17 9 DRUG INTERACTIONS ......................................................................................................

1 Serious Drug Interactions ............................................................................................... 2 Drug Interactions Overview ..........................................................................................

4 Drug-Drug Interactions.................................................................................................. 5 Drug-Food Interactions .................................................................................................

6 Drug-Herb Interactions ................................................................................................. 7 Drug-Laboratory Test Interactions ................................................................................

26 10 CLINICAL PHARMACOLOGY ............................................................................................. 1 Mechanism of Action ................................................................................................

2 Pharmacodynamics .................................................................................................. 3 Pharmacokinetics .....................................................................................................

27 11 STORAGE,STABILITY AND DISPOSAL................................................................................ 29 12 SPECIAL HANDLING INSTRUCTIONS ................................................................................

29 13 PHARMACEUTICAL INFORMATION ................................................................................. 30 14 CLINICAL TRIALS ..............................................................................................................

1 Clinical Trials by Indication ....................................................................................... 2 Comparative Bioavailability Studies.......................................................................... 32 15 MICROBIOLOGY ..............................................................................................................

34 16 NON-CLINICAL TOXICOLOGY ........................................................................................... 34 17 SUPPORTING PRODUCT […]

05/ 2023