Product Monograph - Enalapril Maleate/HCTZ
RECENT MAJOR LABEL CHANGES
| 1 INDICATIONS, 1.1 Pediatrics | 05/2023 |
|---|---|
| 1 INDICATIONS, 1.2 Geriatrics | 05/2023 |
| 2 CONTRAINDICATIONS | 05/ 2023 |
| 4 DOSAGE AND ADMINISTRATION, 4.4 Administration |
| 05/2023 | |
| 4 DOSAGE AND ADMINISTRATION, 4.5 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 ................................................................................................................... 4
1.1 Pediatrics ........................................................................................................................ 4
1.2 Geriatrics ......................................................................................................................... 4
2 CONTRAINDICATIONS ....................................................................................................... 4
3 SERIOUS WARNINGS AND PRECAUTIONS BOX .................................................................. 5
4 DOSAGE AND ADMINISTRATION ....................................................................................... 5
4.1 Dosing Considerations ..................................................................................................... 5
4.2 Recommended Dose and Dosage Adjustment ................................................................ 5
4.4 Administration ................................................................................................................ 6
4.5 Missed Dose .................................................................................................................... 7
5 OVERDOSAGE ................................................................................................................... 7
6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING....................................... 7
7 WARNINGS AND PRECAUTIONS ........................................................................................ 8
7.1 Special Populations ....................................................................................................... 14
7.1.2 Breast-feeding .......................................................................................................... 14
7.1.3 Pediatrics .................................................................................................................. 14
7.1.4 Geriatrics .................................................................................................................. 14
8 ADVERSE REACTIONS ...................................................................................................... 14
8.1 Adverse Reaction Overview .......................................................................................... 14
8.2 Clinical Trial Adverse Reactions ..................................................................................... 15
8.3 Less Common Clinical Trial Adverse Reactions ............................................................. 16
8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ............................................................................................................................... 16
8.5 Post-Market Adverse Reactions .................................................................................... 17
9 DRUG INTERACTIONS ...................................................................................................... 19
9.1 Serious Drug Interactions ............................................................................................... 19
9.2 Drug Interactions Overview .......................................................................................... 19
9.4 Drug-Drug Interactions .................................................................................................. 19
9.5 Drug-Food Interactions ................................................................................................. 26
9.6 Drug-Herb Interactions ................................................................................................. 26
9.7 Drug-Laboratory Test Interactions ................................................................................ 26
10 CLINICAL PHARMACOLOGY ............................................................................................. 26
10.1 Mechanism of Action ................................................................................................ 26
10.2 Pharmacodynamics .................................................................................................. 27
10.3 Pharmacokinetics ..................................................................................................... 27
11 STORAGE,STABILITY AND DISPOSAL ................................................................................ 29
12 SPECIAL HANDLING INSTRUCTIONS ................................................................................ 29
13 PHARMACEUTICAL INFORMATION ................................................................................. 30
14 CLINICAL TRIALS .............................................................................................................. 31
14.1 Clinical Trials by Indication ....................................................................................... 31
14.2 Comparative Bioavailability Studies.......................................................................... 32
15 MICROBIOLOGY .............................................................................................................. 34
16 NON-CLINICAL TOXICOLOGY ........................................................................................... 34
17 SUPPORTING PRODUCT MONOGRAPHS.......................................................................... 45
PATIENT MEDICATION INFORMATION .................................................................................. 46
PART I: HEALTH PROFESSIONAL INFORMATION
1 INDICATIONS
ENALAPRIL MALEATE / HCTZ (enalapril and hydrochlorothiazide) is indicated for:
- Treatment of essential hypertension in patients for whom combination therapy with enalapril and hydrochlorothiazide is appropriate.
In using ENALAPRIL MALEATE / HCTZ consideration should be given to the risk of angioedema (see 7 WARNINGS AND PRECAUTIONS - General).
ENALAPRIL MALEATE / HCTZ is not indicated for initial therapy.
1.1 Pediatrics
Pediatrics (<18 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of enalapril maleate / hydrochlorothiazide has not been established; therefore, Health Canada has not authorized an indication for pediatric use.
1.2 Geriatrics
Geriatrics (> 65 years of age): Evidence from clinical studies and experience suggests that use in the geriatric population is associated with differences in safety or effectiveness.
2 CONTRAINDICATIONS
ENALAPRIL MALEATE / HCTZ is contraindicated in:
- Patients who are hypersensitive to this product or to any ingredient in the formulation. For a complete listing, see the 6 DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product monograph.
- Patients with a history of angioneurotic edema relating to previous treatment with an angiotensin converting enzyme inhibitor.
- Patients with hereditary or idiopathic angioedema.
- Patients with anuria or hypersensitivity to other sulfonamide-derived drugs due to the hydrochlorothiazide component
- Concomitant use of angiotensin converting enzyme inhibitors (ACEIs) – including the enalapril component ofENALAPRIL MALEATE / HCTZ with aliskiren-containing drugs in patients with diabetes mellitus (type 1 or type 2) or moderate to severe renal impairment (GFR < 60 mL/min/1.73m2) is contraindicated (see 7 WARNINGS AND PRECAUTIONS - Cardiovascular, and 9.4 DRUG-DRUG INTERACTIONS).
- ENALAPRIL MALEATE / HCTZ is contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer ENALAPRIL MALEATE / HCTZ within 36 hours of switching to or from sacubitril/valsartan, a product containing a neprilysin inhibitor. (See 7 WARNINGS AND PRECAUTIONS - General and 9.4 DRUG-DRUG INTERACTIONS.)
3 SERIOUS WARNINGS AND PRECAUTIONS BOX
Serious Warnings and Precautions
|
|---|
4 DOSAGE AND ADMINISTRATION
4.1 Dosing Considerations
- Dosage must be individualized.
- The fixed combination is not for initial therapy.
- Special attention for dialysis patients.
- The splitting of ENALAPRIL MALEATE / HCTZ 10 mg/25 mg tablets is not advised.
4.2 Recommended Dose and Dosage Adjustment
The dose of ENALAPRIL MALEATE / HCTZ should be determined by the titration of the individual components. If the fixed combination represents the dose and dosing frequency determined by this titration, the use of ENALAPRIL MALEATE / 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.
Once the patient has been successfully titrated with the individual components as described below, ENALAPRIL MALEATE / HCTZ may be substituted if the titrated doses and dosing schedule can be achieved by the fixed combination.
Patients usually do not require doses in excess of 50 mg of hydrochlorothiazide daily, particularly when combined with antihypertensive agents. Therefore, since each tablet of ENALAPRIL MALEATE / HCTZ contains either 12.5 mg or 25 mg of hydrochlorothiazide (in combination with 5 mg or 10 mg of enalapril respectively), the total daily dosage of ENALAPRIL MALEATE / HCTZ should not exceed four tablets of ENALAPRIL MALEATE / HCTZ 5 mg / 12.5 mg or two tablets of ENALAPRIL MALEATE / HCTZ 10 mg /25 mg. If further blood pressure control is indicated, additional doses of enalapril or other nondiuretic, antihypertensive agents should be considered.
For enalapril monotherapy the recommended initial dose in patients not on diuretics is 5 mg of enalapril once a day. Dosage should be adjusted according to blood pressure response. The usual dosage range of enalapril is 10 to 40 mg per day administered in a single dose or two divided doses. In some patients treated once daily, the antihypertensive effects may diminish toward the end of the dosing interval. In such patients an increase in dosage or twice-daily administration should be considered. If blood pressure is not controlled with enalapril alone, a diuretic may be added.
In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally may occur following the initial dose of enalapril. The diuretic should, if possible, be discontinued for two to three days before beginning therapy with enalapril to reduce the likelihood of hypotension (see 7 WARNINGS AND PRECAUTIONS - Cardiovascular). If the patient's blood pressure is not controlled with enalapril alone, diuretic therapy may be resumed.
If the diuretic cannot be discontinued, an initial dose of 2.5 mg of enalapril should be used to determine whether excessive hypotension occurs.
Geriatrics (> 65 years of age): In the elderly the starting dose of enalapril should be 2.5 mg since some elderly patients may be more responsive to enalapril than younger patients.
Dosing Adjustment in Renal Impairment: In patients with mild to moderate renal impairment (creatinine clearance > 30 mL/min), the usual dose titration of the individual components is required. The recommended initial dose of enalapril, when used alone in patients with mild renal impairment, is 5 mg. In patients with moderate renal impairment, the initial dose of enalapril, when used alone, is 2.5 mg.
When concomitant diuretic therapy is required in patients with severe renal impairment, a loop diuretic, rather than a thiazide diuretic is preferred for use with enalapril. Therefore, for patients with severe renal dysfunction, ENALAPRIL MALEATE / HCTZ is not recommended (see 7 WARNINGS AND PRECAUTIONS - Renal).
Drug Discontinuation
If angioedema occurs, ENALAPRIL MALEATE / HCTZ should be promptly discontinued and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient (see 7 WARNINGS AND PRECAUTIONS - General).
If increasing azotemia and oliguria occur during treatment of severe progressive renal disease the diuretic should be discontinued (see 7 WARNINGS AND PRECAUTIONS - Renal).
ENALAPRIL MALEATE / HCTZ should be discontinued and appropriate treatment should be given if the patient presents with acute respiratory distress (see 7 WARNINGS AND PRECAUTIONS - Respiratory)
When pregnancy is detected, ENALAPRIL MALEATE / HCTZ should be discontinued as soon as possible (see 7 WARNINGS AND PRECAUTIONS – Pregnant Women).
If photosensitivity reactions occur during treatment with hydrochlorothiazide-containing drugs, treatment should be stopped (see 7 WARNINGS AND PRECAUTIONS - Photosensitivity).
4.4 Administration
ENALAPRIL MALEATE / HCTZ is for oral administration. ENALAPRIL MALEATE / HCTZ can be taken with or without food. The splitting of ENALAPRIL MALEATE / HCTZ 10 mg/25 mg tablets is not advised.
4.5 Missed Dose
Patients should be instructed that if they miss a dose of ENALAPRIL MALEATE / HCTZ, they should take the next dose at the regularly scheduled time. Patient should not double the dose.
5 OVERDOSAGE
No specific information is available on the treatment of overdosage with ENALAPRIL MALEATE / HCTZ. Treatment is symptomatic and supportive. Therapy with ENALAPRIL MALEATE / HCTZ should be discontinued and the patient observed closely. Suggested measures include induction of emesis and/or gastric lavage, and correction of dehydration, electrolyte imbalance and hypotension by established procedures.
Enalapril: The most prominent feature of overdosage reported to date is marked hypotension, beginning some six hours after ingestion of tablets, concomitant with blockade of the renin-angiotensin system, and stupor. Serum enalaprilat levels 100 times and 200 times higher than usually seen after therapeutic doses have been reported after ingestion of 300 mg and 440 mg of enalapril, respectively. Enalaprilat may be removed from the general circulation by hemodialysis (see 7 WARNINGS AND PRECAUTIONS - Cardiovascular).
The recommended treatment of overdosage is intravenous infusion of normal saline solution.
Hydrochlorothiazide: The most common signs and symptoms observed 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.
| For management of a suspected drug overdose, contact your regional poison control centre. |
|---|
6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING
Table 1 – Dosage Forms, Strengths, Composition and Packaging
| Route of Administration | Dosage Form / Strength | Non-medicinal Ingredients |
| oral | Tablet 5 mg / 12.5 mg | Anhydrous lactose, FD&C Blue No. 2, iron oxide yellow and zinc stearate |
| Tablet 10 mg / 25 mg | Anhydrous lactose, iron oxide red and zinc stearate |
ENALAPRIL MALEATE / HCTZ 5 mg / 12.5 mg tablets:Each green, squared capsule, biconvex, unscored tablet contains 5 mg enalapril maleate and 12.5 mg hydrochlorothiazide. Engraved “5/12.5” on one side and plain on the other side. Available in bottles of 100.
ENALAPRIL MALEATE / HCTZ 10 mg / 25 mg tablets: Each rust, oval, biconvex, scored tablet contains 10 mg enalapril maleate and 25 mg hydrochlorothiazide. Engraved “10 scored 25” on one side and plain on the other side. Available in bottles of 100.
7 WARNINGS AND PRECAUTIONS
Please see 3 Serious warnings and precautions box.
General
Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely in patients treated with enalapril maleate and hydrochlorothiazide. This may occur at any time during treatment and may be life threatening.
Very rarely, fatalities have been reported due to angioedema associated with laryngeal edema or tongue edema. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery. However, where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy which may include subcutaneous adrenaline solution 1:1000 (0.3 mL to 0.5 mL) and/or measures to ensure a patent airway should be administered promptly when indicated.
Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since this may be life threatening and treatment with antihistamines and corticosteroids may not be sufficient.
In patients who experience angioedema, future administration is contraindicated (see 2 CONTRAINDICATIONS).
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).
Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema. Caution should be used when these drugs are used concomitantly (see 9.4 DRUG-DRUG INTERACTIONS).
Patients receiving concomitant ACE inhibitor and neprilysin inhibitor therapy may be at increased risk for angioedema (see 2 CONTRAINDICATIONS and 9.4 DRUG-DRUG INTERACTIONS).
Patients receiving concomitant ACE inhibitor and dipeptidyl peptidase IV (DPP-IV_ inhibitors such as alogliptin, linagliptin, saxagliptin, and sitagliptin may be at increased risk for angioedema (see 9.4 DRUG-DRUG INTERACTIONS). Caution should be used when these drugs are used concomitantly.
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 Desensitization: There have been isolated reports of patients experiencing sustained life-threatening anaphylactoid reactions while receiving ACE inhibitors during desensitizing treatment with hymenoptera (bees, wasp) 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.
Anaphylactoid Reactions during LDL Apheresis: Rarely, patients receiving ACE inhibitors during low-density lipoprotein (LDL)-apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.
Carcinogenesis and Mutagenesis
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 (see8.5 Post Market Adverse Reactions). The photosensitizing action of hydrochlorothiazide may be a possible mechanism for NMSC (see 16 NON-CLINICAL TOXICOLOGY).
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
Hypotension: Patients in whom enalapril and diuretic are initiated simultaneously can develop symptomatic hypotension (see 9.4 DRUG-DRUG INTERACTIONS).
Symptomatic hypotension has occurred after administration of enalapril, 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. Therefore, ENALAPRIL MALEATE / HCTZ should not be used to start therapy or when a dose change is needed. 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. Because of the potential fall in blood pressure in these patients, therapy with enalapril should be started under very close medical supervision, usually in a hospital. Such patients should be followed closely for the first two weeks of treatment and whenever the dose of enalapril and/or hydrochlorothiazide is increased. In patients with ischemic heart or cerebrovascular disease, an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident (see 8.5 Post-Market Adverse Reactions).
If hypotension occurs, the patient should be placed in supine position and, if necessary, receive an intravenous infusion of normal saline. 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.
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.
Dual Blockade of the Renin-Angiotensin System (RAS): There is evidence that co-administration of angiotensin converting enzyme inhibitors (ACEIs), such as the enalapril component of Enalapril Maleate/Hydrochlorothiazide, or of angiotensin receptor antagonists (ARBs) with aliskiren increases the risk of hypotension, syncope, stroke, hyperkalemia and deterioration of renal function, including renal failure, in patients with diabetes mellitus (type 1 or type 2) and/or moderate to severe renal impairment (GFR < 60 mL/min/1.73m2). Therefore, the use of Enalapril Maleate/Hydrochlorothiazide, in combination with aliskiren-containing drugs is contraindicated in these patients (see 2 CONTRAINDICATIONS). Further, co-administration of ACEIs, including the enalapril component of Enalapril Maleate/Hydrochlorothiazide, 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.
Driving and Operating Machinery
Occasionally dizziness and fatigue may occur, especially when starting therapy (see 8 ADVERSE REACTIONS). 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. Several cases of agranulocytosis and neutropenia have been reported in which a causal relationship to enalapril cannot be excluded.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 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.
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 enalapril (including enalapril maleate and hydrochlorothiazide) (see 9.4 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.
The use of ACEIs - including the enalapril component of Enalapril Maleate / Hydrochlorothiazide - or ARBs with aliskiren-containing drugs is contraindicated in patients with moderate to severe renal impairment (GFR < 60 mL/min/1.73m2). (See 2 CONTRAINDICATIONS and 9.4 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 clearance values of 30 mL/min or below (i.e., moderate or severe renal insufficiency).
Azotemia: Azotemia may be precipitated or increased by hydrochlorothiazide. Cumulative effects of the drug may develop in patients with impaired renal function.
Hyperkalemia: Elevated serum potassium (greater than 5.7 mEq/L) was observed in approximately one percent of hypertensive patients in clinical trials with enalapril alone. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was a cause of discontinuation of therapy in 0.28% of hypertensive patients. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium supplements, potassium-containing salt substitutes or other drugs that may increase serum potassium (e.g., trimethoprim-containing products). The use of potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes or other drugs that may increase serum potassium particularly in patients with impaired renal function should be given only for documented hypokalemia and with caution and frequent monitoring of serum potassium since they may lead to a significant increase in serum potassium. Hyperkalemia can cause serious, sometimes fatal, arrhythmias. If concomitant use of ENALAPRIL MALEATE / HCTZ and any of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium (see 9.4 DRUG-DRUG INTERACTIONS).
Respiratory
Very rare severe cases of acute respiratory distress syndrome (ARDS) including pneumonitis and pulmonary edema have been reported after taking hydrochlorothiazide. (See 8.5 Post-Market Adverse Reactions).
Pulmonary oedema typically develops within minutes to hours after hydrochlorothiazide intake. At the onset, symptoms include dyspnoea, fever, pulmonary deterioration and hypotension. Hydrochlorothiazide should not be administered to patients who previously experienced ARDS following hydrochlorothiazide intake.
Sensitivity/Resistance
Hypersensitivity Reactions: 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.
Photosensitivity
Photosensitivity reactions have been reported with the use of thiazide diuretics.
7.1 Special Populations
7.1.1 Pregnant Women: ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women.
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, associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.
Prematurity, and patent ductus arteriosus and other structural cardiac malformations, as well as neurologic malformations, have also been reported following exposure in the first trimester of pregnancy.
Infants with a history of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function; however, limited experience with those procedures has not been associated with significant clinical benefit.
Enalapril has been removed from the neonatal circulation by peritoneal dialysis with some clinical benefit and may, theoretically, be removed by exchange transfusion, although there is no experience with the latter procedure.
7.1.2 Breast-feeding
Both enalapril and thiazides appear in human milk. Use of ACE inhibitors (ENALAPRIL MALEATE / HCTZ) is not recommended during breast-feeding.
7.1.3 Pediatrics
Pediatrics (0-18 years): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.
7.1.4 Geriatrics
See 4 DOSAGE AND ADMINISTRATION.
8 ADVERSE REACTIONS
8.1 Adverse Reaction Overview
Adverse Drug Reaction Overview
In clinical trials involving 1580 hypertensive patients, including over 300 patients treated for one year or more, the most severe adverse reactions were: angioedema (0.3%), syncope (1.3%) and renal failure (0.1%).
The most frequent clinical adverse experiences in controlled trials were: dizziness (8.6%), headache (5.5%), fatigue (3.9%) and cough (3.5%).
Adverse experiences that have occurred have been those that were previously reported with enalapril or hydrochlorothiazide when used separately for the treatment of hypertension.
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.
Adverse reactions occurring in greater than one percent of patients treated with Enalapril Maleate / Hydrochlorothiazide in controlled trials are shown below.
Table 2: Hypertension
| Percent of Patients in Controlled Studies | ||
Enalapril Maleate / Hydrochlorothiazide (n = 1580) Incidence (%) | Placebo (n = 230) Incidence (%) | |
Body as a Whole Fatigue Orthostatic Effects Asthenia Cardiovascular Chest Pain Syncope Orthostatic Hypotension Palpitations Dermatologic Rash Digestive Diarrhea Nausea | 3.9 2.3 2.4 1.1 1.3 1.5 1.0 1.3 2.1 2.5 | 2.6 0.0 0.9 * * * * * 1.7 1.7 |
| Percent of Patients in Controlled Studies | ||
Enalapril Maleate / Hydrochlorothiazide (n = 1580) Incidence (%) | Placebo (n = 230) Incidence (%) | |
Vomiting Abdominal Pain Musculoskeletal Muscle Cramps Nervous/Psychiatric Headache Dizziness Paresthesia Respiratory Cough Urogenital Impotence | 1.6 1.1 2.7 5.5 8.6 1.1 3.5 2.2 | * * 0.9 9.1 4.3 * 0.9 0.5 |
* No data available
8.3 Less Common Clinical Trial Adverse Reactions
Cardiovascular: Hypotension, myocardial infarction, tachycardia
Digestive: Dysphagia, dyspepsia, constipation, flatulence, dry mouth
Hearing: Tinnitus
Hematologic: Anemia
Hypersensitivity: Angioedema
Metabolic and Nutritional: Gout
Musculoskeletal: Back pain, arthralgia
Nervous System/Psychiatric: Insomnia, nervousness, somnolence, vertigo
Respiratory: Dyspnea
Skin: Pruritus, hyperhidrosis, diaphoresis
Special Senses: Taste disturbance
Urogenital: Renal failure, oliguria, proteinuria, decreased libido, urinary tract infection
8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data
Clinical Trial Findings
Hyperkalemia: (see 7 WARNINGS AND PRECAUTIONS - Renal)
Creatinine, Blood Urea Nitrogen (BUN): In controlled clinical trials minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in about 0.6% of patients with essential hypertension treated with Enalapril Maleate/Hydrochlorothiazide.
In patients treated with enalapril alone, increases in serum creatinine and BUN were reported in about 20% of patients with renovascular hypertension and in about 0.2% of patients with essential hypertension.
Hemoglobin and Hematocrit: Decreases in hemoglobin and hematocrit (mean approximately 0.34 g% and 1.0 vol% respectively) occurred frequently in hypertensive patients treated with enalapril, but were rarely of clinical importance. In clinical trials, less than 0.1% of patients discontinued therapy due to anemia.
Others: Elevations of liver enzymes and/or serum bilirubin have occurred (see 7 WARNINGS AND PRECAUTIONS - Hepatic/Biliary/Pancreatic).
8.5 Post-Market Adverse Reactions
Adverse Reactions Reported in Uncontrolled Trials and/or Marketing Experience:
Other serious clinical adverse experiences occurring since the drug was marketed or adverse experiences occurring in 0.5 to 1.0 percent of patients in clinical trials are listed below and, within each category, are in order of decreasing severity.
Body as a Whole
Anaphylactoid reactions (see 7 WARNINGS AND PRECAUTIONS - General), asthenia
Cardiovascular
Cardiac arrest; myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high-risk patients (see 7 WARNINGS AND PRECAUTIONS - Cardiovascular); pulmonary embolism and infarction, pulmonary edema, angina pectoris, arrhythmia including atrial tachycardia and bradycardia, atrial fibrillation, hypotension, palpitation, Raynaud’s phenomenon.
Digestive
Ileus, pancreatitis, hepatic failure, hepatitis (hepatocellular or cholestatic jaundice), liver function abnormalities (see 7 WARNINGS AND PRECAUTIONS Hepatic/Biliary/Pancreatic), melena, anorexia, dyspepsia, constipation, flatulence, glossitis, stomatitis, dry mouth.
Endocrine
Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Hematologic
Rare cases of neutropenia, thrombocytopenia, hemolytic anemia and bone marrow depression.
Metabolic and Nutritional
Gout
Musculoskeletal
Muscle cramps, arthralgia.
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. A systematic review and meta-analysis undertaken by Health Canada suggested that, with important uncertainty, 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).
Nervous/Psychiatric
Vertigo, depression, confusion, ataxia, somnolence, insomnia, nervousness, peripheral neuropathy (e.g., paresthesia, dysesthesia), dream abnormality.
Respiratory
Bronchospasm, rhinorrhea, sore throat and hoarseness, asthma, upper respiratory infection, pulmonary infiltrates, eosinophilic pneumonitis, respiratory distress, pneumonitis and pulmonary edema. Acute respiratory distress has been reported in very rare instances.
Skin
Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, pemphigus, herpes zoster, erythema multiforme, urticaria, pruritus, alopecia, flushing, diaphoresis, photosensitivity.
Special Senses
Blurred vision, taste alteration, anosmia, tinnitus, conjunctivitis, dry eyes, tearing, hearing impairment.
Urogenital
Renal failure, oliguria, renal dysfunction (see 7 WARNINGS AND PRECAUTIONS and 4 DOSAGE AND ADMINISTRATION), flank pain, gynecomastia, impotence, decreased libido.
A symptom complex has been reported which may include some or all of the following: fever, serositis, vasculitis, myalgia/myositis, arthralgia/arthritis, a positive antinuclear antibody (ANA), elevated erythrocyte sedimentation rate, eosinophilia and leukocytosis. Rash, photosensitivity or other dermatologic manifestations may occur. These symptoms may be reversible upon discontinuation of therapy. In very rare cases, intestinal angioedema has been reported with angiotensin converting enzyme inhibitors including enalapril.
Laboratory Test Findings: Hyponatremia
9 DRUG INTERACTIONS
9.1 Serious Drug Interactions
Serious Drug Interactions
|
|---|
9.2 Drug Interactions Overview
See Drug-Drug Interaction table
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 potential magnitude and seriousness of the interaction (i.e., those identified as contraindicated).
Table 3 - Established or Potential Drug-Drug Interactions
| Proper Name | Source of Evidence | Effect | Clinical comment |
|---|---|---|---|
| Agents Increasing Serum Potassium | T | Concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium or other drugs that may increase serum potassium (e.g., trimethoprim-containing products), may lead to increases in serum potassium. | Since enalapril decreases the production of aldosterone, potassium-sparing diuretics or potassium supplements should be given only for documented hypokalemia and with caution and frequent monitoring of serum potassium particularly in patients with impaired renal function since they may lead to a significant increase in serum potassium. If concomitant use of Enalapril Maleate/ Hydrochlorothiazide and any of these agents is deemed appropriate, they should be used with caution and frequent monitoring of serum potassium. Potassium containing salt substitutes should also be used with caution. |
| Agents Affecting Sympathetic Activity | Agents affecting sympathetic activity (e.g., ganglionic blocking agents or adrenergic neuron blocking agents) may be used with caution. Beta-adrenergic blocking drugs add some further antihypertensive effect to enalapril. | Effect: Beta-adrenergic blocking drugs add some further antihypertensive effect to enalapril. Clinical Outcome: Agents affecting sympathetic activity (e.g., ganglionic blocking agents or adrenergic neuron blocking agents) may be used with caution | |
| Alcohol, barbiturates, or narcotics | C | Potentiation of orthostatic hypotension may occur. | Avoid alcohol, barbiturates or narcotics, especially with initiation of therapy. |
| Amphotericin B | T | Amphotericin B increases the risk of hypokalemia induced by thiazide diuretics. | Monitor serum potassium level. |
| Proper Name | Source of Evidence | Effect | Clinical comment |
|---|---|---|---|
| Antidiabetic agents (e.g. CT insulin and oral hypoglycemic agents) | CT | Thiazide-induced hyperglycemia may compromise blood sugar control. Depletion of serum potassium augments glucose intolerance. | Monitor glycemic control, supplement potassium if necessary, to maintain potassium levels, and adjust diabetes medications as required. |
| Antihypertensive drugs | CT | Hydrochlorothiazide may potentiate the action of other antihypertensive drugs (e.g. guanethidine, methyldopa, betablockers, vasodilators, calcium channel blockers, ACEI, ARB, and direct renin inhibitors). | |
| Antineoplastic drugs, including cyclophosphamide and methotrexate | C | Concomitant use of thiazide diuretics may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects. | Hematological status should be closely monitored in patients receiving this combination. Dose adjustment of cytotoxic agents may be required. |
| Bile acid sequestrants, e.g. cholestyramine and Cholestipol Resins | CT | Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively. Administration of thiazide 4 hours after a bile acid sequestrant reduced absorption of hydrochlorothaizide by 30 to 35%. | Give thiazide 2to 4 hours before or 6 hours after the bile acid sequestrant. Maintain a consistent sequence of administration. Monitor blood pressure, and increase dose of thiazide, if necessary. |
| Calcium and vitamin D supplements | C | Thiazides decrease renal excretion of calcium and increase calcium release | Monitor serum calcium, especially with concomitant use of high doses of calcium |
| Proper Name | Source of Evidence | Effect | Clinical comment |
|---|---|---|---|
| from bone. | supplements. Dose reduction or withdrawal of calcium and/or vitamin D supplements may be necessary. | ||
| Carbamazepine | C | Carbamazepine may cause clinically significant hyponatremia. Concomitant use with thiazide diuretics may potentiate hyponatremia. | Monitor serum sodium levels. Use with caution. |
| Corticosteroids, and adrenocorticotropic hormone (ACTH) | T | Intensified electrolyte depletion, particularly hypokalemia, may occur. | Monitor serum potassium, and adjust medications, as required. |
| Digoxin | CT | Thiazide-induced electrolyte disturbances, i.e. hypokalemia, hypomagnesemia, increase the risk of digoxin toxicity, which may lead to fatal arrhythmic events. | Concomitant administration of hydrochlorothiazide and digoxin requires caution. Monitor electrolytes and digoxin levels closely. Supplement potassium or adjust doses of digoxin or thiazide, as required. |
| Diuretics | CT | Patients on diuretics, and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with enalapril. | The possibility of hypotensive effects with enalapril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with enalapril. |
Drugs that alter GI motility, i.e., anti- cholinergic agents, such as atropine and prokinetic agents, such as. metoclopramide, domperidone | CT, T | Bioavailability of thiazide diuretics may be increased by anticholinergic agents due to a decrease in gastrointestinal motility and gastric emptying. Conversely, prokinetic drugs may decrease the bioavailability of thiazide diuretics. | Dose adjustment of thiazide may be required. |
| Dual blockade of the Renin-Angiotensin | Dual Blockade of the Renin-Angiotensin System (RAS) | See 2 CONTRAINDICATIONS and 7 WARNINGS AND |
| Proper Name | Source of Evidence | Effect | Clinical comment |
|---|---|---|---|
| System (RAS) with ACEIs, ARBs or aliskiren-containing drugs | with ACEIs, ARBs or aliskiren-containing drugs is contraindicated in patients with diabetes and/or renal impairment, and is generally not recommended in other patients, since such treatment has been associated with an increased incidence of severe hypotension, renal failure, and hyperkalemia. | PRECAUTIONS, Cardiovascular, Dual Blockade of the Renin-Angiotensin System (RAS). | |
| 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 enalapril. | See 7 WARNING AND PRECAUTIONS – Hepatic/Biliary/Pancreatic | |
| Gout medications (allopurinol, uricosurics, xanthine oxidase inhibitors) | T, RC | Thiazide-induced hyperuricemia may compromise control of gout by allopurinol and probenecid. The co-administration of hydrochlorothiazide and allopurinol may increase the incidence of hypersensitivity reactions to allopurinol. | Dose adjustment of gout medications may be required. |
| Lithium | CT | Thiazide diuretics reduce the renal clearance of lithium and add a high risk of lithium toxicity. | Concomitant use of thiazide diuretics with lithium is generally not recommended. If such use is deemed necessary, reduce lithium dose by 50% and monitor lithium levels closely. |
| Proper Name | Source of Evidence | Effect | Clinical comment |
|---|---|---|---|
| Nonsteroidal anti- inflammatory drugs (NSAID) Including Cyclooxygenase-2 Inhibitors | CT | The antihypertensive effect of enalapril may be diminished with concomitant non-steroidal anti-inflammatory drug use including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors). In some patients with compromised renal function (e.g., elderly patients or patients who are volume-depleted including those on diuretic therapy) who are being treated with NSAIDS including selective COX-2 inhibitors, the co-administration of ACE inhibitors or angiotensin II receptor antagonists may result in further deterioration of renal function. Cases of acute renal failure, usually reversible, have also been reported. This combination should therefore be administered with caution in this patient population. It has been reported in the literature that in patients with established atherosclerotic disease, heart failure, or with diabetes with end organ damage, dual blockade of the renin-angiotensin-aldosterone system is associated with a higher frequency of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) as | If combination use is necessary, monitor renal function, serum potassium, and blood pressure closely. Dose adjustments may be required. |
| Proper Name | Source of Evidence | Effect | Clinical comment | |
|---|---|---|---|---|
| compared to use of a single renin-angiotensin aldosterone system agent. | ||||
| Pressor Amines (e.g., norepinephrine) | T | In the presence of thiazide diuretics, possible decreased response to pressor amines may be seen but not sufficient to preclude their use. | ||
| Probenecid | The rate of elimination of hydrochlorothiazide is decreased somewhat by the coadministration of probenecid without, however, an accompanying reduction in diuresis. | |||
| Selective serotonin reuptake inhibitors (SSRIs, e.g. citalopram, escitalopram, sertraline) | T, C | Concomitant use with thiazide diuretics may potentiate hyponatremia. | Monitor serum sodium levels. Use with caution. | |
| Skeletal muscle relaxants of the curare family, e.g., tubocurare | C | Thiazide drugs may increase the responsiveness of some skeletal muscle relaxants, such as curare derivatives. | ||
| Topiramate | CT | Additive hypokalemia. Possible thiazide-induced increase in topiramate serum concentrations. | Monitor serum potassium and topiramate levels. | |
| Dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g. alogliptin, linagliptin, saxagliptin, sitagliptin) | C | Patients taking concomitant DPP-IV inhibitors may be at increased risk for angioedema | Caution should be used when using DPP-IV and ACE inhibitors concomitantly (see 7 WARNING AND PRECAUTIONS). | |
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
Interactions with laboratory tests have not been established.
10 CLINICAL PHARMACOLOGY
10.1 Mechanism of Action
ENALAPRIL MALEATE / HCTZ combines the action of an angiotensin converting enzyme inhibitor, enalapril, and that of a diuretic, hydrochlorothiazide.
Enalapril: Angiotensin converting enzyme (ACE) is a peptidyl dipeptidase which catalyses the conversion of angiotensin I to the pressor substance, angiotensin II. After absorption, enalapril, a pro-drug, is hydrolyzed to enalaprilat, its active metabolite, which inhibits ACE. Inhibition of ACE results in decreased plasma angiotensin II, which leads to increased plasma renin activity (due to removal of negative feedback of renin release) and decreased aldosterone secretion. Although the latter decrease is small, it results in a small increase in serum potassium. In patients treated with enalapril and a thiazide diuretic there was essentially no change in serum potassium (see 7 WARNINGS AND PRECAUTIONS).
ACE is identical to kininase II. Thus, enalapril may also block the degradation of bradykinin, a potent vasodepressor peptide. However, the role that this plays in the therapeutic effects of enalapril is unknown.
While the mechanism through which enalapril lowers blood pressure is believed to be primarily the suppression of the renin-angiotensin-aldosterone system, enalapril also lowers blood pressure in patients with low-renin hypertension.
Hydrochlorothiazide: Hydrochlorothiazide is a diuretic and antihypertensive which interferes with the renal tubular mechanism of electrolyte reabsorption. It increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate. While this compound is predominantly a saluretic agent, in vitro studies have shown that it has a carbonic anhydrase inhibitory action which seems to be relatively specific for the renal tubular mechanism. It does not appear to be concentrated in erythrocytes or the brain in sufficient amounts to influence the activity of carbonic anhydrase in those tissues.
10.2 Pharmacodynamics
Enalapril
Administration of enalapril to patients with hypertension results in a reduction of both supine and standing blood pressure. Abrupt withdrawal of enalapril has not been associated with a rapid increase in blood pressure. In most patients studied, after oral administration of an individual dose of enalapril, the onset of antihypertensive activity is seen at one hour with peak reduction of blood pressure achieved by 4 to 6 hours. At recommended doses, the antihypertensive effect has been shown to be maintained for at least 24 hours. In some patients the effect may diminish towards the end of the dosing interval (see 4 DOSAGE AND ADMINISTRATION). On occasion, achievement of optimal blood pressure reduction may require several weeks of therapy.
In hemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate. Following administration of enalapril, there was an increase in renal blood flow; glomerular filtration rate was usually unchanged.
When used in hypertensive, normolipidemic patients, enalapril had no effect on plasma lipoprotein fractions.
Studies in dogs indicate that enalapril crosses the blood brain barrier poorly, if at all; enalaprilat does not enter the brain.
Hydrochlorothiazide is useful in the treatment of hypertension. It may be used alone or as an adjunct to other antihypertensive drugs. Hydrochlorothiazide does not affect normal blood pressure.
Onset of the diuretic action following oral administration occurs in 2 hours and the peak action in about 4 hours. Diuretic activity lasts about 6 to 12 hours.
10.3 Pharmacokinetics
Table 4: Summary of Enalaprilat’s Pharmacokinetic Parameters in Healthy Volunteers Further to a 10 mg Oral Dose of Enalapril
| Cmax ng/mL | t½ (h)* | AUC0-∞ng•h/mL | |
| Single dose mean | 32.3 | 11 | 423 |
* Effective half-life of accumulation.
Table 5: – Summary of Hydrochlorothiazide’s Pharmacokinetic Parameters in Healthy Volunteers Further to a 25 mg Oral Dose of Hydrochlorothiazide
| Cmax ng/mL | t½ (h) | AUC0-36 (ng•h/mL) | Renal Clearance (mL/min) | Volume of distribution (L/kg) | |
| Single dose mean | 127 | 5.6 – 14.8 | 978 | 257 | 0.83 |
Enalapril
Absorption:
Following oral administration, enalapril is rapidly absorbed with peak serum concentrations of enalapril occurring within one hour. Based on urinary recovery the extent of absorption of enalapril is approximately 60%.
The absorption of enalapril is not influenced by the presence of food in the gastrointestinal tract.
Metabolism:
Following absorption, enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent angiotensin converting enzyme inhibitor (which itself is poorly absorbed). Peak serum concentrations of enalaprilat occur 3 to 4 hours after an oral dose of enalapril. Except for conversion to enalaprilat, there is no evidence of significant metabolism of enalapril.
Elimination:
Excretion of enalapril is primarily renal. Approximately 94% of the dose is recovered in the urine and feces as enalaprilat or enalapril. The principal components in urine are enalaprilat, accounting for about 40% of the dose, and intact enalapril.
The serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently associated with binding to ACE. The effective half-life for accumulation of enalaprilat following multiple doses of enalapril is 11 hours.
Hydrochlorothiazide
Absorption: Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract with an oral bioavailability of about 65% to 75%. Peak concentrations of hydrochlorothiazide were reached approximately 2 hours after dosing.
Distribution: Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk. Its apparent volume of distribution is 0.83 L/kg.
Metabolism: Hydrochlorothiazide is not metabolized.
Elimination: Hydrochlorothiazide is eliminated rapidly by the kidney. The plasma half-life is 5.6 to 14.8 hours when the plasma levels can be followed for at least 24 hours. At least 61% of the oral dose is eliminated unchanged within 24 hours.
Enalapril – Hydrochlorothiazide
Concomitant administration of enalapril and hydrochlorothiazide has little, or no effect on the bioavailability of either drug. The combination tablet is bioequivalent to concomitant administration of the separate entities.
Special Populations and Conditions
Pediatrics: Safety and effectiveness in pediatric patients have not been established.
Race: The antihypertensive effect of angiotensin converting enzyme inhibitors is generally lower in black than in non-black patients.
Renal Insufficiency: The disposition of enalapril and enalaprilat in patients with renal insufficiency is similar to that in patients with normal renal function until the glomerular filtration rate is 30 mL/min (0.50 mL/s) or less. With renal function ≤ 30 mL/min (≤ 0.50 mL/s), peak and trough enalaprilat levels increase, time to peak concentration increases and time to steady state may be delayed. The effective half-life of enalaprilat following multiple doses of enalapril is prolonged at this level of renal insufficiency (see 4 DOSAGE AND ADMINISTRATION). Enalaprilat is dialyzable at the rate of 62 mL/min (1.03 mL/s).
11 STORAGE, STABILITY AND DISPOSAL
Store at controlled room temperature (15°C to 30°C). Protect from moisture.
12 SPECIAL HANDLING INSTRUCTIONS
There are no special handling instructions necessary for this medicinal product.
PART II: SCIENTIFIC INFORMATION
13 PHARMACEUTICAL INFORMATION
Drug Substance
| Proper Name: | Enalapril maleate | Hydrochlorothiazide |
|---|---|---|
| Chemical name: | L-Proline, 1-[N-[1- (ethoxicarbonyl)-3- Phenylpropyl)-3- Phenylpropyl]-L-alanyl]-, (S)-, (Z)-2-butenedioate salt (1:1) (1:1) | 6-chloro-3,4-dihydro-2H- 1,2,4-benzothiadiazine-7- sulfonamide 1, 1-dioxide. |
| Molecular formula: | C20H28N2O5.C4H4O4 | C7H8ClN3O4S2 |
| Molecular mass: | 492.53 g/mol | 297.74 g/mol |
| Structural Formula: |  |  |
| Physicochemical properties: | Enalapril maleate is a white to off-white crystalline powder which melts at approx. 143° C to 144°C. It is sparingly soluble in water (pH 3.4), soluble in ethanol, and freely soluble in methanol and dimethylformamide. The pKa1 and pKa2 of the base moiety are 3.0 and 5.4 respectively. | Hydrochlorothiazide is a white or practically white, odourless crystalline compound with low solubility in water, freely soluble in sodium hydroxide solution, in n-butylamine, and in dimethylformamide; sparingly soluble in methanol; insoluble in ether, in chloroform, and in dilute mineral acids. |
14 CLINICAL TRIALS
14.1 Clinical Trials by Indication
Hypotension
Table 6 - Summary of patient demographics for clinical trials in specific indication
| Study # | Trial design | Dosage, route of administration and duration | Study subjects (n = number) | Mean age (range) |
| 2951 | Multicenter, double-blind randomized, parallel, active controlled study (24 investigators) | Oral Enalapril 10 mg twice daily Or HCTZ 25 mg twice daily Or Enalapril 10 / HCTZ 25 twice daily. The dose was titrated from 1 to 2 tablets twice daily after 4 weeks if DBP ≥ 90 mm Hg. Total Duration on Treatment: 8 weeks | 546 (221 in enalapril, 222 in HCTZ and 103 in enalapril / HCTZ combination groups) | 21 to 65 years |
| 16 | Multicenter, double-blind randomized, parallel, active controlled study (6 investigators) | Oral Enalapril 10 / Hydrochlorothiazide 25 once daily. Or Propranolol 40 / HCTZ 25 twice daily. The dose was titrated after 4 and 8 weeks if DBP > 85 mm Hg. Total Duration on Treatment: 12 weeks | 151 (76 in enalapril / HCTZ and 75 in propranolol HCTZ groups) | 20 to 68 years |
HCTZ: Hydrochlorothiazide
Table 7 - Results of study 2951 in patients with hypertension
| Primary endpoints | Associated value and statistical significance for enalapril / HCTZ | Associated value and statistical significance for enalapril alone | Associated value and statistical significance for HCTZ alone |
| Mean Change from baseline in supine DBP at 4 weeks | -19.9*,+ | -11.4 | -11.4 |
| Mean Change from baseline in supine DBP at 8 weeks | -21.4 *,+ | -11.5 | -13.2 |
*,+ Significantly greater than HCTZ and enalapril respectively, (p < 0.01)
Table 8 - Results of study 16 in patients with hypertension
| Primary endpoints | Associated value and statistical significance for enalapril / HCTZ | Associated value and statistical significance for active control / HCTZ |
| Mean Change from baseline in supine DBP at 4 weeks | -14.4 | -12.6 |
| Mean Change from baseline in supine DBP at 8 weeks | -14.9 | -13.6 |
| Mean Change from baseline in supine DBP at 12 weeks | -16.8 | -16.5 |
14.2 Comparative Bioavailability Studies
A randomized, single dose, double-blinded, 2-way crossover comparative bioavailability study, conducted under fasting conditions was performed on healthy male volunteers. The rate and extent of absorption of enalapril and hydrochlorothiazide were compared following a single oral dose of ENALAPRIL MALEATE / HCTZ Tablets (enalapril maleate/hydrochlorothiazide) 10 mg/25 mg Tablets and VASERETIC® (enalapril sodium/hydrochlorothiazide) 10 mg/25 mg Tablets in 24 volunteers. The results from measured data of both the analytes (enalapril and hydrochlorothiazide) are summarized in the following tables:
Table 9: Summary Table of the Comparative Bioavailability Data
Enalapril (A single enalapril / hydrochlorothiazide dose: 1 x 10/25 mg tablet) From Measured Data/Fasting Conditions Geometric Mean# Arithmetic Mean (CV%) | ||||
| Parameter | ENALAPRIL MALEATE / HCTZ (enalapril maleate / Hydrochlorothiazide) Tablets* | VASERETIC® (enalapril sodium / hydrochlorothiazide) Tablets† | % Ratio of Geometric Means# | Confidence Interval# |
AUCt (ng•h/mL) | 122.269 124.971 (23) | 125.996 127.956 (19) | 97.0 | 92.1 - 102.3 |
AUCinf (ng•h/mL) | 123.414 126.098 (22) | 128.506 130.679 (18) | 96.0 | 91.1 - 101.3 |
Enalapril (A single enalapril / hydrochlorothiazide dose: 1 x 10/25 mg tablet) From Measured Data/Fasting Conditions Geometric Mean# Arithmetic Mean (CV%) | ||||
| Parameter | ENALAPRIL MALEATE / HCTZ (enalapril maleate / Hydrochlorothiazide) Tablets* | VASERETIC® (enalapril sodium / hydrochlorothiazide) Tablets† | % Ratio of Geometric Means# | Confidence Interval# |
Cmax (ng/mL) | 75.034 76.699 (22) | 75.841 76.951 (18) | 98.9 | 94.2 - 103.9 |
| Tmax§(h) | 0.85 (26) | 0.89 (22) | ||
| T½§(h) | 2.13 (44) | 2.41 (44) | ||
§ Arithmetic means (CV %) only. # Based on the least squares estimate. † VASERETIC® Tablets is manufactured by Merck frost Canada Ltd, Canada and was purchased in Canada. * ENALAPRIL MALEATE / HCTZ Tablets is manufactured by AA Pharma Inc., Canada | ||||
Table 10: Summary Table of the Comparative Bioavailability Data
Hydrochlorothiazide (A single enalapril / hydrochlorothiazide dose: 1 x 10/25 mg tablet) From Measured Data/Fasting Conditions Geometric Mean# Arithmetic Mean (CV%) | ||||
| Parameter | ENALAPRIL MALEATE / HCTZ (enalapril maleate / hydrochlorothiazide) Tablets* | VASERETIC® (enalapril sodium / hydrochlorothiazide) Tablets † | % Ratio of Geometric Means# | Confidence Interval# |
AUCt (ng•h/mL) | 962.64 977.10 (18) | 967.83 992.16 (22) | 99.5 | 93.5 - 105.8 |
| AUCinf | 1017.55 | 1026.02 | 99.2 | 93.5 - 105.2 |
Hydrochlorothiazide (A single enalapril / hydrochlorothiazide dose: 1 x 10/25 mg tablet) From Measured Data/Fasting Conditions Geometric Mean# Arithmetic Mean (CV%) | ||||
| (ng•h/mL) | 1033.48 (18) | 1050.77 (22) | ||
Cmax (ng/mL) | 133.58 135.82 (19) | 137.07 143.23 (31) | 97.5 | 89.3 - 106.3 |
| Tmax§(h) | 2.31 (35) | 2.23 (46) | ||
| T½§(h) | 9.38 (8) | 9.57 (10) | ||
§ Arithmetic means (CV %) only. # Based on the least squares estimate. † VASERETIC® Tablets is manufactured by Merck frost Canada Ltd, Canada and was purchased in Canada. *ENALAPRIL MALEATE / HCTZ Tablets is manufactured by AA Pharma Inc., Canada. | ||||
HCTZ: Hydrochlorothiazide
15 MICROBIOLOGY
No microbiological information is required for this drug product.
16 NON-CLINICAL TOXICOLOGY
Enalapril Maleate
Table 11 - Mechanism of Action
| Study | Species/Strain | Number of Animals/Group | Route | Dose | Results |
| Effect of enalapril maleate on total serum ACE in rats and dogs | Male Sprague/ Dawley rats | 12 experimental 6 placebo | P.O. | 10 mg/kg/day for 7 or 14 days | 79% increase in ACE after 7 days & 140% after 14 days |
| Male beagle hounds | 3 dogs | P.O. | 10 mg/kg (free base) for 7 or 14 days | 30% increase in ACE after 7 days & 48% after 14 days | |
| 3 dogs | P.O. | 30 mg/kg/day | 1.5-fold |
| Study | Species/Strain | Number of Animals/Group | Route | Dose | Results | |
| for 3 days | increase in ACE | |||||
| In vivo ACE inhibition in anesthetized and unanesthetized rats and dogs | Male Sprague/ Dawley rats (Blue Spruce) | 6 rats | I.V. P.O. | 3, 10, 30 mcg/kg 0.1, 0.3, 1.0 and 3.0 mg/kg | The ED50 is 14.0 mcg/kg I.V. and 0.29 mg/kg p.o. | |
| Mongrel or beagle dogs (male & female) | 6 dogs per dose | I.V. | 30, 130, 430,1430 mcg/kg | Dose related inhibition of pressor response to angiotensin ED50: Enalaprilat: 6.4 mcg/kg Enalapril maleate: 278 mcg/kg | ||
| Effect of enalaprilat on canine hind limb vasodilator response to bradykinin and vasoconstrictor response to angiotensins | Anesthetized dogs male or female | 4 dogs | I.V. | 0.3 to 100 mcg/kg | Local inhibition of ACE: (enalaprilat) ED50 = 4.8 (4.4 to 5.2 mcg/kg) I.V. | |
Table 12 - Effects on Blood Pressure
| Study | Species/Strain | Number of Animals/Group | Route | Dose | Results |
| Antihypertensive activity in sodium- deficient rats | Male Sprague/ Dawley rats | 6 rats/group and at least 8 treatment groups | P.O. | Enalapril 1 to 10 mg/kg | Enalapril produced a dose-dependent decrease in systolic BP for 3 or more hours |
| Effect on renal hypertensive rats (Grollman technique) | Male Sprague/ Dawley rats | Most groups = 6 to 8 rats/treatment group | P.O. | Enalapril3.0 mg/kg | Enalapril produced a mean decrease in systolic pressure of ≈ 20 mmHg and |
| Study | Species/Strain | Number of Animals/Group | Route | Dose | Results | |
| a slight tachycardia | ||||||
| Relationship between angiotensin 1 blockade and blood pressure lowering in spontaneous hypertensive rats, renal hypertensive rats, and renal hypertensive dogs and normotensive sodium depleted dogs | Sprague/ Dawley rats normotensive dogs (mongrel) | At least 4 to 5 rats/group and at least 3 dogs per group | P.O. | Enalapril 0.1 to 3 mg/kg | Time course of blood pressure decrease did not coincide with time course for maximal inhibition of angiotensin 1 pressor response | |
Table 13 - Other Effects
| Study | Species/Strain | Number of Animals/Group | Route | Dose | Results |
| Effects in acute renal failure in dogs | Mongrel dogs | 4/group | P.O. | 1.0 mg/kg b.i.d. for 3 days | No further deterioration of acute renal failure occurred. |
| Whole body autoradiography | Golden hamsters | Min. 16 | P.O. | 5 mg/kg | No radioactivity was found in the spinal cord or brain of either male or female hamsters. |
Enalapril Maleate and Hydrochlorothiazide
In unanesthetized spontaneously hypertensive rats (7 to 8/group) enalapril alone when given orally at a dose of 3.0 mg/kg twice daily for three consecutive days reduced mean arterial blood pressure by 10 to 15 mmHg. A substantially greater fall in mean arterial blood pressure averaging 20, 41 and 34 mmHg (from the pretreatment value on Day 1) was observed in a similar 3-day experiment when enalapril, 3 mg/kg/day orally, was coadministered with an oral dose of hydrochlorothiazide, 50 mg/kg/day.
A similar enhanced antihypertensive response was observed in chronic perinephritic hypertensive dogs when enalapril, 10 mg/kg orally was coadministered with an oral dose of hydrochlorothiazide, 15 mg/kg.
In a renal study in conscious dogs (6 dogs/group) the combination of enalapril 3 mg/kg plus hydrochlorothiazide (0.1, 0.3 and 1.0 mg/kg) given orally over three days showed no synergistic effect of the two compounds on urinary sodium excretion.
When hydrochlorothiazide, 10 mg/kg p.o., was given in combination with enalapril, at doses of 3, 10 and 30 mg/kg orally, only the combination of 10 mg/kg hydrochlorothiazide plus 10 or 30 mg/kg of enalapril orally for three days produced increases in sodium excretion which were greater than the sum of the effects of hydrochlorothiazide plus enalapril. Decreases in plasma potassium were observed at oral doses of 3 and 10 mg/kg but not at 30 mg/kg.
A 16-fold increase in plasma renin activity was observed with the combination treatment of enalapril 30 mg/kg and hydrochlorothiazide 10 mg/kg orally.
General Toxicology
Table 14 - Enalapril Maleate - Acute Toxicity - LD50 Values:
| Route | Species | Sex | MSDRLa | NMB/RLb |
| Oral | Mouse | Male Female | 2 g/kg 2 g/kg | 3.5 g/kg 3.5 g/kg |
| Rat | Male Female | 2 g/kg 2 g/kg | 3.5 g/kg 3.0 g/kg | |
| Intravenous | Mouse | Male Female | - 750 mg/kg | 900 mg/kg 900 mg/kg |
| Rat | Male Female | - - | 950 mg/kg 850 mg/kg | |
| Subcutaneous | Mouse | Male Female | - - | 1150 mg/kg 1500 mg/kg |
| Rat | Male Female | - - | 1750 mg/kg 1400 mg/kg |
a Merck Sharp and Dohme Research Laboratories, WestPoint, PA, USA
b Nippon Merck-Banyu Co., Menuma, Japan
Signs of toxicity: ptosis, decreased activity, bradypnea, loss of righting, ataxia, dyspnea, and clonic convulsions.
Table 15 - Sub-Acute and Chronic Toxicity
| Species | Duration | Number of Animals/Group | Route | Dose (mg/kg/day) | Effects |
| Rat | 1-Month | 10 M + 10 F | Oral | 0, 10, 30, 90 | At all doses: Slight decrease in body weight gain. At 30 & 90 mg/kg/day: Dose-related increase in BUN in males. |
| Rat | 3-Months | 15 M + 15 F | Oral | 0, 10, 30, 90 | At all doses: Slight decrease in body weight gain and in serum sodium, slight increase in serum potassium. Small increase in kidney weight and decrease in heart weight. At 30 & 90 mg/kg/day: Dose-related increase in BUN. |
| Rat | 1-Year | 25 M + 25 F | Oral | 0, 10, 30, 90 | 6-month interim kill: Males given 90 mg/kg/day had a significantly (p ≤ 0.05) greater kidney weight than controls. 1 year: Dose-related decrease in weight gain (7 to 19%) Dose-related increase in serum urea nitrogen in males given 30 and 90 mg/kg/day (values up to 52.9 and 89.2 mg/100 mL respectively). Three high dose females showed elevated serum urea nitrogen levels. Serum potassium values were increased (0.1 to 0.8 mEq/L) in male rats on the high dose. Males given 90 mg/kg/day had a significantly (p ≤ 0.05) |
| Species | Duration | Number of Animals/Group | Route | Dose (mg/kg/day) | Effects |
| greater kidneyweight than controls | |||||
| Rat | 1-Month | 20 M + 20 F | Oral | 0, 90 & 90 with physiologic saline for drinking | Unsupplemented: Less weight gain (8 to 19%), increase in serum urea nitrogen (up to 62.8 mg%). Supplemented: Body weight gain and serum urea nitrogen levels similar to controls. |
| Rat (sodium depleted) | 3 Weeks | 30 M + 30 F | Oral | 0, 90 | A marked potentiation in toxicity included: death, weight loss, marked increases in serum urea nitrogen, creatinine and potassium, renal tubular degeneration. |
| Dog Beagle | 1-Month | 3 M + 3 F | Oral | 0, 10, 30, 90 (4 doses only) reduced to 60 | At 30 mg: One dog showed increase in BUN and renal tubular degeneration (4 doses only). At high doses: 6/6: deaths (7 to 12 days) Increase in serum urea nitrogen, glucose, SGOT, SGPT, and potassium; decrease in serum sodium and chloride; renal tubular degeneration and increased hepatocellular fat. |
| Dog Beagle | 3-Months | 3 M + 3 F | Oral | 0, 10, 30, 90 (7 doses only) | At all doses: Slight decrease in serum sodium. At 30 mg: 2/6: deaths Increase in BUN and serum glucose; renal tubular degeneration. |
| Species | Duration | Number of Animals/Group | Route | Dose (mg/kg/day) | Effects |
| At 90 mg: 5/6 deaths Increase in BUN, serum glucose, SGOT, SGPT, alkaline phosphatase and potassium. Decrease in serum chloride; renal tubular degeneration, increased hepatocellular fat; hepatocellular necrosis. | |||||
| Dog Beagle | 1-Year | 5 M + 5 F | Oral | 0, 3, 5, 15 | No drug-induced changes were seen. |
| Dog Beagle | 15-days | 3 M + 3 F | Oral | 0, 60 with and without saline supplementa tion | Unsupplemented treated dogs: 3/6: deaths 4/6: increase in serum urea nitrogen 3/6: decrease in serum chloride; increase in SGOT, SGPT and potassium 1/6: increase in alkaline phosphatase 1/6: hepatocellular lesions (in 1st animal which died) 5/6: renal lesions (3 moderate, 2 slight renal tubular necrosis) Saline supplemented treated dogs: 0/6: deaths 3/6: increase in serum urea nitrogen 1/6: very slight renal tubular necrosis and moderate renal tubular cell vacuolation |
| Dog Beagle | 15-days | 3 M + 3 F | Oral | 0, 90 with and without saline supplementa tion | Unsupplemented treated dogs: 6/6: deaths 6/6: increase in serum urea nitrogen, creatinine and |
| Species | Duration | Number of Animals/Group | Route | Dose (mg/kg/day) | Effects |
SGPT 5/6: increase in SGOT 2/6: increase in serum potassium 5/6: marked renal tubular degeneration 1/6: moderate renal tubular degeneration 6/6: slight to marked thymic atrophy 3/6: ulceration of distal esophagus 2/6: oral mucosal lesions Supplemented treated dogs: 2/6: deaths 6/6: increase in serum urea nitrogen, creatinine 3/6: increase in SGOT and SGPT 0/6: increase in potassium 2/6: moderate renal tubular degeneration 4/6: slight renal tubular degeneration 4/6: slight to moderate thymic atrophy 3/6: liver degeneration |
Table 16 - Teratology Studies
| Species | Number of Animals/Group | Dose (mg/kg/day) | Duration of Dosing | Results |
| Rat (Charles River CD) | 20 F | 0, 10, 30, 90 | Day 15 of gestation through Day 20 of lactation | At all dosage levels: – Decreased maternal weight gain during days 15to 20 – Dose-related retardation in growth of F1 offspring during lactation |
| Species | Number of Animals/Group | Dose (mg/kg/day) | Duration of Dosing | Results |
| At 90 mg/kg/day: – Mean Day 1 pup weight/litter was significantly less than that of controls | ||||
| Rat (Charles River CD) | 25 F | 0, 10, 100, 200, 100 + saline, 200 + saline | Days 6 through Day 17 of gestation | Decreased maternal weight gain at 100 and 200 mg/kg/day in unsupplemented rats. No treatment-related effects on reproductive status or teratogenic effects in any of the groups. |
| Rat (CLEA Japan Inc-JCL:SD) | 25F | 0, 12, 120, 1200, 1200 + saline | Days 6 through Day 17 of gestation | Unsupplemented treated rats: – Average maternal body weight gain significantly reduced at all doses |
At 1200 mg/kg/day – Slight but significant decrease in fetal weight – Increase in the number of fetuses with the 14th rib skeletal variation – Decrease in the number of fetuses with ossified caudal vertebrae Supplemented treated rats: – No evidence of maternotoxicity or fetotoxicity | ||||
| Rabbit (New Zealand albino) | 18 F | 0, 3, 10, 30 (with saline) | Days 6 through Day 18 of gestation | At 3 and 10 mg/kg/day: – No treatment-related effects on reproductive status or teratogenicity was observed At 30 mg/kg/day: – 4 deaths – Reduced food and water intake – Significant increase in the mean number of resorptions per litter – 2 abortions – No evidence of teratogenicity was observed |
Table 17 - Fertility and Postnatal Evaluation Studies
| Species | Number of Animals/Group | Dose (mg/kg/day) | Duration of Dosing | Results |
| Rat (Charles River CD) | 15 M + 30 F | 0, 10, 30, 90 | Males 70 days prior to mating to termination of females.Females 15 days prior to mating and throughout gestation. | No effects on reproductive status were observed at any dose. Males at 30 & 90 mg/kg/day:
Females at 30 & 90 mg/kg/day:
Pups: Reduced body weights in F1 pups at 90 mg/kg/day on Day 1 postpartum and secondarily a delay in postnatal development.Increased incidence of deaths of F1 pups at 30 and 90 mg/kg/day during lactation. |
Mutagenicity Studies:Enalapril was not mutagenic in the Ames microbial mutagen test with or without metabolic activation, in the Rec-Assay, sister chromatid exchange with cultured chinese hamster cells, (up to 20 mg/mL) and the micro-nucleus test with mice.
In vitro chromosomal aberration test - enalapril was clastogenic at 10 and 20 mg/mL but not at 5 mg/mL.
Carcinogenicity: There was no evidence of a carcinogenic effect when enalapril was administered for 106 weeks to rats (Charles River CD-1) at doses up to 90 mg/kg/day (150 times the maximum daily human dose).
Enalapril has also been administered for 94 weeks to male and female mice (Charles River CD-1) at doses up to 90 and 180 mg/kg/day, respectively, (150 and 300 times the maximum daily dose for humans) and no evidence of carcinogenicity was noted.
Animal Data
Maternal and fetal toxicity occurred in some rabbits given enalapril at doses of 1 mg/kg/day or more. Saline supplementation prevented the maternal and fetal toxicity seen at doses of 3 and 10 mg/kg/day, but not at 30 mg/kg/day (50 times the maximum human dose). Enalapril was not teratogenic in rabbits.
There was no fetotoxicity or teratogenicity in rats treated with enalapril at doses up to 200 mg/kg/day (333 times the maximum human dose). Fetotoxicity expressed as a decrease in average fetal weight, occurred in rats given 1200 mg/kg/day of enalapril, but did not occur when these animals were supplemented with saline. Enalapril crosses the placental barrier in rats and hamsters.
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.
Enalapril Maleate - Hydrochlorothiazide
The acute LD50 of hydrochlorothiazide (479 to 551 mg/kg) was lowered (390 to 353 mg/kg) by one hour pretreatment with orally administered enalapril (14 to211 mg/kg). This change was slight and at doses which would not be of clinical significance. No effect was seen on the acute oral toxicity of enalapril in mice by the prior oral administration of 900 mg/kg of
hydrochlorothiazide.
17 SUPPORTING PRODUCT MONOGRAPHS
- 1. VASERETIC® enalapril and hydrochlorothiazide tablets, 5 mg and 10 mg, submission control no. 265020, Product Monograph, Organon Canada Inc. Nov 04, 2022