Teva-Lisinopril/HCTZ (Type P) Product Monograph

INDICATIONS AND CLINICAL USE

TEVA-LISINOPRIL/HCTZ (TYPE P) is indicated for the treatment of essential hypertension in patients for whom combination therapy is appropriate.

In using TEVA-LISINOPRIL/HCTZ (TYPE P), consideration should be given to the risk of angioedema (see WARNINGS).

TEVA-LISINOPRIL/HCTZ (TYPE P) is not indicated for initial therapy. Patients in whom lisinopril and diuretic are initiated simultaneously can develop symptomatic hypotension (see PRECAUTIONS, Drug Interactions).

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

CONTRAINDICATIONS

TEVA-LISINOPRIL/HCTZ (TYPE P) is contraindicated in patients who:

• are hypersensitive to any component of this product;
• have a history of angioneurotic edema relating to previous treatment with an angiotensin-converting enzyme inhibitor; and
• have hereditary or idiopathic angioedema.

Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.

Concomitant use of angiotensin converting enzyme inhibitors (ACEIs) – including the lisinopril component of TEVA-LISINOPRIL/HCTZ (TYPE P) – 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 WARNINGS, Dual Blockade of the Renin-Angiotensin System (RAS), PRECAUTIONS, Renal Impairment, and DRUG INTERACTIONS, Dual Blockade of the Renin-Angiotensin System (RAS) with ACEIs, ARBs or aliskiren-containing drugs).

WARNINGS

Angioedema

Angioedema has been reported in patients treated with lisinopril and hydrochlorothiazide. This may occur at any time during treatment. Angioedema associated with shock may be fatal. If angioedema occurs, TEVA-LISINOPRIL/HCTZ (TYPE P) should be promptly discontinued and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient. 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. When there is airway obstruction, emergency therapy should be administered promptly when indicated. This includes giving subcutaneous adrenaline (0.5 mL 1:1000), and/or maintaining a patent airway. The patient should be under close medical supervision until complete and sustained symptom resolution has occurred.

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 CONTRAINDICATIONS).

Hypotension

Symptomatic hypotension has occurred after administration of lisinopril, 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, TEVA-LISINOPRIL/HCTZ (TYPE P) 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 blood pressure could potentially fall, patients at risk for hypotension should start therapy with lisinopril 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 lisinopril 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 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 may not be a contraindication to further doses. These can usually be given to hypertensive patients without difficulty once the blood pressure has increased after volume expansion. However, lower doses of lisinopril and/or concomitant diuretic therapy should be considered.

Dual Blockade of the Renin-Angiotensin System (RAS)

There is evidence that co-administration of angiotensin converting enzyme inhibitors (ACEIs), such as the lisinopril component in TEVA-LISINOPRIL/HCTZ (TYPE P), 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 TEVA-LISINOPRIL/HCTZ (TYPE P) in combination with aliskiren-containing drugs is contraindicated in these patients (see CONTRAINDICATIONS). Further, co-administration of ACEIs, including the lisinopril component of TEVA-LISINOPRIL/HCTZ (TYPE P), 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.

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 lisinopril 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.

Azotemia

Azotemia may be precipitated or increased by hydrochlorothiazide. Cumulative effects of the drug may develop in patients with impaired renal function. If increasing azotemia and oliguria occur during treatment of severe progressive renal disease the diuretic should be discontinued.

Patients with Impaired Liver Function

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

Should the patient receiving TEVA-LISINOPRIL/HCTZ (TYPE P) experience any unexplained symptoms (see Information for Patients), 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 TEVA-LISINOPRIL/HCTZ (TYPE P) should be considered when appropriate.

There are no adequate studies in patients with cirrhosis and/or liver dysfunction. TEVA-LISINOPRIL/HCTZ (TYPE P) 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.

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.

Ophthalmologic

Acute Myopia and Secondary Angle-Closure Glaucoma: Hydrochlorothiazide, a sulphonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulphonamide or penicillin allergy.

Use in Pregnancy

ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected, TEVA-LISINOPRIL/HCTZ (TYPE P) should be discontinued as soon as possible.

The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function, 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.

Lisinopril 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.

Animal Data

Lisinopril was not teratogenic in mice treated on days 6 - 15 of gestation with up to 1000 mg/kg/day (625 times the maximum recommended human dose). There was an increase in fetal resorptions at doses down to 100 mg/kg; at doses of 1000 mg/kg this was prevented by saline supplementation. There was no fetotoxicity or teratogenicity in rats treated with up to 300 mg/kg/day (188 times the maximum recommended dose) of lisinopril at days 6 - 17 of gestation. In rats receiving lisinopril from day 15 of gestation through day 21 postpartum, there was an increased incidence in pup deaths on days 2 - 7 postpartum and a lower average body weight of pups on day 21 postpartum. The increase in pup deaths and decrease in pup weight did not occur with maternal saline supplementation.

Lisinopril, at doses up to 1 mg/kg/day, was not teratogenic when given throughout the organogenic period in saline supplemented rabbits. Saline supplementation (physiologic saline in place of tap water) was used to eliminate maternotoxic effects and enable evaluation of the teratogenic potential at the highest possible dosage level. The rabbit has been shown to be extremely sensitive to angiotensin-converting enzyme inhibitors (captopril and enalapril) with maternal and fetotoxic effects apparent at or below the recommended therapeutic dosage levels in man.

Fetotoxicity was demonstrated in rabbits by an increased incidence of fetal resorptions at an oral dose of lisinopril of 1 mg/kg/day and by an increased incidence of incomplete ossification at the lowest dose tested (0.1 mg/kg/day). A single intravenous dose of 15 mg/kg of lisinopril administered to pregnant rabbits on gestation days 16, 21 or 26 resulted in 88% to 100% fetal death.

By whole body autoradiography, radioactivity was found in the placenta following administration of labelled lisinopril to pregnant rats, but none was found in the fetuses.

Use in Nursing Mothers

The presence of concentrations of ACE inhibitors have been reported in human milk. Use of ACE inhibitors is not recommended during breast-feeding.

PRECAUTIONS

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 lisinopril component of TEVA-LISINOPRIL/HCTZ (TYPE P) – or ARBs with aliskiren-containing drugs is contraindicated in patients with moderate to severe renal impairment (GFR < 60 mL/min/1.73 m²) (see CONTRAINDICATIONS and DRUG INTERACTIONS, Dual Blockade of the Renin-Angiotensin System (RAS) with ACEIs, ARBs or aliskiren-containing drugs).

Use of TEVA-LISINOPRIL/HCTZ (TYPE P) 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).

Hyperkalemia

In clinical trials hyperkalemia (serum potassium >5.7 mEq/L) occurred in approximately 1.4% of hypertensive patients. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was not a cause of discontinuation of therapy. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene or amiloride), potassium supplements or potassium-containing salt substitutes (see also DRUG INTERATIONS, Agents Increasing Serum Potassium).

The use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes particularly in patients with impaired renal function may lead to a significant increase in serum potassium. Hyperkalemia can cause serious, sometimes fatal, arrhythmias.

If concomitant use of TEVA-LISINOPRIL/HCTZ (TYPE P) and any of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium.

Valvular Stenosis, Hypertrophic Cardiomyopathy

There is concern on theoretical grounds that patients with aortic stenosis or hypertrophic cardiomyopathy might be at particular risk of decreased coronary perfusion when treated with vasodilators.

TEVA-LISINOPRIL/HCTZ (TYPE P) should be given with caution to these patients.

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

Surgery/Anesthesia

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

Cough

A dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose of TEVA-LISINOPRIL/HCTZ (TYPE P) has been reported.

Such a possibility should be considered as part of the differential diagnosis of the cough.

Use in the Elderly

In general, blood pressure response and adverse experiences were similar in younger and older patients given similar doses of lisinopril. Pharmacokinetic studies, however, indicate that maximum blood levels and area under the plasma concentration time curve (AUC) are doubled in older patients so that dosage adjustments should be made with particular caution.

Pediatric Use

TEVA-LISINOPRIL/HCTZ (TYPE P) has not been studied in children and, therefore, use in this age group is not recommended.

Anaphylactoid Reactions during Membrane Exposure

Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g., polyacrylonitrile [PAN]) and treated concomitantly with an ACE inhibitor. Dialysis should be stopped immediately if symptoms such as nausea, abdominal cramps, burning, angioedema, shortness of breath and severe hypotension occur. Symptoms are not relieved by antihistamines. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Anaphylactoid Reactions during LDL Apheresis

Rarely, patients receiving ACE inhibitors during low density lipoprotein (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.

Anaphylactoid Reactions during Hymenoptera 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.

DRUG INTERACTIONS

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).

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

INFORMATION FOR PATIENTS

Angioedema: Angioedema, including laryngeal edema, may occur during treatment with TEVA-LISINOPRIL/HCTZ (TYPE P). Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in breathing) and to take no more drug until they have consulted with the prescribing physician.

Hypotension: Patients should be cautioned to report lightheadedness especially during the first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the drug until they have consulted with the prescribing physician.

All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with their physician.

Neutropenia: Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which may be a sign of neutropenia.

Impaired Liver Function: Patients should be advised to return to the physician if he/she experiences any symptoms possibly related to liver dysfunction. This would include “viral-like symptoms” in the first weeks to months of therapy (such as fever, malaise, muscle pain, rash or adenopathy which are possible indicators of hypersensitivity reactions), or if abdominal pain, nausea or vomiting, loss of appetite, jaundice, itching or any other unexplained symptoms occur during therapy.

Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without consulting their physician.

Pregnancy: Patients should be advised to stop taking the medication and to report promptly to their physician if they become pregnant, since the use of TEVA-LISINOPRIL/HCTZ (TYPE P) during pregnancy can cause injury and even death of the developing fetus.

Nursing Mothers: Patients should be advised not to breast-feed while taking TEVA-LISINOPRIL/HCTZ (TYPE P), as it is possible that TEVA-LISINOPRIL/HCTZ (TYPE P) passes into breast milk.

NOTE: As with many other drugs, certain advice to patients being treated with TEVA-LISINOPRIL/HCTZ (TYPE P) is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.

ADVERSE REACTIONS

In clinical trials involving 930 patients, including 100 patients treated for 50 weeks or more, the most severe clinical adverse reactions were syncope (0.8%), and hypotension (1.9%). The most frequent clinical adverse reactions were: dizziness (7.5%), headache (5.2%), cough (3.9%), fatigue (3.7%) and orthostatic effects (3.2%).

Discontinuation of treatment due to adverse reactions occurred in 4.4% of patients, mainly because of dizziness, cough, fatigue or muscle cramps.

Adverse reactions that have occurred in clinical trials or in marketing experience are those which have been previously reported with lisinopril and hydrochlorothiazide when used separately for the treatment of hypertension.

Adverse reactions occurring in hypertensive patients treated with lisinopril and hydrochlorothiazide in controlled trials are shown below.

*See lisinopril and hydrochlorothiazide (Marketing Experience Only)

Laboratory Test Findings

Hypokalemia, Hyperkalemia: (see PRECAUTIONS).

Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen (3.8%) and serum creatinine (4.2%) were observed in patients with essential hypertension treated with lisinopril and hydrochlorothiazide. More marked increases have also been reported and were more likely to occur in patients with bilateral renal artery stenosis (see PRECAUTIONS).

Increases in blood urea nitrogen and serum creatinine, usually reversible upon discontinuation of therapy, were observed in 1.1 and 1.6% of patients respectively with essential hypertension treated with lisinopril alone.

Serum Uric Acid, Glucose, Magnesium, Cholesterol, Triglycerides and Calcium: (see PRECAUTIONS).

Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.5 g percent and 1.5 vol percent, respectively) occurred frequently in hypertensive patients treated with lisinopril and hydrochlorothiazide but were rarely of clinical importance unless another cause of anemia coexisted. In clinical trials, 0.4% of patients discontinued therapy due to anemia.

Rarely, hemolytic anemia has been reported.

Agranulocytosis and bone marrow depression, manifested as anemia, thrombocytopenia or leucopenia, have been caused by angiotensin-converting enzyme inhibitors, including lisinopril.

Several cases of agranulocytosis and neutropenia have been reported in which a causal relationship to lisinopril cannot be excluded (see WARNINGS, Neutropenia/Agranulocytosis).

Other (Causal Relationship Unknown): Rarely, elevations of liver enzymes and/or serum bilirubin have occurred.

Adverse Reactions Reported in Uncontrolled Trials and/or Marketing Experience.

Lisinopril and hydrochlorothiazide tablets

Cardiovascular

Myocardial infarction or cerebrovascular accident possibly secondary to excessive hypotension in high risk patients (see WARNINGS).

Tachycardia

Dermatologic

Alopecia

Urticaria

Pruritus

Diaphoresis

Severe Skin Disorders

Erythema multiforme

Pemphigus

Stevens-Johnson syndrome

Toxic epidermal necrolysis

Cutaneous pseudolymphoma

Gastrointestinal

Abdominal pain and indigestion

Dry mouth

Pancreatitis

Vomiting

Hematologic

Hemolytic anemia

Hepatic

Liver function abnormalities

Hepatitis

Jaundice (hepatocellular and/or cholestatic)

Hepatic failure

Metabolic

Cases of hypoglycemia in diabetic patients on oral antidiabetic agents or insulin have been reported.

Nervous System

Mood alterations

Mental confusion

Paresthesia

Vertigo

Respiratory

Bronchospasm

Rhinitis

Sinusitis

Special Senses

Taste disorder

Urogenital

Uremia

Oliguria/anuria

Renal dysfunction

Acute renal failure

Impotence

A symptom complex has been reported which may include fever, vasculitis, myalgia, arthralgia/arthritis, a positive ANA, elevated ESR, eosinophilia, and leukocytosis. Rash, photosensitivity, or other dermatologic manifestations may also occur.

Lisinopril and hydrochlorothiazide tablets (Marketing Experience Only)

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported (see WARNINGS).

In very rare cases, intestinal angioedema has been reported with angiotensin-converting enzyme inhibitors, including lisinopril.

Cases of pancreatitis have been reported.

Endocrine

Syndrome of inappropriate antidiuretic hormone secretion (SIADH)

No other adverse events have been reported with lisinopril and hydrochlorothiazide which have not been reported with lisinopril or hydrochlorothiazide individually.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

No specific information is available on the treatment of overdosage with Lisinopril and Hydrochlorothiazide. Treatment is symptomatic and supportive. Therapy with TEVA-LISINOPRIL/HCTZ (TYPE P) should be discontinued and the patient observed closely. Suggested measures include induction of emesis and/or gastric lavage, if ingestion is recent, and correction of dehydration, electrolyte imbalance and hypotension by established procedures.

Lisinopril

The most likely features of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution. Lisinopril may be removed from general circulation by hemodialysis.

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.

DOSAGE AND ADMINISTRATION

Dosage must be individualized. The fixed combination is not for initial therapy. The dose of TEVA-LISINOPRIL/HCTZ (TYPE P) should be determined by the titration of the individual components.

Once the patient has been successfully titrated with the individual components as described below, either one TEVA-LISINOPRIL/HCTZ (TYPE P) 10/12.5 mg or, one or two 20/12.5 mg or 20/25 mg tablets once daily may be substituted if the titrated doses are the same as those in the fixed combination (see INDICATIONS AND CLINICAL USE and WARNINGS).

Patients usually do not require doses in excess of 50 mg of hydrochlorothiazide daily, particularly when combined with antihypertensive agents.

For lisinopril monotherapy the recommended initial dose in patients not on diuretics is 10 mg of lisinopril once a day. Dosage should be adjusted according to blood pressure response. The usual dosage range of lisinopril is 10 to 40 mg administered in a single daily dose. The antihypertensive effect may diminish toward the end of the dosing interval regardless of the administered dose, but most commonly with a dose of 10 mg daily. This can be evaluated by measuring blood pressure just prior to dosing to determine whether satisfactory control is being maintained for 24 hours. If it is not, an increase in dose should be considered. The maximum dose used in long term controlled clinical trials was 80 mg/day. If blood pressure is not controlled with lisinopril alone, a low dose of a diuretic may be added. Hydrochlorothiazide 12.5 mg has been shown to provide an additive effect. After the addition of a diuretic, it may be possible to reduce the dose of lisinopril.

Diuretic Treated Patients

In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally may occur following the initial dose of lisinopril. The diuretic should, if possible, be discontinued for two to three days before beginning therapy with lisinopril to reduce the likelihood of hypotension (see WARNINGS). The dosage of lisinopril should be adjusted according to blood pressure response. If the patient’s blood pressure is not controlled with lisinopril alone, diuretic therapy may be resumed as described above.

If the diuretic cannot be discontinued, an initial dose of 5 mg of lisinopril alone should be administered and the patient remain under medical supervision for at least two hours, and until blood pressure has stabilized for at least an additional hour (see WARNINGS and PRECAUTIONS, Drug Interactions).

Dosage Adjustment in Renal Impairment

In patients with creatinine clearance greater than 30 mL/min, the usual dose titration of the individual components is required.

For patients with creatinine clearance between 10 and 30 mL/min, the starting dose of lisinopril is 2.5 - 5.0 mg/day. The dosage may then be titrated upward until blood pressure is controlled or to a maximum of 40 mg daily.

When concomitant diuretic therapy is required in patients with moderate or severe renal impairment (creatinine clearance < 30 mL/min), a loop diuretic, rather than a thiazide diuretic is preferred for use with lisinopril. Therefore, for patients with moderate or severe renal dysfunction the lisinopril-hydrochlorothiazide combination tablet is not recommended (see PRECAUTIONS - Renal Impairment, and Anaphylactoid Reactions during Membrane Exposure).

PHARMACEUTICAL INFORMATION

DRUG SUBSTANCE

Drug Substance: Lisinopril

Common name: Lisinopril

Chemical Name: 1-[N²-[(S)-1-Carboxy-3-phenylpropyl]-L-lysyl]-L-proline dihydrate

Structural Formula:

NH HH HO₂C H₂N N CO₂H HO 2 H₂O

Molecular Formula: C₂₁H₃₁N₃O_{5 •} 2H₂O

Molecular Weight: 441.52

Description: Lisinopril is a white to off-white, crystalline powder. It is soluble in water, sparingly soluble in methanol and practically insoluble in acetone and in ethanol.

Drug Substance: Hydrochlorothiazide

Common name: Hydrochlorothiazide

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

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

Structural Formula:

Molecular Formula: C₇H₈ClN₃O₄S₂

Molecular Weight: 297.74

Description: Hydrochlorothiazide is a white to off-white, crystalline powder. It is practically insoluble in water, but freely soluble in sodium hydroxide solution.

COMPOSITION

Each TEVA-LISINOPRIL/HCTZ (TYPE P) tablet contains corn starch, dibasic calcium phosphate, magnesium stearate, mannitol, pregelatinized corn starch, FD & C Blue #2 Aluminum Lake (10/12.5 mg tablet), yellow iron oxide (20/12.5 mg and 20/25 mg tablet) and red iron oxide (20/25 mg tablet).

STABILITY AND STORAGE RECOMMENDATIONS

Store between 15°C - 30°C. Protect from light and moisture.

AVAILABILITY OF DOSAGE FORMS

TEVA-LISINOPRIL/HCTZ (TYPE P) 10 mg/12.5 mg are blue, hexagon-shaped, biconvex tablets, engraved with N on one side and 10/12.5 on the other side. Each tablet contains 10 mg of lisinopril (as lisinopril dihydrate) and 12.5 mg of hydrochlorothiazide. Available in bottles of 100 and blister pack boxes of 30.

TEVA-LISINOPRIL/HCTZ (TYPE P) 20 mg/12.5 mg are yellow, hexagon-shaped, scored tablets, engraved with N on one side and 20 over scoreline 12.5 on the other side. Each tablet contains 20 mg of lisinopril (as lisinopril dihydrate) and 12.5 mg of hydrochlorothiazide. Available in bottles of 100.

TEVA-LISINOPRIL/HCTZ (TYPE P) 20 mg/25 mg are peach, hexagon-shaped tablets, engraved with N on one side and 20/25 on the other side. Each tablet contains 20 mg of lisinopril (as lisinopril dihydrate) and 25 mg of hydrochlorothiazide. Available in bottles of 100.

CLINICAL TRIALS

A blinded, single dose, randomized, three-period, six-sequence, three-treatment, crossover study between Lisinopril/Hydrochlorothiazide 20 mg/ 12.5 mg Tablets (Teva Canada Limited, Canada) and Prinzide^® 20 mg/ 12.5 mg Tablets (Merck Frosst Canada & Co.) in 35 healthy subjects (male and female) under fasting conditions. A second reference product (Zestoretic^®) was administered but not included in the statistical analysis presented in the following summary tables.

* TEVA-LISINOPRIL/HCTZ 20 mg / 12.5 mg Tablets (Teva Canada Limited, Canada)

s Prinzide® 20 mg / 12.5 mg Tablets (Merck Frosst Canada & Co.) were purchased in Canada

§ Expressed as the arithmetic mean (CV%) only

^a Based on least-squares mean estimates.

+ Due to the design of the study, meaningful AUC_I and T_½ parameters could not be calculated.

* TEVA-LISINOPRIL/HCTZ 20 mg / 12.5 mg Tablets (Teva Canada Limited, Canada)

s Prinzide® 20 mg / 12.5 mg Tablets (Merck Frosst Canada & Co.) were purchased in Canada

§ Expressed as the arithmetic mean (CV%) only

^a Based on least-squares mean estimates.

A blinded, single dose, randomized, three-period, six-sequence, three-treatment, crossover study between Lisinopril/Hydrochlorothiazide 20 mg/ 25 mg Tablets (Teva Canada Limited, Canada) and Prinzide^® 20 mg/ 25 mg Tablets (Merck Frosst Canada & Co.) in 36 healthy subjects (male and female) under fasting conditions. A second reference product (Zestoretic^®) was administered but not included in the statistical analysis presented in the following summary tables.

* TEVA-LISINOPRIL/HCTZ 20 mg / 25 mg Tablets (Teva Canada Limited, Canada)

s Prinzide® 20 mg / 25 mg Tablets (Merck Frosst Canada & Co.) were purchased in Canada

§ Expressed as the arithmetic mean (CV%) only

+ Due to the design of the study, meaningful AUC_I and T_½ parameters could not be calculated.

* TEVA-LISINOPRIL/HCTZ 20 mg / 25 mg Tablets (Teva Canada Limited, Canada)

s Prinzide® 20 mg / 25 mg Tablets (Merck Frosst Canada & Co.) were purchased in Canada

§ Expressed as the arithmetic mean (CV%) only

PHARMACOLOGY

Lisinopril

* Inhibition of enzymatic activity of hog plasma ACE using ¹⁴C labeled substrate.

** Blockage of functional (pressor) response to AI challenge.

Lisinopril and Hydrochlorothiazide

In spontaneously hypertensive rats (SHR) lisinopril was studied in an oral dose of 1.25 mg/kg daily, given alone or concomitantly with hydrochlorothiazide 50 mg/kg orally, for 3 days. Reductions in blood pressure were recorded (tail cuff method) on each of the 3 treatment days, reaching normotensive levels (113 - 116 mmHg) on Day 3 at 4 - 8 hours after the concomitant therapy.

TOXICOLOGY

Acute Toxicity of Lisinopril

LD₅₀ Values:

Signs of toxicity: Following oral administration to mice decreased activity and one male death (1/10) occurred. No signs of toxicity occurred in rats after oral administration. Dogs given 6 g/kg had transient diarrhea and increases in serum urea nitrogen. Intravenous administration to mice produced bradypnea, ataxia, clonic convulsions, exophthalmia, and tremors. After intraperitoneal administration in rats, ataxia and one female death (1/10) occurred. No signs of toxicity or death occurred in the males.

Subacute/Chronic Toxicology (lisinopril)

^a Dosing terminated Week 11, rats killed Week 27.

Teratology Studies (Lisinopril)

Fertility and Late Gestation and Lactation with Postnatal Evaluation Studies (Lisinopril)

Genotoxicity Studies (Lisinopril)

Carcinogenicity Studies (Lisinopril)

Toxicology (Lisinopril and Hydrochlorothiazide)

Teratology (lisinopril and hydrochlorothiazide)

Mutagenicity (lisinopril and hydrochlorothiazide)

The results of a battery of mutogenic and chromosomal aberration studies (Ames test, mammalian cell mutagenesis assay, an in vitro alkaline elution test for single strand DNA breaks, an in vitro chromosomal aberration assay in Chinese hamster ovary cells, and in vivo mouse bone marrow chromosome aberration) failed to reveal a genotoxic potential for the combination of lisinopril and hydrochlorothiazide.

REFERENCES

1. 1. Ajayi AA, Campbell BC, Howie CA, Reid JL. Acute and chronic effects of the converting enzyme inhibitors enalapril and lisinopril on reflex control of heart rate in normotensive man. J Hypertens 1985;3:47-53.
2. 2. Beermann B, Groschinsky-Grind M. Pharmacokinetics of hydrochlorothiazide in man. Eur J Clin Pharmacol 1977;12:297-303.
3. 3. Biollaz J, Schelling JL, Jacot des Combes B, Brunner DB, Desponds G, Brunner HR, Ulm EH, Hichens M, Gomez HJ. Enalapril maleate and a lysine analogue (MK-521) in normal volunteers: Relationship between plasma drug levels and the renin angiotensin system. Br J Clin Pharmacol 1982;14:363-368.
4. 4. Bussien JP, Waeber B, Nussberger J, Gomez HJ, Brunner HR. Once-daily lisinopril in hypertensive patients: Effect on blood pressure and the renin-angiotensin system. Curr Therapeutic Research 1985;37:342-351.
5. 5. Cirillo VJ, Gomez HJ, Salonen J, Salonen R, Rissanen V, Bolognese JA, Nyberg R, Kristianson K. Lisinopril: Dose-peak effect relationship in essential hypertension. Br J Clin Pharmacol 1988;25:533-538.
6. 6. Donohoe JF, Kelly J, Laher MS, Doyle GD. Lisinopril in the treatment of hypertensive patients with renal impairment. Am J Med 1988;85(Suppl 3B):31-34.
7. 7. Laher MS, Natin D, Rao SK, Jones RW, Carr P. Lisinopril in elderly patients with hypertension. J Cardiovasc Pharmacol 1987;9(Suppl 3):S69-S71.
8. 8. Lancaster SG, Todd PA. Lisinopril: A preliminary review of its Pharmacokinetics Properties, and Therapeutic Use in Hypertension and Congestive Heart Failure. Drugs 1988;35:646-669.
9. 9. Millar JA, Derkx FHM, McLean K, Reid JL. Pharmacodynamics of converting enzyme inhibition: The cardiovascular endocrine and autonomic effects of MK-421 (enalapril) and MK-521. Br J Clin Pharmacol 1982;14:347-355.
10. 10. Rotmensch HH, Vlasses PH, Swanson BN, Irvin JD, Harris KE, Merrill DD, Ferguson RD. Antihypertensive efficacy of once daily MK-521, a new nonsulfhydryl angiotensin-converting enzyme inhibitor. Am J Cardiol 1984;53:116-119.
11. 11. Ulm EH, Hichens M, Gomez HJ, Till AE, Hand E, Vassil TC, Biollaz J, Brunner HR, Schelling JL. Enalapril maleate and a lysine analogue (MK-521): Disposition in man. Br J Clin Pharmacol 1982;14:357-362.
12. 12.

    Product Monograph for PRINZIDE^® by Merck Frosst Canada Ltd., Quebec, Canada.

    Date of Preparation: May 30, 2005. Date of Revision: June 13 2013.

13. 13.

    A blinded, single dose, randomized, 3-way crossover study between

    Lisinopril/Hydrochlorothiazide 20 mg/12.5 mg Tablets (Teva Canada Limited, Canada) and

    Zestoretic^® 20 mg/12.5 mg Tablets (AstraZeneca Canada Inc.) and Prinzide^® 20 mg/12.5 mg

    Tablets (Merck Frosst Canada & Co.). Data on file at Teva Canada Limited.

14. 14.

    A blinded, single dose, randomized, 3-way crossover study between

    Lisinopril/Hydrochlorothiazide 20 mg/25 mg Tablets (Teva Canada Limited, Canada) and Zestoretic^® 20 mg/25 mg Tablets (AstraZeneca Canada Inc.) and Prinzide^® 20 mg/25 mg Tablets (Merck Frosst Canada & Co.). Data on file at Teva Canada Limited.