GD-Quinapril Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Hypertension

GD-quinapril (quinapril hydrochloride) is indicated in the treatment of essential hypertension. It is usually administered in association with other drugs, particularly thiazide diuretics.

The safety and efficacy of GD-quinapril in renovascular hypertension has not been established; therefore, use in this condition is not recommended.

Congestive Heart Failure

GD-quinapril is indicated in the treatment of congestive heart failure as adjunctive therapy when added to diuretics and/or digitalis glycosides.

Treatment with GD-quinapril should be initiated under close medical supervision.

Geriatrics (>65 years of age)

Of the total number of subjects in clinical studies of quinapril, 21% were ≥65 years old. (There was no distinction between patients >65 or >75 years.) No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience did not identify differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Pediatrics (<18 years of age)

The safety and effectiveness of GD-quinapril in children have not been established, therefore use in this age group is not recommended.

CONTRAINDICATIONS

GD-quinapril is contraindicated in:

• Patients who are hypersensitive to the drug or to any ingredient in the formulation. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.
• Patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme (ACE) inhibitor (see WARNINGS AND PRECAUTIONS, General, Head and Neck Angioedema).
• Combination with sacubitril/valsartan due to increased risk of angioedema.
• Women who are pregnant, intend to become pregnant, or of childbearing potential who are not using adequate contraception (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women and ADVERSE REACTIONS).
• Nursing women (see WARNINGS AND PRECAUTIONS, Special Populations, Nursing Women).

• Combination with aliskiren-containing medicines in patients with:

  • diabetes mellitus (type 1 or type 2)
  • moderate to severe kidney insufficiency (GFR < 60 mL/min/1.73 m²) ,
  • hyperkalemia (> 5mMol/L) or

  • congestive heart failure who are hypotensive (see WARNINGS AND PRECAUTIONS, Dual blockade of the Renin-Angiotensin System (RAS) and

    • Renal Impairment, and DRUG INTERACTIONS, Aliskiren-containing medicines and Angiotensin receptor blockers (ARBs) or other ACE inhibitors).

• Combination with angiotensin receptor blockers (ARBs) or other ACE inhibitors in patients with:

  • diabetes with end organ damage,
  • moderate to severe kidney insufficiency (GFR < 60 mL/min/1.73m²),
  • hyperkalemia (> 5mMol/L) or
  • congestive heart failure who are hypotensive (see DRUG INTERACTIONS, Angiotensin receptor blockers (ARBs) or other ACE inhibitors).
• Patients with hereditary problems of galactose intolerance, glucose-galactose malabsorption or the Lapp lactase deficiency as GD-quinapril contains lactose (see WARNINGS AND PRECAUTIONS, Sensitivity/Resistance).

WARNINGS AND PRECAUTIONS

General

Head and Neck Angioedema

Head and neck angioedema has been reported in patients treated with quinapril. Angioedema associated with laryngeal involvement may be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, GD-quinapril should be discontinued immediately, the patient treated appropriately in accordance with accepted medical care, and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment, although antihistamines may be useful in relieving symptoms. Where there is involvement of the tongue, glottis or larynx, likely to cause airway

Serious Warnings and Precautions

When used in pregnancy, angiotensin converting enzyme (ACE) inhibitors can cause injury or even death of the developing fetus. When pregnancy is detected, GD-quinapril should be discontinued as soon as possible.

obstruction, appropriate therapy (including but not limited to 0.3 to 0.5 mL of subcutaneous epinephrine solution 1:1000) should be administered promptly (see ADVERSE REACTIONS).

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

Patients taking a concomitant mTOR inhibitor (e.g. temsirolimus), DPP-4 inhibitor (e.g. sitagliptin) or neutral endopeptidase (NEP) inhibitor may be at increased risk for angioedema. Caution should be used when either initiating ACE inhibitor therapy in patients already taking a mTOR, DPP-4 inhibitor or NEP inhibitor or vice versa (see DRUG INTERACTIONS).

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

Intestinal Angioedema

Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Cardiovascular

Dual blockade of the Renin-Angiotensin System (RAS)

Dual blockade of the Renin-Angiotensin System (RAS): There is evidence that co-administration of angiotensin converting enzyme (ACE) inhibitors, such as GD-quinapril, or of angiotensin receptor antagonists (ARBs) with aliskiren increases the risk of hypotension, syncope, stroke, hyperkalemia and deterioration of renal function, including acute renal failure, in patients with diabetes mellitus (type 1 or type 2) and/or moderate to severe kidney insufficiency (GFR < 60 mL/min/1.73 m²). Therefore, the use of GD-quinapril in combination with aliskiren-containing drugs is contraindicated in these patients (see CONTRAINDICATIONS).

Further, co-administration of ACE inhibitors, including GD-quinapril, 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. Administration should be limited to individually defined cases with close monitoring of renal function and blood potassium levels (see CONTRAINDICATIONS).

Hypotension

Symptomatic hypotension has occurred after administration of quinapril, usually after the first or second dose or when the dose was increased. It is more likely to occur in patients who are volume depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. In patients with ischemic heart or cerebrovascular disease, an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident (See ADVERSE REACTIONS). Because of the potential fall in blood pressure in these patients, therapy with GD-quinapril should be started under close medical supervision (see DOSAGE AND ADMINISTRATION). Such patients should be followed closely for the first weeks of treatment and whenever the dose of GD-quinapril is increased. In patients with severe congestive heart failure, with or without associated renal insufficiency, excessive hypotension has been observed and may be associated with oliguria and/or progressive azotemia, and rarely with acute failure and/or death.

If hypotension occurs, the patient should be placed in supine position and, if necessary, receive an intravenous infusion of 0.9% sodium chloride. A transient hypotensive response is not a contraindication to further doses which usually can be given without difficulty once the blood pressure has increased after volume expansion. However, lower doses of GD-quinapril and/or reduced concomitant diuretic therapy should be considered.

Valvular Stenosis

There is concern on theoretical grounds that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators because they do not develop as much afterload reduction.

Endocrine and Metabolism

Hyperkalemia

Elevated serum potassium (>5.7 mMol/L) was observed in approximately 2% of patients receiving quinapril. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was a cause of discontinuation of therapy in <0.1% of hypertensive patients. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of agents to treat hypokalemia potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs known to raise serum potassium levels. Because of the risk of hyperkalemia it is advised that combination therapy be initiated with caution and the patient’s serum potassium levels be closely monitored (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Test, Hyperkalemia, ADVERSE REACTIONS, and DRUG INTERACTIONS, Agents Increasing Serum Potassium, Trimethoprim-containing products).

Hyponatraemia and SIADH

Syndrome of Inappropriate Anti-diuretic Hormone (SIADH) and subsequent hypronatraemia has been observed in some patients treated with other ACE inhibitors. It is recommended that serum sodium levels be monitored regularly in the elderly and in other patients at risk of hyponatraemia.

Hypoglycemia and Diabetes

ACE inhibitors may reduce insulin resistance and may lead to hypoglycemia in diabetic patients on insulin or oral hypoglycemic agents; closer monitoring of diabetic patients may be required.

Hematologic

Neutropenia/Agranulocytosis

Agranulocytosis and bone marrow depression have been caused by ACE inhibitors. Agranulocytosis did occur during quinapril treatment in 1 patient with a history of neutropenia during previous captopril therapy. Periodic monitoring of white blood cell counts should be considered, especially in patients with collagen vascular disease and/or renal disease.

Hepatic

Patients with Impaired Liver Function

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

Elevations of liver enzymes and/or serum bilirubin have been reported for quinapril (see ADVERSE REACTIONS). Should the patient receiving GD-quinapril experience any unexplained symptoms particularly during the first weeks or months of treatment, it is recommended that a full set of liver function tests and any other necessary investigation be carried out. Discontinuation of GD-quinapril should be considered when appropriate.

There are no adequate studies in patients with cirrhosis and/or liver dysfunction. GD-quinapril 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.

Quinapril, when combined with a diuretic 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. The metabolism of quinapril to quinaprilat is normally dependent upon hepatic esterase. Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deesterification of quinapril.

Immune

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 agents.

Anaphylactoid Reactions during LDL Apheresis

Rarely, patients receiving ACE inhibitors during low density lipoprotein apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding the ACE inhibitor therapy prior to each apheresis.

Anaphylactoid Reactions during Desensitization

There have been isolated reports of patients experiencing sustained life threatening anaphylactoid reactions while receiving ACE inhibitors during desensitizing treatment with hymenoptera (bees, wasps) venom. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld for at least 24 hours, but they have reappeared upon inadvertent rechallenge to an ACE inhibitor.

Nitritoid Reactions-Gold

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and symptomatic hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including GD-quinapril (see DRUG INTERACTIONS).

Neurologic

Driving and Operating Machinery

The ability to engage in activities such as operating machinery or operating a motor vehicle may be impaired, especially when initiating quinapril therapy.

Peri-Operative Considerations

Surgery/Anaesthesia

In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, quinapril will block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

Renal

Renal Impairment

The use of ACE inhibitors, including GD-quinapril, with ARBs or aliskiren-containing drugs is contraindicated in patients with moderate to severe kidney insufficiency (GFR < 60 mL/min/1.73m²) (see CONTRAINDICATIONS and DRUG INTERACTIONS, Aliskiren-containing medicines and Angiotensin receptor blockers (ARBs) or other ACE inhibitors).

As a consequence of inhibiting the renin-angiotensin-aldosterone system (RAAS), changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the RAAS, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).

Use of GD-quinapril should include appropriate assessment of renal function (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).

Respiratory

Cough

Cough has been reported with the use of ACE inhibitors, including quinapril. Characteristically, the cough is dry and persistent and usually disappears only after withdrawal or lowering of the dose of quinapril. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of the cough.

Sensitivity/Resistance

Due to the presence of lactose, patients with hereditary problems of galactose intolerance, glucose-galactose malabsorption or the Lapp lactase deficiency should not take GD-quinapril (see CONTRAINDICATIONS).

Special Populations

Pregnant Women

Quinapril is contraindicated in pregnancy (see CONTRAINDICATIONS and ADVERSE REACTIONS). ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, GD-quinapril should be discontinued as soon as possible.

The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.

Prematurity, and patent ductus arteriosus and other structural cardiac malformations, as well as 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.

If oligohydramnios is observed, a non-stress test (NST), and/or a biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. If concerns regarding fetal well-being still persist, a contraction stress testing (CST) should be considered. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Animal Data: No fetotoxic or teratogenic effects were observed in rats at doses as high as 300 mg/kg/day (180x the maximum daily human dose), despite maternal toxicity at 150 mg/kg/day. Offspring body weights were reduced in rats treated late in gestation and during lactation with doses of ≥25 mg/kg/day. Quinapril hydrochloride was not teratogenic in rabbits; however, maternal and embryo toxicity were seen in some rabbits at 1 mg/kg/day.

No adverse effects on fertility or reproduction were observed in rats at dose levels ≤100 mg/kg/day (60x the maximum daily human dose) (see TOXICOLOGY, Table 4).

Nursing Women

The presence of concentrations of ACE inhibitor has been reported in human milk. The use of GD-quinapril is contraindicated during breast-feeding (see CONTRAINDICATIONS).

Pediatrics (<18 years of age)

The safety and effectiveness of GD-quinapril in children have not been established, therefore use in this age group is not recommended.

Geriatrics (>65 years of age)

Of the total number of subjects in clinical studies of quinapril, 21% were ≥65 years old. (There was no distinction between patients >65 or >75 years.) No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).

Elderly patients exhibited increased area under the plasma concentration time curve and peak levels for quinaprilat compared to values observed in younger patients; this appeared to relate to decreased renal function rather than to age itself.

Monitoring and Laboratory Tests

Hematology: Periodic monitoring of white blood cell counts should be considered, especially in patients with collagen vascular disease and/or renal disease (see WARNINGS AND PRECAUTIONS, Hematologic, Neutropenic/Agranulocytisis).

Hyperkalemia: Patients with renal insufficiency, diabetes mellitus or concomitantly taking agents to treat hypokalemia may be at increased risk of developing hyperkalemia. Serum potassium should be monitored regularly (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Hyperkalemia).

Hyponatraemia: (see WARNINGS and PRECAUTIONS, Endocrine and Metabolism, Hyponatraemia and SIADH).

It is recommended that serum sodium levels be monitored regularly in the elderly and in other patients at risk of hyponatraemia.

Creatinine and Blood Urea Nitrogen: Increases (>1.25x the upper limit of normal) in serum creatinine and blood urea nitrogen (BUN) were observed in 2% each of patients treated with quinapril alone. Increases were more likely to occur in patients receiving concomitant diuretic therapy than in those on quinapril alone (see WARNINGS AND PRECAUTIONS, Renal, Renal Impairment). These increases often reversed on continued therapy. In controlled studies of heart failure, increases in BUN and serum creatinine were observed in 11% and 8%, respectively, of patients treated with quinapril. Most often, these patients were receiving diuretics with or without digitalis. Use of GD-quinapril should include appropriate assessment of renal function.

Hepatic: Elevations of liver enzymes and/or serum bilirubin have occurred in patients receiving GD-quinapril. If a patient receiving GD-quinapril experience any unexplained symptoms, particularly during the first weeks or months of treatment, a full set of liver function tests and any other investigation should be carried out. Discontinuation of GD-quinapril should be considered when appropriate. In patients with pre-existing liver abnormalities, baseline liver function tests should be obtained before administration of the drug and response and metabolic effects should be closely monitored (see WARNINGS AND PRECAUTIONS, Hepatic, Patients with Impaired Liver Function).

ADVERSE REACTIONS

Hypertension

Quinapril hydrochloride monotherapy was evaluated for safety in 2005 hypertensive patients, including 313 elderly patients, enrolled in placebo-controlled clinical trials. There was no increase in the incidence of adverse events (AEs) in elderly patients given the same daily dosages. Quinapril was evaluated for long-term safety in >1100 patients treated for ≥1 year. AEs were usually mild and transient in nature.

The most serious AE was angioedema (0.1%). Renal insufficiency (1 case), agranulocytosis (1 case) and mild azotemia (2 cases in CHF patients) have been reported. Myocardial infarction and cerebrovascular accident occurred, possibly secondary to excessive hypotension in high risk patients (see WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension).

The most frequent AEs in controlled clinical trials were headache (8.1%), dizziness (4.1%), cough (3.2%), fatigue (3.2%), rhinitis (3.2%), nausea and/or vomiting (2.3%), and abdominal pain (2.0%).

Discontinuation of therapy because of AEs was required in 4.7% of patients treated with quinapril in placebo-controlled trials.

Congestive Heart Failure (CHF)

Out of the 1108 patients with CHF, 605 (55%) experience ≥1 AE. In controlled clinical trials, 525 of these patients were evaluated for safety. The frequencies of AEs were similar for both sexes as well as for younger (< 65 years) and older (> 65 years) patients.

The most serious non-fatal AEs/reactions were angioedema (0.1%), chest pain of unknown origin (0.8%), angina pectoris (0.4%), hypotension (0.1%) and impaired renal function (see WARNINGS AND PRECAUTIONS, Renal, Renal Impairment). Myocardial infarct and cerebrovascular accident occurred (see WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension). Rare cases of eosinophilic pneumonitis have been reported. Hepatitis or hepatic failure have rarely been observed with other ACE inhibitors.

The most frequent AEs in controlled clinical trials were dizziness (11.2%), cough (7.6%), chest pain (6.5%), dyspnea (5.5%), fatigue (5.1%), and nausea/vomiting (5.0%).

Discontinuation due to AEs in controlled clinical trials was required for 41 (8.0%) patients. Hypotension (0.8%) and cough (0.8%) were the most common reasons for withdrawal.

AEs occurring in ≥ 0.5% of 2005 hypertensive patients treated with quinapril monotherapy and in 525 patients with CHF treated with quinapril as adjunctive therapy, in controlled clinical trials, are presented in the table below:

AEs occurring in <0.5% of patients with hypertension or CHF include:

Body as a whole: Allergy, chill, dehydration, face edema, weight increase

Cardiovascular: Atrial flutter, cerebrovascular accident, heart failure vasodilatation, ventricular tachycardia

Digestive System: Anorexia, bloody stools, constipation, GI hemorrhage, tongue edema

Hemic and Lymphatic System: Agranulocytosis, anemia, including hemolytic anemia

Nervous System: Amnesia, anxiety, arthralgia, confusion

Musculoskeletal System: Arthritis

Respiratory System: Asthma, hoarseness

Skin and Appendages: Dermatitis, eczema, Stevens-Johnson syndrome, urticaria

Urogenital system: Dysuria, impaired renal function, polyuria

Special senses: Tinnitus

Laboratory Deviations: Azotemia, elevated BUN, hematuria, hyperglycemia, WBC decreased

Clinical adverse experiences probably, possibly, or definitely related, or of uncertain relationship to therapy occurring in 0.5% to < 1.0% of the patients treated with quinapril (with or without concomitant diuretic) in controlled or uncontrolled clinical trials and less frequent events seen in clinical trials or post-marketing experience (indicated by a *) included:

Body as a Whole: Anaphylactoid reaction*; photosensitivity reaction*

Cardiovascular: Postural hypotension*, syncope*, vasodilation

Congenital and familial/genetic disorders:

Fetal/neonatal injury including: anuria, hypotension, oligohydramnios, skull hypoplasia, reversible or irreversible renal failure, and death (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, Pregnant Women)

Gastrointestinal: Flatulence, pancreatitis*

Hemic and Lymphatic: Thrombocytopenia*

Integumentary: Alopecia*, exfoliative dermatitis*, pemphigus*

Urogenital: Urinary tract infection

Other: Athralgia, edema (peripheral and generalized), hemolytic anemia*

DRUG INTERACTIONS

Drug-Drug Interactions

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

Drug-Food Interactions

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

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Test Interactions

Interactions with laboratory products/methods have not been established.

Drug-Lifestyle Interactions

Lifestyle interactions have not been established.

DOSAGE AND ADMINISTRATION

Dosage of GD-quinapril (quinapril hydrochloride) must be individualized.

Hypertension

Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure (BP) elevation and salt restriction. The dosage of other antihypertensive agents being used with GD-quinapril may need to be adjusted.

Monotherapy:

The recommended initial dose of GD-quinapril in patients not on diuretics is 10 mg once daily. An initial dose of 20 mg once daily can be considered for patients without advanced age, renal impairment, or concomitant heart failure and who are not volume depleted (see WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension). Dosage should be adjusted according to BP response, generally at intervals of 2-4 weeks. A dose of 40 mg daily should not be exceeded.

In some patients treated once daily, the antihypertensive effect may diminish towards the end of the dosing interval. This can be evaluated by measuring BP just prior to dosing to determine whether satisfactory control is being maintained for 24 hours. If it is not, either 2x daily administration with the same total daily dose, or an increase in dose should be considered. If BP is not controlled with GD-quinapril alone, a diuretic may be added. After the addition of a diuretic, it may be possible to reduce the dose of GD-quinapril.

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

Dosing Adjustment in Renal Impairment: For use in hemodialysis patients, see WARNINGS and PRECAUTIONS, Anaphylactoid Reactions during Membrane Exposure. Quinapril should be administered on days when dialysis is not performed.

Starting doses should be reduced according to the following guidelines:

Patients should subsequently have dosage titrated (as described above) to the optimal response.

Dosage in the Elderly (>65 years): The recommended initial dosage of GD-quinapril is 10 mg once daily (depending on renal function), followed by titration (as described above) to the optimal response.

Congestive Heart Failure

GD-quinapril is indicated as adjunctive therapy to diuretics, and/or cardiac glycosides. Therapy should be initiated under close medical supervision. BP and renal function should be monitored, both before and during treatment with GD-quinapril, because severe hypotension and, more rarely, consequent renal failure have been reported (see WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension).

Initiation of therapy requires consideration of recent diuretic therapy and the possibility of severe salt/volume depletion. If possible, the dose of diuretic should be reduced before beginning treatment, to reduce the likelihood of hypotension. Serum potassium should also be monitored (see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS).

The recommended starting dose is 5 mg once daily, to be administered under close medical supervision to determine the initial effect on BP. After the initial dose, the patient should be observed for ≥2 hours, or until the pressure has stabilized for ≥1 additional hour (See WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension). This dose may improve symptoms of heart failure, but increases in exercise duration have generally required higher doses. Therefore, if the initial dosage of GD-quinapril is well tolerated or after effective management of symptomatic hypotension following initiation of therapy, the dose should then be increased gradually to 10 mg once daily, then 20 mg once daily, and to 40 mg per day given in 2 equally divided doses, depending on the patient's response. The maximum daily dose is 40 mg.

The dose titration may be done at weekly intervals, as indicated by the presence of residual signs or symptoms of heart failure.

Renal Impairment or Hyponatremia: Kinetic data indicate that quinapril elimination is dependent on the level of renal function. The recommended initial dose of GD-quinapril is 5 mg in patients with a creatinine clearance of 30- 60 mL/min and 2.5 mg in patients with a creatinine clearance of 10- 30 mL/min. There is insufficient data for dosage recommendation in patients with a creatinine clearance <10 mL/min. If the initial dose is well tolerated, GD-quinapril may be administered the following day as a 2x daily regimen. In the absence of excessive hypotension or significant deterioration of renal function, the dose may be increased at weekly intervals based on clinical and hemodynamic response (See WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS).

OVERDOSAGE

No data are available regarding overdosage with quinapril. The most likely clinical manifestation would be symptoms attributable to severe hypotension, which should be normally treated by intravenous volume expansion with 0.9% sodium chloride. Hemodialysis and peritoneal dialysis have little effect on the elimination of quinapril and quinaprilat.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

GD-quinapril (quinapril hydrochloride) is a nonpeptide, nonsulphydryl inhibitor of angiotensin converting enzyme (ACE), which is used in the treatment of hypertension.

ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor angiotensin II. After absorption, quinapril is rapidly de-esterified to quinaprilat (quinapril diacid), its principal active metabolite. Its primary mode of action is to inhibit circulating and tissue ACE, thereby decreasing vasopressor activity and aldosterone secretion. Although the decrease in aldosterone is small, it results in a small increase in serum K⁺ (see WARNINGS AND PRECAUTIONS). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. Although quinapril had antihypertensive activity in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to ACE inhibitor monotherapy than non-black patients.

ACE is identical to kininase II. Thus, quinapril may interfere with the degradation of bradykinin, a potent peptide vasodilator. However, it is not known whether this system contributes to the therapeutic effects of quinapril.

In animal studies, the antihypertensive effect of quinapril outlasts its inhibitory effect on circulating ACE. Tissue ACE inhibition more closely correlates with the duration of antihypertensive effects and this may be related to enzyme binding characteristics.

Pharmacodynamics

Hypertension

Administration of 10- 40 mg of quinapril to patients with essential hypertension results in a reduction of both sitting and standing BP with minimal effect on heart rate. Antihypertensive activity commences within 1 hour with peak effects usually achieved by 2-4 hours after dosing. Achievement of maximum BP lowering effects may require 2 weeks of therapy in some patients. At the recommended doses, antihypertensive effects are maintained throughout the 24-hour dosing interval in most patients. While the dose response relationship is relatively flat, a dose of 40 mg was somewhat more effective at trough than 10-20 mg, and 2x daily dosing tended to give a somewhat lower BP than 1x daily dosing with the same total daily dose. The antihypertensive effect of quinapril was maintained during long-term therapy with no evidence of loss of effectiveness.

Hemodynamic assessments in patients with essential hypertension indicate that BP reduction produced by quinapril is accompanied by a reduction in total peripheral resistance and renal vascular resistance with little or no change in heart rate and cardiac index. There was an increase in renal blood flow which was not significant. Little or no change in glomerular filtration rate (GFR) or filtration fraction was observed.

Quinapril has been shown to reduce microalbuminuria in patients with essential hypertension independently of changes in systemic BP.

When quinapril is given together with thiazide-type diuretics, the antihypertensive effects are approximately additive.

Congestive heart failure

Administration of quinapril to patients with congestive heart failure (CHF) reduces peripheral vascular resistance, systolic and diastolic BP, pulmonary capillary wedge pressure, and increases cardiac output. The onset of effects was observed within 1 hour and maximal effects occurred at 1.25- 4 hours after administration of quinapril. Peak hemodynamic effects correlated well with peak plasma levels of quinaprilat (1- 4 hours after administration).

Exercise tolerance was improved with quinapril therapy.

The effect of quinapril on survival in patients with heart failure has not been evaluated.

Pharmacokinetics

Following oral administration of GD-quinapril, peak plasma concentrations of quinapril occur within 1 hour. Based on the recovery of quinapril and its metabolites in urine, the extent of absorption is ≥60%. Following absorption, quinapril is de-esterified to its major active metabolite, quinaprilat (quinapril diacid) a potent ACE inhibitor, and to minor inactive metabolites. Quinapril has an apparent half-life in plasma of approximately 1 hour. Peak plasma quinaprilat concentrations occur approximately 2 hours after an oral dose of GD-quinapril. Quinaprilat is eliminated primarily by renal excretion and has an effective accumulation half-life of approximately 3 hours. Quinaprilat has an elimination half-life in plasma of approximately 2 hours with a prolonged terminal phase of 25 hours. Approximately 97% of either quinapril or quinaprilat circulating in plasma is bound to proteins.

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

The disposition of quinapril and quinaprilat in patients with renal insufficiency is similar to that in patients with normal renal function until creatinine clearance is ≤60 mL/min. With creatinine clearance <60 mL/min, peak and trough quinaprilat concentrations increase, apparent half-life increases, and time to steady state may be delayed. The elimination of quinaprilat may be reduced in elderly patients (>65 years) and in those with heart failure; this reduction is attributable to decrease in renal function (see DOSAGE and ADMINISTRATION). Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired de-esterification of quinapril.

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

Studies in rats indicate that quinapril and its metabolites do not cross the blood-brain barrier.

Special Populations and Conditions

Geriatrics:

Therapeutic effects appear to be the same for elderly (>65 years of age) and younger adult patients given the same daily dosages, with no increase in AEs in elderly patients.

Race:

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

STORAGE AND STABILITY

Store at controlled room temperature, 15-30^oC. Protect from moisture. Dispense in well-closed containers.

DOSAGE FORMS, COMPOSITION AND PACKAGING

GD-quinapril (quinapril hydrochloride) tablets are supplied as follows:

GD-quinapril 5 mg: Contains 5 mg quinapril per tablet. Brown, film-coated, elliptical tablets, debossed "PD 527" on one side and "5" on the other side. Bottles of 90 tablets.

GD-quinapril 10 mg: Contains 10 mg quinapril per tablet. Brown, film-coated, triangular tablets, debossed "PD 530" on one side and "10" on the other side. Bottles of 90 tablets.

GD-quinapril 20 mg: Contains 20 mg quinapril per tablet. Brown, film-coated, round tablets, debossed "PD 532" on one side and "20" on the other side. Bottles of 90 tablets.

GD-quinapril 40 mg: Contains 40 mg quinapril per tablet. Brown, film-coated, elliptical tablets, debossed "PD 535" on one side and "40" on the other side. Bottles of 90 tablets.

Composition

GD-quinapril tablets contain 5 mg, 10 mg, 20 mg or 40 mg quinapril per tablet (as the hydrochloride salt). Each tablet also contains candelilla wax, crospovidone, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, magnesium carbonate, magnesium stearate, polyethylene glycol, synthetic red iron oxide and titanium dioxide.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

DRUG SUBSTANCE

Proper Name: Quinapril Hydrochloride

Chemical Name: [3S-[2[R*(R*)],3R*]] 2-[2-[[1-(ethoxycarbonyl)-3- phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3- isoquinolinecarboxylic acid monohydrochloride

Molecular Formula: C₂₅H₃₀N₂O₅.HCl

Molecular Weight: 474.98

Molecular Structure:

Description: Quinapril hydrochloride is a white to off-white amorphous powder that is freely soluble in aqueous solvents. The pH of a 1% solution in distilled water is 2.5.

Solubility: Solvent % w/v solubility at RT

Water >10

0.1N HCl >10

Methanol >5

95% Ethanol >5

Acetone >5

Chloroform >5

PEG 400 >10

Propylene Glycol >10

Dissociation Constants: pK_a1 = 2.8

pK_a2 = 5.4

Partition Coefficients: Medium Log-P

0.1N HCl 0.86

0.05M phosphate buffer, pH 2.5 0.68

0.05M phosphate buffer, pH 4.0 1.35

0.05M phosphate buffer, pH 7.4 0.33

Melting Range: Melts with decomposition, 108-115^oC

DETAILED PHARMACOLOGY

Mechanism of Action

In Vitro Studies: Quinapril was shown to be an inhibitor of angiotensin converting enzyme (ACE) in both plasma and tissue. In assays utilizing human plasma as sources of ACE, the diacid form of quinapril (quinaprilat) exhibited greater inhibition of ACE activity than quinapril (6.4 x 10^-10M and 8.4 x 10^-8M, respectively). In rabbit and rat aortic strips, quinapril (10^-7M , 10^-5M) specifically suppressed the contractile responses elicited by angiotensin I (50% contraction at approximately 10^-7M and 10^-6M angiotensin I, respectively), but had no effect on contractions induced by angiotensin II and potassium chloride.

In Vivo Studies: Following oral dosing of quinapril, captopril or enalapril (0.1- 3 mg/kg) to conscious normotensive rats, plasma ACE inhibition was assessed in vivo by the decrease in pressor response to intravenous (IV) angiotensin I, angiotensin II, norepinephrine and bradykinin. Quinapril produced a dose-dependent reduction (44% at 0.1 mg/kg, 81% at 0.3 mg/kg) of angiotensin I (0.32 μg/kg IV) pressor response and potentiated the response to bradykinin (154% after 0.3 mg/kg quinapril), but had no effect on angiotensin II and norepinephrine responses. Quinapril was equipotent to captopril and enalapril, but had a longer duration of action than captopril. In the conscious dog, oral administration of quinapril (0.1- 3 mg/kg) resulted in plasma ACE inhibition comparable to that of enalapril and captopril.

In human subjects, quinapril at single oral doses of 10- 20 mg/day produced 95- 100% inhibition of plasma ACE activity at 0.5 hour postdose, with >80% inhibition persisting at 24 hours postdose. Multiple oral doses of quinapril to humans for 12-weeks (20- 80 mg/day) confirmed the inhibitory effect on plasma ACE and showed that it produces corresponding decreases in angiotensin II with significant increases in plasma renin activity. Once or 2x daily dosing did not alter the results.

TOXICOLOGY

Acute Toxicity

The acute oral (PO) and intravenous (IV) toxicity of quinapril are summarized in Table 2.

Quinapril showed a low order of acute toxicity. Clinical signs of toxicity in both mice and rats were depression or hypoactivity, prostration and ataxia. Peak mortality occurred within 24 hours in oral studies and within 15 minutes in IV studies. Asymptomatic oral dose levels were 500 mg/kg in mice and 1000 mg/kg in rats.

In the dog study, escalating oral doses of 50- 400 mg/kg were given over 13-consecutive days. Vomiting occurred after doses of ≥150 mg/kg. BPs decreased with increasing dose. At 400 mg/kg, the female had elevated creatinine and blood urea nitrogen (BUN) levels, decreased sodium and chloride levels, and granular casts in the urine. Gastric erosions and ulcers were seen in both animals and renal tubular dilatation was noted in the female.

The results of quinapril toxicity from subacute, chronic, reproductive, genetic, and carcinogenicity studies are given in Tables 3-7, respectively. Table 8 summarizes the results of toxicity studies with quinaprilat, the major active metabolite of quinapril.

Table 7: Carcinogenicity Studies of Quinapril

C. Genotoxicity Studies:

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