Mavik Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

MAVIK^® (trandolapril) is indicated for:

• Treatment of Mild to Moderate Essential Hypertension. It may be used alone or in association with thiazide diuretics.

The safety and efficacy of MAVIK^® in patients with renovascular hypertension has not been established, therefore its use in these conditions is not recommended.

• Treatment Following Acute Myocardial Infarction in clinically stable patients with left ventricular dysfunction, with or without symptoms of heart failure, to improve survival and reduce hospitalizations for heart failure.

Sufficient experience in the treatment of patients with severe heart failure [(New York Heart Association (NYHA) Class IV] immediately after myocardial infarction is not yet available.

Geriatrics (≥ 65 years of age):

Although clinical experience has not identified differences in response between the elderly (≥ 65 years) and younger patients (< 65 years), greater sensitivity of some older individuals cannot be ruled out (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics).

Pediatrics (< 18 years of age):

The safety and effectiveness of MAVIK^® in children <18 years of age have not been established. Therefore, MAVIK^® is not indicated in this patient population.

CONTRAINDICATIONS

MAVIK^® (trandolapril) is contraindicated in:

• Patients who are pregnant, planning to become pregnant or of childbearing potential who are not using adequate contraception (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women).
• Nursing women (see WARNINGS AND PRECAUTIONS, Special Populations, Nursing Women).
• Patients who are hypersensitive to this drug, to any other Angiotensin Converting Enzyme (ACE) inhibitor, or to any ingredient in the formulation or component of the container. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING.
• Patients with a history of angioedema associated with administration of an ACE inhibitor.
• Patients with hereditary/ idiopathic angioedema.
• Combination with sacubitril/valsartan due to an increased risk of angioedema. Do not initiate MAVIK^® until at least 36 hours have elapsed following the last dose of sacubitril/valsartan. In the case of a switch from MAVIK^® to sacubitril/valsartan, do not start sacubitril/valsartan until at least 36 hours have elapsed following the last dose of MAVIK^®. (see WARNINGS AND PRECAUTIONS, Immune, Angioedema and DRUG INTERACTIONS, Drug-Drug Interactions).

• Combination with other ACE inhibitors, angiotensin receptor blockers or aliskiren-containing medicines in patients with:

  • ○ diabetes mellitus (type 1 or type 2)
  • ○ moderate to severe renal impairment (GFR < 60 ml/min/1.73m²)
  • ○ hyperkalemia (> 5mMol/L) or
  • ○ congestive heart failure who are hypotensive

(see WARNINGS AND PRECAUTIONS, Dual Blockade of the Renin-Angiotensin-Aldosterone System (RAAS); WARNINGS AND PRECAUTIONS, Renal, Renal Impairment; WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension; and DRUG INTERACTIONS, Table 3).

• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption (see WARNINGS AND PRECAUTIONS, Other, Lactose).
• Patients with hypotensive or hemodynamically unstable states.
• Patients with hemodynamically significant bilateral artery stenosis, or severe stenosis of the artery of a solitary functioning kidney (see WARNINGS AND PRECAUTIONS, Renal).

WARNINGS AND PRECAUTIONS

General

Ability to Operate Machinery

Depending on individual susceptibility, the patients’ ability to drive a vehicle or operate machinery may be impaired, especially in the initial stages of treatment.

Cardiovascular

Hypotension

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

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

If hypotension develops in patients receiving treatment following acute myocardial infarction, consideration should be given to discontinuation of MAVIK^® (see ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions, Treatment Following Acute Myocardial Infarction, and DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, Treatment Following Acute Myocardial Infarction).

Aortic Stenosis

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

Dual Blockade of the Renin-Angiotensin-Aldosterone System (RAAS)

There is evidence that co-administration of angiotensin converting enzyme (ACE) inhibitors, such as MAVIK^®, or of angiotensin II receptor blockers (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); moderate to severe renal impairment (GFR < 60 ml/min/1.73m²); hyperkalemia (> 5 mMol/L) and/or congestive heart failure who are hypotensive. Therefore, the use of MAVIK^® in combination with aliskiren-containing drugs is contraindicated in these patients (see CONTRAINDICATIONS). Further, co-administration of ACE inhibitors, including MAVIK^®, with other agents blocking the RAAS, such as ARBs or aliskiren-containing drugs, is generally not recommended in any patients, since such treatment has been associated with an increased incidence of severe hypotension, renal failure, and hyperkalemia. See CONTRAINDICATIONS, DRUG INTERACTIONS.

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. The concomitant use of ACE inhibitors and angiotensin II receptor blockers (ARBs) in patients with diabetic nephropathy is contraindicated (see CONTRAINDICATIONS).

For additional information, see DRUG INTERACTIONS.

Ear/Nose/Throat

As with other ACE inhibitors, dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose of MAVIK^®, has been reported. Such possibility should be considered as part of the differential diagnosis of cough.

Endocrine and Metabolism

Hyperkalemia and Potassium-Sparing Diuretics

Elevated serum potassium has been observed in hypertensive patients, especially those with renal dysfunction. In clinical trials, increases in serum potassium (upper limit of normal range 5.0 mmol/L) were observed in approximately 2.2% of patients treated with MAVIK^®; in most cases these resolved despite continued therapy. Hyperkalemia was not a cause of discontinuation of therapy in any hypertensive patient. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, the concomitant use of agents to treat hypokalemia or other drugs associated with increases in serum potassium (potassium-sparing diuretics, potassium supplements, potassium containing salt substitutes) and/ or left ventricular dysfunction after myocardial infarction; or the concomitant use of other active substances associated with increases in serum potassium (e.g. co-trimoxazole also known as trimethoprim/sulfamethoxazole). (see DRUG INTERACTIONS, Drug-Drug Interactions).

Hematologic

Neutropenia/agranulocytosis

Agranulocytosis and bone marrow depression have been caused by ACE inhibitors. The risk of neutropenia appears to be dose- and type-related and is dependent on the patient’s clinical status. These reactions are more frequent in patients with renal impairment, especially those with a collagen vascular disease. Current experience with MAVIK^® shows the incidence to be rare. Periodic monitoring of white blood cell counts and protein levels in urine should be considered, especially in patients with collagen vascular disease (e.g., lupus erythematosus and scleroderma) especially associated with impaired renal function and concomitant therapy, particularly with corticosteroids and antimetabolites. It is reversible after discontinuation of the ACE inhibitor.

Hepatic/Biliary/Pancreatic

Patients with Impaired Liver Function

MAVIK^® should be used with caution in patients with pre-existing liver abnormalities. In such patients, baseline liver function tests should be obtained before administration of the drug and response and metabolic effect should be closely monitored.

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

Elevations of liver enzymes and/or serum bilirubin have been reported with MAVIK^® (see ADVERSE REACTIONS). Should the patient receiving MAVIK^® experience any unexplained symptoms, particularly during the first weeks or months of treatment, it is recommended that a full set of liver function tests and any other necessary investigations be carried out. Discontinuation of MAVIK^® should be considered when appropriate (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Insufficiency).

Immune

Angioedema

Angioedema has been reported in patients taking ACE inhibitors, including MAVIK^®. Angioedema associated with laryngeal involvement may be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, MAVIK^® 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. Where there is involvement of tongue, glottis, or larynx, likely to cause airway obstruction, appropriate therapy (including, but not limited to 0.3-0.5 mL of subcutaneous epinephrine solution 1:1000) should be administered promptly (see ADVERSE REACTIONS).

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).

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

The risk for angioedema may be increased in patients taking a concomitant mTOR (mammalian target of rapamycin) inhibitor (e.g. sirolimus, everolimus, temsirolimus) or neutral endopeptidase (NEP) inhibitor. Caution should be used when initiating ACE inhibitor therapy in patients already taking a mTOR, or NEP inhibitor or vice versa. (see DRUG INTERACTIONS Drug-Drug Interactions). Do not initiate MAVIK until at least 36 hours have elapsed following the last dose of sacubitril/valsartan. In the case of a switch from MAVIK to sacubitril/valsartan, do not start sacubitril/valsartan until at least 36 hours have elapsed following the last dose of MAVIK. (see CONTRAINDICATIONS and DRUG INTERACTIONS Drug-Drug Interactions).

Intestinal angioedema has also 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.

Anaphylactoid Reactions during Desensitization

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

Anaphylactoid Reactions during Low-Density Lipoprotein (LDL)-Apharesis

Life-threatening anaphylactoid reactions have been noted when patients on LDL-apharesis with dextran sulfate take ACE inhibitors at the same time. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.

Anaphylactoid Reactions during Membrane Exposure

Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes (e.g., polyacrylonitrile [PAN]) and treated concomitantly with an ACE inhibitor. 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.

Other

Lactose

This medicine contains lactose, therefore patients with rare hereditary forms of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption syndrome should not take this medicine (see CONTRAINDICATIONS).

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 MAVIK^® (see DRUG

INTERACTIONS).

Peri-Operative Considerations

The hypotensive effects of certain inhalation anesthetics may be enhanced by ACE inhibitors. In patients undergoing surgery or anesthesia with agents producing hypotension, MAVIK^® will block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it may be corrected by volume repletion (see DRUG INTERACTIONS, Table 3, Inhalation anesthetics).

Renal

Renal Impairment

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

The use of ACE inhibitors – including MAVIK^®- with aliskiren-containing drugs is contraindicated in patients with moderate to severe renal impairment (GFR < 60 ml/min/1.73m²) (see CONTRAINDICATIONS and DRUG INTERACTIONS, Table 3).

Use of MAVIK^® should include appropriate assessment of renal function.

Special Populations

Pregnant Women

ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected or if the patient is planning to become pregnant, MAVIK^® should be discontinued as soon as possible. MAVIK^® is contraindicated during pregnancy (see CONTRAINDICATIONS).

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 ACE inhibitor 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 BP and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function; however, limited experience with those procedures has not been associated with significant clinical benefit.

It is not known if trandolapril or trandolaprilat can be removed from the body by hemodialysis.

Animal Data

In rats, there was an increased incidence of minor defects (dilation of renal pelvis and ureters) over control values at a dose of 1000 mg/kg/day. The incidence of pelvic cavitation and dilated ureters was increased with the 10 and 100 mg/kg/day dose (see TOXICOLOGY, Reproduction and Teratology).

In two studies without supplementation in rabbits, covering the 0.1 to 0.8 mg/kg dose range, maternal deaths were seen at all doses with a dose-related incidence. These were associated with fetal toxicity and increased fetal loss. No teratological effect was seen. Supplementation with electrolytes allowed doses of 2 to 8 mg/kg to be given: maternal toxicity was again seen, particularly at 8 mg/kg, with weight loss and abortion. No teratological effect was seen.

In cynomolgus monkeys, abortions were 3/10, 6/10, 5/11 and 7/10 at 0, 10, 50 or 250 mg/kg/day respectively, and 1/10, 4/10, 4/10 and 7/10 at 0, 5, 25 or 125 mg/kg/day, respectively, when trandolapril was given from days 20-50 of gestation. Apart from one animal with a kinked tail in the group receiving 250 mg/kg/day, no other evidence of teratological effects attributable to treatment were observed.

Nursing Women

Following administration of radio-labelled trandolapril to lactating rats, radio-labelled trandolapril or its metabolites have been detected in the milk.

The presence of concentrations of ACE inhibitor has been reported in human milk. Use of ACE inhibitors is contraindicated during breast-feeding (see CONTRAINDICATIONS). Alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.

Pediatrics (< 18 years of age)

The safety and effectiveness of MAVIK^® in children <18 years of age have not been established. Therefore, MAVIK^® is not indicated in this patient population.

Geriatrics (≥ 65 years of age)

Although clinical experience has not identified differences in response between the elderly (≥ 65 years) and younger patients (< 65 years), greater sensitivity of some older individuals cannot be ruled out (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Geriatrics).

ADVERSE REACTIONS

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Essential Hypertension

MAVIK^® (trandolapril) was evaluated for safety in double-blind, placebo-controlled and open-label studies, which included 2581 patients with mild to moderate essential hypertension. Of these, 265 patients were ≥65 years of age. A total of 126 patients prematurely discontinued across the various trials due to adverse events (AEs). In long-term open-label trials, 1049 patients received trandolapril therapy, of which 212 continued treatment for 24 months, 689 for ≥12 months, and 911 for ≥6 months.

Severe adverse reactions occurring in long-term clinical trials (n=1049) with doses of trandolapril ranging from 0.5-8 mg included cough (3.9%), headache (2.3%), asthenia (2.1%), dizziness (1.7%), palpitations (0.7%), hypotension (0.5%), nausea (0.5%), pruritus (0.5%), and malaise (0.5%).

One serious adverse reaction was judged to be possibly related to MAVIK^® therapy. This involved a rapid supraventricular arrhythmia with atrial flutter which occurred in a 68 year old male patient with a known history of heart disease.

The adverse reactions (corresponding to possibly, probably or definitely related to treatment) with an incidence ≥ 1% in all double-blind, placebo-controlled trials and open-label Phase 3 hypertension trials (n=2581) are shown in Table 1.

Table 1. Adverse Reactions by Body System (SOC) Patients Receiving Trandolapril in Phase 3 Hypertension Trials ≥ 1%

Treatment Following Acute Myocardial Infarction

In a survival study in patients with left ventricular dysfunction following myocardial infarction, 876 patients randomized to trandolapril, and 873 to placebo, were treated for an average of 2 years. A total of 209 patients prematurely discontinued across the various trials due to AEs.

The most serious adverse reactions occurring more frequently with trandolapril than with placebo included dizziness (2.6%) and hypotension (1.5%). The most frequent clinical adverse reactions occurring more frequently with trandolapril than with placebo were cough, dizziness and hypotension.

The adverse reactions (corresponding to possibly, probably or definitely related to treatment) with an incidence ≥ 1%, occurring in a higher percentage of trandolapril-treated patients than in placebo-treated patients, are presented in Table 2.

Table 2. Adverse Reactions Reported With Trandolapril in Post Myocardial Infarction Patients in Study III (TRACE) That Occurred at a Frequency ≥ 1%

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Rare cases of angioedema affecting the face, extremities, lips, tongue, glottis and/or larynx have been reported in patients treated with ACE inhibitors, including MAVIK^®.

A symptom complex has been reported which may include fever, vasculitis, myalgia, arthralgia/arthritis, a positive anti-nuclear antibody (ANA), elevated erythrocyte sedimentation rate (ESR), eosinophilia and leukocytosis. Rash, photosensitivity or other dermatologic manifestations may also occur.

Abnormal Hematologic and Clinical Chemistry Findings

Clinical Laboratory Test Findings:

Blood creatinine increased, blood alkaline phosphatase increased, blood urea increased, blood lactate dehydrogenase increased, electrocardiogram abnormal, hyperkalemia, hyperuricemia, laboratory test abnormal, liver function test abnormal (aspartate aminotransferase increased, alanine aminotransferase increased, hepatic enzymes increased, blood potassium increased, gamma-glutamyltransferase increased, lipase increased, immunoglobulin increased), platelet count decreased, transaminases increased.

Hematologic Findings:

Hematocrit decreased, and hemoglobin decreased.

Post-Market Adverse Drug Reactions

DRUG INTERACTIONS

Drug-Drug Interactions

Table 3. Established or Potential Drug Interactions Associated with Trandolapril

Drug-Food Interactions

Food

Patients should be told not to use salt substitutes or foods containing potassium without consulting their physician (see WARNINGS AND PRECAUTIONS). Food does not affect the C_max and AUC of trandolapril and trandolaprilat, however food prolongs the T_max of trandolaprilat by approximately 2 hours.

Alcohol

Alcohol enhances the bioavailability of ACE inhibitors and therefore increases the risk of hypotension.

Drug-Herb Interactions

Interactions with herbal products have not been evaluated.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been evaluated.

Drug-Lifestyle Interactions

Interactions with lifestyle have not been evaluated.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Essential Hypertension

Dosage of MAVIK^® (trandolapril) must be individualized. Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of BP elevation and salt restriction. The dosage of other antihypertensive agents being used with MAVIK^® may need to be adjusted. See WARNINGS AND PRECAUTIONS; and DRUG INTERACTIONS.

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, an increase in dose should be considered. If BP is not controlled with MAVIK^® alone, a diuretic may be added.

Diuretic-Treated Patients

Symptomatic hypotension occasionally may occur following the initial dose of MAVIK^® 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 MAVIK^® to reduce the likelihood of hypotension (see WARNINGS AND PRECAUTIONS). If the diuretic cannot be discontinued, an initial dose of 0.5 mg MAVIK^® should be used with careful medical supervision for several hours and until BP has stabilized. The dosage of MAVIK^® should subsequently be titrated to the optimal response.

Recommended Dose and Dosage Adjustment

The recommended initial dosage of MAVIK^® is 1 mg once daily. Dosage should be adjusted according to BP response at intervals of 2-4 weeks up to a maximum of 4 mg once daily. The usual maintenance dose is 1-2 mg once daily.

Dosage in the Elderly

In elderly patients with normal renal and hepatic function, no dosage adjustment is necessary (see WARNINGS AND PRECAUTIONS, Geriatrics).

However, as some elderly patients may be particularly susceptible to ACE inhibitors, administration of low initial doses and evaluation of the BP response and of the renal function at the beginning of the treatment is recommended.

Dosage in Renal Impairment

Creatinine clearance <30 mL/min/1.73 m²: For patients with a creatinine clearance <30 mL/min/1.73 m², the recommended initial dose is 0.5 mg MAVIK^® once daily. Dosage may be titrated upward until BP is controlled or to a maximum total daily dose of 1 mg.

Creatinine clearance <10 mL/min/1.73 m²: In patients with severe renal impairment (creatinine clearance <10 mL/min/1.73 m²), do not exceed a single daily dosage of 0.5 mg.

Dosage in Liver Impairment

The recommended initial dose is 0.5 mg MAVIK^® once daily (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Insufficiency).

Treatment Following Acute Myocardial Infarction

Dosage should be individualized. Initiation of therapy requires consideration of concomitant medication and baseline BP in hemodynamically stable patients.

≥3 days following acute myocardial infarction in patients with left ventricular dysfunction: Start with a dose of 1 mg MAVIK^® once daily.

After 2 days at 1 mg once daily: Increase the dose to 2 mg once daily. For patients who cannot tolerate this dose, the 1 mg once daily dose can be maintained.

After 1 month: Increase dosage to 4 mg once daily in patients tolerating the 2 mg once daily dose. Again, for patients who cannot tolerate the 4 mg once daily dose, the 2 mg once daily dose can be maintained.

The dose must be reduced when it is clinically necessary (see WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension). If hypotension preventing the patient from standing or walking is observed and is not explained by other factors, the dose must be reduced.

For patients with renal or liver impairment, institute a starting dose no higher than 0.5 mg once daily.

Missed Dose

If the patient forgets to take a capsule, he should take one as soon as he remembers, if he remembers on the same day. If not, he should not take the missed capsule at all. He should wait until it is time to take the next dose. He should never double-up on a dose to make up for the one he has missed.

Administration

MAVIK^® may be taken before, during or after meals (see DRUG INTERACTIONS, Drug-Food Interactions).

OVERDOSAGE

Limited data are available regarding overdosage of MAVIK^® (trandolapril) in humans. The most likely clinical manifestation of overdosage of an ACE inhibitor such as MAVIK^® would be symptoms attributable to severe hypotension which should normally be treated by intravenous volume expansion with normal saline. After ingestion of an overdose of trandolapril capsules, total intestinal lavage should be considered.

Blood pressure should be monitored and if hypotension develops, volume expansion should be considered. There is no specific antidote for trandolapril overdose. Symptoms expected with ACE inhibitor also include: shock, stupor, bradycardia, electrolyte disturbance and renal failure. It is not known if trandolapril or trandolaprilat can be removed from the body by hemodialysis.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

MAVIK^® (trandolapril) is a non-sulphydryl angiotensin converting enzyme (ACE) inhibitor.

ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the pharmacologically active substance, angiotensin II, which is a vasopressor agent. In addition, angiotensin II stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in a decreased plasma angiotensin II level. The resulting lack of negative feedback on renal renin secretion leads to an increased plasma renin activity.

ACE is identical to kininase II. Thus, trandolapril administration may interfere with the degradation of the potent peptide vasodilator bradykinin, which may contribute to the therapeutic activity of trandolapril. Trandolapril is a prodrug, which is hydrolysed to its active diacid form, trandolaprilat, a potent ACE inhibitor.

The antihypertensive effect of trandolapril is due to a reduction in peripheral vascular resistance with little or no change in cardiac output and heart rate. The decrease in BP is not accompanied by water or sodium retention. No modification was found in the urinary excretion of chloride and potassium.

Pharmacodynamics

Administration of MAVIK^® to patients with mild to moderate essential hypertension results in a reduction of both supine and standing BP usually with little or no orthostatic change or change in heart rate. Symptomatic postural hypotension is infrequent, although this may occur in patients who are salt- and/or volume-depleted (see WARNINGS AND PRECAUTIONS).

In mild to moderate hypertensive patients, significant reductions in BP were seen at 2 hours, and peak antihypertensive effects were seen after approximately 8 hours. At the recommended doses, antihypertensive effects are maintained throughout the 24-hour dosing interval in most patients who responded to trandolapril. Abrupt withdrawal of MAVIK^® has not resulted in rapid increase in BP.

Following single oral therapeutic doses in healthy male volunteers, a rapid onset of ACE inhibition was observed. The peak inhibition was reached between 2-4 hours after the initial dose.

The effectiveness of MAVIK^® appears to be similar in the elderly (≥ 65 years of age) and younger adult patients given the same daily doses.

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

The antihypertensive effect of MAVIK^® and thiazide diuretics used concurrently is greater than that seen with either drug used alone.

Pharmacokinetics

Absorption

Following a single oral administration of MAVIK^® to healthy volunteers, trandolapril was detectable in the plasma 30 minutes later with peak concentrations reached within 1 hour. Trandolaprilat, the active metabolite, reached peak plasma concentrations after approximately

6 hours. Plasma concentrations of both trandolapril and trandolaprilat were dose dependent. While food can delay the rate of absorption of trandolapril, there is no clinically significant effect on other pharmacokinetic and pharmacodynamic parameters of trandolaprilat.

Approximately 40-60% of an administered oral dose of trandolapril is absorbed.

Distribution

Eighty percent (80%) of the circulating trandolapril and ≤94% of the circulating trandolaprilat are bound to plasma proteins. The protein binding is not saturable for trandolapril but is saturable for trandolaprilat.

Metabolism

Trandolapril undergoes extensive first-pass metabolism in the liver, and this is the reason for its low bioavailability: 7.5% (ranging from 4-14%). In the liver it is transformed into its biologically active diacid form, trandolaprilat. Trandolaprilat itself is poorly absorbed after oral administration. Minor metabolic pathways lead to the formation of diketopiperazine derivatives of trandolapril and trandolaprilat. These molecules have no ACE inhibitory activity. Glucuronide conjugated derivatives of trandolapril and trandolaprilat are also produced.

Excretion

With once-daily dosing, a steady-state of trandolaprilat plasma concentrations is reached within 4 days in healthy male and female subjects as well as in patients with chronic renal failure. Similar results were found in young (< 65 years) as well as old (≥ 65 years) male and female patients suffering from mild to moderate essential hypertension. As is the case with several other ACE inhibitors, trandolaprilat has a polyphasic elimination profile with a slow terminal phase, probably the result of binding to ACE and a subsequently slow dissociation from the enzyme. Over the first 16-20 hours following oral administration of MAVIK^®, there is a rapid elimination phase of trandolaprilat. Beyond this time, there is a prolonged terminal elimination phase. The effective half-life (t_½) for accumulation of trandolaprilat has been estimated to be in the range of 16-24 hours. The accumulation ratio as measured in hypertensive patients was about 1.5. Trandolapril’s elimination half-life (t_½) is on average 0.7 hours.

In healthy male volunteers the excretion, in urine and feces, of trandolapril following an 8 mg single oral dose of 14C-labelled drug is virtually complete after 7 days (99.2 ± 3.4%): 82% of the dose was eliminated in 48 hours and 93% of the dose in 72 hours. In this dual route of excretion, urinary and fecal recoveries accounted for 33% and 66% of the total excretion, respectively. Trandolaprilat represents 46% of the urinary and 57% of the fecal excretion. The glucuronide derivatives of trandolapril and trandolaprilat excreted represent each about 13% of total urinary excretion and, 2% and 4% of total fecal excretion. The diketopiperazine of trandolaprilat was 7% of the total urinary excretion. The amounts of trandolapril excreted unchanged and the corresponding diketopiperazine are negligible (< 0.5% of the dose).

Renal clearance of trandolaprilat varies depending on dose, as seen in Table 4.

Table 4. Renal Clearance of Trandolaprilat after a Single Oral Administration of Trandolapril to Healthy Subjects

Special Populations and Conditions

Pediatrics (<18 years of age)

Trandolapril pharmacokinetics has not been evaluated in patients <18 years of age.

Geriatrics

No data is available.

Gender

No data is available.

Race

Ethnic differences: In African American patients, ACE-inhibitors are less effective in lowering blood pressure than in Caucasian patients.

Hepatic Insufficiency

In patients with moderate to severe impairment of liver function, plasma trandolapril levels were approximately 10x higher than in healthy subjects. The plasma concentrations of trandolaprilat and the quantities excreted in the urine were also increased, although to a lesser degree. The dose should therefore be reduced in these patients (see DOSAGE AND ADMINISRTATION).

In one study, cirrhotic patients who received a single dose of MAVIK^® 2 mg exhibited a 9-fold increase in trandolapril C_max and AUC values compared to healthy subjects. The C_max and AUC values of trandolaprilat were about doubled (see DOSAGE AND ADMINISRTATION).

Renal Insufficiency

In patients with creatinine clearance ≤ 30 mL/min/1.73m², the C_max and AUC of trandolaprilat were approximately doubled after repeated oral administration, as compared to those of normal subjects.

Genetic Polymorphism

No data is available.

STORAGE AND STABILITY

Store MAVIK^® (trandolapril) between 15º-25ºC in its original container. MAVIK^® should not be stored beyond the date indicated on the container.

DOSAGE FORMS, COMPOSITION AND PACKAGING

MAVIK^® capsules are formulated for oral administration and contain trandolapril as medicinal ingredient.

MAVIK^® 0.5 mg capsules: red opaque body, yellow opaque cap, size no. 4 capsules.

MAVIK^® 1.0 mg capsules: red opaque body, orange opaque cap, size no. 4 capsules.

MAVIK^® 2.0 mg capsules: red opaque body, red opaque cap, size no. 4 capsules.

MAVIK^® 4.0 mg capsules: red opaque body, maroon opaque cap, size no. 2 capsules.

All MAVIK^® dosages are available in HDPE plastic bottles of 100, or blister-packs.

Medicinal Ingredients

MAVIK^® capsules 0.5 mg. 1.0 mg, 2.0 mg and 4.0 mg contain the medicinal ingredient trandolapril in quantities of 0.5 mg, 1.0 mg, 2.0 mg and 4.0 mg, respectively.

Listing of Non-Medicinal Ingredients

Each MAVIK^® capsule contains the following non-medicinal ingredients: lactose, maize starch, povidone and sodium stearyl fumarate (as filler and gliding agents), and empty gelatin capsules.

Empty gelatin capsules for all potencies of trandolapril are composed of gelatin NF and colouring agents specific to each potency (see Table 5 below).

Table 5. Composition of Empty Gelatin Capsules for All Trandolapril Strengths

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Proper name:	Trandolapril
Chemical name:	(2S, 3aR, 7aS)-1-[(S)-N-[(S)-1-(ethoxycarbonyl)-3-phenylpropyl] alanyl] hexahydro-2-indolinecarboxylic acid
Molecular formula and molecular mass:	C24H34N2O5	430.5
Structural formula:
Physicochemical properties:	White crystalline powder with a melting point of approximately 125°C and a pKa=5.6. Practically insoluble in water, and freely soluble in chloroform, dichloromethane and methanol. It is free of odour with a bitter taste.

CLINICAL TRIALS

Study Demographics and Trial Design

Hypertension

Table 6. Summary of Patient Demographics for Clinical Trials in Patients with Mild to Moderate Essential Hypertension

Left Ventricular Dysfunction Following Acute Myocardial Infarction

Table 7. Summary of Patient Demographics for Study III (TRACE) in Patients with Left Ventricular Dysfunction Following Acute Myocardial Infarction

Study Results

Hypertension

Studies I and II compared the efficacy and tolerance of trandolapril to placebo. Trandolapril administered once daily at doses of 1 mg, 2 mg and 4 mg for 4-6 weeks was effective at lowering average trough supine diastolic blood pressure (DBP) in non-black patients with mild to moderate essential hypertension.

Left Ventricular Dysfunction Following Acute Myocardial Infarction

Table 8. Results of Study III (TRACE) Trial in Patients with Left Ventricular Dysfunction after Acute Myocardial Infarction

It can be seen in Table 8 and Figure 1 that trandolapril provides a statistically significant reduction in death from all causes (final analysis of the intent-to-treat population).

Figure 1. Cumulative Mortality from All Causes among Patients Receiving Trandolapril or Placebo

DETAILED PHARMACOLOGY

Animal

Pharmacodynamics

Mechanism of Action

Table 9 summarizes the trandolapril mechanism of action in animal models.

Table 9. Trandolapril Mechanism of Action

Effects on Blood Pressure

Table 10 summarizes the effects of trandolapril on BP in animal models.

Table 10. Effects of Trandolapril on Blood Pressure

Pharmacokinetics

Table 11 summarizes the pharmacokinetic parameters following oral administration of trandolapril to animals and man.

Table 11. Pharmacokinetic Parameters Following Oral Administration of Trandolapril to Animals and Man

TOXICOLOGY

Acute Toxicity

Table 12 summarizes the species-specific LD50 values for both oral and intraperitoneal administrations of trandolapril.

Table 12. Species-Specific LD50 Values for Both Oral and Intraperitoneal Administrations of Trandolapril

The symptoms observed in mice were: slight hypotonicity, pilo-erection, hunched back, motor incoordination, lethargy, locomotion difficulties and tremors. Deaths occurred within 48 hours after intraperitoneal administration and 3 hours after oral administration. Residual signs of toxicity persisted for a maximum of 3 days. On autopsy macroscopic examination revealed lesions of the liver, lungs and gastrointestinal tract. In rats, pilo-erection and epistaxis were the main clinical signs of toxicity after oral administration. After intraperitoneal administration clinical signs were similar to those found in mice. Autopsy findings included: lung congestion, hemorrhagic appearance of pancreas and internal wall of abdominal cavity, deformation of lobes of liver and hypertrophy of spleen and kidneys. A dose of 200 mg/kg in the dog caused the death of 2/4 animals, 24 hours after administration. Hypotonicity, hypomobility, dehydration and respiratory difficulties were observed in the surviving animals. Autopsy revealed hemorrhagic thymus lesions of the liver, lungs and gastrointestinal tract.

Chronic Toxicity

Table 13 summarizes the chronic toxic1ity results for oral administrations of trandolapril in animals.

Table 13. Summary of Chronic Toxicity Results of Oral Administrations of Trandolapril in Animals

Mutagenicity and Carcinogenicity

Trandolapril was not mutagenic in the Ames microbial mutagen test, the gene conversion test with S. cerevisiae, and in V79 cells. Detection of chromosomal aberrations in human lymphocytes and in Chinese hamster CHO cells as well as the micronucleus test in mice were all negative.

There was no evidence of a carcinogenic effect when trandolapril was administered by gavage for 18 months to male and female CDI mice at doses ≤25 mg/kg/day or to male and female Sprague Dawley rats at doses ≤8 mg/kg/day.

Reproduction and Teratology

Table 14 summarizes the reproduction and teratology results following administrations of trandolapril in animals.

Table 14. Reproduction and Teratology Results Following Administrations of Trandolapril in Animals

REFERENCES

1. 1. Bevan EG, et al. Effect of Renal Function on the Pharmacokinetics and Pharmacodynamics of Trandolapril. Brit J Pharmacol 1992;33 (2): 237p.
2. 2. Brown NL, et al. Angiotensin-converting Enzyme Inhibition, Antihypertensive Activity and Hemodynamic Profile of Trandolapril (RU44570). Eur J Pharmacol 1988;148:79-91.
3. 3. Chevillard C, et al. Cardiovascular Actions and Tissue-converting Enzyme Inhibitory Effects of Chronic Enalapril and Trandolapril Treatment of Spontaneously Hypertensive Rats. J Cardiovasc Pharmacol 1989;14:297-301.
4. 4. Conen H, et al. Pharmacologic Profile of Trandolapril, a New Angiotensin-converting Enzyme Inhibitor. Am Hear J 1993;125:1525-1531.
5. 5. De Ponti F, et al. Pharmacological Activity and Safety of Trandolapril (RU 44570) in Healthy Volunteers. Eur J Clin Pharmacol 1991; 40:149-153.
6. 6. Dutrey-Dupagne C, et al. Effects of the Converting Enzyme Inhibitor Trandolapril on Short-term Variability of Blood Pressure in Essential Hypertension. Clin Auton Res 1991; 1:303-307.
7. 7. Gaillard CA, Leeuw PW. Clinical Experiences with Trandolapril. Am Heart J 1993; 125:1542-1546.
8. 8. Guidicelli JF, et al. Angiotensin-converting Enzyme Inhibition: Systemic and Regional Hemodynamics in Rats and Humans. Am J Hypertens 1991; 4:258S-262S.
9. 9. Køber L, et al. A Clinical Trial of the Angiotensin-converting-Enzyme Inhibition Trandolapril in Patients with Left Ventricular Dysfunction after Myocardial Infarction. N.E. J Med 1995; 333(25):1671-1676.
10. 10. Mancia G, et al. Evaluation of the Antihypertensive Effect of Once-a-day Trandolapril by 24-hour Ambulatory Blood Pressure Monitoring. Am J Cardiol 1992; 70:60D-66D.
11. 11. Nguyen Cong Duc L, Brunner HR. Trandolapril in Hypertension: Overview of a New Angiotensin-converting Enzyme Inhibitor. Am J Cardiol 1992; 70:27D-34D.
12. 12. Patat A, et al. Safety and Tolerance of Single Oral Doses of Trandolapril (RU44570), a New Angiotensin-converting Enzyme Inhibitor. Eur J Clin Pharmacol 1989; 36:17-23.