Mavik (Trandolapril)

MAVIK™

Knoll

Trandolapril

Angiotensin Converting Enzyme Inhibitor

Action And Clinical Pharmacology: Trandolapril is a nonsulfydryl angiotensin converting enzyme (ACE) inhibitor, which is used in the treatment of mild to moderate essential hypertension and following acute myocardial infarction in stabilized patients with left ventricular dysfunction.

Angiotensin converting enzyme (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 angiotensin converting enzyme 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.

Angiotensin converting enzyme 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 hydrolyzed to its 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 blood pressure is not accompanied by water or sodium retention. No modification was found in the urinary excretion of chloride and potassium. Administration of trandolapril to patients with essential hypertension results in reduction of both supine and standing blood pressure.

Pharmacokinetics: Following a single oral administration of trandolapril 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 to 60% of an administered oral dose of trandolapril is absorbed. Trandolapril undergoes extensive first-pass metabolism in the liver, and this is the reason that its bioavailability is low: 7.5% (ranging from 4 to 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.

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.
In healthy male volunteers the excretion, in urine and feces, of trandolapril following an 8 mg single oral dose of 4-labelled drug is virtually complete after 7 days (99±3%): 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. Over the first 16 to 20 hours following oral administration of trandolapril, there is a rapid elimination phase of trandolaprilat. Beyond this time, there is a prolonged terminal elimination phase. No adjustment in dosage is necessary when elderly patients are treated with trandolapril.

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

In patients with moderate to severe impairment of liver function, plasma trandolapril levels were approximately 10 times 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.

In one study, cirrhotic patients who received a single dose of trandolapril 2 mg exhibited a 9-fold increase in trandolapril Cmax and AUC values. The Cmax and AUC values of trandolaprilat were about doubled.

Pharmacodynamics: Administration of trandolapril to patients with mild to moderate essential hypertension results in a reduction of both supine and standing blood pressure 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).

In mild to moderate hypertensive patients, significant reductions in blood pressure 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 trandolapril has not resulted in rapid increase in blood pressure.

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

The effectiveness of trandolapril appears to be similar in the elderly (over 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 nonblacks.

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

Indications And Clinical Uses: Essential Hypertension: In the treatment of patients with mild to moderate essential hypertension. It may be used alone or in association with thiazide diuretics.

Trandolapril should normally be used in patients in whom treatment with a diuretic or a beta-blocker was found ineffective or has been associated with unacceptable adverse effects.

Trandolapril can also be tried as an initial agent in those patients in whom use of diuretics and/or beta-blockers are contraindicated or in patients with medical conditions in which these drugs frequently cause serious adverse effects.

The safety and efficacy of trandolapril in patients with renovascular hypertension have not been established and therefore, its use in these conditions is not recommended.

Treatment Following Acute Myocardial Infarction: 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 (NYHA class IV) immediately after myocardial infarction is not yet available.

General: In using trandolapril, consideration should be given to the risk of angioedema (see Warnings).

Pregnancy: When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury or even death of the developing fetus. When pregnancy is detected trandolapril should be discontinued as soon as possible (see Warnings, Pregnancy and Information for the Patient).

Contra-Indications: In patients who are hypersensitive to this drug, or to any ingredient in the formulation, or in those patients who have a history of angioedema.

Manufacturers’ Warnings In Clinical States: Angioedema: Angioedema has been reported in patients taking ACE inhibitors, including trandolapril. Angioedema associated with laryngeal involvement may be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, trandolapril 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 to 0.5 mL of s.c. epinephrine solution 1:1 000) should be administered promptly (see Adverse Effects).

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 nonblack patients.

Hypotension: Symptomatic hypotension has occurred after administration of trandolapril, 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 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 could result in a myocardial infarction or cerebrovascular accident (see Adverse Effects). Because of the potential fall in blood pressure in these patients, therapy with trandolapril should be started under close medical supervision. Such patients should be followed closely for the first weeks of treatment and whenever the dose of trandolapril 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 i.v. 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 the blood pressure has increased after volume expansion. However, lower doses of trandolapril 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 trandolapril (see Adverse Effects, Treatment Following Myocardial Infarction, and Dosage, Treatment Following Myocardial Infarction).

Neutropenia/Agranulocytosis: Agranulocytosis and bone marrow depression have been caused by ACE inhibitors. Current experience with trandolapril shows the incidence to be rare. Periodic monitoring of white blood cell counts should be considered, especially in patients with collagen vascular disease and/or renal disease.

Pregnancy : 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, trandolapril should be discontinued as soon as possible.

In rare cases (probably less than 1 in every 1 000 pregnancies) in which no alternative to ACE inhibitor therapy will be found, the mother(s) should be apprised of the potential hazard(s) to her (their) fetus(es). Serial ultrasound examinations should be performed to assess fetal development and well-being and the volume of amniotic fluid.

If oligohydramnios is observed, trandolapril should be discontinued unless it is considered life-saving for the mother. A nonstress 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 the fetus has sustained irreversible injury.

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

Human Data: It is not known whether exposure limited to the first trimester of pregnancy can adversely affect fetal outcome. 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 have also been reported, although it is not clear whether these occurrences were due to the ACE inhibitor exposure.

Animal Data: Teratology studies in the rat were carried out at doses of 0, 100, 300 or 1 000 mg/kg/day. An increased incidence of minor defects (dilation of renal pelvis and ureters) over control values was found at the 1 000 mg/kg/day dose series. In fertility studies, where doses of 0, 1, 10 or 100 mg/kg/day were used, the incidence of pelvic cavitation and dilated ureters was increased with the 10 and 100 mg/kg/day dose.

Teratology studies were carried out in the rabbit both without and with electrolyte supplementation. In 2 studies without supplementation covering the dose range 0.1 to 0.8 mg/kg, 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.

Two teratology studies were carried out in the cynomolgus monkey (doses of 0, 10, 50 or 250 mg/kg/day and also 5, 25 or 125 mg/kg/day): dosing was on days 20 to 50 of gestation with examination of the fetuses following cesarean section on day 100. Abortions were 3/10, 6/10, 5/11 and 7/10 at respectively 0, 10, 50 or 250 mg/kg/day and 1/10, 4/10, 4/10 and 7/10 at 0, 5, 25 or 125 mg/kg/day. Apart from 1 animal with a kinked tail in the group receiving 250 mg/kg/day, no other evidence of teratological effects attributable to treatment were observed.

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.

Use of trandolapril should include appropriate assessment of renal function.

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.

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 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 desensitization 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.

Hyperkalemia and Potassium-sparing Diuretics: Increases in serum potassium (upper limit of normal range 5 mmol/L) were observed in approximately 2.2% of patients in clinical trials treated with trandolapril. 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 may include renal insufficiency, diabetes mellitus, and the concomitant use of agents to treat hypokalemia or other drugs associated with increases in serum potassium (see Precautions, Drug Interactions).

Surgery/Anesthesia: In patients undergoing surgery or anesthesia with agents producing hypotension, trandolapril 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.

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.

Patients with Impaired Liver Function: Trandolapril 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 close monitoring of response and metabolic effects should apply.

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 trandolapril (see Adverse Effects). Should the patient receiving trandolapril 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 trandolapril should be considered when appropriate (see Pharmacology, Pharmacokinetics).

Lactation: Trandolapril is not recommended in nursing mothers as there are no studies available. Following administration of radiolabelled trandolapril to lactating rats, radioactivity was measured in the milk.

Children: The safety and effectiveness of trandolapril in children have not been established; therefore use in this group is not recommended.

Geriatrics: Although clinical experience has not identified differences in response between the elderly (³65 years) and younger patients (
Cough: As with other ACE inhibitors, dry, persistent cough, which usually disappears only after withdrawal or lowering of the dose of trandolapril, has been reported. Such possibility should be considered as part of the differential diagnosis of cough.

Drug Interactions: Alcohol: Alcohol enhances the bioavailability of ACE inhibitors.

Concomitant Diuretic Therapy: Patients concomitantly taking ACE inhibitors and diuretics, and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy. The possibility of adverse hypotensive effects after the first dose of trandolapril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with trandolapril. If it is not possible to discontinue the diuretic, the starting dose of trandolapril should be reduced and the patient should be closely observed for several hours following the initial dose until blood pressure has stabilized (see Warnings and Dosage).

Agents Increasing Serum Potassium: Since trandolapril decreases aldosterone production, elevation of serum potassium may occur. Potassium sparing diuretics such as spironolactone, triamterene or amiloride, or potassium supplements should be given only for documented hypokalemia and with caution and frequent monitoring of serum potassium, since a significant increase in serum potassium could occur.

Salt substitutes which contain potassium should be used with caution.

Agents Causing Renin Release: The antihypertensive effect of trandolapril is augmented by antihypertensive agents that cause renin release (e.g., diuretics).

Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concurrently ACE inhibitors and lithium. Lithium based drugs should be administered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be further increased.

Antacids: They decrease the bioavailability of ACE inhibitors (it is recommended to ingest these products separately).

Digoxin: In one open-label study conducted in 8 healthy male volunteers, in which multiple therapeutic doses of both trandolapril and digoxin were administered, no changes were found in serum levels of trandolapril, trandolaprilat and digoxin. Pharmacodynamically the combination had a synergistic effect on left ventricular functions, as evidenced by the improvement in systolic time-intervals.

Warfarin: In a multidose, double-blind, placebo-controlled, pharmacodynamic interaction study with 20 healthy volunteers administered trandolapril (2 mg) and therapeutic doses of warfarin, no clinically significant effects on the anticoagulant properties of warfarin were found.

Nifedipine SR: A study evaluating the potential pharmacokinetic and pharmacodynamic interaction between nifedipine (20 mg) (sustained release) and trandolapril (4 mg) was conducted in 12 healthy male volunteers. After a single dose, no pharmacokinetic or pharmacodynamic interaction was found between the two products.

Nonsteroidal Anti-inflammatory Agents: The antihypertensive effects of ACE inhibitors may be reduced with concomitant administration of nonsteroidal anti-inflammatory agents. As with other ACE inhibitors, the combination of trandolapril with nonsteroidal anti-inflammatory agents predisposes to a risk of hyperkalemia particularly in cases of renal failure.

Allopurinol, Cytostatic, Immunosuppressive Agents, Systemic Corticosteroids or Procainamide: Concomitant administration with ACE inhibitors may lead to an increased risk of leukopenia.

Information for the Patient: Angioedema: Angioedema, including laryngeal edema, may occur especially following the first dose of trandolapril. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema, such as swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing. They should immediately stop taking trandolapril and consult with their physician (see Warnings).

Hypotension: Patients should be cautioned to report lightheadedness, especially during the first few days of trandolapril therapy. If actual syncope occurs, the patients should be told to discontinue the drug and consult with their 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.

Agranulocytosis/Neutropenia: Patients should be told to report promptly to their physician any indication of infection (e.g., sore throat, fever) as this may be a sign of neutropenia (see Warnings and Adverse Effects).

Impaired Liver Function: Patients should be advised to return to their physician if they experience 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 or foods containing potassium without consulting their physician (see Precautions).

Pregnancy: Since the use of trandolapril during pregnancy can cause injury and even death of the developing fetus, patients should be advised to report promptly to their physician if they become pregnant.

Adverse Reactions: Essential Hypertension: The safety experience in controlled and open-label studies includes 1 988 patients with mild to moderate essential hypertension who received trandolapril therapy. Of these, 265 patients were 65 years of age or older. In placebo and active drug-controlled trials, 1 409 patients received trandolapril. In open-label trials, 1 098 received trandolapril therapy, of which 212 continued treatment for 24 months, 689 for at least 12 months, and 911 for at least 6 months.

Severe adverse events occurring in controlled clinical trials (n=1 049) with doses of trandolapril ranging from 0.5 mg to 8 mg included headache (1.8%), pharyngitis (1%), nausea (0.3%), dizziness (0.3%), hot flushes (0.3%), bronchitis (0.3%), arthralgia (0.3%), pancreatitis (0.3%), tachycardia (0.2%), stomatitis (0.2%), urinary tract infection (0.2%).

One serious adverse event was judged to be possibly related to trandolapril 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 events ³1%, and premature discontinuations due to these events, in controlled trials (N=1 409), regardless of relationship to treatment.

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.

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

The adverse events with an incidence ³ 3%, occurring in a higher percentage of trandolapril treated patients than in placebo treated patients, regardless of relationship to treatment are presented in Table II. The incidence of premature discontinuations, due to these adverse events, are also presented.

Rash (2.7%), cerebral ischemia (2.6%), thrombocytopenia (2.4%), uremia (2.3%), stomach ulcer (2.2%), diarrhea (2.1%), atrial flutter (1.8%), sepsis (1.0%) and taste perversion (1.0%) were noted to occur in a frequency greater than placebo.

General: Adverse events

Body as a Whole: abnormal feeling, abdominal pain, pain in extremities and myalgia.

Cardiovascular: palpitation, hypotension, chest pain, syncope, hypertension, migraine, tachycardia, edema, angina pectoris myocardial infarction, postural hypotension.

Dermatologic: urticaria, pruritus, rash, pemphigus, Stevens-Johnson syndrome.

Gastrointestinal: vomiting, constipation, dyspepsia, anorexia, hepatitis, pancreatitis, esophagitis.

Nervous: anxiety, depression, paresthesia, sleep disorder, decreased libido, hot flushes, somnolence, insomnia, sweating, tremor, cerebrovascular accident.

Respiratory: dyspnea, epistaxis.

Hematologic: leukopenia, thrombocytopenia, hemolytic anemia.

Metabolic and Nutritional Disorder: edema, peripheral edema.

Urogenital System: kidney failure, urinary tract infection, polyurea.

Other Adverse Events: gout, impotence, tinnitus, abnormal vision, arthralgia, dry mouth, taste disorders, increased sweating, myoclonus, anaphylactoid reactions, glaucoma, leukocytoclastic vasculitis.

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

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.

Clinical Laboratory Test Findings: increased creatinine, increased lactic dehydrogenase, increased alkaline phosphatase, increased blood urea nitrogen, occasional elevation of transaminases, increased bilirubin, hyperglycemia.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: No data are available regarding overdosage of trandolapril in humans. The most likely clinical manifestation would be symptoms attributable to severe hypotension, which should normally be treated by i.v. volume expansion with normal saline. It is not known if trandolapril or trandolaprilat can be removed from the body by hemodialysis.

Dosage And Administration: Essential Hypertension: Dosage must be individualized. Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation and salt restriction. The dosage of other antihypertensive agents being used with trandolapril may need to be adjusted.

The drug may be taken before, during or after meals.

Monotherapy: The recommended initial dosage is 1 mg once daily. Dosage should be adjusted according to blood pressure response at intervals of 2 to 4 weeks up to a maximum of 4 mg once daily. The usual maintenance dose is 1 to 2 mg once daily.

In some patients treated once daily, the antihypertensive effect may diminish towards the end of the dosing interval. 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. If blood pressure is not controlled with trandolapril alone, a diuretic may be added.

Diuretic-treated Patients: Symptomatic hypotension occasionally may occur following the initial dose and is more likely in patients who are currently being treated with a diuretic. The diuretic should, if possible, be discontinued for 2 to 3 days before beginning therapy with trandolapril to reduce the likelihood of hypotension (see Warnings). If the diuretic cannot be discontinued, an initial dose of 0.5 mg trandolapril should be used with careful medical supervision for several hours and until blood pressure has stabilized. The dosage of trandolapril should subsequently be titrated to the optimal response.

Renal Impairment: For patients with a creatinine clearance below 30 mL/min/1.73 m the recommended initial dose is 0.5 mg once daily. Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 1 mg.

In patients with severe renal impairment (creatinine clearance below 10 mL/min/1.73 m a daily dosage of 0.5 mg in a single dose should not be exceeded.

Liver Impairment: The recommended initial dose is 0.5 mg once daily.

A single oral dose of 2 mg of trandolapril was administered to patients with hepatic cirrhosis. Compared to healthy subjects receiving the same dose, Cmax and AUC values of trandolapril increased by approximately 9 times; Cmax and AUC of trandolaprilat were nearly doubled (see Pharmacology, Pharmacokinetics and Precautions, Patients with Impaired Liver Function).

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

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

Treatment Following Acute Myocardial Infarction: Dosage should be individualized. Initiation of therapy requires consideration of concomitant medication and baseline blood pressure in hemodynamically stable patients.

A starting dose of 1 mg trandolapril once daily should be initiated no earlier than the third day following acute myocardial infarction in patients with left ventricular dysfunction.

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

After 1 month, patients tolerating the 2 mg once daily dose should have their dosage increased to 4 mg once daily. 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, 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, a starting dose no higher than 0.5 mg once daily should be instituted.

Availability And Storage: 0.5 mg: Each red opaque body and yellow opaque cap, no. 4 gelatin capsule, contains: trandolapril 0.5 mg. Nonmedicinal ingredients: maize starch, lactose, povidone and sodium stearyl fumarate; capsule cap: titanium dioxide and yellow iron oxide; capsule body: erythrosine, titanium dioxide and yellow iron oxide. HDPE plastic bottles of 100.

1 mg: Each red opaque body and orange opaque cap, no. 4 gelatin capsule, contains: trandolapril 1 mg. Nonmedicinal ingredients: maize starch, lactose, povidone and sodium stearyl fumarate; capsule cap: titanium dioxide and yellow iron oxide; capsule body: erythrosine, titanium dioxide and yellow iron oxide. HDPE plastic bottles of 100.

2 mg: Each red opaque body and red opaque cap, no. 4 gelatin capsule, contains: trandolapril 2 mg. Nonmedicinal ingredients: maize starch, lactose, povidone and sodium stearyl fumarate; capsule cap: erythrosine, titanium dioxide and yellow iron oxide; capsule body: erythrosine, titanium dioxide and yellow iron oxide. HDPE plastic bottles of 100.

Store in original container at room temperature, below 25°C and not beyond the date indicated on the container.

MAVIK™ Knoll Trandolapril Angiotensin Converting Enzyme Inhibitor

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