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Trandolapril and Verapamil (Systemic)


VA CLASSIFICATION
Primary: CV401

Commonly used brand name(s): Tarka.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antihypertensive—

Indications

Accepted

Hypertension (treatment)—The combination of trandolapril and verapamil is indicated for the treatment of hypertension {01}. However, it is not indicated for initial treatment of hypertension {01}.
—For additional information on initial therapeutic guidelines related to the treatment of hypertension, see Appendix III.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Trandolapril: 430.54 {01}
    Verapamil hydrochloride: 491.08 {01}

Mechanism of action/Effect:

Trandolapril is a nonsulfhydryl angiotensin-converting enzyme (ACE) inhibitor {01}. It is a prodrug for trandolaprilat, the active metabolite {01}. ACE catalyzes the conversion of angiotensin I to the vasoconstrictor, angiotensin II {01}. Trandolaprilat is thought to lower blood pressure by inhibiting ACE activity {01}. Angiotensin II stimulates secretion of aldosterone and inhibits the release of renin through a negative feedback mechanism {01}. When ACE activity is inhibited, angiotensin II formation is reduced and the interruption of the negative feedback mechanism results in increased plasma renin concentrations {01}. The reduction of angiotensin II formation also decreases aldosterone secretion and vasoconstriction {01}. The decrease in aldosterone secretion produces a slight increase in serum potassium concentrations {01}. Inhibition of ACE by trandolapril is not affected by verapamil {01}.

Verapamil is a calcium channel blocking agent that inhibits the movement of calcium ions across cell membranes of arterial smooth muscle and cardiac muscle {01}. The reduced influx of calcium ions results in a relaxation of arterial smooth muscle and a decrease in the contractility of cardiac muscle cells (a negative inotropic effect) {01}. Blood pressure is reduced with no change in heart rate {01}. Verapamil reduces afterload, dilates the main coronary arteries and arterioles, and inhibits coronary artery spasm {01}. The negative inotropic effect is offset by the decrease in afterload and a reflex increase in adrenergic tone {01}. The inhibition of calcium ion movement also results in prolongation of the atrioventricular (AV) nodal effective refractory period and slowed AV conduction {01}. However, verapamil may shorten the antegrade effective refractory period of accessory bypass tracts {01}. The cardiac conduction effects of verapamil are not altered by trandolapril {01}.

When trandolapril is given in combination with verapamil, the antihypertensive effects are additive {01}.


Other actions/effects:

ACE is also known as kininase II, an enzyme that degrades bradykinin {01}. Therefore, trandolapril may increase concentrations of bradykinin, producing a therapeutic vasodilating effect {01}.

Absorption:

Trandolapril—Absolute bioavailability, approximately 10% {01}.

Verapamil—Absolute bioavailability, range 20 to 35% {01}. The area under the plasma concentration–time curve (AUC) for verapamil increases by approximately 65% when 4 mg of trandolapril is given in combination with 240 mg of extended-release verapamil {01}.

Food decreases the bioavailability of verapamil, but does not alter the bioavailability of trandolapril {01}.

Protein binding:

Trandolapril—High (80%), concentration-independent {01}.

Trandolaprilat—High (range, 65 to 94%), concentration-dependent {01}.

Verapamil—High (90%) {01}.

Biotransformation:

Trandolapril—Converted primarily in the liver (de-esterified) to its active metabolite, trandolaprilat {01}. Trandolaprilat is approximately eight times more potent than trandolapril {01}.

Verapamil—Extensively metabolized in the liver, producing 12 metabolites {01}. The primary active metabolite of verapamil is norverapamil {01}.

Half-life:


Elimination:

Effective: Trandolaprilat—Approximately 10 hours {01}.

Terminal: Verapamil—6 to 11 hours {01}.

Note: In patients with hepatic function impairment, the elimination half-life of verapamil is prolonged up to 14 to 16 hours {01}.



Time to peak concentration:

When 4 mg of trandolapril is given in combination with 240 mg of extended-release verapamil, the time to peak concentration (C max) for verapamil increases by approximately 54% {01}. Trandolapril's pharmacokinetics are not affected by concurrent administration of verapamil {01}.


Trandolapril:

0.5 to 2 hours {01}.



Trandolaprilat:

2 to 12 hours {01}.



Verapamil:

4 to 15 hours {01}; food delays the time to peak concentration by approximately 7 hours {01}.


Elimination:


Trandolapril—
        Renal: Approximately 33% {01}.
        Fecal: Approximately 66% {01}.



Verapamil—
        Renal: Approximately 70% {01}.
        Fecal: Approximately 16% {01}.



In dialysis—
        Verapamil: Not removable by hemodialysis {01}.
        Trandolapril or trandolaprilat: It is not known if removable by hemodialysis {01}.



Precautions to Consider

Cross-sensitivity and/or related problems

Patients hypersensitive to other angiotensin-converting enzyme (ACE) inhibitors may also be hypersensitive to trandolapril {01}.

Carcinogenicity

No evidence of carcinogenicity was found in long-term studies with trandolapril in mice and rats given oral doses of 25 mg per kg (mg/kg) of body weight (85 mg per square meter of body surface area [mg/m 2]) per day and 8 mg/kg (60 mg/m 2) per day, respectively {01}. Assuming a 50-kg individual, these doses represent 313 and 32 times for mice, and 100 and 23 times for rats, the maximum recommended human daily dose (MRHDD) of 4 mg based on body weight and body surface area, respectively {01}.

No evidence of carcinogenicity was found in 2-year studies with verapamil in rats at dietary doses of 10, 35, and 120 mg/kg per day or approximately 1, 3.5, and 12 times the MRHDD (480 mg or 9.6 mg/kg per day), respectively {01}.

Tumorigenicity

Tumorigenic potential was not found in an 18-month study with verapamil in rats given a low (sixfold) multiple of the maximum recommended human dose, but not the maximum tolerated dose, of verapamil {01}.

Mutagenicity

Mutagenicity was not detected for trandolapril in the Ames test, the point mutation and chromosome aberration assays in Chinese hamster V79 cells, and the micronucleus test in mice {01}.

Mutagenicity was not detected for verapamil in the Ames test, in five test strains at 3 mg per plate, with or without metabolic activation {01}.

Pregnancy/Reproduction
Fertility—
No impairment of fertility was found in rats administered doses of trandolapril of up to 100 mg/kg (710 mg/m 2) per day, or 1250 and 260 times the MRHDD based on body weight and body surface area, respectively {01}.

No impairment of fertility was found in female rats administered dietary doses of verapamil up to 55 mg/kg per day, which is 5.5 times the MRHDD {01}. Effects of verapamil on male fertility have not been determined {01}.

Pregnancy—
Angiotensin-converting enzyme (ACE) inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women during the second and third trimesters {01}. Trandolapril and verapamil combination should be discontinued as soon as possible when pregnancy is detected unless no alternative therapy can be used {01}. In the latter instance, serial ultrasound examinations should be performed to assess the intra-amniotic environment {01}. If oligohydramnios is observed, trandolapril and verapamil combination should be discontinued unless it is considered lifesaving for the mother {01}. Perinatal diagnostics, such as contraction-stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may also be appropriate during the applicable week of pregnancy {01}. Oligohydramnios may not appear until after the fetus has sustained irreversible damage {01}.

Fetal exposure to ACE inhibitors during the second and third trimesters can cause hypotension, reversible or irreversible renal failure, anuria, neonatal skull hypoplasia, and death in the fetus or neonate {01}. Maternal oligohydramnios, which may result from decreased fetal renal function, has been reported and associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development {01}. Other adverse effects that have been reported are prematurity, intrauterine growth retardation, and patent ductus arteriosus, although how these occurrences are related to ACE inhibitor exposure is not clear {01}. These adverse effects do not appear to be associated with intrauterine ACE inhibitor exposure limited to the first trimester {01}.

Infants exposed in utero to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia {01}. Oliguria should be treated with support of blood pressure and renal perfusion {01}. Dialysis or exchange transfusion may be necessary to reverse hypotension and/or substitute for disordered renal function {01}.

Teratogenic effects were not observed in rabbits given doses of 0.8 mg/kg per day, in rats given doses of 1000 mg/kg per day, or in monkeys given doses of 25 mg/kg per day of trandolapril {01}. These doses represent 10, 1250, and 312 times the maximum projected human dose by weight (assuming a 50-kg woman), respectively {01}.

FDA Pregnancy Category C (first trimester) {01}.

FDA Pregnancy Category D (second and third trimesters) {01}.

Breast-feeding

Verapamil is distributed into human breast milk {01}. Trandolapril and/or its metabolites are distributed into the milk of lactating rats {01}.

It is recommended that trandolapril and verapamil combination not be administered to women who are breast-feeding {01}.

Pediatrics

No information is available on the relationship of age to the effects of the combination of trandolapril and verapamil in pediatric patients. Safety and efficacy in children younger than 18 years of age have not been established {01}.


Geriatrics


Use of trandolapril and verapamil combination in a limited number of patients 65 years of age and older (23% of patients in placebo-controlled studies) has not demonstrated geriatrics-specific problems that would limit the usefulness of this combination in the elderly {01}. However, when compared with younger individuals, the bioavailability and area under the plasma concentration–time curve (AUC) of verapamil are increased by 87 and 80%, respectively, in the elderly {01}. The bioavailability and AUC of trandolapril are increased by approximately 35% in the elderly {01}. Verapamil clearance is reduced in the elderly, resulting in an increase in elimination half-life {01}. The elderly may also experience greater sensitivity to the drug effects compared with younger individuals {01}.


Pharmacogenetics

Black patients, who may have predominantly low renin hypertension, have responded well to trandolapril therapy {01}.

Surgical

Patients taking an ACE inhibitor and undergoing major surgery or anesthesia with agents that produce hypotension may experience excessive hypotension {01}. If hypotension in these patients is thought to be due to ACE inhibition, it can be corrected by volume expansion {01}. Verapamil may prolong recovery from the neuromuscular blocking agent vecuronium {01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Anesthetics, inhalation{01}    (concurrent use with verapamil has been shown to depress cardiovascular activity in animals by decreasing the inward movement of calcium ions {01}; a dosage adjustment may be necessary {01})


» Beta-adrenergic blocking agents{01} , systemic or ophthalmic    (heart rate, atrioventricular [AV] conduction, and cardiac contractility may be decreased with concurrent verapamil use {01}; asymptomatic bradycardia with a wandering atrial pacemaker in a patient using both timolol eyedrops and oral verapamil has been reported {01}; concurrent use with verapamil should be closely monitored {01})


Carbamazepine{01}    (concurrent use with verapamil may increase carbamazepine serum concentrations {01}; patient may experience carbamazepine side effects, such as diplopia, headache, ataxia, or dizziness {01})


Cimetidine{01}    (concurrent use may decrease clearance of verapamil {01})


Cyclosporine{01}    (concurrent use with verapamil may increase cyclosporine serum concentrations {01})


» Digitalis glycosides{01}    (chronic verapamil therapy may increase serum digoxin concentrations by 50 to 75% {01}; verapamil may reduce total body clearance and extrarenal clearance of digitoxin by 27% and 29%, respectively {01}; the effect of this interaction is magnified in patients with hepatic cirrhosis {01}; the patient should be monitored and the dose of digoxin or digitoxin may need to be reduced or temporarily discontinued {01})


» Disopyramide{01}    (an interaction with verapamil is possible, although information on this interaction is not currently available {01}; it is recommended that disopyramide not be given 48 hours before or 24 hours after trandolapril and verapamil combination administration {01})


» Diuretics{01}    (concurrent use with ACE inhibitors may have additive hypotensive effects {01}; the diuretic may need to be discontinued or salt intake cautiously increased prior to initiation of trandolapril and verapamil combination therapy {01}; the initial combination dose may need to be reduced if it is not possible to discontinue the diuretic {01})


» Diuretics, potassium-sparing{01} or
» Potassium-containing salt substitutes{01} or
» Potassium supplements{01}    (concurrent use with ACE inhibitor therapy may increase the risk of hyperkalemia {01}; serum potassium concentrations should be monitored appropriately {01})


Flecainide{01}    (concurrent use with verapamil may have additive effects on myocardial contractility, AV conduction, and repolarization [resulting in an additive negative inotropic effect and prolongation of AV conduction] {01})


Lithium{01}    (increased sensitivity to the neurotoxic effects of lithium has been reported when used concurrently with trandolapril and verapamil combination {01}; concurrent ACE inhibitor use has resulted in increased serum lithium concentrations and symptoms of lithium toxicity {01}; the risk of lithium toxicity may be increased if a diuretic is also used concurrently {01}; frequent monitoring of serum lithium concentrations is recommended {01})


Neuromuscular blocking agents, especially vecuronium{01}    (concurrent use with verapamil may have an additive neuromuscular blocking effect or prolong recovery from blockade {01}; a dosage adjustment of either drug may be necessary {01})


Phenobarbital{01}    (concurrent use may increase clearance of verapamil {01})


Quinidine{01}    (concurrent use with verapamil has resulted in significant hypotension in a small number of patients with hypertrophic cardiomyopathy [HCM]; therefore, concurrent use is not recommended in these patients {01}; increases in serum concentrations of quinidine have been reported with concurrent verapamil use {01}; quinidine's effects on AV conduction are counteracted by concurrent verapamil use {01})


Rifampin{01}    (concurrent use may reduce bioavailability of oral verapamil {01})


Theophylline{01}    (concurrent use with verapamil may inhibit theophylline clearance and increase serum theophylline concentrations {01})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Liver function tests, including:
Alkaline phosphatase, serum{01} and
Bilirubin, serum{01} and
Lactate dehydrogenase (LDH), serum{01} and
Transaminases, serum{01}    (increases in values may be transient; however, significant increases may be the result of ACE inhibitor– or verapamil-associated hepatotoxicity {01})


Leukocyte count{01} and
Lymphocyte count{01} and
Neutrophil count{01} and
Platelet count{01}    (decreased counts may occur as a result of ACE inhibitor–associated bone marrow depression or agranulocytosis, especially in patients with a collagen-vascular disease or renal function impairment {01})


Potassium, serum{01}    (concentrations may be slightly increased as a result of decreases in aldosterone secretion {01}. In clinical trials, elevated serum potassium concentrations usually were isolated values and resolved despite continued therapy {01}. None of the patients in clinical trials discontinued trandolapril and verapamil combined therapy because of hyperkalemia {01})


Sodium, serum{01}    (concentrations may be slightly decreased {01})


Blood urea nitrogen (BUN){01} and
Creatinine, serum{01}    (increases in concentrations may occur, especially in patients with renal insufficiency, diuretic pretreatment, and renal artery stenosis {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under extraordinary circumstances, this medication should not be used when the following medical problems exist:
» Accessory bypass tract accompanied by atrial flutter or fibrillation{01}    (patients receiving intravenous verapamil have developed a rapid ventricular response or ventricular fibrillation as a result of an increase in antegrade conduction over the accessory pathway, bypassing the AV node {01}. Although this risk has not been established with oral verapamil, it should not be given to these patients {01})


» Angioedema, ACE inhibitor–associated, history of    (increased risk of development of trandolapril-related angioedema {01})


» Atrioventricular (AV) block, second- or third-degree, except in patients with a functioning artificial ventricular pacemaker{01}    (risk of complete AV block with concurrent verapamil use {01})


» Cardiogenic shock{01} or
» Hypotension (systolic pressure less than 90 mm Hg){01}    (concurrent verapamil use may aggravate these conditions {01})


» Hypersensitivity to trandolapril, any other ACE inhibitor, or verapamil{01}
» Left ventricular dysfunction, severe (ejection fraction less than 30%, pulmonary wedge pressure above 20 mm Hg, or severe symptoms of cardiac failure){01} or
» Ventricular dysfunction with concurrent use of a beta-adrenergic blocking agent{01}    (increased risk of further deterioration of ventricular function and of developing congestive heart failure or pulmonary edema with verapamil use {01})


» Sick sinus syndrome, except in patients with a functioning artificial ventricular pacemaker{01}    (verapamil may interfere with sinus node impulse generation and precipitate sinus arrest or sinoatrial block {01})


Risk-benefit should be considered when the following medical problems exist
Collagen vascular disease, such as systemic lupus erythematosus (SLE) or scleroderma{01}    (increased risk of developing agranulocytosis and bone marrow depression with ACE inhibitor therapy {01})


» Congestive heart failure    (verapamil has a negative inotropic effect which may cause a worsening of symptoms, particularly in patients with an impaired inotropic state {01}; patients with or without renal function impairment may experience excessive hypotension as a result of trandolapril therapy {01}; excessive hypotension may be associated with oliguria, azotemia, acute renal failure, and/or death in patients who are particularly susceptible to changes in the renin-angiotensin-aldosterone system {01})


Dehydration (sodium or volume depletion due to excessive perspiration, vomiting, diarrhea, prolonged diuretic therapy, dialysis, or dietary salt restriction{01} )    (increased risk of symptomatic hypotension with trandolapril {01})


Diabetes mellitus{01}    (increased risk of hyperkalemia with ACE inhibitor therapy {01})


Dialysis with high-flux membranes{01} or
Low-density lipoprotein apheresis with dextran sulfate absorption{01}    (anaphylactoid reactions have been reported in patients undergoing these procedures and concurrently taking an ACE inhibitor {01})


Duchenne's muscular dystrophy{01}    (verapamil may decrease neuromuscular transmission {01}; verapamil component dosage may need to be decreased {01})


» Hepatic function impairment{01}    (verapamil elimination half-life may be prolonged and clearance may be decreased due to decreased hepatic metabolism {01}; PR interval may be prolonged or signs of overdosage may be seen with verapamil use {01}; trandolapril and trandolaprilat serum concentrations may be increased. In patients with mild to moderate alcoholic cirrhosis, plasma concentrations of trandolapril and trandolaprilat were ninefold and twofold greater, respectively, than in normal individuals {01}; a dosage adjustment may be necessary {01})


Hymenoptera venom, treatment{01}    (life-threatening anaphylactoid reactions have been reported in two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors {01})


» Hypertrophic cardiomyopathy (HCM), especially in patients refractory to or intolerant of propranolol{01}    (in clinical trials, 120 HCM patients receiving doses of up to 720 mg of verapamil per day experienced serious adverse effects, such as second-degree AV block, pulmonary edema with or without severe hypotension, severe hypotension, sinus arrest, and sinus bradycardia {01}. See Side/Adverse Effects section)


» Renal function impairment{01}    (clearance of verapamil metabolites may be reduced {01}; PR interval may be prolonged or signs of overdosage may be seen with verapamil use {01}; plasma concentrations of trandolapril and trandolaprilat may be increased due to reduced renal clearance {01}; increased risk of developing hyperkalemia {01}; increased risk of developing agranulocytosis and bone marrow depression {01}; increases in blood urea nitrogen [BUN] and serum creatinine concentrations may occur, especially in patients on diuretic therapy {01}; a dosage reduction or discontinuation of the diuretic and/or one or both components of trandolapril and verapamil combination may be necessary {01}; renal function should be monitored during the initiation of therapy {01})


Ventricular dysfunction, mild{01}    (increased risk of worsening ventricular function {01}; this condition should be controlled with digitalis and/or diuretics before treatment with verapamil {01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Blood pressure measurements{01}    (periodic monitoring is necessary for titration of dose according to the patient's response {01})


Electrocardiogram (ECG) determinations{01}    (monitoring for abnormal PR interval prolongation associated with verapamil therapy may be necessary in patients with renal or hepatic function impairment {01})


Leukocyte count determinations{01}    (periodic monitoring may be necessary in patients with a collagen-vascular disease or renal function impairment {01})


Potassium, serum concentrations{01}    (monitoring may be necessary in patients at risk for hyperkalemia, such as those with renal insufficiency, diabetes mellitus, or those concurrently taking potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes {01})


Renal function determinations{01}    (monitoring may be necessary during the first few weeks of therapy in patients with renal function impairment {01})




Side/Adverse Effects

Note: Asymptomatic atrioventricular (AV) block and transient bradycardia, sometimes accompanied by nodal escape rhythms, have occurred with verapamil therapy {01}. This is a result of AV conduction slowing by verapamil {01}. Patients without pre-existing conduction defects treated with verapamil can experience AV block {01}. During the early titration period, prolongation of the PR interval can be correlated with verapamil plasma concentrations {01}. Higher degrees of AV block have infrequently occurred (0.8%) {01}. Verapamil dosage should be reduced or the combination discontinued if marked first-degree AV block or progressive development to second- or third-degree AV block occurs {01}.
In clinical trials, 120 hypertrophic cardiomyopathy (HCM) patients receiving doses of up to 720 mg of verapamil per day experienced serious adverse effects, such as second-degree AV block, pulmonary edema with or without severe hypotension, severe hypotension, sinus arrest, and sinus bradycardia {01}. Most of these patients were refractory to or intolerant of propranolol {01}. Three patients who had severe left ventricular outflow obstruction and a past history of left ventricular dysfunction experienced pulmonary edema and died {01}. Eight other patients who had abnormally high (over 20 mm Hg) capillary wedge pressure and a severe left ventricular outflow obstruction experienced pulmonary edema and/or severe hypotension {01}. Eleven percent of patients experienced sinus bradycardia, 4% experienced second-degree AV block, and 2% experienced sinus arrest {01}. Most adverse effects were minimized by reducing the dosage of verapamil {01}.
Verapamil has caused lenticular and/or suture line changes at doses of 30 mg/kg per day or greater and cataracts at doses of 62.5 mg/kg per day or greater in beagle dogs {01}. These changes did not occur in long-term toxicology studies in rats and have not been reported to occur in humans {01}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence rare
    
Angioedema{01} (sudden trouble in swallowing or breathing; swelling of face, mouth, hands, or feet; hoarseness)
    
bradycardia{01} (slow heartbeat)
    
bronchitis{01} (cough that produces mucus; shortness of breath; wheezing)
    
chest pain{01}
    
dyspnea{01} (difficulty in breathing)
    
edema{01} (generalized swelling)
    
hepatotoxicity{01} (dark urine; fever; malaise; right upper quadrant pain; yellow eyes or skin)
    
hyperkalemia{01} (confusion; irregular heartbeat; nervousness; numbness or tingling in hands, feet, or lips; shortness of breath or difficulty in breathing; weakness or heaviness of legs)—hyperkalemia occurred during clinical trials in approximately 0.4% of trandolapril-treated patients and 0.8% of patients treated with trandolapril and verapamil combined{01}
    
hypotension{01} (lightheadedness or fainting)—hypotension and near-syncope occurred in 0.6% and 0.1% of patients, respectively, in clinical trials{01}
    
neutropenia or agranulocytosis{01} (chills; fever; sore throat)—occurs rarely in uncomplicated hypertension; occurs more frequently in patients with renal function impairment, especially if accompanied by a collagen-vascular disease{01}

Note: Angioedema is associated with ACE inhibitor therapy and may involve the face, extremities, lips, tongue, glottis, or larynx {01}. Angioedema associated with laryngeal edema, resulting in airway obstruction, could be fatal {01}. During clinical trials, angioedema occurred in 0.15% of patients {01}.
Hepatotoxicity has been reported in 3.2% of patients taking trandolapril and verapamil combination {01}. Clinical symptoms of verapamil-associated hepatotoxicity include malaise, fever, and/or right upper quadrant pain {01}. ACE inhibitor–associated hepatotoxicity occurs by a mechanism that is not understood, but is manifest as a syndrome of cholestatic jaundice, fulminant hepatic necrosis, and death {01}. Trandolapril and verapamil combination therapy should be discontinued in patients who develop jaundice {01}. Patients should receive appropriate medical follow-up {01}.




Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Constipation{01}
    
cough, dry, persistent{01}
    
dizziness{01}
    
fatigue{01}

Note: Cough has been reported with ACE inhibitors and is thought to be due to increased concentrations of bradykinin as a result of kininase II inhibition {01}. In clinical trials of combination therapy and trandolapril alone, the incidence of cough was 4.6% and 2%, respectively {01}.


Incidence rare
    
Diarrhea{01}
    
extremity or joint pain{01}
    
nausea{01}
    
pruritus{01} (itching)





Overdose
For specific information on the agents used in the management of trandolapril and verapamil combination overdose, see:    • Atropine in Anticholinergics/Antispasmodics (Systemic) monograph; and/or
   • Dobutamine, dopamine , and/or isoproterenol in Sympathomimetic Agents—Cardiovascular Use (Parenteral-Systemic) monograph


For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing).

Clinical effects of overdose
Acute and chronic

Note: No information is available on the clinical effects of overdose with trandolapril and verapamil combination {01}. However, verapamil overdose has caused conduction system abnormalities, such as junctional rhythm with AV dissociation and high-degree AV block, including asystole {01}. Effects secondary to hypoperfusion, such as convulsions, hyperglycemia, hyperkalemia, metabolic acidosis, and renal dysfunction, may also occur {01}.

The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Bradycardia {01} ( slow heartbeat)
    
hypotension, severe {01} ( dizziness or fainting)


Treatment of overdose


Specific treatment:
Trandolapril overdose is clinically manifest as severe hypotension resulting from the hypotensive effects of vasodilation and hypovolemia {01}. Trandolapril overdose is usually treated by infusion of normal saline solution {01}.

Verapamil overdose has been effectively treated with beta-adrenergic stimulation or parenteral administration of calcium solutions to increase calcium ion flux across the slow channel {01}.
   • For bradycardia and conduction system abnormalities—Atropine, isoproterenol, and cardiac pacing {01}.
   • For cardiac failure—Inotropic agents, such as isoproterenol, dopamine, and dobutamine; and diuretics {01}. Asystole should be managed by appropriate measures, including cardiopulmonary resuscitation {01}.
   • For hypotension—Intravenous fluids, calcium solutions (e.g. 10% calcium chloride injection), and vasopressors, such as dopamine and dobutamine {01}.



Monitoring:
Patients with trandolapril and verapamil combination overdoses should be observed for at least 48 hours under continuous hospital care {01}.

Overdoses with the extended-release formulation of verapamil have been associated with delayed pharmacodynamic effects {01}. Verapamil slows gastrointestinal transit time and has been reported to form concretions within the stomach or intestines {01}. Plain radiographs of the abdomen cannot detect concretions and no form of medical gastrointestinal emptying has proven efficacious in removing them {01}. Endoscopy is a possible method for removing concretions when overdose symptoms are unusually prolonged {01}.

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Trandolapril and Verapamil (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to trandolapril, other angiotensin-converting enzyme (ACE) inhibitors, or verapamil

Pregnancy—ACE inhibitor–associated fetal and neonatal hypotension, skull hypoplasia, renal failure, and death reported in humans





Breast-feeding—Verapamil is distributed into breast milk; use of the combination product is not recommended in nursing mothers





Use in the elderly—Bioavailability and AUC of trandolapril and verapamil are increased; increased elimination half-life of verapamil; elderly patients may experience greater sensitivity to drug effects

Surgical
Anesthesia with hypotension-producing agents may cause excessive hypotension; prolonged recovery from neuromuscular blockade
Other medications, especially beta-adrenergic blocking agents, digitalis glycosides, disopyramide, diuretics, potassium-containing salt substitutes, potassium-sparing diuretics, or potassium supplements
Other medical problems, especially accessory bypass tract accompanied by atrial flutter or fibrillation, cardiogenic shock, congestive heart failure, hepatic function impairment, history of ACE inhibitor–associated angioedema, hypertrophic cardiomyopathy (HCM), hypotension (systolic pressure less than 90 mm Hg), renal function impairment, second- or third-degree atrioventricular (AV) block (except in patients with a functioning artificial ventricular pacemaker), severe left ventricular dysfunction, sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker), and ventricular dysfunction with concurrent beta-adrenergic blocking agent use

Proper use of this medication
» Compliance with therapy; taking medication at the same time each day to maintain the therapeutic effect

Swallowing tablets whole without crushing or chewing

Taking with food

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next scheduled dose; not doubling doses

» Proper storage

Precautions while using this medication
Regular visits to the physician to check progress

Notifying physician immediately if pregnancy is suspected {01}

Not taking other medications, especially potassium supplements or salt substitutes that contain potassium, unless discussed with physician

Caution when driving or doing other things requiring alertness because of possible dizziness, lightheadedness, and syncope due to symptomatic hypotension

Reporting any signs of infection (fever, sore throat, chills) to physician because of risk of neutropenia

Reporting any signs of facial or extremity swelling and difficulty in swallowing or breathing because of risk of angioedema {01}

To prevent dehydration and hypotension, checking with physician if severe nausea, vomiting, or diarrhea occurs and continues

Caution when exercising or during hot weather because of the risk of dehydration and hypotension due to reduced fluid volume

Caution if any kind of surgery (including dental surgery) or emergency treatment is required


Side/adverse effects
Signs of potential side effects, especially angioedema, bradycardia, bronchitis, chest pain, dyspnea, edema, hepatotoxicity, hyperkalemia, hypotension, neutropenia or agranulocytosis


General Dosing Information
Dosage must be adjusted to meet the individual requirements of each patient, on the basis of clinical response.

Combination trandolapril and verapamil therapy should only be used in patients who have failed to achieve the desired antihypertensive effect with one or the other as single therapy at its respective maximally recommended dose and shortest dosing interval, or when the dose of one or the other as single therapy cannot be increased further because of dose-limiting side effects {01}. For dosage ranges for the individual agents when given as single therapy, see    • Trandolapril (Systemic) monograph; and/or
   • Verapamil in Calcium Channel Blocking Agents (Systemic) monograph.


Black patients, who may have predominantly low renin hypertension, have responded well to trandolapril therapy {01}.

Hepatic function impairment prolongs the elimination half-life of verapamil by up to 14 to 16 hours and decreases clearance by as much as 30% {01}. Patients with hepatic function impairment should be administered approximately 30% of the normal dose {01}. In clinical trials, patients with mild to moderate alcoholic cirrhosis had plasma concentrations of trandolapril and trandolaprilat ninefold and twofold greater, respectively, than in normal individuals {01}. A dosage decrease should be considered in these patients {01}.

In patients with a creatinine clearance below 30 mL per min (mL/min) and in hemodialysis patients, the plasma concentrations of trandolapril and trandolaprilat are approximately twofold greater and renal clearance is reduced by about 85% compared with normal individuals {01}.

Diet/Nutrition
Food decreases verapamil bioavailability; however, trandolapril and verapamil combination should be taken with food {01}.

For treatment of adverse effects
Recommended treatment consists of the following:    • For treatment of symptomatic hypotension; the patient should be placed in a supine position and, if necessary, normal saline may be administered intravenously {01}. The individual component dose of trandolapril and/or verapamil or the concurrent diuretic may need to be reduced {01}.
   • For treatment of acute cardiovascular adverse effects, such as severe hypotension or AV block, emergency measures should be initiated; treatment involves intravenous administration of isoproterenol, norepinephrine, atropine, or 10% calcium gluconate solution {01}. In patients with hypertrophic cardiomyopathy (HCM), treatment involves administration of alpha-adrenergic agonists, such as phenylephrine, metaraminol, or methoxamine to maintain blood pressure {01}. Use of isoproterenol and norepinephrine should be avoided in these patients {01}. Inotropic agents such as dopamine or dobutamine may be administered if needed {01}.
   • For treatment of ACE inhibitor–associated angioedema with swelling confined to the face and lips; treatment, other than withdrawal of the medication, is usually not necessary, although antihistamines may relieve the symptoms {01}.
   • Treatment of ACE inhibitor–associated angioedema involving the face, tongue, glottis, and/or larynx may include the following:    —Withdrawal of trandolapril and verapamil combination and close observation of the patient to ensure full resolution of the symptoms {01}.
   —Subcutaneous epinephrine {01}.
   —Corticosteroids {01}.
   —Antihistamines {01}.




Oral Dosage Forms

TRANDOLAPRIL AND VERAPAMIL HYDROCHLORIDE EXTENDED-RELEASE TABLETS

Usual adult dose
Antihypertensive
Oral, 1 or 2 tablets a day, as determined by individual titration with the component agents {01}.


Usual adult prescribing limits
4 mg trandolapril and 240 mg verapamil hydrochloride {01}.

Usual pediatric dose
Safety and efficacy have not been established in patients below 18 years of age {01}.

Strength(s) usually available
U.S.—


1 mg trandolapril in immediate-release form and 240 mg verapamil hydrochloride in extended-release form{01} (Rx) [Tarka]


2 mg trandolapril in immediate-release form and 180 mg verapamil hydrochloride in extended-release form{01} (Rx) [Tarka]


2 mg trandolapril in immediate-release form and 240 mg verapamil hydrochloride in extended-release form{01} (Rx) [Tarka]


4 mg trandolapril in immediate-release form and 240 mg verapamil hydrochloride in extended-release form{01} (Rx) [Tarka]

Packaging and storage:
Store between 15 and 25 ºC (59 and 77 ºF), unless otherwise specified by the manufacturer {01}. Store in a well closed container {01}.

Auxiliary labeling:
   • Do not take other medicines without your doctor's advice {01}.
   • Take with food {01}.



Developed: 08/10/1998



References
  1. Tarka package insert (Knoll–US), Rev 8/96.
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