Tarka (Trandolapril – Verapamil HCl)



Trandolapril – Verapamil HCl


Action And Clinical Pharmacology: Tarka is a formulation containing slow-release verapamil, a phenylalkylamine calcium channel blocker, along with immediate-release trandolapril, an angiotensin converting enzyme (ACE) inhibitor.

Verapamil is a calcium channel blocker that exerts its pharmacologic effects by modulating the influx of ionic calcium across the cell membrane of the arterial smooth muscle as well as in conductile and contractile myocardial cells. Verapamil exerts antihypertensive effects by decreasing systemic vascular resistance, usually without reflex tachycardia. During isometric or dynamic exercise, verapamil does not blunt hemodynamic response in patients with normal ventricular function. Verapamil does not alter total serum calcium levels.

Trandolapril is a pro-drug. Trandolaprilat, its major active metabolite, inhibits ACE in human subjects and in animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the more pharmacologically active substance, angiotensin II. Angiotensin II has vasoconstrictor activity and also stimulates aldosterone secretion by the adrenal cortex.

Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.

ACE is identical to kininase II, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor, play a role in the therapeutic effect of Tarka remains to be elucidated.

Pharmacokinetics and Metabolism: Following a single oral dose of Tarka in healthy subjects, peak plasma concentrations are reached within 0.5 to 2 hours for trandolapril and within 4 to 15 hours for verapamil. Peak plasma concentrations of the active desmethyl metabolite of verapamil, norverapamil, are reached within 5 to 15 hours. Cleavage of the ester group by hydrolysis converts trandolapril to its active diacid metabolite, trandolaprilat, which reaches peak plasma concentrations within 2 to 12 hours.

Trandolaprilat has an effective elimination half-life of approximately 10 hours while that of verapamil, as verapamil SR, is 6 to 11 hours. Steady-state plasma concentrations of the two components are achieved after about a week of once-daily dosing of Tarka. At steady-state, plasma concentrations of verapamil and trandolaprilat are up to 2-fold higher than those observed after a single oral Tarka dose.

Verapamil SR is a racemic mixture consisting of equal portions of the R enantiomer and the S enantiomer. More than 90% of the orally administered dose of verapamil SR is absorbed. Upon oral administration, there is rapid stereo selective biotransformation during the first pass of verapamil through the portal circulation. The S enantiomer is pharmacologically more active than the R enantiomer. There is a nonlinear correlation between the verapamil dose administered and verapamil plasma levels.

In healthy men, orally administered verapamil undergoes extensive metabolism by the cytochrome P450 system. The particular isoenzymes involved are CYP3A4, CYP1A2, and CYP2C family. Thirteen metabolites have been identified in urine. Norverapamil can reach steady-state plasma concentrations approximately equal to those of verapamil itself. The cardiovascular activity of norverapamil appears to be approximately 20% that of verapamil. Approximately 70% of an administered dose is excreted as metabolites in the urine and 16% or more in the feces within 5 days. About 3 to 4% is excreted in the urine as unchanged drug. R-verapamil is 94% bound to plasma albumin, while S-verapamil is 88% bound. In addition, R-verapamil is 92% and S-verapamil 86% bound to alpha-1 acid glycoprotein. The degree of biotransformation during the first pass of verapamil may vary according to the status of the liver in different patient populations. In patients with hepatic insufficiency, metabolism is delayed and elimination half-life prolonged up to 14-16 hours (see Warnings, Hepatic Insufficiency and Dosage).

Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery. Verapamil is excreted in human milk.

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%). 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.

Effect of Food: Administration of Tarka with a high-fat meal does not alter the bioavailability of trandolapril, whereas verapamil peak concentrations and area under the curve (AUC) decrease 42% and 27%, respectively, relative to administration in the fasting state. Norverapamil values are also decreased 22% and 17%, respectively, in the fed state. Food thus decreases verapamil bioavailability, and results in a narrower peak to trough ratio.

Geriatrics: The pharmacokinetics of verapamil and trandolaprilat are significantly different in the elderly (65 years), compared to younger subjects. AUCs are increased approximately 80% with verapamil and 35% with trandolaprilat. In the elderly, verapamil clearance is reduced resulting in increases in elimination half-life (see Precautions, Geriatrics).

Patients with Hepatic Impairment: In patients with hepatic insufficiency, verapamil clearance is reduced by 30% and the elimination half-life is prolonged up to 14 to 16 hours (see Precautions, Patients with Hepatic Impairment and Dosage).

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 1 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.

Patients With Renal Impairment: The results of an i.v. pharmacokinetic study suggest that renal clearance of verapamil may be decreased in patients with renal disease (see Dosage).

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

Pharmacodynamics: Controlled clinical studies have shown that the effects of concurrent use of verapamil SR and trandolapril are additive with respect to lowering systolic and diastolic blood pressure.

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

Indications And Clinical Uses: For the treatment of mild to moderate essential hypertension in patients for whom combination therapy is appropriate.

Tarka is not indicated for initial therapy. Patients in whom trandolapril and verapamil SR are initiated simultaneously can develop symptomatic hypotension (see Warnings, Hypotension).

Patients should be titrated with the individual drugs. If the fixed combination represents the dosage determined by this titration, the use of Tarka may be more convenient in the management of patients. If during maintenance therapy dosage adjustment is necessary, it is advisable to use individual drugs.

Both trandolapril and verapamil SR should normally be used in those patients in whom treatment with a diuretic or a b-blocker were found to be ineffective or were associated with unacceptable adverse effects. They can be tried as initial agents in those patients in whom diuretics and/or b-blockers are contraindicated or in patients with medical conditions in which these drugs frequently cause serious adverse effects.

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

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

Contra-Indications: Tarka is contraindicated due to the verapamil component, in patients with: Complicated myocardial infarction (patients who have ventricular failure manifested by pulmonary congestion). Severe left ventricular dysfunction (see Warnings, Heart Failure). Hypotension (systolic pressure less than 90 mm Hg) or cardiogenic shock. Second or third degree AV block (except in patients with a functioning artificial ventricular pacemaker). Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker). Marked bradycardia. Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff-Parkinson-White, Lown-Ganong-Levine syndromes) (see Warnings, Accessory Bypass Tract). Known hypersensitivity to verapamil.

Tarka is contraindicated due to the trandolapril component, in patients with: A history of angioedema associated with prior angiotensin converting enzyme inhibitor (ACE) therapy. Known hypersensitivity to any angiotensin converting enzyme inhibitor.

Manufacturers’ Warnings In Clinical States: Hypotension: Concomitant therapy with ACE inhibitors and verapamil may result in hypotension. In controlled studies, hypotension was observed in 0.6% of uncomplicated hypertensive patients receiving Tarka. Dizziness occurred more frequently than with placebo (see Adverse Effects). In patients with angina or arrhythmias using antihypertensive drugs, the additional antihypertensive effect of Tarka should be taken into consideration.

Verapamil: Hypotensive symptoms of lethargy and weakness with faintness have been reported following single oral doses of verapamil and even after some months of treatment. In some patients it may be necessary to reduce the dose.

Trandolapril: 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. 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. If symptoms persist, the dosage should be reduced or the drug discontinued.

Heart Failure: Verapamil: Because of the drug’s negative inotropic effect, verapamil should not be used in patients with poorly compensated congestive heart failure, unless the failure is complicated by or caused by a dysrhythmia. If verapamil is used in such patients, they must be digitalized prior to treatment.

It has been reported that digoxin plasma levels may increase with chronic verapamil administration (see Precautions, Drug Interactions : Digitalis) The use of verapamil in the treatment of hypertension is not recommended in patients with heart failure caused by systolic dysfunction.

Trandolapril: Trandolapril, as an ACE inhibitor, may cause excessive hypotension in patients with congestive heart failure (see Warnings, Hypotension).

Conduction Disturbance: Verapamil: Verapamil slows conduction across the AV node and rarely may produce second or third degree AV block, bradycardia and in extreme cases, asystole.

Verapamil causes dose-related suppression of the SA node. In some patients, sinus bradycardia may occur, especially in patients with a sick sinus syndrome (SA nodal disease), which is more common in older patients (see Contraindications).

Bradycardia: Verapamil: The total incidence of bradycardia with verapamil (ventricular rate less than 50 beats/min) was 1.4% in controlled studies. Asystole in patients other than those with sick sinus syndrome is usually of short duration (few seconds or less), with spontaneous return to AV nodal or normal sinus rhythm. If this does not occur promptly, appropriate treatment should be initiated immediately (see Overdose: Symptoms and Treatment).

Accessory Bypass Tract (Wolff-Parkinson-White or Lown-Ganong-Levine): Verapamil: Verapamil may result in significant acceleration of ventricular response during atrial fibrillation or atrial flutter in the Wolff-Parkinson-White (WPW) or Lown-Ganong-Levine syndromes after receiving i.v. verapamil. Although a risk of this occurring with oral verapamil has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is contraindicated (see Contraindications).

Concomitant Use With b-blockers: Verapamil: Generally, oral verapamil should not be given to patients receiving b-blockers since the depressant effects on myocardial contractility, heart rate and AV conduction may be additive. However, in exceptional cases when in the opinion of the physician concomitant use in angina and arrhythmias is considered essential, such use should be instituted gradually under careful supervision. If combined therapy is used, close surveillance of vital signs and clinical status should be carried out and the need for continued concomitant treatment periodically assessed.

Verapamil gives no protection against the dangers of abrupt b-blocker withdrawal and such withdrawal should be done by the gradual reduction of the dose of b-blocker. Then verapamil may be started with the usual dose.

Patients with Hypertrophic Cardiomyopathy: Verapamil: In 120 patients with hypertrophic cardiomyopathy (most of them refractory or intolerant to propranolol) who received therapy with verapamil at doses up to 720 mg/day, a variety of serious adverse effects were seen. Three patients died in pulmonary edema; all had severe left ventricular outflow obstruction and a past history of left ventricular dysfunction. Eight other patients had pulmonary edema and/or severe hypotension; abnormally high (over 20 mm Hg) capillary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. Sinus bradycardia occurred in 11% of the patients, second-degree AV block in 4% and sinus arrest in 2%. It must be appreciated that this group of patients had a serious disease with a high mortality rate. Most adverse effects responded well to dose reduction, but in some cases verapamil use had to be discontinued.

Angioedema: Trandolapril: 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 non-black patients.

Neutropenia/Agranulocytosis: Trandolapril: 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: Trandolapril: ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, Tarka should be discontinued as soon as possible.

The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE-inhibitor exposure.

Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, trandolapril should be discontinued unless it is considered lifesaving for the mother. Contraction stress testing (CST), a nonstress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories 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 disordered renal function; however, limited experience with these procedures has not been associated with significant clinical benefits. It is not known if trandolapril, or trandolaprilat can be removed from the body by hemodialysis.

Elevated Liver Enzymes/Hepatic Failure: Verapamil: Elevations of transaminases, with and without concomitant elevations in alkaline phosphatase and bilirubin, have been reported. Several cases of hepatocellular injury related to verapamil have been proven by rechallenge. Clinical symptoms of malaise, fever, and/or right upper quadrant pain, in addition to elevations of AST, ALT, and alkaline phosphatase have been reported. Periodic monitoring of liver function in patients receiving Tarka is, therefore, prudent.

Trandolapril: In rare instances, ACE inhibitors have been associated with a syndrome of cholestatic jaundice, fulminant hepatic necrosis and death. The mechanism of this syndrome is not understood.

Patients receiving Tarka who develop jaundice should discontinue therapy and receive appropriate medical follow-up.

Precautions: Patients with Hepatic Impairment: In patients with impaired liver function, the elimination half-life of verapamil is prolonged four-fold and the plasma concentrations of trandolapril and, to a lesser extent, of its principle active metabolite, trandolaprilat, are increased (see Pharmacology, Pharmacokinetics and Metabolism). Accordingly, a decreased dosage of Tarka should be used in these patients (see Dosage).

In these patients, careful monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effects should be carried out during Tarka therapy.

Patients with Renal Impairment: Verapamil: About 70% of an administered dose of verapamil is excreted as metabolites in the urine. In 1 study in healthy volunteers, the total body clearance after i.v. administration of verapamil was 12.08 mL/min/kg, while in patients with advanced renal disease it was reduced to 5.33 mL/min/kg. This pharmacokinetic finding suggests that renal clearance of verapamil in patients with renal disease is decreased. In 2 studies with oral verapamil no difference in pharmacokinetics could be demonstrated. Therefore, until further data are available, verapamil should be used with caution in patients with impaired renal function. These patients should be carefully monitored for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effect (see Dosage).

Trandolapril: 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: Trandolapril: 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: Trandolapril: 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: Trandolapril: 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.

Patients with Attenuated (Decreased) Neuromuscular Transmission: Verapamil: It has been reported that verapamil decreases neuromuscular transmission in patients with Duchenne’s muscular dystrophy, and that verapamil prolongs recovery from the neuromuscular blocking agent vecuronium. Accordingly, it may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission (see Precautions, Surgery/Anesthesia).

Surgery/Anesthesia: Trandolapril: In patients undergoing major surgery or during anesthesia with agents that produce 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 can be corrected by volume expansion (see Precautions, Patients with Attenuated (Decreased) Neuromuscular Transmission).

Hyperkalemia and Potassium-sparing Diuretics: In clinical trials, hyperkalemia (serum potassium >6 mEq/L) occurred in approximately 0.4% of hypertensive patients receiving trandolapril and in 0.8% of patients receiving trandolapril concurrently with verapamil SR. In most cases, elevated serum potassium levels were isolated values, which resolved despite continued therapy. None of these patients were discontinued from the trials because of hyperkalemia.

Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes (see Precautions, Drug Interactions : Agents Increasing Serum Potassium).

Cough: Trandolapril: 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.

Geriatrics: 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 to Tarka cannot be ruled out (see Pharmacology, Pharmacokinetics and Metabolism).

Caution should be exercised when verapamil is administered to elderly patients (65 years) especially those prone to developing hypotension or those with a history of cerebrovascular insufficiency (see Dosage). The adverse reactions occurring more frequently include dizziness and constipation. Serious adverse events associated with heart block have occurred in the elderly.

Children: The safety and effectiveness of Tarka in children below the age of 18 have not been established. Therefore, use in this group is not recommended.

Lactation: Tarka is not recommended in these patients because of the potential for adverse reactions in nursing infants. The verapamil component of Tarka is secreted in human milk. Following administration of radio-labeled trandolapril to lactating rats, radioactivity has been detected in the milk.

Labor and Delivery: It is not known whether the use of verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention.

Drug Interactions : As with all drugs, care should be exercised when treating patients with multiple medications. Calcium channel blockers undergo biotransformation by the cytochrome P450 system. Coadministration of verapamil with other drugs which follow the same route of biotransformation may result in altered bioavailability of verapamil or these drugs. Dosages of similarly metabolized drugs, particularly those of low therapeutic ratio, and especially in patients with renal and/or hepatic impairment, may require adjustment when starting or stopping concomitantly administered verapamil to maintain optimum therapeutic blood levels.

Drugs known to be inhibitors of the cytochrome P450 system include: azole antifungals, cimetidine, cyclosporine, erythromycin, quinidine, terfenadine, warfarin.

Drugs known to be inducers of the cytochrome P450 system include: phenobarbital, phenytoin, rifampin.

Drugs known to be biotransformed via P450 include: benzodiazepines, flecainide, imipramine, propafenone, theophylline.

Alcohol: Verapamil may increase blood alcohol concentrations and prolong its effects. Alcohol enhances the bioavailability of ACE inhibitors.

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

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.

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

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

Antidepressants/Major Tranquilizers: As with all antihypertensive agents, there is an elevated risk of orthostatic hypotension when combining Tarka with major tranquilizers or tricyclic antidepressants, such as imipramine.

Antineoplastic Agents: Verapamil inhibits P-glycoprotein mediated transport of antineoplastic agents out of tumor cells, resulting in their decreased metabolic clearance. Dosage adjustments of antineoplastic agents should be considered when verapamil is administered concomitantly.

ASA: Potential adverse reactions in terms of bleeding due to synergistic antiplatelet effects of ASA and verapamil should be taken into consideration in patients taking the 2 agents concomitantly.

b-Blockers: Concomitant therapy with b-adrenergic blockers and verapamil may result in additive negative effects on heart rate, atrioventricular conduction, and/or cardiac contractility.

Asymptomatic bradycardia (<36 beats/min) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a b-adrenergic blocker) eye drops and oral verapamil.

Carbamazepine: The concomitant oral administration of verapamil and carbamazepine may potentiate the effects of carbamazepine neurotoxicity. Symptoms include nausea, diplopia, headache, ataxia or dizziness.

Cimetidine: The interaction between cimetidine and chronically administered verapamil has not been studied. Variable results on clearance have been obtained in acute studies of healthy volunteers; clearance of verapamil was either reduced or unchanged.

Concomitant Diuretic Therapy: Patients concomitantly taking antihypertensive therapy with diuretics, especially those on recently instituted diuretic therapy, may occasionally experience an excessive reduction of blood pressure after initiation of nondiuretic therapy. The possibility of hypotensive effects after initiation of antihypertensive therapy can be minimized by either discontinuing the diuretic or increasing salt intake (except in patients with heart failure) prior to initiation of antihypertensive therapy. If it is not possible to discontinue the diuretic, the initial dose of antihypertensive therapy should be reduced and the patient observed closely for several hours following initiation of therapy (see Warnings, Hypotension and Dosage).

Cyclosporine: Verapamil therapy may increase serum levels of cyclosporine.

Digoxin: Chronic verapamil treatment can increase serum digoxin levels by 50 to 75% during the first week of therapy, and this can result in digoxin toxicity. In patients with hepatic cirrhosis, the influence of verapamil on digoxin kinetics is magnified. Verapamil may reduce total body clearance and extrarenal clearance of digitoxin by 27% and 29%, respectively.

Maintenance digoxin doses should be reduced when verapamil is administered, and the patient should be carefully monitored to avoid over-or underdigitalization. Whenever overdigitalization is suspected, the daily dose of digoxin should be reduced or temporarily discontinued. Upon discontinuation of Tarka, the patient should be reassessed to avoid underdigitalization.

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.

Disopyramide: Data on possible interactions between verapamil and disopyramide are not available. Therefore, disopyramide should not be administered within 48 hours before or 24 hours after Tarka administration.

Flecainide: A study of healthy volunteers showed that the concomitant administration of flecainide and verapamil may have additive effects on myocardial contractility, AV conduction, and repolarization. Concomitant therapy with flecainide and Tarka may result in additive negative inotropic effect and prolongation of AV conduction.

Inhalation Anesthetics: Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil, should be titrated carefully to avoid excessive hemodynamic effects.

Lithium: Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil-lithium therapy with either no change or an increase in serum lithium levels.

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.

Neuromuscular Blocking Agents: Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarizing). It may, therefore, be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly.

Nitrates: No cardiovascular adverse events have been attributed to any interaction between nitrates and verapamil.

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

Phenobarbital: Phenobarbital therapy may increase the clearance of verapamil.

Quinidine: In a small number of patients with hypertrophic cardiomyopathy, concomitant use of verapamil and quinidine resulted in significant hypotension. Until further data are obtained, combined therapy of Tarka and quinidine in patients with hypertrophic cardiomyopathy should be avoided.

The electrophysiological effects of quinidine and verapamil on AV conduction were studied in 8 patients. Verapamil significantly counteracted the effects of quinidine on AV conduction. There has been a report of increased quinidine levels during verapamil therapy.

Rifampin: Therapy with rifampin may markedly reduce oral verapamil bioavailability.

Sulfinpyrazone: Increased clearance and decreased bioavailability of verapamil may occur when administered concomitantly with sulfinpyrazone.

Theophylline: Tarka therapy may inhibit the clearance and increase the plasma levels of theophylline, due to verapamil.

Warfarin: In a multi-dose placebo-controlled pharmacodynamic study in healthy volunteers, the anticoagulant effect of warfarin was not significantly changed by trandolapril.

Adverse Reactions: The combination of trandolapril and verapamil SR has been evaluated in over 1 957 subjects and patients. Of these, 541 patients (including 23% elderly patients) participated in North American placebo-controlled clinical trials, and 251 were studied in European placebo-controlled clinical trials. This combination has been evaluated for long-term safety in 272 patients treated for 1 year or more.

The most frequent adverse events in controlled clinical trials conducted in North America with trandolapril and verapamil SR were (n=541): first degree AV block (3.9%); cough (4.6%); constipation (3.3%) and dizziness (3.1%).

The most serious adverse reactions with Tarka are second degree AV block, angina, hypotension and angioedema.

Discontinuation of therapy because of adverse events in North American placebo-controlled hypertension studies was required in 2.6% and 1.9% of patients treated with Tarka and placebo, respectively.

Hypotension: In hypertensive patients in North American controlled and uncontrolled trials, hypotension occurred in 0.6% and near syncope occurred in 0.1% (possibly, probably or definitely related to combination treatment). Hypotension or syncope was a cause for discontinuation of therapy in 0.4% of hypertensive patients in North American controlled studies (see Warnings, Hypotension).

Other clinical adverse experiences possibly, probably, or definitely related to drug treatment, occurring in 0.3% or more of patients treated with Tarka in controlled, or uncontrolled trials (N=990) and less frequent, clinically significant events (in italics) include the following: Cardiovascular: angina, second degree AV block, bundle branch block , edema, flushing, hypotension, myocardial infarction , palpitations, premature ventricular contractions, nonspecific ST-T changes, near syncope, tachycardia.

CNS: drowsiness, hypesthesia, insomnia, loss of balance, paresthesia, vertigo.

Dermatologic: pruritus , rash.

Emotional, Mental, Sexual States: anxiety, impotence, abnormal mentation .

Eye, Ear, Nose, Throat: epistaxis, tinnitus , upper respiratory tract infection, blurred vision .

Gastrointestinal: dyspepsia, dry mouth, nausea.

General Body Function: chest pain, malaise, weakness.

Genitourinary: endometriosis, hematuria, nocturia, polyuria, proteinuria.

Hemopoietic: decreased leukocytes, decreased neutrophils .

Metabolism and Endocrine Function: increased alkaline phophatase, increased liver enzymes, increased potassium, increased AST.

Musculoskeletal System: arthralgia, myalgia, gout, increased uric acid .

Pulmonary: dyspnea.

Angioedema: Angioedema and/or facial edema has been reported in 3 (0.15%) patients receiving Tarka in North American and European studies (N=1 957). Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis, and/or larynx occurs, treatment with Tarka should be discontinued and appropriate therapy instituted immediately (see Warnings, Angioedema).

In addition to those reported above, other adverse experiences have previously been reported with the individual components, verapamil and trandolapril: Verapamil Component Adverse Reactions: Cardiovascular: CHF/pulmonary edema, third degree AV block, atrioventricular dissociation, claudication, syncope (see Warnings, Hypotension).

Digestive: nausea, gingival hyperplasia, reversible paralytic ileus.

Hemic and Lymphatic: ecchymosis or bruising.

Nervous System: cerebrovascular accident, confusion, psychotic symptoms, shakiness, somnolence.

Skin: exanthema, hair loss, hyperkeratosis, purpura (vasculitis), sweating, urticaria, Stevens-Johnson syndrome, erythema multiforme.

Urogenital: gynecomastia, galactorrhea/hyperprolactinemia, increased urination, spotty menstruation.

Trandolapril Component Adverse Reactions: Body as a Whole: asthenia, abnormal feeling, abdominal pain, pain in extremities.

Cardiovascular: hypertension, migraine, syncope.

Dermatology: urticaria, pemphigus, Stevens-Johnson syndrome.

Gastrointestinal: gastrointestinal pain, gastrointestinal disorder, anorexia, abnormal liver function test, vomiting.

Nervous System: depression, sleep disorder, decreased libido, hot flushes.

Respiratory: bronchitis, pharyngitis.

Other: cramps, increased urinary frequency, edema, taste disorders, anaphylactoid reaction.

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 Testing Findings: Hematology: leukopenia, neutropenia, lymphopenia, thrombocytopenia (see Warnings, Neutropenia/Agranulocytosis).

Serum Electrolytes: hyperkalemia (see Precautions, Hyperkalemia and Potassium-sparing Diuretics), hyponatremia.

Renal Function Tests: Increases in creatinine and blood urea nitrogen levels occurred in 1.1% and 0.3%, respectively, of patients receiving Tarka with or without hydrochlorothiazide therapy. None of these increases required discontinuation of treatment. Increases in these laboratory values are more likely to occur in patients with renal insufficiency or those pretreated with a diuretic and, based on experience with other ACE inhibitors, would be expected to be especially likely in patients with renal artery stenosis (see Precautions, Patients with Renal Impairment).

Liver Function Tests: Elevations of liver enzymes (AST, ALT, LDH, and alkaline phosphatase) and/or serum bilirubin occurred. Discontinuation for elevated liver enzymes occurred in 0.9% of patients (see Warnings, Elevated Liver Enzymes/Hepatic Failure).

Symptoms And Treatment Of Overdose: Symptoms and Treatment: To date, there have been no reports of overdosage of Tarka in humans. Given this absence of practical experience with overdosage, the following is a synopsis of experiences gained with the individual mono-components; mainly with verapamil.

Verapamil Overdosage: Based on reports of intentional overdosage of verapamil, the following symptoms have been observed. Hypotension occurs, varying from transient to severe. Conduction disturbances seen included: prolongation of AV conduction time, AV dissociation, nodal rhythm, ventricular fibrillation and ventricular asystole.

Treatment of overdosage should be supportive. Gastric lavage should be undertaken, even later than 12 hours after ingestion, if no gastrointestinal motility is present. b-adrenergic stimulation or parenteral administration of calcium solutions may increase calcium ion influx across the slow channel.

These pharmacologic interventions have been effectively used in treatment of overdosage with verapamil. Clinically significant hypotensive reactions should be treated with vasopressor agents. AV block is treated with atropine and cardiac pacing. Asystole should be handled by the usual Advanced Cardiac Life Support measures including the use of vasopressor agents, e.g., isoproterenol HCl. Verapamil is not removed by hemodialysis.

In case of overdosage with large amounts of verapamil SR it should be noted that the release of the active drug and the absorption in the intestine may take more than 48 hours. Depending on the time of ingestion, incompletely dissolved tablets may be present along the entire length of the gastrointestinal tract which function as active drug depots. Extensive elimination measures are indicated, such as induced vomiting, removal of the contents of the stomach and the small intestine under endoscopy, intestinal lavage and high enemas.

Actual treatment and dosage should depend on the severity of the clinical situation and the judgment of the treating physician.

Trandolapril Overdosage: The most likely clinical manifestations of overdosage of trandolapril 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.

No data are available to suggest that physiological maneuvers (e.g., maneuvers to change pH of the urine) might accelerate elimination of trandolapril and its metabolites.

Dosage And Administration: Dosage must be individualized. The fixed combination is not for initial therapy. The dose of Tarka should be determined by titration of the individual components.

Tarka tablets should not be divided, crushed or chewed. Tarka should be taken with food (see Pharmacology, Effect of Food).

Once the patient has been successfully titrated with the individual components as described below, Tarka may be substituted if the titrated doses and dosing schedule can be achieved by the fixed combination (see Indications and Warnings, Hypotension). Tarka is available at doses of 1/180 mg, 2/180 mg and 4/240 mg of trandolapril and verapamil SR, respectively.

For Verapamil Monotherapy: The dosage should be individualized by titration depending on patient tolerance and responsiveness to verapamil. Titration should be based on therapeutic efficacy and safety, evaluated weekly and approximately 24 hours after the previous dose.

The usual initial adult dose is 180 to 240 mg/day. If required, the dose may be increased up to 240 mg twice a day. A maximum daily dose of 480 mg should not be exceeded.

The antihypertensive effects of verapamil SR are evident within the first week of therapy. Optimal doses are usually lower in patients also receiving diuretics since additive antihypertensive effects can be expected.

Geriatrics: Lower dosages of verapamil SR, i.e., 120 mg a day, may be warranted in elderly patients (i.e., 65 years and older). The dosage should be carefully and gradually adjusted depending on patient tolerability and response.

Patients with Hepatic and Renal Impairment: Verapamil SR should be administered cautiously to patients with liver or renal function impairment. The dosage should be carefully and gradually adjusted depending on patient tolerance and response. These patients should be monitored carefully for abnormal prolongation of the PR interval or other signs of overdosage. Verapamil SR should not be used in severe hepatic dysfunction (see Precautions, Patients with Hepatic Impairment).

Switching from Verapamil Tablets to Verapamil SR: When switching from verapamil tablets to verapamil SR, the total daily dose in mg may remain the same.

For Trandolapril Monotherapy: The recommended initial dosage for trandolapril 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 toward 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 alone, a diuretic may be added.

Diuretic-treated Patients: Symptomatic hypotension occasionally may occur following the initial dose of trandolapril 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. 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.

Dosage in Renal Impairment: For patients with a creatinine clearance below 30 mL/min/1.73 m the recommended initial dose is 0.5 mg trandolapril 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.

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

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

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.

Availability And Storage: 1/180 mg: Each yellow, oval, film-coated tablet embossed with the Knoll triangle mark and “181” on one side and “TARKA” on the other side, contains: trandolapril 1 mg in an immediate release form and verapamil HCl 180 mg in a sustained release form. Nonmedicinal ingredients: cornstarch, dioctyl sodium sulfosuccinate, ethanol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, purified water, silicon dioxide, sodium alginate, sodium stearyl fumarate, synthetic iron oxides, talc and titanium dioxide. Bottles of 100.

2/180 mg: Each salmon, oval, film-coated tablet embossed with the Knoll triangle and “182” on one side and “TARKA” on the other side, contains: trandolapril 2 mg in an immediate release form and verapamil HCl 180 mg in a sustained release form. Nonmedicinal ingredients: cornstarch, dioctyl sodium sulfosuccinate, ethanol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, purified water, silicon dioxide, sodium alginate, sodium stearyl fumarate, synthetic iron oxides, talc and titanium dioxide. Bottles of 100.

4/240 mg : Each reddish-brown, oval, film-coated tablet embossed with the Knoll triangle and “244” on one side and “TARKA” on the other side, contains: trandolapril 4 mg in an immediate release form and verapamil HCl 240 mg in a sustained release form. Nonmedicinal ingredients: cornstarch, dioctyl sodium sulfosuccinate, ethanol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, purified water, silicon dioxide, sodium alginate, sodium stearyl fumarate, synthetic iron oxides, talc and titanium dioxide. Bottles of 100.

Store at 15 to 25°C. Protect from light and moisture. Do not use beyond the expiry date indicated on the label.

TARKA® Knoll Trandolapril – Verapamil HCl Antihypertensive

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