Trandolapril and Verapamil Hydrochloride 1 mg; 240 mg Tablet, Film Coated, Extended Release, 90-count — NDC 68462-294-90 (Billing 68462-0294-90)

WARNINGS Heart Failure Verapamil Component Verapamil has a negative inotropic effect which, in most patients, is compensated by its afterload reduction (decreased systemic vascular resistance) properties without a net impairment of ventricular performance. In clinical experience with 4,954 patients, 87 (1.8%) developed congestive heart failure or pulmonary edema. Verapamil should be avoided in patients with severe left ventricular dysfunction (e.g., ejection fraction less than 30%, pulmonary wedge pressure above 20 mmHg, or severe symptoms of cardiac failure) and in patients with any degree of ventricular dysfunction if they are receiving a beta adrenergic blocker (see PRECAUTIONS - Drug Interactions ).

Patients with milder ventricular dysfunction should, if possible, be controlled with optimum doses of digitalis and/or diuretics before verapamil treatment (Note interactions with digoxin under: PRECAUTIONS ). Trandolapril Component Trandolapril, as an ACE inhibitor, may cause excessive hypotension in patients with congestive heart failure (see WARNINGS - Hypotension ). Hypotension Verapamil Component Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels which may result in dizziness or symptomatic hypotension.

Trandolapril Component Trandolapril can cause symptomatic hypotension. Like other ACE inhibitors, trandolapril has only rarely been associated with symptomatic hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who are salt- or volume-depleted as a result of prolonged treatment with diuretics, dietary salt restriction, dialysis, diarrhea, or vomiting.

Volume and/or salt depletion should be corrected before initiating treatment with trandolapril (see PRECAUTIONS - Drug Interactions and ADVERSE REACTIONS ). In controlled studies, hypotension was observed in 0.6% of patients receiving any combination of trandolapril and verapamil hydrochloride extended-release. In patients with concomitant congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia, and, rarely, with acute renal failure and death (see DOSAGE AND ADMINISTRATION ).

If symptomatic hypotension occurs, the patient should be placed in the supine position and, if necessary, normal saline may be administered intravenously. A transient hypotensive response is not a contraindication to further doses; however, lower doses of verapamil HCl extended-release and/or trandolapril or reduced concomitant diuretic therapy should be considered. Elevated Liver Enzymes/Hepatic Failure Verapamil Component Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported.

Such elevations have sometimes been transient and may disappear even in the face of continued verapamil treatment. Several cases of hepatocellular injury related to verapamil have been proven by rechallenge; half of these had clinical symptoms (malaise, fever, and/or right upper quadrant pain) in addition to elevations of SGOT, SGPT, and alkaline phosphatase. Trandolapril Component ACE inhibitors rarely have been associated with a syndrome of cholestatic jaundice, fulminant hepatic necrosis, and death.

The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice should discontinue the ACE inhibitor and receive appropriate medical follow-up. Liver abnormalities were noted in 3.2% of patients taking any of several combinations of trandolapril/verapamil doses.

Periodic monitoring of liver function in patients taking trandolapril and verapamil hydrochloride extended-release tablets is therefore prudent. Accessory Bypass Tract (Wolff-Parkinson-White or Lown-Ganong-Levine Syndromes) Verapamil Component Some patients with paroxysmal and/or chronic atrial fibrillation or atrial flutter… [Excerpted — this section continues on DailyMed.]

ADVERSE REACTIONS Trandolapril and verapamil hydrochloride extended-release tablets have been evaluated in over 1,957 subjects and patients. Of these, 541 patients, including 23% elderly patients, participated in U.S. controlled clinical trials, and 251 were studied in foreign controlled clinical trials. In clinical trials with trandolapril and verapamil hydrochloride extended-release tablets, no adverse experiences peculiar to this combination drug have been observed.

Adverse experiences that have occurred have been limited to those that have been previously reported with verapamil or trandolapril. Trandolapril and verapamil hydrochloride extended-release tablets have been evaluated for long-term safety in 272 patients treated for 1 year or more. Adverse experiences were usually mild and transient.

Discontinuation of therapy because of adverse events in U.S. placebo-controlled hypertension studies was required in 2.6% and 1.9% of patients treated with trandolapril and verapamil hydrochloride extended-release tablets and placebo, respectively. Adverse experiences occurring in 1% or more of the 541 patients in placebo-controlled hypertension trials who were treated with a range of trandolapril (0.5 to 8 mg) and verapamil (120 to 240 mg) combinations are shown below. ADVERSE EVENTS OCCURRING IN ≥ 1% OF TRANDOLAPRIL AND VERAPAMIL HYDROCHLORIDE EXTENDED-RELEASE TABLETS PATIENTS IN U.S.

PLACEBO-CONTROLLED TRIALS Trandolapril and Verapamil Hydrochloride Extended-Release Tablets (N = 541) % Incidence (% Discontinuance) PLACEBO (N = 206) % Incidence (% Discontinuance) AV Block First Degree 3.9 (0.2) 0.5 (0) Bradycardia 1.8 (0) 0 (0) Bronchitis 1.5 (0) 0.5 (0) Chest Pain 2.2 (0) 1 (0) Constipation 3.3 (0) 1 (0) Cough 4.6 (0) 2.4 (0) Diarrhea 1.5 (0.2) 1 (0) Dizziness 3.1 (0) 1.9 (0.5) Dyspnea 1.3 (0.4) 0 (0) Edema 1.3 (0) 2.4 (0) Fatigue 2.8 (0.4) 2.4 (0) Headache(s) + 8.9 (0) 9.7 (0.5) Increased Liver Enzymes* 2.8 (0.2) 1 (0) Nausea 1.5 (0.2) 0.5 (0) Pain Extremity(ies) 1.1 (0.2) 0.5 (0) Pain Back + 2.2 (0) 2.4 (0) Pain Joint(s) 1.7 (0) 1 (0) Upper Respiratory Tract Infection(s) + 5.4 (0) 7.8 (0) Upper Respiratory Tract Congestion + 2.4 (0) 3.4 (0) * Also includes increase in SGPT, SGOT, Alkaline Phosphatase + Incidence of adverse events is higher in Placebo group than trandolapril and verapamil hydrochloride extended-release tablets patients Other clinical adverse experiences possibly, probably, or definitely related to drug treatment occurring in 0.3% or more of patients treated with trandolapril/verapamil combinations with or without concomitant diuretic in controlled or uncontrolled trials (N = 990) and less frequent, clinically significant events (in italics) include the following: Cardiovascular Angina, AV block second degree, bundle branch block, edema, flushing, hypotension, myocardial infarction, palpitations, premature ventricular contractions, nonspecific ST-T changes, near syncope, tachycardia.

Central Nervous System 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 Diarrhea, dyspepsia, dry mouth, nausea. General Body Function Chest pain, malaise, weakness.

Genitourinary Endometriosis, hematuria, nocturia, polyuria, proteinuria. Hemopoietic Decreased leukocytes, decreased neutrophils. Musculoskeletal System Arthralgias/myalgias, gout (increased uric acid).

Pulmonary Dyspnea. Angioedema Angioedema has been reported in 3 (0.15%) patients receiving trandolapril and verapamil hydrochloride extended-release tablets in U.S. and foreign 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 trandolapril and verapamil hydrochloride extended-release tablets should be discontinu… [Excerpted — this section continues on DailyMed.]

Drug Interactions In vitro metabolic studies indicate that verapamil is metabolized by cytochrome P450 including CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Verapamil has been shown to be an inhibitor of CYP3A4 enzymes and P-glycoprotein (P-gp). Clinically significant interactions have been reported with inhibitors of CYP3A4 (e.g. erythromycin, ritonavir) causing elevation of plasma levels of verapamil while inducers of CYP3A4 (e.g. rifampin) have caused a lowering of plasma levels of verapamil.

Therefore, patients receiving inhibitors or inducers of the cytochrome P450 system should be monitored for drug interactions. Ivabradine Concurrent use of verapamil increases exposure to ivabradine and may exacerbate bradycardia and conduction disturbances. Avoid co-administration of verapamil and ivabradine.

Digitalis Clinical use of verapamil in digitalized patients has shown the combination to be well tolerated if digoxin doses are properly adjusted. 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 under-digitalization. Whenever overdigitalization is suspected, the daily dose of digoxin should be reduced or temporarily discontinued.

Upon discontinuation of any verapamil-containing regime including trandolapril and verapamil hydrochloride extended-release tablets, the patient should be reassessed to avoid underdigitalization. No clinically significant pharmacokinetic interaction has been found between trandolapril (or its metabolites) and digoxin. Lithium Verapamil Component 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 concomitant lithium and ACE inhibitor therapy. Trandolapril and verapamil hydrochloride extended-release tablets and lithium should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.

Clarithromycin Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent clarithromycin. Erythromycin Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent erythromycin ethylsuccinate. 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. No clinically significant pharmacokinetic interaction has been found between trandolapril (or its metabolites) and cimetidine. Antiarrhythmic Agents Verapamil Component Disopyramide Phosphate Data on possible interactions between verapamil and disopyramide phosphate are not available.

Therefore, disopyramide should not be administered within 48 hours before or 24 hours after verapamil 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 verapamil may result in additive negative inotropic effect and prolongation of atrioventricular conduction.

Quinidine In a small number of patients with hypertrophic cardiomyopathy (IHSS), concomitant use of verapamil and quinidine resulted in significant hypotension. Until further da… [Excerpted — this section continues on DailyMed.]

PRECAUTIONS Use in Patients with Impaired Hepatic Function Trandolapril and verapamil hydrochloride extended-release tablets have not been evaluated in subjects with impaired hepatic function. Verapamil Component Since verapamil is highly metabolized by the liver, it should be administered cautiously to patients with impaired hepatic function. Severe liver dysfunction prolongs the elimination half-life of immediate release verapamil to about 14 to 16 hours; hence, approximately 30% of the dose given to patients with normal liver function should be administered to these patients.

Careful monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effects (see OVERDOSAGE ) should be carried out. Trandolapril Component Trandolapril and trandolaprilat concentrations increase in patients with impaired liver function. Use in Patients with Impaired Renal Function Trandolapril and verapamil hydrochloride extended-release tablets have not been evaluated in patients with impaired renal function.

Verapamil Component About 70% of an administered dose of verapamil is excreted as metabolites in the urine. Verapamil is not removed by hemodialysis. Until further data are available, verapamil should be administered cautiously to patients with impaired renal function.

These patients should be carefully monitored for abnormal prolongation of the PR interval or other signs of overdosage (see OVERDOSAGE ). Trandolapril Component As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including trandolapril, may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death.

In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine have been observed in some patients following ACE inhibitor therapy. These increases were almost always reversible upon discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy.

Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when ACE inhibitors have been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of any diuretic and/or the ACE inhibitor may be required.

Evaluation of hypertensive patients should always include assessment of renal function (see DOSAGE AND ADMINISTRATION ). Use in Patients with Attenuated (Decreased) Neuromuscular Transmission Verapamil Component 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. It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission (see PRECAUTIONS - Surgery/Anesthesia ).

Hyperkalemia and Potassium-Sparing Diuretics Trandolapril Component In clinical trials, hyperkalemia (serum potassium > 6.00 mEq/L) occurred in approximately 0.4 percent of hypertensive patients receiving trandolapril and in 0.8% of patients receiving a dose of trandolapril (0.5 to 8 mg) in combination with a dose of verapamil hydrochloride SR (120 to 240 mg). 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 con… [Excerpted — this section continues on DailyMed.]