Trandolapril and Verapamil Hydrochloride

INDICATIONS AND USAGE Trandolapril and verapamil hydrochloride extended-release tablets are indicated for the treatment of hypertension. This fixed combination drug is not indicated for the initial therapy of hypertension (see DOSAGE AND ADMINISTRATION ). In using trandolapril and verapamil hydrochloride extended-release tablets, consideration should be given to the fact that an angiotensin converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease, and that available data are insufficient to show that trandolapril does not have similar risk (see WARNINGS - Neutropenia/Agranulocytosis ).

DOSAGE AND ADMINISTRATION The recommended usual dosage range of trandolapril for hypertension is 1 to 4 mg per day administered in a single dose or two divided doses. The recommended usual dosage range of verapamil hydrochloride sustained-release tablets for hypertension is 120 to 480 mg per day administered in a single dose or two divided doses. The hazards (see WARNINGS ) of trandolapril are generally independent of dose; those of verapamil are a mixture of dose-dependent phenomena (primarily dizziness, AV block, constipation) and dose-independent phenomena, the former much more common than the latter. Therapy with any combination of trandolapril and verapamil will thus be associated with both sets of dose-independent hazards. The dose-dependent side effects of verapamil have not been shown to be decreased by the addition of trandolapril nor vice versa. Rarely, the dose-independent hazards of trandolapril are serious. To minimize dose-independent hazards, it is usually appropriate to begin therapy with trandolapril and verapamil hydrochloride extended-release tablets only after a patient has either (a) failed to achieve the desired antihypertensive effect with one or the other monotherapy at its respective maximally recommended dose and shortest dosing interval, or (b) the dose of one or the other monotherapy cannot be increased further because of dose-limiting side effects. Clinical trials with trandolapril and verapamil hydrochloride extended-release tablets have explored only once-a-day doses. The antihypertensive effect and or adverse effects of adding 4 mg of trandolapril once-a-day to a dose of 240 mg verapamil hydrochloride sustained-release tablets administered twice-a-day has not been studied, nor have the effects of adding as little of 180 mg verapamil hydrochloride sustained-release tablets to 2 mg trandolapril administered twice-a-day been evaluated. Over the dose range of verapamil hydrochloride sustained-release tablets 120 to 240 mg once-a-day and trandolapril 0.5 to 8 mg once-a-day, the effects of the combination increase with increasing doses of either component. Replacement Therapy For convenience, patients receiving trandolapril (up to 8 mg) and verapamil (up to 240 mg) in separate tablets, administered once-a-day, may instead wish to receive trandolapril and verapamil hydrochloride extended-release tablets containing the same component doses. Trandolapril and verapamil hydrochloride extended-release tablets should be administered with food.

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…

CONTRAINDICATIONS Trandolapril and verapamil hydrochloride extended-release tablets are contraindicated in patients who are hypersensitive to any ACE inhibitor or verapamil. Because of the verapamil component, trandolapril and verapamil hydrochloride extended-release tablets are contraindicated in: 1. Severe left ventricular dysfunction (see WARNINGS ). 2. Hypotension (systolic pressure less than 90 mmHg) or cardiogenic shock. 3. Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker). 4. Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker). 5. Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g. Wolff-Parkinson-White, Lown-Ganong-Levine syndromes) (see WARNINGS ). 6. Patients taking flibanserin (see PRECAUTIONS - Drug Interactions ). Because of the trandolapril component, trandolapril and verapamil hydrochloride extended-release tablets are contraindicated in patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme (ACE) inhibitor. Do not co-administer aliskiren with trandolapril and verapamil hydrochloride extended-release tablets in patients with diabetes (see PRECAUTIONS - Drug Interactions ). Trandolapril and verapamil hydrochloride extended-release tablets are contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer trandolapril and verapamil hydrochloride extended-release tablets within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor (see WARNINGS ).

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…

Pregnancy Female patients of childbearing age should be told about the consequences of exposure to trandolapril and verapamil hydrochloride extended-release tablets during pregnancy (see WARNINGS ). Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.

Nursing Mothers Verapamil is excreted in human milk. Radiolabeled trandolapril or its metabolites are secreted in rat milk. Trandolapril and verapamil hydrochloride extended-release tablets should not be administered to nursing mothers.

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…