Data from FDA - Curated by EPG Health - Last updated 24 October 2017

Indication(s)

INDICATIONS AND USAGE Trandolapril/verapamil hydrochloride ER 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/verapamil hydrochloride ER 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 ).

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Advisory information

contraindications
CONTRAINDICATIONS Trandolapril/verapamil hydrochloride ER tablets are contraindicated in patients who are hypersensitive to any ACE inhibitor or verapamil. Because of the verapamil component, trandolapril/verapamil hydrochloride ER tablets are contraindicated in: Severe left ventricular dysfunction (see WARNINGS ). Hypotension (systolic pressure less than 90 mmHg) or cardiogenic shock. Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker). Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker). Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g. Wolff-Parkinson-White, Lown-Ganong-Levine syndromes) (see WARNINGS ). Because of the trandolapril component, trandolapril/verapamil hydrochloride ER 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/verapamil hydrochloride ER tablets in patients with diabetes (see PRECAUTIONS, Drug Interactions ). Trandolapril/verapamil hydrochloride ER tablets are contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer trandolapril/verapamil hydrochloride ER tablets within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor (see WARNINGS ).
Special warnings and precautions
Dual Blockade of the Renin-Angiotensin System (RAS) Trandolapril Component Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on trandolapril/verapamil hydrochloride ER tablets and other agents that affect the RAS. Do not co-administer aliskiren with trandolapril/verapamil hydrochloride ER tablets in patients with diabetes. Avoid use of aliskiren with trandolapril/verapamil hydrochloride ER tablets in patients with renal impairment (GFR <60 ml/min).
Adverse reactions
ADVERSE REACTIONS Trandolapril/verapamil hydrochloride ER 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/verapamil hydrochloride ER 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/verapamil hydrochloride ER 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/verapamil hydrochloride ER 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 (0.5-8 mg) and verapamil (120-240 mg) combinations are shown below. ADVERSE EVENTS OCCURRING in ≥ 1% of TRANDOLAPRIL/VERAPAMIL HYDROCHLORIDE ER TABLETS PATIENTS IN U.S. PLACEBO-CONTROLLED TRIALS TRANDOLAPRIL/VERAPAMIL HYDROCHLORIDE ER TABLETS (N = 541) % Incidence (% Discontinuance) PLACEBO (N = 206) % Incidence (% Discontinuance) AV Block First Degree 3.9 (0.2) 0.5 (0.0) Bradycardia 1.8 (0.0) 0.0 (0.0) Bronchitis 1.5 (0.0) 0.5 (0.0) Chest Pain 2.2 (0.0) 1.0 (0.0) Constipation 3.3 (0.0) 1.0 (0.0) Cough 4.6 (0.0) 2.4 (0.0) Diarrhea 1.5 (0.2) 1.0 (0.0) Dizziness 3.1 (0.0) 1.9 (0.5) Dyspnea 1.3 (0.4) 0.0 (0.0) Edema 1.3 (0.0) 2.4 (0.0) Fatigue 2.8 (0.4) 2.4 (0.0) Headache(s)+ 8.9 (0.0) 9.7 (0.5) Increased Liver Enzymes* 2.8 (0.2) 1.0 (0.0) Nausea 1.5 (0.2) 0.5 (0.0) Pain Extremity(ies) 1.1 (0.2) 0.5 (0.0) Pain Back+ 2.2 (0.0) 2.4 (0.0) Pain Joint(s) 1.7 (0.0) 1.0 (0.0) Upper Respiratory Tract Infection(s)+ 5.4 (0.0) 7.8 (0.0) Upper Respiratory Tract Congestion+ 2.4 (0.0) 3.4 (0.0) * Also includes increase in SGPT, SGOT, Alkaline Phosphatase + Incidence of adverse events is higher in Placebo group than trandolapril/verapamil hydrochloride ER 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/verapamil hydrochloride ER 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/verapamil hydrochloride ER tablets should be discontinued and appropriate therapy instituted immediately (see WARNINGS ). Hypotension (See WARNINGS ). In hypertensive patients, hypotension occurred in 0.6% and near syncope occurred in 0.1%. Hypotension or syncope was a cause for discontinuation of therapy in 0.4% of hypertensive patients. Treatment of Acute Cardiovascular Adverse Reactions The frequency of cardiovascular adverse reactions which require therapy is rare, hence, experience with their treatment is limited. Whenever severe hypotension or complete AV block occur following oral administration of trandolapril/verapamil hydrochloride ER tablets (verapamil component), the appropriate emergency measures should be applied immediately, e.g., intravenously administered isoproterenol HCl, levarterenol bitartrate, atropine (all in the usual doses), or calcium gluconate (10% solution). In patients with hypertrophic cardiomyopathy (IHSS), alpha-adrenergic agents (phenylephrine, metaraminol bitartrate or methoxamine) should be used to maintain blood pressure, and isoproterenol and levarterenol should be avoided. If further support is necessary, inotropic agents (dopamine or dobutamine) may be administered. Actual treatment and dosage should depend on the severity and the clinical situation and the judgment and experience of the treating physician. Other Other adverse experiences (in addition to those in table and listed above) that have been reported with the individual components are listed below. Verapamil Component Cardiovascular (See WARNINGS ). CHF/pulmonary edema, AV block 3°, atrioventricular dissociation, claudication, purpura (vasculitis), syncope. Digestive System Gingival hyperplasia. Reversible, (upon discontinuation of verapamil) nonobstructive, paralytic ileus has been infrequently reported in association with the use of verapamil. Hemic and Lymphatic Ecchymosis or bruising. Nervous System Cerebrovascular accident, confusion, psychotic symptoms, shakiness, somnolence. Skin Exanthema, hair loss, hyperkeratosis, maculae, sweating, urticaria, Stevens-Johnson syndrome, erythema multiform. Urogenital Gynecomastia, galactorrhea/hyperprolactinemia, increased urination, spotty menstruation. Trandolapril Component Emotional, Mental, Sexual States Decreased libido. Gastrointestinal Pancreatitis. Clinical Laboratory Test Findings Hematology (See WARNINGS ). Low white blood cells, low neutrophils, low lymphocytes, low platelets. Serum Electrolytes Hyperkalemia (see PRECAUTIONS ), hyponatremia. Renal Function Tests Increases in creatinine and blood urea nitrogen levels occurred in 1.1 percent and 0.3 percent, respectively, of patients receiving trandolapril/verapamil hydrochloride ER tablets 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 and WARNINGS ). Liver Function Tests Elevations of liver enzymes (SGOT, SGPT, LDH, and alkaline phosphatase) and/or serum bilirubin occurred. Discontinuation for elevated liver enzymes occurred in 0.9 percent of patients (see WARNINGS ). Post Marketing Experience There has been a single postmarketing report of paralysis (tetraparesis) associated with the combined use of verapamil and colchicine. This may have been caused by colchicine crossing the blood-brain barrier due to CYP3A4 and P-gp inhibition by verapamil. Combined use of verapamil and colchicine is not recommended (see PRECAUTIONS - Drug Interactions ).

Usage information

Dosing and administration
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 Isoptin-SR 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/verapamil hydrochloride ER 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/verapamil hydrochloride ER 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 Isoptin-SR administered twice-a-day has not been studied, nor have the effects of adding as little of 180 mg Isoptin-SR to 2 mg trandolapril administered twice-a-day been evaluated. Over the dose range of Isoptin-SR 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 tablets of trandolapril/verapamil hydrochloride ER tablets containing the same component doses. Trandolapril/verapamil hydrochloride ER tablets should be administered with food.
Pregnancy and lactation
Nursing Mothers Verapamil is excreted in human milk. Radiolabeled trandolapril or its metabolites are secreted in rat milk. Trandolapril/verapamil hydrochloride ER tablets should not be administered to nursing mothers.

Interactions

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/verapamil hydrochloride ER 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

More information

Category Value
Authorisation number NDA020591
Agency product number V3888OEY5R
Orphan designation No
Product NDC 59762-0152,59762-0132,59762-0142,59762-0122
Date Last Revised 09-10-2017
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder Greenstone LLC
Warnings WARNING: FETAL TOXICITY When pregnancy is detected, discontinue trandolapril/verapamil hydrochloride ER tablets as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus (see WARNINGS: Fetal Toxicity).