Verapamil does not interfere with ACE inhibition by trandolapril. Trandolapril does not alter the effect of verapamil on intra-cardiac conduction.
Verapamil dilates the main coronary arteries and coronary arterioles, both in normal and ischemic regions, and is a potent inhibitor of coronary artery spasm. This property increases myocardial oxygen delivery in patients with coronary artery spasm, and is responsible for the effectiveness of verapamil in vasospastic (Prinzmetal’s or variant) as well as unstable angina at rest.
Verapamil regularly reduces the total systemic resistance (afterload) by dilating peripheral arterioles. By decreasing the influx of calcium, verapamil prolongs the effective refractory period within the AV node and slows AV conduction in a rate-related manner.
Normal sinus rhythm is usually not affected, but in patients with sick sinus syndrome, verapamil may interfere with sinus node impulse generation and may induce sinus arrest or sinoatrial block. Atrioventricular block can occur in patients without preexisting conduction defects (see WARNINGS).
Verapamil does not alter the normal atrial action potential or intraventricular conduction time, but depresses amplitude, velocity of depolarization and conduction in depressed atrial fibers. Verapamil may shorten the antegrade effective refractory period of accessory bypass tracts. Acceleration of ventricular rate and/or ventricular fibrillation has been reported in patients with atrial flutter or atrial fibrillation and a coexisting accessory AV pathway following administration of verapamil (see WARNINGS).
Hemodynamics and Myocardial Metabolism: Verapamil reduces afterload and myocardial contractility. Improved left ventricular diastolic function in patients with idiopathic hypertrophic subaortic stenosis (IHSS) and those with coronary heart disease has also been observed with verapamil therapy. In most patients, including those with organic cardiac disease, the negative inotropic action of verapamil is countered by a reduction of afterload and cardiac index is usually not reduced. However, in patients with severe left ventricular dysfunction (e.g., pulmonary wedge pressure about 20 mmHg or ejection fraction less than 30%), or in patients taking beta-adrenergic blocking agents or other cardio-depressant drugs, deterioration of ventricular function may occur (see PRECAUTIONS — Drug Interactions).
Pulmonary Function: Verapamil does not induce bronchoconstriction and hence, does not impair ventilatory function.
After a single 2 mg dose of trandolapril, inhibition of ACE activity reaches a maximum (70 to 85%) at 4 hours with about 10% decline at 24 hours. Eight days after dosing, ACE inhibition is still 40%.
Four placebo-controlled dose response studies were conducted using once daily oral dosing of trandolapril in doses from 0.25 to 16 mg per day in 827 black and non-black patients with mild to moderate hypertension. The minimal effective once daily dose was 1 mg in non-black patients and 2 mg in black patients. Further decreases in trough supine diastolic blood pressure were obtained in non-black patients with higher doses, and no further response was seen with doses above 4 mg (up to 16 mg). The antihypertensive effect diminished somewhat at the end of the dosing interval.
During chronic therapy, the maximum reduction in blood pressure with any dose is achieved within one week. Following 6 weeks of monotherapy in placebo-controlled trials in patients with mild to moderate hypertension, once daily doses of 2 to 4 mg lowered supine or standing systolic/diastolic blood pressure 24 hours after dosing by an average 7 to 10/4 to 5 mmHg below placebo responses in non-black patients. Once daily doses of 2 to 4 mg lowered blood pressures 4 to 6/3 to 4 mmHg below placebo responses in black patients.
In controlled clinical trials, once daily doses of trandolapril and verapamil hydrochloride extended-release tablets, trandolapril 4 mg/verapamil HCl extended-release 240 mg or trandolapril 2 mg/verapamil HCl extended-release 180 mg, decreased placebo-corrected seated pressure (systolic/diastolic) 24 hours after dosing by about 7 to 12/6 to 8 mmHg. Each of the components of trandolapril and verapamil hydrochloride extended-release tablets added to the antihypertensive effect. Treatment effects were consistent across age groups (<65, ≥65 years), and gender (male, female).
Blood pressure reductions were significantly greater for the trandolapril and verapamil hydrochloride extended-release tablet 4 mg/240 mg combination than for either of the components used alone.
The antihypertensive effects of trandolapril and verapamil hydrochloride extended-release tablets have continued during therapy for at least 1 year.
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).
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:
- 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).
- 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).
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, as an ACE inhibitor, may cause excessive hypotension in patients with congestive heart failure (see WARNINGS — Hypotension).
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