Trandolapril and Verapamil Hydrochloride Ref.[110106] Active ingredients:

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.

No specific information is available on the treatment of overdosage with trandolapril and verapamil hydrochloride extended-release tablets.

Verapamil Component

Overdose with verapamil may lead to pronounced hypotension, bradycardia, and conduction system abnormalities (e.g., junctional rhythm with AV dissociation and high degree AV block, including asystole). Other symptoms secondary to hypoperfusion (e.g., metabolic acidosis, hyperglycemia, hyperkalemia, renal dysfunction, and convulsions) may be evident.

Treat all verapamil overdoses as serious and maintain observation for at least 48 hours, preferably under continuous hospital care. Delayed pharmacodynamic consequences may occur with the sustained release formulation. Verapamil is known to decrease gastrointestinal transit time. In cases of overdose, verapamil hydrochloride sustained-release tablets have occasionally been reported to form concretions within the stomach or intestines. These concretions have not been visible on plain radiographs of the abdomen, and no medical means of gastrointestinal emptying is of proven efficacy in removing them. Endoscopy might reasonably be considered in cases of overdose when symptoms are unusually prolonged. Verapamil cannot be removed by hemodialysis.

Treatment of overdosage should be supportive. Beta adrenergic stimulation or parenteral administration of calcium solutions may increase calcium ion flux across the slow channel, and have been used effectively in treatment of deliberate overdosage with verapamil. The following measures may be considered:

Bradycardia and Conduction System Abnormalities

Atropine, isoproterenol, and cardiac pacing.

Hypotension

Intravenous fluids, vasopressors (e.g., dopamine, dobutamine), calcium solutions (e.g., 10% calcium chloride solution).

Cardiac Failures

Inotropic agents (e.g., isoproterenol, dopamine, dobutamine), diuretics. Asystole should be handled by the usual measures including cardiopulmonary resuscitation.

Trandolapril Component

The oral LD₅₀ of trandolapril in mice was 4875 mg/kg in males and 3990 mg/kg in females. In rats, an oral dose of 5000 mg/kg caused low mortality (1 male out of 5; 0 females). In dogs, an oral dose of 1000 mg/kg did not cause mortality and abnormal clinical signs were not observed.

In humans, the most likely clinical manifestation would be symptoms attributable to severe hypotension. Laboratory determinations of serum levels of trandolapril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of trandolapril overdose. 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. It is not known if trandolapril or trandolaprilat can be usefully removed from the body by hemodialysis.

Angiotensin II could presumably serve as a specific antagonist antidote in the setting of trandolapril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of trandolapril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat trandolapril overdose by infusion of normal saline solution.

Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].