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Trandolapril and Verapamil Hydrochloride
Overview
What is Trandolapril and Verapamil Hydrochloride?
Trandolapril/verapamil hydrochloride ER tablets combine a slow release formulation of a calcium channel blocker, verapamil hydrochloride, and an immediate release formulation of an angiotensin converting enzyme inhibitor, trandolapril.
What does Trandolapril and Verapamil Hydrochloride look like?
What are the available doses of Trandolapril and Verapamil Hydrochloride?
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What should I talk to my health care provider before I take Trandolapril and Verapamil Hydrochloride?
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How should I use Trandolapril and Verapamil Hydrochloride?
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
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 ).
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 ) 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.
What interacts with Trandolapril and Verapamil Hydrochloride?
- Trandolapril/verapamil hydrochloride ER tablets are contraindicated in patients who are hypersensitive to any ACE inhibitor or verapamil.
- Severe left ventricular dysfunction (see ).
- 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 ).
- Because of the verapamil component, trandolapril/verapamil hydrochloride ER tablets are contraindicated in:
- 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 ).
- 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 ).
What are the warnings of Trandolapril and Verapamil Hydrochloride?
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 ). 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: ).
Trandolapril Component
Trandolapril, as an ACE inhibitor, may cause excessive hypotension in patients with congestive heart failure (see ).
Hypotension
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Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels which may result in dizziness or symptomatic hypotension.
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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 and ).
In controlled studies, hypotension was observed in 0.6% of patients receiving any combination of trandolapril and verapamil HCl ER.
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 ).
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 ER and/or trandolapril or reduced concomitant diuretic therapy should be considered.
Elevated Liver Enzymes/Hepatic Failure
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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.
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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/verapamil hydrochloride ER tablets is therefore prudent.
Accessory Bypass Tract (Wolff-Parkinson-White or Lown-Ganong-Levine Syndromes)
Some patients with paroxysmal and/or chronic atrial fibrillation or atrial flutter and a coexisting accessory AV pathway have developed increased antegrade conduction across the accessory pathway bypassing the AV node, producing a very rapid ventricular response or ventricular fibrillation after receiving intravenous verapamil (or digitalis). Although a risk of this occurring with oral verapamil has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is contraindicated (see ).
Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral verapamil.
Atrioventricular Block
The effect of verapamil on AV conduction and the SA node may lead to asymptomatic first-degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms. PR interval prolongation is correlated with verapamil plasma concentrations, especially during the early titration phases of therapy. Higher degrees of AV block, however, were infrequently (0.8%) observed. Marked first-degree block or progressive development to second- or third-degree AV block requires a reduction in dosage or, in rare instances, discontinuation of verapamil HCl and institution of appropriate therapy depending upon the clinical situation.
Patients with Hypertrophic Cardiomyopathy (IHSS)
In 120 patients with hypertrophic cardiomyopathy (most of them refractory or intolerant to propranolol) who received therapy with verapamil at doses up to 720 mg/day, a variety of serious adverse effects were seen. Three patients died in pulmonary edema; all had severe left ventricular outflow obstruction and a past history of left ventricular dysfunction. Eight other patients had pulmonary edema and/or severe hypotension; abnormally high (over 20 mmHg) capillary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. Sinus bradycardia occurred in 11% of the patients, second-degree AV block in 4% and sinus arrest in 2%. It must be appreciated that this group of patients had a serious disease with a high mortality rate. Most adverse effects responded well to dose reduction and only rarely did verapamil have to be discontinued.
Anaphylactoid and Possibly Related Reactions
Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors, including trandolapril may be subject to a variety of adverse reactions, some of them serious.
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Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors including trandolapril. Symptoms suggestive of angioedema or facial edema occurred in 0.13% of trandolapril-treated patients. Two of the four cases were life-threatening and resolved without treatment or with medication (corticosteroids). Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue or glottis occurs, treatment with trandolapril/verapamil hydrochloride ER tablets should be discontinued immediately, the patient treated in accordance with accepted medical care and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment; antihistamines may be useful in relieving symptoms. (see and ).
Patients receiving coadministration of an ACE inhibitor with an mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) or a neprilysin inhibitor (e.g., sacubitril) may be at increased risk for angioedema.
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Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions did not occur when ACE inhibitors were temporarily withheld, but they reappeared when the ACE inhibitors were inadvertently readministered.
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Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.
Neutropenia/Agranulocytosis
Another ACE inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression rarely in patients with uncomplicated hypertension, but more frequently in patients with renal impairment, especially if they also have a collagen-vascular disease such as systemic lupus erythematosus or scleroderma. Available data from clinical trials of trandolapril or trandolapril/verapamil hydrochloride ER tablets are insufficient to show that trandolapril does not cause agranulocytosis at similar rates. As with other ACE inhibitors, periodic monitoring of white blood cell counts in patients with collagen-vascular disease and/or renal disease should be considered.
Fetal Toxicity
Pregnancy Category D
Trandolapril Component
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue trandolapril/verapamil hydrochloride ER tablets as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue trandolapril/verapamil hydrochloride ER tablets, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of exposure to trandolapril/verapamil hydrochloride ER tablets for hypotension, oliguria, and hyperkalemia (see ).
Doses of 0.8 mg/kg/day (9.4 mg/m2/day) in rabbits, 1000 mg/kg/day (7000 mg/m2/day) in rats, and 25 mg/kg/day (295 mg/m2/day) in cynomolgus monkeys did not produce teratogenic effects. These doses represent 10 and 3 times (rabbits), 1250 and 2564 times (rats), and 312 and 108 times (monkeys) the maximum projected human dose of 4 mg based on body-weight and body-surface-area, respectively assuming a 50 kg woman.
Trandolapril in doses of 0.8 mg/kg/day in rabbits, 100.0 mg/kg/day in rats, and 25 mg/kg/day in cynomolgus monkeys (10, 1250, and 312 times the maximum projected human dose, respectively, assuming a 50 kg woman) did not produce teratogenic effects.
What are the precautions of Trandolapril and Verapamil Hydrochloride?
Use in Patients with Impaired Hepatic Function
Trandolapril/verapamil hydrochloride ER tablets have not been evaluated in subjects with impaired hepatic function.
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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 ) should be carried out.
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Trandolapril and trandolaprilat concentrations increase in patients with impaired liver function.
Use in Patients with Impaired Renal Function
Trandolapril/verapamil hydrochloride ER tablets have not been evaluated in patients with impaired renal function.
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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 ).
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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.
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Use in Patients with Attenuated (Decreased) Neuromuscular Transmission
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 ).
Hyperkalemia and Potassium-sparing Diuretics
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 (0.5-8 mg) in combination with a dose of verapamil SR (120-240 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 concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with trandolapril (see ).
Cough
Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. In controlled trials of trandolapril, cough was present in 2% of trandolapril patients and 0% of patients given placebo. There was no evidence of a relationship to dose.
Surgery/anesthesia
In patients undergoing major surgery or during anesthesia with agents that produce hypotension, trandolapril will block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion (see ).
Drug Interactions
In vitro
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
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/verapamil hydrochloride ER 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 data are obtained, combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy should probably be avoided.
The electrophysiological effects of quinidine and verapamil on AV conduction were studied in 8 patients. Verapamil significantly counteracted the effects of quinidine on AV conduction. There has been a report of increased quinidine levels during verapamil therapy.
Antihypertensive Agents
Concomitant use of trandolapril/verapamil hydrochloride ER tablets with other antihypertensive agents including diuretics, vasodilators, beta-adrenergic blockers, and alpha-antagonists may result in additive hypotensive effects. There are reports that verapamil may result in higher concentrations of the alpha-agonists prazosin and terazosin.
Dual Blockade of the Renin-Angiotensin System (RAS)
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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).
Beta Blockers
Verapamil Component
Concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects on heart rate, atrioventricular conduction, and/or cardiac contractility. Drug interaction studies have indicated that the maximum concentrations of metoprolol and propanolol are increased after the administration of verapamil. The use of verapamil in combination with a beta-adrenergic blocker should be used only with caution, and close monitoring.
Asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta-adrenergic blocker) eyedrops and oral verapamil.
Trandolapril Component
As with other ACE inhibitors, patients on diuretics, especially those on recently instituted diuretic therapy, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with trandolapril/verapamil hydrochloride ER tablets. The possibility of exacerbation of hypotensive effects with trandolapril/verapamil hydrochloride ER tablets may be minimized by either discontinuing the diuretic or cautiously increasing salt intake prior to initiation of treatment with trandolapril/verapamil hydrochloride ER tablets. If it is not possible to discontinue the diuretic, the starting dose of trandolapril/verapamil hydrochloride ER tablets should be reduced (see ). No clinically significant pharmacokinetic interaction has been found between trandolapril (or its metabolites) and furosemide.
Agents Increasing Serum Potassium
Trandolapril Component
Trandolapril can attenuate potassium loss caused by thiazide diuretics and increase serum potassium when used alone. Use of potassium-sparing diuretics (spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes concomitantly with ACE inhibitors can increase the risk of hyperkalemia. If concomitant use of such agents is indicated, they should be used with caution and with appropriate monitoring of serum potassium (see ).
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Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including trandolapril/verapamil hydrochloride ER tablets.
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No clinically significant pharmacokinetic interaction has been found between trandolapril (or its metabolites) and nifedipine.
The anticoagulant effect of warfarin was not significantly changed by trandolapril.
Carcinogenesis, Mutagenesis, Impairment of Fertility
An 18-month toxicity study in rats, at a low multiple (6 fold) of the maximum recommended human dose, and not the maximum tolerated dose, did not suggest a tumorigenic potential. There was no evidence of a carcinogenic potential of verapamil administered in the diet of rats for two years at doses of 10, 35, and 120 mg/kg per day or approximately 1x, 3.5x, and 12x, respectively, the maximum recommended human daily dose (480 mg per day or 9.6 mg/kg/day).
Verapamil was not mutagenic in the Ames test in 5 test strains at 3 mg per plate, with or without metabolic activation.
Studies in female rats at daily dietary doses up to 5.5 times (55 mg/kg/day) the maximum recommended human dose did not show impaired fertility. Effects on male fertility have not been determined.
Trandolapril Component
Long-term studies were conducted with oral trandolapril administered by gavage to mice (78 weeks) and rats (104 and 106 weeks). No evidence of carcinogenic potential was seen in mice dosed up to 25 mg/kg/day (85 mg/m/day) or rats dosed up to 8 mg/kg/day (60 mg/m/day). These doses are 313 and 32 times (mice), and 100 and 23 times (rats) the maximum recommended human daily dose (MRHDD) of 4 mg based on body-weight and body-surface-area, respectively assuming a 50 kg individual. The genotoxic potential of trandolapril was evaluated in the microbial mutagenicity (Ames) test, the point mutation and chromosome aberration assays in Chinese hamster V79 cells, and the micronucleus test in mice. There was no evidence of mutagenic or clastogenic potential in these and assays.
Reproduction studies in rats did not show any impairment of fertility at doses up to 100 mg/kg/day (710 mg/m/day) of trandolapril, or 1250 and 260 times the MRHDD on the basis of body-weight and body-surface-area, respectively.
Pregnancy
Female patients of childbearing age should be told about the consequences of exposure to trandolapril/verapamil hydrochloride ER tablets during pregnancy. 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/verapamil hydrochloride ER tablets should not be administered to nursing mothers.
Geriatric Use
In placebo-controlled studies, where 23% of patients receiving trandolapril/verapamil hydrochloride ER tablets were 65 years and older, and 2.4% were 75 years and older, no overall differences in effectiveness or safety were observed between these patients and younger patients. However, greater sensitivity of some older individual patients cannot be ruled out.
Pediatric Use
Neonates with a history of exposure to trandolapril/verapamil hydrochloride ER tablets:
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
The safety and effectiveness of trandolapril/verapamil hydrochloride ER tablets in children below the age of 18 have not been established.
Animal Pharmacology and/or Animal Toxicology
In chronic animal toxicology studies, verapamil caused lenticular and/or suture line changes at 30 mg/kg/day or greater and frank cataracts at 62.5 mg/kg/day or greater in the beagle dog but not the rat. Development of cataracts due to verapamil has not been reported in man.
What are the side effects of Trandolapril and Verapamil Hydrochloride?
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.
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:
| 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) |
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 ).
Hypotension
(See ). 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.
Array
Array
Clinical Laboratory Test Findings
Array
(See ). Low white blood cells, low neutrophils, low lymphocytes, low platelets.
Array
Hyperkalemia (see ), hyponatremia.
Array
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 and ).
Array
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 ).
Array
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 ).
What should I look out for while using Trandolapril and Verapamil Hydrochloride?
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:
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 ).
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 ).
What might happen if I take too much Trandolapril and Verapamil Hydrochloride?
No specific information is available on the treatment of overdosage with trandolapril/verapamil hydrochloride ER tablets.
How should I store and handle Trandolapril and Verapamil Hydrochloride?
Trandolapril/verapamil hydrochloride ER 2/180 mg tablets are supplied as pink, oval, film-coated tablets containing 2 mg trandolapril in an immediate release form and 180 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 182 on one side and plain on the other side.NDC Trandolapril/verapamil hydrochloride ER 1/240 mg tablets are supplied as white, oval, film-coated tablets containing 1 mg trandolapril in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 241 on one side and plain on the other side.NDCTrandolapril/verapamil hydrochloride ER 2/240 mg tablets are supplied as gold, oval, film-coated tablets containing 2 mg trandolapril in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 242 on one side and plain on the other side.NDC Trandolapril/verapamil hydrochloride ER 4/240 mg tablets are supplied as reddish-brown, oval, film-coated tablets containing 4 mg trandolapril in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 244 on one side and plain on the other side.NDC Dispense in well-closed container with safety closure.Trandolapril/verapamil hydrochloride ER 2/180 mg tablets are supplied as pink, oval, film-coated tablets containing 2 mg trandolapril in an immediate release form and 180 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 182 on one side and plain on the other side.NDC Trandolapril/verapamil hydrochloride ER 1/240 mg tablets are supplied as white, oval, film-coated tablets containing 1 mg trandolapril in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 241 on one side and plain on the other side.NDCTrandolapril/verapamil hydrochloride ER 2/240 mg tablets are supplied as gold, oval, film-coated tablets containing 2 mg trandolapril in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 242 on one side and plain on the other side.NDC Trandolapril/verapamil hydrochloride ER 4/240 mg tablets are supplied as reddish-brown, oval, film-coated tablets containing 4 mg trandolapril in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 244 on one side and plain on the other side.NDC Dispense in well-closed container with safety closure.Trandolapril/verapamil hydrochloride ER 2/180 mg tablets are supplied as pink, oval, film-coated tablets containing 2 mg trandolapril in an immediate release form and 180 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 182 on one side and plain on the other side.NDC Trandolapril/verapamil hydrochloride ER 1/240 mg tablets are supplied as white, oval, film-coated tablets containing 1 mg trandolapril in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 241 on one side and plain on the other side.NDCTrandolapril/verapamil hydrochloride ER 2/240 mg tablets are supplied as gold, oval, film-coated tablets containing 2 mg trandolapril in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 242 on one side and plain on the other side.NDC Trandolapril/verapamil hydrochloride ER 4/240 mg tablets are supplied as reddish-brown, oval, film-coated tablets containing 4 mg trandolapril in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 244 on one side and plain on the other side.NDC Dispense in well-closed container with safety closure.Trandolapril/verapamil hydrochloride ER 2/180 mg tablets are supplied as pink, oval, film-coated tablets containing 2 mg trandolapril in an immediate release form and 180 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 182 on one side and plain on the other side.NDC Trandolapril/verapamil hydrochloride ER 1/240 mg tablets are supplied as white, oval, film-coated tablets containing 1 mg trandolapril in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 241 on one side and plain on the other side.NDCTrandolapril/verapamil hydrochloride ER 2/240 mg tablets are supplied as gold, oval, film-coated tablets containing 2 mg trandolapril in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 242 on one side and plain on the other side.NDC Trandolapril/verapamil hydrochloride ER 4/240 mg tablets are supplied as reddish-brown, oval, film-coated tablets containing 4 mg trandolapril in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 244 on one side and plain on the other side.NDC Dispense in well-closed container with safety closure.Trandolapril/verapamil hydrochloride ER 2/180 mg tablets are supplied as pink, oval, film-coated tablets containing 2 mg trandolapril in an immediate release form and 180 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 182 on one side and plain on the other side.NDC Trandolapril/verapamil hydrochloride ER 1/240 mg tablets are supplied as white, oval, film-coated tablets containing 1 mg trandolapril in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 241 on one side and plain on the other side.NDCTrandolapril/verapamil hydrochloride ER 2/240 mg tablets are supplied as gold, oval, film-coated tablets containing 2 mg trandolapril in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 242 on one side and plain on the other side.NDC Trandolapril/verapamil hydrochloride ER 4/240 mg tablets are supplied as reddish-brown, oval, film-coated tablets containing 4 mg trandolapril in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 244 on one side and plain on the other side.NDC Dispense in well-closed container with safety closure.Trandolapril/verapamil hydrochloride ER 2/180 mg tablets are supplied as pink, oval, film-coated tablets containing 2 mg trandolapril in an immediate release form and 180 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 182 on one side and plain on the other side.NDC Trandolapril/verapamil hydrochloride ER 1/240 mg tablets are supplied as white, oval, film-coated tablets containing 1 mg trandolapril in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 241 on one side and plain on the other side.NDCTrandolapril/verapamil hydrochloride ER 2/240 mg tablets are supplied as gold, oval, film-coated tablets containing 2 mg trandolapril in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 242 on one side and plain on the other side.NDC Trandolapril/verapamil hydrochloride ER 4/240 mg tablets are supplied as reddish-brown, oval, film-coated tablets containing 4 mg trandolapril in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 244 on one side and plain on the other side.NDC Dispense in well-closed container with safety closure.Trandolapril/verapamil hydrochloride ER 2/180 mg tablets are supplied as pink, oval, film-coated tablets containing 2 mg trandolapril in an immediate release form and 180 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 182 on one side and plain on the other side.NDC Trandolapril/verapamil hydrochloride ER 1/240 mg tablets are supplied as white, oval, film-coated tablets containing 1 mg trandolapril in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 241 on one side and plain on the other side.NDCTrandolapril/verapamil hydrochloride ER 2/240 mg tablets are supplied as gold, oval, film-coated tablets containing 2 mg trandolapril in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 242 on one side and plain on the other side.NDC Trandolapril/verapamil hydrochloride ER 4/240 mg tablets are supplied as reddish-brown, oval, film-coated tablets containing 4 mg trandolapril in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 244 on one side and plain on the other side.NDC Dispense in well-closed container with safety closure.Trandolapril/verapamil hydrochloride ER 2/180 mg tablets are supplied as pink, oval, film-coated tablets containing 2 mg trandolapril in an immediate release form and 180 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 182 on one side and plain on the other side.NDC Trandolapril/verapamil hydrochloride ER 1/240 mg tablets are supplied as white, oval, film-coated tablets containing 1 mg trandolapril in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 241 on one side and plain on the other side.NDCTrandolapril/verapamil hydrochloride ER 2/240 mg tablets are supplied as gold, oval, film-coated tablets containing 2 mg trandolapril in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 242 on one side and plain on the other side.NDC Trandolapril/verapamil hydrochloride ER 4/240 mg tablets are supplied as reddish-brown, oval, film-coated tablets containing 4 mg trandolapril in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 244 on one side and plain on the other side.NDC Dispense in well-closed container with safety closure.Trandolapril/verapamil hydrochloride ER 2/180 mg tablets are supplied as pink, oval, film-coated tablets containing 2 mg trandolapril in an immediate release form and 180 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 182 on one side and plain on the other side.NDC Trandolapril/verapamil hydrochloride ER 1/240 mg tablets are supplied as white, oval, film-coated tablets containing 1 mg trandolapril in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 241 on one side and plain on the other side.NDCTrandolapril/verapamil hydrochloride ER 2/240 mg tablets are supplied as gold, oval, film-coated tablets containing 2 mg trandolapril in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 242 on one side and plain on the other side.NDC Trandolapril/verapamil hydrochloride ER 4/240 mg tablets are supplied as reddish-brown, oval, film-coated tablets containing 4 mg trandolapril in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 244 on one side and plain on the other side.NDC Dispense in well-closed container with safety closure.
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
Verapamil is a calcium channel blocker that exerts its pharmacologic effects by modulating the influx of ionic calcium across the cell membrane of the arterial smooth muscle as well as in conductile and contractile myocardial cells. Verapamil exerts antihypertensive effects by decreasing systemic vascular resistance, usually without orthostatic decreases in blood pressure or reflex tachycardia. During isometric or dynamic exercise, verapamil does not alter systolic cardiac function in patients with normal ventricular function. Verapamil does not alter total serum calcium levels.
Non-Clinical Toxicology
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:
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 ).
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 ).
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.
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:
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
While we update our database periodically, we cannot guarantee it is always updated to the latest version.
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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