Trandolapril And Verapamil Hydrochloride - Trandolapril And Verapamil Hydrochloride tablet, Film Coated, Extended Release prescribing information
WARNING: FETAL TOXICITY
- When pregnancy is detected, discontinue trandolapril and verapamil hydrochloride extended-release 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 ) .
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.
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:
- 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 ).
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.
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 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 and verapamil hydrochloride extended-release 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 and verapamil hydrochloride extended-release 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 ).
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 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 and verapamil hydrochloride extended-release 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)
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 and verapamil hydrochloride extended-release tablets and other agents that affect the RAS.
Do not co-administer aliskiren with trandolapril and verapamil hydrochloride extended-release tablets in patients with diabetes. Avoid use of aliskiren with trandolapril and verapamil hydrochloride extended-release 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.
Concomitant Diuretic Therapy
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 and verapamil hydrochloride extended-release tablets. The possibility of exacerbation of hypotensive effects with trandolapril and verapamil hydrochloride extended-release tablets may be minimized by either discontinuing the diuretic or cautiously increasing salt intake prior to initiation of treatment with trandolapril and verapamil hydrochloride extended-release tablets. If it is not possible to discontinue the diuretic, the starting dose of trandolapril and verapamil hydrochloride extended-release tablets should be reduced (see DOSAGE AND ADMINISTRATION ). 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 PRECAUTIONS ).
HMG-CoA Reductase Inhibitors (“Statins”)
Verapamil Component
The use of HMG-CoA reductase inhibitors that are CYP3A4 substrates in combination with verapamil has been associated with reports of myopathy/rhabdomyolysis.
Co-administration of multiple doses of 10 mg of verapamil with 80 mg simvastatin resulted in exposure to simvastatin 2.5-fold that following simvastatin alone. Limit the dose of simvastatin in patients on verapamil to 10 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required as verapamil may increase the plasma concentration of these drugs.
Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
Trandolapril Component
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including trandolapril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving trandolapril and NSAID therapy.
The antihypertensive effect of ACE inhibitors, including trandolapril may be attenuated by NSAIDs.
Neprilysin Inhibitor
Trandolapril Component
Patients taking concomitant neprilysin inhibitors (e.g., sacubitril) may be at increased risk for angioedema (see WARNINGS ).
Flibanserin
Verapamil component
Use of a moderate CYP3A4 inhibitor such as verapamil with flibanserin significantly increases flibanserin concentrations, which can lead to severe hypotension and syncope. Concomitant use is contraindicated (see CONTRAINDICATIONS ). Discontinue trandolapril and verapamil hydrochloride extended-release tablets at least 2 weeks prior to starting flibanserin. Do not administer trandolapril and verapamil hydrochloride extended-release tablets within 2 days of discontinuing flibanserin.
Other (Verapamil Component)
Nitrates
Verapamil has been given concomitantly with short- and long-acting nitrates without any undesirable drug interactions. The pharmacologic profile of both drugs and the clinical experience suggest beneficial interactions.
Carbamazepine
Verapamil may increase carbamazepine concentrations during combined therapy. This may produce carbamazepine side effects such as diplopia, headache, ataxia, or dizziness.
Anti-Infective Agents
Therapy with rifampin may markedly reduce oral verapamil bioavailability. There have been reports that erythromycin and telithromycin may increase concentrations of verapamil.
Barbiturates
Phenobarbital therapy may increase verapamil clearance.
Immunosuppressive Agents
Verapamil therapy may increase serum levels of cyclosporin, sirolimus and tacrolimus.
Theophylline
Verapamil therapy may inhibit the clearance and increase the plasma levels of theophylline.
Tranquilizers/Anti-Depressants
Due to metabolism via the CYP enzyme system, there have been reports that verapamil may increase the concentrations of buspirone, midazolam, almotriptan and imipramine.
Colchicine
Colchicine is a substrate for both CYP3A and the efflux transporter, P-gp. Verapamil is known to inhibit CYP3A and P-gp. When verapamil and colchicine are administered together, the potential inhibition of P-gp and/or CYP3A by verapamil may lead to increased exposure to colchicine (see PRECAUTIONS - Drug Interactions ).
Dabigatran
Verapamil, a P-gp inhibitor, increases exposure to dabigatran (a thrombin inhibitor) when administered concomitantly; however, no dose adjustment of dabigatran is required when administered with verapamil.
Other
Concentrations of verapamil may be increased by the concomitant administration of protease inhibitors such as ritonavir, and reduced by the concomitant administration of sulfinpyrazone, or St John’s Wort.
Concentrations of doxorubicin may be increased by the administration of verapamil.
There have been reports that verapamil may elevate the concentrations of the oral anti-diabetic glyburide.
Inhalation Anesthetics
Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil, should be titrated carefully to avoid excessive cardiovascular depression.
Neuromuscular Blocking Agents
Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly.
Gold
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 and verapamil hydrochloride extended-release tablets.
Other (Trandolapril Component)
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.
Mammalian Target of Rapamycin (mTOR) Inhibitors
Patients taking concomitant mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema (see WARNINGS - Angioedema ).
Anti-Diabetic Agents
The concomitant use of ACE inhibitors such as trandolapril with antidiabetic medications (insulin or oral hypoglycemic agents) may result in increased blood glucose lowering effects.
DESCRIPTION
Trandolapril and verapamil hydrochloride extended-release tablets combine a slow release formulation of a calcium channel blocker, verapamil hydrochloride, USP, and an immediate release formulation of an angiotensin converting enzyme inhibitor, trandolapril, USP.
Verapamil Component
Verapamil hydrochloride, USP is chemically described as benzeneacetonitrile, α [3-[[2-(3,4-dimethoxyphenyl) -ethyl] methylamino] propyl] -3,4-dimethoxy-α -(1-methylethyl)-, monohydrochloride, (±). Its molecular formula is C 27 H 38 N 2 O 4 • HCl and its structural formula is:
Verapamil hydrochloride, USP is a white or practically white crystalline powder, with a molecular weight of 491.06 g/mol. It is soluble in water, freely soluble in chloroform, sparingly soluble in alcohol and practically insoluble in ether. It is practically odorless and has a bitter taste.
Trandolapril Component
Trandolapril, USP is the ethyl ester prodrug of a nonsulfhydryl angiotensin converting enzyme (ACE) inhibitor, trandolaprilat. It is chemically described as (2S,3aR,7aS)- 1- [(S)-2-[[(S)-1-(EthoxyCarbonyl)-3-phenylpropyl] amino]Propanoyl]octahydro-1H-indole-2-carboxylic acid. Its molecular formula is C 24 H 34 N 2 O 5 and its structural formula is:
Trandolapril, USP is a white or almost white powder with a molecular weight of 430.54 g/mol. It is practically insoluble in water; freely soluble in methylene chloride; sparingly soluble in absolute alcohol.
Trandolapril and verapamil hydrochloride extended-release tablets are formulated for oral administration, containing verapamil hydrochloride, USP as a controlled release formulation and trandolapril, USP as an immediate release formulation. The tablet strengths are trandolapril and verapamil hydrochloride extended-release tablets 1 mg/240 mg, trandolapril and verapamil hydrochloride extended-release tablets 2 mg/180 mg, trandolapril and verapamil hydrochloride extended-release tablets 2 mg/240 mg, and trandolapril and verapamil hydrochloride extended-release tablets 4 mg/240 mg. The tablets also contain the following ingredients: colloidal silicon dioxide, corn starch, croscarmellose sodium, ferric oxide red, hypromellose, lactose monohydrate, povidone, sodium alginate, sodium stearyl fumarate, magnesium stearate, and microcrystalline cellulose. The film coating contains: 1 mg/240 mg – hypromellose, titanium dioxide, and polyethylene glycol; 2 mg/180 mg – hypromellose, titanium dioxide, polyethylene glycol, iron oxide red, and FD&C blue #2; 2 mg/240 mg – hypromellose, titanium dioxide, polyethylene glycol, iron oxide yellow, iron oxide black, and iron oxide red; 4 mg/240 mg – hypromellose, titanium dioxide, polyethylene glycol, iron oxide yellow, iron oxide red, and iron oxide black.
CLINICAL PHARMACOLOGY
Verapamil hydrochloride and trandolapril have been used individually and in combination for the treatment of hypertension. For the four dosing strengths, the antihypertensive effect of the combination is approximately additive to the individual components.
Verapamil Component
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.
Trandolapril Component
Trandolapril is de-esterified to its diacid metabolite, trandolaprilat. Both inhibit angiotensin-converting enzyme (ACE) in human subjects and in animals. Trandolaprilat is about 8 times more potent than trandolapril. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex.
Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. In controlled clinical trials, treatment with trandolapril and verapamil hydrochloride extended-release tablets resulted in mean increases in potassium of 0.1 mEq/L (see PRECAUTIONS ). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity (PRA).
ACE is identical to kininase II, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effect of trandolapril and verapamil hydrochloride extended-release tablets remains to be elucidated.
While the mechanism through which trandolapril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, trandolapril has an antihypertensive effect even in patients with low renin hypertension. Trandolapril is an effective antihypertensive in all races studied. Both black patients (usually a predominantly low renin group) and non-black patients respond to 2 to 4 mg of trandolapril.
Pharmacokinetics and Metabolism
Trandolapril and Verapamil Hydrochloride Extended-Release Tablets
Following a single oral dose of trandolapril and verapamil hydrochloride extended-release tablets in healthy subjects, peak plasma concentrations are reached within 0.5 to 2 hours for trandolapril and within 4 to 15 hours for verapamil. Peak plasma concentrations of the active desmethyl metabolite of verapamil, norverapamil, are reached within 5 to 15 hours. Cleavage of the ester group converts trandolapril to its active diacid metabolite, trandolaprilat, which reaches peak plasma concentrations within 2 to 12 hours. The pharmacokinetics of trandolapril and trandolaprilat are not altered when trandolapril is administered in combination with verapamil, compared to monotherapy.
The AUC and C max for both verapamil and norverapamil are increased when 240 mg of controlled release verapamil is administered concomitantly with 4 mg trandolapril. The increase in C max is 54 and 30% and the AUC is increased by 65 and 32% for verapamil and norverapamil, respectively. Administration of trandolapril and verapamil hydrochloride extended-release tablets 4 mg/240 mg (4 mg trandolapril and 240 mg verapamil hydrochloride extended-release) with a high-fat meal does not alter the bioavailability of trandolapril whereas verapamil peak concentrations and area under the curve (AUC) decrease 37% and 28%, respectively. Food thus decreases verapamil bioavailability and the time to peak plasma concentration for both verapamil and norverapamil are delayed by approximately 7 hours. Both optical isomers of verapamil are similarly affected.
The elimination half-life of trandolapril is about 6 hours. At steady state, the effective half-life of trandolaprilat is 22.5 hours. Like all ACE inhibitors, trandolaprilat also has a prolonged terminal elimination phase, involving a small fraction of administered drug, probably representing binding to plasma and tissue ACE.
The terminal half-life of verapamil is 6 to 11 hours. Steady-state plasma concentrations of the two components are achieved after about a week of once-daily dosing of trandolapril and verapamil hydrochloride extended-release tablets. At steady-state, plasma concentrations of verapamil and trandolaprilat are up to two-fold higher than those observed after a single oral trandolapril and verapamil hydrochloride extended-release tablets dose.
The pharmacokinetics of verapamil and trandolaprilat are significantly different in the elderly (≥65 years) than in younger subjects. The bioavailability of verapamil and norverapamil are increased by 87% and 77%, respectively, and that of trandolapril by approximately 35% in the elderly. AUCs are approximately 80% and 35% higher, respectively.
Verapamil Component
With the immediate release formulation, more than 90% of the orally administered dose is absorbed with peak plasma concentrations of verapamil observed 1 to 2 hours after dosing. A delayed rate but similar extent of absorption is observed for the sustained release formulation when compared to the immediate release formulation. Because of the rapid biotransformation of verapamil during its first pass through the portal circulation, absolute bioavailability ranges from 20% to 35%. A nonlinear correlation exists between verapamil dose and plasma concentrations.
In early dose titration with verapamil, a relationship exists between plasma concentrations of verapamil and prolongation of the PR interval. However, during chronic administration, this relationship may disappear. No relationship has been established between the plasma concentration of verapamil and reduction in blood pressure.
In healthy subjects, orally administered verapamil undergoes extensive metabolism in the liver. Twelve metabolites have been identified in plasma; all except norverapamil are present in trace amounts only. Approximately 70% of an administered dose is excreted as metabolites in the urine and 16% or more in the feces within 5 days. Urinary excretion of unchanged drug is about 3% to 4% of the dose. Verapamil is approximately 90% bound to plasma proteins.
In patients with hepatic insufficiency, verapamil clearance is decreased about 30% and the elimination half-life is prolonged up to 14 to 16 hours (see PRECAUTIONS ). In patients with liver dysfunction, a dosage adjustment may be required. In the elderly (≥65 years), verapamil clearance is reduced resulting in increases in elimination half-life.
Trandolapril Component
Following oral administration of trandolapril, the absolute bioavailability of trandolapril is approximately 10% as trandolapril and 70% as trandolaprilat. Plasma concentrations of trandolaprilat but not trandolapril increase in proportion with dose. Plasma concentrations of trandolaprilat decline in a triphasic manner. The more prolonged terminal elimination phase probably represents a small fraction of dose saturably bound to ACE.
After an oral radiolabeled dose of trandolapril, excretion of trandolapril and metabolites account for 33% of the dose in the urine and about 66% in the feces. Less than 1% of the dose is excreted in the urine as unchanged drug. Serum protein binding of trandolapril is about 80%, and is independent of concentration. Binding of trandolaprilat is concentration-dependent, varying from 65% at 1000 ng/mL to 94% at 0.1 ng/mL, indicating saturation of binding with increasing concentration.
Compared to normal subjects, the plasma concentrations of trandolapril and trandolaprilat are approximately 2-fold greater and renal clearance is reduced by about 85% in patients with creatinine clearance below 30 mL/min and in patients on hemodialysis. Dosage adjustment is recommended in renally impaired patients (see DOSAGE AND ADMINISTRATION ).
Following oral administration in patients with mild to moderate alcoholic cirrhosis, plasma concentrations of trandolapril and trandolaprilat were, respectively, 9-fold and 2-fold greater than in normal subjects, but inhibition of ACE activity was not affected. Lower doses should be considered in patients with hepatic insufficiency (see DOSAGE AND ADMINISTRATION ).
Pharmacodynamics
Trandolapril and Verapamil Hydrochloride Extended-Release Tablets
Verapamil does not interfere with ACE inhibition by trandolapril. Trandolapril does not alter the effect of verapamil on intra-cardiac conduction.
Verapamil Component
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.
Trandolapril Component
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.
CLINICAL STUDIES
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.
HOW SUPPLIED
Trandolapril and Verapamil Hydrochloride Extended-Release Tablets, 1 mg/240 mg are supplied as white to pinkish white colored, oval, biconvex, film-coated tablets with ‘294’ debossed on one side and plain on the other side containing 1 mg trandolapril, USP in an immediate-release form and 240 mg verapamil hydrochloride, USP in an extended-release form.
NDC 68462-294-90 — bottles of 90
NDC 68462-294-01 — bottles of 100
NDC 68462-294-10 — bottles of 1000
Trandolapril and Verapamil Hydrochloride Extended-Release Tablets, 2 mg/180 mg are supplied as pink colored, oval, biconvex, film-coated tablets with ‘295’ debossed on one side and plain on the other side containing 2 mg trandolapril, USP in an immediate-release form and 180 mg verapamil hydrochloride, USP in an extended-release form.
NDC 68462-295-90 — bottles of 90
NDC 68462-295-01 — bottles of 100
NDC 68462-295-10 — bottles of 1000
Trandolapril and Verapamil Hydrochloride Extended-Release Tablets, 2 mg/240 mg are supplied as cream colored, oval, biconvex, film-coated tablets with ‘296’ debossed on one side and plain on the other side containing 2 mg trandolapril, USP in an immediate-release form and 240 mg verapamil hydrochloride, USP in an extended-release form.
NDC 68462-296-90 — bottles of 90
NDC 68462-296-01 — bottles of 100
NDC 68462-296-10 — bottles of 1000
Trandolapril and Verapamil Hydrochloride Extended-Release Tablets, 4 mg/240 mg are supplied as brown colored, oval, biconvex, film-coated tablets with ‘G38’ debossed on one side and plain on the other side containing 4 mg trandolapril, USP in an immediate-release form and 240 mg verapamil hydrochloride, USP in an extended-release form.
NDC 68462-329-01 — bottles of 100
NDC 68462-329-10 — bottles of 1000
Dispense in well-closed container with safety closure.
Storage:
Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].
Distributed by: 
Glenmark Pharmaceuticals Inc., USA Elmwood Park, NJ 07407
Questions? 1 (888) 721-7115 www.glenmarkpharma-us.com
April 2025
