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TARKA®
(trandolapril/verapamil hydrochloride ER tablets)
USE IN PREGNANCY
When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, TARKA should be discontinued as soon as possible.See WARNINGS - Fetal/Neonatal Morbidity and Mortality.
DESCRIPTION
TARKA (trandolapril/verapamil hydrochloride ER) combines a slow release formulation of a calcium channel blocker, verapamil hydrochloride, and an immediate release formulation of an angiotensin converting enzyme inhibitor, trandolapril.
Verapamil Component
Verapamil hydrochloride is chemically described as benzeneacetonitrile, α[3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]propyl]-3, 4-dimethoxy-α-(1-methylethyl) hydrochloride. Its empirical formula is C27H38N2O4 HCl and its structural formula is:
Verapamil hydrochloride is an almost white crystalline powder, with a molecular weight of 491.08. It is soluble in water, chloroform, and methanol. It is practically free of odor, with a bitter taste.
Trandolapril Component
Trandolapril is the ethyl ester prodrug of a nonsulfhydryl angiotensin converting enzyme (ACE) inhibitor, trandolaprilat. It is chemically described as (2S,3aR,7aS)-1-[(S)-N-[(S)-Carboxy-3-phenylpropyl]alanyl] hexahydro-2-indolinecarboxylic acid, 1-ethyl ester. Its empirical formula is C24 H34 N2O5 and its structural formula is:
Trandolapril is a colorless, crystalline substance with a molecular weight of 430.54. It is soluble (>100 mg/mL) in chloroform, dichloromethane, and methanol.
TARKA tablets are formulated for oral administration, containing verapamil hydrochloride as a controlled release formulation and trandolapril as an immediate release formulation. The tablet strengths are trandolapril 2 mg/verapamil hydrochloride ER 180 mg, trandolapril 1 mg/verapamil hydrochloride ER 240 mg, trandolapril 2 mg/verapamil hydrochloride ER 240 mg, and trandolapril 4 mg/verapamil hydrochloride ER 240 mg. The tablets also contain the following ingredients: corn starch, dioctyl sodium sulfosuccinate, ethanol, hydroxypropyl cellulose, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, purified water, silicon dioxide, sodium alginate, sodium stearyl fumarate, synthetic iron oxides, talc, and titanium dioxide.
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 TARKA 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 TARKA 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
TARKA
Following a single oral dose of TARKA in healthy subjects, peak plasma concentrations are reached within 0.5-2 hours for trandolapril and within 4-15 hours for verapamil. Peak plasma concentrations of the active desmethyl metabolite of verapamil, norverapamil, are reached within 5-15 hours. Cleavage of the ester group converts trandolapril to its active diacid metabolite, trandolaprilat, which reaches peak plasma concentrations within 2-12 hours. The pharmacokinetics of trandolapril and trandolaprilat are not altered when trandolapril is administered in combination with verapamil, compared to monotherapy. The AUC and Cmax for both verapamil and norverapamil are increased when 240 mg of controlled release verapamil is administered concomitantly with 4 mg trandolapril. The increase in Cmax is 54 and 30% and the AUC is increased by 65 and 32% for verapamil and norverapamil, respectively. Administration of TARKA 4/240 (4 mg trandolapril and 240 mg verapamil hydrochloride ER) 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.
Trandolaprilat has an effective elimination half-life of approximately 10 hours but like all ACE inhibitors, it has a prolonged terminal elimination half-life. The terminal half-life of verapamil is 6-11 hours. Steady-state plasma concentrations of the two components are achieved after about a week of once-daily dosing of TARKA. At steady-state, plasma concentrations of verapamil and trandolaprilat are up to two-fold higher than those observed after a single oral TARKA 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.
Pharmacodynamics
TARKA
Verapamil does not interfere with ACE inhibition by trandolapril. Trandolapril does not alter the effect of verapamil on intra-cardiac conduction.
CLINICAL STUDIES
In controlled clinical trials, once daily doses of TARKA, trandolapril 4 mg/verapamil HCl ER 240 mg or trandolapril 2 mg/verapamil HCl ER 180 mg, decreased placebo-corrected seated pressure (systolic/diastolic) 24 hours after dosing by about 7-12/6-8 mmHg. Each of the components of TARKA 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 TARKA 4/240 combination than for either of the components used alone.
The antihypertensive effects of TARKA have continued during therapy for at least 1 year.
Indications and Usage
TARKA is 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 TARKA, 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).
Contraindications
TARKA is contraindicated in patients who are hypersensitive to any ACE inhibitor or verapamil.
Because of the verapamil component, TARKA is contraindicated in:
- Severe left ventricular dysfunction (see WARNINGS).
- Hypotension (systolic pressure less than 90 mmHg) or cardiogenic shock.
- Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker).
- Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker).
- Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g. Wolff-Parkinson-White, Lown-Ganong-Levine syndromes) (see WARNINGS).
Because of the trandolapril component, TARKA is contraindicated in patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme (ACE) inhibitor.
WARNINGS
Heart Failure
Hypotension
Elevated Liver Enzymes/Hepatic Failure
Accessory Bypass Tract (Wolff-Parkinson-White or Lown-Ganong-Levine Syndromes)
Atrioventricular Block
Patients with Hypertrophic Cardiomyopathy (IHSS)
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.
Neutropenia/Agranulocytosis
Fetal/Neonatal Morbidity and Mortality
Precautions
Use in Patients with Impaired Hepatic Function
TARKA has not been evaluated in subjects with impaired hepatic function.
Use in Patients with Impaired Renal Function
TARKA has not been evaluated in patients with impaired renal function.
Use in Patients with Attenuated (Decreased) Neuromuscular Transmission
Hyperkalemia and Potassium-sparing Diuretics
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
Drug Interactions
Beta Blockers
Antiarrhythmic Agents
Other
Concomitant Diuretic Therapy
Other
Carcinogenesis, Mutagenesis, Impairment of Fertility
Pregnancy
Pregnancy Categories C (first trimester) and D (second and third trimesters). See WARNINGS - Fetal/Neonatal Morbidity and Mortality.
Nursing Mothers
Verapamil is excreted in human milk. Radiolabeled trandolapril or its metabolites are secreted in rat milk. TARKA should not be administered to nursing mothers.
Geriatric Use
In placebo-controlled studies, where 23% of patients receiving TARKA 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
The safety and effectiveness of TARKA 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.
ADVERSE REACTIONS
TARKA has 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 TARKA, 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. TARKA has 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 TARKA 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.
| TARKA (N = 541) % Incidence (% Discontinuance) | PLACEBO (N = 206) % Incidence (% Discontinuance) | |
* Also includes increase in SGPT, SGOT, Alkaline Phosphatase + Incidence of adverse events is higher in Placebo group than TARKA patients | ||
| 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) |
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 TARKA 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 TARKA 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 TARKA (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.
Fetal/Neonatal Morbidity and Mortality
See WARNINGS - Fetal Neonatal Morbidity and Mortality.
Other adverse experiences (in addition to those in table and uled above) that have been reported with the individual components are uled below.
Verapamil Component
Trandolapril Component
Clinical Laboratory Test Findings
OVERDOSAGE
No specific information is available on the treatment of overdosage with TARKA.
Verapamil Component
Overdose with verapamil may lead to pronounced hypotension, bradycardia, and conduction system abnormalities (e.g., junctional rhythm with AV dissociation and high degree AV block, including asystole). Other symptoms secondary to hypoperfusion (e.g., metabolic acidosis, hyperglycemia, hyperkalemia, renal dysfunction, and convulsions) may be evident.
Treat all verapamil overdoses as serious and maintain observation for at least 48 hours, preferably under continuous hospital care. Delayed pharmacodynamic consequences may occur with the sustained release formulation. Verapamil is known to decrease gastrointestinal transit time. In cases of overdose, tablets of ISOPTIN SR have occasionally been reported to form concretions within the stomach or intestines. These concretions have not been visible on plain radiographs of the abdomen, and no medical means of gastrointestinal emptying is of proven efficacy in removing them. Endoscopy might reasonably be considered in cases of overdose when symptoms are unusually prolonged. Verapamil cannot be removed by hemodialysis.
Treatment of overdosage should be supportive. Beta adrenergic stimulation or parenteral administration of calcium solutions may increase calcium ion flux across the slow channel, and have been used effectively in treatment of deliberate overdosage with verapamil. The following measures may be considered:
Trandolapril Component
The oral LD50 of trandolapril in mice was 4875 mg/kg in males and 3990 mg/kg in females. In rats, an oral dose of 5000 mg/kg caused low mortality (1 male out of 5; 0 females). In dogs, an oral dose of 1000 mg/kg did not cause mortality and abnormal clinical signs were not observed.
In humans, the most likely clinical manifestation would be symptoms attributable to severe hypotension. Laboratory determinations of serum levels of trandolapril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of trandolapril overdose. No data are available to suggest that physiological maneuvers (e.g., maneuvers to change pH of the urine) might accelerate elimination of trandolapril and its metabolites. It is not known if trandolapril or trandolaprilat can be usefully removed from the body by hemodialysis.
Angiotensin II could presumably serve as a specific antagonist antidote in the setting of trandolapril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of trandolapril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat trandolapril overdose by infusion of normal saline solution.
Dosage and Administration
The recommended usual dosage range of trandolapril for hypertension is 1 to 4 mg per day administered in a single dose or two divided doses. The recommended usual dosage range of Isoptin-SR for hypertension is 120 to 480 mg per day administered in a single dose or two divided doses.
The hazards (see WARNINGS) of trandolapril are generally independent of dose; those of verapamil are a mixture of dose-dependent phenomena (primarily dizziness, AV block, constipation) and dose-independent phenomena, the former much more common than the latter. Therapy with any combination of trandolapril and verapamil will thus be associated with both sets of dose-independent hazards. The dose-dependent side effects of verapamil have not been shown to be decreased by the addition of trandolapril nor visa versa.
Rarely, the dose-independent hazards of trandolapril are serious. To minimize dose-independent hazards, it is usually appropriate to begin therapy with TARKA 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 TARKA have explored only once-a-day doses. The antihypertensive effect and or adverse effects of adding 4 mg of trandolapril once-a-day to a dose of 240 mg Isoptin-SR administered twice-a-day has not been studied, nor have the effects of adding as little of 180 mg Isoptin-SR to 2 mg trandolapril administered twice-a-day been evaluated. Over the dose range of Isoptin-SR 120 to 240 mg once-a-day and trandolapril 0.5 to 8 mg once-a-day, the effects of the combination increase with increasing doses of either component.
Replacement Therapy
For convenience, patients receiving trandolapril (up to 8 mg) and verapamil (up to 240 mg) in separate tablets, administered once-a-day, may instead wish to receive tablets of TARKA containing the same component doses.
TARKA should be administered with food.
HOW SUPPLIED
TARKA 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 embossed with a triangle and 182 on one side and plain on the other side.
NDC 0074-3287-13 - bottles of 100
TARKA 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 embossed with a triangle and 241 on one side and plain on the other side.
NDC 0074-3288-13 - bottles of 100
TARKA 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 embossed with a triangle and 242 on one side and plain on the other side.
NDC 0074-3289-13 - bottles of 100
TARKA 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 embossed with a triangle and 244 on one side and plain on the other side.
NDC 0074-3290-13 - bottles of 100
Dispense in well-closed container with safety closure.
Storage
Store at 15°-25°C (59°-77°F) see USP.
Abbott Laboratories
North Chicago, IL 60064, U.S.A.