tarka
Generic Name: (
Trandolapril and Verapamil Hydrochloride )
Dosage Type: tablet, film coated Organization: Abbott Laboratories
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, a[3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]propyl]-3,
4-dimethoxy-a-(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.
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 10% 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
TARKA
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 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 (70-85%) at 4 hours with about 1% 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 1.0 mg in non-black patients and
2.0 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 7-10/4-5 mmHg below placebo
responses in non-black patients. Once daily doses of 2 to 4 mg lowered blood
pressures 4-6/3-4 mmHg below placebo responses in black patients.
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
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 DRUG
INTERACTIONS). Patients with milder ventricular dysfunction should,
if possible, be controlled with optimum doses of digitalis and/or diuretics
before verapamil treatment (Note interactions with digoxin under: PRECAUTIONS).
Trandolapril Component
Trandolapril, as an ACE inhibitor, may cause excessive
hypotension in patients with congestive heart failure (see WARNINGS
- Hypotension).
Hypotension
Verapamil Component
Occasionally, the pharmacologic action of verapamil
may produce a decrease in blood pressure below normal levels which may result
in dizziness or symptomatic hypotension.
Trandolapril Component
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 PRECAUTIONS
-Drug Interactions and ADVERSE REACTIONS).
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 DOSAGE AND ADMINISTRATION).
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
Verapamil Component
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.
Trandolapril Component
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 TARKA is
therefore prudent.
Accessory Bypass Tract (Wolff-Parkinson-White or Lown-Ganong-Levine
Syndromes)
Verapamil Component
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 CONTRAINDICATIONS).
Treatment is usually DC-cardioversion. Cardioversion
has been used safely and effectively after oral verapamil.
Atrioventricular Block
Verapamil Component
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)
Verapamil Component
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.
Angioedema
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 TARKA
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. Where there is involvement of the tongue,
glottis, or larynx, likely to cause airway obstruction, emergency therapy,
including but not limited to subcutaneous epinephrine solution 1:1,000 (0.3
to 0.5 mL) should be promptly administered. (see PRECAUTIONS
- Information for Patients and ADVERSE
REACTIONS).
Anaphylactoid Reactions During Desensitization
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.
Anaphylactoid Reactions During Membrane Exposure
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
Trandolapril Component
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 TARKA 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/Neonatal Morbidity and Mortality
Trandolapril Component
ACE inhibitors can cause fetal and neonatal morbidity
and death when administered to pregnant women. Several dozen cases have been
reported in the world literature. When pregnancy is detected, ACE inhibitors
should be discontinued as soon as possible.
The
use of ACE inhibitors during the second and third trimesters of pregnancy
has been associated with fetal and neonatal injury, including hypotension,
neonatal skull hypoplasia, anuria, reversible or irreversible renal failure,
and death. Oligohydramnios has also been reported, presumably resulting from
decreased fetal renal function; oligohydramnios in this setting has been associated
with fetal limb contractures, craniofacial deformation, and hypoplastic lung
development. Prematurity, intrauterine growth retardation, and patent ductus
arteriosus have also been reported, although it is not clear whether these
occurrences were due to the ACE-inhibitor exposure.
These
adverse effects do not appear to have resulted from intrauterine ACE-inhibitor
exposure that has been limited to the first trimester. Mothers whose embryos
and fetuses are exposed to ACE inhibitors only during the first trimester
should be so informed. Nonetheless, when patients become pregnant, physicians
should make every effort to discontinue the use of TARKA as soon as possible.
Rarely (probably less often than once in every thousand
pregnancies), no alternative to ACE inhibitors will be found. In these rare
cases, the mothers should be apprised of the potential hazards to their fetuses,
and serial ultrasound examinations should be performed to assess the intra-amniotic
environment.
If oligohydramnios is observed,
TARKA should be discontinued unless it is considered life-saving for the mother.
Contraction stress testing (CST), a non-stress test (NST), or biophysical
profiling (BPP) may be appropriate, depending upon the week of pregnancy.
Patients and physicians should be aware, however, that oligohydramnios may
not appear until after the fetus has sustained irreversible injury.
Infants with histories of in utero exposure to ACE inhibitors
should be closely observed for hypotension, oliguria, and hyperkalemia. If
oliguria occurs, attention should be directed toward support of blood pressure
and renal perfusion. Exchange transfusion or dialysis may be required as
a means of reversing hypotension and/or substituting for disordered renal
function.
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, 1,250, and 312 times the maximum projected human dose, respectively,
assuming a 50 kg woman) did not produce teratogenic effects.
Precautions
Use in Patients with Impaired Hepatic Function
TARKA has not been evaluated in subjects with impaired
hepatic function.
Verapamil Component
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 OVERDOSAGE) should be carried
out.
Trandolapril Component
Trandolapril and trandolaprilat concentrations
increase in patients with impaired liver function.
Use in Patients with Impaired Renal Function
TARKA has not been evaluated in patients with impaired
renal function.
Verapamil Component
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 OVERDOSAGE).
Trandolapril Component
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.
Evaluation of hypertensive patients should
always include assessment of renal function (see DOSAGE
AND ADMINISTRATION).
Use in Patients with Attenuated (Decreased) Neuromuscular Transmission
Verapamil Component
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 PRECAUTIONS - Surgery/Anesthesia.)
Hyperkalemia and Potassium-sparing Diuretics
Trandolapril Component
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 PRECAUTIONS - Drug Interactions).
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
Trandolapril Component
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 PRECAUTIONS - Use
in Patients with Attenuated (Decreased) Neuromuscular Transmission.)
Drug Interactions
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 digoxintoxicity. 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 TARKA (trandolapril/verapamil hydrochloride ER), the patient
should be reassessed to avoid underdigitalization. Neither trandolapril nor
its metabolites have been found to interact with digoxin.
Lithium
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. TARKA 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.
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. Neither trandolapril nor its metabolites
have been found to interact with cimetidine.
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. The use of verapamil in combination
with a beta-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.
Antiarrhythmic Agents
Verapamil Component
Disopyramide
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.
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.
Other
Verapamil Component
Carbamazepine
Verapamil may increase carbamazepine concentrations
during combined therapy. This may produce carbamazepine side effects such
as diplopia, headache, ataxia, or dizziness.
Rifampin
Therapy with rifampin may markedly reduce
oral verapamil bioavailability.
Phenobarbital
Phenobarbital therapy may increase verapamil
clearance.
Cyclosporin
Verapamil therapy may increase serum levels
of cyclosporin.
Theophylline
Verapamil therapy may inhibit the clearance
and increase the plasma levels of theophylline.
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.
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 TARKA. The possibility of exacerbation of hypotensive effects with TARKA
may be minimized by either discontinuing the diuretic or cautiously increasing
salt intake prior to initiation of treatment with TARKA. If it is not possible
to discontinue the diuretic, the starting dose of TARKA should be reduced
(see DOSAGE AND ADMINISTRATION).
Agents Increasing Serum Potassium
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.)
Other
Trandolapril Component
Neither trandolapril nor its metabolites have
been found to interact with furosemide or nifedipine. The anticoagulant effect
of warfarin was not significantly changed by trandolapril.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Verapamil Component
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.
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/m2/day) or rats dosed up
to 8 mg/kg/day (60 mg/m2/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 in vitro and in
vivo assays.
Reproduction studies
in rats did not show any impairment of fertility at doses up to 100 mg/kg/day
(710 mg/m2/day) of trandolapril, or 1250 and 260 times the MRHDD
on the basis of body-weight and body-surface-area, respectively.
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.
ADVERSE EVENTS OCCURRING in = 1% of TARKA PATIENTS IN U.S. PLACEBO-CONTROLLED TRIALS
|
|
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 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 TARKA 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.)
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:
Bradycardia and Conduction System Abnormalities
Atropine, isoproterenol, and cardiac pacing.
Hypotension
Intravenous fluids, vasopressors (e.g., dopamine,
dobutamine), calcium solutions (e.g., 10% calcium chloride solution).
Cardiac Failures
Inotropic agents (e.g., isoproterenol, dopamine,
dobutamine), diuretics. Asystole should be handled by the usual measures
including cardiopulmonary resuscitation.
Trandolapril Component
The oral LD50 of trandolapril in mice
was 4875 mg/kg in males and 3990 mg/kg in females. In rats, an oral dose
of 5000 mg/kg caused low mortality (1 male out of 5; 0 females). In
dogs, an oral dose of 1000 mg/kg did not cause mortality and abnormal clinical
signs were not observed.
In humans, the most
likely clinical manifestation would be symptoms attributable to severe hypotension.
Laboratory determinations of serum levels of trandolapril and its metabolites
are not widely available, and such determinations have, in any event, no established
role in the management of trandolapril overdose. No data are available to
suggest that physiological maneuvers (e.g., maneuvers to change pH of the
urine) might accelerate elimination of trandolapril and its metabolites.
It is not known if trandolapril or trandolaprilat can be usefully removed
from the body by hemodialysis.
Angiotensin
II could presumably serve as a specific antagonist antidote in the setting
of trandolapril overdose, but angiotensin II is essentially unavailable outside
of scattered research facilities. Because the hypotensive effect of trandolapril
is achieved through vasodilation and effective hypovolemia, it is reasonable
to treat trandolapril overdose by infusion of normal saline solution.
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.
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Revised: 02/2006Abbott Laboratories