Dosing and uses of Tarka (trandolapril/verapamil)
Adult dosage forms and strengths
trandolapril/verapamiL
tablet
- 2mg/180mg
- 1mg/240mg
- 2mg/240mg
- 4mg/240mg
Combines an immediate-release formulation of an angiotensin converting enzyme inhibitor, trandolapril and a slow-release formulation of a calcium channel blocker, verapamil hydrochloride
Hypertension
Not indicated for initial therapy
Usual dose: Trandolapril 1- 4 mg/verapamil HCl ER 180-240 mg PO qDay
For convenience, patients receiving trandolapril (up to 8 mg) and verapamil (up to 240 mg) in separate tablets, administered qDay, may instead receive tablets of combination containing the same component doses
Clinical trials with combination have explored only qDay dosing
Renal Impairment
CrCl < 30 mL/min: Adjust regimen
Hepatic Impairment
Not studied
Administration
Administer with food
Tablets contain verapamil hydrochloride as a controlled release formulation and trandolapril as an immediate release formulation
Pediatric dosage forms and strengths
<18 years: Safety/efficacy not established
Tarka (trandolapril/verapamil) adverse (side) effects
>10%
VerapamiL
- Headache (1-12 %)
- Gingival hyperplasia (≤ 19%)
- Constipation (7-12%)
TrandolapriL
- Hypotension (1-11%)
- Dizziness (1-23%)
- Increased uric acid (15%)
- Cough (2-35%)
1-10%
VerapamiL
- Dizziness (4%)
- Dyspepsia (3%)
- Edema (2%)
- Fatigue (2%)
- Lethargy (3%)
- Pain (2%)
- Sleep disturbance (1%)
- Increased liver enzymes (1%)
- Pulmonary edema (2%)
- Flushing (1%)
- Hypotension (4%)
- Nausea (3%)
TrandolapriL
- Syncope (6%)
- Bradycardia (1-5%)
- Stroke (3%)
- Gastritis (4%)
- Diarrhea (1%)
- Weakness (3%)
- Myalgia (5%)
< 1%
TrandolapriL
- Angioedema
- ARF if renal artery stenosis
- Cough
VerapamiL
- Abdominal discomfort
- Arthralgia
- Extrapyramidal symptoms
- Gastrointestinal distress
- Hyperkeratosis
- Gynecomastia
Warnings
Black box warnings
Trandolapril: Discontinue as soon as possible when pregnancy is detected; affects renin-angiotensin system causing oligohydramnios, which may result in fetal injury and/or death
Contraindications
Hypersensitivity to either component
Second- or third-degree AV block (unless permanent pacemaker in place)
Hypotension (systolic pressure less than 90 mmHg) or cardiogenic shock
Concomitant use with aliskiren in patients with diabetes mellitus
Sick sinus syndrome (unless permanent pacemaker in place)
Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g. Wolff-Parkinson-White, Lown-Ganong-Levine syndromes)
Pregnancy (2nd and 3rd trimesters): significant risk of fetal and neonatal morbidity and mortality
Do not coadminister with aliskiren in patients with diabetes
History of angioedema
Severe left ventricular dysfunction
Cautions
Aortic stenosis, hypotension (initially or after dose increases) reported
Persistent progressive dermatologic reactions reported
Avoid taking with grapefruit juice
Use caution in heart failure or compromised ventricular function
Use caution in liver or renal impairment
Use caution and monitor closely if adminstered with concurrent beta blocker therapy
Excessive hypotension may occur if administered with concomitant diuretics, hypovolemia, hyponatremia
Dual blockade of the renin angiotensin system with ARBs, ACE inhibitors, or aliskiren associated with increased risk for hypotension, hyperkalemia, and renal function changes (including acute renal failure) compared to monotherapy
Avoid concomitant use of verapamil and quinidine in patients with hypertrophic cardiomyopathy; may cause significant hypotension
Hemodialysis with high flux membrane and low-density lipoprotein apharesis associated with anaphylactoid reactions
Avoid verapamil in patients with severe left ventricular dysfunction (e.g., ejection fraction < 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
ACE inhibitors may cause excessive hypotension in patients with congestive heart failure
Verapamil may produce a decrease in blood pressure below normal levels which may result in dizziness or symptomatic hypotension
ACE inhibitors rarely associated with syndrome of cholestatic jaundice, fulminant hepatic necrosis, and death; mechanism of this syndrome is not understood; patients receiving ACE inhibitors who develop jaundice should discontinue therapy
Not for administration to patients with paroxysmal and/or chronic atrial fibrillation or atrial flutter and a coexisting accessory AV pathway
Reduce dose if marked first-degree block or progressive development to second-or third-degree AV block; in rare instances, discontinuation of verapamil HCl and institution of appropriate therapy depending upon clinical situation may be necessary
Patients receiving coadministration of an ACE inhibitor with an mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) may be at increased risk for angioedema
Discontinue immediately if If laryngeal stridor or angioedema of the face, tongue or glottis occurs
Administration of other ACE inhibitors have been associated with 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; consider periodic monitoring of white blood cell counts in patients with collagen-vascular disease and/or renal disease
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
Pregnancy and lactation
Pregnancy category: C (1st trimester); D (2nd and 3rd trimester)
Lactation: excreted in breast milk, use caution
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Tarka (trandolapril/verapamil)
Mechanism of action
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
Trandolapril competitively inhibits angiotensin-converting enzymes resulting in decreased plasma angiotensin II concentrations and consequently, blood pressure may be reduced in part through decreased vasoconstriction, increased renin activity, and decreased aldosterone secretion
Verapamil, a nondihydropyridine calcium-channel blocker, inhibits transmembrane influx of extracellular Ca ions across membranes of myocardial cells and vascular smooth muscle cells, without changing serum calcium concentrations, resulting in inhibition of cardiac and vascular smooth muscle contraction, thereby dilating main coronary and systemic arteries
Pharmacokinetics
TrandolapriL
- Half-life: 6 (trandolapril); 22.5 hr (trandolaprilat)
- Onset: 1-2 hr
- Duration: 72 hr
- Vd: 18 L
- Peak plasma time: 1 hr (trandolapril); 4-10 hr (trandolaprilat)
- Bioavailability: 10% (trandolapril); 70% (trandolaprilat)
- Protein bound: 80% (trandolapril); 65-94% (trandolaprilat)
- Metabolism: Liver, undergoes hepatic biotransformation to trandolaprilat
- Metabolites: Trandolaprilat (active)
- Clearance: 52 L/hr (total body); 1-4 L/hr (renal)
- Excretion: Urine 33%, feces 66%
- Dialyzable: Yes
VerapamiL
- Half-life: 4-12 hr (parent drug); 6-10 hr (norverapamil); increases to 14-16 hr in liver disease patients (norverapamil)
- Bioavailability: 20-35%
- Onset: 1-2 hr (peak effect)
- Duration: 6-8 hr (PO); 10-20 min (IV)
- Vd: 3.9 L/kg
- Peak plasma time: 1-2 hr (immediate release); 11 hr (extended release); 4-5 hr (delayed release); 5-9 hr (sustained release)
- Protein bound: 90%
- Metabolism: Liver via P450 enzyme CYP3A4
- Metabolites: Norverapamil (active)
- Clearance: 0.5-1 L/kg
- Excretion: Urine (70%); feces (16%)
- Dialyzable: HD No
