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.)
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