SIDE EFFECTS
TEVETEN® HCT 600/12.5 mg has been evaluated for safety in 268 patients
in double-blind, controlled clinical trials. Most of these patients were treated
with TEVETEN® HCT 600/12.5 mg for 29 to 60 days. Eprosartan/hydrochlorothiazide
combination therapy has been evaluated for safety in 890 patients in open-label,
long-term clinical trials. Approximately 50% of these patients were treated
with eprosartan/hydrochlorothiazide for over 2 years. Eprosartan/hydrochlorothiazide
combination therapy was well tolerated. Most adverse events were of mild or
moderate severity and did not require discontinuation of therapy. Adverse experiences
were similar in patients regardless of age, gender, or race. In the controlled
clinical trials, about 3% of the 268 patients treated with TEVETEN® HCT
600/12.5 mg discontinued therapy due to clinical adverse experiences.
Adverse Events Occurring at an Incidence of Greater Than 3% Among TEVETEN®
HCT Treated Patients
The following table lists adverse events that occurred at an incidence of > 3%
among TEVETEN® HCT 600/12.5 mg- or monotherapy-treated patients who participated
in the controlled clinical trials. Of the 268 patients who received TEVETEN®
HCT 600/12.5 mg during the double-blind treatment period in the controlled trials,
110 patients were reported to have adverse events.
Table 1: Incidence of Adverse Events > 3% During the Double-Blind
Treatment Period by Preferred Term and Treatment Grouping: Controlled Studies
|
Placebo
|
Eprosartan
600 mg
(N=275) |
HCTZ
12.5 mg
(N=117) |
HCTZ
25 mg
(N=52) |
Eprosartan
600 mg/HCTZ
12.5 mg
(N=268) |
Preferred Term |
n (%) |
n (%) |
n (%) |
n (%) |
n (%) |
Dizziness
|
4 (1.6) |
5 (1.8) |
2 (1.7) |
2 (3.8) |
11 (4.1) |
Headache
|
22 (8.9) |
10 (3.6) |
4 (3.4) |
3 (5.8) |
9 (3.4) |
Back pain
|
6 (2.4) |
7 (2.5) |
2 (1.7) |
2 (3.8) |
7 (2.6) |
Fatigue
|
6 (2.4) |
5 (1.8) |
1 (0.9) |
2 (3.8) |
5 (1.9) |
Myalgia
|
8 (3.3) |
2 (0.7) |
3 (2.6) |
0 (0.0) |
1 (0.4) |
Upper Respiratory Tract Infection
|
8 (3.3) |
2 (0.7) |
0 (0.0) |
2 (3.8) |
1 (0.4) |
Sinusitis
|
4 (1.6) |
1 (0.4) |
0 (0.0) |
2 (3.8) |
0 (0.0) |
Viral Infection
|
4 (1.6) |
0 (0.0) |
2 (1.7) |
2 (3.8) |
0 (0.0) |
The adverse events reported in over 600 patients that received TEVETEN®/hydrochlorothiazide
combination therapy for at least 1 year in the open-label, long-term clinical
trials were comparable to those reported in the controlled trials.
Eprosartan Mesylate: In addition to the adverse events above,
potentially important adverse events that are included in the current labeling
for TEVETEN® monotherapy are listed below. Most of these adverse events
occurred in < 1% of patients, or were as frequent or more frequent in the
placebo group. It is not known if these events were related to eprosartan usage:
Body as a Whole: alcohol intolerance, asthenia, substernal chest
pain, dependent edema, peripheral edema, facial edema, fatigue, fever, hot flushes,
influenza-like symptoms, injury, malaise, pain, rigors, viral infection; Cardiovascular:
angina pectoris, bradycardia, abnormal ECG, specific abnormal ECG, extrasystoles,
atrial fibrillation, hypotension (including orthostatic hypotension), tachycardia,
palpitations; Gastrointestinal: abdominal pain, anorexia, constipation,
diarrhea, dry mouth, dyspepsia, esophagitis, flatulence, gastritis, gastroenteritis,
gingivitis, nausea, periodontitis, toothache, vomiting; Hematologic:
anemia, purpura; Liver and Biliary: increased SGOT, increased
SGPT; Metabolic and Nutritional: increased creatine phosphokinase,
diabetes mellitus, glycosuria, gout, hypercholesterolemia, hyperglycemia, hyperkalemia,
hypokalemia, hyponatremia, hypertriglyceridemia; Musculoskeletal:
arthralgia, arthritis, aggravated arthritis, arthrosis, skeletal pain, tendinitis;
Nervous System/Psychiatric: anxiety, ataxia, depression, dizziness,
insomnia, migraine, neuritis, nervousness, paresthesia, somnolence, tremor,
vertigo; Resistance Mechanism: herpes simplex, otitis externa,
otitis media, upper respiratory tract infection; Respiratory:
asthma, bronchitis, coughing, epistaxis, pharyngitis, rhinitis; Skin and
Appendages: eczema, furunculosis, pruritus, rash, maculopapular rash,
increased sweating; Special Senses: conjunctivitis, abnormal vision,
xerophthalmia, tinnitus; Urinary: albuminuria, cystitis, hematuria,
micturition frequency, polyuria, renal calculus, urinary incontinence, urinary
tract infection; Vascular: leg cramps, peripheral ischemia.
Hydrochlorothiazide: Other adverse events that have been reported
for hydrochlorothiazide, without regard to causality, are listed below: Body
as a Whole: weakness; Cardiovascular: hypotension (including
orthostatic hypotension); Digestive: pancreatitis, jaundice (intrahepatic
cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation,
gastric irritation, nausea, anorexia; Hematologic: aplastic anemia,
agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia; Hypersensitivity:
anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis),
respiratory distress including pneumonitis, and pulmonary edema, photosensitivity,
fever, urticaria, rash, purpura; Metabolic: electrolyte imbalance
including hyponatremia, hypokalemia, and hypochloremic alkalosis, hyperglycemia,
glycosuria, hyperuricemia; Musculoskeletal: muscle spasm; Nervous
System/Psychiatric: vertigo, paresthesias, restlessness; Renal:
renal failure, renal dysfunction, interstitial nephritis, azotemia; Skin:
erythema multiform, including Stevens-Johnson syndrome, exfoliative dermatitis,
including toxic epidermal necrolysis, alopecia; Special Senses:
transient blurred vision, xanthopsia; Urogenital: impotence.
Laboratory Test Findings
In placebo-controlled studies, clinically important changes in standard laboratory
parameters were rarely associated with administration of TEVETEN®. Patients
were rarely withdrawn from TEVETEN® because of laboratory test results.
Laboratory test findings that have been reported for TEVETEN® are listed
below: Creatinine, Blood Urea Nitrogen: Minor elevations in creatinine
and in BUN occurred in 0.6% and 1.3%, respectively, of patients taking TEVETEN®
and 0.9% and 0.3%, respectively, of patients given placebo in controlled clinical
trials. Two patients were withdrawn from clinical trials for elevations in serum
creatinine and BUN, and three additional patients were withdrawn for increases
in serum creatinine. Liver Function Tests: Minor elevations of
ALAT, ASAT, and alkaline phosphatase occurred for comparable percentages of
patients taking TEVETEN® or placebo in controlled clinical trials. An elevated
ALAT of > 3.5 x ULN occurred in 0.1% of patients taking TEVETEN® (one
patient) and in no patient given placebo in controlled clinical trials. Four
patients were withdrawn from clinical trials for an elevation in liver function
tests. Hemoglobin: A greater than 20% decrease in hemoglobin was
observed in 0.1% of patients taking TEVETEN® (one patient) and in no patient
given placebo in controlled clinical trials. Two patients were withdrawn from
clinical trials for anemia. Leukopenia: A WBC count of ≤ 3.0 x
103/mm3 occurred in 0.3% of
patients taking TEVETEN® and in 0.3% of patients given placebo in controlled
clinical trials. One patient was withdrawn from clinical trials for leukopenia.
Neutropenia: A neutrophil count of ≤ 1.5 x 103/mm3
occurred in 1.3% of patients taking TEVETEN® and in 1.4% of patients given
placebo in controlled clinical trials. No patient was withdrawn from any clinical
trials for neutropenia. Thrombocytopenia: A platelet count of
≤ 100 x 109/L occurred in 0.3% of patients taking TEVETEN®
(one patient) and in no patient given placebo in controlled clinical trials.
Four patients receiving TEVETEN® in clinical trials were withdrawn for thrombocytopenia.
In one case, thrombocytopenia was present prior to dosing with TEVETEN®.
Serum Potassium: A potassium value of ≥ 5.6 mmol/L occurred in
0.9% of patients taking TEVETEN® and 0.3% of patients given placebo in controlled
clinical trials. One patient was withdrawn from clinical trials for hyperkalemia
and three for hypokalemia.
Additional Information: Among the adverse events reported for patients
receiving either TEVETEN® monotherapy or TEVETEN®/hydrochlorothiazide
combination therapy in the TEVETEN® HCT clinical trials, some adverse events
are not included in the current labeling for either TEVETEN® or hydrochlorothiazide
monotherapy. The adverse events which are not currently included in the labeling
for TEVETEN® or hydrochlorothiazide monotherapy include the following: angioedema,
bilirubinemia, blood urea nitrogen increased, edema periorbital, eosinophilia,
and NPN increased. The majority of these adverse events were reported in the
open-label, long-term trials and were reported in small numbers of patients
receiving TEVETEN® alone or TEVETEN® in combination with hydrochlorothiazide.
All of these adverse events were either not reported in patients receiving TEVETEN®
monotherapy or combination therapy with hydrochlorothiazide during the double-blind
period of the controlled trials, or were reported at an incidence of .1% or
in only one patient per treatment group in the controlled trials. The overall
safety profile of the TEVETEN®/hydrochlorothiazide combination treatment
is as expected based on the safety profile of each of the components and what
is generally known about the patient population.