Congestive Heart Failure Post-Myocardial Infarction
In EPHESUS, safety was evaluated in 3307 patients treated with INSPRA and 3301 placebo-treated
patients. The overall incidence of adverse events reported with INSPRA (78.9%) was
similar to placebo (79.5%). Adverse events occurred at a similar rate regardless
of age, gender, or race. Patients discontinued treatment due to an adverse event
at similar rates in either treatment group (4.4% INSPRA vs. 4.3% placebo).
Adverse events that occurred more frequently in patients treated with INSPRA than
placebo were hyperkalemia (3.4% vs 2.0%) and increased creatinine (2.4% vs 1.5%).
Discontinuations due to hyperkalemia or abnormal renal function were less than 1.0%
in both groups. Hypokalemia occurred less frequently in patients treated with INSPRA
(0.6% vs. 1.6%).
The rates of sex hormone related adverse events are shown in Table 3.
Table 3. Rates of Sex Hormone Related Adverse Events in EPHESUS
Hypertension
INSPRA has been evaluated for safety in 3091 patients treated for hypertension.
A total of 690 patients were treated for over 6 months and 106 patients were treated
for over 1 year.
In placebo-controlled studies, the overall rates of adverse events were 47% with
INSPRA and 45% with placebo. Adverse events occurred at a similar rate regardless
of age, gender, or race. Therapy was discontinued due to an adverse event in 3%
of patients treated with INSPRA and 3% of patients given placebo. The most common
reasons for discontinuation of INSPRA were headache, dizziness, angina pectoris/myocardial
infarction, and increased GGT. The adverse events that were reported at a rate of
at least 1% of patients and at a higher rate in patients treated with INSPRA in
daily doses of 25 to 400 mg versus placebo are shown in Table 4.
Table 4. Rates (%) of Adverse Events Occurring in Placebo-Controlled Hypertension
Studies in ≥1% of Patients Treated with INSPRA (25 to 400 mg) and at a More Frequent
Rate than in Placebo-Treated Patients
Gynecomastia and abnormal vaginal bleeding were reported with INSPRA but not with
placebo. The rates of these sex hormone related adverse events are shown in Table
5. The rates increased slightly with increasing duration of therapy. In females,
abnormal vaginal bleeding was also reported in 0.8% of patients on antihypertensive
medications (other than spironolactone) in active control arms of the studies with
INSPRA.
Table 5. Rates of Sex Hormone Related Adverse Events with INSPRA in Hypertension
Clinical Studies
Clinical Laboratory Test Findings
Congestive Heart Failure Post-Myocardial Infarction:
Creatinine- Increases of more than 0.5 mg/dL were reported for 6.5% of patients
administered INSPRA and for 4.9% of placebo-treated patients.
Potassium- In EPHESUS, the frequency of patients with changes in potassium
(<3.5 mEq/L or >5.5 mEq/L or ≥6.0 mEq/L) receiving INSPRA compared with placebo
are displayed in Table 6.
Table 6. Hypokalemia (<3.5 mEq/L) or Hyperkalemia (>5.5 or ≥6.0 mEq/L) in EPHESUS
Table 7 shows the rates of hyperkalemia in EPHESUS as assessed by baseline renal
function (creatinine clearance).
Table 7. Rates of Hyperkalemia (>5.5 mEq/L) in EPHESUS by Baseline Creatinine
Clearance*
Table 8 shows the rates of hyperkalemia in EPHESUS as assessed by two baseline characteristics:
presence/absence of proteinuria from baseline urinalysis and presence/absence of
diabetes. (See PRECAUTIONS, Hyperkalemia in Patients Treated for Congestive Heart
Failure.)
Table 8. Rates of Hyperkalemia (>5.5 mEq/L) in EPHESUS by Proteinuria and History
of Diabetes*
Hypertension:
Potassium- In placebo-controlled fixed-dose studies, the mean increases in
serum potassium were dose related and are shown in Table 9 along with the frequencies
of values >5.5 mEq/L.
Table 9. Changes in Serum Potassium in the Placebo-Controlled, Fixed-Dose Hypertension
Studies of INSPRA
Patients with both type 2 diabetes and microalbuminuria are at increased risk of
developing persistent hyperkalemia. In a study in such patients taking INSPRA 200
mg, the frequencies of maximum serum potassium levels >5.5 mEq/L were 33% with
INSPRA given alone and 38% when INSPRA was given with enalapril.
Rates of hyperkalemia increased with decreasing renal function. In all studies serum
potassium elevations >5.5 mEq/L were observed in 10.4% of patients treated with
INSPRA with baseline calculated creatinine clearance <70 mL/min, 5.6% of patients
with baseline creatinine clearance of 70 to 100 mL/min, and 2.6% of patients with
baseline creatinine clearance of >100 mL/min. (See WARNINGS, Hyperkalemia in Patients
Treated for Hypertension.)
Sodium- Serum sodium decreased in a dose-related manner. Mean decreases ranged
from 0.7 mEq/L at 50 mg daily to 1.7 mEq/L at 400 mg daily. Decreases in sodium
(<135 mEq/L) were reported for 2.3% of patients administered INSPRA and 0.6%
of placebo-treated patients.
Triglycerides- Serum triglycerides increased in a dose-related manner. Mean
increases ranged from 7.1 mg/dL at 50 mg daily to 26.6 mg/dL at 400 mg daily. Increases
in triglycerides (above 252 mg/dL) were reported for 15% of patients administered
INSPRA and 12% of placebo-treated patients.
Cholesterol- Serum cholesterol increased in a dose-related manner. Mean changes
ranged from a decrease of 0.4 mg/dL at 50 mg daily to an increase of 11.6 mg/dL
at 400 mg daily. Increases in serum cholesterol values greater than 200 mg/dL were
reported for 0.3% of patients administered INSPRA and 0% of placebo-treated patients.
Liver Function Tests- Serum alanine aminotransferase (ALT) and gamma glutamyl
transpeptidase (GGT) increased in a dose-related manner. Mean increases ranged from
0.8 U/L at 50 mg daily to 4.8 U/L at 400 mg daily for ALT and 3.1 U/L at 50 mg daily
to 11.3 U/L at 400 mg daily for GGT. Increases in ALT levels greater than 120 U/L
(3 times upper limit of normal) were reported for 15/2259 patients administered
INSPRA and 1/351 placebo-treated patients. Increases in ALT levels greater than
200 U/L (5 times upper limit of normal) were reported for 5/2259 of patients administered
INSPRA and 1/351 placebo-treated patients. Increases of ALT greater than 120 U/L
and bilirubin greater than 1.2 mg/dL were reported 1/2259 patients administered
INSPRA and 0/351 placebo-treated patients. Hepatic failure was not reported in patients
receiving INSPRA.
BUN/Creatinine- Serum creatinine increased in a dose-related manner. Mean
increases ranged from 0.01 mg/dL at 50 mg daily to 0.03 mg/dL at 400 mg daily. Increases
in blood urea nitrogen to greater than 30 mg/dL and serum creatinine to greater
than 2 mg/dL were reported for 0.5% and 0.2%, respectively, of patients administered
INSPRA and 0% of placebo-treated patients.
Uric Acid- Increases in uric acid to greater than 9 mg/dL were reported in
0.3% of patients administered INSPRA and 0% of placebo-treated patients.