ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Hyperkalemia [See WARNINGS AND PRECAUTIONS]
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.
Clinical Trials Experience
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), with the most common reasons for discontinuation being hyperkalemia, myocardial infarction, and abnormal renal function.
Adverse reactions 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 2.
Table 2. Rates of Sex Hormone-Related Adverse Events in EPHESUS | Rates in Males | Rates in Females |
| Gynecomastia | Mastodynia | Either | Abnormal Vaginal Bleeding |
| INSPRA | 0.4% | 0.1% | 0.5% | 0.4% |
| Placebo | 0.5% | 0.1% | 0.6% | 0.4% |
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 3.
Table 3. 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 | INSPRA
(n=945) | Placebo
(n=372) |
| Note: Adverse events that are too general to be informative or are very common in the treated population are excluded. |
| Metabolic | | |
| Hypercholesterolemia | 1 | 0 |
| Hypertriglyceridemia | 1 | 0 |
| Digestive | | |
| Diarrhea | 2 | 1 |
| Abdominal pain | 1 | 0 |
| Urinary | | |
| Albuminuria | 1 | 0 |
| Respiratory | | |
| Coughing | 2 | 1 |
| Central/Peripheral Nervous System | | |
| Dizziness | 3 | 2 |
| Body as a Whole | | |
| Fatigue | 2 | 1 |
| Influenza-like symptoms | 2 | 1 |
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 4. 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 4. Rates of Sex Hormone-Related Adverse Events with INSPRA in Hypertension Clinical Studies | Rates in Males | Rates in Females |
| Gynecomastia | Mastodynia | Either | Abnormal Vaginal Bleeding |
| All controlled studies | 0.5% | 0.8% | 1.0% | 0.6% |
| Controlled studies lasting ≥ 6 months | 0.7% | 1.3% | 1.6% | 0.8% |
| Open-label, long-term study | 1.0% | 0.3% | 1.0% | 2.1% |
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 [see CLINICAL STUDIES], the frequencies 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 5.
Table 5. Hypokalemia (<3.5 mEq/L) or Hyperkalemia (>5.5 or ≥6.0 mEq/L) in EPHESUS | Potassium (mEq/L) | INSPRA
(N=3251)
n (%) | Placebo
(N=3237)
n (%) |
| < 3.5 | 273 | 424 (13.1) |
| >5.5 | 508 (15.6) | 363 (11.2) |
| ≥ 6.0 | 180 (5.5) | 126 (3.9) |
Table 6 shows the rates of hyperkalemia in EPHESUS as assessed by baseline renal function (creatinine clearance).
Table 6. Rates of Hyperkalemia (>5.5 mEq/L) in EPHESUS by Baseline Creatinine ClearanceEstimated using the Cockroft-Gault formula. | Baseline Creatinine Clearance | INSPRA
(N=508)
n (%) | Placebo
(N=363)
n (%) |
| ≤30 mL/min | 160 (32) | 82 (23) |
| 31—50 mL/min | 122 (24) | 46 (13) |
| 51—70 mL/min | 86 (17) | 48 (13) |
| >70 mL/min | 56 (11) | 32 (9) |
Table 7 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 WARNINGS AND PRECAUTIONS.]
Table 7. Rates of Hyperkalemia (>5.5 mEq/L) in EPHESUS by Proteinuria and History of DiabetesDiabetes assessed as positive medical history at baseline; proteinuria assessed by positive dipstick urinalysis at baseline. | INSPRA
(N=508)
n (%) | Placebo
(N=363)
n (%) |
| Proteinuria, no Diabetes | 81 (16) | 40 (11) |
| Diabetes, no Proteinuria | 91 (18) | 47 (13) |
| Proteinuria and Diabetes | 132 (26) | 58 (16) |
Hypertension
Potassium: In placebo-controlled fixed-dose studies, the mean increases in serum potassium were dose-related and are shown in Table 8 along with the frequencies of values >5.5 mEq/L.
Table 8. Increases in Serum Potassium in the Placebo-Controlled, Fixed-Dose Hypertension Studies of INSPRA | Mean Increase mEq/L | % >5.5 mEq/L |
| Daily Dosage | n | | |
| Placebo | 194 | 0 | 1 |
| 25 | 97 | 0.08 | 0 |
| 50 | 245 | 0.14 | 0 |
| 100 | 193 | 0.09 | 1 |
| 200 | 139 | 0.19 | 1 |
| 400 | 104 | 0.36 | 8.7 |
Patients with both type 2 diabetes and microalbuminuria are at increased risk of developing persistent hyperkalemia. In a study of 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 AND PRECAUTIONS.]
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.
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of INSPRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Skin: angioneurotic edema, rash
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