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Inspra

Inspra

SIDE EFFECTS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

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 0.40% 0.10% 0.50% 0.40%
Placebo 0.50% 0.10% 0.60% 0.40%

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)
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 Syste
   Dizziness 3 2
Body as a Whole
  Fatigue 2 1
  Influenza-like symptoms 2 1
Note: Adverse events that are too general to be informative or are very common in the treated population are excluded.

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 0.50% 0.80% 1.00% 0.60%
Controlled studies lasting ≥ 6 months 0.70% 1.30% 1.60% 0.80%
Open-label, long-term study 1.00% 0.30% 1.00% 2.10%

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 EPHESUSCongestive Heart Failure Post-Myocardial Infarction

Potassium (mEq/L) INSPRA
(N=3251)
n (%)
Placebo
(N=3237)
n (%)
< 3.5 273 (8.4) 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 Clearance*

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)
* Estimated using the Cockroft-Gault formula.

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 Diabetes*

  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)
* Diabetes assessed as positive medical history at baseline; proteinuria assessed by positive dipstick urinalysis at baseline.

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

Daily Dosage n Mean Increase mEq/L % > 5.5 mEq/L
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

Read the Inspra (eplerenone) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

CYP3A4 Inhibitors

Because eplerenone metabolism is predominantly mediated via CYP3A4, do not use INSPRA with drugs that are strong inhibitors of CYP3A4 [see CONTRAINDICATIONS and CLINICAL PHARMACOLOGY].

In patients with hypertension taking moderate CYP3A4 inhibitors, reduce the starting dose of INSPRA to 25 mg once daily [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

ACE Inhibitors and Angiotensin II Receptor Antagonists

The risk of hyperkalaemia may increase when eplerenone is used in combination with an angiotensin converting enzyme (ACE) inhibitor and/or an angiotensin receptor blocker (ARB). A close monitoring of serum potassium and renal function is recommended, especially in patients at risk for impaired renal function, e.g., the elderly [see WARNINGS AND PRECAUTIONS].

Congestive Heart Failure Post-Myocardial Infarction

In EPHESUS [see Clinical Studies], 3020 (91%) patients receiving INSPRA 25 to 50 mg also received ACE inhibitors or angiotensin II receptor antagonists (ACEI/ARB). Rates of patients with maximum potassium levels > 5.5 mEq/L were similar regardless of the use of ACEI/ARB.

Hypertension

In clinical studies of patients with hypertension, the addition of INSPRA 50 to 100 mg to ACE inhibitors and angiotensin II receptor antagonists increased mean serum potassium slightly (about 0.09– 0.13 mEq/L). In a study in diabetics with microalbuminuria, INSPRA 200 mg combined with the ACE inhibitor enalapril 10 mg increased the frequency of hyperkalemia (serum potassium > 5.5 mEq/L) from 17% on enalapril alone to 38%.

Lithium

A drug interaction study of eplerenone with lithium has not been conducted. Lithium toxicity has been reported in patients receiving lithium concomitantly with diuretics and ACE inhibitors. Serum lithium levels should be monitored frequently if INSPRA is administered concomitantly with lithium.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

A drug interaction study of eplerenone with an NSAID has not been conducted. The administration of other potassium-sparing antihypertensives with NSAIDs has been shown to reduce the antihypertensive effect in some patients and result in severe hyperkalemia in patients with impaired renal function. Therefore, when INSPRA and NSAIDs are used concomitantly, patients should be observed to determine whether the desired effect on blood pressure is obtained and monitored for changes in serum potassium levels.

Read the Inspra Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 6/3/2013
This monograph has been modified to include the generic and brand name in many instances.

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