`• Concomitant use with strong CYP3A4 inhibitors (4, 7.1)
`
`For the treatment of hypertension:
`
`
`• Type 2 diabetes with microalbuminuria (4)
`
`• Serum creatinine >2.0 mg/dL in males, >1.8 mg/dL in females (4)
`• Creatinine clearance <50 mL/min (4)
`
`
`• Concomitant use of potassium supplements or potassium-sparing
`diuretics (4)
`
`
`
`
`
`-----------------------WARNINGS AND PRECAUTIONS-------------------
`
`
`• Hyperkalemia: Patients with decreased renal function and diabetics with
`proteinuria are at increased risk. Proper patient selection and monitoring
`
`and avoiding certain concomitant medications can minimize the risk.
`
`(5.1)
`
`
`------------------------------ADVERSE REACTIONS--------------------------
`CHF Post-MI: Most common adverse reactions (>2% and more frequent
`
`than with placebo): hyperkalemia and increased creatinine. (6.1)
`Hypertension: Most common adverse reactions (≥2% and more frequent
`than with placebo): dizziness, diarrhea, coughing, fatigue and flu-like
`
`symptoms. (6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc at
`1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`------------------------------DRUG INTERACTIONS--------------------------
`
`
`• CYP3A4 Inhibitors: Reduce the starting dose for hypertension to 25 mg
`
`
`once daily when used with moderate CYP3A4 inhibitors (e.g.,
`
`
`
`verapamil, erythromycin, saquinavir, fluconazole). (2.4, 7.1, 12.3)
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`
`Revised: APR 2008
`
`
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`INSPRA safely and effectively. See full prescribing information for
`
`INSPRA.
`
`INSPRA (eplerenone) tablets
`Initial U.S. Approval: 2002
`
`
`
`------------------------INDICATIONS AND USAGE--------------------------
`INSPRA is an aldosterone antagonist indicated for:
`
`
`• Improving survival of stable patients with LV systolic dysfunction
`(LVEF ≤40%) and CHF after an acute myocardial infarction. (1.2)
`
`
`• Hypertension, alone or combined with other agents. (1.3)
`
`----------------------DOSAGE AND ADMINISTRATION-------------------
`
`CHF Post-MI: Initiate treatment with 25 mg once daily. Titrate to
`maximum of 50 mg once daily within 4 weeks, as tolerated. Dose
`adjustments may be required based on potassium levels. (2.1)
`
`Hypertension: 50 mg once daily, alone or combined with other
`
`antihypertensive agents. For inadequate response, increase to 50 mg twice
`daily. Higher dosages are not recommended. (2.2)
`
`
`
`For all patients:
`
`Measure serum potassium before starting INSPRA and periodically
`
`thereafter. (2.3)
`
`---------------------DOSAGE FORMS AND STRENGTHS-----------------
`Tablets: 25 mg, 50 mg (3)
`
`
`-------------------------------CONTRAINDICATIONS------------------------
`For all patients:
`
`
`• Serum potassium >5.5 mEq/L at initiation (4)
`
`
`
`
`• Creatinine clearance ≤30 mL/min (4)
`___________________________________________________________________________________________________________________________________
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1
`INDICATIONS AND USAGE
`1.1 Patient Selection Considerations
`1.2 Congestive Heart Failure Post-Myocardial Infarction
`1.3 Hypertension
`
`DOSAGE AND ADMINISTRATION
`2.1 Congestive Heart Failure Post-Myocardial Infarction
`2.2 Hypertension
`2.3 Recommended Monitoring
`2.4 Dose Modifications for Specific Populations
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1 Hyperkalemia
`5.2
`Impaired Hepatic Function
`5.3
`Impaired Renal Function
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Clinical Laboratory Test Findings
`6.3 Postmarketing Experience
`
`* Sections or subsections omitted from the full prescribing information
`DRUG INTERACTIONS
`7.1 CYP3A4 Inhibitors
`are not listed.
`
`7.2 ACE Inhibitors and Angiotensin II Receptor Antagonists
`
`
`7.3 Lithium
`___________________________________________________________________________________________________________________________________
`
`
`7.4 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
`USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`14 CLINICAL STUDIES
`
`14.1 Congestive Heart Failure Post-Myocardial Infarction
`14.2 Hypertension
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`
`
`8
`
`
`
`
`
`
`
`
`
`
`
`
`2
`
`
`
`
`6
`
`
`7
`
`JANSSEN EXHIBIT 2129
`Mylan v. Janssen IPR2016-01332
`
`

`

`4 CONTRAINDICATIONS
`For All Patients
`
`INSPRA is contraindicated in all patients with:
`
`
`• serum potassium >5.5 mEq/L at initiation,
`
`
`• creatinine clearance ≤30 mL/min, or
`
`• concomitant administration of strong CYP3A4 inhibitors (e.g.,
`
`ketoconazole, itraconazole, nefazodone, troleandomycin,
`
`clarithromycin, ritonavir, and nelfinavir). [See DRUG
`
`INTERACTIONS (7.1), CLINICAL PHARMACOLOGY (12.3).]
`
`
`
`
`For Patients Treated for Hypertension
`
`INSPRA is contraindicated for the treatment of hypertension in
`patients with:
`type 2 diabetes with microalbuminuria,
`•
`
`serum creatinine >2.0 mg/dL in males or >1.8 mg/dL in females,
`•
`•
`creatinine clearance <50 mL/min, or
`•
` concomitant administration of potassium supplements or
`
`potassium-sparing diuretics (e.g., amiloride, spironolactone, or
`
`
`triamterene). [See WARNINGS AND PRECAUTIONS (5.1),
`
`ADVERSE REACTIONS (6.2), DRUG INTERACTIONS (7), and
`
`CLINICAL PHARMACOLOGY (12.3).]
`
`
`
`
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Hyperkalemia
`
`
`Minimize the risk of hyperkalemia with proper patient selection and
`
`monitoring, and avoidance of certain concomitant medications [See
`CONTRAINDICATIONS (4), ADVERSE REACTIONS (6.2), and DRUG
`INTERACTIONS (7)]. Monitor patients for the development of
`
`hyperkalemia until the effect of INSPRA is established. Patients who
`develop hyperkalemia (>5.5 mEq/L) may continue INSPRA therapy with
`
`proper dose adjustment. Dose reduction decreases potassium levels. [See
`
`
`
`DOSAGE AND ADMINISTRATION (2.1).]
`
`
`The rates of hyperkalemia increase with declining renal function. [See
`ADVERSE REACTIONS (6.2).] Patients with hypertension who have
`serum creatinine levels >2.0 mg/dL (males) or >1.8 mg/dL (females) or
`
`creatinine clearance ≤50 mL/min should not be treated with INSPRA. [See
`
`CONTRAINDICTIONS (4).] Patients with CHF post-MI who have serum
`
`creatinine levels >2.0 mg/dL (males) or >1.8 mg/dL (females) or creatinine
`clearance ≤50mL/min should be treated with INSPRA with caution.
`
`
`Diabetic patients with CHF post-MI should also be treated with
`caution, especially those with proteinuria. The subset of patients in the
`
`EPHESUS study with both diabetes and proteinuria on the baseline
`
`urinalysis had increased rates of hyperkalemia compared to patients with
`either diabetes or proteinuria. [See ADVERSE REACTIONS (6.2).]
`
`
`5.2
`Impaired Hepatic Function
`
`Mild-to-moderate hepatic impairment did not increase the incidence of
`
`hyperkalemia. In 16 subjects with mild-to-moderate hepatic impairment
`
`
`who received 400 mg of eplerenone, no elevations of serum potassium
`
`above 5.5 mEq/L were observed. The mean increase in serum potassium
`
`
`
`was 0.12 mEq/L in patients with hepatic impairment and 0.13 mEq/L in
`normal controls. The use of INSPRA in patients with severe hepatic
`
`impairment has not been evaluated. [See CLINICAL PHARMACOLOGY
`
`
`(12.3).]
`
`
`5.3
`Impaired Renal Function
`
`Patients with decreased renal function are at increased risk of
`hyperkalemia. [See CONTRAINDICATIONS (4),WARNINGS AND
`
`
`
`PRECAUTIONS (5.1), ADVERSE REACTIONS (6.1).]
`
`
`
`
`6 ADVERSE REACTIONS
`
`The following adverse reactions are discussed in greater detail in other
`sections of the labeling:
`
`Hyperkalemia [See WARNINGS AND PRECAUTIONS (5.1)]
`
`
`
`
`•
`
`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.
`
`6.1 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
`
`
`2
`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`1
`
`INDICATIONS AND USAGE
`1.1 Patient Selection Considerations
`
`
`Serum potassium levels should be measured before initiating INSPRA
`
`therapy, and INSPRA should not be prescribed if serum potassium is >5.5
`
`
`mEq/L. [See CONTRAINDICATIONS (4)].
`
`1.2 Congestive Heart Failure Post-Myocardial Infarction
`
`
`INSPRA is indicated to improve survival of stable patients with left
`ventricular (LV) systolic dysfunction (ejection fraction ≤40%) and clinical
`evidence of congestive heart failure (CHF) after an acute myocardial
`
`
`infarction (MI).
`1.3 Hypertension
`
`INSPRA is indicated for the treatment of hypertension. INSPRA may
`be used alone or in combination with other antihypertensive agents.
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Congestive Heart Failure Post-Myocardial Infarction
`
`
`Treatment should be initiated at 25 mg once daily and titrated to the
`recommended dose of 50 mg once daily, preferably within 4 weeks as
`tolerated by the patient. INSPRA may be administered with or without
`
`
`food.
` Once treatment with INSPRA has begun, adjust the dose based on the
`serum potassium level as shown in Table 1.
`
`
`Table 1. Dose Adjustment in Congestive Heart Failure Post-MI
`Serum
`Dose Adjustment
`Action
`
`
`Potassium
`
`(mEq/L)
`
`< 5.0
`
`Increase
`
`25 mg every other day to 25 mg once daily
`
`
`
`25 mg once daily to 50 mg once daily
`Maintain No adjustment
`Decrease
`50 mg once daily to 25 mg once daily
`25 mg once daily to 25 mg every other day
`
`
`25 mg every other day to withhold
`
`Withhold Restart at 25 mg every other day when
`
`potassium levels fall to <5.5 mEq/L
`
`5.0–5.4
`5.5–5.9
`
`≥ 6.0
`
`
`
`
`2.2 Hypertension
`The recommended starting dose of INSPRA is 50 mg administered
`
`once daily. The full therapeutic effect of INSPRA is apparent within 4
`
`weeks. For patients with an inadequate blood pressure response to 50 mg
`
`
`once daily the dosage of INSPRA should be increased to 50 mg twice
`
`daily. Higher dosages of INSPRA are not recommended because they have
`
`
`no greater effect on blood pressure than 100 mg and are associated with an
`
`increased risk of hyperkalemia. [See CLINICAL STUDIES (14.2).]
`
`
`
`2.3 Recommended Monitoring
`
`
`
`
`Serum potassium should be measured before initiating INSPRA
`
`therapy, within the first week, and at one month after the start of treatment
`
`or dose adjustment. Serum potassium should be assessed periodically
`thereafter. Patient characteristics and serum potassium levels may indicate
`[See WARNINGS AND
`that additional monitoring is appropriate.
`
`
`PRECAUTIONS (5.1), ADVERSE REACTIONS (6.2).] In the EPHESUS
`
`
`study [See CLINICAL STUDIES (14.1)], the majority of hyperkalemia was
`
`
`
`observed within the first three months after randomization.
`
`In all patients taking INSPRA who start taking a moderate CYP3A4
`
`inhibitor, check serum potassium and serum creatinine in 3-7 days.
`
`
`2.4 Dose Modifications for Specific Populations
`
`
`
`For hypertensive patients receiving moderate CYP3A4 inhibitors (e.g.,
`erythromycin, saquinavir, verapamil, and fluconazole), the starting dose of
`[See DRUG
`
`INSPRA should be reduced to 25 mg once daily.
`
`
`
`INTERACTIONS (7.1).]
`
`No adjustment of the starting dose is recommended for the elderly or
`
`for patients with mild-to-moderate hepatic impairment. [See CLINICAL
`
`PHARMACOLOGY (12.3).]
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`• 25 mg tablets: yellow diamond biconvex film-coated tablets
`debossed with Pfizer on one side and NSR over 25 on the other
`
`
`
`• 50 mg tablets: yellow diamond biconvex film-coated tablets
`debossed with Pfizer on one side and NSR over 50 on the other
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`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
`0.6%
`
`0.5%
`
`0.8%
`
`1.0%
`
`All controlled
`studies
`Controlled studies
`lasting ≥ 6 months
`Open-label, long-
`
`term study
`
`
`6.2 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 (14.1)], 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.
`
`
`0.7%
`
`1.0%
`
`1.3%
`
`0.3%
`
`1.6%
`
`1.0%
`
`0.8%
`
`2.1%
`
`
`
`
`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 (%)
`
`273 (8.4)
`
`508 (15.6)
`
`180 (5.5)
`
`Placebo
`
`(N=3237)
`n (%)
`
`424 (13.1)
`
`363 (11.2)
`
`126 (3.9)
`
`< 3.5
`>5.5
`≥ 6.0
`
`
`
`
`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
`INSPRA
`Placebo
`
`
`(N=508)
`Clearance
`(N=363)
`n (%)
`n (%)
` 160 (32)
`82 (23)
`
`
`≤30 mL/min
`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 (5.1).]
`
`
`
`
`
`Table 7. Rates of Hyperkalemia ( >5.5 mEq/L)
`
`
`
`
`in EPHESUS by Proteinuria and History of Diabetes*
`
`INSPRA
`Placebo
`(N=508)
`(N=363)
`
`
`
`n (%)
`n (%)
`Proteinuria, no Diabetes
`40 (11)
`81 (16)
`
`
`Diabetes, no Proteinuria
`47 (13)
`91 (18)
`
`
`Proteinuria and Diabetes
`58 (16)
`132 (26)
`
`
`* 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.
`
`
`
`
`
` 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
`0.4%
`
`0.4%
`
`0.1%
`
`0.5%
`
`INSPRA
`
`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)
`
`1
`
`1
`
`2
`1
`
`1
`
`2
`
`
`Placebo
`
`(n=372)
`
`0
`0
`
`1
`0
`
`0
`
`1
`
`
`
`
`Metabolic
`Hypercholesterolemia
`
`Hypertriglyceridemia
`Digestive
`Diarrhea
`Abdominal pain
`Urinary
`
`
`Albuminuria
`Respiratory
`
`
`Coughing
`Central/Peripheral Nervous
`
`System
`
`2
`3
`Dizziness
`
`
`Body as a Whole
`
`1
`2
`Fatigue
`
`1
`2
`Influenza-like symptoms
`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.
`
`
`
`
`3
`
`
`

`

`AND ADMINISTRATION (2.3, 2.4) and CLINICAL PHARMACOLOGY
`
`
`(12.3).]
`
`
`7.2 ACE Inhibitors and Angiotensin II Receptor Antagonists
`Congestive Heart Failure Post-Myocardial Infarction
`
`In EPHESUS [see CLINICAL STUDIES (14.1)], 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%.
`7.3 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.
`
`7.4 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.
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`Pregnancy Category B
`There are no adequate and well-controlled studies in pregnant women.
`
`INSPRA should be used during pregnancy only if the potential benefit
`justifies the potential risk to the fetus.
`
`Teratogenic Effects
`
`Embryo-fetal development studies were conducted with doses up to
`1000 mg/kg/day in rats and 300 mg/kg/day in rabbits (exposures up to 32
`
`and 31 times the human AUC for the 100 mg/day therapeutic dose,
`
`respectively). No teratogenic effects were seen in rats or rabbits, although
`
`decreased body weight in maternal rabbits and increased rabbit fetal
`resorptions and post-implantation loss were observed at the highest
`administered dosage. Because animal reproduction studies are not always
`
`predictive of human response, INSPRA should be used during pregnancy
`
`
`only if clearly needed.
`8.3 Nursing Mothers
`
`
`The concentration of eplerenone in human breast milk after oral
`administration is unknown. However, preclinical data show that eplerenone
`and/or metabolites are present in rat breast milk (0.85:1 [milk:plasma]
`AUC ratio) obtained after a single oral dose. Peak concentrations in
`plasma and milk were obtained from 0.5 to 1 hour after dosing. Rat pups
`
`
`exposed by this route developed normally. Because many drugs are
`
`excreted in human milk and because of the unknown potential for adverse
`effects on the nursing infant, a decision should be made whether to
`discontinue nursing or discontinue the drug, taking into account the
`importance of the drug to the mother.
`8.4 Pediatric Use
`In a 10-week study of 304 hypertensive pediatric patients age 4 to 17
`
`years treated with INSPRA up to 100 mg per day, doses that produced
`
`
`exposure similar to that in adults, INSPRA did not lower blood pressure
`
`
`
`effectively. In this study and in a 1-year pediatric safety study in 149
`
`
`patients, the incidence of reported adverse events was similar to that of
`
`adults.
`
`INSPRA has not been studied in hypertensive patients less than 4 years
`old because the study in older pediatric patients did not demonstrate
`effectiveness.
`INSPRA has not been studied in pediatric patients with heart failure.
`
`
`
`
`
`
`8.5 Geriatric Use
`Congestive Heart Failure Post-Myocardial Infarction
`
`
`4
`
`
`
`1
`0
`0
`1
`1
`8.7
`
`
`
`
`
`
`
`
`
` Table 8. Increases in Serum Potassium in the
`
`Placebo-Controlled, Fixed-Dose Hypertension Studies of INSPRA
`Mean Increase
`% >5.5 mEq/L
`mEq/L
`
`
`0
`0.08
`0.14
`0.09
`0.19
`0.36
`
`Daily Dosage
`Placebo
`25
`50
`100
`200
`400
`
`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
` [See WARNINGS AND PRECAUTIONS
`
`
`clearance of >100 mL/min.
`
`(5.1).]
`
`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.
`6.3 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
`
`
`
`7 DRUG INTERACTIONS
`
`7.1 CYP3A4 Inhibitors
`Because eplerenone metabolism is predominantly mediated via
`
`CYP3A4, do not use INSPRA with drugs that are strong inhibitors of
`CYP3A4. [See CONTRAINDICATIONS (4) and CLINICAL
`
`PHARMACOLOGY (12.3).]
`
`In patients with hypertension taking moderate CYP3A4 inhibitors,
`
`reduce the starting dose of INSPRA to 25 mg once daily. [See DOSAGE
`
`
`
`n
`
`194
`97
`245
`193
`139
`104
`
`
`
`
`
`

`

`brain) tissues and increases blood pressure through induction of sodium
`
`reabsorption and possibly other mechanisms.
`
`
`Eplerenone has been shown to produce sustained increases in plasma
`
`renin and serum aldosterone, consistent with inhibition of the negative
`regulatory feedback of aldosterone on renin secretion. The resulting
`
`increased plasma renin activity and aldosterone circulating levels do not
`overcome the effects of eplerenone.
`
`Eplerenone selectively binds to recombinant human mineralocorticoid
`
`receptors relative to its binding to recombinant human glucocorticoid,
`progesterone, and androgen receptors.
`
`12.3 Pharmacokinetics
`
`Eplerenone is cleared predominantly by cytochrome P450 (CYP) 3A4
`
`metabolism, with an elimination half-life of 4 to 6 hours. Steady state is
`reached within 2 days. Absorption is not affected by food. Inhibitors of
`
`CYP3A4 (e.g., ketoconazole, saquinavir) increase blood levels of
`eplerenone.
`
`Absorption and Distribution
`
`Mean peak plasma concentrations of eplerenone are reached
`approximately 1.5 hours following oral administration. The absolute
`
`bioavailability of eplerenone is 69% following administration of a 100 mg
`
`oral tablet. Both peak plasma levels (Cmax) and area under the curve (AUC)
`
`
`
`
`are dose proportional for doses of 25 to 100 mg and less than proportional
`
`
`at doses above 100 mg.
`
`The plasma protein binding of eplerenone is about 50% and it is
`primarily bound to alpha 1-acid glycoproteins. The apparent volume of
`
`distribution at steady state ranged from 43 to 90 L. Eplerenone does not
`
`preferentially bind to red blood cells.
`Metabolism and Excretion
`
` No
`Eplerenone metabolism is primarily mediated via CYP3A4.
`
`active metabolites of eplerenone have been identified in human plasma.
`Less than 5% of an eplerenone dose is recovered as unchanged drug
`in the urine and feces. Following a single oral dose of radiolabeled drug,
`approximately 32% of the dose was excreted in the feces and
`approximately 67% was excreted in the urine. The elimination half-life of
`eplerenone is approximately 4 to 6 hours. The apparent plasma clearance is
`
`approximately 10 L/hr.
`Age, Gender, and Race
`
`The pharmacokinetics of eplerenone at a dose of 100 mg once daily
`
`has been investigated in the elderly (≥65 years), in males and females, and
`
`in Blacks. At steady state, elderly subjects had increases in Cmax (22%) and
`
`
`AUC (45%) compared with younger subjects (18 to 45 years). The
`pharmacokinetics of eplerenone did not differ significantly between males
`and females. At steady state, Cmax was 19% lower and AUC was 26%
`
`
`lower in Blacks. [See DOSAGE AND ADMINISTRATION (2.4) and USE
`
`
`IN SPECIFIC POPULATIONS (8.5).]
`
`
`Renal Impairment
`The pharmacokinetics of eplerenone was evaluated in patients with
`varying degrees of renal impairment and in patients undergoing
`hemodialysis. Compared with control subjects, steady state AUC and Cmax
`
`were increased by 38% and 24%, respectively, in patients with severe renal
`impairment and were decreased by 26% and 3%, respectively, in patients
`undergoing hemodialysis. No correlation was observed between plasma
`
`
`clearance of eplerenone and creatinine clearance. Eplerenone is not
`
`removed by hemodialysis. [See WARNINGS AND PRECAUTIONS (5.3).]
`
`
`Hepatic Impairment
`
`The pharmacokinetics of eplerenone 400 mg has been investigated in
`patients with moderate (Child-Pugh Class B) hepatic impairment and
`compared with normal subjects. Steady state Cmax and AUC of eplerenone
`were increased by 3.6% and 42%, respectively.
`
`Heart Failure
`
`The pharmacokinetics of eplerenone 50 mg was evaluated in 8 patients
`
`with heart failure (NYHA classification II–IV) and 8 matched (gender, age,
`weight) healthy controls. Compared with the controls, steady state AUC
`
`
`
`and Cmax in patients with stable heart failure were 38% and 30% higher,
`
`
`
`respectively.
`Drug-Drug Interactions [See DRUG INTERACTIONS (7).]
`
`Eplerenone is metabolized primarily by CYP3A4. Inhibitors of
`CYP3A4 cause increased exposure [see DRUG INTERACTIONS (7.1)].
`Drug-drug interaction studies were conducted with a 100 mg dose of
`eplerenone.
`
`A pharmacokinetic study evaluating the administration of a single
`dose of INSPRA 100 mg with ketoconazole 200 mg two times a day, a
`
`strong inhibitor of the CYP3A4 pathway, showed a 1.7-fold increase in
`Cmax of eplerenone and a 5.4-fold increase in AUC of eplerenone.
`
`
`Of the total number of patients in EPHESUS, 3340 (50%) were 65
`and over, while 1326 (20%) were 75 and over. Patients greater than 75
`years did not appear to benefit from the use of INSPRA. [See CLINICAL
`
`STUDIES (14.1).]
`
`No differences in overall incidence of adverse events were observed
`between elderly and younger patients. However, due to age-related
`decreases in creatinine clearance, the incidence of laboratory-documented
`hyperkalemia was increased in patients 65 and older. [See WARNINGS
`
`
`
`
`AND PRECAUTIONS (5.1).]
`
`Hypertension
`Of the total number of subjects in clinical hypertension studies of
`
`
`INSPRA, 1123 (23%) were 65 and over, while 212 (4%) were 75 and over.
`No overall differences in safety or effectiveness were observed between
`
`elderly subjects and younger subjects.
`
`
`10 OVERDOSAGE
`
`No cases of human overdosage with eplerenone have been reported.
`Lethality was not observed in mice, rats, or dogs after single oral doses that
`provided Cmax exposures at least 25 times higher than in humans receiving
`eplerenone 100 mg/day. Dogs showed emesis, salivation, and tremors at a
`
`Cmax 41 times the human therapeutic Cmax, progressing to sedation and
`convulsions at higher exposures.
`
`The most likely manifestation of human overdosage would be
`
`anticipated to be hypotension or hyperkalemia. Eplerenone cannot be
`
`removed by hemodialysis. Eplerenone has been shown to bind extensively
`
`
`to charcoal. If symptomatic hypotension should occur, supportive
`
`treatment should be instituted. If hyperkalemia develops, standard
`treatment should be initiated.
`
`11 DESCRIPTION
`INSPRA contains eplerenone, a blocker of aldosterone binding at the
`
`mineralocorticoid receptor.
`Eplerenone is chemically