Inspra

INSPRA may be administered with or without food.

The full consequence of using INSPRA in patients taking herbal preparations and/or salt substitutes has not been established, and caution should be exercised. Theoretically, patients who are taking herbal preparations that affect blood pressure or contain high levels of potassium may be at risk of hypotension/hypertension or hyperkalemia (see Warnings and Precautions). Clinicians should consider discontinuing the herbal preparation or salt substitute or closely monitoring patients using such a combination. Such preparations may include (but not limited to): dandelion, potassium iodine, laminaria, morinda, oleander, phosphate salts and potassium preparations, cat’s claw, cod liver oil, and licorice.

INSPRA (eplerenone) metabolism is predominantly mediated via CYP3A4 and therefore, INSPRA should not be used with drugs described as strong inhibitors of CYP3A4 in their labeling (see Contraindications and Dosage and Administration).

Caution should be used in patients treated with moderate 3A4 inhibitors; dosing should not exceed 25 mg QD.

A drug interaction study of INSPRA with an NSAID has not been conducted. The administration of potassium-sparing antihypertensives drugs 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 or COX-2 Inhibitors are used concomitantly, blood pressure, renal function and serum potassium should be closely monitored.

St. John’s Wort was found to decrease exposure and to increase clearance of INSPRA significantly indicating that concomitant use of strong inducers of CYP3A4 such as phenobarbital, phenytoin, rifampicin, carbamazepine should be avoided.

A drug interaction study of INSPRA 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, as excretion may be altered as a result of modifications in sodium balance induced by the aldosterone antagonist. Lithium has also been reported to increase plasma renin activity and aldosterone levels.

In EPHESUS, 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 mmol/L were similar regardless of the use of ACEI/ARB. However, as ACEI/ARB can also increase serum potassium levels in some patients, concomitant use with INSPRA dictates that greater caution should be exercised.

Mild-to-Moderate Hepatic Impairment: No initial dosage adjustment is necessary. Severe Hepatic Impairment (see Contraindications and Warnings and Precautions).

Following withholding INSPRA due to serum potassium ≥6.0 mmol/L and the return of potassium levels within acceptable limits, INSPRA can be restarted at a test dose of 25 mg every other day. There are no conclusive data to demonstrate that 25 mg every other day is effective. After a test period of one week on 25 mg every other day, serum potassium levels should be measured. If potassium levels return within acceptable limits, the dose can be increased to 25 mg every day and serum potassium should be measured after one week. It could then be determined if INSPRA therapy should be continued or stopped.

INSPRA dosing should not exceed 25 mg when mild to moderate inhibitors of CYP3A4 are co-administered (see Drug Interactions).

Mild Renal Impairment: No initial dosage adjustment is necessary. Moderate-to-Severe Renal Impairment (see Contraindications and Warnings and Precautions).

Adverse events reported below are those with suspected relationship to treatment and in excess of placebo, taken from EPHESUS. Adverse events are listed by body system and absolute frequency. Frequencies are defined as common (>1% to ≤10%) or uncommon (>0.1% to ≤1%).

In post-marketing experience, the following additional undesirable effects have been reported:

Common: hyperkalemia. Uncommon: dehydration, hypercholesterolemia, hypertriglyceridemia, hyponatremia.

Uncommon: asthenia, malaise.

Uncommon: atrial fibrillation, myocardial infarction, cardiac failure left.

Uncommon: pharyngitis.

Common: dizziness. Uncommon: headache.

Common: renal function abnormal.

angioneurotic edema, rash.

Uncommon: back pain, leg cramp.

Increases of more than 44 µmol/L were reported in 6.5% of patients administered INSPRA and in 4.9% of placebo-treated patients.

Rates of Hyperkalemia (>5.5 mmol/L) in EPHESUS by Proteinuria and History of Diabetes^a

Common: hypotension. Uncommon: postural hypotension.

Uncommon: BUN increase, creatinine increase.

Uncommon: eosinophilia.

In EPHESUS, a mean increase of 0.17 mmol/L in blood urea nitrogen (BUN) was reported in patients treated with INSPRA and a mean 0.31 mmol/L decrease for placebo-treated patients. BUN increased in 1.6% and 1.0% of subjects, respectively.

Common: diarrhea, nausea. Uncommon: flatulence, vomiting.

Uncommon: insomnia.

Each yellow, diamond, biconvex film-coated tablet, debossed with Pfizer on one side and NSR over 50 on the other, contains: eplerenone 50 mg. Nonmedicinal ingredients: croscarmellose sodium, hypromellose, iron oxide red, iron oxide yellow, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium lauryl sulfate, talc and titanium dioxide. Blister packs of 30.

Each yellow, diamond, biconvex film-coated tablet, debossed with Pfizer on one side and NSR over 25 on the other, contains: eplerenone 25 mg. Nonmedicinal ingredients: croscarmellose sodium, hypromellose, iron oxide red, iron oxide yellow, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium lauryl sulfate, talc and titanium dioxide. Blister packs of 30.

There were 1641 (46%) patients treated with INSPRA in EPHESUS who were 65 and over, while 616 (18.6%) were 75 and over. Patients greater than 75 years did not appear to benefit from the use of INSPRA. No differences in overall incidence of adverse events were observed between elderly and younger patients. However, due at least in part, to age-related decreases in creatinine clearance, the incidence of laboratory-documented hyperkalemia was increased in patients 65 and older (see Hyperkalemia).

Preclinical studies on safety pharmacology, genotoxicity, carcinogenic potential and toxicity to reproduction revealed no special hazard for humans.

In repeat dose toxicity studies, prostate atrophy was observed in rats and dogs at exposure levels several-fold above clinical exposure levels. The prostatic changes were not associated with adverse functional consequences. The clinical relevance of these findings is unknown.

Studies in rats and rabbits showed no teratogenic effects, although decreased body weight in maternal rabbits and increased rabbit fetal resorptions and post-implantation loss were observed at the highest administered dosage.

In 16 subjects with mild-to-moderate hepatic impairment (Child-Pugh Class B) who received 400 mg of INSPRA, no elevations of serum potassium above 5.5 mmol/L were observed. C_max was not significantly changed but AUC was increased by 42% and INSPRA clearance 30% lower compared to matched controls. The dose recommended is 8 times smaller and, therefore, no dose adjustment is necessary in patients with mild to moderate hepatic impairment.

The use of INSPRA in patients with severe hepatic impairment has not been evaluated and therefore, INSPRA is not recommended in these patients (see Dosage and Administration and Action and Clinical Pharmacology, Special Populations and Conditions).

The principal risk of INSPRA (eplerenone) is hyperkalemia. Hyperkalemia, if not recognized in a timely manner, can cause serious, sometimes fatal, arrhythmias. All patients prescribed INSPRA must have their serum potassium level measured before initiating INSPRA therapy, within one week after the first dose, and measured periodically thereafter (see Dosage and Administration).

Hyperkalemia can be minimized by appropriate patient selection, avoidance of certain concomitant treatments, thoroughly informing the patient and periodic monitoring until the effect of INSPRA has been established.

For patient selection and medications which should not be prescribed concomitantly with INSPRA or prescribed with caution, see Contraindications, Drug Interactions; and Adverse Reactions.

INSPRA should not be administered to patients with initial serum potassium >5.0 mmol/L, serum creatinine >221 µmol/L and/or creatinine clearance <50 mL/min. The incidence of hyperkalemia increases with declining renal function (see Adverse Reactions, Table 3).

Diabetic patients with heart failure (HF) post myocardial infarction (MI), especially those with proteinuria, should also be treated with caution. The subset of patients in EPHESUS with both diabetes and proteinuria on the baseline urinalysis had increased rates of hyperkalemia (see Adverse Reactions, Other Abnormal Hematologic and Clinical Chemistry Findings, Potassium).

See Contraindications; Warnings and Precautions, Hyperkalemia and Adverse Reactions.

Pregnancy: There are no INSPRA studies in pregnant women. Eplerenone did not impair fertility and was not teratogenic in animals but the risk to the fetus of pregnant women is not known. Therefore, INSPRA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

The safety and effectiveness of INSPRA have not been established in pediatric patients and INSPRA is not recommended in this patient population.

It has not been determined if INSPRA is present in human breast milk, however it was present in rat breast milk at a milk to plasma ratio of 0.85. 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.

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 C_max and AUC of eplerenone were increased by 3.6% and 42%, respectively (see Dosage and Administration).

Eplerenone binds to the mineralocorticoid receptor and blocks the binding of aldosterone, a component of the renin-angiotensin-aldosterone-system (RAAS). Aldosterone synthesis, which occurs primarily in the adrenal gland, is modulated by multiple factors, including angiotensin II and non-RAAS mediators, such as adrenocorticotropic hormone (ACTH) and potassium. Aldosterone binds to mineralocorticoid receptors in both epithelial (e.g., kidney) and nonepithelial (e.g., heart, blood vessels, and brain) tissues, and increases blood pressure through induction of sodium reabsorption and possibly other mechanisms through both genomic and non-genomic effects.

Eplerenone metabolism is primarily mediated via CYP3A4. No 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.

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 increase blood levels of eplerenone.

The pharmacokinetics of eplerenone was evaluated in patients with varying degrees of renal insufficiency and in patients undergoing hemodialysis. Compared with control subjects, steady-state AUC and C_max 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, Hyperkalemia).

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 C_max in patients with stable heart failure were 38% and 30% higher, respectively.

(See Drug Interactions.)

Drug-drug interaction studies were conducted with a 100 mg dose of eplerenone.

Eplerenone is metabolized primarily by CYP3A4. A potent inhibitor of CYP3A4 (ketoconazole) caused increased exposure of 5.4 fold; while less potent CYP3A4 inhibitors (erythromycin, saquinavir, verapamil, and fluconazole) resulted in increases ranging from 2.0-2.9 fold. Grapefruit juice caused only a small increase (about 25%) in exposure (see Drug Interactions).

Eplerenone is not an inhibitor of CYP1A2, CYP3A4, CYP2C19, CYP2C9, or CYP2D6. Eplerenone did not inhibit the metabolism of amiodarone, amlodipine, astemizole, chlorzoxazone, cisapride, dexamethasone, dextromethorphan, diclofenac, 17α-ethinyl estradiol, fluoxetine, losartan, lovastatin, mephobarbital, methylphenidate, methylprednisolone, metoprolol, midazolam, nifedipine, phenacetin, phenytoin, simvastatin, tolbutamide, triazolam, verapamil, and warfarin in vitro. Eplerenone is not a substrate or an inhibitor of P-Glycoprotein at clinically relevant doses.

No clinically significant drug-drug pharmacokinetic interactions were observed when eplerenone was administered with cisapride, cyclosporine, digoxin, glyburide, midazolam, oral contraceptives (norethindrone/ethinyl estradiol), simvastatin, or warfarin. St. Johns Wort (a CYP3A4 inducer) caused a small (about 30%) decrease in eplerenone AUC.

No significant changes in eplerenone pharmacokinetics were observed when eplerenone was administered with aluminum and magnesium-containing antacids.

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.

In dose-ranging studies of chronic heart failure (NYHA classification II-IV), the addition of eplerenone to standard therapy resulted in expected dose-dependent increases in aldosterone. Similarly, in a cardiorenal substudy of EPHESUS, therapy with eplerenone led to a significant increase in aldosterone. These results are consistent with blockade of the mineralocorticoid receptor in these populations.

No consistent effects of eplerenone on heart rate, QRS duration, or PR or QT interval were observed in 147 normal subjects evaluated for electrocardiographic changes during pharmacokinetic studies.

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. The pharmacokinetics of eplerenone did not differ significantly between males and females. At steady state, elderly subjects had increases in C_max (22%) and AUC (45%) compared with younger subjects (18 to 45 years). At steady state, C_max was 19% lower and AUC was 26% lower in blacks (see Warnings and Precautions, Geriatrics and Dosage and Administration).

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 (C_max) 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.