Inspra

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Inspra uses


1 INDICATIONS AND USAGE

Inspra tablets are an aldosterone antagonist indicated for:

1.1 Congestive Heart Failure Post-Myocardial Infarction

Inspra tablets are indicated to improve survival of stable patients with left ventricular (LV) systolic dysfunction (ejection fraction less than or equal to 40%) and clinical evidence of congestive heart failure (CHF) after an acute myocardial infarction (MI).

1.2 Hypertension

Inspra tablets are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular (CV) events, primarily strokes and MI. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes.

Control of high blood pressure should be part of comprehensive CV risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce CV morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent CV outcome benefit has been a reduction in the risk of stroke, but reductions in MI and CV mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased CV risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

Inspra tablets may be used alone or in combination with other antihypertensive agents.

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2 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.

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)

2.1 Congestive Heart Failure Post-Myocardial Infarction

Initiate treatment at 25 mg once daily and titrate to the recommended dose of 50 mg once daily, preferably within 4 weeks as tolerated by the patient.

Once treatment with Inspra has begun, adjust the dose based on the serum potassium level as shown in Table 1.


Serum

Potassium

(mEq/L)


Dose Adjustment


less than 5


25 mg every other day to 25 mg once daily

25 mg once daily to 50 mg once daily


5 to 5.4


No adjustment


5.5 to 5.9


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


greater than or equal to 6


Withhold and restart at 25 mg every other day when potassium levels fall to less than 5.5 mEq/L

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 increase the dosage of Inspra 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 ].

2.3 Recommended Monitoring

Measure serum potassium before initiating Inspra therapy, within the first week, and at one month after the start of treatment or dose adjustment. Assess serum potassium periodically thereafter.

Check serum potassium and serum creatinine within 3 to 7 days of a patient initating a moderate CYP3A inhibitor ACE inhibitors, angiotensin-II blockers or non-steroidal-anti-inflammatories.

2.4 Dose Modifications for Use with Moderate CYP3A Inhibitors

In post-MI CHF patients receiving a moderate CYP3A inhibitor (e.g., erythromycin, saquinavir, verapamil, and fluconazole), do not exceed 25 mg once daily. In patients with hypertension receiving a moderate CYP3A inhibitor, initiate at 25 mg once daily. For inadequate blood pressure response, dosing may be increased to a maximum of 25 mg twice daily .

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3 DOSAGE FORMS AND STRENGTHS


Tablets: 25 mg, 50 mg (3)

4 CONTRAINDICATIONS

For All Patients

Inspra is contraindicated in all patients with:


For Patients Treated for Hypertension

Inspra is contraindicated for the treatment of hypertension in patients with:


For all patients:


For the treatment of hypertension:

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5 WARNINGS AND PRECAUTIONS

5.1 Hyperkalemia

The risk of hyperkalemia is higher in patients with impaired renal function, proteinuria, diabetes and those concomitantly treated with ACEs, ARBs, NSAIDs and moderate CYP3A inhibitors. Minimize the risk of hyperkalemia with proper patient selection and monitoring [see Dosage and Administration (2.1), 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 to 5.9 mEq/L) may continue Inspra therapy with proper dose adjustment. Dose reduction decreases potassium levels. Patients on moderate CYP3A inhibitors that cannot be avoided should have their dose of Inspra reduced [see Drug Interactions (7.2)].

5.4 Allergic Reaction

Inspra Tablets 50 mg contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

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6 ADVERSE REACTIONS

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


CHF Post-MI : Most common adverse reactions (greater than 2% and more frequent than with placebo): hyperkalemia and increased creatinine. (6.1)

Hypertension : In clinical studies, adverse reactions with Inspra were uncommon. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

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.

Congestive Heart Failure Post-Myocardial Infarction

In EPHESUS, safety was evaluated in 3,307 patients treated with Inspra and 3,301 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, MI, 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.

Hypertension

Inspra has been evaluated for safety in 3,091 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/MI, and increased GGT.

Gynecomastia and abnormal vaginal bleeding were reported with Inspra but not with placebo. The rates increased with increasing duration of therapy.

6.2 Post-Marketing 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

6.3 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 (less than 3.5 mEq/L or greater than 5.5 mEq/L or greater than or equal to 6.0 mEq/L) receiving Inspra compared with placebo are displayed in Table 2.


Potassium (mEq/L)


Inspra

(N=3,251)

n (%)


Placebo

(N=3,237)

n (%)


less than 3.5


273 (8.4)


424 (13.1)


greater than 5.5


508 (15.6)


363 (11.2)


greater than or equal to 6.0


180 (5.5)


126 (3.9)


Rates of hyperkalemia increased with decreasing renal function.


Baseline Creatinine Clearance


Inspra

(N=508)

n (%)


Placebo

(N=363)

n (%)


less than or equal to 30 mL/min


160 (32)


82 (23)


31 mL/min to 50 mL/min


122 (24)


46 (13)


51 mL/min to 70 mL/min


86 (17)


48 (13)


greater than 70 mL/min


56 (11)


32 (9)


The rates of hyperkalemia in EPHESUS in the Inspra treated group vs. placebo were increased in patients with proteinuria (16% vs 11%), diabetes (18% vs. 13%) or both (26% vs. 16%).

Hypertension

Potassium

In placebo-controlled fixed-dose studies, the mean increases in serum potassium were dose-related and are shown in Table 4 along with the frequencies of values greater than 5.5 mEq/L.


Mean Increase mEq/L


% greater than 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

7 DRUG INTERACTIONS

7.1 CYP3A Inhibitors

Inspra metabolism is predominantly mediated via CYP3A. Do not use Inspra with drugs that are strong inhibitors of CYP3A [see Contraindications (4) and Clinical Pharmacology (12.3)].

In post-MI CHF patients taking a moderate CYP3A inhibitor, do not exceed 25 mg once daily. In patients with hypertension taking a moderate CYP3A inhibitor, initiate at 25 mg once daily. For inadequate blood pressure response, dosing may be increased to a maximum of 25 mg twice daily [see Dosage and Administration (2.3, 2.4) and Clinical Pharmacology (12.3)].

7.2 ACE Inhibitors and Angiotensin II Receptor Antagonists

The risk of hyperkalaemia increase when Inspra is used in combination with an ACE inhibitor and/or an 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 ].

7.3 Lithium

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.

7.4 Nonsteroidal Anti-Inflammatory Drugs

A drug interaction study of Inspra 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, monitor blood pressure and 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. 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 Inspra in human breast milk after oral administration is unknown. However, preclinical data show that Inspra 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, decide whether to discontinue nursing or discontinue the drug.

8.4 Pediatric Use

In a 10-week study of 304 hypertensive pediatric patients age 4 to 16 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

Of the total number of patients in EPHESUS, 3,340 (50%) were 65 and over, while 1,326 (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, 1,123 (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, however due to age-related decreases in creatine clearance, the risk of hyperkalemia may be increased [see Warnings and Precautions (5.1)].

10 OVERDOSAGE

No cases of human overdosage with Inspra 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 Inspra 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. Inspra cannot be removed by hemodialysis. Inspra 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 tablets contain Inspra, a blocker of aldosterone binding at the mineralocorticoid receptor.

Inspra is chemically described as Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-, γ-lactone, methyl ester, (7α,11α,17α)-. Its empirical formula is C24H30O6 and it has a molecular weight of 414.50.

The structural formula of Inspra is represented below:

Inspra is an odorless, white to off-white crystalline powder. It is very slightly soluble in water, with its solubility essentially pH-independent. The octanol/water partition coefficient of Inspra is approximately 7.1 at pH 7.0.

Inspra tablets for oral administration contain 25 mg or 50 mg of Inspra and the following inactive ingredients: lactose monohydrate, silicified microcrystalline cellulose, croscarmellose sodium, hypromellose, talc, magnesium stearate, titanium dioxide, polyethylene glycol. In addition, the 25 mg tablets also contain polysorbate and the 50 mg tablets also contain FD&C yellow No. 5 (tartrazine) and FD&C yellow No. 6, polydextrose and triacetin.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Inspra binds to the mineralocorticoid receptor and blocks the binding of aldosterone, a component of the renin-angiotensin-aldosterone-system. 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.

Inspra 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 Inspra.

Inspra selectively binds to human mineralocorticoid receptors relative to its binding to recombinant human glucocorticoid, progesterone, and androgen receptors.

12.3 Pharmacokinetics

Inspra is cleared predominantly by cytochrome P450 (CYP) 3A4 metabolism, with an elimination half-life of 3 to 6 hours. Steady state is reached within 2 days. Absorption is not affected by food. Inhibitors of CYP3A (e.g., ketoconazole, saquinavir) increase blood levels of Inspra.

Absorption and Distribution

Mean peak plasma concentrations of Inspra are reached approximately 1.5 to 2 hours following oral administration. Absorption is not affected by food. The absolute bioavailability of Inspra 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 mg to 100 mg and less than proportional at doses above 100 mg. Upon repeat dosing, steady state levels are reached within 2 days.

The plasma protein binding of Inspra is about 50% and it is primarily bound to alpha 1-acid glycoproteins. The apparent volume of distribution at steady state ranged from 42 L to 90 L. Inspra does not preferentially bind to red blood cells.

Metabolism and Excretion

Inspra metabolism is primarily mediated via CYP3A4. No active metabolites of Inspra have been identified in human plasma.

Less than 5% of an Inspra 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 Inspra is approximately 3 to 6 hours. The apparent plasma clearance is approximately 10 L/hr.

Age, Gender, and Race

The pharmacokinetics of Inspra at a dose of 100 mg once daily has been investigated in the elderly (greater than or equal to 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 Inspra 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 Inspra 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 Inspra and creatinine clearance. Inspra is not removed by hemodialysis.

Hepatic Impairment

The pharmacokinetics of Inspra 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 Inspra were increased by 3.6% and 42%, respectively.

Heart Failure

The pharmacokinetics of Inspra 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

Inspra is metabolized primarily by CYP3A4. Inhibitors of CYP3A cause increased exposure [see Drug Interactions (7.1)].

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

Following a single dose of Inspra 100 mg and CYP3A inhibitor ketoconazole 200 mg twice a day, eplerenone’s Cmax was 1.7-fold and AUC was 5.4-fold compared with Inspra alone.

Administration of Inspra with moderate CYP3A inhibitors (e.g., erythromycin 500 mg BID, verapamil 240 mg once daily, saquinavir 1200 mg three times a day, fluconazole 200 mg once daily) resulted in increases in Cmax of Inspra ranging from 40% to 60 % and AUC from 100% to 190%.

Grapefruit juice caused a 25% increase in exposure.

Inspra is not an inhibitor of CYP1A2, CYP3A4, CYP2C19, CYP2C9, or CYP2D6. Inspra 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, or warfarin in vitro. Inspra is not a substrate or an inhibitor of P-Glycoprotein at clinically relevant doses.

No clinically significant drug-drug pharmacokinetic interactions were observed when Inspra was administered with cisapride, cyclosporine, digoxin, glyburide, midazolam, oral contraceptives (norethindrone/ethinyl estradiol), simvastatin, or warfarin. St. John’s wort (a CYP3A inducer) caused a small (about 30%) decrease in Inspra AUC.

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Inspra was non-genotoxic in a battery of assays including in vitro bacterial mutagenesis (Ames test in Salmonella spp. and E. Coli), in vitro mammalian cell mutagenesis (mouse lymphoma cells), in vitro chromosomal aberration (Chinese hamster ovary cells), in vivo rat bone marrow micronucleus formation, and in vivo/ex vivo unscheduled DNA synthesis in rat liver.

There was no drug-related tumor response in heterozygous P53 deficient mice when tested for 6 months at dosages up to 1000 mg/kg/day (systemic AUC exposures up to 9 times the exposure in humans receiving the 100 mg/day therapeutic dose). Statistically significant increases in benign thyroid tumors were observed after 2 years in both male and female rats when administered Inspra 250 mg/kg/day (highest dose tested) and in male rats only at 75 mg/kg/day. These dosages provided systemic AUC exposures approximately 2 to 12 times higher than the average human therapeutic exposure at 100 mg/day. Repeat dose administration of Inspra to rats increases the hepatic conjugation and clearance of thyroxin, which results in increased levels of TSH by a compensatory mechanism. Drugs that have produced thyroid tumors by this rodent-specific mechanism have not shown a similar effect in humans.

Male rats treated with Inspra at 1000 mg/kg/day for 10 weeks (AUC 17 times that at the 100 mg/day human therapeutic dose) had decreased weights of seminal vesicles and epididymides and slightly decreased fertility. Dogs administered Inspra at dosages of 15 mg/kg/day and higher (AUC 5 times that at the 100 mg/day human therapeutic dose) had dose-related prostate atrophy. The prostate atrophy was reversible after daily treatment for 1 year at 100 mg/kg/day. Dogs with prostate atrophy showed no decline in libido, sexual performance, or semen quality. Testicular weight and histology were not affected by Inspra in any test animal species at any dosage.

14 CLINICAL STUDIES

14.1 Congestive Heart Failure Post-Myocardial Infarction

The Inspra post-acute myocardial infarction heart failure efficacy and survival study was a multinational, multicenter, double-blind, randomized, placebo-controlled study in patients clinically stable 3 to 14 days after an acute MI with LV dysfunction (as measured by left ventricular ejection fraction [LVEF] less than or equal to 40%) and either diabetes or clinical evidence of CHF (pulmonary congestion by exam or chest x-ray or S3). Patients with CHF of valvular or congenital etiology, patients with unstable post-infarct angina, and patients with serum potassium greater than 5.0 mEq/L or serum creatinine greater than 2.5 mg/dL were to be excluded. Patients were allowed to receive standard post-MI drug therapy and to undergo revascularization by angioplasty or coronary artery bypass graft surgery.

Patients randomized to Inspra were given an initial dose of 25 mg once daily and titrated to the target dose of 50 mg once daily after 4 weeks if serum potassium was less than 5.0 mEq/L. Dosage was reduced or suspended anytime during the study if serum potassium levels were greater than or equal to 5.5 mEq/L [see Dosage and Administration (2.1)].

EPHESUS randomized 6,632 patients (9.3% U.S.) at 671 centers in 27 countries. The study population was primarily white (90%, with 1% Black, 1% Asian, 6% Hispanic, 2% other) and male (71%). The mean age was 64 years (range, 22 to 94 years). The majority of patients had pulmonary congestion (75%) by exam or x-ray and were Killip Class II (64%). The mean ejection fraction was 33%. The average time to enrollment was 7 days post-MI. Medical histories prior to the index MI included hypertension (60%), coronary artery disease (62%), dyslipidemia (48%), angina (41%), type 2 diabetes (30%), previous MI (27%), and CHF (15%).

The mean dose of Inspra was 43 mg/day. Patients also received standard care including aspirin (92%), ACE inhibitors (90%), beta-blockers (83%), nitrates (72%), loop diuretics (66%), or HMG-CoA reductase inhibitors (60%).

Patients were followed for an average of 16 months (range, 0 to 33 months). The ascertainment rate for vital status was 99.7%.

The co-primary endpoints for EPHESUS were (1) the time to death from any cause, and (2) the time to first occurrence of either cardiovascular mortality [defined as sudden cardiac death or death due to progression of CHF, stroke, or other CV causes] or CV hospitalization (defined as hospitalization for progression of CHF, ventricular arrhythmias, acute MI, or stroke).

For the co-primary endpoint for death from any cause, there were 478 deaths in the Inspra group (14.4%) and 554 deaths in the placebo group (16.7%). The risk of death with Inspra was reduced by 15% [hazard ratio equal to 0.85 (95% confidence interval 0.75 to 0.96; p = 0.008 by log rank test)]. Kaplan-Meier estimates of all-cause mortality are shown in Figure 1 and the components of mortality are provided in Table 5.

Figure 1 Kaplan-Meier Estimates of All-Cause Mortality


Inspra (N=3,319)

n (%)


Placebo

(N=3,313)

n (%)


Hazard

Ratio


p-value


Death from any cause


478 (14.4)


554 (16.7)


0.85


0.008


CV Death


407 (12.3)


483 (14.6)


0.83


0.005


Non-CV Death


60 (1.8)


54 (1.6)


Unknown or unwitnessed death


11 (0.3)


17 (0.5)


Most CV deaths were attributed to sudden death, acute MI, and CHF.

The time to first event for the co-primary endpoint of CV death or hospitalization, as defined above, was longer in the Inspra group (hazard ratio 0.87, 95% confidence interval 0.79 to 0.95, p = 0.002). An analysis that included the time to first occurrence of CV mortality and all CV hospitalizations (atrial arrhythmia, angina, CV procedures, progression of CHF, MI, stroke, ventricular arrhythmia, or other CV causes) showed a smaller effect with a hazard ratio of 0.92 (95% confidence interval 0.86 to 0.99; p = 0.028). The combined endpoints, including combined all-cause hospitalization and mortality were driven primarily by CV mortality. The combined endpoints in EPHESUS, including all-cause hospitalization and all-cause mortality, are presented in Table 6.


Event


Inspra

n (%)


Placebo

n (%)


CV death or hospitalization for progression of CHF, stroke, MI or ventricular arrhythmiaCo-Primary Endpoint

Death

Hospitalization


885(26.7)

407(12.3)

606(18.3)


993 (30.0)

483(14.6)

649(19.6)


CV death or hospitalization for progression of CHF, stroke, MI, ventricular arrhythmia, atrial arrhythmia, angina, CV procedures, or other CV causes (PVD; Hypotension)

Death

Hospitalization


1,516(45.7)

407(12.3)

1,281(38.6)


1,610 (48.6)

483 (14.6)

1,307 (39.5)


All-cause death or hospitalization

Death

Hospitalization


1,734(52.2)

478(14.4)

1,497(45.1)


1,833(55.3)

554(16.7)

1,530(46.2)


Mortality hazard ratios varied for some subgroups as shown in Figure 2. Mortality hazard ratios appeared favorable for Inspra for both genders and for all races or ethnic groups, although the numbers of non-Caucasians were low (648, 10%). Patients with diabetes without clinical evidence of CHF and patients greater than 75 years did not appear to benefit from the use of Inspra. Such subgroup analyses must be interpreted cautiously.

Figure 2 Hazard Ratios of All-Cause Mortality by Subgroups

Analyses conducted for a variety of CV biomarkers did not confirm a mechanism of action by which mortality was reduced.

Figure 1 Figure 2

14.2 Hypertension

The safety and efficacy of Inspra have been evaluated alone and in combination with other antihypertensive agents in clinical studies of 3091 hypertensive patients. The studies included 46% women, 14% Blacks, and 22% elderly (age greater than or equal to 65). The studies excluded patients with elevated baseline serum potassium (greater than 5.0 mEq/L) and elevated baseline serum creatinine (generally greater than 1.5 mg/dL in males and greater than 1.3 mg/dL in females).

Two fixed-dose, placebo-controlled, 8- to 12-week monotherapy studies in patients with baseline diastolic blood pressures of 95 mm Hg to 114 mm Hg were conducted to assess the antihypertensive effect of Inspra. In these two studies, 611 patients were randomized to Inspra and 140 patients to placebo. Patients received Inspra in doses of 25 mg to 400 mg daily as either a single daily dose or divided into two daily doses. The mean placebo-subtracted reductions in trough cuff blood pressure achieved by Inspra in these studies at doses up to 200 mg are shown in Figure 3 and Figure 4.

Figure 3 Inspra Dose Response-Trough Cuff SBP Placebo- Subtracted Adjusted Mean Change from Baseline in Hypertension Studies

Figure 4 Inspra Dose Response-Trough Cuff DBP Placebo- Subtracted Adjusted Mean Change from Baseline in Hypertension Studies

Patients treated with Inspra 50 mg to 200 mg daily experienced significant decreases in sitting systolic and diastolic blood pressure at trough with differences from placebo of 6 mm Hg to 13 mm Hg (systolic) and 3 mm Hg to 7 mm Hg (diastolic). These effects were confirmed by assessments with 24-hour ambulatory blood pressure monitoring (ABPM). In these studies, assessments of 24-hour ABPM data demonstrated that Inspra, administered once or twice daily, maintained antihypertensive efficacy over the entire dosing interval. However, at a total daily dose of 100 mg, Inspra administered as 50 mg twice per day produced greater trough cuff (4/3 mm Hg) and ABPM (2/1 mm Hg) blood pressure reductions than 100 mg given once daily.

Blood pressure lowering was apparent within 2 weeks from the start of therapy with Inspra, with maximal antihypertensive effects achieved within 4 weeks. Stopping Inspra following treatment for 8 to 24 weeks in six studies did not lead to adverse event rates in the week following withdrawal of Inspra greater than following placebo or active control withdrawal. Blood pressures in patients not taking other antihypertensives rose 1 week after withdrawal of Inspra by about 6/3 mm Hg, suggesting that the antihypertensive effect of Inspra was maintained through 8 to 24 weeks.

Blood pressure reductions with Inspra in the two fixed-dose monotherapy studies and other studies using titrated doses, as well as concomitant treatments, were not significantly different when analyzed by age, gender, or race with one exception. In a study in patients with low renin hypertension, blood pressure reductions in Blacks were smaller than those in whites during the initial titration period with Inspra.

Inspra has been studied concomitantly with treatment with ACE inhibitors, ARB, calcium channel blockers, beta-blockers, and hydrochlorothiazide. When administered concomitantly with one of these drugs Inspra usually produced its expected antihypertensive effects.

There was no significant change in average heart rate among patients treated with Inspra in the combined clinical studies. No consistent effects of Inspra on heart rate, QRS duration, or PR or QT interval were observed in 147 normal subjects evaluated for electrocardiographic changes during pharmacokinetic studies.

Figure 3 Figure 4

16 HOW SUPPLIED/STORAGE AND HANDLING

Inspra Tablets, for oral administration, are available as

25 mg

White, round, film-coated tablets, debossed with “SZ” on one side and “12” on the other side and supplied as:

NDC 0185-5368-30 bottles of 30

NDC 0185-5368-09 bottles of 90

50 mg

Yellow, round, film-coated tablets, debossed with “SZ” on one side and “16” on the other side and supplied as:

NDC 0185-5369-30 bottles of 30

NDC 0185-5369-09 bottles of 90

Store at 20° to 25°C (68° to 77°F).

Dispense contents in a tight, light-resistant container as defined in the USP with a child-resistant closure, as required.

Protect from light and moisture.

KEEP TIGHTLY CLOSED.

17 PATIENT COUNSELING INFORMATION

Advise patients receiving Inspra tablets:


Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Manufactured by

Sandoz Inc.

Princeton, NJ 08540

46192571

Rev. September 2016

MF5368REV09/16

NDC 0185-5368-30

Inspra Tablets

25 mg

Rx only

30 Tablets

Sandoz

25 mg x 30 Tablets

NDC 0185-5369-30

Inspra Tablets

50 mg

Contains FD&C Yellow No. 5 (tartrazine) as a color additive.

Rx only

30 Tablets

Sandoz

50 mg x 30 Tablets

Inspra pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Inspra available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Inspra destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Inspra Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Inspra pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."EPLERENONE TABLET [EON LABS, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."EPLERENONE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "Eplerenone". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Inspra?

Depending on the reaction of the Inspra after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Inspra not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Inspra addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Inspra, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Inspra consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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