irbesartan 150 MG Oral Tablet

Generic Name: IRBESARTAN
Brand Name: IRBESARTAN
  • Substance Name(s):
  • IRBESARTAN

DRUG INTERACTIONS

7 Lithium: Risk of lithium toxicity.

(7) Non-Steroidal Anti-inflammatory Drugs (NSAIDs) and COX-2 inhibitors: Increased risk of renal impairment.

Reduced antihypertensive effects.

(7) Dual blockade of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia.

(7) 7.1 Agents Increasing Serum Potassium Coadministration of irbesartan with other drugs that raise serum potassium levels may result in hyperkalemia, sometimes severe.

Monitor serum potassium in such patients.

7.2 Lithium Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of irbesartan and lithium.

Monitor lithium levels in patients receiving irbesartan and lithium.

7.3 Non-Steroidal Anti-inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists (including irbesartan) may result in deterioration of renal function, including possible acute renal failure.

These effects are usually reversible.

Monitor renal function periodically in patients receiving irbesartan and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including irbesartan, may be attenuated by NSAIDs including selective COX-2 inhibitors.

7.4 Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy.

Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy.

In general, avoid combined use of RAS inhibitors.

Closely monitor blood pressure, renal function and electrolytes in patients on irbesartan and other agents that affect the RAS.

Do not coadminister aliskiren with irbesartan in patients with diabetes.

Avoid use of aliskiren with irbesartan in patients with renal impairment (GFR <60 mL/min).

OVERDOSAGE

10 No data are available in regard to overdosage in humans.

However, daily doses of 900 mg for 8 weeks were well-tolerated.

The most likely manifestations of overdosage are expected to be hypotension and tachycardia; bradycardia might also occur from overdose.

Irbesartan is not removed by hemodialysis.

Acute oral toxicity studies with irbesartan in mice and rats indicated acute lethal doses were in excess of 2000 mg/kg, about 25-fold and 50-fold the MRHD (300 mg) on a mg/m 2 basis, respectively.

DESCRIPTION

11 Irbesartan, USP is an angiotensin II receptor (AT 1 subtype) antagonist.

Irbesartan, USP is a non-peptide compound, chemically described as a 2-butyl-3-[ p -( o -1 H -tetrazol-5-ylphenyl)benzyl]-1,3-diazaspiro[4.4]non-1-en-4-one.

Its molecular formula is C 25 H 28 N 6 O, and the structural formula: Irbesartan, USP is a white to off-white crystalline powder with a molecular weight of 428.53.

It is a nonpolar compound with a partition coefficient (octanol/water) of 10.1 at pH of 7.4.

Irbesartan, USP is slightly soluble in alcohol and methylene chloride and practically insoluble in water.

Irbesartan tablets, USP are available for oral administration as unscored tablets containing 75 mg, 150 mg, or 300 mg of irbesartan, USP.

Inactive ingredients include: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose and pregelatinized starch.

CLINICAL STUDIES

14 14.1 Hypertension The antihypertensive effects of irbesartan were examined in 7 placebo-controlled 8- to 12-week trials in patients with baseline diastolic blood pressures of 95 to 110 mmHg.

Doses of 1 to 900 mg were included in these trials in order to fully explore the dose-range of irbesartan.

These studies allowed comparison of once- or twice-daily regimens at 150 mg/day, comparisons of peak and trough effects, and comparisons of response by sex, age, and race.

Two of the seven placebo-controlled trials identified above examined the antihypertensive effects of irbesartan and hydrochlorothiazide in combination.

The 7 studies of irbesartan monotherapy included a total of 1915 patients randomized to irbesartan (1-900 mg) and 611 patients randomized to placebo.

Once-daily doses of 150 mg and 300 mg provided statistically and clinically significant decreases in systolic and diastolic blood pressure with trough (24 hours post dose) effects after 6 to 12 weeks of treatment compared to placebo, of about 8-10/5-6 mmHg and 8-12/5-8 mmHg, respectively.

No further increase in effect was seen at dosages greater than 300 mg.

The dose-response relationships for effects on systolic and diastolic pressure are shown in Figures 1 and 2.

Once-daily administration of therapeutic doses of irbesartan gave peak effects at around 3 to 6 hours and, in one ambulatory blood pressure monitoring study, again around 14 hours.

This was seen with both once-daily and twice-daily dosing.

Trough-to-peak ratios for systolic and diastolic response were generally between 60% and 70%.

In a continuous ambulatory blood pressure monitoring study, once-daily dosing with 150 mg gave trough and mean 24-hour responses similar to those observed in patients receiving twice-daily dosing at the same total daily dose.

In controlled trials, the addition of irbesartan to hydrochlorothiazide doses of 6.25 mg, 12.5 mg, or 25 mg produced further dose-related reductions in blood pressure similar to those achieved with the same monotherapy dose of irbesartan.

HCTZ also had an approximately additive effect.

Analysis of age, sex, and race subgroups of patients showed that men and women, and patients over and under 65 years of age, had generally similar responses.

Irbesartan was effective in reducing blood pressure regardless of race, although the effect was somewhat less in blacks (usually a low-renin population).

The effect of irbesartan is apparent after the first dose, and it is close to its full observed effect at 2 weeks.

At the end of an 8-week exposure, about 2/3 of the antihypertensive effect was still present one week after the last dose.

Rebound hypertension was not observed.

There was essentially no change in average heart rate in irbesartan-treated patients in controlled trials.

14.2 Nephropathy in Type 2 Diabetic Patients The Irbesartan Diabetic Nephropathy Trial (IDNT) was a randomized, placebo- and active-controlled, double-blind, multicenter study conducted worldwide in 1715 patients with type 2 diabetes, hypertension (SeSBP >135 mmHg or SeDBP >85 mmHg), and nephropathy (serum creatinine 1.0 to 3.0 mg/dL in females or 1.2 to 3.0 mg/dL in males and proteinuria ≥900 mg/day).

Patients were randomized to receive irbesartan 75 mg, amlodipine 2.5 mg, or matching placebo once-daily.

Patients were titrated to a maintenance dose of irbesartan 300 mg, or amlodipine 10 mg, as tolerated.

Additional antihypertensive agents (excluding ACE inhibitors, angiotensin II receptor antagonists and calcium channel blockers) were added as needed to achieve blood pressure goal (≤135/85 or 10 mmHg reduction in systolic blood pressure if higher than 160 mmHg) for patients in all groups.

The study population was 66.5% male, 72.9% below 65 years of age, and 72% White (Asian/Pacific Islander 5.0%, Black 13.3%, Hispanic 4.8%).

The mean baseline seated systolic and diastolic blood pressures were 159 mmHg and 87 mmHg, respectively.

The patients entered the trial with a mean serum creatinine of 1.7 mg/dL and mean proteinuria of 4144 mg/day.

The mean blood pressure achieved was 142/77 mmHg for irbesartan, 142/76 mmHg for amlodipine, and 145/79 mmHg for placebo.

Overall, 83.0% of patients received the target dose of irbesartan more than 50% of the time.

Patients were followed for a mean duration of 2.6 years.

The primary composite endpoint was the time to occurrence of any one of the following events: doubling of baseline serum creatinine, end-stage renal disease (ESRD; defined by serum creatinine ≥6 mg/dL, dialysis, or renal transplantation), or death.

Treatment with irbesartan resulted in a 20% risk reduction versus placebo (p=0.0234) (see Figure 3 and Table 1).

Treatment with irbesartan also reduced the occurrence of sustained doubling of serum creatinine as a separate endpoint (33%), but had no significant effect on ESRD alone and no effect on overall mortality (see Table 1).

Figure 3: IDNT: Kaplan-Meier Estimates of Primary Endpoint (Doubling of Serum Creatinine, End-Stage Renal Disease or All-Cause Mortality) The percentages of patients experiencing an event during the course of the study can be seen in Table 1 below: Table 1: IDNT: Components of Primary Composite Endpoint Irbesartan N=579 (%) Comparison With Placebo Comparison With Amlodipine Placebo N=569 (%) Hazard Ratio 95% CI Amlodipine N=567 (%) Hazard Ratio 95% CI Primary Composite Endpoint 32.6 39.0 0.80 0.66-0.97 (p=0.0234) 41.1 0.77 0.63-0.93 Breakdown of first occurring event contributing to primary endpoint 2x creatinine 14.2 19.5 –­ –­ 22.8 –­ –­ ESRD 7.4 8.3 –­ –­ 8.8 –­ –­ Death 11.1 11.2 –­ –­ 9.5 –­ —­ Incidence of total events over entire period of follow-up 2x creatinine 16.9 23.7 0.67 0.52-0.87 25.4 0.63 0.49-0.81 ESRD 14.2 17.8 0.77 0.57-1.03 18.3 0.77 0.57-1.03 Death 15.0 16.3 0.92 0.69-1.23 14.6 1.04 0.77-1.40 The secondary endpoint of the study was a composite of cardiovascular mortality and morbidity (myocardial infarction, hospitalization for heart failure, stroke with permanent neurological deficit, amputation).

There were no statistically significant differences among treatment groups in these endpoints.

Compared with placebo, irbesartan significantly reduced proteinuria by about 27%, an effect that was evident within 3 months of starting therapy.

Irbesartan significantly reduced the rate of loss of renal function (glomerular filtration rate), as measured by the reciprocal of the serum creatinine concentration, by 18.2%.

Table 2 presents results for demographic subgroups.

Subgroup analyses are difficult to interpret, and it is not known whether these observations represent true differences or chance effects.

For the primary endpoint, irbesartan’s favorable effects were seen in patients also taking other antihypertensive medications (angiotensin II receptor antagonists, angiotensin-converting­-enzyme inhibitors, and calcium channel blockers were not allowed), oral hypoglycemic agents, and lipid-lowering agents.

Table 2: IDNT: Primary Efficacy Outcome Within Subgroups Baseline Factors Irbesartan N=579 (%) Comparison With Placebo Placebo N=569 (%) Hazard Ratio 95% Cl Sex Male 27.5 36.7 0.68 0.53-0.88 Female 42.3 44.6 0.98 0.72-1.34 Race White 29.5 37.3 0.75 0.60-0.95 Non-White 42.6 43.5 0.95 0.67-1.34 Age (years) <65 31.8 39.9 0.77 0.62-0.97 ≥65 35.1 36.8 0.88 0.61-1.29

HOW SUPPLIED

16 /STORAGE AND HANDLING Irbesartan Tablets, USP 75 mg are available as white to off-white, biconvex, oval shaped tablets, debossed with ‘447’ on one side and ‘C’ on the other.

Bottle of 30’s (child Resistant closure) NDC 59746-447-30 Bottle of 90’s (child Resistant closure) NDC 59746-447-90 Bottle of 500’s NDC 59746-447-05 Irbesartan Tablets, USP 150 mg are available as white to off-white, biconvex, oval shaped tablets, debossed with ‘448’ on one side and ‘C’ on the other.

Bottle of 30’s (child Resistant closure) NDC 59746-448-30 Bottle of 90’s (child Resistant closure) NDC 59746-448-90 Bottle of 500’s NDC 59746-448-05 Irbesartan Tablets, USP 300 mg are available as white to off-white, biconvex, oval shaped tablets, debossed with ‘449’ on one side and ‘C’ on the other.

Bottle of 30’s (child Resistant closure) NDC 59746-449-30 Bottle of 90’s (child Resistant closure) NDC 59746-449-90 Bottle of 500’s NDC 59746-449-05 Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].

For more information about irbesartan tablets, USP call 1-800-313-4623.

DOSAGE FORMS AND STRENGTHS

3 Irbesartan tablets, USP 75 mg are available as white to off-white, biconvex, oval shaped tablets, debossed with ‘447’ on one side and ‘C’ on the other.

Irbesartan tablets, USP 150 mg are available as white to off-white, biconvex, oval shaped tablets, debossed with ‘448’ on one side and ‘C’ on the other.

Irbesartan tablets, USP 300 mg are available as white to off-white, biconvex, oval shaped tablets, debossed with ‘449’ on one side and ‘C’ on the other.

Tablets: 75 mg, 150 mg, 300 mg (3)

INDICATIONS AND USAGE

1 Irbesartan tablets are angiotensin II receptor blocker (ARB) indicated for: Treatment of hypertension, to lower blood pressure.

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

(1.1) Treatment of diabetic nephropathy in hypertensive patients with type 2 diabetes, an elevated serum creatinine, and proteinuria.

(1.2) 1.1 Hypertension Irbesartan tablets are indicated for the treatment of hypertension, to lower blood pressure.

Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular (CV) events, primarily strokes and myocardial infarction.

These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake.

Many patients will require more than 1 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 cardiovascular 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 cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular 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.

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

1.2 Nephropathy in Type 2 Diabetic Patients Irbesartan tablets are indicated for the treatment of diabetic nephropathy in patients with type 2 diabetes and hypertension, an elevated serum creatinine, and proteinuria (>300 mg/day).

In this population, irbesartan tablets reduces the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end-stage renal disease (need for dialysis or renal transplantation) [see Clinical Studies (14.2) ] .

BOXED WARNING

WARNING: FETAL TOXICITY • When pregnancy is detected, discontinue irbesartan tablets as soon as possible.

• Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [see Warnings and Precautions (5.1) ] .

WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning.

When pregnancy is detected, discontinue irbesartan tablets as soon as possible.

(5.1) Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

(5.1)

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Hypotension: Correct volume or salt depletion prior to administration.

(5.2) Monitor renal function and serum potassium.

(5.3) 5.1 Fetal Toxicity Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.

Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.

Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.

When pregnancy is detected, discontinue irbesartan as soon as possible [see Use in Specific Populations (8.1) ] .

5.2 Hypotension in Volume or Salt-Depleted Patients In patients with an activated renin-angiotensin system, such as volume or salt-depleted patients (e.g.

those being treated with high doses of diuretics), symptomatic hypotension may occur after initialization of treatment with irbesartan.

Correct volume or salt depletion prior to administration of irbesartan or use a lower starting dose [see Dosage and Administration (2.4) ].

5.3 Impaired Renal Function Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system.

Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe heart failure, or volume depletion) may be at particular risk of developing acute renal failure or death on irbesartan.

Monitor renal function periodically in these patients.

Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on irbesartan [see Drug Interactions (7.3) ].

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Pregnancy Advise female patients of childbearing age about the consequences of exposure to irbesartan during pregnancy.

Discuss treatment options with women planning to become pregnant.

Patients should be asked to report pregnancies to their physicians as soon as possible.

Potassium Supplements Advise patients receiving irbesartan not to use potassium supplements or salt substitutes containing potassium without consulting their healthcare provider [see Drug Interactions (7.1) ].

Manufacured by: Jubilant Generics Limited Roorkee – 247661, India Marketed by: Jubilant Cadista Pharmaceuticals Inc.

Salisbury, MD 21801, USA Revised: 01/2019

DOSAGE AND ADMINISTRATION

2 Indication Dose Hypertension (2.2) 150 to 300 mg once daily Diabetic Nephropathy (2.3) 300 mg once daily 2.1 General Considerations Irbesartan tablets may be administered with other antihypertensive agents and with or without food.

2.2 Hypertension The recommended initial dose of irbesartan tablets is 150 mg once daily.

The dosage can be increased to a maximum dose of 300 mg once daily as needed to control blood pressure [see Clinical Studies (14.1) ].

2.3 Nephropathy in Type 2 Diabetic Patients The recommended dose is 300 mg once daily [see Clinical Studies (14.2) ] .

2.4 Dose Adjustment in Volume and Salt-Depleted Patients The recommended initial dose is 75 mg once daily in patients with depletion of intravascular volume or salt (e.g., patients treated vigorously with diuretics or on hemodialysis) [see Warnings and Precautions (5.2) ].