GIZLAN DUO

Irbesartan is an angiotensin

II receptor (AT 1 subtype) antagonist.

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

Its empirical formula is

C 25 H 28 N 6 O, and the structural formula: Irbesartan is a white to off-white crystalline powder with a molecular weight of 428.5.

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

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

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

Inactive ingredients include: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hypromellose, and magnesium stearate.

Irbesartan tablets are an 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.

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

II is a potent vasoconstrictor formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II).

II is the primary vasoactive hormone of the renin-angiotensin system, and an important component in the pathophysiology of hypertension.

It also stimulates aldosterone secretion by the adrenal cortex.

Irbesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively binding to the AT 1 angiotensin II receptor found in many tissues (e.g., vascular smooth muscle, adrenal gland).

There is also an

AT 2 receptor in many tissues, but it is not involved in cardiovascular homeostasis.

Irbesartan is a specific competitive antagonist of AT 1 receptors with a much greater affinity (more than 8500-fold) for the AT 1 receptor than for the AT 2 receptor and no agonist activity.

Blockade of the

AT 1 receptor removes the negative feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and circulating angiotensin II do not overcome the effects of irbesartan on blood pressure.

Irbesartan does not inhibit

ACE or renin or affect other hormone receptors uteror ion channels known to be involved in the cardiovascular regulation of blood pressure and sodium homeostasis. 12.2 Pharmacodynamics In healthy subjects, single oral irbesartan doses of up to 300 mg produced dose-dependent inhibition of the pressor effect of angiotensin II infusions.

Inhibition was complete (100%) 4 hours following oral doses of 150 mg or 300 mg and partial inhibition was sustained for 24 hours (60% and 40% at 300 mg and 150 mg, respectively).

In hypertensive patients, angiotensin II receptor inhibition following chronic administration of irbesartan causes a 1.5-fold to 2-fold rise in angiotensin II plasma concentration and a 2-fold to 3-fold increase in plasma renin levels.

Aldosterone plasma concentrations generally decline following irbesartan administration, but serum potassium levels are not significantly affected at recommended doses.

In hypertensive patients, chronic oral doses of irbesartan (up to 300 mg) had no effect on glomerular filtration rate, renal plasma flow, or filtration fraction.

In multiple dose studies in hypertensive patients, there were no clinically important effects on fasting triglycerides, total cholesterol or HDL-cholesterol.

There was no effect on serum uric acid during chronic oral administration, and no uricosuric effect. 12.3 Pharmacokinetics Absorption The oral absorption of irbesartan is rapid and complete with an average absolute bioavailability of 60% to 80%.

Following oral administration of irbesartan tablets, peak plasma concentrations of irbesartan are attained at 1.5 to 2 hours after dosing.

Food does not affect the bioavailability of irbesartan.

Irbesartan exhibits linear pharmacokinetics over the therapeutic dose range.

Irbesartan is 90% bound to serum proteins (primarily albumin and α 1 -acid glycoprotein) with negligible binding to cellular components of blood.

The average volume of distribution is to 93 liters.

Studies in animals indicate that radiolabeled irbesartan weakly crosses the blood-brain barrier and placenta.

Irbesartan is excreted in the milk of lactating rats.

Total plasma and renal clearances are in the range of to 176 mL/min and 3.0 to 3.5 mL/min, respectively.

The terminal elimination half-life of irbesartan averages to 15 hours.

Steady-state concentrations are achieved within 3 days.

Limited accumulation of irbesartan (<20%) is observed in plasma upon repeated once-daily dosing and is not clinically relevant.

Irbesartan is an orally active agent that does not require biotransformation into an active form.

Irbesartan is metabolized via glucuronide conjugation and oxidation.

Following oral or intravenous administration of 14 C-labeled irbesartan, more than 80% of the circulating plasma radioactivity is attributable to unchanged irbesartan.

The primary circulating metabolite is the inactive irbesartan glucuronide conjugate (approximately 6%).

The remaining oxidative metabolites do not add appreciably to irbesartan’s pharmacologic activity.

In vitro studies indicate irbesartan is oxidized primarily by CYP2C9; metabolism by CYP3A4 is negligible.

Irbesartan and its metabolites are excreted by both biliary and renal routes.

Following either oral or intravenous administration of 14 C-labeled irbesartan, about 20% of radioactivity is recovered in the urine and the remainder in the feces, as irbesartan or irbesartan glucuronide.

No sex-related differences in pharmacokinetics are observed in healthy elderly (age 65-80 years) or in healthy young (age 18-40 years) subjects.

In studies of hypertensive patients, there is no sex difference in half-life or accumulation, but somewhat higher plasma concentrations of irbesartan are observed in females (11%-44%).

No sex-related dosage adjustment is necessary.

In elderly subjects (age 65-80 years), irbesartan elimination half-life is not significantly altered, but AUC and C max values are about 20% to 50% greater than those of young subjects (age 18-40 years).

No dosage adjustment is necessary in the elderly.

Race/ethnicity In healthy black subjects, irbesartan AUC values are approximately 25% greater than whites; there is no difference in C max values.

Renal impairment

The pharmacokinetics of irbesartan is not altered in patients with renal impairment or in patients on hemodialysis.

Irbesartan is not removed by hemodialysis.

No dosage adjustment is necessary in patients with mild to severe renal impairment unless a patient with renal impairment is also volume depleted.

Hepatic insufficiency

The pharmacokinetics of irbesartan following repeated oral administration are not significantly affected in patients with mild to moderate cirrhosis of the liver.

No dosage adjustment is necessary in patients with hepatic insufficiency.

In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites with the known cytochrome CYP2C9 substrates/inhibitors sulphenazole, tolbutamide and nifedipine.

However, in clinical studies the consequences of concomitant irbesartan on the pharmacodynamics of warfarin were negligible.

Based on in vitro data, no interaction would be expected with drugs whose metabolism is dependent upon cytochrome P450 isoenzymes 1A1, 1A2, 2A6, 2B6, 2D6, 2E1, or 3A4.

In separate studies of patients receiving maintenance doses of warfarin, hydrochlorothiazide, or digoxin, irbesartan administration for 7 days has no effect on the pharmacodynamics of warfarin (prothrombin time) or pharmacokinetics of digoxin.

The pharmacokinetics of irbesartan are not affected by coadministration of nifedipine or hydrochlorothiazide.

The following important adverse reactions are described elsewhere in the labeling: Hypotension in Volume or Salt-Depleted Patients Impaired Renal Function Nephropathy in type 2 diabetic patients: The most common adverse reactions which were more frequent than placebo were hyperkalemia dizziness, orthostatic dizziness, and orthostatic hypotension.

To report SUSPECTED ADVERSE

REACTIONS, contact Solco Healthecare US LLC.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 the clinical trials of another drug and may not reflect the rates observed in practice.

The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Irbesartan tablets have been evaluated for safety in more than 4300 patients with hypertension and about 5000 subjects overall.

This experience includes 1303 patients treated for over 6 months and 407 patients for 1 year or more.

In placebo-controlled clinical trials, the following adverse reactions were reported in at least 1% of patients treated with irbesartan tablets (n=1965) and at a higher incidence versus placebo (n=641), excluding those too general to be informative and those not reasonably associated with the use of drug because they were associated with the condition being treated or are very common in the treated population, include: diarrhea (3% vs 2%), dyspepsia/heartburn (2% vs 1%), and fatigue (4% vs 3%).

Irbesartan use was not associated with an increased incidence of dry cough, as is typically associated with ACE inhibitor use.

In placebo-controlled studies, the incidence of cough in irbesartan-treated patients was 2.8% versus 2.7% in patients receiving placebo.

Nephropathy in

Type 2 Diabetic Patients Hyperkalemia: In the Irbesartan Diabetic Nephropathy Trial (IDNT) (proteinuria ≥900 mg/day, and serum creatinine ranging from 1.0-3.0 mg/dL), the percent of patients with potassium >6 mEq/L was 18.6% in the irbesartan tablets group versus 6.0% in the placebo group.

Discontinuations due to hyperkalemia in the irbesartan tablets group were 2.1% versus 0.4% in the placebo group.

In IDNT, the adverse reactions were similar to those seen in patients with hypertension with the exception of an increased incidence of orthostatic symptoms which occurred more frequently in the irbesartan tablets versus placebo group: dizziness (10.2% vs 6.0%), orthostatic dizziness (5.4% vs 2.7%) and orthostatic hypotension (5.4% vs 3.2%). 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of irbesartan tablets.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or to establish a causal relationship to drug exposure.

Urticaria; angioedema (involving swelling of the face, lips, pharynx, and/or tongue); anaphylactic reaction including anaphylactic shock; increased liver function tests; jaundice; hepatitis; hyperkalemia; anemia; thrombocytopenia; increased cpk; tinnitus; and hypoglycemia in diabetic patients.

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) base on body surface area, respectively.

Irbesartan tablets are contraindicated in patients who are hypersensitive to any component of this product.

Do not coadministrate aliskiren with irbesartan tablets in patients with diabetes.

Hypersensitivity to any component of this product.

Coadministration with aliskiren in patients with diabetes.

Hypertension to 300 mg once daily Diabetic Nephropathy 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. 2.3 Nephropathy in Type 2 Diabetic Patients The recommended dose is 300 mg once daily. 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) .

Irbesartan tablets are available as white to off-white biconvex oval tablets, debossed with “HH” on one side and HH;330 on other side NDC: 70518-1690-00 NDC: 70518-1690-01 PACKAGING: 90 in 1 BOTTLE PLASTIC PACKAGING: 90 in 1 BOTTLE PLASTIC Store at 20oC-25oC (68oF-77oF); excursions permitted to 15oC-30oC (59oF-86oF) .

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