Irbesartan

The percentages of patients experiencing an event during the course of the study can be seen in Table 1 below:

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.

IRBESARTAN INDICATIONS AND USAGE

Hypertension
 
Irbesartan tablets, USP are indicated for the treatment of hypertension. They may be used alone or in combination with other antihypertensive agents.

Nephropathy in Type 2 Diabetic Patients 
 
Irbesartan tablets, USP are indicated for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (>300 mg/day) in patients with type 2 diabetes and hypertension. In this population, irbesartan tablets, USP 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) (see CLINICAL PHARMACOLOGY: Clinical Studies ).

IRBESARTAN CONTRAINDICATIONS

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

Do not co-administer aliskiren with irbesartan tablets in patients with diabetes (see  PRECAUTIONS,  Drug Interactions ).

WARNINGS

Fetal Toxicity

Pregnancy Category D
 
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. These adverse outcomes are usually associated with use of these drugs in the second and third trimesters of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and
fetus.
 
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue irbesartan, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to irbesartan for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS: Pediatric Use ).
 
When pregnant rats were treated with irbesartan from day 0 to day 20 of gestation (oral doses of 50 mg/kg/day, 180 mg/kg/day, and 650 mg/kg/day), increased incidences of renal pelvic cavitation, hydroureter and/or absence of renal papilla were observed in fetuses at doses ≥50 mg/kg/day (approximately equivalent to the maximum recommended human dose [MRHD], 300 mg/day, on a body surface area basis). Subcutaneous edema was observed in fetuses at doses ≥180 mg/kg/day (about 4 times the MRHD on a body surface area basis). As these anomalies were not observed in rats in which irbesartan exposure (oral doses of 50, 150, and 450 mg/kg/day) was limited to gestation days 6 to 15, they appear to reflect late gestational effects of the drug. In pregnant rabbits, oral doses of 30 mg irbesartan/kg/day were associated with maternal mortality and abortion. Surviving females receiving this dose (about 1.5 times the MRHD on a body surface area basis) had a slight increase in early resorptions and a corresponding decrease in live fetuses. Irbesartan was found to cross the placental barrier in rats and rabbits.
 
Radioactivity was present in the rat and rabbit fetus during late gestation and in rat milk following oral doses of radiolabeled irbesartan.

Hypotension in Volume- or Salt-Depleted Patients

Excessive reduction of blood pressure was rarely seen (<0.1%) in patients with uncomplicated hypertension. Initiation of antihypertensive therapy may cause symptomatic hypotension in patients with intravascular volume- or sodium-depletion, e.g., in patients treated vigorously with diuretics or in patients on dialysis. Such volume depletion should be corrected prior to administration of irbesartan, or a low starting dose should be used (see DOSAGE AND ADMINISTRATION ).
 
If hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

PRECAUTIONS

Impaired Renal Function

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin-converting-enzyme inhibitors has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Irbesartan would be expected to behave similarly.
 
In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or BUN have been reported. There has been no known use of irbesartan in patients with unilateral or bilateral renal artery stenosis, but a similar effect should be anticipated.

Information for Patients

Pregnancy
 
Female patients of childbearing age should be told 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.

Drug Interactions

No significant drug-drug pharmacokinetic (or pharmacodynamic) interactions have been found in interaction studies with hydrochlorothiazide, digoxin, warfarin, and nifedipine.

In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites with the known cytochrome CYP 2C9 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 had no effect on the pharmacodynamics of warfarin (prothrombin time) or pharmacokinetics of digoxin. The pharmacokinetics of irbesartan were not affected by coadministration of nifedipine or hydrochlorothiazide.

Concomitant use of potassium-sparing diuretics, potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium.
 
Non-Steroidal Anti-Inflammatory Agents 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, coadministration 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.

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. 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).

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of carcinogenicity was observed when irbesartan was administered at doses of up to 500/1000 mg/kg/day (males/females, respectively) in rats and 1000 mg/kg/day in mice for up to 2 years. For male and female rats, 500 mg/kg/day provided an average systemic exposure to irbesartan (AUC_{0-24 hour}, bound plus unbound) about 3 and 11 times, respectively, the average systemic exposure in humans receiving the maximum recommended dose (MRD) of 300 mg irbesartan/day, whereas 1000 mg/kg/day (administered to females only) provided an average systemic exposure about 21 times that reported for humans at the MRD. For male and female mice, 1000 mg/kg/day provided an exposure to irbesartan about 3 and 5 times, respectively, the human exposure at 300 mg/day.

Irbesartan was not mutagenic in a battery of in vitro tests (Ames microbial test, rat hepatocyte DNA repair test, V79 mammalian-cell forward gene-mutation assay). Irbesartan was negative in several tests for induction of chromosomal aberrations (in vitro-human lymphocyte assay; in vivo-mouse micronucleus study).

Irbesartan had no adverse effects on fertility or mating of male or female rats at oral doses ≤650 mg/kg/day, the highest dose providing a systemic exposure to irbesartan (AUC_{0-24 hour}, bound plus unbound) about 5 times that found in humans receiving the maximum recommended dose of 300 mg/day.

Pregnancy

Pregnancy Category D
 
See WARNINGS: Fetal Toxicity .

Nursing Mothers

It is not known whether irbesartan is excreted in human milk, but irbesartan or some metabolite of irbesartan is secreted at low concentration in the milk of lactating rats. Because of the 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.

Pediatric Use

Neonates with a history of in utero exposure to irbesartan:
 
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
 
Irbesartan, in a study at a dose of up to 4.5 mg/kg/day, once daily, did not appear to lower blood pressure effectively in pediatric patients ages 6 to 16 years.
 
Irbesartan has not been studied in pediatric patients less than 6 years old.

Geriatric Use

Of 4925 subjects receiving irbesartan in controlled clinical studies of hypertension, 911 (18.5%) were 65 years and over, while 150 (3%) were 75 years and over. No overall differences in effectiveness or safety were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. (See CLINICAL PHARMACOLOGY: Pharmacokinetics , Special Populations , and Clinical Studies .)

IRBESARTAN ADVERSE REACTIONS

Hypertension
 
Irbesartan has 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. Treatment with irbesartan was well-tolerated, with an incidence of adverse events similar to placebo. These events generally were mild and transient with no relationship to the dose of irbesartan.
 
In placebo-controlled clinical trials, discontinuation of therapy due to a clinical adverse event was required in 3.3% of patients treated with irbesartan, versus 4.5% of patients given placebo.
 
In placebo-controlled clinical trials, the following adverse event experiences reported in at least 1% of patients treated with irbesartan (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%).
 
The following adverse events occurred at an incidence of 1% or greater in patients treated with irbesartan, but were at least as frequent or more frequent in patients receiving placebo: abdominal pain, anxiety/nervousness, chest pain, dizziness, edema, headache, influenza, musculoskeletal pain, pharyngitis, nausea/vomiting, rash, rhinitis, sinus abnormality, tachycardia, and urinary tract infection.

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.
 
The incidence of hypotension or orthostatic hypotension was low in irbesartan-treated patients (0.4%), unrelated to dosage, and similar to the incidence among placebo-treated patients (0.2%). Dizziness, syncope, and vertigo were reported with equal or less frequency in patients receiving irbesartan compared with placebo.
 
In addition, the following potentially important events occurred in less than 1% of the 1965 patients and at least 5 patients (0.3%) receiving irbesartan in clinical studies, and those less frequent, clinically significant events (listed by body system). It cannot be determined whether these events were causally related to irbesartan:

Body as a Whole: fever, chills, facial edema, upper extremity edema

Cardiovascular: flushing, hypertension, cardiac murmur, myocardial infarction, angina pectoris, arrhythmic/conduction disorder, cardio-respiratory arrest, heart failure, hypertensive crisis

Dermatologic: pruritus, dermatitis, ecchymosis, erythema face, urticaria

Endocrine/Metabolic/Electrolyte Imbalances: sexual dysfunction, libido change, gout

Gastrointestinal: constipation, oral lesion, gastroenteritis, flatulence, abdominal distention

Musculoskeletal/Connective Tissue: extremity swelling, muscle cramp, arthritis, muscle ache, musculoskeletal chest pain, joint stiffness, bursitis, muscle weakness

Nervous System: sleep disturbance, numbness, somnolence, emotional disturbance, depression, paresthesia, tremor, transient ischemic attack, cerebrovascular accident

Renal/Genitourinary: abnormal urination, prostate disorder

Respiratory: epistaxis, tracheobronchitis, congestion, pulmonary congestion, dyspnea, wheezing

Special Senses: vision disturbance, hearing abnormality, ear infection, ear pain, conjunctivitis, other eye disturbance, eyelid abnormality, ear abnormality

Nephropathy in Type 2 Diabetic Patients
 
In clinical studies in patients with hypertension and type 2 diabetic renal disease, the adverse drug experiences were similar to those seen in patients with hypertension with the exception of an increased incidence of orthostatic symptoms (dizziness, orthostatic dizziness, and orthostatic hypotension) observed in IDNT (proteinuria ≥900 mg/day, and serum creatinine ranging from 1 to 3 mg/dL). In this trial, orthostatic symptoms occurred more frequently in the irbesartan group (dizziness 10.2%, orthostatic dizziness 5.4%, orthostatic hypotension 5.4%) than in the placebo group (dizziness 6%, orthostatic dizziness 2.7%, orthostatic hypotension 3.2%).

Postmarketing Experience
 
The following adverse reactions have been identified during post-approval use of irbesartan. 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to irbesartan.
 
The following have been reported: urticaria; angioedema (involving swelling of the face, lips, pharynx, and/or tongue); increased liver function tests; jaundice; hepatitis; hyperkalemia, and thrombocytopenia.
 
Impaired renal function, including cases of renal failure, has been reported.
 
Cases of increased CPK and rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
 
Laboratory Test Findings
 
Hypertension
 
In controlled clinical trials, clinically important differences in laboratory tests were rarely associated with administration of irbesartan.

Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in less than 0.7% of patients with essential hypertension treated with irbesartan alone versus 0.9% on placebo. (See PRECAUTIONS: Impaired Renal Function .)

Hematologic: Mean decreases in hemoglobin of 0.2 g/dL were observed in 0.2% of patients receiving irbesartan compared to 0.3% of placebo-treated patients. Neutropenia (<1000 cells/mm³ occurred at similar frequencies among patients receiving irbesartan (0.3%) and placebo-treated patients (0.5%).

Nephropathy in Type 2 Diabetic Patients
 
Hyperkalemia: In IDNT (proteinuria ≥900 mg/day, and serum creatinine ranging from 1 to 3 mg/dL), the percent of patients with hyperkalemia (>6 mEq/L) was 18.6% in the irbesartan group versus 6% in the placebo group. Discontinuations due to hyperkalemia in the irbesartan group were 2.1% versus 0.4% in the placebo group.

OVERDOSAGE

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.
 
To obtain up-to-date information about the treatment of overdosage, a good resource is a certified regional Poison Control Center. Telephone numbers of certified Poison Control Centers are listed in the Physicians’ Desk Reference (PDR). In managing overdose, consider the possibilities of multiple-drug interactions, drug-drug interactions, and unusual drug kinetics in the patient.
 
Laboratory determinations of serum levels of irbesartan are not widely available, and such determinations have, in any event, no known established role in the management of irbesartan overdose. 
 
Acute oral toxicity studies with irbesartan in mice and rats indicated acute lethal doses were in excess of 2000 mg/kg, about 25- and 50-fold the MRHD (300 mg) on a mg/m² basis, respectively.

IRBESARTAN DOSAGE AND ADMINISTRATION

Irbesartan tablets may be administered with other antihypertensive agents and with or without food.

Hypertension 
 
The recommended initial dose of irbesartan tablets is 150 mg once daily. Patients requiring further reduction in blood pressure should be titrated to 300 mg once daily. 
 
A low dose of a diuretic may be added, if blood pressure is not controlled by irbesartan tablets alone. Hydrochlorothiazide has been shown to have an additive effect (see CLINICAL PHARMACOLOGY: Clinical Studies ). Patients not adequately treated by the maximum dose of 300 mg once daily are unlikely to derive additional benefit from a higher dose or twice-daily dosing.
 
No dosage adjustment is necessary in elderly patients, or in patients with hepatic impairment or mild to severe renal impairment.

Nephropathy in Type 2 Diabetic Patients 
 
The recommended target maintenance dose is 300 mg once daily. There are no data on the clinical effects of lower doses of irbesartan tablets on diabetic nephropathy (see CLINICAL PHARMACOLOGY: Clinical Studies ).

Volume- and Salt-Depleted Patients 
 
A lower initial dose of irbesartan tablets (75 mg) is recommended in patients with depletion of intravascular volume or salt (e.g., patients treated vigorously with diuretics or on hemodialysis) (see WARNINGS: Hypotension in Volume- or Salt-Depleted Patients ).

HOW SUPPLIED

Irbesartan Tablets USP, 150 mg are white to off-white, biconvex, oval shaped uncoated tablets debossed with ‘T32’ on one side and plain on other side.

Unit dose packages of 30 (3 x 10) NDC 68084-007-21

Storage
Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]
 
PACKAGING INFORMATION

American Health Packaging unit dose blisters (see How Supplied section) contain drug product from Aurobindo Pharma Limited as follows:

(150 mg / 30 UD) NDC 68084-007-21 packaged from NDC 65862-638

Packaged and Distributed by:

American Health Packaging

Columbus, OH 43217

8200721/1212

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