IRBESARTAN- irbesartan_tablet

Angiotensin II is a potent vasoconstrictor formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin 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 2 1 1 2 1 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). Absorption 1 14 In vitro Excretion 14 Specific Populations Geriatrics max Race/Ethnicity max Renal Impairment [see Warnings and Precautions (5. 2) Dosage and Administration (2. 4) Hepatic Insufficiency Drug-Drug Interactions In vitro in vitro.

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

Indication Dose Hypertension (2. 2) 150 to 300 mg once daily Diabetic Nephropathy (2. 3) 300 mg once daily Irbesartan tablets may be administered with other antihypertensive agents and with or without food. 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) The recommended dose is 300 mg once daily [see Clinical Studies (14. 2) The recommended initial dose is 75 mg once daily in patients with depletion of intravascular volume or salt (e. , patients treated vigorously with diuretics or on hemodialysis) [see Warnings and Precautions (5.

The following important adverse reactions are described elsewhere in the labeling: Hypotension in Volume or Salt-Depleted Patients [see Warnings and Precautions (5. 2) Impaired Renal Function [see Warnings and Precautions (5. 3) 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. 1) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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. Hypertension Nephropathy in Type 2 Diabetic Patients The following adverse reactions have been identified during postapproval 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. 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.

Irbesartan is contraindicated in patients who are hypersensitive to any component of this product. Hypersensitivity to any component of this product. (4) Coadministration with aliskiren in patients with diabetes.

Nursing Mothers: Potential for adverse effects in infants. 3) Risk Summary [see Clinical Considerations] Clinical Considerations Disease-associated maternal and/or embryo-fetal risk Hypertension in pregnancy increases the maternal risk for preeclampsia, gestational diabetes, premature delivery, and delivery complications (e. , need for cesarean section and postpartum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Data There are no available data on the presence of irbesartan in human milk, effects on milk production, or the breastfed infant. Irbesartan or some metabolite of irbesartan is secreted in the milk of lactating rats [ see Clinical Pharmacology (12. 3) 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. Of 4925 subjects receiving irbesartan in controlled clinical studies of hypertension, 911 (18. 5%) were 65 years and over, while 150 (3. 0%) 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 (12. 3) Clinical Studies (14.

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) Coadministration of irbesartan with other drugs that raise serum potassium levels may result in hyperkalemia, sometimes severe. Monitor serum potassium in such patients. 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. 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. 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.

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. 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) based on body surface area, respectively.
NONCLINICAL TOXICOLOGY
No evidence of carcinogenicity was observed when irbesartan was administered at dosages 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 in vitro in vitro in vivo 0-24 hour
CLINICAL STUDIES
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. 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. figure1 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 mg/dL in females or 1. 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. 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 w ith Placebo Comparison w ith Amlodipine Placebo N=569 (%) Hazard Ratio 95% CI Amlodipine N=567 (%) Hazard Ratio 95% CI Primary Composite Endpoint 32. 93 Breakdown of first occurring event contributing to primary endpoint 2x creatinine 14. 5 --­ --­ 22. 8 --­ --­ ESRD 7. 3 --­ --­ 8. 8 --­ --­ Death 11. 2 --­ --­ 9. 5 --­ ---­ Incidence of total events over entire period of follow-up 2x creatinine 16. 03 Death 15. 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. 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. 88 Female 42. 34 Race White 29. 95 Non-White 42. 34 Age (years) <65 31.

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