Irbesartan Drug Information
Generic name: IRBESARTAN
Angiotensin 2 Receptor Blocker [EPC]
Uses of Irbesartan
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.
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).
Dosage & Administration of Irbesartan
Nephropathy in Type 2 Diabetic Patients
The recommended dose is 300 mg once daily.
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).
| Indication | Dose |
|---|---|
| Hypertension ( 2.2 ) | 150 to 300 mg once daily |
| Diabetic Nephropathy ( 2.3 ) | 300 mg once daily |
Side Effects of Irbesartan
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. Hypertension Irbesartan tablets have been evaluated for safety in more than 4300 patients with hypertension and about 5000 subjects overall.
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.
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%).
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.
Warnings & Cautions for Irbesartan
Fetal Toxicity
Irbesartan tablets can cause fetal harm when administered to a pregnant woman. 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 tablets as soon as possible.
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 tablets. Correct volume or salt depletion prior to administration of irbesartan tablets or use a lower starting dose.
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 tablets. 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 tablets.
Drug Interactions with Irbesartan
Agents Increasing Serum Potassium Coadministration of irbesartan tablets with other drugs that raise serum potassium levels may result in hyperkalemia, sometimes severe. Monitor serum potassium in such patients.
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.
Nonsteroidal 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, 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. 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 tablets and other agents that affect the RAS. Do not coadminister aliskiren with irbesartan tablets in patients with diabetes. Avoid use of aliskiren with irbesartan tablets in patients with renal impairment (GFR <60 mL/min). 1
Contraindications for Irbesartan
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.
Overdosage Information for Irbesartan
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.
Clinical Studies of Irbesartan
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.
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. Patients were randomized to receive irbesartan tablets 75 mg, amlodipine 2.5 mg, or matching placebo once-daily.
Patients were titrated to a maintenance dose of irbesartan tablets 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 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 tablets, 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 tablets resulted in a 20% risk reduction versus placebo (p=0.0234) (see Figure 3 and Table 1).
Treatment with irbesartan tablets 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). 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 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 tablets significantly reduced proteinuria by about 27%, an effect that was evident within 3 months of starting therapy. Irbesartan tablets 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 tablets’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 Figure 3
| Comparison with Placebo | Comparison with Amlodipine | ||||||
|---|---|---|---|---|---|---|---|
| Irbesartan N=579 (%) | 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 | |||||||
| 2× 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 | |||||||
| 2× 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 |
| Comparison with Placebo | ||||
|---|---|---|---|---|
| Baseline Factors | Irbesartan N=579 (%) | Placebo N=569 (%) | Hazard Ratio | 95% Cl |
| Gender | ||||
| 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 |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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