Irbesartan

Take the missed dose as soon as you remember it. However, if it is almost time for your next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

All ARBs should not be used during pregnancy. When used in the second or third trimester of pregnancy, irbesartan and similar drugs may cause injury and even death to the fetus. Irbesartan should not be used during pregnancy. When pregnancy is detected, irbesartan should be stopped as soon as possible.

It is not known whether irbesartan is secreted into human milk. Irbesartan is secreted into the milk of rats.

Tablets: 75 mg, 150 mg and 300 mg.

Tablets should be stored at room temperature, 15 C -30 C (59 F - 86 F).

>10%

Hyperkalemia (19%)

1-10%

Dizziness (10%)

Upper respiratory tract infection (URTI) (9%)

Orthostatic hypotension (5%)

Fatigue (4%)

Diarrhea (3%)

Dyspepsia (2%)

Postmarketing Reports

Urticaria; angioedema (involving swelling of the face, lips, pharynx, or tongue); elevated liver function testresults; jaundice; hepatitis; hyperkalemia, and thrombocytopenia

Impaired renal function, including cases of renal failure, has been reported

Increased creatine phosphokinase (CPK) levels and rhabdomyolysis have been reported in patients receiving angiotensin-receptor blockers (ARBs)

Take irbesartan exactly as prescribed. Do not adjust your dose unless your doctor instructs you to do so.

Irbesartan comes as a tablet to be taken by mouth, usually once a day, with a full glass of water. It may be taken with or without food. To maintain a steady level of this medicine in your blood, it is best to take it at the same time each day.

If you forget to take a dose, take it as soon as you remember, unless it is almost time for your next dose. In that case, skip the missed dose and continue with normal dosing. Do not take a double dose.

Do not stop taking irbesartan without talking to your doctor.

WARNING: FETAL TOXICITY

• When pregnancy is detected, discontinue irbesartan as soon as possible.
• Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).1 2 3 4 5 6 14 15 16 17 18 21 22 23 500

Angiotensin II receptor antagonists are recommended as one of several preferred agents for the initial management of hypertension; other options include ACE inhibitors, calcium-channel blockers, and thiazide diuretics.501 502 503 504 While there may be individual differences with respect to specific outcomes, these antihypertensive drug classes all produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.501 502 503 504 Individualize choice of therapy; consider patient characteristics (e.g., age, ethnicity/race, comorbidities, cardiovascular risk) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, cost).500 501 502 503 504 515

Angiotensin II receptor antagonists or ACE inhibitors may be preferred in hypertensive patients with diabetes mellitus or chronic kidney disease; angiotensin II receptor antagonists also may be preferred, as an alternative to ACE inhibitors, in hypertensive patients with heart failure or ischemic heart disease and/or post-MI.500 501 502 504 520 523 524 527 534 535 536 543

Black hypertensive patients generally tend to respond better to monotherapy with calcium-channel blockers or thiazide diuretics than to angiotensin II receptor antagonists.500 501 504 However, diminished response to an angiotensin II receptor antagonist is largely eliminated when administered concomitantly with a calcium-channel blocker or thiazide diuretic.500 504

The optimum BP threshold for initiating antihypertensive drug therapy is controversial.501 504 505 506 507 508 515 523 530 Further study needed to determine optimum BP thresholds/goals; individualize treatment decisions.501 503 507 515 526 530

JNC 7 recommends initiation of drug therapy in all patients with uncomplicated hypertension and BP ≥140/90 mm Hg;500 JNC 8 panel recommends SBP threshold of 150 mm Hg for patients ≥60 years of age.501 Although many experts agree that SBP goal of <150 mm Hg may be appropriate for patients ≥80 years of age,502 504 505 530 application of this goal to those ≥60 years of age is controversial, especially for those at higher cardiovascular risk.501 502 505 506 508 511 515

In the past, initial antihypertensive drug therapy was recommended for patients with diabetes mellitus or chronic kidney disease who had BP ≥130/80 mm Hg;500 503 current hypertension management guidelines generally recommend a BP threshold of 140/90 mm Hg for these individuals (same as for the general population of patients without these conditions), although a goal of <130/80 mm Hg may still be considered.501 502 503 504 520 530 535 536 541

Diabetic Nephropathy

Management of diabetic nephropathy manifested by elevated Scr and proteinuria (urinary protein excretion >300 mg daily) in patients with type 2 diabetes mellitus and hypertension.1

A recommended agent in the management of patients with diabetes mellitus and persistent albuminuria who have modestly elevated (30–300 mg/24 hours) or higher (>300 mg/24 hours) levels of urinary albumin excretion; slows rate of progression of renal disease in such patients.49 51 52 53 520 535 536

Heart Failure

Angiotensin II receptor antagonists have been used in the management of heart failure†.524 528 800

Because of their established benefits, ACE inhibitors have been the preferred drugs for inhibition of the renin-angiotensin-aldosterone (RAA) system in patients with heart failure and reduced left ventricular ejection fraction (LVEF); 524 however, some evidence indicates that therapy with an ACE inhibitor (enalapril) may be less effective than angiotensin receptor-neprilysin inhibitor (ARNI) therapy (e.g., sacubitril/valsartan) in reducing cardiovascular death and heart failure-related hospitalization.701 702 703 800

Angiotensin II receptor antagonists may be used as an alternative for those patients in whom an ACE inhibitor or ARNI is inappropriate.524 800

No additional therapeutic benefit when angiotensin II receptor antagonist used in combination with an ACE inhibitor.a b

ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend that patients with chronic symptomatic heart failure and reduced LVEF (NYHA class II or III) who are able to tolerate an ACE inhibitor or angiotensin II receptor antagonist be switched to therapy containing an ARNI to further reduce morbidity and mortality.800

Absorption

Bioavailability

Peak plasma concentration generally achieved 1.5–2 hours after oral dose.1 Absolute bioavailability is about 60–80%.1 26

Onset

Antihypertensive effect evident within 2 weeks, with maximum BP reduction after 2–4 weeks.1 26

Food

Food does not affect bioavailability.1 26

Distribution

Extent

Crosses the placenta and is distributed in the fetus in animals.1 26

Crosses the blood-brain barrier poorly, if at all, in animals.1 15

Distributed into milk in rats; not known whether distributed into human milk.1 26

Plasma Protein Binding

90% (principally albumin and α1-acid glycoprotein).1 26

Elimination

Metabolism

Undergoes hepatic metabolism by glucuronide conjugation and oxidation (principally by CYP2C9) to inactive metabolites.1 26

Elimination Route

Eliminated in urine and feces (via bile).1 26

Half-life

Terminal elimination half-life: 11–15 hours.1

Special Populations

Not removed by hemodialysis.1 26 Pharmacokinetics not substantially altered by hemodialysis or renal impairment.1 26

In addition to the use of irbesartan, treatment for your high blood pressure may include weight control and changes in the types of foods you eat, especially foods high in sodium (salt). Your doctor will tell you which of these is most important for you. You should check with your doctor before changing your diet.

Many patients who have high blood pressure will not notice any signs of the problem. In fact, many may feel normal. It is very important that you take your medicine exactly as directed and that you keep your appointments with your doctor even if you feel well.

Remember that irbesartan will not cure your high blood pressure but it does help control it. Therefore, you must continue to take it as directed if you expect to lower your blood pressure and keep it down. You may have to take high blood pressure medicine for the rest of your life. If high blood pressure is not treated, it can cause serious problems such as heart failure, blood vessel disease, stroke, or kidney disease.

You may take irbesartan with or without food.

Take all other medicines your doctor has prescribed to treat your condition.

Dosing

The dose of irbesartan will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of irbesartan. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For high blood pressure:
    • Adults—At first, 150 milligrams (mg) once a day. Your doctor may increase your dose if needed. However, the dose is usually not more than 300 mg per day.
    • Children younger than 6 years of age—Use and dose must be determined by your doctor.
  • For diabetic nephropathy:
    • Adults—300 milligrams (mg) once a day.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of irbesartan, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

• It is used to treat high blood pressure.
• It is used to protect kidney function in diabetic patients who have protein loss.
• It may be given to you for other reasons. Talk with the doctor.

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 (eg, patients treated vigorously with diuretics or on hemodialysis) (see WARNINGS: Hypotension in Volume- or Salt-Depleted Patients).

Irbesartan is an angiotensin receptor antagonist. Angiotensin II acts as a vasoconstrictor. In addition to causing direct vasoconstriction, angiotensin II also stimulates the release of aldosterone. Once aldosterone is released, sodium as well as water are reabsorbed. The end result is an elevation in blood pressure. Irbesartan binds to the AT1 angiotensin II receptor. This binding prevents angiotensin II from binding to the receptor thereby blocking the vasoconstriction and the aldosterone secreting effects of angiotensin II.

Absorption

Rapid and complete

Distribution

Vd: 53 to 93 L

Metabolism

Hepatic, via glucuronide conjugation and oxidation; oxidation occurs primarily by cytochrome P450 isoenzyme CYP2C9

Excretion

Feces (80%); urine (20%)

Acute coronary syndrome (secondary prevention of cardiovascular events)

Based on the American Heart Association/American College of Cardiology (AHA/ACC) guidelines for the management of patients with non-ST-elevation acute coronary syndromes (NSTE-ACS) and the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines for the management of patients with ST-elevation myocardial infarction (STEMI), an ARB (eg, irbesartan) is recommended and effective in patients with NSTE-ACS or STEMI who have indications for but are intolerant of ACE inhibitors; this includes patients with heart failure, MI, or anterior MI who have a left ventricular ejection fraction (LVEF) ≤0.4. In post-STEMI patients, initiate within the first 24 hours.

Improve kidney outcomes in hypertensive patients with chronic kidney disease (CKD) (diabetic and nondiabetic population)

Based on the Eighth Joint National Committee (JNC 8) guidelines for the management of high blood pressure in adults, an ARB (eg, irbesartan) or an ACE inhibitor is effective and recommended to improve kidney outcomes in adult patients with CKD and hypertension. This recommendation applies to hypertensive CKD patients, with and without proteinuria, and regardless of race and diabetes status.

Based on the American Diabetes Association Standards of Medical Care in Diabetes, in CKD patients with diabetes and hypertension, an ARB (eg, irbesartan) or an ACE inhibitor is effective and strongly recommended in patients with an eGFR <60 mL/minute/1.73 m2 and/or a UACR ≥300 mg/g for the prevention of CKD progression. In patients with modestly elevated UACR (30 to 299 mg/g), ARBs or ACE inhibitor are also recommended to reduce the progression to more advanced albuminuria.

Additional Off-Label Use:

Slow the rate of progression of aortic-root dilation in pediatric patients with Marfan syndrome

When pregnancy is detected, discontinue irbesartan as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus.

Concerns related to adverse effects:

• Angioedema: Angioedema has been reported rarely with some angiotensin II receptor antagonists (ARBs) and may occur at any time during treatment (especially following first dose). It may involve the head and neck (potentially compromising airway) or the intestine (presenting with abdominal pain). Patients with idiopathic or hereditary angioedema or previous angioedema associated with ACE-inhibitor therapy may be at an increased risk. Prolonged frequent monitoring may be required, especially if tongue, glottis, or larynx are involved, as they are associated with airway obstruction. Patients with a history of airway surgery may have a higher risk of airway obstruction. Discontinue therapy immediately if angioedema occurs. Aggressive early management is critical. Intramuscular (IM) administration of epinephrine may be necessary. Do not readminister to patients who have had angioedema with ARBs.

• Hyperkalemia: May occur; risk factors include renal dysfunction, diabetes mellitus, concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium containing salts. Use cautiously, if at all, with these agents and monitor potassium closely.

• Hypotension: Symptomatic hypotension may occur upon initiation in patients who are salt- or volume-depleted (eg, those treated with high-dose diuretics); correct volume depletion prior to administration. This transient hypotensive response is not a contraindication to further treatment with irbesartan.

• Renal function deterioration: May be associated with deterioration of renal function and/or increases in serum creatinine, particularly in patients with low renal blood flow (eg, renal artery stenosis, chronic kidney disease, severe heart failure, volume depletion) whose glomerular filtration rate (GFR) is dependent on efferent arteriolar vasoconstriction by angiotensin II; deterioration may result in oliguria, acute renal failure, and progressive azotemia. Small increases in serum creatinine may occur following initiation; consider discontinuation only in patients with progressive and/or significant deterioration in renal function.

Disease-related concerns:

• Aortic/mitral stenosis: Use with caution in patients with significant aortic/mitral stenosis.

• Renal artery stenosis: Use with caution in patients with unstented unilateral/bilateral renal artery stenosis. When unstented bilateral renal artery stenosis is present, use is generally avoided due to the elevated risk of deterioration in renal function unless possible benefits outweigh risks.

• Renal impairment: Use with caution with preexisting renal insufficiency.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pregnancy: [US Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected.

• Surgical patients: In patients on chronic angiotensin receptor blocker (ARB) therapy, intraoperative hypotension may occur with induction and maintenance of general anesthesia; however, discontinuation of therapy prior to surgery is controversial. If continued preoperatively, avoidance of hypotensive agents during surgery is prudent (Hillis 2011).