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Pronunciation:

(ir be SAR tan)

U.S. Brand Names:

Avapro®

Generic Available:

Canadian Brand Names:

Avapro®

Use:

Treatment of hypertension alone or in combination with other antihypertensives; treatment of diabetic nephropathy in patients with type 2 diabetes mellitus (noninsulin dependent, NIDDM) and hypertension

Pregnancy Risk Factor:

C/D (2nd and 3rd trimesters)

Pregnancy Implications:

The drug should be discontinued as soon as possible after detection of pregnancy. Drugs which act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death.

Lactation:

Excretion in breast milk unknown/contraindicated

Contraindications:

Hypersensitivity to irbesartan or any component of the formulation; hypersensitivity to other A-II receptor antagonists; bilateral renal artery stenosis; pregnancy (2nd and 3rd trimesters)

Warnings/Precautions:

Avoid use or use smaller doses in patients who are volume depleted; correct depletion first. Deterioration in renal function can occur with initiation. Use with caution in unilateral renal artery stenosis and pre-existing renal insufficiency; significant aortic/mitral stenosis. Safety and efficacy have not been established in pediatric patients <6 years of age.

Adverse Reactions:

Unless otherwise indicated, percentage of incidence is reported for patients with hypertension.

>10%: Endocrine & metabolic: Hyperkalemia (19%, diabetic nephropathy)

1% to 10%:

Cardiovascular: Orthostatic hypotension (5%, diabetic nephropathy)

Central nervous system: Fatigue (4%), dizziness (10%, diabetic nephropathy)

Gastrointestinal: Diarrhea (3%), dyspepsia (2%)

Respiratory: Upper respiratory infection (9%), cough (2.8% versus 2.7% in placebo)

>1% but frequency placebo: Abdominal pain, anxiety, chest pain, edema, headache, influenza, musculoskeletal pain, nausea, nervousness, pharyngitis, rash, rhinitis, sinus abnormality, syncope, tachycardia, urinary tract infection, vertigo, vomiting

<1% (Limited to important or life-threatening): Abdominal distension, abnormal urination, angina, arrhythmia, arthritis, bronchitis, bursitis, cardiopulmonary arrest, cerebrovascular accident, chest pain (noncardiac), chills, congestion, conjunctivitis, constipation, depression, dermatitis, dyspnea, ear infection, ear pain, ecchymosis, epistaxis, erythema, facial edema, fever, flatulence, flushing, gastroenteritis, gout, hearing abnormality, heart failure, hypertension, hypertensive crisis, hypotension, libido decreased, MI, muscle aches, muscle cramps, muscle weakness, numbness, orthostatic hypotension, paresthesia, prostate disorder, pruritus, pulmonary congestion, serum creatinine increased (0.7% versus 0.9% in placebo), sexual dysfunction, sleep disturbance, somnolence, TIA, tremor, upper extremity edema, vision disturbance, wheezing. May be associated with worsening of renal function in patients dependent on renin-angiotensin-aldosterone system.

Postmarketing reports: Angioedema, jaundice, transaminases increased, urticaria; rhabdomyolysis has been reported (rarely) with angiotensin-receptor antagonists

Overdosage/Toxicology:

Likely manifestations of overdose include hypotension and tachycardia. Treatment is supportive. Not removed by hemodialysis.

Drug Interactions:

Substrate of CYP2C8/9 (minor); Inhibits CYP2C8/9 (moderate), 2D6 (weak), 3A4 (weak)

CYP2C8/9 substrates: Irbesartan may increase the levels/effects of CYP2C8/9 substrates. Example substrates include amiodarone, fluoxetine, glimepiride, glipizide, nateglinide, phenytoin, pioglitazone, rosiglitazone, sertraline, and warfarin.

Lithium: Risk of toxicity may be increased by irbesartan; monitor lithium levels.

NSAIDs: May decrease angiotensin II antagonist efficacy; effect has been seen with losartan, but may occur with other medications in this class; monitor blood pressure

Potassium-sparing diuretics (amiloride, potassium, spironolactone, triamterene): Increased risk of hyperkalemia.

Potassium supplements may increase the risk of hyperkalemia.

Trimethoprim (high dose) may increase the risk of hyperkalemia.

Ethanol/Nutrition/Herb Interactions:

Herb/Nutraceutical: Avoid dong quai if using for hypertension (has estrogenic activity). Avoid ephedra, yohimbe, ginseng (may worsen hypertension). Avoid garlic (may have increased antihypertensive effect).

Stability:

Store at room temperature of 15°C to 30°C (59°F to 86°F).

Mechanism of Action:

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.

Pharmacodynamics/Kinetics:

Onset of action: Peak effect: 1-2 hours

Duration: >24 hours

Distribution: Vd: 53-93 L

Protein binding, plasma: 90%

Metabolism: Hepatic, primarily CYP2C9

Bioavailability: 60% to 80%

Half-life elimination: Terminal: 11-15 hours

Time to peak, serum: 1.5-2 hours

Excretion: Feces (80%); urine (20%)

Dosage:

Oral:

Hypertension:

Children:

<6 years: Safety and efficacy have not been established.

6-12 years: Initial: 75 mg once daily; may be titrated to a maximum of 150 mg once daily

Children 13 years and Adults: 150 mg once daily; patients may be titrated to 300 mg once daily

Note: Starting dose in volume-depleted patients should be 75 mg

Nephropathy in patients with type 2 diabetes and hypertension: Adults: Target dose: 300 mg once daily

Dosage adjustment in renal impairment: No dosage adjustment necessary with mild to severe impairment unless the patient is also volume depleted.

Dietary Considerations:

May be taken with or without food.

Patient Education:

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Take exactly as directed; do not discontinue without consulting prescriber. May be taken with or without food. Take first dose at bedtime. This medication does not replace other antihypertensive interventions; follow prescriber's instructions for diet and lifestyle changes. May cause dizziness, fainting, or lightheadedness (use caution when driving or engaging in tasks that require alertness until response to drug is known); nausea, vomiting, or abdominal pain (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help); or diarrhea (buttermilk, boiled milk, yogurt may help). Report chest pain or palpitations, skin rash, fluid retention (swelling of extremities), respiratory difficulty or unusual cough, or other persistent adverse reactions. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. This drug should not be used in the 2nd or 3rd trimester of pregnancy. Consult prescriber for appropriate contraceptive measures if necessary. Do not breast-feed.

Anesthesia and Critical Care Concerns/Other Considerations:

Cardiovascular Considerations:

The angiotensin II receptor antagonists appear to have similar indications as the ACE inhibitors. While these drugs have been shown to be effective in treating hypertension, their efficacy in heart failure is being vigorously evaluated. The angiotensin II antagonists are especially useful in providing an alternative therapy in those patients who have intractable cough in response to ACE inhibitor therapy. Similar to ACE inhibitors, pre-existing volume depletion caused by diuretic therapy may potentiate hypotension in response to angiotensin II antagonists. Concomitant NSAID therapy may attenuate blood pressure control; use of NSAIDs should be avoided or limited, with monitoring of blood pressure control. In the setting of heart failure, NSAID use may be associated with an increased risk for fluid accumulation and edema.

Because of the lack of effect on the response to bradykinin, angiotensin receptor blockers are less likely to be associated with nonrenin-angiotensin effects such as cough and angioedema. Because of a different site of action in comparison to ACE inhibitors, the angiotensin II antagonists do not cause increases in levels of bradykinin. These different sites of action have lead to the supposition that the ACE inhibitors and the angiotensin II antagonists may be used in combination for enhanced response. This possibility is currently being evaluated.

Dental Health: Effects on Dental Treatment:

Key adverse event(s) related to dental treatment: Orthostatic hypotension.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

No information available to require special precautions

Mental Health: Effects on Mental Status:

May cause anxiety, dizziness, nervousness

Mental Health: Effects on Psychiatric Treatment:

None reported

Dosage Forms:

Tablet: 75 mg, 150 mg, 300 mg

International Brand Names:

Aprovel® (AR, BE, BR, CH, CL, CO, CR, DE, DK, DO, EC, ES, FI, FR, GB, GT, HN, HU, ID, IE, IT, MX, NL, NO, PA, PL, PT, RO, RU, SE, SG, SI, SV, TH, ZA); Avapro® (AR, AU, BR, CA, MX); Irban® (IL); Irovel® (IN); Irvell® (ID); Karvea® (AU, DE, ES, TR)

References

Chobanian AV, Bakris GL, Black HR, et al, "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report,"JAMA, 2003, 289(19):2560-71.

Conlin P, Moore T, Swartz S, et al, "Effect of Indomethacin on Blood Pressure Lowering by Captopril and Losartan in Hypertensive Patients,"Hypertension, 2000, 36(3):461-5.

"Consensus Recommendations for the Management of Chronic Heart Failure. On Behalf of the Membership of the Advisory Council to Improve Outcomes Nationwide in Heart Failure,"Am J Cardiol, 1999, 83(2A):1A-38A.

Hunt SA, Baker DW, Chin MH, et al, "ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: Executive Summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure),"J Am Coll Cardiol, 2001, 38(7):2101-13.

"K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. Kidney Disease Outcome Quality Initiative,"Am J Kidney Dis, 2002, 39(2 Suppl 2):1-246. Available at: http://www.kidney.org/professionals/doqi/kdoqi/toc.htm. Accessed August 1, 2003.

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