Irbesartan
Angiotensin II receptor blocker for hypertension and diabetic nephropathy
Irbesartan is an oral angiotensin II receptor blocker (ARB, sartan) that was launched in 1997 by Sanofi and Bristol Myers Squibb under the brand names Aprovel and Karvea. Numerous generics are now available, including fixed combinations with hydrochlorothiazide (CoAprovel, irbesartan HCT generics). Irbesartan is approved for the treatment of essential arterial hypertension and for renal protection in adults with type 2 diabetes and hypertension with micro or macroalbuminuria.
The pivotal IRMA 2 study documented a significant delay in the progression from micro to macroalbuminuria, and the IDNT study demonstrated a slowing of renal function loss in diabetic nephropathy. This makes irbesartan, alongside losartan, an important renoprotective sartan. In the guidelines of the European Society of Cardiology, the European Society of Hypertension and Kidney Disease Improving Global Outcomes (KDIGO), RAAS blockade (ACE inhibitor or ARB) is the standard in diabetic nephropathy.
Mechanism of Action
Irbesartan selectively and with high affinity blocks the angiotensin II type 1 receptor (AT1). Angiotensin II is the central effector peptide of the renin angiotensin aldosterone system (RAAS) and acts via the AT1 receptor to produce vasoconstriction, stimulate aldosterone release, promote sodium and water retention and contribute to vascular wall remodelling and fibrosis. AT1 blockade abolishes these effects.
Unlike ACE inhibitors, irbesartan does not inhibit the angiotensin converting enzyme reaction and does not affect bradykinin breakdown. The dry irritating cough seen in up to 10 percent of patients on ACE inhibitors is largely absent with sartans. This is a clinically important advantage and a common reason for switching to a sartan in patients intolerant to ACE inhibitors.
The half life is 11 to 15 hours, allowing once daily dosing. Metabolism is hepatic via CYP2C9, and elimination is predominantly biliary as the glucuronide. Dose adjustment in renal impairment is usually not required; caution is warranted in bilateral renal artery stenosis or advanced renal failure with high RAAS dependence.
Indications
- Essential arterial hypertension in adults and adolescents from 6 years of age
- Diabetic nephropathy in type 2 diabetes with hypertension and micro or macroalbuminuria, to slow progression of renal function loss
- Treatment resistant hypertension in combination with calcium channel blockers, diuretics and additional agents
- ACE inhibitor intolerance as the preferred alternative, particularly in dry irritating cough
In current guidelines ACE inhibitors and ARBs are considered equivalent first line options, and the choice is made pragmatically on the basis of tolerability and cost.
Dosage and Administration
Hypertension: starting dose 150 mg once daily, increased to 300 mg once daily or combined with hydrochlorothiazide if blood pressure control is inadequate. Diabetic nephropathy: target dose 300 mg once daily.
Adolescents 13 to 16 years: start 75 mg, increase to 150 mg. Children 6 to 12 years: start 75 mg, increase to 150 mg if response is insufficient. Administration is once daily at the same time each day, with or without food.
Renal impairment: no formal dose adjustment; monitor creatinine and potassium regularly. Hepatic impairment: no adjustment in mild to moderate impairment; data are limited in severe hepatic impairment, use with caution. Haemodialysis: starting dose 75 mg because of possible hypotension.
Side Effects
Common: dizziness, headache, fatigue, orthostatic hypotension (especially initially in volume depletion), hyperkalaemia (particularly with potassium sparing diuretics or in renal impairment), tachycardia, nausea, muscle and joint pain.
Uncommon: sleep disturbance, sexual dysfunction, rash, urticaria, elevated liver enzymes, elevated creatine kinase, chest pain.
Rare to very rare: angioedema (less common than with ACE inhibitors but possible), vasculitis, agranulocytosis, hyponatraemia, acute renal failure in pre existing haemodynamic RAAS dependence, sprue like enteropathy (reported for the ARB class).
Important: concomitant use of a sartan with an ACE inhibitor or a direct renin inhibitor is contraindicated, because there is no benefit and the risk of hyperkalaemia, renal failure and hypotension is increased.
Interactions
- Potassium sparing diuretics (spironolactone, eplerenone, triamterene, amiloride), potassium supplements, potassium containing salt substitutes: increased risk of hyperkalaemia
- Lithium: plasma lithium concentrations rise; avoid the combination if possible or monitor closely
- NSAIDs including COX 2 inhibitors: attenuated effect, increased risk of acute renal failure in volume depletion and in elderly patients
- ACE inhibitors, direct renin inhibitor (aliskiren): dual RAAS blockade is contraindicated
- Other antihypertensives: additive blood pressure lowering effect, usually desired
- CYP2C9 substrates (warfarin, phenytoin): clinically usually without relevance; check INR when switching warfarin
Special Notes
Pregnancy: irbesartan is absolutely contraindicated in pregnancy. In the second and third trimesters the compound can cause fetal renal and bone development damage, oligohydramnios and death. In women wishing to conceive a prior switch to other antihypertensives such as labetalol, nifedipine sustained release or methyldopa is required. Breastfeeding: not recommended, data on transfer into breast milk are limited.
Contraindications: pregnancy and breastfeeding, severe hepatic and renal dysfunction, bilateral renal artery stenosis, hyperkalaemia above 5.5 mmol/l, concurrent use of an ACE inhibitor or aliskiren in diabetes or renal dysfunction.
Volume depletion and sodium depletion: check fluid status before starting therapy; in diuretic pretreated patients titrate carefully because of orthostatic risk. In acute conditions with fluid loss (fever, diarrhoea, vomiting) pause therapy as appropriate (sick day rule).
Monitoring: blood pressure, creatinine and potassium before starting therapy, after 2 to 4 weeks and then regularly. In diabetic nephropathy additionally the albumin to creatinine ratio and eGFR to assess treatment success.
Cough: unlike ACE inhibitors, irbesartan is practically not associated with a dry irritating cough. This makes the compound the preferred option in ACE inhibitor induced cough, which considerably impairs adherence.
You might also be interested in
- Losartan, the first sartan of the class
- Enalapril, ACE inhibitor as an alternative first line
- Eplerenone, selective aldosterone antagonist after myocardial infarction
- Chlortalidone, thiazide diuretic for combination therapy
- Lowering high blood pressure, overview of all measures
Frequently Asked Questions
What is the difference between a sartan and an ACE inhibitor?
Both block the renin angiotensin aldosterone system. ACE inhibitors reduce the formation of angiotensin II and simultaneously inhibit bradykinin breakdown, which explains the typical irritating cough. Sartans such as irbesartan block the AT1 receptor directly without affecting bradykinin. Their effect on blood pressure and organ protection is comparable, and sartans are often better tolerated because the cough is absent.
Why does my creatinine rise after starting therapy?
Sartans lower intraglomerular pressure in the kidney, which can transiently raise creatinine by up to 30 percent. This effect reflects the desired renoprotective action and is usually not a reason to discontinue. A markedly larger rise or concurrent hyperkalaemia requires medical reassessment.
Can I take irbesartan during pregnancy?
No. Sartans are absolutely contraindicated in pregnancy and can cause severe renal damage and other developmental abnormalities in the fetus. If you wish to conceive or if pregnancy is confirmed, contact your treating physician immediately so that you can be switched to a pregnancy compatible alternative such as methyldopa or labetalol.
Why is combining with liquorice not recommended?
Liquorice contains glycyrrhizin, which can have a pseudoaldosterone like effect with sodium retention, potassium loss and a rise in blood pressure. Under irbesartan this weakens the blood pressure lowering effect and increases the risk of hypertension. Patients should avoid excessive liquorice intake (more than 50 g per day).
Sources
- EMA, Aprovel (Irbesartan) EPAR
- AWMF, S3 guideline on hypertension and diabetic nephropathy
- Gelbe Liste, irbesartan drug profile
- BfArM, Federal Institute for Drugs and Medical Devices
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