Side Effects of Avapro (irbesartan)

Avapro (irbesartan) is an angiotensin receptor blocker (ARB) used to treat high blood pressure (hypertension) and diabetic nephropathy or kidney disease. 

Angiotensin, formed in the blood by the action of angiotensin converting enzyme (ACE), is a powerful chemical that attaches to angiotensin receptors found in many tissues but primarily on smooth muscle cells of blood vessels. 

Angiotensin's attachment to the receptors causes the blood vessels to narrow (vasoconstrict), which leads to an increase in blood pressure (hypertension). Avapro blocks the angiotensin receptor. By blocking the action of angiotensin, Avapro dilates blood vessels and reduces blood pressure. 

Common side effects of Avapro include

• dizziness,
• increased blood potassium (hyperkalemia),
• diarrhea,
• abdominal pain or heartburn,
• fatigue, and
• reduced blood pressure when rising from a sitting or standing position (orthostatic hypotension).

Serious side effects of Avapro include

• impotence,
• reduced kidney function,
• allergic reactions,
• inflammation and destruction of muscle (rhabdomyolysis), and
• swelling of soft tissues including those of the throat and larynx (angioedema).

Drug interactions of Avapro include potassium-sparing diuretics, potassium supplements, or salt substitutes containing potassium because the combination may lead to elevated potassium in the blood (hyperkalemia) and toxicity from potassium. 

• Combining Avapro or other ARBs with nonsteroidal anti-inflammatory drugs (NSAIDs) in patients who are elderly, fluid-depleted (including those on diuretic therapy), or with poor kidney function may result in reduced kidney function, including kidney failure. These effects usually are reversible.
• There have been reports that aspirin and other NSAIDs such as ibuprofen, indomethacin, and naproxen may reduce the effects of ARBs. 

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

It is unknown if Avapro is secreted into human milk. Consult your doctor before breastfeeding.

The most common side effects of irbesartan are:

• dizziness,
• hyperkalemia,
• diarrhea,
• abdominal pain or
• heartburn,
• fatigue, and
• reduced blood pressure when rising from a sitting or standing position (orthostatic hypotension).

Other important side effects patients may experience include:

• impotence,
• reduced renal function, and
• allergic reactions.

Rhabdomyolysis (inflammation and destruction of muscle) and angioedema (swelling of soft tissues including those of the throat and larynx) are rare but serious side effects of irbesartan.

The following important adverse reactions are described elsewhere in the labeling:

• Hypotension in Volume- or Salt-depleted Patients
• Impaired Renal Function

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

Avapro has been evaluated for safety in more than 4300 patients with hypertension and about 5000 subjects overall. This experience includes 1303 patients treated for over 6 months and 407 patients for 1 year or more.

In placebo-controlled clinical trials, the following adverse reactions were reported in at least 1% of patients treated with Avapro (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.

Nephropathy In Type 2 Diabetic Patients

• Hyperkalemia: In the Irbesartan Diabetic Nephropathy Trial (IDNT) (proteinuria ≥ 900 mg/day, and serum creatinine ranging from 1.0-3.0 mg/dL), the percent of patients with potassium > 6 mEq/L was 18.6% in the Avapro group versus 6.0% in the placebo group.
• Discontinuations due to hyperkalemia in the Avapro 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 Avapro versus placebo group: dizziness (10.2% vs 6.0%), orthostatic dizziness (5.4% vs 2.7%) and orthostatic hypotension (5.4% vs 3.2%).

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of Avapro. 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); increased liver function tests; jaundice; hepatitis; hyperkalemia; thrombocytopenia; increased CPK; tinnitus.

Agents Increasing Serum Potassium

• Coadministration of Avapro 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.

Non-Steroidal 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, 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.
• 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-Angiotens In 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 Avapro and other agents that affect the RAS.
• Do not co-administer aliskiren with Avapro in patients with diabetes. Avoid use of aliskiren with Avapro in patients with renal impairment (GFR < 60 mL/min).