Avapro

Irbesartan is the generic form of the brand-name drug Avapro, which is used to treat high blood pressure.

It's also used to treat kidney disease that's caused by diabetes, as well as heart failure.

The prescription medicine is in a class of drugs known as angiotensin receptor blockers (ARBs), which work by relaxing blood vessels.

Avapro is typically prescribed along with recommendations for healthy lifestyle changes, such as diet and exercise. It's either taken alone, or sometimes combined with other medicines.

The Food and Drug Administration (FDA) approved irbesartan in 1997. It's manufactured by Sanofi-Aventis and Bristol-Myers Squibb Company.

Irbesartan Warnings

Before taking irbesartan, tell you doctor if you have or have ever had:

• Allergies to medications
• Heart failure or blood vessel problems
• Stroke or heart attack
• Kidney disease (or if you're on dialysis)
• Angioedema (a condition that causes swelling of the hands, face, eyes, lips, throat, or tongue; hoarseness; or swallowing and breathing difficulties)
• Either high blood potassium levels or low blood sodium levels
• Low blood volume

Also let your physician know if you have diabetes and are taking the drug aliskiren (Tekturna, Amturnide, Tekamlo).

This medicine might not work as well in African Americans. Talk to your doctor if this is a concern for you.

Let your doctor know if you're on a low-salt diet or if you're dehydrated before taking this medicine.

Tell your physician if you experience diarrhea, vomiting, or excessive sweating while taking irbesartan, because you may be at an increased risk for developing low blood pressure.

Check with your healthcare provider before using a salt substitute or any product that has potassium in it while using irbesartan.

This medicine shouldn't be given to a child younger than 16. Safety and effectiveness in this age group haven't been established.

Be sure to let your doctor know you're taking this medicine before having any type of surgery, including a dental procedure.

This medicine will help control high blood pressure, but it won't cure the condition.

It might take up to two weeks before you experience the full benefits of the drug. Don't stop taking irbesartan without first talking to your doctor.

Your physician will probably want to perform frequent lab tests while you take this medicine. Keep all appointments with your doctor and laboratory.

Pregnancy and Irbesartan

Irbesartan contains a black-box warning because it can cause serious injury or death to an unborn baby if it's taken in the last six months of pregnancy.

Tell your doctor immediately if you're pregnant or might become pregnant while taking this medicine.

It's not known whether irbesartan is found in breast milk. Don't breast-feed a baby while taking this medicine.

AVAPRO (irbesartan) is an angiotensin II receptor (AT1 subtype) antagonist.

Irbesartan is a non-peptide compound, chemically described as a 2-butyl-3-[p-(o-1H-tetrazol-5- ylphenyl)benzyl]-1,3-diazaspiro[4.4]non-1-en-4-one.

Its empirical formula is C25H28N6O, and the structural formula:

Irbesartan is a white to off-white crystalline powder with a molecular weight of 428.5. It is a nonpolar compound with a partition coefficient (octanol/water) of 10.1 at pH of 7.4. Irbesartan is slightly soluble in alcohol and methylene chloride and practically insoluble in water.

AVAPRO is available for oral administration in unscored tablets containing 75 mg, 150 mg, or 300 mg of irbesartan. Inactive ingredients include: lactose, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, poloxamer 188, silicon dioxide, and magnesium stearate.

Pregnancy

Advise female patients of childbearing age about the consequences of exposure to AVAPRO during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.

Potassium Supplements

Advise patients receiving AVAPRO not to use potassium supplements or salt substitutes containing potassium without consulting their healthcare provider [see DRUG INTERACTIONS].

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

Avapro 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 Avapro without talking to your doctor.

Take Avapro exactly as prescribed by your doctor. Follow the directions on your prescription label carefully. Your doctor will determine the best dose for you based on the medical condition being treated, other conditions you have, medicines you take, and your body's repsonse to Avapro.

Hypertension (high blood pressure)

• The recommended starting dose is Avapro 150 mg daily.

Nephropathy (kidney disease) in patients with type 2 diabetes

• The recommended maintenance dose of Avapro is 300 mg.

• Store Avapro tablets at room temperature, away from excess light and moisture.
• Keep this and all medicines out of the reach of children.

Drinking alcohol can further lower your blood pressure and may increase certain side effects of irbesartan.

Do not use potassium supplements or salt substitutes while you are taking irbesartan, unless your doctor has told you to.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

General

BP Monitoring and Treatment Goals

• Carefully monitor BP during initial titration or subsequent upward adjustment in dosage.500 501

• When available, use evidence-based dosing information (i.e., dosages shown in randomized controlled trials to reduce complications of hypertension) to determine target dosages; target dosages usually can be achieved within 2–4 weeks but may take up to several months.501

• If adequate BP response not achieved with a single antihypertensive agent, add a second drug with demonstrated benefit; if goal BP still not achieved with optimal dosages of 2 antihypertensive agents, add a third drug.501 May maximize dosage of the first drug before adding a second drug, or add a second drug before maximizing dosage of the initial drug.501

• Consider initiating antihypertensive therapy with a combination of drugs if patient's BP exceeds goal BP by >20/10 mm Hg.500 501 503 504

• Goal is to achieve and maintain optimal control of BP; individualize specific target BP based on consideration of multiple factors, including patient age and comorbidities, and currently available evidence from clinical studies.500 501 (See Hypertension under Uses.)

Administration

Oral Administration

Administer orally once daily without regard to meals.1 21

Dosage

Adults

JNC 8 expert panel recommends initial dosage of 75 mg once daily and target dosage of 300 mg once daily based on dosages used in randomized controlled studies.501

Manufacturer recommends initial dosage of 150 mg once daily in adults without intravascular volume depletion.1 In adults with depletion of intravascular volume, the usual initial dosage is 75 mg once daily.1 24

Manufacturer states usual dosage is 150–300 mg once daily; no additional therapeutic benefit with higher dosages or with twice-daily dosing.1

If intolerable adverse effects occur, consider dosage reduction; if adverse effects worsen or fail to resolve, may need to discontinue and switch to another antihypertensive drug class.501

Manufacturer states fixed-combination preparation can be used for initial treatment of hypertension in patients who are likely to need multiple drugs to achieve their BP goals.26 Consider potential benefits and risks of initiating therapy with the fixed combination.26

If BP is not adequately controlled by monotherapy with irbesartan or hydrochlorothiazide, can switch to fixed-combination tablets (irbesartan 150 mg and 12.5 mg hydrochlorothiazide; then irbesartan 300 mg and hydrochlorothiazide 12.5 mg), administered once daily.26 Can increase dosage to irbesartan 300 mg and hydrochlorothiazide 25 mg daily, if needed, to control BP.26

In patients receiving fixed-combination tablets as initial therapy, the usual starting dosage is irbesartan 150 mg and hydrochlorothiazide 12.5 mg once daily.26 May increase dosage after 1–2 weeks of therapy to a maximum of irbesartan 300 mg and hydrochlorothiazide 25 mg once daily.26

Initial dosage of 75 mg once daily used in clinical trial.1 Increase dosage to target maintenance dosage of 300 mg once daily.1 No data available on effects of lower dosages.1

Special Populations

Hepatic Impairment

No initial dosage adjustments necessary.1 26

Renal Impairment

No initial dosage adjustments necessary.1 26

Irbesartan/hydrochlorothiazide fixed combination not recommended in patients with severe renal impairment.26

Geriatric Patients

No initial dosage adjustments necessary.1 26

Volume- and/or Salt-depleted Patients

Correct volume and/or salt depletion prior to initiation of therapy or initiate therapy using lower initial dosage (75 mg once daily).1 24 26 Fixed-combination tablets containing irbesartan and hydrochlorothiazide are not recommended as initial therapy in patients with intravascular volume depletion.26

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

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

• 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.

Use Avapro as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take with or without food.
• Take this medicine at the same time of day.
• Keep taking Avapro as you have been told by your doctor or other health care provider, even if you feel well.
• To gain the most benefit, do not miss doses.
• Drink lots of noncaffeine liquids unless told to drink less liquid by your doctor.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

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-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 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).

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- and 50-fold the MRHD (300 mg) on a mg/m2 basis, respectively.

90 Tablets

NDC 0024-5851-90

Avapro®
(irbesartan)
Tablets
150 mg

Rx only

SANOFI

• Angiotensin Receptor Blockers (ARBs)

Usual Adult Dose for Diabetic Nephropathy:

Initial dose: 150 mg orally once a day with or without food.
Maintenance dose: 150 to 300 mg orally once a day.

Usual Adult Dose for Hypertension:

Initial dose: 150 mg orally once a day with or without food.
Maintenance dose: 150 to 300 mg orally once a day.

Usual Pediatric Dose for Hypertension:

6 to 12 years:
Initial dose: 75 mg once daily.
Maintenance dose: 75 mg to 150 mg once daily.

13 to 18 years:
Initial dose: 150 mg once daily.
Maintenance dose: 150 mg to 300 mg once daily.

Applies to irbesartan: oral tablet

General

The most common adverse reactions were hyperkalemia, headache, and dizziness.[Ref]

Metabolic

Hyperkalemia (5.5 mEq/L or greater) occurred in 29.4% of hypertensive diabetic patients with microalbuminuria and normal renal function and in 46.3% of hypertensive diabetic patients with chronic renal insufficiency and overt proteinuria.[Ref]

Very common (10% or more): Hyperkalemia (up to 46.3%)
Uncommon (0.1% to 1%): Weight gain
Rare (less than 0.1%): Gout, decreased appetite, increased appetite
Frequency not reported: Hyperkalemia[Ref]

Nervous system

Very common (10% or more): Headache (up to 12.3%), dizziness (up to 10.2%)
Common (1% to 10%): Orthostatic dizziness
Uncommon (0.1% to 1%): Numbness, somnolence, vertigo, paresthesia
Rare (less than 0.1%): Syncope, tremor, coordination disturbance, taste disturbance
Frequency not reported: Tinnitus, dysgeusia, transient ischemic attack, cerebrovascular accident[Ref]

Respiratory

Common (1% to 10%): Upper respiratory tract infection, sinus abnormality, cough, pharyngitis, rhinitis
Uncommon (0.1% to 1%): Epistaxis, dyspnea
Frequency not reported: Tracheobronchitis, congestion, pulmonary congestion, wheezing[Ref]

Gastrointestinal

Common (1% to 10%): Nausea/vomiting, diarrhea, dyspepsia/heartburn, abdominal pain
Uncommon (0.1% to 1%): Constipation, flatulence, dry mouth, abdomen distention
Rare (less than 0.1%): Abnormal stool, oral lesion, dysphagia, esophagitis
Frequency not reported: Gastroenteritis[Ref]

Other

Common (1% to 10%): Fatigue, chest pain, edema
Uncommon (0.1% to 1%): Weakness, malaise, upper extremity edema, extremity swelling, hearing abnormality
Rare (less than 0.1%): Breast disorder, cold sensation, warmth sensation, pain, head/neck edema, medication bad taste
Frequency not reported: Ear pain, ear abnormality, fever, chills, facial edema
Postmarketing reports: Asthenia[Ref]

Musculoskeletal

Common (1% to 10%): Musculoskeletal pain, musculoskeletal trauma, plasma creatine kinase increased
Uncommon (0.1% to 1%): Muscle cramp
Rare (less than 0.1%): Arthritis, muscle ache, myalgia, extremity weakness, lower extremity stiffness
Frequency not reported: Arthralgia, musculoskeletal chest pain, joint stiffness, bursitis, muscle weakness
Postmarketing reports: Rhabdomyolysis[Ref]

Cardiovascular

Common (1% to 10%): Orthostatic hypotension, tachycardia
Uncommon (0.1% to 1%): Flushing, subjective rhythm disturbance, ECG abnormality, cardiac murmur, cardiac rhythm disturbance, atrial rhythm disturbance, bradycardia, hypotension
Rare (less than 0.1%): Conduction disorder, myocardial infarction, hot flashes
Frequency not reported: Hypertension, angina pectoris, arrhythmic disorder, cardiorespiratory arrest, heart failure, hypertensive crisis[Ref]

Psychiatric

Common (1% to 10%): Anxiety/nervousness
Uncommon (0.1% to 1%): Libido change, sleep disturbance, depression, emotion labile/disturbance
Rare (less than 0.1%): Stress related disorder, disturbing dreams[Ref]

Dermatologic

Common (1% to 10%): Rash
Uncommon (0.1% to 1%): Pruritus, facial erythema, hyperhidrosis
Rare (less than 0.1%): Dermatitis, acne, scalp-hair abnormality
Frequency not reported: Angioedema, urticaria, leukocytoclastic vasculitis, ecchymosis[Ref]

Genitourinary

Common (1% to 10%): Urinary tract infection
Uncommon (0.1% to 1%): Sexual dysfunction, urination abnormality
Frequency not reported: Prostate disorder[Ref]

Hematologic

Common (1% to 10%): Hemoglobin decreased
Uncommon (0.1% to 1%): Neutropenia
Rare (less than 0.1%): Anemia
Postmarketing reports: Thrombocytopenia[Ref]

Immunologic

Common (1% to 10%): Influenza
Frequency not reported: Hypersensitivity reactions, ear infection[Ref]

Renal

Uncommon (0.1% to 1%): BUN increased, serum creatinine increased
Frequency not reported: Impaired renal function, renal failure[Ref]

Ocular

Uncommon (0.1% to 1%): Vision disturbance
Rare (less than 0.1%): Eye disturbance, eyelid abnormality, visual field abnormality
Frequency not reported: Conjunctivitis[Ref]

Hepatic

Uncommon (0.1% to 1%): Jaundice
Frequency not reported: Hepatitis, abnormal liver function
Postmarketing reports: Elevated liver function tests[Ref]

Some side effects of Avapro may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Use is not recommended and a decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. Excreted into human milk: Unknown Excreted into animal milk: Yes Comments: The effects in the nursing infant are unknown.