Avapro

Brand name:Avapro
Pronounced: AVE-ah-pro
Generic name: Irbesartan

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DESCRIPTION

AVAPRO® (irbesartan) is an angiotensin II receptor (AT 1 subtype) antagonist.

Irbesartan is a non-peptide compound,chemically described as a 2-butyl-3-[[ 29-( 1H-tetrazol-5-yl) [1, 19-biphenyl]-4-yl] methyl]1,3-diazaspiro[4,4] non-1-en-4-one.

Its empirical formula is C25H28N6O.

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.

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INDICATIONS

AVAPRO (irbesartan) is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.

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SIDE EFFECTS

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. Treatment with AVAPRO was well tolerated, with an incidence of adverse events similar to placebo. These events generally were mild and transient with no relationship to the dose of AVAPRO.

In placebo-controlled clinical trials, discontinuation of therapy due to a clinical adverse event was required in 3.3 percent of patients treated with AVAPRO, versus 4.5 percent of patients given placebo.

In placebo-controlled clinical trials, the adverse event experiences that occurred in at least 1% of patients treated with AVAPRO (n= 1965) and at a higher incidence versus placebo (n= 641) included diarrhea (3% vs. 2%), dyspepsia/heartburn (2% vs. 1%), musculoskeletal trauma (2% vs. 1%), fatigue (4% vs. 3%), and upper respiratory infection (9% vs. 6%). None of these differences were significant.

The following adverse events occurred at an incidence of 1% or greater in patients treated with irbesartan, but were at least as frequent or more frequent in patients receiving placebo: abdominal pain, anxiety/nervousness, chest pain, dizziness, edema, headache, influenza, musculoskeletal pain, pharyngitis, nausea/vomiting, rash, rhinitis, sinus abnormality, tachycardia and urinary tract infection.

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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.

The incidence of hypotension or orthostatic hypotension was low in irbesartan treated patients (0.4%), unrelated to dosage, and similar to the incidence among placebo treated patients (0.2%). Dizziness, syncope, and vertigo were reported with equal or less frequency in patients receiving irbesartan compared with placebo.

In addition, the following potentially important events occurred in less than 1% of the 1965 patients and at least 5 patients (0.3%) receiving irbesartan in clinical studies, and those less frequent, clinically significant events (listed by body system). It cannot be determined whether these events were causally related to irbesartan:

Body as a Whole: fever, chills, facial edema, upper extremity edema;

Cardiovascular: flushing, hypertension, cardiac murmur, myocardial infarction, angina pectoris, arrhythmic/conduction disorder, cardio-respiratory arrest, heart failure, hypertensive crisis;

Dermatologic: pruritus, dermatitis, ecchymosis, erythema face, urticaria;

Endocrine/Metabolic/Electrolyte Imbalances: sexual dysfunction, libido change, gout;

Gastrointestinal: constipation, oral lesion, gastroenteritis, flatulence, abdominal distention;

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Musculoskeletal/Connective Tissue: extremity swelling, muscle cramp, arthritis, muscle ache, musculoskeletal chest pain, joint stiffness, bursitis, muscle weakness;

Nervous System: sleep disturbance, numbness, somnolence, emotional disturbance, depression, paresthesia, tremor, transient ischemic attack, cerebrovascular accident;

Renal/Genitourinary: abnormal urination, prostate disorder;

Respiratory: epistaxis, tracheobronchitis, congestion, pulmonary congestion, dyspnea, wheezing;

Special Senses: vision disturbance, hearing abnormality, ear infection, ear pain, conjunctivitis, other eye disturbance, eyelid abnormality, ear abnormality.

Post-Marketing Experience

The following adverse reactions have been reported in post-marketing experience: Rare cases of urticaria and angioedema (involving swelling of the face, lips, pharynx, and/or tongue) have been reported.

Laboratory Test Findings

In controlled clinical trials, clinically important differences in laboratory tests were rarely associated with administration of AVAPRO (irbesartan).

Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in less than 0.7% of patients with essential hypertension treated with AVAPRO alone versus 0.9% on placebo. (See PRECAUTIONS: Impaired Renal Function)

Hematologic: Mean decreases in hemoglobin of 0.2 g/dL were observed in 0.2% of patients receiving AVAPRO compared to 0.3% of placebo treated patients. Neutropenia (<1000 cells/mm3) occurred at similar frequencies among patients receiving AVAPRO (0.3%) and placebo treated patients (0.5%).

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WARNINGS

Fetal/Neonatal Morbidity and Mortality

Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin-converting-enzyme inhibitors. When pregnancy is detected, AVAPRO should be discontinued as soon as possible.

The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.

These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester.

Mothers whose embryos and fetuses are exposed to an angiotensin Il receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of AVAPRO as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin system will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment.

If oligohydramnios is observed, AVAPRO should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.

When pregnant rats were treated with irbesartan from day 0 to day 20 of gestation (oral doses of 50, 180, and 650 mg/kg/day), increased incidences of renal pelvic cavitation, hydroureter and/or absence of renal papilla were observed in fetuses at doses >/=50 mg/kg/day [approximately equivalent to the maximum recommended human dose (MRHD), 300 mg/day, on a body surface area basis]. Subcutaneous edema was observed in fetuses at doses >/=180 mg/kg/day (about 4 times the MRHD on a body surface area basis). As these anomalies were not observed in rats in which irbesartan exposure (oral doses of 50, 150 and 450 mg/kg/day) was limited to gestation days 6–15, they appear to reflect late gestational effects of the drug. In pregnant rabbits, oral doses of 30 mg irbesartan/kg/day were associated with maternal mortality and abortion. Surviving females receiving this dose (about 1.5 times the MRHD on a body surface area basis) had a slight increase in early resorptions and a corresponding decrease in live fetuses. Irbesartan was found to cross the placental barrier in rats and rabbits.

Radioactivity was present in the rat and rabbit fetus during late gestation and in rat milk following oral doses of radiolabeled irbesartan.

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INFORMATION

Pregnancy: Female patients of childbearing age should be told about the consequences of second-and third-trimester exposure to drugs that act on the renin-angiotensin system, and they should also be told that these consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible.