Avapro tablet

Warning: fetal toxicity

  • When pregnancy is detected, discontinue AVAPRO as soon as possible.
  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. See WARNINGS: Fetal Toxicity.

Description

AVAPRO ®* (irbesartan) is an angiotensinII receptor (AT 1subtype) antagonist.

*Registered trademark

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

Its empirical formula is C 25H 28N 6O,and the structural formula:

Irbesartan is a white to off-white crystalline powder with a molecularweight 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 methylenechloride and practically insoluble in water.

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

Clinical pharmacology

Mechanism of action

Angiotensin II is a potent vasoconstrictor formed from angiotensinI in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininaseII). Angiotensin II is the principal pressor agent of the renin-angiotensinsystem (RAS) and also stimulates aldosterone synthesis and secretion by adrenalcortex, cardiac contraction, renal resorption of sodium, activity of the sympatheticnervous system, and smooth muscle cell growth. Irbesartan blocks the vasoconstrictorand aldosterone-secreting effects of angiotensin II by selectively bindingto the AT 1angiotensin II receptor. There is also anAT 2receptor in many tissues, but it is not involvedin cardiovascular homeostasis.

Irbesartan is a specific competitive antagonist of AT 1receptorswith a much greater affinity (more than 8500-fold) for the AT 1receptorthan for the AT 2receptor and no agonist activity.

Blockade of the AT 1receptor removes thenegative feedback of angiotensin II on renin secretion, but the resultingincreased plasma renin activity and circulating angiotensin II do not overcomethe effects of irbesartan on blood pressure.

Irbesartan does not inhibit ACE or renin or affect other hormonereceptors or ion channels known to be involved in the cardiovascular regulationof blood pressure and sodium homeostasis. Because irbesartan does not inhibitACE, it does not affect the response to bradykinin; whether this has clinicalrelevance is not known.

Pharmacokinetics

Irbesartan is an orally active agent that does not require biotransformationinto an active form. The oral absorption of irbesartan is rapid and completewith an average absolute bioavailability of 60% to 80%. Following oral administrationof AVAPRO, peak plasma concentrations of irbesartan are attained at 1.5 to2 hours after dosing. Food does not affect the bioavailability of AVAPRO.

Irbesartan exhibits linear pharmacokinetics over the therapeuticdose range.

The terminal elimination half-life of irbesartan averaged 11 to15 hours. Steady-state concentrations are achieved within 3 days. Limitedaccumulation of irbesartan (<20%) is observed in plasma upon repeated once-dailydosing.

Metabolism and elimination

Irbesartan is metabolized via glucuronide conjugation and oxidation.Following oral or intravenous administration of 14C-labeledirbesartan, more than 80% of the circulating plasma radioactivity is attributableto unchanged irbesartan. The primary circulating metabolite is the inactiveirbesartan glucuronide conjugate (approximately 6%). The remaining oxidativemetabolites do not add appreciably to irbesartans pharmacologic activity.

Irbesartan and its metabolites are excreted by both biliary andrenal routes. Following either oral or intravenous administration of 14C-labeledirbesartan, about 20% of radioactivity is recovered in the urine and the remainderin the feces, as irbesartan or irbesartan glucuronide.

In vitrostudies of irbesartan oxidation by cytochromeP450 isoenzymes indicated irbesartan was oxidized primarily by 2C9; metabolismby 3A4 was negligible. Irbesartan was neither metabolized by, nor did it substantiallyinduce or inhibit, isoenzymes commonly associated with drug metabolism (1A1,1A2, 2A6, 2B6, 2D6, 2E1). There was no induction or inhibition of 3A4.

Distribution

Irbesartan is 90% bound to serum proteins (primarily albumin and 1-acid glycoprotein) with negligible binding to cellularcomponents of blood. The average volume of distribution is 53litersto 93 liters. Total plasma and renal clearances are in the range of 157 mL/minto 176mL/min and 3.0 mL/min to 3.5 mL/min, respectively.With repetitive dosing, irbesartan accumulates to no clinically relevant extent.

Studies in animals indicate that radiolabeled irbesartan weaklycrosses the blood-brain barrier and placenta. Irbesartan is excreted in themilk of lactating rats.

Special populations

Gender

No gender-related differences in pharmacokinetics were observedin healthy elderly (age 65-80 years) or in healthy young (age 18-40 years)subjects. In studies of hypertensive patients, there was no gender differencein half-life or accumulation, but somewhat higher plasma concentrations ofirbesartan were observed in females (11-44%). No gender-related dosage adjustmentis necessary.

Geriatric

In elderly subjects (age 65-80 years), irbesartan elimination half-lifewas not significantly altered, but AUC and C maxvalueswere about 20% to 50% greater than those of young subjects (age 18-40 years).No dosage adjustment is necessary in the elderly.

Race

In healthy black subjects, irbesartan AUC values were approximately25% greater than whites; there were no differences in C maxvalues.

Renal insufficiency

The pharmacokinetics of irbesartan were not altered in patientswith renal impairment or in patients on hemodialysis. Irbesartan is not removedby hemodialysis. No dosage adjustment is necessary in patients with mild tosevere renal impairment unless a patient with renal impairment is also volumedepleted. (See WARNINGS: Hypotension in Volume- orSalt-Depleted Patients and DOSAGE ANDADMINISTRATION .)

Hepatic insufficiency

The pharmacokinetics of irbesartan following repeated oral administrationwere not significantly affected in patients with mild to moderate cirrhosisof the liver. No dosage adjustment is necessary in patients with hepatic insufficiency.

Drug interactions

Pharmacodynamics

In healthy subjects, single oral irbesartan doses of up to 300mg produced dose-dependent inhibition of the pressor effect of angiotensinII infusions. Inhibition was complete (100%) 4hours followingoral doses of 150 mg or 300 mg and partial inhibition was sustained for 24hours(60% and 40% at 300 mg and 150 mg, respectively).

In hypertensive patients, angiotensin II receptor inhibition followingchronic administration of irbesartan causes a 1.5- to 2-fold rise in angiotensinII plasma concentration and a 2- to 3-fold increase in plasma renin levels.Aldosterone plasma concentrations generally decline following irbesartan administration,but serum potassium levels are not significantly affected at recommended doses.

In hypertensive patients, chronic oral doses of irbesartan (upto 300 mg) had no effect on glomerular filtration rate, renal plasma flow,or filtration fraction. In multiple dose studies in hypertensive patients,there were no clinically important effects on fasting triglycerides, totalcholesterol, HDL-cholesterol, or fasting glucose concentrations. There wasno effect on serum uric acid during chronic oral administration, and no uricosuriceffect.

Clinical studies

Hypertension

The antihypertensive effects of AVAPRO (irbesartan) were examinedin 7 major placebo-controlled 8 to 12 week trials in patients with baselinediastolic blood pressures of 95 mmHg to 110 mmHg. Doses of 1 mg to 900 mgwere included in these trials in order to fully explore the dose-range ofirbesartan. These studies allowed comparison of once- or twice-daily regimensat 150mg/day, comparisons of peak and trough effects, andcomparisons of response by gender, age, and race. Two of the 7 placebo-controlledtrials identified above examined the antihypertensive effects of irbesartanand hydrochlorothiazide in combination.

The 7 studies of irbesartan monotherapy included a total of 1915patients randomized to irbesartan (1-900 mg) and 611 patients randomized toplacebo. Once-daily doses of 150 mg and 300 mg provided statistically andclinically significant decreases in systolic and diastolic blood pressurewith trough (24 hours post-dose) effects after 6 to 12 weeks of treatmentcompared to placebo, of about 8-10/5-6 mmHg and 8-12/5-8 mmHg, respectively.No further increase in effect was seen at dosages greater than 300 mg. Thedose-response relationships for effects on systolic and diastolic pressureare shown in Figures 1 and 2.

Once-daily administration of therapeutic doses of irbesartan gavepeak effects at around 3 to 6 hours and, in one ambulatory blood pressuremonitoring study, again around 14 hours. This was seen with both once-dailyand twice-daily dosing. Trough-to-peak ratios for systolic and diastolic responsewere generally between 60% to 70%. In a continuous ambulatory blood pressuremonitoring study, once-daily dosing with 150 mg gave trough and mean 24-hourresponses similar to those observed in patients receiving twice-daily dosingat the same total daily dose.

In controlled trials, the addition of irbesartan to hydrochlorothiazidedoses of 6.25 mg, 12.5mg, or 25mg producedfurther dose-related reductions in blood pressure similar to those achievedwith the same monotherapy dose of irbesartan. HCTZ also had an approximatelyadditive effect.

Analysis of age, gender, and race subgroups of patients showedthat men and women, and patients over and under 65 years of age, had generallysimilar responses. Irbesartan was effective in reducing blood pressure regardlessof race, although the effect was somewhat less in blacks (usually a low-reninpopulation).

The effect of irbesartan is apparent after the first dose, andit is close to its full observed effect at 2 weeks. At the end of an 8-weekexposure, about 2/3 of the antihypertensive effect was still present one weekafter the last dose. Rebound hypertension was not observed. There was essentiallyno change in average heart rate in irbesartan-treated patients in controlledtrials.

Nephropathy in type 2 diabetic patients

The Irbesartan Diabetic Nephropathy Trial (IDNT) was a randomized,placebo- and active-controlled, double-blind, multicenter study conductedworldwide in 1715 patients with type 2 diabetes, hypertension (SeSBP >135mmHg or SeDBP >85 mmHg), and nephropathy (serum creatinine 1.0 to 3.0 mg/dLin females or 1.2 to 3.0 mg/dL in males and proteinuria 900mg/day).Patients were randomized to receive AVAPRO 75 mg, amlodipine 2.5 mg, or matchingplacebo once-daily. Patients were titrated to a maintenance dose of AVAPRO300mg, or amlodipine 10mg, as tolerated.Additional antihypertensive agents (excluding ACE inhibitors, angiotensinII receptor antagonists and calcium channel blockers) were added as neededto achieve blood pressure goal (135/85 or 10 mmHg reduction in systolic bloodpressure if higher than 160 mmHg) for patients in all groups.

The study population was 66.5% male, 72.9% below 65 years of ageand 72% White, (Asian/Pacific Islander 5.0%, Black 13.3%, Hispanic 4.8%).The mean baseline seated systolic and diastolic blood pressures were 159 mmHgand 87 mmHg, respectively. The patients entered the trial with a mean serumcreatinine of 1.7 mg/dL and mean proteinuria of 4144mg/day.

The mean blood pressure achieved was 142/77 mmHg for AVAPRO, 142/76mmHg for amlodipine, and 145/79 mmHg for placebo. Overall, 83.0% of patientsreceived the target dose of irbesartan more than 50% of the time. Patientswere followed for a mean duration of 2.6years.

The primary composite endpoint was the time to occurrence of anyone of the following events: doubling of baseline serum creatinine, end-stagerenal disease (ESRD; defined by serum creatinine 6 mg/dL, dialysis, or renaltransplantation) or death. Treatment with AVAPRO resulted in a 20% risk reductionversus placebo (p=0.0234) (see Figure 3 and Table 1).Treatment with AVAPRO also reduced the occurrence of sustained doubling ofserum creatinine as a separate endpoint (33%), but had no significant effecton ESRD alone and no effect on overall mortality (see Table1).

Figure 3:IDNT: Kaplan-Meier Estimates Of Primary Endpoint (Doubling of Serum Creatinine, End-Stage Renal Disease or All-Cause Mortality

The percentages of patients experiencing an event during the courseof the study can be seen in Table 1 below:

Table 1:IDNT: Components of Primary Composite Endpoint
ComparisonWith Placebo ComparisonWith Amlodipine
AVAPRO
N=579
(%)
Placebo
N=569
(%)
Hazard
Ratio
95% CI Amlodipine
N=567
(%)
Hazard
Ratio
95% CI
Primary
Composite
Endpoint
32.6 39.0 0.80 0.66-0.97
(p=0.0234)
41.1 0.77 0.63-0.93
Breakdownof first occurring event contributing to primary endpoint
2xcreatinine 14.2 19.5 --- --- 22.8 --- ---
ESRD 7.4 8.3 --- --- 8.8 --- ---
Death 11.1 11.2 --- --- 9.5 --- ----
Incidence of totalevents over entire period of follow-up
2xcreatinine 16.9 23.7 0.67 0.52-0.87 25.4 0.63 0.49-0.81
ESRD 14.2 17.8 0.77 0.57-1.03 18.3 0.77 0.57-1.03
Death 15.0 16.3 0.92 0.69-1.23 14.6 1.04 0.77-1.40

The secondary endpoint of the study was a composite of cardiovascularmortality and morbidity (myocardial infarction, hospitalization for heartfailure, stroke with permanent neurological deficit, amputation). There wereno statistically significant differences among treatment groups in these endpoints.Compared with placebo, AVAPRO significantly reduced proteinuria by about 27%,an effect that was evident within 3 months of starting therapy. AVAPRO significantlyreduced the rate of loss of renal function (glomerular filtration rate), asmeasured by the reciprocal of the serum creatinine concentration, by 18.2%.

Table 2 presents results for demographic subgroups. Subgroup analysesare difficult to interpret and it is not known whether these observationsrepresent true differences or chance effects. For the primary endpoint, AVAPROsfavorable effects were seen in patients also taking other antihypertensivemedications (angiotensin II receptor antagonists, angiotensin-converting-enzymeinhibitors and calcium channel blockers were not allowed), oral hypoglycemicagents, and lipid-lowering agents.

Table 2:IDNT: Primary EfficacyOutcome Within Subgroups
ComparisonWith Placebo
Baseline Factors AVAPRO
N=579
(%)
Placebo
N=569
(%)
Hazard
Ratio
95%Cl
Gender
Male 27.5 36.7 0.68 0.53-0.88
Female 42.3 44.6 0.98 0.72-1.34
Race
White 29.5 37.3 0.75 0.60-0.95
Non-White 42.6 43.5 0.95 0.67-1.34
Age (years)
<65 31.8 39.9 0.77 0.62-0.97
65 35.1 36.8 0.88 0.61-1.29

Indications and usage

Hypertension

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

Nephropathy in type 2 diabetic patients

AVAPRO is indicated for the treatment of diabetic nephropathy withan elevated serum creatinine and proteinuria (>300 mg/day) in patients withtype 2 diabetes and hypertension. In this population, AVAPRO reduces the rateof progression of nephropathy as measured by the occurrence of doubling ofserum creatinine or end-stage renal disease (need for dialysis or renal transplantation)(see CLINICAL PHARMACOLOGY: Clinical Studies ).

Contraindications

AVAPRO is contraindicated in patients who are hypersensitive toany component of this product.

Do not coadminister aliskiren with AVAPRO in patients with diabetes (see PRECAUTIONS: Drug Interactions ).

Warnings

Fetal toxicity

Pregnancy category d

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue AVAPRO as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimesters of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue AVAPRO, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in uteroexposure to AVAPRO for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS: Pediatric Use ).

When pregnant rats were treated with irbesartan from day 0 to day 20 of gestation (oral doses of 50 mg/kg/day, 180 mg/kg/day, 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 to 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.

Hypotension in volume- or salt-depleted patients

Excessive reduction of blood pressure was rarely seen (<0.1%)in patients with uncomplicated hypertension. Initiation of antihypertensivetherapy may cause symptomatic hypotension in patients with intravascular volume-or sodium-depletion, eg, in patients treated vigorously withdiuretics or in patients on dialysis. Such volume depletion should be correctedprior to administration of AVAPRO, or a low starting dose should be used (see DOSAGE AND ADMINISTRATION ).

If hypotension occurs, the patient should be placed in the supineposition and, if necessary, given an intravenous infusion of normal saline.A transient hypotensive response is not a contraindication to further treatment,which usually can be continued without difficulty once the blood pressurehas stabilized.

Precautions

Impaired renal function

As a consequence of inhibiting the renin-angiotensin-aldosteronesystem, changes in renal function may be anticipated in susceptible individuals.In patients whose renal function may depend on the activity of the renin-angiotensin-aldosteronesystem (eg, patients with severe congestive heart failure), treatment withangiotensin-converting-enzyme inhibitors has been associated with oliguriaand/or progressive azotemia and (rarely) with acute renal failure and/or death.AVAPRO would be expected to behave similarly.

In studies of ACE inhibitors in patients with unilateral or bilateralrenal artery stenosis, increases in serum creatinine or BUN have been reported.There has been no known use of AVAPRO in patients with unilateral or bilateralrenal artery stenosis, but a similar effect should be anticipated.

Information for patients

Pregnancy

Female patients of childbearing age should be told 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.

Drug interactions

No significant drug-drug pharmacokinetic (or pharmacodynamic) interactionshave been found in interaction studies with hydrochlorothiazide, digoxin, warfarin, and nifedipine.

In vitrostudies show significant inhibition ofthe formation of oxidized irbesartan metabolites with the known cytochromeCYP 2C9 substrates/inhibitors sulphenazole, tolbutamide and nifedipine. However,in clinical studies the consequences of concomitant irbesartan on the pharmacodynamicsof warfarin were negligible. Based on in vitrodata, no interactionwould be expected with drugs whose metabolism is dependent upon cytochromeP450 isoenzymes 1A1, 1A2, 2A6, 2B6, 2D6, 2E1, or 3A4.

In separate studies of patients receiving maintenance doses ofwarfarin, hydrochlorothiazide, or digoxin, irbesartan administration for 7days had no effect on the pharmacodynamics of warfarin (prothrombin time)or pharmacokinetics of digoxin. The pharmacokinetics of irbesartan were notaffected by coadministration of nifedipine or hydrochlorothiazide.

Concomitant use of potassium-sparing diuretics, potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium.

Non-steroidal anti-inflammatory agents 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, coadministration 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. Closely monitor blood pressure, renal function, and electrolytes in patients on AVAPRO and other agents that affect the RAS.

Do not coadminister aliskiren with AVAPRO in patients with diabetes. Avoid use of aliskiren with AVAPRO in patients with renal impairment (GFR <60 mL/min).

Carcinogenesis, mutagenesis, impairment of fertility

No evidence of carcinogenicity was observed when irbesartan wasadministered at doses of up to 500/1000 mg/kg/day (males/females, respectively)in rats and 1000 mg/kg/day in mice for up to 2 years. For male and femalerats, 500 mg/kg/day provided an average systemic exposure to irbesartan (AUC 0-24hour, bound plus unbound) about 3 and 11 times, respectively,the average systemic exposure in humans receiving the maximum recommendeddose (MRD) of 300 mg irbesartan/day, whereas 1000 mg/kg/day (administeredto females only) provided an average systemic exposure about 21 times thatreported for humans at the MRD. For male and female mice, 1000 mg/kg/day providedan exposure to irbesartan about 3 and 5 times, respectively, the human exposureat 300 mg/day.

Irbesartan was not mutagenic in a battery of in vitrotests(Ames microbial test, rat hepatocyte DNA repair test, V79 mammalian-cell forwardgene-mutation assay). Irbesartan was negative in several tests for inductionof chromosomal aberrations ( in vitro-human lymphocyte assay; invivo-mouse micronucleus study).

Irbesartan had no adverse effects on fertility or mating of maleor female rats at oral doses 650mg/kg/day, the highestdose providing a systemic exposure to irbesartan (AUC 0-24 hour,bound plus unbound) about 5 times that found in humans receiving the maximumrecommended dose of 300 mg/day.

Pregnancy

Pregnancy category d

Nursing mothers

It is not known whether irbesartan is excreted in human milk, butirbesartan or some metabolite of irbesartan is secreted at low concentrationin the milk of lactating rats. Because of the potential for adverse effectson the nursing infant, a decision should be made whether to discontinue nursingor discontinue the drug, taking into account the importance of the drug tothe mother.

Pediatric use

Neonates with a history of in uteroexposure to AVAPRO:

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

Irbesartan, in a study at a dose of up to 4.5 mg/kg/day, once daily,did not appear to lower blood pressure effectively in pediatric patients ages6 to 16 years.

AVAPRO has not been studied in pediatric patients less than 6 yearsold.

Geriatric use

Of 4925 subjects receiving AVAPRO (irbesartan) in controlled clinicalstudies of hypertension, 911 (18.5%) were 65 years and over, while 150 (3.0%)were 75 years and over. No overall differences in effectiveness or safetywere observed between these subjects and younger subjects, but greater sensitivityof some older individuals cannot be ruled out. (See CLINICALPHARMACOLOGY: Pharmacokinetics , SpecialPopulations , and Clinical Studies .)

Adverse reactions

Hypertension

AVAPRO has been evaluated for safety in more than 4300 patientswith hypertension and about 5000 subjects overall. This experience includes1303 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 eventssimilar to placebo. These events generally were mild and transient with norelationship to the dose of AVAPRO.

In placebo-controlled clinical trials, discontinuation of therapydue to a clinical adverse event was required in 3.3% of patients treated withAVAPRO, versus 4.5% of patients given placebo.

In placebo-controlled clinical trials, the following adverse eventexperiences reported in at least 1% of patients treated with AVAPRO (n=1965)and at a higher incidence versus placebo (n=641), excluding those too generalto be informative and those not reasonably associated with the use of drugbecause they were associated with the condition being treated or are verycommon in the treated population, include: diarrhea (3% vs 2%), dyspepsia/heartburn(2% vs 1%), and fatigue (4% vs 3%).

The following adverse events occurred at an incidence of 1% orgreater in patients treated with irbesartan, but were at least as frequentor 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 urinarytract infection.

Irbesartan use was not associated with an increased incidence ofdry cough, as is typically associated with ACE inhibitor use. In placebo-controlledstudies, the incidence of cough in irbesartan-treated patients was 2.8% versus2.7% in patients receiving placebo.

The incidence of hypotension or orthostatic hypotension was lowin irbesartan-treated patients (0.4%), unrelated to dosage, and similar tothe incidence among placebo-treated patients (0.2%). Dizziness, syncope, andvertigo were reported with equal or less frequency in patients receiving irbesartancompared with placebo.

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

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

Cardiovascular:flushing, hypertension, cardiacmurmur, 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:sexualdysfunction, libido change, gout

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

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 ischemicattack, cerebrovascular accident

Renal/Genitourinary:abnormal urination, prostatedisorder

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

Nephropathy in type 2 diabetic patients

In clinical studies in patients with hypertension and type 2 diabeticrenal disease, the adverse drug experiences were similar to those seen inpatients with hypertension with the exception of an increased incidence oforthostatic symptoms (dizziness, orthostatic dizziness, and orthostatic hypotension)observed in IDNT (proteinuria 900 mg/day, and serum creatinine rangingfrom 1.0-3.0 mg/dL). In this trial, orthostatic symptoms occurred more frequentlyin the AVAPRO group (dizziness 10.2%, orthostatic dizziness 5.4%, orthostatichypotension 5.4%) than in the placebo group (dizziness 6.0%, orthostatic dizziness2.7%, orthostatic hypotension 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to AVAPRO.

The following have been reported: urticaria; angioedema (involving swelling of the face, lips, pharynx,and/or tongue); increased liver function tests; jaundice; hepatitis; hyperkalemia, and thrombocytopenia.

Impaired renal function, including cases of renal failure, has been reported.

Cases of increased CPK and rhabdomyolysis have been reported in patients receivingangiotensin II receptor blockers.

Laboratory test findings

Hypertension

In controlled clinical trials, clinically important differencesin laboratory tests were rarely associated with administration of AVAPRO.

Creatinine, Blood Urea Nitrogen:Minor increasesin blood urea nitrogen (BUN) or serum creatinine were observed in less than0.7% of patients with essential hypertension treated with AVAPRO alone versus0.9% on placebo. (See PRECAUTIONS: Impaired RenalFunction .)

Hematologic:Mean decreases in hemoglobin of 0.2g/dL were observed in 0.2% of patients receiving AVAPRO compared to 0.3% ofplacebo-treated patients. Neutropenia (<1000cells/mm 3)occurred at similar frequencies among patients receiving AVAPRO (0.3%) andplacebo-treated patients (0.5%).

Nephropathy in type 2 diabetic patients

Hyperkalemia:In IDNT (proteinuria 900 mg/day,and serum creatinine ranging from 1.0-3.0mg/dL),the percent of patients with hyperkalemia (>6 mEq/L) was 18.6% in the AVAPROgroup versus 6.0% in the placebo group. Discontinuations due to hyperkalemiain the AVAPRO group were 2.1% versus 0.4% in the placebo group.

Overdosage

No data are available in regard to overdosage in humans. However,daily doses of 900 mg for 8weeks were well-tolerated. Themost likely manifestations of overdosage are expected to be hypotension andtachycardia; bradycardia might also occur from overdose. Irbesartan is notremoved by hemodialysis.

To obtain up-to-date information about the treatment of overdosage,a good resource is a certified regional Poison Control Center. Telephone numbersof certified Poison Control Centers are listed in the PhysiciansDesk Reference(PDR). In managing overdose, consider the possibilitiesof multiple-drug interactions, drug-drug interactions, and unusual drug kineticsin the patient.

Laboratory determinations of serum levels of irbesartan are notwidely available, and such determinations have, in any event, no known establishedrole in the management of irbesartan overdose.

Acute oral toxicity studies with irbesartan in mice and rats indicatedacute lethal doses were in excess of 2000 mg/kg, about 25- and 50-fold the MRHD (300mg) on a mg/m 2basis,respectively.

Dosage and administration

AVAPRO may be administered with other antihypertensive agents andwith or without food.

Hypertension

The recommended initial dose of AVAPRO (irbesartan) is 150 mg oncedaily. Patients requiring further reduction in blood pressure should be titratedto 300 mg once daily.

A low dose of a diuretic may be added, if blood pressure is notcontrolled by AVAPRO alone. Hydrochlorothiazide has been shown to have anadditive effect (see CLINICAL PHARMACOLOGY: ClinicalStudies ). Patients not adequately treated by the maximum doseof 300 mg once daily are unlikely to derive additional benefit from a higherdose or twice-daily dosing.

No dosage adjustment is necessary in elderly patients, or in patientswith hepatic impairment or mild to severe renal impairment.

Nephropathy in type 2 diabetic patients

The recommended target maintenance dose is 300 mg once daily. Thereare no data on the clinical effects of lower doses of AVAPRO on diabetic nephropathy(see CLINICAL PHARMACOLOGY: Clinical Studies ).

Volume- and salt-depleted patients

A lower initial dose of AVAPRO (75 mg) is recommended in patientswith depletion of intravascular volume or salt (eg, patients treated vigorouslywith diuretics or on hemodialysis) (see WARNINGS:Hypotension in Volume- or Salt-Depleted Patients ).

How supplied

Product: 63629-3373

Spl unclassified section



Distributed by:
Bristol-Myers Squibb Sanofi-Synthelabo Partnership
New York, NY 10016

1192327A8
1192328A8

Rev September 2012

Ingredients and appearance - Product information

Avapro tablet- Irbesartan

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 63629-3373
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Irbesartan ( UNII: J0E2756Z7N)( Irbesartan - UNII: J0E2756Z7N ) 150 mgin 1

Inactive Ingredients

Ingredient Name Code
Lactose, unspecified form ( UNII: J2B2A4N98G)
Microcrystalline cellulose ( UNII: OP1R32D61U)
Starch, corn ( UNII: O8232NY3SJ)
Croscarmellose sodium ( UNII: M28OL1HH48)
Poloxamer 188 ( UNII: LQA7B6G8JG)
Silicon dioxide ( UNII: ETJ7Z6XBU4)
Magnesium stearate ( UNII: 70097M6I30)

Product Characteristics

Color WHITE Score 1
Shape OVAL Size 14 mm
Imprint Code 2772

Packaging

# Item Code Package Description Marketing Start Date
1 NDC: 63629-3373-1 30 in 1 BOTTLE 1997/09/30
2 NDC: 63629-3373-2 60 in 1 BOTTLE 1997/09/30
3 NDC: 63629-3373-3 90 in 1 BOTTLE 1997/09/30
4 NDC: 63629-3373-4 180 in 1 BOTTLE 1997/09/30

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
NDA NDA020757 USA 1997/09/30

Labeler - Bryant Ranch Prepack( 171714327)

Establishment

Name ID/FEI Business Operations
Bryant Ranch Prepack 171714327 REPACK( 63629-3373), RELABEL( 63629-3373)

Irbesartan