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AVAPRO
Overview
What is AVAPRO?
AVAPRO* (irbesartan) is an angiotensin
II receptor (AT subtype) antagonist.
*Registered trademark
Irbesartan is a non-peptide compound, chemically described as
a 2-butyl-3-[-(-1-tetrazol-5-ylphenyl)benzyl]-1,3-diazaspiro[4.4]non-1-en-4-one.
Its empirical formula is CHNO,
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.
What does AVAPRO look like?
What are the available doses of AVAPRO?
Sorry No records found.
What should I talk to my health care provider before I take AVAPRO?
Sorry No records found
How should I use AVAPRO?
AVAPRO (irbesartan) is indicated for the treatment of hypertension.
It may be used alone or in combination with other antihypertensive agents.
AVAPRO may be administered with other antihypertensive agents and
with or without food.
What interacts with AVAPRO?
AVAPRO is contraindicated in patients who are hypersensitive to any component of this product.
Do not coadminister aliskiren with AVAPRO in patients with diabetes (see ).
What are the warnings of AVAPRO?
Fetal Toxicity
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 exposure to AVAPRO for hypotension, oliguria, and hyperkalemia (see ).
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 antihypertensive
therapy may cause symptomatic hypotension in patients with intravascular volume-
or sodium-depletion, eg, in patients treated vigorously with
diuretics or in patients on dialysis. Such volume depletion should be corrected
prior to administration of AVAPRO, or a low starting dose should be used (see ).
If hypotension occurs, the patient should be placed in the supine
position 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 pressure
has stabilized.
What are the precautions of AVAPRO?
Impaired Renal Function
As a consequence of inhibiting the renin-angiotensin-aldosterone
system, changes in renal function may be anticipated in susceptible individuals.
In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone
system (eg, patients with severe congestive heart failure), treatment with
angiotensin-converting-enzyme inhibitors has been associated with oliguria
and/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 bilateral
renal artery stenosis, increases in serum creatinine or BUN have been reported.
There has been no known use of AVAPRO in patients with unilateral or bilateral
renal artery stenosis, but a similar effect should be anticipated.
Information for Patients
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) interactions
have been found in interaction studies with hydrochlorothiazide, digoxin, warfarin, and nifedipine.
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In separate studies of patients receiving maintenance doses of
warfarin, hydrochlorothiazide, or digoxin, irbesartan administration for 7
days had no effect on the pharmacodynamics of warfarin (prothrombin time)
or pharmacokinetics of digoxin. The pharmacokinetics of irbesartan were not
affected 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 was
administered 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 female
rats, 500 mg/kg/day provided an average systemic exposure to irbesartan (AUC, bound plus unbound) about 3 and 11 times, respectively,
the average systemic exposure in humans receiving the maximum recommended
dose (MRD) of 300 mg irbesartan/day, whereas 1000 mg/kg/day (administered
to females only) provided an average systemic exposure about 21 times that
reported for humans at the MRD. For male and female mice, 1000 mg/kg/day provided
an exposure to irbesartan about 3 and 5 times, respectively, the human exposure
at 300 mg/day.
Irbesartan was not mutagenic in a battery of tests
(Ames microbial test, rat hepatocyte DNA repair test, V79 mammalian-cell forward
gene-mutation assay). Irbesartan was negative in several tests for induction
of chromosomal aberrations (-human lymphocyte assay; -mouse micronucleus study).
Irbesartan had no adverse effects on fertility or mating of male
or female rats at oral doses ≤650 mg/kg/day, the highest
dose providing a systemic exposure to irbesartan (AUC,
bound plus unbound) about 5 times that found in humans receiving the maximum
recommended dose of 300 mg/day.
Pregnancy
See .
Nursing Mothers
It is not known whether irbesartan is excreted in human milk, but
irbesartan or some metabolite of irbesartan is secreted at low concentration
in the milk of lactating rats. Because of the potential for adverse effects
on the nursing infant, a decision should be made whether to discontinue nursing
or discontinue the drug, taking into account the importance of the drug to
the mother.
Pediatric Use
Neonates with a history of exposure 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 ages
6 to 16 years.
AVAPRO has not been studied in pediatric patients less than 6 years
old.
Geriatric Use
Of 4925 subjects receiving AVAPRO (irbesartan) in controlled clinical
studies 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 safety
were observed between these subjects and younger subjects, but greater sensitivity
of some older individuals cannot be ruled out. (See , , and .)
What are the side effects of AVAPRO?
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.
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% of patients treated with
AVAPRO, versus 4.5% of patients given placebo.
In placebo-controlled clinical trials, the following adverse event
experiences 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%).
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.
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:
Cardiovascular:
Dermatologic:
Endocrine/Metabolic/Electrolyte Imbalances:
Gastrointestinal:
Musculoskeletal/Connective Tissue:
Nervous System:
Renal/Genitourinary:
Respiratory:
Special Senses:
Nephropathy in Type 2 Diabetic Patients
In clinical studies in patients with hypertension and type 2 diabetic
renal disease, the adverse drug experiences were similar to those seen in
patients with hypertension with the exception of an increased incidence of
orthostatic symptoms (dizziness, orthostatic dizziness, and orthostatic hypotension)
observed in IDNT (proteinuria ≥900 mg/day, and serum creatinine ranging
from 1.0-3.0 mg/dL). In this trial, orthostatic symptoms occurred more frequently
in the AVAPRO group (dizziness 10.2%, orthostatic dizziness 5.4%, orthostatic
hypotension 5.4%) than in the placebo group (dizziness 6.0%, orthostatic dizziness
2.7%, 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 receiving
angiotensin II receptor blockers.
Laboratory Test Findings
Hypertension
In controlled clinical trials, clinically important differences
in laboratory tests were rarely associated with administration of AVAPRO.
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Hematologic:
Nephropathy in Type 2 Diabetic Patients
Array
What should I look out for while using AVAPRO?
AVAPRO is contraindicated in patients who are hypersensitive to
any component of this product.
Do not coadminister aliskiren with AVAPRO in patients with diabetes (see ).
What might happen if I take too much AVAPRO?
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.
To obtain up-to-date information about the treatment of overdosage,
a good resource is a certified regional Poison Control Center. Telephone numbers
of certified Poison Control Centers are listed in the (PDR). In managing overdose, consider the possibilities
of multiple-drug interactions, drug-drug interactions, and unusual drug kinetics
in the patient.
Laboratory determinations of serum levels of irbesartan are not
widely available, and such determinations have, in any event, no known established
role in the management of irbesartan overdose.
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/m basis,
respectively.
How should I store and handle AVAPRO?
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Keep tightly closed (protect from moisture). Protect from light.Product: 63629-3373NDC: 63629-3373-4 180 TABLET in a BOTTLENDC: 63629-3373-1 30 TABLET in a BOTTLENDC: 63629-3373-2 60 TABLET in a BOTTLENDC: 63629-3373-3 90 TABLET in a BOTTLEProduct: 63629-3373NDC: 63629-3373-4 180 TABLET in a BOTTLENDC: 63629-3373-1 30 TABLET in a BOTTLENDC: 63629-3373-2 60 TABLET in a BOTTLENDC: 63629-3373-3 90 TABLET in a BOTTLEProduct: 63629-3373NDC: 63629-3373-4 180 TABLET in a BOTTLENDC: 63629-3373-1 30 TABLET in a BOTTLENDC: 63629-3373-2 60 TABLET in a BOTTLENDC: 63629-3373-3 90 TABLET in a BOTTLEProduct: 63629-3373NDC: 63629-3373-4 180 TABLET in a BOTTLENDC: 63629-3373-1 30 TABLET in a BOTTLENDC: 63629-3373-2 60 TABLET in a BOTTLENDC: 63629-3373-3 90 TABLET in a BOTTLEProduct: 63629-3373NDC: 63629-3373-4 180 TABLET in a BOTTLENDC: 63629-3373-1 30 TABLET in a BOTTLENDC: 63629-3373-2 60 TABLET in a BOTTLENDC: 63629-3373-3 90 TABLET in a BOTTLE
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
Angiotensin II is a potent vasoconstrictor formed from angiotensin
I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase
II). Angiotensin II is the principal pressor agent of the renin-angiotensin
system (RAS) and also stimulates aldosterone synthesis and secretion by adrenal
cortex, cardiac contraction, renal resorption of sodium, activity of the sympathetic
nervous system, and smooth muscle cell growth. Irbesartan blocks the vasoconstrictor
and aldosterone-secreting effects of angiotensin II by selectively binding
to the AT angiotensin II receptor. There is also an
AT receptor in many tissues, but it is not involved
in cardiovascular homeostasis.
Irbesartan is a specific competitive antagonist of AT receptors
with a much greater affinity (more than 8500-fold) for the AT receptor
than for the AT receptor and no agonist activity.
Blockade of the AT receptor removes the
negative feedback of angiotensin II on renin secretion, but the resulting
increased plasma renin activity and circulating angiotensin II do not overcome
the effects of irbesartan on blood pressure.
Irbesartan does not inhibit ACE or renin or affect other hormone
receptors or ion channels known to be involved in the cardiovascular regulation
of blood pressure and sodium homeostasis. Because irbesartan does not inhibit
ACE, it does not affect the response to bradykinin; whether this has clinical
relevance is not known.
Non-Clinical Toxicology
AVAPRO is contraindicated in patients who are hypersensitive to any component of this product.Do not coadminister aliskiren with AVAPRO in patients with diabetes (see ).
No significant drug-drug pharmacokinetic (or pharmacodynamic) interactions have been found in interaction studies with hydrochlorothiazide, digoxin, warfarin, and nifedipine.
In separate studies of patients receiving maintenance doses of warfarin, hydrochlorothiazide, or digoxin, irbesartan administration for 7 days had no effect on the pharmacodynamics of warfarin (prothrombin time) or pharmacokinetics of digoxin. The pharmacokinetics of irbesartan were not affected 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.
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (eg, patients with severe congestive heart failure), treatment with angiotensin-converting-enzyme inhibitors has been associated with oliguria and/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 bilateral renal artery stenosis, increases in serum creatinine or BUN have been reported. There has been no known use of AVAPRO in patients with unilateral or bilateral renal artery stenosis, but a similar effect should be anticipated.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
While we update our database periodically, we cannot guarantee it is always updated to the latest version.
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