Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3178
| Predicate | Object |
|---|---|
| rdf:type | |
| rdfs:label |
AVAPRO (Tablet)
|
| dailymed-instance:dosage |
AVAPRO may be administered with other antihypertensive agents and
with or without food.<br/>Hypertension: The recommended initial dose of AVAPRO (irbesartan) is 150 mg once
daily. Patients requiring further reduction in blood pressure should be titrated
to 300 mg once daily. A low dose of a diuretic may be added, if blood pressure is not
controlled by AVAPRO alone. Hydrochlorothiazide has been shown to have an
additive effect (see CLINICAL PHARMACOLOGY: Clinical
Studies). Patients not adequately treated by the maximum dose
of 300 mg once daily are unlikely to derive additional benefit from a higher
dose or twice-daily dosing. No dosage adjustment is necessary in elderly patients, or in patients
with hepatic impairment or mild to severe renal impairment.<br/>Nephropathy in Type 2 Diabetic Patients: The recommended target maintenance dose is 300 mg once daily. There
are no data on the clinical effects of lower doses of AVAPRO on diabetic nephropathy
.<br/>Volume- and Salt-Depleted Patients: A lower initial dose of AVAPRO (75 mg) is recommended in patients
with depletion of intravascular volume or salt (eg, patients treated vigorously
with diuretics or on hemodialysis) (see WARNINGS:
Hypotension in Volume- or Salt-Depleted Patients).
|
| dailymed-instance:descripti... |
AVAPRO* (irbesartan) is an angiotensin
II receptor (ATsubtype) antagonist. *Registered trademark 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 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.
|
| dailymed-instance:clinicalP... |
Mechanism of Action: 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 ATangiotensin II receptor. There is also an
ATreceptor in many tissues, but it is not involved
in cardiovascular homeostasis. Irbesartan is a specific competitive antagonist of ATreceptors
with a much greater affinity (more than 8500-fold) for the ATreceptor
than for the ATreceptor and no agonist activity. Blockade of the ATreceptor 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.<br/>Pharmacokinetics: Irbesartan is an orally active agent that does not require biotransformation
into an active form. The oral absorption of irbesartan is rapid and complete
with an average absolute bioavailability of 60% to 80%. Following oral administration
of AVAPRO, peak plasma concentrations of irbesartan are attained at 1.5 to
2 hours after dosing. Food does not affect the bioavailability of AVAPRO. Irbesartan exhibits linear pharmacokinetics over the therapeutic
dose range. The terminal elimination half-life of irbesartan averaged 11 to
15 hours. Steady-state concentrations are achieved within 3 days. Limited
accumulation of irbesartan (<20%) is observed in plasma upon repeated once-daily
dosing.<br/>Metabolism and Elimination: Irbesartan is metabolized via glucuronide conjugation and oxidation.
Following oral or intravenous administration ofC-labeled
irbesartan, more than 80% of the circulating plasma radioactivity is attributable
to unchanged irbesartan. The primary circulating metabolite is the inactive
irbesartan glucuronide conjugate (approximately 6%). The remaining oxidative
metabolites do not add appreciably to irbesartan's pharmacologic activity. Irbesartan and its metabolites are excreted by both biliary and
renal routes. Following either oral or intravenous administration ofC-labeled
irbesartan, about 20% of radioactivity is recovered in the urine and the remainder
in the feces, as irbesartan or irbesartan glucuronide. In vitro studies of irbesartan oxidation by cytochrome
P450 isoenzymes indicated irbesartan was oxidized primarily by 2C9; metabolism
by 3A4 was negligible. Irbesartan was neither metabolized by, nor did it substantially
induce or inhibit, isoenzymes commonly associated with drug metabolism (1A1,
1A2, 2A6, 2B6, 2D6, 2E1). There was no induction or inhibition of 3A4.<br/>Distribution: Irbesartan is 90% bound to serum proteins (primarily albumin and��-acid glycoprotein) with negligible binding to cellular
components of blood. The average volume of distribution is 53 liters
to 93 liters. Total plasma and renal clearances are in the range of 157 mL/min
to 176 mL/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 weakly
crosses the blood-brain barrier and placenta. Irbesartan is excreted in the
milk of lactating rats.<br/>Special Populations:<br/>Gender: No gender-related differences in pharmacokinetics were observed
in healthy elderly (age 65-80 years) or in healthy young (age 18-40 years)
subjects. In studies of hypertensive patients, there was no gender difference
in half-life or accumulation, but somewhat higher plasma concentrations of
irbesartan were observed in females (11-44%). No gender-related dosage adjustment
is necessary.<br/>Geriatric: In elderly subjects (age 65-80 years), irbesartan elimination half-life
was not significantly altered, but AUC and Cvalues
were about 20% to 50% greater than those of young subjects (age 18-40 years).
No dosage adjustment is necessary in the elderly.<br/>Race: In healthy black subjects, irbesartan AUC values were approximately
25% greater than whites; there were no differences in Cvalues.<br/>Renal Insufficiency: The pharmacokinetics of irbesartan were not altered in patients
with renal impairment or in patients on hemodialysis. Irbesartan is not removed
by hemodialysis. No dosage adjustment is necessary in patients with mild to
severe renal impairment unless a patient with renal impairment is also volume
depleted. (See WARNINGS: Hypotension in Volume- or
Salt-Depleted Patients and DOSAGE AND
ADMINISTRATION.)<br/>Hepatic Insufficiency: The pharmacokinetics of irbesartan following repeated oral administration
were not significantly affected in patients with mild to moderate cirrhosis
of the liver. No dosage adjustment is necessary in patients with hepatic insufficiency.<br/>Drug Interactions:<br/>Pharmacodynamics: In healthy subjects, single oral irbesartan doses of up to 300
mg produced dose-dependent inhibition of the pressor effect of angiotensin
II infusions. Inhibition was complete (100%) 4 hours following
oral doses of 150 mg or 300 mg and partial inhibition was sustained for 24 hours
(60% and 40% at 300 mg and 150 mg, respectively). In hypertensive patients, angiotensin II receptor inhibition following
chronic administration of irbesartan causes a 1.5- to 2-fold rise in angiotensin
II 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 (up
to 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, total
cholesterol, HDL-cholesterol, or fasting glucose concentrations. There was
no effect on serum uric acid during chronic oral administration, and no uricosuric
effect.<br/>Clinical Studies:<br/>Hypertension: The antihypertensive effects of AVAPRO (irbesartan) were examined
in 7 major placebo-controlled 8 to 12 week trials in patients with baseline
diastolic blood pressures of 95 mmHg to 110 mmHg. Doses of 1 mg to 900 mg
were included in these trials in order to fully explore the dose-range of
irbesartan. These studies allowed comparison of once- or twice-daily regimens
at 150 mg/day, comparisons of peak and trough effects, and
comparisons of response by gender, age, and race. Two of the 7 placebo-controlled
trials identified above examined the antihypertensive effects of irbesartan
and hydrochlorothiazide in combination. The 7 studies of irbesartan monotherapy included a total of 1915
patients randomized to irbesartan (1-900 mg) and 611 patients randomized to
placebo. Once-daily doses of 150 mg and 300 mg provided statistically and
clinically significant decreases in systolic and diastolic blood pressure
with trough (24 hours post-dose) effects after 6 to 12 weeks of treatment
compared 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. The
dose-response relationships for effects on systolic and diastolic pressure
are shown in Figures 1 and 2. Once-daily administration of therapeutic doses of irbesartan gave
peak effects at around 3 to 6 hours and, in one ambulatory blood pressure
monitoring study, again around 14 hours. This was seen with both once-daily
and twice-daily dosing. Trough-to-peak ratios for systolic and diastolic response
were generally between 60% to 70%. In a continuous ambulatory blood pressure
monitoringstudy, once-daily dosing with 150 mg gave trough and mean 24-hour
responses similar to those observed in patients receiving twice-daily dosing
at the same total daily dose. In controlled trials, the addition of irbesartan to hydrochlorothiazide
doses of 6.25 mg, 12.5 mg, or 25 mg produced
further dose-related reductions in blood pressure similar to those achieved
with the same monotherapy dose of irbesartan. HCTZ also had an approximately
additive effect. Analysis of age, gender, and race subgroups of patients showed
that men and women, and patients over and under 65 years of age, had generally
similar responses. Irbesartan was effective in reducing blood pressure regardless
of race, although the effect was somewhat less in blacks (usually a low-renin
population). The effect of irbesartan is apparent after the first dose, and
it is close to its full observed effect at 2 weeks. At the end of an 8-week
exposure, about 2/3 of the antihypertensive effect was still present one week
after the last dose. Rebound hypertension was not observed. There was essentially
no change in average heart rate in irbesartan-treated patients in controlled
trials.<br/>Nephropathy in Type 2 Diabetic Patients: The Irbesartan Diabetic Nephropathy Trial (IDNT) was a randomized,
placebo- and active-controlled, double-blind, multicenter study conducted
worldwide in 1715 patients with type 2 diabetes, hypertension (SeSBP>135
mmHg or SeDBP>85 mmHg), and nephropathy (serum creatinine 1.0 to 3.0 mg/dL
in females or 1.2 to 3.0 mg/dL in males and proteinuria���900 mg/day).
Patients were randomized to receive AVAPRO 75 mg, amlodipine 2.5 mg, or matching
placebo once-daily. Patients were titrated to a maintenance dose of AVAPRO
300 mg, or amlodipine 10 mg, as tolerated.
Additional antihypertensive agents (excluding ACE inhibitors, angiotensin
II receptor antagonists and calcium channel blockers) were added as needed
to achieve blood pressure goal (���135/85 or 10 mmHg reduction in systolic blood
pressure if higher than 160 mmHg) for patients in all groups. The study population was 66.5% male, 72.9% below 65 years of age
and 72% White, (Asian/Pacific Islander 5.0%, Black 13.3%, Hispanic 4.8%).
The mean baseline seated systolic and diastolic blood pressures were 159 mmHg
and 87 mmHg, respectively. The patients entered the trial with a mean serum
creatinine of 1.7 mg/dL and mean proteinuria of 4144 mg/day. The mean blood pressure achieved was 142/77 mmHg for AVAPRO, 142/76
mmHg for amlodipine, and 145/79 mmHg for placebo. Overall, 83.0% of patients
received the target dose of irbesartan more than 50% of the time. Patients
were followed for a mean duration of 2.6 years. The primary composite endpoint was the time to occurrence of any
one of the following events: doubling of baseline serum creatinine, end-stage
renal disease (ESRD; defined by serum creatinine���6 mg/dL, dialysis, or renal
transplantation) or death. Treatment with AVAPRO resulted in a 20% risk reduction
versus placebo (p=0.0234) (see Figure 3 and Table 1).
Treatment with AVAPRO also reduced the occurrence of sustained doubling of
serum creatinine as a separate endpoint (33%), but had no significant effect
on ESRD alone and no effect on overall mortality (see Table
1). The percentages of patients experiencing an event during the course
of the study can be seen in Table 1 below: The secondary endpoint of the study was a composite of cardiovascular
mortality and morbidity (myocardial infarction, hospitalization for heart
failure, stroke with permanent neurological deficit, amputation). There were
no 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 significantly
reduced the rate of loss of renal function (glomerular filtration rate), as
measured by the reciprocal of the serum creatinine concentration, by 18.2%. Table 2 presents results for demographic subgroups. Subgroup analyses
are difficult to interpret and it is not known whether these observations
represent true differences or chance effects. For the primary endpoint, AVAPRO's
favorable effects were seen in patients also taking other antihypertensive
medications (angiotensin II receptor antagonists, angiotensin-converting-enzyme
inhibitors and calcium channel blockers were not allowed), oral hypoglycemic
agents, and lipid-lowering agents.
|
| dailymed-instance:activeIng... | |
| dailymed-instance:contraind... |
AVAPRO is contraindicated in patients who are hypersensitive to
any component of this product.
|
| dailymed-instance:supply |
AVAPRO (irbesartan) is available as
white to off-white biconvex oval tablets, debossed with a heart shape on one
side and a portion of the NDC code on the other. Unit-of-use bottles contain
30, 90, or 500 tablets and blister packs contain 100 tablets, as follows:<br/>Storage: Store at 25��C (77��F); excursions permitted to 15��C - 30��C (59��F - 86��F) [see USP Controlled Room Temperature].
|
| dailymed-instance:genericDr... | |
| dailymed-instance:boxedWarn... |
USE IN PREGNANCY: When used in pregnancy during the second and third trimesters,
drugs that act directly on the renin-angiotensin system can cause injury and
even death to the developing fetus. When pregnancy is detected, AVAPRO
should be discontinued as soon as possible. See WARNINGS:
Fetal/Neonatal Morbidity and Mortality.
|
| dailymed-instance:activeMoi... | |
| dailymed-instance:inactiveI... | |
| dailymed-instance:possibleD... | |
| dailymed-instance:precautio... |
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.<br/>Information for Patients:<br/>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.<br/>Drug Interactions: No significant drug-drug pharmacokinetic (or pharmacodynamic) interactions
have been found in interaction studies with hydrochlorothiazide, digoxin,
warfarin, and nifedipine. In vitro studies show significant inhibition of
the formation of oxidized irbesartan metabolites with the known cytochrome
CYP 2C9 substrates/inhibitors sulphenazole, tolbutamide and nifedipine. However,
in clinical studies the consequences of concomitant irbesartan on the pharmacodynamics
of warfarin were negligible. Based on in vitro data, no interaction
would be expected with drugs whose metabolism is dependent upon cytochrome
P450 isoenzymes 1A1, 1A2, 2A6, 2B6, 2D6, 2E1, or 3A4. 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.<br/>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 in vitro 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 (in vitro-human lymphocyte assay; in
vivo-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.<br/>Pregnancy:<br/>Pregnancy Categories C (first trimester) and D (second and third trimesters): See WARNINGS: Fetal/Neonatal Morbidity
and Mortality.<br/>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.<br/>Pediatric Use: 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.<br/>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 CLINICAL
PHARMACOLOGY: Pharmacokinetics, Special
Populations, and Clinical Studies.)
|
| dailymed-instance:overdosag... |
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 Physicians'
Desk Reference (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
maximum recommended human dose (300 mg) on a mg/mbasis,
respectively.
|
| dailymed-instance:genericMe... |
IRBESARTAN
|
| dailymed-instance:fullName |
AVAPRO (Tablet)
|
| dailymed-instance:adverseRe... |
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: 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 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<br/>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%).<br/>Post-Marketing Experience: The following have been very rarely reported in post-marketing
experience: urticaria; angioedema (involving swelling of the face, lips, pharynx,
and/or tongue); increased liver function tests; jaundice; and hepatitis. Hyperkalemia
has been rarely reported. Rare cases of rhabdomyolysis have been reported in patients receiving
angiotensin II receptor blockers.<br/>Laboratory Test Findings:<br/>Hypertension: In controlled clinical trials, clinically important differences
in laboratory tests were rarely associated with administration of AVAPRO. 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/mm)
occurred at similar frequencies among patients receiving AVAPRO (0.3%) and
placebo-treated patients (0.5%).<br/>Nephropathy in Type 2 Diabetic Patients: Hyperkalemia: In IDNT (proteinuria���900 mg/day,
and serum creatinine ranging from 1.0-3.0 mg/dL),
the percent of patients with hyperkalemia (>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.
|
| dailymed-instance:warning |
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
II 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 a 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 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.<br/>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 . 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.
|
| dailymed-instance:indicatio... |
Hypertension: AVAPRO (irbesartan) is indicated for the treatment of hypertension.
It may be used alone or in combination with other antihypertensive agents.<br/>Nephropathy in Type 2 Diabetic Patients: AVAPRO is indicated for the treatment of diabetic nephropathy with
an elevated serum creatinine and proteinuria (>300 mg/day) in patients with
type 2 diabetes and hypertension. In this population, AVAPRO reduces the rate
of progression of nephropathy as measured by the occurrence of doubling of
serum creatinine or end-stage renal disease (need for dialysis or renal transplantation)
.
|
| dailymed-instance:represent... | |
| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
AVAPRO
|