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.
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.
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%).
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 isozymes 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.
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