SIDE EFFECTS
Irbesartan-hydrochlorothiazide
AVALIDE (irbesartan-hydrochlorothiazide) Tablets has been
evaluated for safety in 898 patients treated for essential
hypertension. In clinical trials with AVALIDE, no adverse
experiences peculiar to this combination drug product have
been observed. Adverse experiences have been limited to
those that were reported previously with irbesartan and/or
hydrochlorothiazide (HCTZ).The overall incidence of adverse
experiences reported with the combination was comparable
to placebo. In general, treatment with AVALIDE was well
tolerated. For the most part, adverse experiences have been
mild and transient in nature and have not required discontinuation
of therapy. In controlled clinical trials, discontinuation
of AVALIDE therapy due to clinical adverse experiences was
required in only 3.6%. This incidence was significantly
less (p=0.023) than the 6.8% of patients treated with placebo
who discontinued therapy.
In these double-blind controlled clinical trials, the following
adverse experiences reported with AVALIDE occurred in >1%
of patients, and more often on the irbesartan-hydrochlorothiazide
combination then on placebo, regardless of drug relationship:
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Irbesartan/HCTZ (n=898) (%)
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Placebo (n=236) (%)
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Irbesartan (n=400) (%)
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HCTZ (n=380) (%)
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Body as a Whole
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Chest Pain
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2
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1
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2
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2
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Fatigue
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7
|
3
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4
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3
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Influenza
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3
|
1
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2
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2
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Cardiovascular
|
|
|
|
|
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Edema
|
3
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3
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2
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2
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Tachycardia
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1
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0
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1
|
1
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Gastrointestinal
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|
|
|
|
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Abdominal Pain
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2
|
1
|
2
|
2
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|
Dyspepsia/heartburn
|
2
|
1
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0
|
2
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|
Nausea/vomiting
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3
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0
|
2
|
0
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Immunology
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|
|
|
|
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Allergy
|
1
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0
|
1
|
1
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Musculoskeletal
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|
|
|
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Pain
|
7
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5
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6
|
10
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Nervous System
|
|
|
|
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Dizziness
|
8
|
4
|
6
|
5
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Dizziness Orthostatic
|
1
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0
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1
|
1
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Renal/Genitourinary
|
|
|
|
|
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Abnormality Urination
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2
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1
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1
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2
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The following adverse events were also reported at a rate
of 1% or greater, but were as, or more, common in the placebo
group: headache, sinus Abnormality, cough, URI, pharyngitis,
diarrhea, rhinitis, urinary tract infection, rash, anxiety/nervousness,
and muscle cramp.
Adverse events occurred at about the same rates in men and
women, older and younger patients, and black and non-black
patients.
Irbesartan
Other adverse experiences that have been reported
with irbesartan, without regard to causality are listed
below: Body as a Whole: fever, chills, orthostatic effects,
facial edema, upper extremity edema Cardiovascular: flushing,
hypertension, cardiac murmur, myocardial infarction, angina
pectoris, hypotension, syncope, arrhythmic/conduction disorder,
cardio-respiratory arrest, heart failure, hyper-tensive
crisis Dermatologic: pruritus, dermatitis, ecchymosis, erythema
face, urticaria
Endocrine/Metabolic/Electrolyte Imbalances: sexual dysfunction,
libido change, gout
Gastrointestinal: diarrhea, constipation, gastroenteritis,
flatulence, abdominal distention
Musculoskeletal/Connective Tissue: musculoskeletal trauma,
extremity swelling, muscle cramp, arthritis, muscle ache,
musculoskeletal chest pain, joint stiffness, bursitis, muscle
weakness Nervous System: anxiety/nervousness, sleep disturbance,
numbness, somnolence, vertigo, emotional disturbance, depression,
paresthesia, tremor, transient ischemic attack, cerebrovascular
accident
Renal/Genitourinary: prostate disorder
Respiratory: cough, upper respiratory infection, epistaxis,
tracheobronchitis, congestion, pulmonary congestion, dyspnea,
wheezing Special Senses: vision disturbance, hearing abnormality,
ear infection, ear pain, conjunctivitis.
Hydrochlorothiazide
Other adverse experiences that have been reported with
hydrochlorothiazide, without regard to causality, are
listed below:
Body As A Whole: weakness
Digestive: pancreatitis, jaundice (intrahepatic cholestatic
jaundice), sialadenitis, cramping, gastric irritation
Hematologic: aplastic anemia, agranulocytosis, leukopenia,
hemolytic anemia, thrombocytopenia Hypersensitivity: purpura,
photosensitivity, urticaria, necrotizing angiitis (vasculitis
and cutaneous vasculitis), fever, respiratory distress
including pneumonitis and pulmonary edema, anaphylactic
reactions Metabolic: hyperglycemia, glycosuria, hyperuricemia
Musculoskeletal: muscle spasm
Nervous System/Psychiatric: restlessness
Renal: renal failure, renal dysfunction, interstitial
nephritis
Skin: erythema multiforme including Stevens-Johnson syndrome,
exfoliative dermatitis including toxic epidermal necrolysis
Special Senses: transient blurred vision, xanthopsia.
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). Hyperkalemia
has been rarely reported.
Very rare cases of jaundice have bee reported with irbesartan.
Laboratory Test Findings
In controlled clinical trials, clinically important changes
in standard laboratory parameters were rarely associated
with administration of AVALIDE (irbesartan-hydrochlorothiazide)
Tablets.
Creatinine, Blood Urea Nitrogen: Minor increases in blood
urea nitrogen (BUN) or serum creatinine were observed
in 2.3 and 1.1 percent, respectively, of patients with
essential hypertension treated with AVALIDE alone. No
patient discontinued taking AVALIDE due to increased BUN.
One patient discontinued taking AVALIDE due to a minor
increase in serum creatinine.
Hemoglobin: Mean decreases of approximately 0.2 g/dL
occurred in patients treated with AVALIDE alone, but were
rarely of clinical importance. This compared to a mean
of 0.4 g/dL in patients receiving placebo. No patients
were discontinued due to anemia.
Liver Function Tests: Occasional elevations of liver
enzymes and/or serum bilirubin have occurred. In patients
with essential hypertension treated with AVALIDE alone,
one patient was discontinued due to elevated liver enzymes.
Serum Electrolytes: (See PRECAUTIONS.)
DRUG INTERACTIONS
Irbesartan
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. Concomitant nifedipine or hydrochlorothiazide
had no effect on irbesar-tan pharmacokinetics. 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 (pro-thrombin time) or the pharmacokinetics
of digoxin. The pharmacokinetics of irbesartan were not
affected by coadministration of nifedipine or hydrochlorothiazide.
Hydrochlorothiazide
When administered concurrently the following drugs may
interact with thiazide diuretics: Alcohol, Barbiturates,
Or Narcotics — potentiation of orthostatic hypotension
may occur.
Antidiabetic Drugs (oral agents and insulin) —
dosage adjustment of the antidiabetic drug may be required.
Other Antihypertensive Drugs — additive effect
or potentiation.
Cholestyramine And Colestipol Resins — absorption
of hydrochlorothiazide is impaired in the presence of
anionic exchange resins. Single doses of either cholestyramine
or colestipol resins bind the hydrochlorothiazide and
reduce its absorption from the gastrointestinal tract
by up to 85 and 43 percent, respectively.
Corticosteroids, ACTH — intensified electrolyte
depletion, particularly hypokalemia.
Pressor Amines (e.g., Norepinephrine) — possible
decreased response to pressor amines but not sufficient
to preclude their use.
Skeletal Muscle Relaxants, Nondepolarizing (e.g., Tubocurarine)
— possible increased responsiveness to the muscle
relaxant.
Lithium — should not generally be given with diuretics.
Diuretic agents reduce the renal clearance of lithium
and add a high risk of lithium toxicity. Refer to the
package insert for lithium preparations before use of
such preparations with AVALIDE.
Non-steroidal Anti-inflammatory Drugs — in some
patients, the administration of a non-steroidal anti-inflammatory
agent can reduce the diuretic, natriuretic, and antihypertensive
effects of loop, potassium-sparing and thiazide diuretics.
Therefore, when AVALIDE (irbesartan-hydrochlorothiazide)
Tablets and non-steroidal anti-inflammatory agents are
used concomitantly, the patient should be observed closely
to determine if the desired effect of the diuretic is
obtained.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Irbesartan-Hydrochlorothiazide
No carcinogenicity studies have been conducted with the
irbesartan-hydrochlorothiazide combination.
Irbesartan-hydrochlorothiazide was not mutagenic in standard
in vitro tests (Ames microbial test and Chinese hamster
mammalian-cell forward gene-mutation assay). Irbesartan-hydrochloroth-iazide
was negative in tests for induction of chromosomal aberrations
(in vitro — human lymphocyte assay; in vivo —
mouse micronucleus study).
The combination of irbesartan and hydrochlorothiazide
has not been evaluated in definitive studies of fertility.
Irbesartan
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 two years. For male and female rats,
500 mg/kg/day provided an average systemic exposure to
irbesartan (AUC0–24 hours, bound plus unbound) about
3 and 11 times, respectively, the average systemic exposure
in humans receiving the maximum recommended dose (MRD)
of 300 mg irbesar-tan/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
(AUC0–24 hours, bound plus unbound) about 5 times
that found in humans receiving the maximum recommended
dose of 300 mg/day.
Hydrochlorothiazide
Two-year feeding studies in mice and rats conducted under
the auspices of the National Toxicology Program (NTP)
uncovered no evidence of a carcinogenic potential of hydrochlorothiazide
in female mice (at doses of up to approximately 600 mg/kg/day)
or in male and female rats (at doses of up to approximately
100 mg/kg/day). The NTP, however, found equivocal evidence
for hepatocarcino-genicity in male mice.
Hydrochlorothiazide was not genotoxic in vitro in the
Ames mutagenicity assay of Salmonella typhimurium strains
TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the
Chinese Hamster Ovary (CHO) test for chromosomal aberrations,
or in vivo in assays using mouse germinal cell chromosomes,
Chinese hamster bone marrow chromosomes, and the Drosophila
sex-linked recessive lethal trait gene. Positive test
results were obtained only in the in vitro CHO Sister
Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma
Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide
from 43 to 1300 mg/mL, and in the Aspergillus nidulans
non-disjunction assay at an unspecified concentration.
Hydrochlorothiazide had no adverse effects on the fertility
of mice and rats of either sex in studies wherein these
species were exposed, via their diet, to doses of up to
100 and 4 mg/kg, respectively, prior to mating and throughout
gestation.
Pregnancy
Pregnancy Categories C (first trimester) and D (second
and third trimesters)
(See WARNINGS: Fetal/Neonatal Morbidity and Mortality.)
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.
Thiazides appear in human milk. 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
Safety and effectiveness in pediatric patients have not
been established.
Geriatric Use
Clinical studies of AVALIDE did not include sufficient numbers
of subjects aged 65 and over to determine whether they respond
differently from younger subjects. Other reported clinical
experience has not identified differences in responses between
the elderly and younger patients. In general, dose selection
for an elderly patient should be cautious, usually starting
at the low end of the dosing range, reflecting the greater
frequency of deceased hepatic, renal or cardiac function,
and of concomitant disease or other drug therapy.
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