ADVERSE REACTIONS
Clinical Trials Experience
Because clinical trials are conducted
under widely varying conditions, adverse reaction rates observed in the clinical
trials of a drug cannot be directly compared to rates in the clinical trials
of another drug and may not reflect the rates observed in practice. The adverse
reaction information from clinical trials does, however, provide a basis for
identifying the adverse events that appear to be related to drug use and for
approximating rates.
Irbesartan-Hydrochlorothiazide
AVALIDE Tablets have been evaluated for safety in
1694 patients treated for essential hypertension in 6 clinical trials. In
Studies I through IV with AVALIDE, no adverse events peculiar to this combination
drug product have been observed. Adverse events have been limited to those
that were reported previously with irbesartan or hydrochlorothiazide (HCTZ).
The overall incidence of adverse events was similar with the combination and
placebo. In general, treatment with AVALIDE was well tolerated. For the most
part, adverse events 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 events 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 events reported
with AVALIDE occurred in ≥1% of patients, and more often on the irbesartan-hydrochlorothiazide
combination than on placebo, regardless of drug relationship:
| |
Irbesartan/HCTZ
(n=898)
(%) |
Placebo
(n=236)
(%) |
Irbesartan
(n=400)
(%) |
HCTZ
(n=380)
(%) |
|
Body
as a Whole
|
|
|
|
|
| Chest
Pain |
2 |
1 |
2 |
2 |
| Fatigue |
6 |
3 |
4 |
3 |
| Influenza |
3 |
1 |
2 |
2 |
|
Cardiovascular
|
|
|
|
|
| Edema |
3 |
3 |
2 |
2 |
| Tachycardia |
1 |
0 |
1 |
1 |
|
Gastrointestinal
|
|
|
|
|
| Abdominal
Pain |
2 |
1 |
2 |
2 |
| Dyspepsia/heartburn |
2 |
1 |
0 |
2 |
| Nausea/vomiting |
3 |
0 |
2 |
2 |
|
Immunology
|
|
|
|
|
| Allergy |
1 |
0 |
1 |
1 |
|
Musculoskeletal
|
|
|
|
|
| Musculoskeletal
Pain |
6 |
5 |
6 |
10 |
|
Nervous
System
|
|
|
|
|
| Dizziness |
8 |
4 |
6 |
5 |
| Dizziness
Orthostatic |
1 |
0 |
1 |
1 |
|
Renal/Genitourinary
|
|
|
|
|
| Abnormality
Urination |
2 |
1 |
1 |
2 |
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.
Adverse
events in Studies V and VI were similar to those described above in Studies
I through IV.
Irbesartan
Other
adverse events 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, cardiorespiratory arrest, heart failure,
hypertensive 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 events 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
Initial Therapy
In the moderate hypertension Study V
(mean SeDBP between 90 and 110 mmHg), the types and incidences of adverse
events reported for patients treated with AVALIDE were similar to the adverse
event profile in patients on initial irbesartan or HCTZ monotherapy. There
were no reported events of syncope in the AVALIDE treatment group and there
was one reported event in the HCTZ treatment group. The incidences of pre-specified
adverse events on AVALIDE, irbesartan, and HCTZ, respectively, were: 0.9%,
0%, and 0% for hypotension; 3.0%, 3.8%, and 1.0% for dizziness; 5.5%, 3.8%,
and 4.8% for headache; 1.2%, 0%, and 1.0% for hyperkalemia; and 0.9%, 0%,
and 0% for hypokalemia. The rates of discontinuation due to adverse events
on AVALIDE, irbesartan alone, and HCTZ alone were 6.7%, 3.8%, and 4.8%.
In
the severe hypertension (SeDBP ≥110 mmHg) Study VI, the overall pattern of
adverse events reported through 7 weeks of follow-up was similar in patients
treated with AVALIDE as initial therapy and in patients treated with irbesartan
as initial therapy. The incidences of the pre-specified adverse events on
AVALIDE and irbesartan, respectively, were: 0% and 0% for syncope; 0.6% and
0% for hypotension; 3.6% and 4.0% for dizziness; 4.3% and 6.6% for headache;
0.2% and 0% for hyperkalemia; and 0.6% and 0.4% for hypokalemia. The rates
of discontinuation due to adverse events were 2.1% and 2.2%. [See
Clinical
Studies
.]
Post-Marketing Experience
The following adverse reactions have
been identified during post-approval use of AVALIDE. Because these reactions
are reported voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency or 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 AVALIDE.
The
following have been very rarely reported: urticaria, angioedema (involving
swelling of the face, lips, pharynx, and/or tongue), and hepatitis. Hyperkalemia
has been rarely reported.
Very rare cases of jaundice have been reported with irbesartan.
Impaired renal function, including cases of renal failure in patients at risk, has been reported with irbesartan and AVALIDE.
Cases of increased CPK and rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
Laboratory Abnormalities
In controlled clinical trials, clinically
important changes in standard laboratory parameters were rarely associated
with administration of AVALIDE.
Creatinine,
Blood Urea Nitrogen: Minor increases in blood urea nitrogen (BUN)
or serum creatinine were observed in 2.3% and 1.1%, 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.
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
Warnings and Precautions (5.2, 5.6)
.]
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