WARNINGS AND PRECAUTIONS
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Fetal/Neonatal Morbidity and Mortality
Olmesartan medoxomil. Drugs that
act directly on the renin-angiotensin system can cause fetal and neonatal
morbidity and death when administered to pregnant women. There have been several
dozen cases reported in the world literature of patients who were taking
angiotensin converting enzyme inhibitors. When pregnancy is detected,
discontinue Azor as soon as possible.
During the second and third trimesters of pregnancy, these drugs have been
associated with fetal injury that includes 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 Azor 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 intra-amniotic environment.
If oligohydramnios is observed, discontinue Azor 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 means of reversing hypotension and/or substituting
for disordered renal function.
No teratogenic effects were observed when olmesartan medoxomil was
administered to pregnant rats at oral doses up to 1000 mg/kg/day (240 times the
maximum recommended human dose (MRHD) on a mg/m2 basis)
or pregnant rabbits at oral doses up to 1 mg/kg/day (half the MRHD on a
mg/m2 basis; higher doses could not be evaluated for
effects on fetal development as they were lethal to the does). In rats,
significant decreases in pup birth weight and weight gain were observed at doses
≥1.6 mg/kg/day, and delays in developmental milestones (delayed separation of
ear auricular, eruption of lower incisors, appearance of abdominal hair, descent
of testes, and separation of eyelids) and dose-dependent increases in the
incidence of dilation of the renal pelvis were observed at doses ≥8 mg/kg/day.
The no observed effect dose for developmental toxicity in rats is 0.3 mg/kg/day,
about one-tenth the MRHD of 40 mg/day.
Hypotension in Volume- or Salt-Depleted Patients
Olmesartan medoxomil. Symptomatic
hypotension may be anticipated after initiation of treatment with olmesartan
medoxomil. Patients with an activated renin-angiotensin system, such as volume-
and/or salt-depleted patients (e.g., those being treated with high doses of
diuretics) may be particularly vulnerable. Initiate treatment with Azor under
close medical supervision. If hypotension does occur, place the patient in the
supine position and, if necessary, give 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.
Vasodilation
Amlodipine. Since the vasodilation
attributable to amlodipine in Azor is gradual in onset, acute hypotension has
rarely been reported after oral administration. Nonetheless, exercise caution,
as with any other peripheral vasodilator, when administering Azor, particularly
in patients with severe aortic stenosis.
Patients with Severe Obstructive Coronary Artery Disease
Patients, particularly those with severe obstructive coronary
artery disease, may develop increased frequency, duration, or severity of angina
or acute myocardial infarction on starting calcium channel blocker therapy or at
the time of dosage increase. The mechanism of this effect has not been
elucidated.
Patients with Congestive Heart Failure
Amlodipine. In general, calcium
channel blockers should be used with caution in patients with heart failure.
Amlodipine (5-10 mg per day) has been studied in a placebo-controlled trial of
1153 patients with NYHA Class III or IV heart failure on stable doses of ACE
inhibitor, digoxin, and diuretics. Follow-up was at least 6 months, with a mean
of about 14 months. There was no overall adverse effect on survival or cardiac
morbidity (as defined by life-threatening arrhythmia, acute myocardial
infarction, or hospitalization for worsened heart failure). Amlodipine has been
compared to placebo in four 8-12 week studies of patients with NYHA class II/III
heart failure, involving a total of 697 patients. In these studies, there was no
evidence of worsening of heart failure based on measures of exercise tolerance,
NYHA classification, symptoms, or LVEF.
Patients with Impaired Renal Function
Azor. There are no studies of Azor
in patients with renal impairment.
Olmesartan medoxomil. Changes in renal
function may be anticipated in susceptible individuals treated with olmesartan
medoxomil as a consequence of inhibiting the renin-angiotensin-aldosterone
system. In patients whose renal function may depend upon the activity of the
renin-angiotensin-aldosterone system (e.g., patients with severe congestive
heart failure), treatment with angiotensin converting enzyme inhibitors and
angiotensin receptor antagonists has been associated with oliguria or
progressive azotemia and (rarely) with acute renal failure and/or death. Similar
effects may occur in patients treated with Azor because of the olmesartan
medoxomil component [See Clinical Pharmacology].
In studies of ACE inhibitors in patients with unilateral or bilateral renal
artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have
been reported. There has been no long-term use of olmesartan medoxomil in
patients with unilateral or bilateral renal artery stenosis, but similar effects
would be expected with olmesartan medoxomil and Azor.
Patients with Hepatic Impairment
Amlodipine. Since amlodipine is
extensively metabolized by the liver and the plasma elimination half-life
(t1/2) is 56 hours in patients with severely impaired
hepatic function, exercise caution when administering Azor to patients with
severe hepatic impairment.
Patients
with hepatic impairment have decreased clearance of amlodipine. Starting
amlodipine or adding amlodipine at 2.5 mg in hepatically impaired patients is
recommended. The lowest dose of Azor is 5/20 mg; therefore, initial therapy with
Azor is not recommended in hepatically impaired patients [See
Use in Specific
Populations
].
Laboratory Tests
Azor. There was a greater decrease
in hemoglobin and hematocrit in the combination product compared to either
component. Other laboratory changes can usually be attributed to either
monotherapy component.
Amlodipine. In post-marketing experience,
hepatic enzyme elevations have been reported .
Olmesartan medoxomil. In post-marketing
experience, increased blood creatinine levels and hyperkalemia have been
reported.
USE IN SPECIFIC POPULATIONS
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Pregnancy
Olmesartan medoxomil. Pregnancy
Categories C (first trimester) and D (second and third trimesters). [See
Warnings and
Precautions
].
Amlodipine. No evidence of
teratogenicity or other embryo/fetal toxicity was found when pregnant rats and
rabbits were treated orally with amlodipine maleate at doses of up to 10 mg
amlodipine/kg/day (respectively about 10 and 20 times the maximum recommended
human dose of 10 mg amlodipine on a mg/m2 basis) during
their respective periods of major organogenesis. (Calculations based on a
patient weight of 60 kg). However, litter size was significantly decreased (by
about 50%) and the number of intrauterine deaths was significantly increased
(about 5-fold) in rats receiving amlodipine maleate at a dose equivalent to 10
mg amlodipine/kg/day for 14 days before mating and throughout mating and
gestation. Amlodipine maleate has been shown to prolong both the gestational
period and the duration of labor in rats at this dose. There are no adequate and
well-controlled studies in pregnant women. Amlodipine should be used during
pregnancy only if the potential benefit justifies the potential risk to the
fetus.
Nursing Mothers
It is not known whether the amlodipine or olmesartan medoxomil
components of Azor are excreted in human milk, but olmesartan 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
The safety and effectiveness of Azor in pediatric patients have
not been established.
Amlodipine. The effect of
amlodipine on blood pressure in patients less than 6 years of age is not
known.
Olmesartan medoxomil. Safety and
effectiveness of olmesartan medoxomil in pediatric patients have not been
established.
Geriatric Use
Of the total number of subjects in the double-blind clinical
study of Azor, 20% (384/1940) were 65 years of age or older and 3% (62/1940)
were 75 years or older. No overall differences in safety or effectiveness were
observed between subjects 65 years of age or older and younger subjects.
Elderly patients have decreased clearance of amlodipine. Starting amlodipine
or adding amlodipine at 2.5 mg in patients ≥75 years old is recommended. The
lowest dose of Azor is 5/20 mg; therefore, initial therapy with Azor is not
recommended in patients ≥75 years old.
Amlodipine. 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 decreased hepatic, renal, or cardiac function, and of
concomitant disease or other drug therapy. Elderly patients have decreased
clearance of amlodipine with a resulting increase of AUC of approximately 40% to
60%, and a lower initial dose may be required.
Olmesartan medoxomil. Of the total
number of hypertensive patients receiving olmesartan medoxomil in clinical
studies, more than 20% were 65 years of age and over, while more than 5% were 75
years of age and older. No overall differences in effectiveness or safety were
observed between elderly patients and younger patients. Other reported clinical
experience has not identified differences in responses between the elderly and
younger patients, but greater sensitivity of some older individuals cannot be
ruled out.
Hepatic Impairment
There are no studies of Azor in patients with hepatic
insufficiency, but both amlodipine and olmesartan medoxomil show moderate
increases in exposure in patients with hepatic impairment. Use caution when
administering Azor to patients with severe hepatic impairment.
Patients with hepatic impairment have decreased clearance of amlodipine.
Starting amlodipine or adding amlodipine at 2.5 mg in patients with hepatic
impairment is recommended. The lowest dose of Azor is 5/20 mg; therefore,
initial therapy with Azor is not recommended in hepatically impaired
patients.
Renal Impairment
There are no studies of Azor in patients with renal
impairment.
Amlodipine. The pharmacokinetics
of amlodipine are not significantly influenced by renal impairment. Patients
with renal failure may therefore receive the usual initial dose.
Olmesartan medoxomil. Patients
with renal insufficiency have elevated serum concentrations of olmesartan
compared with patients with normal renal function. After repeated dosing, AUC
was approximately tripled in patients with severe renal impairment (creatinine
clearance <20 mL/min). No initial dosage adjustment is recommended for
patients with moderate to marked renal impairment (creatinine clearance <40
mL/min).
Black Patients
Of the total number of subjects in the double-blind clinical study of Azor, 25%
(481/1940) were black patients. Azor was effective in treating black patients
(usually a low-renin population), and the magnitude of blood pressure reduction
in black patients approached that observed for non-black patients.
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