WARNINGS
1. Paradoxical Bronchospasam:
Combivent® Inhalation Aerosol can produce paradoxical
bronchospasm that can be life threatening. If it occurs,
the preparation should be discontinued immediately and
alternative therapy instituted. It should be reconized
that paradoxical bronchospasm, when associated with inhaled
formulations, frequently occurs with the first use of
a new canister.
2. Cardiovascular Effect: The
albuterol sulfate contained in Combivent® Inhalation
Aerosol, like other beta-adrenergic agonists, can produce
a clinically significant cardiovascular effect in some
patients as measured by pulse rate, blood pressure and/or
symptoms. Although such effects are uncommon after administration
of Combivent® Inhalation Aerosol at recommended doses,
if they occur discontinuation of the drug may be indicated.
In addiion, beta-adrenergic agents have been reported
to produce ECG changes, such as flattening of the T-wave,
prolongation of the QTc interval, and ST segment depression.
Therefore, Combivent® Inhalation Aerosol should be
used with caution in patients with cardiovascular disorders,
especially coronary insufficiency, cardiac arrhythmias
and hypertension.
3. Do Not Exceed Recommended Dose.
Fatalities have been reported in association with excessive
use of inhaled sympathomimetic drugs, in patients with
asthma. The exact cause of death is unknown, but cardiac
arrest following an unexpected development of a severe
acute asthinatic crisis and subsequent hypoxia is suspected.
4. Immediate Hypersensitivity Reactions:
Immediate hypersensitivity reactions may occur after administration
of ipratropium bromide or albuterol sulfate, as demonstrated
by rare cases of urticaria, angioedema, rash, bronchospasm,
anaphylaxis and oropharyngeal edema.
5. Storage Conditions: The
contents of Combivent® Inhalation Aerosol are under
pressure. Do not puncture. Do not use or store near heat
or open flame. Exposure to temperatures above 120o F may
cause bursting. Never throw the container into a fire
or incinerator. Keep out of reach of children.
PRECAUTIONS
General
1.Effects Seen with Anticholineroic Drugs:
Combivent® Inhalation Aerosol contains ipratropium
bromide and therefore, should be used with caution in
patients with narrow-angle glaucoma, prostatic hypertrophy
or bladder-neck obstruction.
2. Effects Seen with Sympathomimetic Drugs:
Preparations containing sympathomimetic
amines such as albuterol sulfate should be used with caution
in patients with convulsive disorders, hyperthyroidism,
or diabetes mellitus and in patients who are unusually
responsive to sympathomimetic amines Beta-adrenergic agents
may also produce significant hypokalemia in some patients
(possibly through intracellular shunting) which has the
potential to produce adverse cardiovascuhr effects. The
decrease in serum potassium is usually transient, not
requiring supplementation
3. Use in Hepatic or Renal Disease:
Combivent® Inhalation Aerosol has not been studied
in patients with hepatic or renal insufficiency. It should
be used with caution in those patient populations.
Carcinogenesis, Mutagenesis, Impairment of
Fertility
Ipratropium bromide: Two-year
oral carcinogenicity studies in rats and mice have revealed
no carcinogenic potential at doses up to 6 mg/kg/day.
This dose corresponds to approximately 360 and 180 times
the maximum recommended human daily inhalation dose in
rats and mice respectively, on a mg/m2 basis. Results
of various mutagenicity studies (Ames test, mouse dominant
lethal test, mouse micronucleus test and chromosome aberration
of bone marrow in Chinese hamsters) were negative. Fertility
of male or female rats at oral doses up to 50 mg/kg/day
(approximately 3000 times the maximum recommended human
daily inhalation dose on a mg/m2 basis) was unaffected
by ipratropium bromide administration At doses above 90
mg/kg/day approximately 5400 times the maximum recommended
human daily inhalation dose on a mg/m2 basis), increased
resorption and decreased conception rates were observed.
Albuterol: Like other agents
in its class, albuterol caused a significant dose-related
increase in the incidence of benign leiomyomas of the
mesovarium in a two-year study in the rat at dietary doses
of 2, 10 and 50 mg/kg/day (approximately 20, 100 and 500
times the maximum recommended human daily inhalation dose
on a mg/m2 basis). In another study this effect was blocked
by the co-administration of propranolol. The relevance
of these findings to humans is not known. An l8 month
study in mice at dietary doses up to 500 mg/kg/day (approximately
2500 times the maximum recommended human daily inhalation
dose on a mg/m2 basis) and a 99-week study in hamsters
at oral doses up to 50 mg/kg/day (approximately 375 times
the maximum recommended human daily inhalation dose on
a mg/m2 basis) revealed no evidence of tumorigenicity.
Studies with albuterol revealed no evidence of mutagenesis.
Reproduction studies in rats with albuterol sulfate revealed
no evidence of impaired fertility.
Pregnancy
Teratogenic Effects:
Ipratropium bromide: Pregnancy
category B Oral reproduction studies were performed at
doses of 10 mg/kg in mice, 100 mg/kg in rats and 125 mg/kg
rabbits. These doses correspond, in each species, respectively,
to approximately 300,. 600 and 15,000 times the maximum
recommended human daily Inhalation dose on a mg/m2 basis.
Inhalation reproduction studies were conducted in rats
and rabbits at doses of 1.5 and 1.8 mg/kg/day (approximately
90 and 210 times the maximum recommended human daily inhalation
dose on a mg/m2 basis). These studies have demonstrated
no evidence of teratogenic effects as a result of ipratropium
bromide.
Albuterol: Pregnancy Category
C. Albuterol has been shown to be teratogenic in mice.
A reproduction study in CD-l mice given albuterol subcutaneously
(0.025, 0.25 and 2.5 mg/kg) showed cleft palate formation
in 5 of 111 (4.5%) fetuses at 0.25 mg/kg (equivalent to
the maximum recommended human daily inhalation dose on
a mg/m2 basis) and in 10 of 108 (9.3%) fetuses at 2.5
mg/kg (approximately 10 times the maximum recommended
human daily inhalation dose on a mg/m2 basis). None was
observed at 0.025 mg/kg (approximately one-tenth the maximum
recommended human daily inhalation dose). Cleft palate
also occurred in 22 of 72 (30.5%) fetuses treated with
2.5 mg/kg isoproterenol (positive control). A reproduction
study with oral albuterol in Stride Dutch rabbits revealed
cranioschisis in 7 of 19 (37%) fetuses at 50 mg/kg (approximately
1000 times the maximum recommended human daily inhalation
dose on a mg/m2 basis).
There are, however, no adequate and well-controlled studies
of Combivent® Inhalation Aerosol, ipratropium bromide,
or albuterol sulfate, in pregnant women. Because animal
reproduction studies are not always predictive of human
response, Combivent® Inhalation Aerosol should be
used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.
Labor and Delivery
Because of the potential for beta-agonist interference
with uterine contractility, use of Combivent® Inhalation
Aerosol for the treatment of COPD during labor should
be restricted to those patients in whom the benefits clearly
outweigh the risk.
Nursing Mothers
It is not known whether the components of Combivent®
Inhalation Aerosol are excreted in human milk.
Ipratropium bromide: Although
lipid insoluble quatemary bases pass into breast milk,
it is unlikely that the active component, ipratropium
bromide, would reach the infant to an important extent,
especially when taken by aerosol. However, because many
drugs are excreted in human milk, caution should be exercised
when Combivent® Inhalation Aerosol is administered
to a nursing mother.
Albuterol: Because of the potential
for tumorigenicity shown for albuterol in animal studies,
a decision should be made whether to discontinue nursing
or to discontinue the drug, taking into account the importance
of the drug to the mother.
Pediatric Use
Safety and effectiveness of Combivent® Inhalation
Aerosol in pediatric patients have not been established.
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