Included as part of the PRECAUTIONS section.
COMBIVENT RESPIMAT can produce
paradoxical bronchospasm that can be life-threatening. If it occurs, therapy
with COMBIVENT RESPIMAT should be discontinued immediately and alternative
The albuterol sulfate contained
in COMBIVENT RESPIMAT, 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. If these symptoms occur, COMBIVENT
RESPIMAT may need to be discontinued. There is some evidence from
post-marketing data and published literature of rare occurrences of myocardial
ischemia associated with albuterol. In addition, beta-adrenergic agents have
been reported to produce electrocardiogram (ECG) changes, such as flattening of
the T wave, prolongation of the QTc interval, and ST segment depression.
Therefore, COMBIVENT RESPIMAT should be used with caution in patients with
cardiovascular disorders; especially coronary insufficiency, cardiac
arrhythmias, and hypertension [see DRUG INTERACTIONS].
Ipratropium bromide, a
component of COMBIVENT RESPIMAT, is an anticholinergic and may increase
intraocular pressure. This may result in precipitation or worsening of
narrow-angle glaucoma. Therefore, COMBIVENT RESPIMAT should be used with
caution in patients with narrow-angle glaucoma [see DRUG INTERACTIONS].
Patients should avoid spraying
COMBIVENT RESPIMAT into the eyes. If a patient sprays COMBIVENT RESPIMAT into
their eyes they may cause acute eye pain or discomfort, temporary blurring of
vision, mydriasis, visual halos, or colored images in association with red eyes
from conjunctival or corneal congestion. Advise patients to consult their
physician immediately if any of these symptoms develop while using COMBIVENT
Ipratropium bromide, a
component of COMBIVENT RESPIMAT, is an anticholinergic and may cause urinary
retention. Therefore, caution is advised when administering this medication to
patients with prostatic hyperplasia or bladder-neck obstruction [see DRUG
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 asthmatic crisis and subsequent
hypoxia is suspected [see DRUG INTERACTIONS].
including urticaria, angioedema, rash, bronchospasm, anaphylaxis, and
oropharyngeal edema may occur after administration of ipratropium bromide or
albuterol sulfate. In clinical trials and post-marketing experience with
ipratropium containing products, hypersensitivity reactions such as skin rash,
pruritus, angioedema of tongue, lips and face, urticaria (including giant
urticaria), laryngospasm and anaphylactic reactions have been reported [see
ADVERSE REACTIONS] If such a reaction occurs, therapy with COMBIVENT
RESPIMAT should be stopped at once and alternative treatment should be
considered [see CONTRAINDICATIONS].
COMBIVENT RESPIMAT contains
albuterol sulfate, a beta-adrenergic sympathomimetic amine and, therefore,
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 produce significant
hypokalemia in some patients (possibly through intracellular shunting) which
has the potential to produce adverse cardiovascular effects. The decrease in
serum potassium is usually transient, not requiring supplementation [see
Patient Counseling Information
See FDA-approved Patient Labeling
Caution patients to avoid spraying the aerosol into their
eyes and be advised that this may result in precipitation or worsening of
narrow-angle glaucoma, mydriasis, increased intraocular pressure, acute eye
pain or discomfort, temporary blurring of vision, visual halos or colored
images in association with red eyes from conjunctival and corneal congestion.
Patients should also be advised that should any combination of these symptoms
develop, they should consult their physician immediately.
Since dizziness, accommodation disorder, mydriasis, and
blurred vision may occur with use of COMBIVENT RESPIMAT, patients should be
cautioned about engaging in activities requiring balance and visual acuity such
as driving a car or operating appliances or machinery.
Inform patients that COMBIVENT RESPIMAT may cause urinary
retention and should be advised to consult their physician if they experience
difficulty with urination.
Frequency Of Use
The action of COMBIVENT RESPIMAT should last 4 to 5 hours
or longer. COMBIVENT RESPIMAT should not be used more frequently than
recommended. Safety and efficacy of additional doses of COMBIVENT RESPIMAT
beyond six inhalations in 24 hours have not been studied. Patients should be
told not to increase the dose or frequency of COMBIVENT RESPIMAT without
consulting a physician. Patients should be instructed that if they find that
treatment with COMBIVENT RESPIMAT becomes less effective for symptomatic
relief, their symptoms become worse, and/or they need to use the product more
frequently than usual, medical attention should be sought immediately.
Preparation For Use And Priming
Instruct patients that priming COMBIVENT RESPIMAT is
essential to ensure appropriate content of the medication in each actuation.
When using the unit for the first time, the COMBIVENT
RESPIMAT cartridge is inserted into the COMBIVENT RESPIMAT inhaler and the unit
is primed. COMBIVENT RESPIMAT patients are to actuate the inhaler toward the
ground until an aerosol cloud is visible and then repeat the process three more
times. The unit is then considered primed and ready for use. If not used for
more than 3 days, patients are to actuate the inhaler once to prepare the
inhaler for use. If not used for more than 21 days, patients are to actuate the
inhaler until an aerosol cloud is visible and then repeat the process three
more times to prepare the inhaler for use. [See FDA-approved Patient
Concomitant Drug Use
Remind patients that while taking COMBIVENT RESPIMAT,
other inhaled drugs should be taken only as directed by a physician.
Inform patients that COMBIVENT RESPIMAT can produce
paradoxical bronchospasm that can be life-threatening. If paradoxical
bronchospasm occurs, patients should discontinue using COMBIVENT RESPIMAT.
Adverse Effects Associated With Beta2-agonists
Inform patients of adverse effects associated with beta2-agonists,
such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.
Patients who are pregnant or nursing should contact their
physician about the use of COMBIVENT RESPIMAT.
FDA-approved Patient Labeling
Instructions for Use is supplied as a tear-off following
the full prescribing information.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Two-year oral carcinogenicity studies in rats and mice
have revealed no carcinogenic activity at doses up to 6 mg/kg/day
(approximately 400 and 200 times the maximum recommended human daily inhalation
dose of ipratropium bromide (MRHDID) in adults on a mg/mÂ² basis, respectively).
Results of various mutagenicity/clastogenicity 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 3400 times the MRHDID in adults on a mg/mÂ² basis) was
unaffected by ipratropium bromide administration. At an oral dose of 500
mg/kg/day (approximately 34,000 times the MRHDID in adults on a mg/mÂ² basis),
ipratropium bromide produced a decrease in the conception rate.
Like other agents in its class, albuterol caused a
significant dose-related increase in the incidence of benign leiomyomas of the
mesovarium in a 2-year study in the rat at dietary doses of 2, 10, and 50
mg/kg/day (approximately 20, 110, and 560 times the MRHDID on a mg/mÂ² basis).
In another study this effect was blocked by the coadministration of
propranolol. The relevance of these findings to humans is not known. An
18-month study in mice at dietary doses up to 500 mg/kg/day (approximately 2800
times the MRHDID on a mg/mÂ² basis) and a 99-week study in hamsters at oral
doses up to 50 mg/kg/day (approximately 470 times the MRHDID on a mg/mÂ² 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.
Use In Specific Populations
Pregnancy Category C.
COMBIVENT RESPIMAT Inhalation Spray
There are no adequate and well-controlled studies of
COMBIVENT RESPIMAT (ipratropium bromide and albuterol sulfate) Inhalation
Spray, ipratropium bromide, or albuterol sulfate, in pregnant women. Animal
reproduction studies have not been conducted with COMBIVENT RESPIMAT. However,
albuterol sulfate has been shown to be teratogenic in mice and rabbits.
COMBIVENT RESPIMAT Inhalation Spray should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Oral reproduction studies were performed in mice, rats
and rabbits at doses approximately 340, 68,000 and 17,000 times, respectively,
the maximum recommended human daily inhalation dose (MRHDID) in adults (on a
mg/m² basis at maternal doses in each species of 10, 1000 and 125
mg/kg/day, respectively). Inhalation reproduction studies were conducted in
rats and rabbits at approximately 100 and 240 times, respectively, the MRHDID
in adults (on a mg/m² basis at maternal doses of 1.5 and 1.8
mg/kg/day, respectively). These studies demonstrated no evidence of teratogenic
effects as a result of ipratropium bromide. Embryotoxicity was observed as
increased resorption in rats at oral doses approximately 6100 times MRHDID in
adults (on a mg/m² basis at maternal doses of 90 mg/kg/day and
above). This effect is not considered relevant to human use due to the large
doses at which it was observed and the difference in route of administration.
Albuterol has been shown to be teratogenic in mice and
rabbits. A reproduction study in CD-1 mice given albuterol subcutaneously
showed cleft palate formation in 5 of 111 (4.5%) fetuses at approximately
equivalent to the MRHDID in adults (on a mg/m² basis at a maternal
dose of 0.25 mg/kg/day) and in 10 of 183 (9.3%) fetuses at approximately 14
times the MRHDID in adults (on a mg/m² basis a maternal dose of 2.5
mg/kg/day). None was observed at less than MRHDID in adults (on a mg/m² basis
at a maternal dose of 0.025 mg/kg/day). Cleft palate also occurred in 22 of 72
(30.5%) fetuses treated with 2.5 mg/kg/day isoproterenol (positive control). A
reproductive study with oral albuterol in Stride Dutch rabbits revealed
cranioschisis in 7 of 19 (37%) fetuses at approximately 1,100 times the MRHDID
in adults (on a mg/m² basis at a maternal dose of 50 mg/kg/day).
Labor And Delivery
Because of the potential for beta-agonist interference
with uterine contractility, use of COMBIVENT RESPIMAT for the treatment of COPD
during labor should be restricted to those patients in whom the benefits
clearly outweigh the risk.
It is not known whether the components of COMBIVENT
RESPIMAT are excreted in human milk.
Because lipid-insoluble quaternary cations pass into
breast milk, caution should be exercised when COMBIVENT RESPIMAT is
administered to a nursing mother.
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.
Safety and effectiveness of COMBIVENT RESPIMAT in
pediatric patients have not been established. COMBIVENT RESPIMAT is indicated
for use in patients with COPD on a regular aerosol bronchodilator who continue
to have evidence of bronchospasm and who require a second bronchodilator. This
disease does not normally occur in children.
In the 12-week trial in COPD, 48% of COMBIVENT RESPIMAT
clinical trial patients were 65 years of age or over. In general, there were no
marked differences between the proportion of patients with adverse reactions
for the COMBIVENT RESPIMAT and CFC-propelled COMBIVENT Inhalation Aerosol
treated patients. Cardiac and lower respiratory disorders occurred less
frequently in the patients under the age of 65 and were balanced across
No overall differences in effectiveness were observed
among treatment groups. Based on available data, no adjustment of COMBIVENT
RESPIMAT dosage in geriatric patients is warranted.