CLINICAL PHARMACOLOGY
Combivent® Inhalation Aerosol is a combination of
the anticholinergic bronchodilator ipratropium bromide,
and the beta2-adrenergic bronchodilator, albuterol sulfate.
Ipratropium Bromide
Mechanism of Action: Ipratropium
bromide is an anticholinergic (parasympatholytic) agent
which, based on animal studies, appears to inhibit vagally
mediated reflexes by antagonizing the action of acetylcholine,
the transmitter agent released from the vagus nerve. Anticholinergics
prevent the increases in intracellular concentration of
cyclic guanosine monophosphate (cyclic G.P. which are
caused by interaction of acetylcholine with the muscarinic
receptor on bronchial smooth muscle.
Pharmacokinetics: The bronchodilation
following inhalation of ipratropium bromide is primarily
a local, site-specific effect, not a systemic one. Much
of an administered dose is swallowed as shown by fecal
excretion studies. Ipratropium bromide is a quaternary
amine. It is not readily absorbed into the systemic circulation
either from the surface of the lung or from the gastrointestinal
tract as confirmed by blood level and renal excretion
studies. Plasma levels of ipratropium bromide were below
the assay sensitivity limit of 100 pg/mL.
The half-life of elimination is about 2 hours after inhalation
or intravenous administration. Ipratropium bromide is
minimally bound (0 to 9% in vitro) to plasma albumin and
a-acid glycoprotein. It is partially metabolized to inactive
ester hydrolysis products. Following intravenous administration,
approximately one-half of the dose is excreted unchanged
in the urine. Studies in rats have shown that ipratropium
bromide does not oenetrate the blood-brain barrier.
The pharmacokinetics of Combivent® Inhalation Aerosol
or ipratropium bromide have not been studied in patients
with hepatic or renal insufficiency or in the elderly
(See PRECAUTIONS). Controlled clinical studies have demonstrated
that ipratropium bromide does not alter either mucociliary
clearance or the volume or viscosity of respiratory secretions.
In studies without a positive control, ipratropium bromide
did not alter pupil size, accommodation or visual acuity
(See ADVERSE REACTIONS). Ventilation/perfusion studies
have shown no clinically significant effects on pulmonary
gas exchange or arterial oxygen tension. At recommended
doses, ipratropium bromide does not produce clinically
significant changes in pulse rate or blood pressure.
Albuterol Sulfate
Mechanism of Action: In-vitro
studies and in-vivo pharmacologic studies have demonstrated
that albuterol has a preferential effect on beta2-adrenergic
receptors compared with isoproterenol. While it is recognized
that beta2-adrenergic receptors are the predominant receptors
on bronchial smooth muscle, recent data indicate that
there is a population of beta2-receptors in the human
heart which comprise between 10% and 50% of cardiac beta-adrenergic
receptors. The precise function of these receptors, however,
is not yet established (See WARNINGS). Activation of beta2-adrenergic
receptors on airway smooth muscle leads to the activation
of adenylyl cyclase and to an increase in the intracellular
concentration of cyclic-3’.5’-adenosine monophosphate
(cyclic AMP). This increase of cyclic AMP leads to the
activation of protein kinase A, which inhibits the phosphorylation
of myosin and lowers intracellular ionic calcium concentrations,
resulting in relaxation. Albuterol relaxes the smooth
muscles of all airways, from the trachea to the terminal
bronchioles, Albuterol acts as a functional antagonist
to relax the airway irrespective of the spasmogen involved,
thus protecting against all bronchoconstrictor challenges.
Increased cyclic AMP concentrations are also associated
with the inhibition of release of mediators from mast
cells in the airway. Albuterol has been shown in most
clinical trials to have more bronchial smooth muscle relaxation
effect than isoproterenol at comparable doses while producing
fewer cardiovascular effects. However, all beta-adrenergic
drugs, including albuterol sulfate, can produce a significant
cardiovascular effect in some patients (See PRECAUTIONS).
Pharmacokinetics: Albuterol
is longer acting than isoproterenol in most patients because
it is not a substrate for the cellular uptake processes
for catecholamines nor for metabolism by catechol-O-methyl
transferase. Instead, the drug is conjugatively metabolized
to albuterol 4’-O-sulfate.
In a pharmacokinetic study in 12 healthy male volunteers
of two inhalations of albuterol sulfate, 103 mcg dose/inhalation
through the mouthpiece, peak plasma albuterol concentrations
ranging from 419 to 802 pg/mL mean 599 + 122 pg/mL were
obtained within three hours post-administration, and following
this single-dose administration, 30.8 + 10.2% of the estimated
mouthpiece dose was excreted unchanged in the 24 hour
urine. Since albuterol sulfate is rapidly and completely
absorbed, this study could not distinguish between pulmonary
and gastrointestinal absorption. Intravenous pharmacokinetics
of albuterol were studied in a comparable group of 16
healthy male volunteers; the mean terminal halflife following
a 30- minute infusion of 1.5 mg was 3.9 hours with a mean
clearance of 439 mL/min/1.73 m2. Intravenous albuterol
studies in rats demonstrated that albuterol crossed the
bloodbrain barrier and reached brain concentrations amounting
to about 5% of the plasma concentrations. In structures
outside the blood-brain barrier (pineal and pituitaryglands),
the drug achieved concentrations more than 100 times those
in whole brain.
Studies in pregnant rats with tritiated albuterol demonstrated
that approximately 10% of the circulating maternal drug
was transferred to the fetus. Disposition in fetal lungs
was comparable to maternal lungs, but fetal liver disposition
was 1% of maternal liver levels. Studies in laboratory
animals (minipigs, rodents, and dogs) have demonstrated
the occurrence of cardiac arrhythmias and sudden death
(with histologic evidence of myocardial necrosis) when
beta-agonists and methylxanthines were adminstered concurrently.
The significance of these findings when applied to humans
is unknown.
Combivent® Inhalation Aerosol
Mechanism of Action: Combivent®
Inhalation Aerosol is expected to maximize the response
to treatment in patients with chronic obstructive pulmonary
disease (COPD) by reducing bronchospasm through two distinctly
different mechanisms, anticholinergic (parasympatholytic)
and sympathomimetic. Simultaneous administration of both
an anticholinergic (ipratropium bromide) and a beta2-sympathomimetic
(albuterol sufate) is designed to benefit the patient
by producing, a greater bronchodilator effect than when
either drug is utilized alone at its recommended dosage.
Pharmacokinetics: In a crossover
pharmacokinetic study in 12 healthy male volunteers comparing
the pattern of absorption and excretion of two inhalations
of Combivent® Inhalation Aerosol to the two active
components individually, the co-administration of ipratropium
bromide and albuterol sulfate from a single canister did
not significantly alter the systemic absorption of either
component. Ipratropium bromide levels remained below detectable
limits (< 100 pg/mL). Peak albuterol level obtained
within 3 hours post-administration was 492 + 132 pg/mL.
Following this single administration, 27.1 + 5.7% of the
estimated mouthpiece dose was excreted unchanged in the
24 hour urine. From a pharmacokinetic perspective, the
synergistic efficacy of Combivent® Inhalation Aerosol
is likely to be due to a local effect on the muscarinic
and beta2- adrenergic receptors in the lung.
Clinical Trials: In two 12-week
randomized, double-blind, active-controlled clinical trials,
1067 patients with chronic obstructive pulmonary disease
(COPD) were evaluated for the bronchodilator efficacy
of Combivent® Inhalation Aerosol (358 patients) in
comparison to its components, ipratropium bromide (362
patients) and albuterol suffate (347 patients).
Serial FEV1, measurements demonstrated that Combivent®
Inhalation Aerosol produced significantly greater improvement
in pulmonary function than either ipratropium bromide
or albuterol sulfate when given separately. The median
time to onset of a 15% increase in FEV1 was 15 minutes
and the median time to peak FEV was one hour for Combivent®
Inhalation Aerosol and its components. The median duration
of effect as measured by FEV1 was 4-5 hours for Combivent®
Inhalation Aerosol compared to 4 hours for ipratropium
bromide and 3 hours for albuterol suffate.
These studies demonstrated that each component of Combivent®
Inhalation Aerosol contributed to the improvement in pulmonary
function produced by the combination, especially during
the first 4-5 hours after dosing, and that Combivent®
Inhalation Aerosol was significantly more effective than
ipratropium bromide or albuterol sulfate administered
alone. In the two controlled twelve-week studies, Combivent®
Inhalation Aerosol did not produce any change in the secondary
efficacy parameters including symptom scores, physician
global assessments and morning PEFR, all of which were
monitored throughout the study period.
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