CLINICAL PHARMACOLOGY
COMBIVENT Inhalation Aerosol is a combination of the
anticholinergic bronchodilator, ipratropium bromide, and the
beta
2-adrenergic bronchodilator, albuterol sulfate.
Mechanism of Action
Ipratropium bromide
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 at the
neuromuscular junctions in
the lung. Anticholinergics prevent the increases in intracellular concentration
of Ca++ which is caused by interaction of acetylcholine with the muscarinic
receptors on bronchial
smooth muscle.
Albuterol sulfate
In vitro studies and in vivo
pharmacology studies have demonstrated that albuterol has a preferential effect on beta
2-adrenergic receptors compared with isoproterenol. While it is recognized that beta
2-adrenergic
receptors are the predominant receptors on bronchial smooth muscle, recent data
indicate that there is a population of beta
2-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 beta
2-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).
COMBIVENT Inhalation Aerosol
Combivent® (ipratropium bromide and albuterol sulfate) 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 beta
2-sympathomimetic (albuterol
sulfate) is designed to benefit the patient by producing a greater
bronchodilator effect than when either drug is utilized alone at its
recommended dosage.
Pharmacokinetics
Ipratropium bromide
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 α1-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. Autoradiographic studies in rats have shown that
ipratropium bromide does not penetrate the
blood-brain barrier.
Albuterol sulfate
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. 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 half-life
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 blood-brain barrier and reached brain concentrations
amounting to about 5% of the plasma concentrations. In structures
outside the
blood-brain barrier (pineal and
pituitary glands), 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 administered concurrently. The significance of these
findings when applied to humans is unknown.
COMBIVENT Inhalation Aerosol
In a crossover pharmacokinetic study in 12 healthy male
volunteers comparing the pattern of absorption and excretion of two inhalations
of Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol to
the two active components individually, the coadministration 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 beta
2-adrenergic receptors in the lung.
Special Populations
The pharmacokinetics of Combivent® (ipratropium bromide and
albuterol sulfate) Inhalation Aerosol or ipratropium bromide have not been
studied in patients with hepatic or renal insufficiency or in the elderly (see
PRECAUTIONS).
Drug-Drug Interactions
No specific pharmacokinetic studies were conducted to evaluate potential drug-drug interactions.
Pharmacodynamics
Ipratropium bromide
The bronchodilation following inhalation of ipratropium
bromide is primarily a local, site-specific effect, not a systemic one.
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.
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 sulfate (347 patients).
Serial FEV1 measurements (shown below as a percent change
from test-day baseline) 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 FEV1 was one
hour for COMBIVENT Inhalation Aerosol and its components. The median duration
of effect as measured by FEV1 was 4 to 5 hours for COMBIVENT Inhalation Aerosol
compared to 4 hours for ipratropium bromide and 3 hours for albuterol sulfate.
Percent Change in Adjusted Meana FEV1 from Test-Day
Baseline - Endpoint Analysis of the Evaluable Data Set
These studies demonstrated that each component of Combivent® (ipratropium bromide and albuterol sulfate)
Inhalation Aerosol contributed to the improvement in pulmonary function
produced by the combination, especially during the first 4 to 5 hours after
dosing, and that COMBIVENT Inhalation Aerosol was significantly more effective
than ipratropium bromide or albuterol sulfate administered alone.
In the 2 controlled 12-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.
