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Ipratropium and Albuterol (Inhalation-Local )



INN:

Albuterol—Salbutamol

BAN:
Albuterol—Salbutamol

VA CLASSIFICATION
Primary: RE190

Commonly used brand name(s): Combivent; DuoNeb.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Bronchodilator—

Indications

Accepted

Pulmonary disease, chronic obstructive (treatment)—Ipratropium and albuterol combination is indicated for the treatment of chronic obstructive pulmonary disease (COPD) in patients who are using an aerosol bronchodilator and who continue to have symptoms of bronchospasm that require treatment with a second bronchodilator {01}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Ipratropium: A synthetic quaternary ammonium compound, chemically related to atropine {01}.
Molecular weight—
    Albuterol sulfate: 576.7 {01}
    Ipratropium bromide: 430.4 {01}

Mechanism of action/Effect:

Ipratropium and albuterol combination reduces bronchospasm through both anticholinergic and sympathomimetic mechanisms. Simultaneous administration of both drugs produces a greater bronchodilator effect than when either drug is used alone at recommended dosages. {01}

Albuterol—Albuterol is a sympathomimetic agent that has a relatively high degree of selectivity for beta 2-adrenergic receptors. Activation of these receptors on airway smooth muscle leads to the activation of the enzyme adenylyl cyclase and to an increase in the intracellular concentration of cyclic-3, 5-adenosine monophosphate (cAMP). Increased cAMP concentrations indirectly lower intracellular ionic calcium, which results in airway smooth muscle relaxation. {01}


Ipratropium—Ipratropium is an anticholinergic agent that produces a local, site-specific effect rather than a systemic effect. It appears to produce bronchodilation by inhibition of cholinergic receptors on bronchial smooth muscle. {01}


Absorption:

Albuterol—Rapidly and completely absorbed, although whether primarily from pulmonary or from gastrointestinal site is unknown {01}.


Ipratropium—Not readily absorbed into the systemic circulation either from the surface of the lung or from the gastrointestinal tract, as confirmed by blood concentration and renal excretion studies {01}.


Onset of action:

Ipratropium and albuterol combination—In clinical trials, the median time to onset of a 15% increase in forced expiratory volume in 1 second (FEV 1) was 15 minutes {01}.

Time to peak effect:

Ipratropium and albuterol combination—1 hour {01}.

Duration of action:

Ipratropium and albuterol combination—4 to 5 hours {01}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients allergic to soybean protein or other legumes, such as peanuts, may be allergic to the soya lecithin contained in the metered-dose inhaler {01}.

Ipratropium—Patients sensitive to atropine or its derivatives may be sensitive to ipratropium {01}.

Carcinogenicity/Tumorigenicity

Albuterol—A 2-year study in rats showed that albuterol, administered orally in doses of 20, 100, and 500 times the maximum recommended human inhalation dose, on a mg per square meter of body surface area (mg/m 2) basis, causes a dose-related increase in the incidence of benign leiomyomas of the mesovarium. This effect was blocked by the administration of propranolol in another study. An 18-month study in mice and a 99-week study in hamsters showed no evidence of tumorigenicity. {01}


Ipratropium—Two-year studies in mice and rats have shown that ipratropium, at oral doses of up to 360 and 180 times, respectively, the maximum recommended human inhalation dose, on a mg/m 2 basis, has no carcinogenic potential.


Mutagenicity

Albuterol—In vitro studies with albuterol showed no evidence of tumorigenicity {01}.


Ipratropium—Results of various in vitro mutagenicity studies were negative {01}.


Pregnancy/Reproduction
Fertility—
Albuterol: Reproduction studies in rats given albuterol sulfate revealed no evidence of impaired fertility. {01}

Ipratropium: Although studies in rats have shown that ipratropium, at oral doses of up to approximately 3000 times the maximum recommended human inhalation dose, on a mg/m 2 basis, does not affect fertility, ipratropium has been shown to increase fetal resorption and decrease conception rates when administered at doses above approximately 5400 times the maximum recommended human inhalation dose, on a mg/m 2 basis {01}.

Pregnancy—
Albuterol: Adequate and well-controlled studies in humans have not been done.

Mice given albuterol subcutaneously at doses one-tenth of, comparable to, and 10 times the maximum recommended human daily inhalation dose on a mg/m 2 basis showed cleft palate formation in 0%, 4.5%, and 9.3% of fetuses, respectively. In rabbits given oral albuterol at doses approximately 1000 times the maximum recommended human daily inhalation dose on a mg/m 2 basis showed cranioschisis in 37% of fetuses. {01}


Ipratropium: Adequate and well-controlled studies in humans have not been done.

Reproduction studies in mice, rats, and rabbits revealed no evidence of teratogenicity {01}.


FDA Pregnancy Category C {01}.

Labor—

Albuterol: Beta-adrenergic agonists have been shown to decrease uterine contractions {01} when administered systemically.

Breast-feeding

It is not known whether ipratropium or albuterol is distributed into breast milk {01}. However, problems in humans have not been documented.

Pediatrics

No information is available on the relationship of age to the effects of the metered-dose inhalation dosage form of ipratropium and albuterol in pediatric patients. Safety and efficacy have not been established.


Geriatrics


Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of ipratropium and albuterol combination in older adults.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Anticholinergics, other, or other medications with anticholinergic activity (see Appendix II ){01}    (concurrent use of other medications with anticholinergic activity together with ipratropium may result in additive effects)


Beta-adrenergic blocking agents {01}    (concurrent use with adrenergic bronchodilators may result in mutual inhibition of therapeutic effects)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Electrocardiogram    (flattened T waves, prolongation of the QT c interval, and ST segment depression have been reported with beta-adrenergic bronchodilators {01})


Potassium, serum    (beta-adrenergic bronchodilators may decrease serum potassium concentrations, especially when the recommended dose is exceeded {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Sensitivity to ipratropium, atropine, or albuterol
» Allergy to soya lecithin, soybean protein, or other legumes such as peanuts
For ipratropium:
» Glaucoma, angle-closure {01}    (an acute attack may be precipitated or condition may be exacerbated if ipratropium-containing inhalation aerosol is sprayed directly into the eyes )


Urinary retention {01}    (rarely, condition may be aggravated)


For albuterol:
Cardiac arrhythmias or
» Coronary insufficiency or
Hypertension    (although uncommon after administration of ipratropium and albuterol combination at recommended doses, albuterol can produce a clinically significant cardiovascular effect in some patients, as measured by pulse rate or blood pressure {01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence rare
    
Angioedema {01}(swelling of the face, lips, or eyelids)
    
bronchospasm, paradoxical or hypersensitivity-induced {01}(shortness of breath; wheezing)
    
chest discomfort or pain {01}
    
irregular heartbeat {01}
    
oropharyngeal edema {01}(swelling of the mouth or throat)
    
skin rash {01}
    
tachycardia {01}(fast heartbeat)
    
urticaria {01}(hives)



Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent (2 to 6%)
    
Coughing {01}
    
headache {01}
    
nausea {01}

Incidence rare
    
Change in sense of taste
    
dizziness {01}
    
dryness of mouth {01}
    
nervousness {01}
    
tremor {01}





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Ipratropium and Albuterol (Inhalation-Local) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to ipratropium, atropine, or albuterol; allergy to soya lecithin, soybean protein, or other legumes such as peanuts
Other medical problems, especially angle-closure glaucoma or coronary insufficiency

Proper use of this medication
Proper administration technique: reading patient instructions carefully before using

Performing three priming sprays before using inhalation aerosol for the first time or if not used for more than 24 hours

To administer inhalation solution, use a jet nebulizer (with face mask or mouthpiece) connected to compressor with good air flow

» Avoiding contact with eyes

» Importance of not using more medication than the recommended dose

» Proper dosing
Missed dose: Using as soon as possible; using any remaining doses for that day at regularly spaced intervals

» Proper storage

Precautions while using this medication
» Checking with physician immediately if difficulty in breathing persists after using this medication or if condition becomes worse


Side/adverse effects
Signs of potential side effects, especially angioedema, paradoxical or hypersensitivity-induced bronchospasm, chest discomfort or pain, irregular heartbeat, oropharyngeal edema, skin rash, tachycardia, and urticaria


General Dosing Information
Three priming sprays should be performed before the metered-dose inhaler is used for the first time or when it has not been used in more than 24 hours {01}.

Inhalation solution should be administered via a jet nebulizer connected to an air compressor with adequate air flow, equipped with a mouthpiece or suitable face mask. Like all other nebulized treatment, the amount delivered to the lungs will depend on patient factors, the jet nebulizer used and the compressor performance. A Pari-LC-Plus™ nebulizer (with face mask or mouthpiece) connected to a PRONEB™ compressor was used in one U.S. clinical study. The safety and efficacy using other nebulizers and compressors have not been established.{02}

Do not exceed the recommended dosage for the inhalation solution. Fatalities have been associated with the excessive use of inhaled products containing sympathomimetic amines and home use of nebulizers.{02}


Inhalation Dosage Forms

Note: The strength of the dosage forms available are expressed in terms of albuterol base.


IPRATROPIUM BROMIDE AND ALBUTEROL SULFATE INHALATION AEROSOL

Usual adult dose
Pulmonary disease, chronic obstructive
Oral inhalation, 2 inhalations four times a day and as required; however, the total number of inhalations should not exceed 12 inhalations in twenty-four hours {01}.


Usual adult prescribing limits
12 inhalations in twenty-four hours {01}.

Usual pediatric dose
Safety and efficacy have not been established.

Usual geriatric dose
See Usual adult dose .

Strength(s) usually available
U.S.—


18 mcg ipratropium bromide and 90 mcg albuterol (base) per metered spray (Rx) [Combivent (chlorofluorocarbons (CFCs))]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F); avoid excessive humidity {01}.

Auxiliary labeling:
   • Shake well before using.
   • For oral inhalation only.

Note: Include patient instructions when dispensing.



IPRATROPIUM BROMIDE AND ALBUTEROL SULFATE INHALATION SOLUTION

Usual adult dose
Pulmonary disease, chronic obstructive
Oral inhalation, one 3 mL vial administered four times a day via nebulization; 2 additional 3 mL doses allowed per day, as needed.
{02}

Usual pediatric dose
Safety and efficacy have not been established.
{02}
Usual geriatric dose
See Usual adult dose .
{02}
Strength(s) usually available
U.S.—


0.5 mg (0.017%) ipratropium bromide and 2.5 mg (0.083%) albuterol (base) per 3 mL vial (Rx) [DuoNeb (sodium chloride) (hydrochloric acid) (edetate disodium )]{02}

Packaging and storage:
Store between 2 and 25 °C (36 and 77 °F); protect from light.
{02}
Auxiliary labeling:
   • For oral inhalation only. {02}

Note: Include patient instructions when dispensing.{02}




Developed: 06/17/1997
Revised: 07/03/2001



References
  1. Combivent package insert (Boehringer Ingelheim—US), Dev 11/96.
  1. Product Information: DuoNeb™, ipratropium bromide and albuterol sulfate. Dey, Napa, CA (PI Issued 3/2001) PI reviewed 6/2001
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