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Bronchodilators, Adrenergic (Inhalation-Local)

This monograph includes information on the following:


Note: Products containing bitolterol were withdrawn from the market by Elan Pharmaceuticals in November 2001.{129}

1) Albuterol
2) Bitolterol  * 
3) Epinephrine
4) Fenoterol *
5) Formoterol
6) Isoetharine 
7) Isoproterenol
8) Metaproterenol
9) Pirbuterol
10) Procaterol *
11) Salmeterol
12) Terbutaline


INN:
Albuterol—Salbutamol

BAN:
Albuterol—Salbutamol
Epinephrine—Adrenaline
Formoterol—Eformoterol


JAN:
Albuterol—Salbutamol
Formoterol—Formoterol Fumarate
Metaproterenol—Orciprenaline

VA CLASSIFICATION
Albuterol
Primary: RE120

Bitolterol
Primary: RE120

Epinephrine
Primary: RE120
Secondary: RE900

Fenoterol
Primary: RE120

Formoterol
Primary: RE120

Isoetharine
Primary: RE120

Isoproterenol
Primary: RE120

Metaproterenol
Primary: RE120

Pirbuterol
Primary: RE120

Procaterol
Primary: RE120

Racepinephrine
Primary: RE120

Salmeterol
Primary: RE120

Terbutaline
Primary: RE120


Commonly used brand name(s): Adrenalin Chloride3; Airet1; Alupent8; Apo-Salvent1; Arm-a-Med Isoetharine6; Arm-a-Med Metaproterenol8; AsthmaNefrin3; Asthmahaler Mist3; Berotec4; Beta-26; Brethaire12; Bricanyl Turbuhaler12; Bronkaid Mist3; Bronkaid Suspension Mist3; Bronkometer6; Bronkosol6; Dey-Lute Isoetharine6; Dey-Lute Metaproterenol8; Foradil5; Gen-Salbutamol Sterinebs P.F.1; Isuprel7; Isuprel Mistometer7; Maxair9; Maxair Autohaler9; Medihaler-Iso7; Nephron3; Novo-Salmol1; Oxeze Turbuhaler5; Oxeze Turbuhaler Foradil5; Primatene Mist3; Pro-Air10; Proventil1; Proventil HFA1; S-23; Serevent11; Serevent Diskhaler11; Serevent Diskus11; Vaponefrin3; Ventodisk1; Ventolin1; Ventolin HFA1; Ventolin Nebules1; Ventolin Nebules P.F.1; Ventolin Rotacaps1; microNefrin3.

Other commonly used names are:


Adrenaline —Epinephrine



Orciprenaline —Metaproterenol



Salbutamol —Albuterol

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

*Not commercially available in the U.S.

Not commercially available in Canada.



Category:


Bronchodilator—Albuterol ; Bitolterol; Epinephrine; Fenoterol; Formoterol; Isoetharine ; Isoproterenol; Metaproterenol; Pirbuterol; Procaterol; Salmeterol ; Terbutaline;

Croup therapy agent— Epinephrine; Racepinephrine ;

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Note: Products containing bitolterol were withdrawn from the market by Elan Pharmaceuticals in November 2001.{129}


Accepted

Asthma (treatment)—Formoterol is indicated for long-term maintenance treatment of asthma in patients with reversible obstructive airway disease, including patients with symptoms of nocturnal asthma, who are using optimal corticosteroid treatment and experiencing regular or frequent breakthrough symptoms requiring regular use of short-acting bronchodilators.{128}{127}

Bronchospasm, asthma-associated (treatment)—Albuterol, bitolterol, fenoterol, metaproterenol, pirbuterol, procaterol, and terbutaline are indicated as bronchodilators for the treatment of bronchospasm associated with asthma{06}{07}{08}{11}{12}{13}{14}{15}{16}{18}{43}{60}.
—Adrenergic bronchodilators that are more selective for the beta 2-receptor and have a longer duration of action are preferred {43}; therefore, epinephrine, isoetharine, and isoproterenol are generally not recommended for this indication.

Bronchospasm, asthma-associated (prophylaxis)— Salmeterol and formoterol are indicated to prevent bronchospasm and reduce the frequency of acute asthma exacerbations in patients with chronic asthma{27}{30}{38}{46}{47} who require regular treatment with an inhaled shorter-acting beta-adrenergic bronchodilator. {17}{48}{117}{118}{119}{120} Patients treated with formoterol should be receiving corticosteroid treatment{117}. Salmeterol may be used with or without concurrent inhaled or systemic corticosteroid therapy{118}{119}. During therapy with salmeterol or formoterol, it is important for patients to have a fast-acting inhaled beta-adrenergic bronchodilator available for relief of acute attacks{17}{117}{120}.
—Generally, regularly scheduled, daily use of short-acting beta 2-agonists is not recommended{43}{58}{117}.

Bronchospasm, exercise-induced (prophylaxis)—Albuterol, [bitolterol] , formoterol 1[ pirbuterol] , procaterol, salmeterol1 , and [terbutaline]1 are indicated for the prevention of exercise-induced bronchospasm{06}{09}{11}{15}{16}{17}{22}{41}{43}{53}{54}{56}{65}{118}{119}{128}. With use of salmeterol and formoterol, it is important for patients to also have a fast-acting inhaled beta-adrenergic bronchodilator available for relief of acute attacks. {17}{128} Adrenergic bronchodilators that are more selective for the beta 2-receptor and have a longer duration of action are preferred; therefore, epinephrine, isoetharine, and isoproterenol are generally not recommended for this indication {43}.

Bronchospasm, chronic bronchitis-associated (prophylaxis and treatment)
Bronchospasm, pulmonary emphysema-associated (prophylaxis and treatment)
Bronchospasm, chronic obstructive pulmonary disease-associated (prophylaxis and treatment)—Albuterol, bitolterol, fenoterol, metaproterenol, pirbuterol, procaterol, salmeterol, and terbutaline are indicated as bronchodilators for the treatment of bronchospasm associated with chronic obstructive airway disease, including bronchitis and pulmonary emphysema{07}{11}{14}{15}{16}{18}{118}{119}. Patients may benefit from the addition of regularly scheduled doses of a beta 2-agonist to ipratropium{59}{62}. Adrenergic bronchodilators that are more selective for the beta 2-receptor and have a longer duration of action are preferred; therefore, epinephrine, isoetharine, and isoproterenol are generally not recommended for these indications.

Chronic obstructive pulmonary disease [COPD] (treatment)—Formoterol is indicated as long-term, twice-daily administration in the treatment of patients with chronic obstructive pulmonary disease including chronic bronchitis and emphysema. {128}{127}

Croup (treatment)—Racepinephrine and nebulized [epinephrine]1 are indicated in the treatment of postintubation{10} and viral croup{10}{49}{50}{52} to temporarily reduce mucosal edema, thereby relieving acute respiratory distress {49}.

[Hyperkalemia (treatment)]1—Albuterol is indicated as a temporary treatment option for hyperkalemia in acute situations in pediatric patients.{130}{131}{132}{133}{134}{135}{136}{137}{138}

Acceptance not established
Although albuterol, epinephrine, and racepinephrine have been used for treatment of acute bronchiolitis in infants, data are insufficient to prove that these medications are effective for this indication. Some studies indicate modest, short-term benefit; however, other results are conflicting.{24}{25}{28}{42}{66}{96}{107}{111}{112}{113}{114}

There is insufficient data to show that albuterol is beneficial for the treatment of hyperkalemia in adults.{130}{131}{132}{133}{134}{135}{136}{137}{138}

Unaccepted
Salmeterol is not indicated for the treatment of acute or breakthrough asthma symptoms when rapid bronchodilation is needed because of its slower onset of action compared to shorter-acting adrenergic bronchodilators {17}{118}{119}.

Formoterol is not indicated in the treatment of acute asthma attacks and should not be used in patients whose asthma can be managed by occasional use of short-acting inhaled beta2-agonists.{117}

Neither formoterol nor salmeterol therapy should be initiated in patients with significantly worsening or acutely deteriorating asthma {17}{117}{118}{119}(rapid worsening over hours to days{97}).

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Albuterol: 239.32 {01}
    Albuterol sulfate: 576.71 {01}
    Bitolterol mesylate: 557.67 {01}
    Epinephrine: 183.21 {01}
    Epinephrine bitartrate: 333.30 {01}
    Fenoterol hydrobromide: 303.36 {01}
    Formoterol fumarate dihydrate: 840.9{117}
    Isoetharine hydrochloride: 275.78 {01}
    Isoetharine mesylate: 335.42 {01}
    Isoproterenol sulfate: 556.64 {01}
    Metaproterenol sulfate: 520.60 {01}
    Pirbuterol acetate: 300.36 {01}
    Procaterol hydrochloride: 326.82 {01}
    Salmeterol xinafoate: 603.76 {01}
    Terbutaline sulfate: 548.66 {01}

Mechanism of action/Effect:

Bronchodilator—Adrenergic bronchodilators act by stimulating beta 2-adrenergic receptors in the lungs to relax bronchial smooth muscle, thereby relieving bronchospasm. This action is believed to result from increased production of cyclic adenosine 3,5-monophosphate (cyclic 3,5-AMP; cAMP) and ensuing reduction in intracellular calcium concentration caused by activation of the enzyme adenylate cyclase that catalyzes the conversion of adenosine triphosphate (ATP) to cAMP. Increased cAMP concentrations, in addition to relaxing bronchial smooth muscle, inhibit release of mediators of immediate hypersensitivity from cells, especially from mast cells. {05} {105}

Croup therapy agent—Epinephrine has alpha-adrenergic stimulating effects that produce constriction of arteries and veins. The resulting decreased mucosal edema is thought to be the mechanism by which epinephrine and racepinephrine are beneficial in the treatment of croup. The L-isomer of racepinephrine is the primary active isomer. {51} {52}


Other actions/effects:

Albuterol, bitolterol, fenoterol, formoterol, isoetharine, pirbuterol, procaterol, salmeterol, and terbutaline have a relatively high degree of selectivity for beta 2-adrenergic receptors. Data indicate that there is a population of beta 2-receptors in the human heart existing in a concentration between 10 and 50% of the cardiac beta-adrenergic receptors; stimulation of these receptors produces tachycardia. {06} {44} {45} Stimulation of beta 2-receptors located in skeletal muscle causes muscle tremor {04}.

Epinephrine, isoproterenol, and metaproterenol have significant beta 1-adrenergic activity in the heart, resulting in an increased rate and force of cardiac contractions {04} {05} {61} {100}.

Other effects of epinephrine include alpha- and beta 2-receptor–mediated stimulation of glycogenolysis and gluconeogenesis {04} {05}.

Limited in vitro and in vivo animal studies and allergen challenge studies in asthmatics demonstrate that some adrenergic bronchodilators have inhibitory effects on several inflammatory response mediators {04} {17} {34} {93} {94} {95}. However, these medications are not considered to have clinically relevant anti-inflammatory effects {29} {102}.

Absorption:

Systemic absorption is rapid following aerosol administration; however, serum concentrations at recommended doses are very low or unmeasurable {06} {07} {13} {14} {15} {17}{120}.

Biotransformation:

Bitolterol—A prodrug hydrolyzed by esterases in tissue and blood to the active compound colterol {07}.

Onset of action:

Albuterol, bitolterol, epinephrine, fenoterol, formoterol, isoetharine, isoproterenol, metaproterenol, pirbuterol, procaterol, and terbutaline—Rapid, within 5 minutes {04} {06} {07} {11} {14} {15} {16} {18} {104}{117}{120}.

Salmeterol—Approximately 10 to 20 minutes {17}.

Time to peak effect:

Epinephrine, isoetharine, and isoproterenol—Within 5 to 15 minutes {104}.

Albuterol, bitolterol, fenoterol, metaproterenol, pirbuterol, procaterol, and terbutaline—Within 30 to 90 minutes; however, for albuterol, fenoterol, pirbuterol, and terbutaline, 75% of maximal effect is achieved within 5 minutes {104}.

Salmeterol—3 to 4 hours; however, approximately 80% of the maximal increase in forced expiratory volume in 1 second (FEV 1) occurs within 1 hour after administration {26} {29}.

Duration of action:

Short-acting (less than 3 hours)—Epinephrine, isoetharine, and isoproterenol {04}.

Intermediate-acting (3 to 6 hours)—Albuterol, bitolterol, fenoterol, metaproterenol, pirbuterol, procaterol, and terbutaline {102} .

Long-acting—Formoterol and salmeterol: Approximately 12 hours {27} {30} {31}{117}.

Note: It is believed that the sustained pharmacological action of salmeterol is due to its lipophilicity and long N-substituted side chain. The side chain has been shown to bind to the exo-site, an area in the beta 2-receptor adjacent to the active site. The phenylethanolamine portion of the salmeterol molecule is then in position to associate with and dissociate from the receptor"s active site. This theory is supported by the fact that the pharmacologic effect of salmeterol in vitro is rapidly and completely reversed by beta-receptor antagonism and resumes once the antagonist is removed. {33} {34} {35} {36}



Precautions to Consider

Carcinogenicity/Tumorigenicity/Mutagenicity

Albuterol—A 2-year study in rats showed that albuterol, administered orally in doses that provided 93, 463, and 2315 times the maximum inhalational dose for a human weighing 50 kilograms (kg), caused a dose-related increase in the incidences of benign leiomyomas of the mesovarium. An 18-month study in mice and a lifetime study in hamsters showed no evidence of tumorigenicity. Studies with albuterol showed no evidence of mutagenesis. {06}

Bitolterol—No tumorigenicity was observed in a 2-year study in rats given oral doses that provided 12 or 62 times the maximal daily human inhalational dose for the inhalation solution, or 23 or 114 times the maximal daily human dose for the metered-dose inhaler, or in an 18-month study in mice given oral doses that provided up to 312 times the maximal daily human inhalational dose for the inhalation solution, or 568 times the maximal daily human dose for the metered-dose inhaler. Bitolterol was not mutagenic in Ames Salmonella and mouse lymphoma mutation assays in vitro . {07}

Epinephrine and fenoterol—Studies to evaluate the carcinogenic, tumorigenic, or mutagenic potential of epinephrine and fenoterol have not been done. There is no evidence from human data that use of these medications may cause problems.

Formoterol—An increase in the frequency of uterine leiomyomas of the uterus was observed in mice given oral formoterol and of leiomyomas of the mesovarium in rats given formoterol by inhalation{117}{120}. In vitro and in vivo studies showed no mutagenic effects of formoterol{117}{120}.

Isoetharine—No evidence of carcinogenicity was observed in chronic toxicity studies in dogs given doses up to the equivalent of approximately 200 times the dose for a 70 kg human for 12 months or in rats given doses of up to the equivalent of approximately 450 times the dose for a 70 kg human {12} .

Isoproterenol—Isoproterenol has not been evaluated for carcinogenicity or mutagenicity {13}.

Metaproterenol—An 18-month study in mice given doses equivalent to 320 and 640 times the maximum recommended dose for a 50 kg human showed an increase in benign ovarian tumors. In a 2-year study in rats given 640 times the maximum recommended human dose, a nonsignificant incidence of benign mesovarian leiomyomas was noted. Mutagenic studies have not been conducted. {09}

Pirbuterol—When administered orally to rats for 24 months and to mice for 18 months in doses equivalent to 200 times the maximum human inhalation dose, no evidence of carcinogenicity was observed. In a 12-month study in rats, direct intragastric administration of pirbuterol in doses equivalent to 6250 times the maximum recommended daily inhalation dose for humans resulted in no increased incidence of tumorigenicity. Studies with pirbuterol showed no evidence of mutagenicity. {15}

Procaterol—A 23-month study in mice given procaterol orally showed no increased incidence of tumorigenicity. When administered orally to rats at doses of 5, 50, and 500 mg per kg per day, a dose-related incidence of mesovarian leiomyomas was observed. Procaterol has not been shown to be mutagenic. {16}

Salmeterol—An 18-month study in mice showed that salmeterol, administered orally in doses that provided 9 and 63 times the human exposure (based on comparison of area under the plasma concentration–time curves [AUCs]), caused a dose-related increase in the incidences of smooth muscle hyperplasia, cystic glandular hyperplasia, leiomyomas of the uterus, and ovarian cysts. A 24-month study in rats given salmeterol orally and by inhalation in doses approximately 55 and 215 times, respectively, the recommended human clinical dose based on mg per square meter of body surface area (mg/m 2) showed dose-related increases in the incidences of mesovarian leiomyomas and ovarian cysts. Similar results have been reported with other beta-adrenergic bronchodilators. Salmeterol produced no significant carcinogenic effects in mice receiving doses that provided 1.3 times the human exposure based on AUC comparison, or in rats given 15 times the recommended human clinical dose based on mg/m 2. Salmeterol was not mutagenic in in vitro tests in microbial or mammalian genes or in human lymphocytes or in an in vivo rat micronucleus test. {17}

Terbutaline—A 2-year study in rats given oral doses equivalent to 1042, 10,417, 20,833, and 41,667 times the recommended daily human adult dose showed dose-related increases in leiomyomas of the mesovarium. The incidence of ovarian cysts was significantly increased at all doses except the highest dose, and mesovarium hyperplasia was increased significantly at 10,417 and 41,667 times the recommended daily human adult dose. A 21-month study in mice given oral doses equivalent to 104, 1042, and 4167 times the recommended daily human adult dose showed no evidence of carcinogenicity. Studies to evaluate mutagenicity have not been done. {18}

Pregnancy/Reproduction
Fertility—
Albuterol, bitolterol, pirbuterol, procaterol, salmeterol, and terbutaline: Reproduction studies in rats showed no significant effects on fertility after administration of these agents {06} {07} {15} {16} {17} {18}.

Formoterol: Fertility was significantly reduced in male rats given oral formoterol 15 mg/kg but not in those given lower doses{117}. Fertility of female rats was not affected by formoterol, even at the high dose{117}.

Isoetharine, isoproterenol, and metaproterenol: Studies with isoetharine, isoproterenol, and metaproterenol have not been done {12} {13} {14}.

Pregnancy—

All adrenergic bronchodilators

Although adequate and well-controlled studies in pregnant women have not been done with inhaled adrenergic bronchodilators, albuterol, bitolterol, fenoterol, isoetharine, isoproterenol, metaproterenol, pirbuterol, procaterol, salmeterol, and terbutaline (but not epinephrine) are used in pregnancy when any potential risk that may be associated with treatment is preferable to the risk of placental hypoxemia from uncontrolled pulmonary disease. {37} {43} Extensive use of adrenergic bronchodilators during pregnancy has provided no evidence that the sympathomimetic class effects seen in animal studies are relevant to human use {19} {37} {43}.



Albuterol

Adequate and well-controlled studies in humans have not been done {06}.

Albuterol has been shown to be teratogenic in mice given doses equivalent to 14 times the human dose. Studies in mice given albuterol subcutaneously at doses comparable to 1.15, 11.5, and 115 times the maximum inhalation dose for a 50-kg human showed cleft palate formation in 0%, 4.5%, and 9.3% of fetuses, respectively. When rabbits were given oral albuterol at doses corresponding to 2315 times the maximum inhalation dose for a 50-kg human, cranioschisis occurred in 37% of their fetuses. {06}

FDA Pregnancy Category C. {06}



Bitolterol

Adequate and well-controlled studies in humans have not been done. {07}

No teratogenic effects were seen in rats and rabbits after administration of oral doses of bitolterol of up to 361 and 557 times the maximal daily human inhalation dose, or in mice after administration of oral doses of bitolterol of up to 188 and 284 times the maximal daily human inhalation doses, for the inhalation solution and the metered-dose inhaler, respectively. When bitolterol was injected subcutaneously into mice at doses of 2, 10, and 20 mg per kg of body weight, the incidence of cleft palate was 5.7%, 3.8%, and 3.3%, respectively. {07}

FDA Pregnancy Category C. {07}



Epinephrine

Adequate and well-controlled studies in humans have not been done. Epinephrine crosses the placenta and, although systemic concentrations are generally low following inhalation therapy, epinephrine usually should be avoided during pregnancy due to its alpha-adrenergic effects; safer and more effective beta 2-adrenergic bronchodilators are preferred. The Collaborative Perinatal Project monitored 189 mother-child pairs exposed to subcutaneous epinephrine during the first trimester as well as anytime during pregnancy. An association was found between first trimester use and the incidence of fetal malformations. An association was also found between use anytime during pregnancy and the incidence of inguinal hernia. Interpretation of these data is complicated in that the severity of the mother"s asthma may contribute to the effects on the fetus. {19} {37} {43}

Epinephrine has been shown to be teratogenic in rats when given systemically in doses of about 25 times the human dose. {08}

FDA Pregnancy Category C {110}.



Fenoterol

Adequate and well-controlled studies in humans have not been done. Direct blood and tissue studies in humans showed that the levels of fenoterol and its conjugates were 10 to 20 times lower in the fetus than in maternal tissues. {11}

Autoradiographic studies in pregnant rats showed no detectable amounts of fenoterol in the fetus. Direct blood and tissue studies in several animal species showed that levels of fenoterol and its conjugates were 10 to 20 times lower in the fetus than in maternal tissues. {11}

FDA Pregnancy Category B. {19}



Formoterol

Adequate and well-controlled studies in humans have not been done{117}.

In studies of rats given formoterol 0.004 to 1.2 mg/kg by inhalation, no undesirable effects on fetal development were observed{117}. However, maternal weight gain was greater in treated rats than in control rats and in proportion to dose. Also, a dose-related tachycardia was observed{117}.

In studies of rabbits given a range of dosages by oral gavage, no undesirable effects were observed at doses up to 3.5 mg/kg{117}. At 60 mg/kg (7000 to 11000 times the recommended human exposure), there was an increase in occurrence of fetal hepatic cysts{117}.



Isoetharine

Studies have not been done in humans. {12}

Studies have not been done in animals. {12}

FDA Pregnancy Category C. {12}



Isoproterenol

Adequate and well-controlled studies have not been done in humans. {13}

Studies performed in rats and rabbits at inhaled doses comparable to 15 times the human dose have not shown harm to the fetus. {13}

FDA Pregnancy Category B. {13}



Metaproterenol

Adequate and well-controlled studies in humans have not been done. {14}

Metaproterenol has been shown to be teratogenic and embryocidal in rabbits when given orally in doses comparable to 620 times the human inhalation dose. Effects included skeletal abnormalities and hydrocephalus with bone separation. Studies in mice, rats, and rabbits showed no teratogenic or embryocidal effects at doses corresponding to 310 times the recommended human inhalation dose. {14}

FDA Pregnancy Category C. {14}



Pirbuterol

Adequate and well-controlled studies in humans have not been done. {15}

Studies performed in rats and rabbits given inhaled pirbuterol at doses of up to 12 and 16 times the maximum human inhalation dose, respectively, showed no teratogenic effects. {15}

FDA Pregnancy Category C. {15}



Procaterol

Adequate and well-controlled studies have not been done in humans. {16}

Studies in rabbits and rats given large doses of inhaled procaterol showed no teratogenic or embryocidal effects. {16}



Salmeterol

Adequate and well-controlled studies have not been done in humans. {17}

In rats, maternal exposure to salmeterol at doses of up to approximately 160 times the recommended human clinical dose based on mg per square meter of body surface (mg/m 2) produced no significant effects. However, Dutch rabbit fetuses exposed to high concentrations of salmeterol in utero developed effects considered to be characteristic of beta-adrenergic stimulation (i.e., precocious eyelid openings, cleft palate, sternebral fusion, limb and paw flexures, and delayed ossification of the frontal cranial bones). No significant effects occurred at 12 times the recommended human clinical dose based on AUC comparisons. In New Zealand rabbits, exposure to oral doses approximately 1600 times the recommended human clinical dose based on mg/m 2 produced only delayed ossification of frontal bones. {17}

FDA Pregnancy Category C. {17}



Terbutaline

Adequate and well-controlled studies in humans have not been done. {18}

Studies in rats and mice at doses of up to 1042 times the human dose showed no teratogenic effects. {18}

FDA Pregnancy Category B. {18}



Labor and delivery—

Beta-adrenergic agonists have been shown to decrease uterine contractions when administered systemically. This effect is unlikely with inhaled beta-adrenergic bronchodilators. {63}

Breast-feeding

It is not known whether albuterol, bitolterol, epinephrine, fenoterol, formoterol, isoetharine, isoproterenol, metaproterenol, pirbuterol, procaterol, salmeterol, or terbutaline is distributed into the breast milk of humans. {06} {07} {11} {12} {13} {14} {15} {16} {17} {18}{117}

Salmeterol is distributed into the milk of lactating rats in concentrations similar to those in plasma. {17}

Formoterol, administered orally, is distributed into the milk of lacatating rats{117}{120}.

Pediatrics

Some children up to 5 years old may have difficulty using a metered dose or powder inhaler device correctly; therefore, use of an inhalation solution may be more appropriate. A spacer device is recommended for use with metered dose inhalers. {77}

Albuterol, bitolterol, epinephrine, isoproterenol, metaproterenol, pirbuterol, procaterol, salmeterol, and terbutaline—Use of these medications in children {20} {21} {22} {23} {39} {40} {70} {76} {77} {78} {79} has not demonstrated pediatrics-specific problems that would limit their usefulness.

Fenoterol—Appropriate studies on the relationship of age to the effects of fenoterol have not been performed in the pediatric population.

Formoterol—Appropriate studies on the relationship of age to the effects of formoterol have not been performed in children under 12 years of age{117}{120}.

Isoetharine—Use of isoetharine in children is not recommended {99}.


Geriatrics


Although not clearly proven, airway responsiveness to these medications may change with age. Additionally, older patients may also be more sensitive to the side effects of beta 2-agonists, including tremor and tachycardia, especially those with preexisting ischemic heart disease. {43}

Albuterol, bitolterol, epinephrine, fenoterol, isoetharine, isoproterenol, metaproterenol, pirbuterol, procaterol, and terbutaline—Appropriate studies on the relationship of age to the effects of these agents have not been performed in the geriatric population. However, no geriatric-specific problems have been documented to date.

Salmeterol—Clinical studies have been conducted in 241 patients 65 years of age and older. No apparent differences in the efficacy and safety of salmeterol were observed in these patients compared with younger patients. {17}

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: Because adrenergic bronchodilators produce low systemic concentrations following oral aerosol or powder inhalation when compared to serum concentrations following systemic administration, drug interactions known to occur with sympathomimetics as a class, especially with those possessing alpha-adrenoceptor activity, are unlikely to occur with use of albuterol, bitolterol, epinephrine, fenoterol, formoterol, isoetharine, isoproterenol, metaproterenol, pirbuterol, procaterol, salmeterol, or terbutaline at recommended doses.
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Beta-adrenergic blocking agents, ophthalmic    ( ophthalmic beta-adrenergic blocking agents are absorbed systemically via the nasolacrimal duct. Respiratory complications associated with the use of timolol have been reported and include bronchospasm, dyspnea, wheezing, decreased pulmonary function, and respiratory failure {106}; therefore, concurrent use may result in inhibition of the beta-adrenergic effects of the adrenergic bronchodilators and worsening of bronchospasm)


» Beta-adrenergic blocking agents, systemic    (concurrent use with adrenergic bronchodilators may result in mutual inhibition of therapeutic effects{117}{120}; beta-blockade may antagonize the bronchodilating effect of these bronchodilators; although antagonists with beta 1-selectivity may be less antagonistic, extreme caution is recommended if these agents are used in patients with bronchospasm because beta-adrenergic blocking agents may induce bronchospasm; use of a nonselective beta-blocking agent also allows for alpha-adrenergic receptor stimulation when epinephrine is administered, which may result in increased vascular resistance when epinephrine aerosol is used in higher-than-recommended doses {73})


Corticosteroids{120},
Diuretics, non potassium-sparing, or{118}
Methylxanthines{120}    (concomitant treatment with corticosteroids, xanthine derivatives, or diuretics may potentiate a possible hypokalemic effect of formoterol, especially in patients with severe asthma)


» Disopyramide
» Quinidine
» Phenothiazines
» Procainamide    (can prolong the QTc-interval and increase the risk of ventricular arrhythmia when used with formoterol{117}{120})


Monoamine oxidase inhibitors or
Tricyclic antidepressants    (the action of salmeterol on the vascular system may be potentiated by these agents; caution should be used with concurrent administration or when salmeterol is given within 2 weeks of discontinuing these agents{118}{119}. Concomitant treatment with formoterol can prolong the QTc-interval and increase the risk of ventricular arrhythmia{117}{120})



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    (transient ventricular premature contractions, atrial arrhythmia, inverted T waves, junctional rhythm, and prolongation of the QTc interval are reported rarely with adrenergic bronchodilators {07} {18}; effects may be more pronounced following nebulization, frequent use of higher doses or an overdose, or with use of fenoterol {17} {67}; arrhythmias may also result from hypoxia or hypokalemia {62})


Glucose, blood    (concentrations may be increased, possibly due to glycogenolysis; clinically significant changes may be more pronounced following nebulization or with frequent use of higher doses or an overdose {69}{120})


Potassium, serum    (concentrations may be decreased, possibly through intracellular shunting; the decrease is dose-related, is usually transient, and may not require supplementation; effects may be more pronounced following nebulization, frequent use of higher doses or an overdose, or use of fenoterol {67} {68} {69} {92})


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
Allergy to lactose or milk    (formoterol powder for inhalation contains lactose{117}{120})


Cardiac arrhythmias or
» Coronary insufficiency    (rarely, inhaled adrenergic bronchodilators, especially epinephrine , may make these conditions worse {03} {06} {17} {102}. Formoterol is contraindicated in patients with tachyarrhythmias{117}{120})


Hypertension, not optimally controlled    (rarely, inhaled epinephrine may make this condition worse {03})


Hyperthyroidism, not optimally controlled, or
Pheochromocytoma, diagnosed or suspected    (signs or symptoms of excessive beta-adrenergic stimulation are more likely to occur {06} {17})


» Sensitivity to an adrenergic bronchodilator
» Sensitivity to sulfites contained in some isoetharine, isoproterenol, and racepinephrine solutions for inhalation

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Pulmonary function monitoring    (objective measures of lung function are essential for diagnosis and for guiding therapeutic decision-making in the treatment of asthma; measurement of forced expiratory airflow, using a spirometer or a peak expiratory flowmeter, is recommended at periodic intervals {43}{117}{120})




Side/Adverse Effects

Note: The side effects of aerosolized adrenergic bronchodilators are due primarily to systemic absorption of the medication, which is limited with usual doses. Higher doses or administration via nebulization is more likely to be associated with side effects than are lower doses. {68} {90}
Fatalities have been reported in association with excessive use of inhaled sympathomimetics. The exact cause of death is unknown. Whether the fatalities are associated with disease severity, substandard quality of care, and/or patient noncompliance has not been established. {80} {89}
For side effects more commonly seen with an overdose, see the Overdose section of this monograph.

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
    
Bronchospasm, paradoxical or hypersensitivity-induced (shortness of breath; troubled breathing; tightness in chest; wheezing)
    
dermatitis, hypersensitivity-induced (angioedema [swelling of face, lips, or eyelids] ; skin rash; urticaria [hives])
    
laryngeal spasm, irritation, or swelling (feeling of choking)— with salmeterol {17}
    
sensitivity reaction to sulfites (chest pain; dizziness, severe, or feeling faint; flushing or redness of skin, continuing ; skin rash, hives, or itching; swelling of face, lips, or eyelids; wheezing or difficulty in breathing )—for isoetharine, isoproterenol, and racepinephrine inhalation solutions containing sulfites {83}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Fast heartbeat {06} {07} {11} {16} {17} {18}
    
headache {06} {07} {11} {14} {15} {16} {17} {18}
    
nervousness {06} {07} {11} {14} {15} {16} {17} {18}
    
trembling {06} {07} {11} {14} {15} {16} {17} {18}

Incidence less frequent
    
Coughing or other bronchial irritation {06} {07} {11} {14} {15} {17}
    
dizziness or light-headedness {06} {07} {11} {14} {15} {18}
    
dryness or irritation of mouth or throat {06} {07} {14}

Incidence rare
    
Chest discomfort or pain {07} {15} {16} {18}
    
drowsiness or fatigue (weakness)
    
hypokalemia
    
increase in blood pressure —with epinephrine {02} {06} {14} {17} {18}
    
irregular heartbeat {06} {07} {11} {14} {15} {16} {17} {18}
    
muscle cramps or twitching {06} {17}
    
nausea and/or vomiting {06} {07} {11} {14} {15} {16} {17} {18}
    
oropharyngeal irritation {122}{123}(irritation of throat or mouth)
    
restlessness {06} {07} {11} {16}
    
trouble in sleeping {07} {18}



Those not indicating need for medical attention
Incidence more frequent
    
Pinkish to red coloration of saliva —with isoproterenol {13}

Incidence less frequent
    
Taste changes {07} {11} {14} {15} {18}





Overdose
Although uncommon, fatalities have been reported in association with excessive use of inhaled sympathomimetics. The exact cause of death is unknown. Whether the fatalities are associated with disease severity, substandard quality of care, and/or patient noncompliance has not been established. {80} {89}

For specific information on the agents used in the management of adrenergic bronchodilator overdose, see:    • Beta-adrenergic Blocking Agents (Systemic) monograph.


For more information on the management of overdose, contact a Poison Control Center (see Poison Control Center Listing).

Clinical effects of overdose

Note: The following effects are more likely to occur following oral or parenteral overdose with an adrenergic bronchodilator {55}; however, they may occur following overdose via inhalation, if sufficient systemic concentrations of medication are achieved.

The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute overdose
More common
    
Hyperglycemia {55}
    
hypokalemia {55}
    
hypotension {55}(dizziness or lightheadedness )
    
lactic acidosis {55}
    
tachycardia {55}(fast heartbeat, continuing)
    
trembling, continuing {55}
    
vomiting {55}

Less common
    
Agitation {55}
    
chest pain {55}— with epinephrine
    
headache {55}—with epinephrine
    
hypercalcemia {55}
    
hypertension —with epinephrine
    
hypophosphatemia {55}
    
leukocytosis {55}
    
peripheral vasoconstriction {55}—with epinephrine
    
respiratory alkalosis {55}

Rare
    
Hallucinations {55}—with nebulized albuterol
    
paranoia {55}— with nebulized albuterol
    
seizures {55}
    
tachyarrhythmias {55}(fast and irregular heartbeat, continuing)


Chronic overdose
More common
    
Hypotension (dizziness or lightheadedness){55}
    
tachycardia (fast heartbeat, continuing)
    
trembling, continuing {55}
    
vomiting {55}

Less common
    
Agitation {55}
    
chest pain {55}— with epinephrine
    
headache {55}—with epinephrine
    
hypertension {55}—with epinephrine
    
peripheral vasoconstriction {55}— with epinephrine

Rare
    
Seizures {55}
    
tachyarrhythmias {55}(fast and irregular heartbeat, continuing)



Treatment of overdose


Specific treatment:
Therapy with any adrenergic bronchodilator should be stopped. {55}

For tachyarrhythmias—Administering a cardioselective beta-adrenergic blocking agent, if necessary; however, caution is needed because beta-adrenergic blocking agents can induce bronchospasm. {55}



Monitoring:
Monitoring the patient carefully, especially for cardiovascular status.



Supportive care:
Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric evaluation.



Patient Consultation

Note: Bitolterol was withdrawn from the market by Elan Pharmaceuticals in November 2001.

As an aid to patient consultation, refer to Advice for the Patient, Bronchodilators, Adrenergic (Inhalation) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to sympathomimetics or sulfites contained in some isoetharine, isoproterenol, and racepinephrine solutions for inhalation

Allergy to lactose contained in formoterol powder for inhalation

Pregnancy—Use of epinephrine is generally avoided
Other medications, especially beta-adrenergic blocking agents, disopyramide, quinidine, phenothiazines, and procainamide
Other medical problems, especially cardiovascular disease

Proper use of this medication

For all adrenergic bronchodilators
» Reading patient instructions carefully before using

» Importance of not using more medication than prescribed

» Proper dosing

Missed dose: If used regularly, using as soon as possible; resuming regular schedule; not doubling doses

» Proper storage

For formoterol and salmeterol
» Importance of not using this medication to treat acute symptoms

» Having a rapid-acting inhaled beta-adrenergic bronchodilator available for symptomatic relief of acute asthma attacks

» Not using more than two times a day or less than 12 hours apart

» Missed dose: If used regularly, using as soon as possible; resuming regular schedule; not doubling doses; using rapid-acting inhaled bronchodilator if symptoms occur before next dose is due

For epinephrine
Not self-medicating without a diagnosis of asthma and follow-up by a physician, or unless directed by a physician if previously hospitalized for asthma; if taking a prescription drug for asthma, not using unless told to do so by physician

For inhalation aerosol dosage form
Avoiding contact with the eyes

Testing or priming inhaler before using first time if required

Proper administration technique

Technique for using spacer with inhaler

Proper cleaning procedure for inhaler

Saving inhaler, refill canister may be available

For powder for inhalation dosage form
Knowing correct administration technique for using inhaler

For inhalation solution dosage form
Knowing correct administration technique for using in a nebulizer

Not using if solution is discolored or cloudy

Not mixing with another inhalation solution in nebulizer unless directed

Precautions while using this medication

For all adrenergic bronchodilators
Regular visits to physician to check progress during therapy

» Checking with physician immediately if difficulty in breathing persists after use of this medication or if condition becomes worse

» For patients also using anti-inflammatory medication, checking with physician before stopping or reducing anti-inflammatory therapy {17}

For salmeterol
» Checking with physician if using four or more inhalations per day of a rapid-acting beta-adrenergic bronchodilator for two or more consecutive days or more than one canister (200 inhalations per canister) in an eight-week period {17}{118}{119}

For albuterol, bitolterol, epinephrine, fenoterol, isoetharine, isoproterenol, metaproterenol, pirbuterol, procaterol, and terbutaline
» Checking with physician immediately if more inhalations than usual of a rapid-acting beta-adrenergic bronchodilator are needed to relieve an acute attack

» If not using anti-inflammatory medication: checking with physician if using a rapid-acting beta-adrenergic bronchodilator to relieve symptoms more than two times per week {43}

» If using anti-inflammatory medication: checking with physician if using more than one canister per month of a rapid-acting beta-adrenergic bronchodilator to relieve symptoms


Side/adverse effects
Signs of potential side effects, especially laryngeal spasm, irritation, or swelling, paradoxical bronchospasm or hypersensitivity


General Dosing Information
For emergency department and hospital treatment of acute, severe bronchospasm associated with asthma, inhaled short-acting beta 2-agonist therapy using the higher dose and administered either as three treatments within the first hour or by continuous nebulization is recommended. Studies have shown that administration of high doses (6 to 12 puffs) of a short-acting beta 2-agonist via metered-dose inhaler with a spacer can produce equivalent bronchodilation when compared with nebulizer therapy {43} {60}. For outpatient management of an asthma exacerbation, two to four puffs of a short-acting beta 2-adrenergic bronchodilator via metered-dose inhaler every 20 minutes, for up to 1 hour if needed, or a single dose via nebulization is recommended as initial treatment {43}.

The use of a spacer device with many adrenergic bronchodilators may be beneficial, especially for young children and older adults. By reducing the need for proper coordination of timing of inhalation with activation of the inhaler and reducing the velocity and mean diameter of the aerosol particles, a spacer reduces the amount of medication deposited in the upper airways and increases the amount deposited in the lower respiratory tract {43} in patients with poor technique.

For dilution of adrenergic bronchodilator solutions for inhalation, only products that do not contain benzyl alcohol {84}, preferably preservative-free products, should be used.

A metered-dose inhaler (MDI) should be primed before it is used for the first time or if it has not recently been used. The amount of medication in a dose from a MDI product may depend on how much time has elapsed since the preceding dose {86} {87} and the position in which the inhaler has been stored {87}. One study found that the medication content of single sprays of albuterol MDI ranged between 23 and 208% of the label claim. Additionally, this study suggests that initial sprays from a new canister contain higher albuterol content than the final sprays from the same canister. Single, unprimed doses (doses taken 4 hours or more after the last spray) from canisters stored in the upright position and activated after 4 or 16 hours averaged a higher medication content than single, unprimed doses from canisters stored with the valve down. Primed sprays (those sprays that were taken within minutes of a previous spray), whether stored with the valve up or valve down, contained a mean of 92% of labeled medication content of single sprays of albuterol MDI. {87} Specific information about when to prime an inhaler, other than the first time it is used, as well as the number of sprays that should be performed, remains to be defined. For salmeterol, the recommendation is to prime the inhaler if it has not been used for 4 weeks or longer {17}, and that four priming sprays should be performed. {118}

The contents of metered dose inhalers should generally not be floated in water to assess the contents since this method may not reliably predict the amount of medication remaining in the canister. A record should be kept of the number of inhalations used. {17} {85}

It is not clear whether clinically significant tachyphylaxis or tolerance to the bronchodilator effects of rapid-acting beta-adrenergic bronchodilators develops with repeated use. {80} {81} For longer-acting salmeterol, a 12-month study demonstrated that regular use does not lead to a loss of bronchodilatory effect {32}. Decreased bronchoprotection was reported in one 8-week study in which the effects of salmeterol on bronchodilation and on airway hyperresponsiveness to methacholine were studied in a small number of asthmatics. {82} In another study, duration of salmeterol"s protective effect against exercise-induced bronchospasm, another potential marker of tolerance, decreased over a 4-week period in some patients. {17} Systemic administration of corticosteroids has been shown to alter beta 2-receptor function on lymphocytes to prevent and reverse tolerance; however, the effect of inhaled or systemic corticosteroids on changes in bronchodilator responses in asthmatics is less clear. There is some evidence that inhaled corticosteroids are unable to prevent tolerance to long-acting beta 2-agonists. {81}

As a way to protect the stratospheric ozone layer, the manufacture of chlorofluorocarbons (CFCs) is being phased out. The 1987 Montreal Protocol, an international treaty that is enforced in the U.S. by the Clean Air Act, banned CFC use as of January 1, 1996. CFC-containing inhalers have been granted a temporary exemption so that alternative propellants can be developed.

ALBUTEROL


Additional Dosing Information
See also General Dosing Information .

Bioequivalence information
Unless a generic albuterol metered-dose inhaler has proven bioequivalence, one product should not be substituted for another without the concurrence of the prescribing physician. Generic albuterol metered-dose inhalers distributed by Zenith Goldline and Dey Laboratories may be substituted for Ventolin {115} {116}. The generic product distributed by Warrick Pharmaceuticals may only be substituted for Proventil {57}.


Inhalation Dosage Forms

Note: The doses and strengths of the available dosage forms are expressed in terms of albuterol (not the sulfate salt).

Note: Bracketed used in the Dosage Forms section refers to categories of use and/or indications that are not included in the U.S. product labeling.


ALBUTEROL INHALATION AEROSOL

Note: Unless a generic albuterol metered-dose inhaler has proven bioequivalence, one product should not be substituted for another without the concurrence of the prescribing physician. Generic albuterol metered-dose inhalers distributed by Zenith Goldline and Dey Laboratories may be substituted for Ventolin {115} {116}. The generic product distributed by Warrick Pharmaceuticals may only be substituted for Proventil {57}.


Usual adult and adolescent dose
Bronchodilator
Oral inhalation, 2 inhalations (180 or 200 mcg albuterol) every four to six hours. For some patients, 1 inhalation (90 or 100 mcg) every four hours may be sufficient. {06}
{126}
Bronchospasm, exercise-induced (prophylaxis)
Oral inhalation, 2 inhalations (180 or 200 mcg) fifteen minutes prior to exercise {06} {74}.


Usual pediatric dose
Bronchodilator
Children up to 4 years of age: Dosage has not been established. {06}

Children 4 years of age and over: See Usual adult and adolescent dose . {06}
{126}
Bronchospasm, exercise-induced (prophylaxis)
Children up to 4 years of age: Dosage has not been established.

Children 4 years of age and over: See Usual adult and adolescent dose .

[Hyperkalemia ]1
For patients weighing less than 25 kg: Oral inhalation, 2.5 mg. {130}{131}{132}{133}{134}{135}{136}{137}{138}

For patients weighing 25 kg or more: Oral inhalation, 5 mg.{130}{131}{132}{133}{134}{135}{136}{137}{138}


Strength(s) usually available
U.S.—


90 mcg albuterol per metered spray (Rx) [Proventil (dichlorodifluoromethane ) (trichloromonofluoromethane) ( oleic acid)] [Ventolin (dichlorodifluoromethane) (trichloromonofluoromethane ) (oleic acid)]

Canada—


100 mcg albuterol per metered spray (Rx) [Apo-Salvent] [Novo-Salmol] [Ventolin]

Note: In Canada, metered dose inhalers are labeled according to the amount of medication delivered from the valve; in the U.S., metered dose inhalers are labeled according to the amount of medication delivered at the mouthpiece or actuator.


Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

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

Note:  Include patient instructions when dispensing.



ALBUTEROL SULFATE INHALATION AEROSOL

Usual adult and adolescent dose
Bronchodilator
Oral inhalation, 2 inhalations (180 mcg albuterol) every four to six hours. For some patients, 1 inhalation (90 mcg) every four hours may be sufficient. {109}{124}{125}

Bronchospasm, exercise-induced (prophylaxis)
Oral inhalation, 2 inhalations (180 mcg albuterol) fifteen to thirty minutes prior to exercise {124}{125} .


Usual pediatric dose
Bronchodilator
Children up to 4 years of age: Dosage has not been established.

Children 4 years of age and over: See Usual adult and adolescent dose . {109}{124}{125}

Bronchospasm, exercise-induced (prophylaxis)
Children up to 4 years of age: Dosage has not been established.

Children 4 years of age and over: See Usual adult and adolescent dose.{124}{125}


Strength(s) usually available
U.S.—


90 mcg (albuterol) per metered spray [Proventil HFA (CFC-free ) (hydrofluoroalkane-134a [1,1,1,2 tetrafluoroethane] ) (oleic acid) (ethanol )]


90 mcg (albuterol) per metered spray [Ventolin HFA (CFC-free) (hydrofluoroalkane-134a [1,1,1,2 tetrafluoroethane])]

Canada—
Not commercially available.

Packaging and storage:
Store between 15 and 25 °C (59 and 77 °F) {109}.

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

Note:  Include patient instructions when dispensing.



ALBUTEROL SULFATE INHALATION SOLUTION

Usual adult and adolescent dose
Bronchodilator
Oral inhalation, administered by nebulization, 2.5 mg (albuterol), delivered over approximately five to fifteen minutes, repeated every four to six hours. {06}


Usual pediatric dose
Bronchodilator
Neonates and infants: Oral inhalation, administered by nebulization, 0.05 to 0.15 mg (albuterol) per kg of body weight delivered over approximately five to fifteen minutes, repeated every four to six hours. {99}

Children up to 12 years of age: Oral inhalation, administered by nebulization, 1.25 to 2.5 mg delivered over approximately five to fifteen minutes, repeated every four to six hours if necessary. {99}

Children 12 years of age and over: See Usual adult and adolescent dose . {06}


Strength(s) usually available
U.S.—


0.83 mg (albuterol) per mL (Rx) [Airet] [Proventil (benzalkonium chloride)] [Ventolin Nebules]


5 mg (albuterol) per mL (Rx) [Proventil (benzalkonium chloride )] [Ventolin (benzalkonium chloride)]

Canada—


0.5 mg (albuterol) per mL (Rx) [Ventolin Nebules P.F.]


1 mg (albuterol) per mL (Rx) [Gen-Salbutamol Sterinebs P.F.] [Ventolin Nebules P.F.]


2 mg (albuterol) per mL (Rx) [Gen-Salbutamol Sterinebs P.F.] [Ventolin Nebules P.F.]


5 mg (albuterol) per mL (Rx) [Apo-Salvent (benzalkonium chloride)] [Ventolin (benzalkonium chloride)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Preparation of dosage form:
For preparation of the inhalation solution, diluents containing benzyl alcohol or preservatives other than benzalkonium chloride are not recommended since the safety of these preservatives has not been established for inhalation therapy.

The 0.5-, 0.83-, 1-, and 2-mg-per-mL solutions do not require dilution prior to administration. The 5-mg-per-mL solution is concentrated and must be diluted in 2.5 mL of sterile 0.9% sodium chloride solution prior to administration. {06}

Stability:
Albuterol inhalation solution is compatible with cromolyn and ipratropium inhalation solutions for up to 1 hour. {101} {103}

Auxiliary labeling:
For oral inhalation only.

Note: Include patient instructions when dispensing.



ALBUTEROL SULFATE POWDER FOR INHALATION

Usual adult and adolescent dose
Bronchodilator
Oral inhalation, 200 or 400 mcg every four to six hours. {06}

Bronchospasm, exercise-induced (prophylaxis)
Oral inhalation, 200 mcg, fifteen minutes before exercise. {06}


Usual pediatric dose
Bronchodilator
Children up to 4 years of age: Dosage has not been established. {06}

Children 4 years of age and over: See Usual adult and adolescent dose . {06}


Strength(s) usually available
U.S.—


200 mcg per capsule (Rx) [Ventolin Rotacaps (lactose)]

Canada—


200 mcg per blister or capsule (Rx) [Ventodisk] [Ventolin Rotacaps (lactose)]


400 mcg per blister or capsule (Rx) [Ventodisk] [Ventolin Rotacaps (lactose)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • For oral inhalation only.

Note: Include patient instructions when dispensing.
Use of albuterol powder for inhalation requires a special device that separates the capsule into halves or pierces the blister and releases the medication.



BITOLTEROL

Note: Products containing bitolterol were withdrawn from the U.S. market by the manufacturer in November 2001.{129}


Summary of Differences
Pharmacology/pharmacokinetics: Biotransformation—A prodrug hydrolyzed by esterases in tissue and blood to the active compound colterol.


Inhalation Dosage Forms

Note: Bracketed uses refer to categories of use and/or indications that are not included in U.S. product labeling.

BITOLTEROL MESYLATE INHALATION AEROSOL

Usual adult and adolescent dose
Bronchodilator
Oral inhalation, 2 inhalations (740 mcg) every eight hours, or 2 inhalations (740 mcg) administered at least one to three minutes apart, followed by 1 additional inhalation (370 mcg) if needed. Dosage per day should not exceed 2 inhalations (740 mcg) every four hours or 3 inhalations (1.11 mg) every six hours. {07}

[Bronchospasm, exercise-induced (prophylaxis)]
Oral inhalation, 2 inhalations (740 mcg) five minutes prior to exercise. {43}


Usual pediatric dose
Bronchodilator
See Usual adult and adolescent dose {43}.

[Bronchospasm, exercise-induced (prophylaxis)]
Oral inhalation, 1 or 2 inhalations (370 or 740 mcg) five minutes prior to exercise. {43}


Strength(s) usually available
U.S.—
Not commercially available.

Note: Withdrawn from the U.S. market in November 2001.{129}


Canada—
Not commercially available.

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F) {07}.

Auxiliary labeling:
   • For oral inhalation only.

Note: Include patient instructions when dispensing.



BITOLTEROL MESYLATE INHALATION SOLUTION

Usual adult and adolescent dose
Bronchodilator
Oral inhalation:

Continuous flow nebulization—2.5 milligrams (mg) (range, 1.5 to 3.5 mg), diluted and delivered over ten to fifteen minutes, three to four times per day, not less than four hours apart. {07}

Intermittent flow nebulization—1 milligram (mg) (range, 0.5 to 1.5 mg), diluted and delivered over ten to fifteen minutes, three to four times per day, not less than four hours apart. {07}


Usual adult and adolescent prescribing limits
The maximum daily dose should not exceed 8 mg with intermittent flow nebulization or 14 mg with continuous flow nebulization. {07}

Usual pediatric dose
Children up to 12 years of age: Dosage has not been established. {07}

Children 12 years of age and over: See Usual adult and adolescent dose . {07}

Strength(s) usually available
U.S.—
Not commercially available.

Note: Withdrawn from the U.S. market in November 2001.{129}


Canada—
Not commercially available.

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F) {07}.

Preparation of dosage form:
Bitolterol inhalation solution should be diluted to 2 to 4 mL with sterile 0.9% sodium chloride solution. {07}

Stability:
Bitolterol inhalation solution should not be mixed with other medications, such as cromolyn sodium or acetylcysteine, at clinically recommended doses due to chemical and/or physical incompatibilities. {07}


EPINEPHRINE

Summary of Differences


Indications:
Epinephrine and racepinephrine inhalation also indicated in treatment of postintubation and infectious croup.



Pharmacology/pharmacokinetics:
Epinephrine also has alpha- and beta 1-adrenergic receptor action.

Duration of action: Short-acting.



Pregnancy:
Not recommended during pregnancy because of alpha-adrenergic agonist activity.



Medical considerations/contraindications:
May worsen heart conditions or hypertension.



Inhalation Dosage Forms

Note: The doses and strengths of the available dosage forms are expressed in terms of epinephrine (not the bitartrate or chloride salt).
Effective June 19, 1996, the Food and Drug Administration amended the final monograph for over-the-counter bronchodilator products by removing pressurized metered-dose aerosol inhaler dosage forms containing epinephrine and epinephrine bitartrate. Initial introduction of such a product now requires an application for approval of safety and efficacy. Products that are currently marketed contain a chlorofluorocarbon (CFC) propellant and will be phased out when the temporary exemption for CFCs expires. {108}


EPINEPHRINE INHALATION AEROSOL USP

Usual adult and adolescent dose
Bronchodilator
Oral inhalation, 1 inhalation (200 to 275 mcg), repeated after at least one minute, if necessary; subsequent dose(s) should not be administered for at least three hours. {02}


Usual pediatric dose
Bronchodilator
Children up to 4 years of age: Dosage must be individualized by physician. {02}

Children 4 years of age and over: See Usual adult and adolescent dose . {02}


Strength(s) usually available
U.S.—


0.125% (OTC)


0.5% (200 mcg per metered spray) (OTC)


0.5% (220 mcg per metered spray) (OTC) [Primatene Mist ( alcohol 34%) (fluorocarbons)]


0.5% (250 mcg per metered spray) (OTC) [Bronkaid Mist ( alcohol 33%) (dichlorodifluoromethane) (dichlorotetrafluoroethane)]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.


EPINEPHRINE INHALATION SOLUTION USP

Usual adult and adolescent dose
Bronchodilator
Oral inhalation, 10 drops administered by hand-bulb nebulizer, 1 to 3 inhalations. Doses should not be repeated more often than every three hours. {03}


Usual pediatric dose
Bronchodilator
Children up to 4 years of age: Dosage must be individualized by physician. {03}

Children 4 years of age and over: See Usual adult and adolescent dose . {03}


Strength(s) usually available
U.S.—


1% (epinephrine) (OTC) [Adrenalin Chloride (benzethonium chloride ) (sodium bisulfite)]

Canada—
Not commercially available.

Note: The solution intended for oral inhalation is more concentrated than those intended for injection and is not to be given parenterally. {03}


Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer, in a tight, light-resistant container.

Stability:
When exposed to air, the solution will turn pinkish to brownish in color because of oxidation. Also, light, heat, alkalies, and certain metals (for example, copper, iron, zinc) may promote deterioration. Do not use if solution is pinkish to brownish in color or contains a precipitate. {03}

Auxiliary labeling:
   • For oral inhalation only.


EPINEPHRINE BITARTRATE INHALATION AEROSOL USP

Usual adult and adolescent dose
Bronchodilator
Oral inhalation, 1 inhalation (160 mcg epinephrine) repeated after one minute, if necessary; subsequent dose(s) should not be administered for at least three hours. {72}


Usual pediatric dose
Bronchodilator
Children up to 4 years of age: Dosage must be individualized by physician {72}.

Children 4 years of age and over: See Usual adult and adolescent dose {72}.


Strength(s) usually available
U.S.—


300 mcg (160 mcg [epinephrine]) per metered spray (OTC) [Asthmahaler Mist (dichlorodifluoromethane) (dichlorotetrafluoroethane ) (trichloromonofluoromethane)] [Bronkaid Suspension Mist]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.


RACEPINEPHRINE INHALATION SOLUTION USP

Usual adult and adolescent dose
Bronchodilator
Oral inhalation, administered by hand-bulb nebulization, 0.5 mL (approximately 10 drops) to provide 1 to 3 inhalations, repeated after three hours if necessary. {10}

Oral inhalation, administered by jet nebulization, 0.2 {88} to 0.5 mL {10} (approximately 4 to 10 drops) of diluted solution, delivered over approximately fifteen minutes, repeated every three or four hours. {10} {88}


Usual pediatric dose
Bronchodilator
Children up to 4 years of age: Dosage must be individualized by physician. {10}

Children 4 years of age and over: See Usual adult and adolescent dose . {10}

Croup
Oral inhalation, administered by nebulization, 0.05 mL per kg of body weight, diluted to 3 mL with 0.9% sodium chloride solution, delivered over approximately fifteen minutes, repeated not more frequently than every two hours, if needed {99}.


Usual pediatric prescribing limits
Croup
0.5 mL per dose {99}.


Strength(s) usually available
U.S.—


2% (OTC) [Vaponefrin (sodium metabisulfite) ( chlorobutanol) (benzoic acid) ( glycerin)]


2.25% (epinephrine) (OTC) [AsthmaNefrin (sodium bisulfite ) (benzoic acid) (chlorobutanol )] [microNefrin (sodium bisulfite) (potassium metabisulfite ) (chlorobutanol) (benzoic acid) (propylene glycol)] [Nephron] [S-2 (sodium bisulfite) ( potassium metabisulfite) (chlorobutanol) (benzoic acid) (propylene glycol)]

Canada—


2.25% (epinephrine) (OTC) [Vaponefrin (sodium metabisulfite )]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer, in a tight, light-resistant container.

Preparation of dosage form:
If administered via hand-bulb nebulizer, racepinephrine inhalation solution does not require dilution; however, if administered via jet nebulizer, it should be diluted to a volume of 3 {10} to 5 mL {88} with sterile 0.9% sodium chloride solution. {10} {88}

Stability:
When exposed to air, the solution will turn pinkish to brownish in color because of oxidation. Also, light, heat, alkalies, and certain metals (for example, copper, iron, zinc) may promote deterioration. Do not use if solution is pinkish to brownish in color or contains a precipitate. {10}


FENOTEROL


Inhalation Dosage Forms

FENOTEROL HYDROBROMIDE INHALATION AEROSOL

Usual adult and adolescent dose
Bronchodilator
Oral inhalation, 2 inhalations (100 or 200 mcg), three to four times a day, if necessary, but not to be administered more often than every four hours. Dosage should not exceed 8 inhalations of the 100 mcg per metered spray formulation or 6 inhalations of the 200 mcg per metered spray formulation per day. {11}


Usual pediatric dose
Bronchodilator
Children up to 12 years of age: Dosage has not been established {11}.

Children 12 years of age and over: See Usual adult and adolescent dose {11}.


Strength(s) usually available
U.S.—
Not commercially available.

Canada—


100 mcg per metered spray (Rx) [Berotec (monofluorotrichloromethane ) (dichlorotetrafluoroethane) ( dichlorodifluoromethane)]


200 mcg per metered spray (Rx) [Berotec (monofluorotrichloromethane ) (dichlorotetrafluoroethane) ( dichlorodifluoromethane)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

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

Note: Include patient instructions when dispensing.



FENOTEROL HYDROBROMIDE INHALATION SOLUTION

Usual adult and adolescent dose
Bronchodilator
Oral inhalation, administered via nebulization, 0.5 mg to 1 mg (up to 2.5 mg in some cases) of diluted solution, delivered over ten to fifteen minutes. Dosage may be repeated every six hours, if necessary. {11}


Usual pediatric dose
Bronchodilator
Children up to 12 years of age: Dosage has not been established {11}.

Children 12 years of age and over: See Usual adult and adolescent dose {11}.


Strength(s) usually available
U.S.—
Not commercially available.

Canada—


1 mg per mL (Rx) [Berotec (benzalkonium chloride)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer.

Preparation of dosage form:
Fenoterol inhalation solution should be diluted to 5 mL with sterile 0.9% sodium chloride solution. {11}

Auxiliary labeling:
   • For oral inhalation only.


FORMOTEROL

Summary of Differences


Indications:
Indicated for long-term treatment of asthma in patients 5{128} years of age and older with reversible obstructive airways, including patients with symptoms of nocturnal asthma, who are receiving corticosteroid treatment and who experience regular or frequent exacerbations of symptoms that require use of a short-acting bronchodilator{117}{120}. Formoterol is not indicated for the treatment of acute bronchospasm{117}{120}. Formoterol treatment should not be initiated in patients with significantly worsening or acutely deteriorating asthma (rapid worsening over hours or days){117}{120}.

Corticosteroids should not be stopped when formoterol is prescribed.{117}{120}



Pharmacology/pharmacokinetics:
Onset of action—1 to 3 minutes{120}

Duration of action—Long-acting (12 hours){117}{120}



Inhalation Dosage Forms

FORMOTEROL FUMARATE DIHYDRATE POWDER FOR INHALATION

Usual adult and adolescent dose
Bronchodilator
Oral inhalation, 12 micrograms (mcg) two times a day, morning and evening, approximately 12 hours apart{117}{120}{128}.

Note: Canadian product information states that some patients may need up to 24 mcg every 12 hours. {127}



Adult and adolescent dosing limits
Bronchodilator
Adults: Not to exceed 24 mcg a day {128}
Note: Canadian product information states that up to 24 mcg twice daily can be prescribed. {127}



Adolescents: Not to exceed 24 mcg a day{117}{120}.


Usual pediatric dose
Children 5 years and older : See Usual adult and adolescent dose.

Safety and efficacy in children under 5 years of age not established{128}.

Note: Canadian product information states that in children 6 years of age and older: See Usual adult and adolescent dose{127}


Strength(s) usually available
U.S.—


12 mcg per metered dose (Rx) [Foradil ( lactose)]{128}

Canada—


6 micrograms (mcg) per inhalation{117} (Rx) [Oxeze Turbuhaler (The rotating knob of the Turbuhaler is light turquoise) (lactose)]


12 micrograms (mcg) per inhalation (Rx) [Oxeze Turbuhaler Foradil (The rotating knob of the Turbuhaler is dark turquoise ) (lactose)]


12 micrograms (mcg) per capsule for inhalation (Rx) [Foradil (lactose)]{127}

Packaging and storage:
Prior to dispensing— store in a refrigerator, 2° to 8°C (36° to 46°F) {128}

After dispensing to patient— store at 20° to 25°C (68° to 77°F) {128}

Note: Canadian product information states to store between 15 and 25 °C {127}


Auxiliary labeling:
   • For oral inhalation only
   • Protect from heat and moisture{117}{128}


ISOETHARINE

Summary of Differences
Pharmacology/pharmacokinetics: Duration of action—short-acting.

Precautions: Pediatrics—Use in children not recommended.


Inhalation Dosage Forms

ISOETHARINE INHALATION SOLUTION USP

Usual adult dose
Bronchodilator
Oral inhalation, administered via nebulization, 2.5 to 10 mg, delivered over approximately fifteen to twenty minutes, repeated every four hours, if needed. {12}


Usual pediatric dose
Use is not recommended. {99}

Strength(s) usually available
U.S.—


0.062% (HCl) (Rx) [Arm-a-Med Isoetharine]


0.08% (Rx) [Dey-Lute Isoetharine]


0.1% (Rx) [Dey-Lute Isoetharine]


0.125% (Rx) [Arm-a-Med Isoetharine]


0.167% (Rx) [Arm-a-Med Isoetharine]


0.17% (Rx) [Dey-Lute Isoetharine]


0.2% (Rx) [Arm-a-Med Isoetharine]


0.25% (Rx) [Arm-a-Med Isoetharine] [Dey-Lute Isoetharine]


1% (Rx) [Beta-2 (sodium bisulfite)] [Bronkosol (acetone sodium bisulfite) (glycerin) ( parabens) (sodium chloride) ( sodium citrate)]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer, in a tight, light-resistant container.

Preparation of dosage form:
For preparation of the inhalation solution, diluents containing benzyl alcohol or preservatives other than benzalkonium chloride are not recommended since the safety of these preservatives has not been established for inhalation therapy.

The 0.062 to 0.25% solutions do not require dilution prior to administration. The 1% solution is concentrated and must be diluted with 1 to 4 mL of sterile 0.9% sodium chloride solution prior to administration.

Stability:
Do not use if solution is pinkish or darker than slightly yellow in color or if it contains a precipitate. {12}

Auxiliary labeling:
   • For oral inhalation only.


ISOETHARINE MESYLATE INHALATION AEROSOL USP

Usual adult and adolescent dose
Bronchodilator
Oral inhalation, 1 or 2 inhalations (340 or 680 mcg) repeated every four hours as needed. {75}


Usual pediatric dose
Use is not recommended. {99}

Strength(s) usually available
U.S.—


0.61% (340 mcg per metered spray) (Rx) [Bronkometer]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Auxiliary labeling:
   • For oral inhalation only. Note: Include patient instructions when dispensing.


ISOPROTERENOL

Summary of Differences


Pharmacology/pharmacokinetics:
Isoproterenol also has beta 1-adrenergic receptor activity.

Duration of action: Short-acting.



Side/adverse effects:
Pinkish to red coloration of saliva.



Inhalation Dosage Forms

ISOPROTERENOL INHALATION SOLUTION USP

Usual adult and adolescent dose
Bronchodilator
Oral inhalation, administered via nebulization, 2.5 mg diluted, and delivered over approximately ten to twenty minutes, repeated every four hours if needed. {98} {99}


Usual pediatric dose
Bronchodilator
Oral inhalation, administered via nebulization, 0.05 to 0.1 mg per kg up to 1.25 mg diluted, and delivered over approximately ten to twenty minutes, repeated every four hours if needed. {98} {99}


Strength(s) usually available
U.S.—


0.25% (2.5 mg per mL) (Rx)


0.5% (5 mg per mL) (Rx) [Isuprel (sodium metabisulfite) (chlorobutanol) (citric acid) (glycerin) (sodium chloride)][Generic](may contain sodium bisulfite)


1% (10 mg per mL) (Rx) [Isuprel (sodium metabisulfite) (chlorobutanol) (saccharin) (sodium chloride) (sodium citrate) (citric acid)]

Canada—


0.5% (5 mg per mL) (Rx) [Isuprel (chlorobutanol)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer, in a tight, light-resistant container.

Preparation of dosage form:
Isoproterenol inhalation solution should be diluted with 1.5 to 2 mL of sterile 0.9% sodium chloride solution. {98} {99}

Stability:
When exposed to air, alkalies, or metals, isoproterenol solutions turn pinkish to brownish in color because of oxidation. Do not use if solution is pinkish to brownish in color or contains a precipitate. {98}

Auxiliary labeling:
   • For oral inhalation only.


ISOPROTERENOL HYDROCHLORIDE INHALATION AEROSOL USP

Usual adult and adolescent dose
Bronchodilator
Oral inhalation, 1 inhalation (120 to 131 mcg) repeated after two to five minutes if necessary, every three to four hours. {98}


Usual pediatric dose
Bronchodilator
Children up to 12 years of age: Use is not recommended. {98}

Children 12 years of age and over: See Usual adult and adolescent dose. {98}


Strength(s) usually available
U.S.—


120 mcg per metered spray (Rx)


131 mcg per metered spray (Rx) [Isuprel Mistometer (alcohol 33%) (ascorbic acid) ( dichlorodifluoromethane) (dichlorotetrafluoroethane )]

Canada—


125 mcg per metered spray (Rx) [Isuprel Mistometer (ethyl alcohol) (ascorbic acid) ( inert propellants)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

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

Note: Include patient instructions when dispensing.



ISOPROTERENOL SULFATE INHALATION AEROSOL USP

Usual adult and adolescent dose
Bronchodilator
Oral inhalation, 1 inhalation (80 mcg) repeated after two to five minutes if necessary, every four to six hours. {13}


Usual pediatric dose
Bronchodilator
Children up to 12 years of age: Dosage has not been established. {13}

Children 12 years of age and over: See Usual adult and adolescent dose. {13}


Strength(s) usually available
U.S.—


80 mcg per metered spray (Rx) [Medihaler-Iso (dichlorodifluoromethane ) (dichlorotetrafluoroethane) ( trichloromonofluoromethane) (sorbitan trioleate )]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

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

Note: Include patient instructions when dispensing.



METAPROTERENOL

Summary of Differences
Pharmacology/pharmacokinetics: Has significant beta 1-adrenergic activity.


Inhalation Dosage Forms

METAPROTERENOL SULFATE INHALATION AEROSOL USP

Usual adult and adolescent dose
Bronchodilator
Oral inhalation, 2 or 3 inhalations (1.3 to 1.95 mg) every three to four hours, not to exceed 12 inhalations per day. {09}


Usual pediatric dose
Bronchodilator
Children up to 12 years of age: Oral inhalation, 1 to 3 inhalations (0.65 to 1.95 mg) every three to four hours, not to exceed 12 inhalations per day. {99}

Children 12 years of age and over: See Usual adult and adolescent dose . {09}


Strength(s) usually available
U.S.—


650 mcg per metered spray (Rx) [Alupent (dichlorodifluoromethane ) (dichlorotetrafluoromethane) ( trichloromonofluoromethane) (sorbitan trioleate )]

Canada—


750 mcg per metered spray (Rx) [Alupent (dichlorodifluoromethane ) (dichlorotetrafluoroethane) ( trichloromonofluoromethane) (sorbitan trioleate )]

Note: In Canada, metered dose inhalers are labeled according to the amount of medication delivered from the valve; in the U.S., metered dose inhalers are labeled according to the amount of medication delivered at the mouthpiece or actuator.


Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 25 °C (59 and 77 °F), unless otherwise specified by manufacturer.

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

Note: Include patient instructions when dispensing.



METAPROTERENOL SULFATE INHALATION SOLUTION USP

Usual adult and adolescent dose
Bronchodilator
Oral inhalation, administered via nebulization, 15 mg (range 10 to 15 mg), repeated three or four times a day, not more often than every four hours. {14}


Usual pediatric dose
Bronchodilator
Children up to 6 years of age: Oral inhalation, administered via nebulization, 5 to 15 mg, repeated three or four times a day, not more often than every four hours. {99}

Children 6 years of age and over: See Usual adult and adolescent dose . {14}


Strength(s) usually available
U.S.—


0.4% (Rx) [Alupent] [Arm-a-Med Metaproterenol] [Dey-Lute Metaproterenol]


0.6% (Rx) [Alupent] [Arm-a-Med Metaproterenol] [Dey-Lute Metaproterenol]


5% (Rx) [Alupent (benzalkonium chloride)]

Canada—


5% (Rx) [Alupent]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer, in a tight, light-resistant container.

Preparation of dosage form:
For preparation of the inhalation solution, diluents containing benzyl alcohol or preservatives other than benzalkonium chloride are not recommended since the safety of these preservatives has not been established for inhalation therapy.

The 0.4% and 0.6% solutions require no dilution prior to administration. The 5% solution is concentrated and must be diluted in approximately 2.5 mL of sterile 0.9% sodium chloride solution prior to administration.

Stability:
Do not use solution if its color is pinkish or darker than slightly yellow or if it contains a precipitate.

Metaproterenol inhalation solution is compatible with cromolyn inhalation solution for up to 1 hour. {103}

Auxiliary labeling:
   • For oral inhalation only.


PIRBUTEROL


Inhalation Dosage Forms

Note: Bracketed uses refer to categories of use and/or indications that are not included in U.S. product labeling.

The doses and strengths of the available dosage forms are expressed in terms of pirbuterol (not the acetate salt).

PIRBUTEROL ACETATE INHALATION AEROSOL

Usual adult and adolescent dose
Bronchodilator
Oral inhalation, 1 or 2 inhalations (200 or 400 mcg pirbuterol) every four to six hours, not to exceed a total dose of 12 inhalations (2.4 mg) per day. {15}

[Bronchospasm, exercise-induced (prophylaxis)]
Oral inhalation, 2 inhalations (400 mcg pirbuterol) five minutes prior to exercise {43}.


Usual pediatric dose
Bronchodilator
See Usual adult and adolescent dose {43}.


Strength(s) usually available
U.S.—


200 mcg (pirbuterol) per metered spray (Rx) [Maxair ( dichlorodifluoromethane) (trichloromonofluoromethane ) (sorbitan trioleate)] [Maxair Autohaler (dichlorodifluoromethane ) (trichloromonofluoromethane) ( sorbitan trioleate)]

Canada—


250 mcg (pirbuterol) per metered spray (Rx) [Maxair]

Note: Maxair Autohaler is a breath-activated inhaler, which automatically releases a spray of medicine when the patient inhales.


Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

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

Note: Include patient instructions when dispensing.



PROCATEROL


Inhalation Dosage Forms

PROCATEROL HYDROCHLORIDE HEMIHYDRATE INHALATION AEROSOL

Usual adult and adolescent dose
Bronchodilator
Oral inhalation, 1 or 2 inhalations (10 or 20 mcg) three times a day. {16}

Bronchospasm, exercise-induced (prophylaxis)
Oral inhalation, 1 or 2 inhalations (10 or 20 mcg) at least fifteen minutes before exertion. {16}


Usual pediatric dose
Bronchodilator
See Usual adult and adolescent dose {43}.


Strength(s) usually available
U.S.—
Not commercially available.

Canada—


10 mcg per metered spray (Rx) [Pro-Air (monofluorotrichloromethane ) (tetrafluorodichloroethane) ( difluorodichloromethane)]

Note: Each canister provides at least 200 inhalations.


Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

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

Note: Include patient instructions when dispensing.



SALMETEROL

Summary of Differences


Indications:
Salmeterol is not indicated for the treatment of acute or breakthrough asthma symptoms when rapid bronchodilation is needed because of its slower onset of action compared to shorter-acting adrenergic bronchodilators.

Salmeterol therapy should not be initiated in patients with significantly worsening or acutely deteriorating asthma (rapid worsening over hours to days).



Pharmacology/pharmacokinetics:
Onset of action—Approximately 10 to 20 minutes.

Time to peak effect—3 to 4 hours; however, approximately 80% of the maximal increase in forced expiratory volume in 1 second (FEV 1) occurs within 1 hour after administration.

Duration of action—Approximately 12 hours.



Inhalation Dosage Forms

Note: The doses and strengths of the available dosage forms are expressed in terms of salmeterol (not the xinafoate salt).

SALMETEROL XINAFOATE INHALATION AEROSOL

Usual adult and adolescent dose
Bronchospasm, asthma-associated (prophylaxis)
Oral inhalation, 2 inhalations (42 or 50 mcg salmeterol) two times a day, morning and evening, approximately twelve hours apart. {17} {71}{121}

Bronchospasm, exercise-induced (prophylaxis)1
Oral inhalation, 2 inhalations (42 mcg salmeterol) at least thirty to sixty minutes before exercise. {17}

Bronchospasm, chronic obstructive pulmonary disease-associated, including chronic bronchitis and emphysema (prophylaxis)
Oral inhalation, 2 inhalations (42 or 50 mcg salmeterol) twice daily approximately 12 hours apart{118}{121}.


Note: Patients receiving chronic therapy should not use additional salmeterol for prevention of exercise-induced bronchospasm. Patients using salmeterol for exercise-induced bronchospasm should not use additional doses for twelve hours after each prophylactic administration. {17}


Usual pediatric dose
Bronchospasm, asthma-associated (prophylaxis)
Children up to 12 years of age: Dosage has not been established.

Children 12 years of age and over: See Usual adult and adolescent dose .
[Children 4 years of age and older: 2 inhalations (50 mcg salmeterol) twice daily.{121}]
Bronchospasm, exercise-induced (prophylaxis)
Children up to 12 years of age: Dosage has not been established.

Children 12 years of age and over: See Usual adult and adolescent dose .


Strength(s) usually available
U.S.—


21 mcg (salmeterol) per metered spray (Rx) [Serevent ( dichlorodifluoromethane) (trichlorofluoromethane )]

Canada—


25 mcg (salmeterol) per metered spray (Rx) [Serevent ( dichlorodifluoromethane) (lecithin) (trichlorofluoromethane)]

Note: In Canada, metered dose inhalers are labeled according to the amount of salmeterol delivered at the valve; in the U.S., metered dose inhalers are labeled according to the amount of salmeterol delivered at the mouthpiece or actuator.


Packaging and storage:
Store between 15 and 30°C (59 and 86°F). Store canister with nozzle down.{118}

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

Note: Include patient instructions when dispensing.



SALMETEROL XINAFOATE POWDER FOR INHALATION

Usual adult and adolescent dose:
Bronchospasm, asthma-associated (prophylaxis)
Oral inhalation, the contents of one blister (50 mcg salmeterol) two times a day. {71}{119}{121}

Bronchospasm, exercise-induced (prophylaxis)
Oral inhalation, the contents of one blister (50 mcg salmeterol) at least 30 minutes before exercise{119}.

Bronchospasm, chronic obstructive pulmonary disease-associated, including chronic bronchitis and emphysema (prophylaxis)
Oral inhalation, the contents of one blister (50 mcg salmeterol) twice daily{121}.


Usual pediatric dose
Bronchospasm, asthma-associated (prophylaxis)
Children 4 years of age and over: See Usual adult and adolescent dose{119}{121} .

Children up to 4 years of age: Safety and efficacy have not been established.{119}

Bronchospasm, exercise-induced (prophylaxis)
Children 4 years of age and over: See Usual adult and adolescent dose{119}.

Children up to 4 years of age: Safety and efficacy have not been established.{119}


Strength(s) usually available
U.S.—


50 mcg (delivering 47 mcg) salmeterol per blister (Rx) [Serevent Diskus{119} (lactose)]

Canada—


50 mcg salmeterol per blister (Rx) [Serevent Diskus (lactose )]


50 mcg salmeterol per blister (Rx) [Serevent Diskhaler (lactose )]
{121}
Packaging and storage:
Store at controlled room temperature, 20 to 25°C (68 to 77°F) in a dry place away from direct heat or sunlight.{119}

Auxiliary labeling:
   • For oral inhalation only.

Note: Use of salmeterol powder for inhalation requires a special device that pierces the blister and releases the medication. Include patient instructions when dispensing.



TERBUTALINE


Inhalation Dosage Forms

Note: Bracketed uses refer to categories of use and/or indications that are not included in U.S. product labeling.

TERBUTALINE SULFATE INHALATION AEROSOL USP

Usual adult and adolescent dose
Bronchodilator
Oral inhalation, 2 inhalations (400 mcg) every four to six hours. {18}

Note: In Canada, the recommended dose from the breath-actuated dry powder inhaler is 1 inhalation (500 mcg), repeated after five minutes if needed. Doses should not exceed 6 inhalations per day {91}.


[Bronchospasm, exercise-induced (prophylaxis)]1
Oral inhalation, 2 inhalations (400 mcg) five to fifteen minutes prior to exercise. {43} {65}


Usual pediatric dose
Bronchodilator
See Usual adult and adolescent dose {43}.


Strength(s) usually available
U.S.—


200 mcg per metered spray (Rx) [Brethaire (dichlorodifluoromethane ) (dichlorotetrafluoroethane) ( trichloromonofluoromethane)]

Canada—


500 mcg per metered spray (Rx) [Bricanyl Turbuhaler]

Note: Bricanyl Turbuhaler is a breath-actuated dry powder inhaler, which automatically releases a dose of terbutaline, without carrier powders or propellants, when the patient inhales. {91}


Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

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

Note: Include patient instructions when dispensing.




Revised: 06/14/2002



References
  1. Fleeger CA, editor. USP dictionary of USAN and international drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc.; 1997.
  1. Epinephrine inhalation aerosol (Primatene Mist, Whitehall). In: PDR Physicians' desk reference for nonprescription drugs. 17th ed. Montvale, NJ: Medical Economics Data Production Co; 1996. p. 843.
  1. Adrenalin Chloride solution package insert (Parke-Davis—US), Rev 4/94.
  1. Jenne JW, Tashkin DP. Beta-adrenergic agonists. In: Weiss EB, Stein M, editors. Bronchial asthma—mechanisms and therapeutics. Boston: Little, Brown and Co; 1993. p. 746-83.
  1. Hardman JG, Limbird LE, Molinoff PB, et al, editors. Goodman and Gilman's the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill; 1996. p. 105-39.
  1. Albuterol package insert (Ventolin, Allen & Hanburys—US), Rev 12/93.
  1. Bitolterol package insert (Tornalate, Dura—US), Rev 1994.
  1. Epinephrine injection package insert (Astra—US), Rev 2/95.
  1. Metaproterenol package insert (Alupent, BI—US), Rev 8/92.
  1. Racepinephrine package insert (Nephron, Nephron Pharm—US), Rev 12/92.
  1. Fenoterol product labeling (Berotec, BI). In: CPS Compendium of pharmaceuticals and specialties: the Canadian reference for health professionals. 32nd ed. Ontario, Canada: Canadian Pharmaceutical Association; 1997. p. 169-71.
  1. Isoetharine package insert (Arm-a-Med—US), Rev 1/95.
  1. Isoproterenol sulfate package insert (Medihaler-Iso, 3M Pharm—US), Rev 11/93.
  1. Metaproterenol package insert (Arm-a-Med—US), Rev 11/94.
  1. Pirbuterol package insert (Maxair, 3M Pharm—US), Rev 3/94.
  1. Procaterol package insert (Pro-Air, Parke-Davis—Canada), Rev 4/92.
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