Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

A)

1) Albuterol sulfate
2) Salbutamol
3) AH 3365
4) CAS 18559-94-9 (albuterol)
5) CAS 51022-70-9 (albuterol sulfate)

1) Levalbuterol hydrochloride
2) Levalbuterol sulfate
3) Levalbuterol tartrate
4) Levosalbutamol
5) CAS 34391-04-3 (levalbuterol)
6) CAS 50293-90-8 (levalbuterol hydrochloride)
7) CAS 148563-16-0 (levalbuterol sulfate)
8) CAS 661464-94-4 (levalbuterol tartrate)

Available Forms Sources

A)

1) ALBUTEROL

a) GENERIC: Inhalation aerosol powder: 0.09 mg/actuation; inhalation solution: 0.021%, 0.042%, 0.083%, 0.63 mg/3 mL, 1.25 mg/3 mL, 0.5%; oral syrup: 2 mg/5 mL; oral tablet: 2 mg, 4 mg; oral tablet, extended release: 4 mg, 8 mg.
b) Accuneb: Inhalation solution: 0.021%, 0.042%
c) Novaplus Vetolin HFA: Inhalation aerosol powder: 0.09 mg/actuation
d) Proair HFA: Inhalation aerosol powder: 0.09 mg/actuation
e) Proventil HFA: Inhalation aerosol powder: 0.09 mg/actuation
f) Proventil: Oral tablet: 4 mg
g) ReliOn Ventolin HFA: Inhalation aerosol powder: 0.09 mg/actuation
h) Ventolin HFA: Inhalation aerosol powder: 0.09 mg/actuation
i) Vospire ER: Oral tablet, extended release: 4 mg
j) VoSpire: Oral tablet, extended release: 4 mg, 8 mg

2) LEVALBUTEROL

a) Inhalation aerosol, delivering 59 mcg levalbuterol tartrate (equivalent to 45 mcg levalbuterol base) per actuation (Prod Info XOPENEX HFA(R) oral inhalation aerosol, 2015).
b) Inhalation solution for nebulization: 0.31 mg/3 mL, 0.63 mg/3 mL, 1.25 mg/3 mL, and 1.25 mg/0.5 mL (as the concentrate) (Prod Info XOPENEX(R) oral inhalation solution, 2015).

B)

1) ALBUTEROL is a selective beta-2 agonist, primarily used to treat bronchial asthma and reversible obstructive airway disease (Prod Info PROVENTIL(R) HFA oral inhalation aerosol, 2007; Prod Info VENTOLIN(R) HFA inhalation aerosol, 2008; Prod Info PROAIR(R) HFA oral inhalation aerosol, 2010)
2) LEVALBUTEROL is the (R)-enantiomer of albuterol and is indicated in patients 4 years of age and older, with reversible obstructive airway disease, for the treatment and prevention of bronchospasm (Prod Info XOPENEX HFA(R) oral inhalation aerosol, 2015; Prod Info XOPENEX(R) oral inhalation solution, 2015).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Used primarily as a bronchodilator for asthma or other pulmonary diseases. Also may be used for the treatment of hyperkalemia. Found in metered dose inhalers, unit doses for nebulizers, and as an oral syrup and tablets.
B) PHARMACOLOGY: Selective beta2-adrenergic agonist which primarily causes smooth muscle relaxation.
C) TOXICOLOGY: Results from over-stimulation of beta-adrenergic activity. In addition, beta-adrenergic selectivity is lost, so beta-1 effects can be seen.
D) EPIDEMIOLOGY: Uncommon poisoning that rarely results in serious morbidity or death.
E) WITH THERAPEUTIC USE

1) Adverse effects with albuterol therapy include tachycardia, tremor, hyperactivity, nausea, vomiting.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Tachycardia, hypertension, tachypnea, tremor, agitation, nausea, vomiting, hypokalemia, and hyperglycemia.
2) SEVERE TOXICITY: Severe effects include hypotension, dysrhythmias, seizures, acidosis and are likely to occur only after ingestion.

0.2.20)

A) Albuterol, albuterol sulfate/ipratropium bromide, and levalbuterol are classified as FDA Pregnancy Category C by the manufacturer. During marketing, cleft palate and limb defects were reported in the infants of women treated with albuterol; however, a direct association between albuterol and congenital defects has not been established. In animal studies, there was evidence of cleft palate formation and cranioschisis. There are no well-controlled studies showing evidence that oral albuterol will stop preterm labor or prevent labor at term and albuterol has not been approved for the management of preterm labor. Serious adverse reactions, including pulmonary edema, have been reported following administration of albuterol to women in labor. In general, the management of asthma in pregnant patients should be the same as that of nonpregnant patients. Poor oxygenation due to uncontrolled asthma represents a greater danger to the fetus than any potential harm associated with the drugs used to treat the disease.

0.2.21)

A) RATS given 20 mg/kg doses for over 2 years developed benign smooth muscle tumors. No such tumors have been seen in humans.

Laboratory Monitoring

A)

B)

C)

D)

E)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) The majority of albuterol overdoses require supportive care only. Activated charcoal can be used for oral ingestions if the patient presents early. Mild symptoms rarely require specific treatment. An antiemetic may be used. Hypokalemia may develop but usually does not require treatment because it only reflects cellular shifts and not a true body potassium depletion. Sinus tachycardia and hypertension rarely require treatment . The presence of other dysrhythmias or hypotension indicates a more severe poisoning.

B) MANAGEMENT OF SEVERE TOXICITY

1) If hypotension is present, intravenous fluid should be used initially. If the hypotension does not respond, a beta-adrenergic blocking agent can be used. First line choices include esmolol or propranolol since the hypotension is often primarily due to the tachycardia. Alternatively, a vasopressor with pure alpha activity such as phenylephrine can be used. Tachycardia can also be treated if necessary with a beta-blocker, but this is rarely warranted. Premature ventricular contractions rarely require treatment.

C) DECONTAMINATION

1) PREHOSPITAL: There is no role for prehospital decontamination.
2) HOSPITAL: In cases of ingestion, activated charcoal can be used if there is a recent, substantial ingestion and the patient is able to protect their airway.

D) ANTIDOTE

1) Beta-adrenergic blockers can be used specifically if there is refractory hypotension, dysrhythmias, or tachycardia requiring treatment. Esmolol (0.025 to 0.1 mg/kg/min IV) or propranolol (0.01 to 0.02 mg/kg IV) are considered first-line treatments. Esmolol is generally preferred as it is titratable.

E) PSYCHOMOTOR AGITATION

1) Sedate patient with benzodiazepines as necessary; large doses may be required.

F) ENHANCED ELIMINATION

1) There is no role for enhanced elimination.

G) PATIENT DISPOSITION

1) HOME CRITERIA: Children with unintentional ingestions of less than 1 mg/kg with mild symptoms can be observed at home. Adults with unintentional overdose and mild symptoms may be observed at home.
2) OBSERVATION CRITERIA: Patients with deliberate ingestions or children with ingestions greater than 1 mg/kg should be evaluated in a health care facility and observed for 4 to 8 hours for the onset of symptoms.
3) ADMISSION CRITERIA: Patients with significant hypotension or dysrhythmias should be admitted.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing severe poisonings.

H) PITFALLS

1) Use of a beta-adrenergic blocking agent in a patient with asthma may precipitate bronchospasm. Avoid overtreatment; most patients do well with supportive care.

I) PHARMACOKINETICS

1) Volume of distribution is about 2 L/kg. The half-life at therapeutic doses of immediate release oral preparations is about 2 to 5 hours; half-life of extended-release tablets is 9.3 hours. Peak onset of action of inhaled forms is 0.5 to 2 hours, of immediate release oral forms is 2 to 3 hours, and of extended-release forms is 6 hours.

J) TOXICOKINETICS

1) Absorption may be delayed in large overdoses, especially with sustained-release formulations.

K) DIFFERENTIAL DIAGNOSIS

1) Methylxanthine and other sympathomimetic overdoses can present in a similar manner.

0.4.3)

A) Symptoms may occur after inhalation, but seem to be less common and less serious than when significant amounts have been ingested.
B) Some decontamination may be accomplished by mouth rinsing for materials left on the oral surfaces after use of an inhaler.
C) Material absorbed via inhalation should be treated as with an oral exposure.

0.4.4)

A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.

0.4.5)

A) OVERVIEW

1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

A)

B)

C)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

E)

1) Adverse effects with albuterol therapy include tachycardia, tremor, hyperactivity, nausea, vomiting.

F)

1) MILD TO MODERATE TOXICITY: Tachycardia, hypertension, tachypnea, tremor, agitation, nausea, vomiting, hypokalemia, and hyperglycemia.
2) SEVERE TOXICITY: Severe effects include hypotension, dysrhythmias, seizures, acidosis and are likely to occur only after ingestion.

Vital Signs

3.3.3)

A) WITH POISONING/EXPOSURE

1) FEVER/CASE REPORT: Mild fever (37.9 degrees C) was reported in a 3-year-old boy after inadvertently ingesting 53 mg of albuterol (4.8 mg/kg) (Aktar et al, 2013).

3.3.5)

A) WITH POISONING/EXPOSURE

1) Tachycardia has been reported with albuterol overdose (Aktar et al, 2013; Wiley et al, 1994a).

Heent

3.4.3)

A) WITH THERAPEUTIC USE

1) CASE REPORT: A report of closed angle glaucoma was associated with a combination of ipratropium bromide and albuterol nebulizer therapy in a 69-year-old woman with acute and chronic airflow obstruction. The 2 drugs may have produced glaucoma as a result of topical absorption secondary to escape of the nebulizer solution from the face mask (Packe et al, 1984; Kalra & Bone, 1988).

3.4.6)

A) WITH THERAPEUTIC USE

1) Throat irritation was reported in 10% of patients (n=202) who were treated with albuterol sulfate inhalation aerosol as compared to 7% of patients (n=201) who were treated with an HFA-134a placebo inhaler during 2 12-week clinical trials, involving patients 12 years of age and older with asthma (Prod Info VENTOLIN(R) HFA inhalation aerosol, 2012).

Cardiovascular

3.5.2)

A) TACHYARRHYTHMIA

1) WITH THERAPEUTIC USE

a) Although albuterol demonstrates selective beta-2 adrenergic stimulation, tachycardia and palpitations occur in 5% of treated patients (Prod Info albuterol sulfate oral tablet, 2009). The mechanism has not been determined; a combination of beta stimulation and reflex cardiac stimulation, secondary to a fall in peripheral resistance, must be considered.
b) PEDIATRIC: In a prospective study of 64 pediatric patients who ingested up to 8.8 mg/kg albuterol; 65% of these patients were tachycardic(Spiller et al, 1992).
c) On the average, the heart rate appears to increase between 10 to 15 beats/minute following therapeutic doses of albuterol (Coleman & Leary, 1973; Choo-Kang et al, 1974; Femi-Pearse et al, 1977).
d) Palpitations were reported in 3 of 7 patients receiving 1,000 mcg aerosol inhalation, and in 1 of 7 receiving 500 mcg inhalation(Phillips et al, 1972).
e) Following albuterol 3 mcg/kg IV in 6 patients with COPD, heart rate increased approximately 30 beats/minute at 1 minute, then decreased by approximately 15 beats/minute (increase) at 8 minutes (Iodice et al, 1980).
f) Seven high risk patients with COPD were given albuterol infusions beginning with 5 mcg/kg and increasing every 15 minutes to 20 mcg/minute. Continuous EKG readings failed to show significant dysrhythmias provoked by albuterol (Crawford & Miles, 1981).

2) WITH POISONING/EXPOSURE

a) In a prospective study of 78 pediatric patients with unintentional overdoses (0.2 to 8.8 mg/kg), 57% exhibited signs of tachycardia (most common toxic effect), while 50% had a widened pulse pressure(Wiley et al, 1994a).
b) In a retrospective study of 24,977 exposures to albuterol in children under 6 years of age, tachycardia developed in 19.09% (Anderson, 2001).
c) CASE REPORT: A 3-year-old boy presented to the emergency department with a mild fever (37.9 degrees C) and tachycardia (144 bpm) approximately 30 minutes after inadvertently ingesting 53 mg of albuterol (4.8 mg/kg). An ECG confirmed the presence of sinus tachycardia. With supportive care, the patient recovered and was discharged 3 days post-ingestion (Aktar et al, 2013).

B) ELECTROCARDIOGRAM ABNORMAL

1) WITH THERAPEUTIC USE

a) During infusion of albuterol in step-wise increments up to 175 ng/kg/min, reductions in serum potassium of up to 0.4 mmol/L were associated in some patients with asymptomatic flattening of the T-wave, emergence of U-waves fused with the preceding T-wave, and a prolongation of the QT interval (Vincent et al, 1985).

C) ATRIAL FIBRILLATION

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 26-year-old asthmatic man, who was on no other medications, developed repeated episodes of atrial fibrillation after inhaling albuterol via a metered-dose inhaler with a spacer device. Atrial fibrillation was recorded on an electrocardiogram 30 minutes after inhalation (Breeden & Safirstein, 1990).

D) VENTRICULAR ARRHYTHMIA

1) WITH THERAPEUTIC USE

a) Although uncommon, ventricular extrasystoles can occur following administration of albuterol. Ventricular extrasystoles appeared in 3 cases observed in one study, all after albuterol, and in 2 of these in a combination with freon inhalation (Thiessen & Pedersen, 1980).
b) CASE REPORT: Unifocal ventricular ectopic beats occurred 12 hours after initiation of albuterol 0.6 mcg/minute IV infusion (increased to 20 mcg/min) in a 24-year-old woman being treated for premature labor (Chew & Lew, 1979). Premature ectopics responded to lidocaine and decrease in dosage with subsequent delivery of a viable infant.
c) CASE REPORT (PEDIATRIC): A 6-year-old boy with fragile X syndrome and a history of VSD developed palpitations 30 minutes after ingesting 0.4 mg/kg of albuterol syrup (2 mg/5 mL). On exam, heart rate was 256 and the ECG showed a wide complex tachycardia which converted to first degree atrioventricular (AV) block with a QRS of 0.12 msec. Electrophysiologic testing later revealed a right bundle block pattern induced by isoproterenol, suggesting that the presenting rhythm was idiopathic ventricular tachycardia. The patient was treated with verapamil and then discharged (Platt et al, 1997).

1) The patient was admitted for pneumonia, two months later, and was given inhaled albuterol 0.05 mg/kg without incident while still taking the verapamil. The authors suggest that the child's underlying predisposition to ventricular tachycardia may have been precipitated by the catecholamine-effect of albuterol.

E) HYPOTENSIVE EPISODE

1) WITH THERAPEUTIC USE

a) Significant decreases in blood pressure secondary to decreased peripheral vascular resistance has been observed following therapeutic doses of albuterol.
b) Intravenous injection of albuterol 50 mcg/mL in saline were given to 10 convalescent asthmatic patients in incremental doses (over 1 minute) every 15 minutes (Spiro et al, 1975). Palpitations, tremor, and postural hypotension were common. When administered as a continuous intravenous infusion at the highest dose rate (25 mcg/min), an increase in heart rate of 18 beats/minute and a fall in systolic and diastolic pressure was observed (May et al, 1975).
c) In normal subjects, 1 and 2 mcg/kg of intravenous albuterol increased heart rate and decreased peripheral vascular resistance; however, inhalation of 200 to 300 mcg had no effect on the cardiovascular system (Coleman & Leary, 1973).
d) CASE REPORT: A 33-year-old man suffered an acute syncopal episode with a sitting systolic of 70 millimeters of mercury (mmHg) approximately 20 minutes following his second dose (2 puffs) of albuterol. He was admitted to the hospital for observation when subtle, non-specific ST segment abnormalities were seen, but recovered without incident. He was not rechallenged (Shurman & Passero, 1984).
e) A fall in systolic blood pressure of over 30 mmHg occurred following an infusion of albuterol at 125 mcg/min for premature labor (Ng & Sen, 1974).

F) MYOCARDIAL INFARCTION

1) WITH THERAPEUTIC USE

a) Myocardial ischemia and infarction have been reported following intravenous administration of albuterol.
b) CASE REPORT: A 32-year-old prima gravida with no evidence of pre-existing heart disease went into labor at 28 weeks and was given albuterol infusion 20 mcg/min for 2 hours, with 10 mcg/min for another 3 hours until contractions ceased (Whitehead et al, 1979).

1) During the infusion, heart rate did not exceed 120 beats/minute and blood pressure remained around 120/70 millimeters of mercury(mmHg). Within 10 minutes of stopping the infusion, the heart rate rose to 160 beats/minute and the blood pressure dropped to 70/40 mmHg. The patient became cold and clammy and complained of chest pain. Twelve hours later, signs and symptoms had disappeared.
2) The authors speculate albuterol may increase the metabolic substrate requirements of cardiac muscle and, if demand exceeds supply, myocardial cellular function may be compromised.

c) CASE REPORT: A 58-year-old asthmatic patient who did not have a previous history of coronary heart disease developed acute, painless myocardial infarction and hypotension following a single intravenous bolus injection of albuterol 200 mcg that was administered during a severe asthmatic attack (Santo et al, 1980).

1) Before injection, blood pressure was 120/80 millimeters of mercury(mmHg) and EKG was normal; immediately after administration of the albuterol, blood pressure dropped to 60/40 mmHg and an EKG tracing revealed ST-segment depression typical of acute anterolateral subendocardial ischemia as well as multiple ventricular premature beats.
2) The patient exhibited no chest pain. The patient made an uneventful recovery and 3 weeks later the EKG reverted to normal.

G) ANGINA

1) WITH THERAPEUTIC USE

a) Angina has been induced by 5 to 10 mg albuterol administered by nebulization (Neville et al, 1982). The authors recommend initial doses of no more than 1 mg in patients with known or suspected coronary artery disease.

H) HYPERTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Hypertension may develop in overdose (Prod Info albuterol sulfate oral tablet, 2009).
b) CASE REPORT: A 3-year-old developed hypertension (128/70) {50th percentile for age 88/52}), tachycardia (185 beats/min), restlessness, and agitation after ingesting 22.8 grams of albuterol sulfate (1.9 mg/kg albuterol)(Ozdemir et al, 2004).

I) SYNCOPE

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 6-year-old girl had four episodes of syncope or near syncope associated with inhaled albuterol. Electrophysiologic studies revealed reproducible polymorphic ventricular tachycardia in the absence of prolonged QT syndrome (Finn et al, 1997).

J) CHEST PAIN

1) WITH THERAPEUTIC USE

a) Chest discomfort has been noted in less than 1% of patients treated with albuterol (Prod Info albuterol sulfate oral tablet, 2009).

Respiratory

3.6.2)

A) HYPOXEMIA

1) WITH THERAPEUTIC USE

a) Although the drug generally improves respiratory activity in the asthmatic, arterial hypoxemia can be exaggerated if albuterol is used in excess (Scherrer & Bachofen, 1972).

B) ACUTE LUNG INJURY

1) WITH THERAPEUTIC USE

a) Beta-adrenergic-induced pulmonary edema has been reported infrequently in the literature during the treatment of premature labor (Hawker, 1984; Hawker, 1984a).

C) BRONCHOSPASM

1) WITH THERAPEUTIC USE

a) Paradoxical bronchospasm may occur with inhaled formulations of albuterol, particularly with the first use of a new canister (Prod Info VENTOLIN(R) HFA inhalation aerosol, 2012).

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM FINDING

1) WITH THERAPEUTIC USE

a) A 2% incidence of insomnia, weakness, and dizziness is reported when albuterol is administered orally to patients. Drowsiness, restlessness, and irritability may also occur in less than 1% of treated patients (Prod Info albuterol sulfate oral tablet, 2009).

B) HEADACHE

1) WITH THERAPEUTIC USE

a) The manufacturer reports a 7% incidence of headache, with albuterol tablets (Prod Info albuterol sulfate oral tablet, 2009). Frontal headache was reported in 4 of 20 patients following the administration of albuterol 4 mg PO TID for chronic reversible bronchial obstruction (Flora, 1976).

C) FEELING NERVOUS

1) WITH THERAPEUTIC USE

a) The manufacturer reports a 20% incidence of nervousness with albuterol tablets (Prod Info albuterol sulfate oral tablet, 2009). Excitability and emotional upset were reported in one of 16 patients with reversible diffuse airway obstruction following 2 to 4 mg oral albuterol given 4 times daily (Epstein et al, 1973). Young children who receive albuterol syrup may experience excitement. A 20% incidence has been reported for the 2 to 6 year age group (Prod Info albuterol sulfate oral syrup, 2006).

D) PSYCHOMOTOR AGITATION

1) WITH THERAPEUTIC USE

a) Agitation was reported in 2 of 20 patients following the administration of albuterol 4 mg orally, three times a day for chronic reversible bronchial obstruction (Flora, 1976).

2) WITH POISONING/EXPOSURE

a) A prospective study reported agitation in 45% (35/78) of children with unintentional albuterol ingestions (Wiley et al, 1994a).
b) In a retrospective study of 24,977 exposures to albuterol in children under 6 years of age, agitation/irritability developed in 11.21% (Anderson, 2001).

E) TREMOR

1) WITH THERAPEUTIC USE

a) A fine muscular tremor is one of the main dose-limiting side effects with albuterol (Larsson & Svedmyr, 1977; Flora, 1976; Epstein et al, 1973). The manufacturer reports a 20% incidence of tremor in patients taking albuterol tablets (Prod Info albuterol sulfate oral tablet, 2009).
b) Rinsing the mouth after inhalation of albuterol had little effect on the occurrence of muscle tremors in eight asthmatic patients. This side effect seems to be of minor importance and is usually well tolerated by patients receiving aerosolized albuterol (Kung et al, 1987).

F) MYOCLONUS

1) WITH THERAPEUTIC USE

a) Myoclonic jerking has been associated with albuterol use in several patients (Micheli et al, 2000).

G) DIZZINESS

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 70-year-old woman developed recurrent episodes of vertigo lasting 36 hours associated with salmeterol use (Lopez-Guillen et al, 1994).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) WITH THERAPEUTIC USE

a) Nausea may occur in up to 2% of patients following ingestion of albuterol tablets(Prod Info albuterol sulfate oral tablet, 2009).

2) WITH POISONING/EXPOSURE

a) In a prospective study of 78 children with unintentional albuterol ingestions, 26% were noted to have vomiting. Toxic doses ranged from 0.2 to 8.8 mg/kg (Wiley et al, 1994a).
b) In a retrospective study of 24,977 exposures to albuterol in children under 6 years of age, vomiting developed in 7.13% (Anderson, 2001).
c) CASE REPORT: Vomiting occurred in a 6-year-old boy 30 minutes after ingesting 0.4 mg/kg of albuterol syrup (2 mg/5 mL) (Platt et al, 1997).

B) GASTROINTESTINAL IRRITATION

1) WITH THERAPEUTIC USE

a) An unusual taste, and drying or irritation of the oropharynx have also been noted (Prod Info albuterol sulfate oral tablet, 2009).

Genitourinary

3.10.2)

A) RETENTION OF URINE

1) WITH THERAPEUTIC USE

a) Difficulty in micturition has been noted in less than 1% of patients treated with albuterol (Prod Info albuterol sulfate oral tablet, 2009).

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) Mild acidosis may be seen after overdose (King et al, 1991).
b) In a prospective study of 78 children with unintentional albuterol ingestions, found 42% exhibited low serum carbon dioxide(Wiley et al, 1994a).

Hematologic

3.13.2)

A) BLOOD COAGULATION PATHWAY FINDING

1) WITH THERAPEUTIC USE

a) An increase in factor VIII concentrations, evaluated by 1 stage assay, was observed in 7 healthy adults taking therapeutic amounts (Ingram et al, 1977). The concentrations of factors V, X, XI and XII were unaffected.

B) HEMORRHAGE

1) WITH THERAPEUTIC USE

a) CASE REPORT: Hemorrhage secondary to an atonic uterus following a spontaneous abortion, has been reported in a 25-year-old asthmatic with an inhaled dose of albuterol 100 mg (Vinall & Jenkins, 1977). A total dose of 1.5 mg intravenous ergometrine, massaging of the uterus, and 40 units of oxytocin by intravenous infusion had no effect on the bleeding. The hemorrhage was finally controlled after 30 minutes of an oxytocin infusion, but control was not complete for 2 hours.

C) THROMBOCYTOPENIC DISORDER

1) WITH THERAPEUTIC USE

a) Decreased peripheral platelet concentrations occur following high dose albuterol therapy, and probably result from stimulation of beta-1 adrenergic receptors (Kutti et al, 1977; Ingram et al, 1977).
b) The peripheral platelet concentration decreased from 200,000 to 172,000 following albuterol doses of 0.27 mcg/kg/min by intravenous infusion in 6 healthy subjects (Kutti et al, 1977).

Dermatologic

3.14.2)

A) URTICARIA

1) WITH THERAPEUTIC USE

a) An intensely pruritic urticarial rash, without angioedema, respiratory problems, or hemodynamic compromise was seen in an adult after a therapeutic dose (Harland et al, 1991).

Endocrine

3.16.2)

A) HYPERGLYCEMIA

1) WITH THERAPEUTIC USE

a) A comparison of the metabolic effects of albuterol in diabetic patients and normal subjects demonstrated that albuterol infused at 5 and 2 mcg/min stimulated hepatic glucose production to a greater extent in diabetic patients than normal subjects.

1) It also caused a greater rise in plasma glucose, free fatty acids, glycerol, and ketone body concentrations in the diabetic patients and produced a marked fall in plasma potassium concentrations.
2) The differences between the diabetic and normal groups were accounted for by an immediate six-fold stimulation of insulin secretion in the normal subjects (Gundogdu et al, 1979).

b) Oral albuterol (4 mg as a single dose) was compared in 10 non-diabetic, 10 chemical diabetic and 5 juvenile diabetic women in late pregnancy. Control measurements were taken within 1 to 3 days following the same protocol but without albuterol, and were not significantly different for any group (Wager et al, 1981).

1) Cardiovascular response in all 3 groups was similar with an increase in heart rate of 13 to 18 beats/min at 90 minutes after drug; systolic pressure measured 7 to 8 mmHg and diastolic pressures fell 9 to 13 millimeters of mercury(mmHg) in each group.
2) Both the non-diabetic and chemical diabetic groups responded with increases in serum insulin and C-peptide measurements consistent with an increase of insulin secretion rather than a disturbance in metabolism of insulin.
3) Without an insulin response, the juvenile diabetic group subsequently had much larger increases in measured glucose, lactate, glycerol, and 3-hydroxy butyrate than the other 2 groups.
4) The response of the chemical diabetic group was intermediate between the non-diabetics and the juvenile diabetics.

c) Metabolic changes produced by albuterol were studied in 6 non-diabetic patients (Schlienger et al, 1980).

1) All patients received a 3 hour infusion of albuterol, 20 mcg/min. On the following day, 3 of the 6 were given somatostatin 100 mg/hour mixed with albuterol infused at the same rate, while the remaining 3 patients received somatostatin alone. On the third day patients of the first sub-group received the same injection of albuterol and somatostatin as before plus exogenous glucagon 90 ng/kg/hour.
2) Somatostatin is shown to inhibit insulin and glucagon secretion. Exogenous glucagon was given in order to reproduce the metabolic conditions of insulin deficient diabetes mellitus. Albuterol alone induced a small rise in blood glucose and insulin, free fatty acids, glycerol and ketone bodies, but no changes in endogenous glucagon. Somatostatin alone produced no significant metabolic variations.
3) In the presence of somatostatin, all albuterol induced metabolic changes were increased. Adding glucagon mainly resulted in higher levels of ketone bodies. While the hyperglycemic, lipolytic and ketogenic effects in non-diabetic patients are partly masked by insulin hypersecretions, they are enhanced in the absence of insulin and, to an even greater extent by an excess of glucagon.

d) AEROSOL

1) While IV administration of albuterol has been shown to have a significant effect on glucose metabolism, a double-blind crossover study comparing 4 mcg/kg IV over 5 minutes to 200-microgram (mcg) aerosol inhalation in 10 adult asthmatics demonstrated only a transient increase in plasma glucose following the aerosol with a significant increase in plasma insulin and glucose and decrease in potassium following IV administration (Neville et al, 1977).
2) In contrast, a significant increase in serum glucose and insulin occurred following simulated albuterol overuse [(10 metered doses of aerosolized albuterol, each separated by 10 minutes; 1038 to 1065 mcg)] (Kung et al, 1987).
3) Dose response curves (DRC) to plasma glucose stimulatory effects of inhaled albuterol were constructed following 14-day treatment periods using either placebo, low dose [(low dose(LD)); 200 mcg four times daily (mcg QID)] or high dose (HD; 1000 mcg QID) in 12 patients.
4) The DRC used 100, 200, 500, 1000, 2000, and 4000 mcg)steps at 20 minute intervals. Increases in plasma glucose were similar following both placebo and LD treatment, but were attenuated following HD treatment. Maximal increases were 1.23 mmol/L in placebo pretreated patients, 1.15 mmol/L in LD, and 0.58 mmol/L in HD treated patients (Lipworth et al, 1989b).
5) No plateau to hypoglycemic effects at cumulative doses up to 4000 mcg was noted in 7 normal volunteers (Lipworth & McDevitt, 1989).

2) WITH POISONING/EXPOSURE

a) In a prospective study of 78 children with unintentional albuterol ingestions, it was found that hyperglycemia was the most common metabolic effect, occurring in about 50% of the cases. There appeared to be no correlation between dose ingested and serum glucose values, however, the patient sample was small. Patients also were not evaluated for pre-existing conditions, such as diabetes mellitus (Wiley et al, 1994a).
b) CASE REPORT: A 22-month-old child who ingested up to 30 mg of albuterol tablets developed a blood glucose of 321 mg/dL and a plus one glucose urinalysis about 1 to 2 hours post-ingestion (King et al, 1991).
c) CASE REPORT: Hyperglycemia developed in a 6-year-old boy after ingesting 0.4 mg/kg of albuterol syrup (2 mg/5 mL). The patient's serum glucose level was 236 mg/dL (Platt et al, 1997).

B) KETOSIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: Diabetic ketoacidosis following albuterol 0.6 to 1.2 mg/hour intravenous infusion occurred in a 19-year-old diabetic girl with premature labor (Leslie & Coats, 1977). Albuterol dose was decreased to 0.05 mg/hour with subsequent diabetic control. The authors comment that infusion at 1.2 mg every hour caused a rapid deterioration of diabetic control with insulin requirements increasing to 32 Units/hour.
b) Diabetic ketoacidosis occurred in 2 women receiving 0.8 to 1.0 mg albuterol every hour by IV infusion for premature labor. Diabetic control was gained in both patients by administering insulin 5 to 26 Units every hour (Thomas et al, 1977).
c) CASE REPORT: Diabetic ketoacidosis was also reported to occur in a 45-year-old asthmatic patient receiving albuterol intravenous infusion up to 15 mcg/min (Leopold & McEvoy, 1977). The patient's condition improved when dose was subsequently decreased to 3 mcg/min.

C) KETONURIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 31-year-old woman receiving albuterol 4 mg orally every 6 hours for the treatment of premature labor, developed heavy ketonuria without associated glucosuria (Scarpello et al, 1980).

1) Blood glucose and ketone concentrations were normal while urine secretion of ketone bodies were increased. This suggests that ketonuria resulted from an altered renal threshold, rather than a change in intermediary metabolism.
2) Plasma ketone concentrations should be measured before stopping albuterol on the basis of ketonuria alone.

D) HYPOGLYCEMIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 3-year-old child presented with agitation, tachycardia and mild hypertension 30 minutes after ingesting 22.8 mg of albuterol. Four hours after admission blood glucose was 45 mg/dL, although the patient was without signs or symptoms of hypoglycemia. He was treated with orange juice and intravenous infusion of 10% dextrose and blood glucose was 94 mg/dL one hour later. Subsequent blood glucose levels were normal, the dextrose infusion was tapered, and he was discharged 24 hours after admission (Ozdemir et al, 2004).

Immunologic

3.19.2)

A) ACUTE ALLERGIC REACTION

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 42-year-old woman with hypertension and obstructive lung disease was admitted to the hospital with mild respiratory distress. Medications prior to this hospitalization included albuterol (2 mg oral tablets twice daily), which was increased to three times daily at admission.

1) About 30 minutes after the third dose, the patient complained of flushing, chest heaviness, and a bright red face. Following the fourth dose, she developed hoarseness, facial erythema, and edema.
2) Diphenhydramine was administered on both occasions and albuterol was discontinued. One month later under supervision she was rechallenged with 4 mg albuterol.
3) Symptoms of hoarseness, erythema, edema, and worsening of breathing sounds resulted. Epinephrine was given.
4) The authors suggested a mechanism involving mast-cell degranulation products or albuterol acting as a hapten stimulating a true IgE response or other hypersensitivity reaction (Shurman & Passero, 1984).

Reproductive

3.20.1)

A) Albuterol, albuterol sulfate/ipratropium bromide, and levalbuterol are classified as FDA Pregnancy Category C by the manufacturer. During marketing, cleft palate and limb defects were reported in the infants of women treated with albuterol; however, a direct association between albuterol and congenital defects has not been established. In animal studies, there was evidence of cleft palate formation and cranioschisis. There are no well-controlled studies showing evidence that oral albuterol will stop preterm labor or prevent labor at term and albuterol has not been approved for the management of preterm labor. Serious adverse reactions, including pulmonary edema, have been reported following administration of albuterol to women in labor. In general, the management of asthma in pregnant patients should be the same as that of nonpregnant patients. Poor oxygenation due to uncontrolled asthma represents a greater danger to the fetus than any potential harm associated with the drugs used to treat the disease.

3.20.2)

A) CONGENITAL DEFECTS

1) During marketing, various congenital anomalies, including cleft palate and limb defects, were reported in the infants of women treated with albuterol; however, multiple medications were being used by some of the mothers and a direct association between albuterol and congenital defects has not been established (Prod Info XOPENEX HFA(R) oral inhalation aerosol, 2015; Prod Info albuterol sulfate 0.083% inhalation solution, 2014; Prod Info albuterol sulfate oral tablets, 2014; Prod Info ipratropium bromide albuterol sulfate inhalation solution, 2014; Prod Info VENTOLIN(R) HFA inhalation aerosol, 2014; Prod Info VoSpire ER(R) oral extended-release tablets, 2012; Prod Info albuterol sulfate oral syrup, 2011).

B) LACK OF EFFECT

1) There have been no case reports of congenital malformations or teratogenic effects associated with albuterol in human pregnancy. Published case reports regarding both oral and IV administration of long-term albuterol therapy during pregnancy have described normal infants (Edmonds & Letchworth, 1982; Addis, 1981; Lind et al, 1980; Boylan & O'Discoll, 1980). Exposure to albuterol from early in the second trimester through the remainder of pregnancy did not result in abnormalities among the infants of 3 patients (Addis, 1981; Lind et al, 1980).

C) ANIMAL STUDIES

1) ALBUTEROL

a) MICE: Cleft palate formation was reported in 4.5% of fetuses when mice were administered 0.25 mg/kg subQ doses (less than to equal the maximum recommended daily inhalation dose (MRDID), three-hundredths the maximum recommended daily oral dose (MRDOD), and 1.25 times the maximum recommended daily nebulization dose (MRDND), on a mg/m(2) basis) and in 9.3% of fetuses at 2.5 mg/kg subQ doses (approximately equal to 14 times the MRDID, three-tenths the MRDOD, and 12.5 times the MRDND, on a mg/m(2) basis) (Prod Info albuterol sulfate 0.083% inhalation solution, 2014; Prod Info albuterol sulfate oral tablets, 2014; Prod Info COMBIVENT(R) RESPIMAT(R) oral inhalation spray, 2014; Prod Info VENTOLIN(R) HFA inhalation aerosol, 2014; Prod Info ipratropium bromide albuterol sulfate inhalation solution, 2014; Prod Info VoSpire ER(R) oral extended-release tablets, 2012; Prod Info albuterol sulfate oral syrup, 2011).
b) RABBITS: Cranioschisis was reported in 37% of fetuses when rabbits were administered 50 mg/kg oral doses (approximately 55 to 1,100 times the MRDID, 25 times the MRDOD, and 250 times the MRDND, on a mg/m(2) basis) (Prod Info albuterol sulfate 0.083% inhalation solution, 2014; Prod Info albuterol sulfate oral tablets, 2014; Prod Info COMBIVENT(R) RESPIMAT(R) oral inhalation spray, 2014; Prod Info ipratropium bromide albuterol sulfate inhalation solution, 2014; Prod Info VENTOLIN(R) HFA inhalation aerosol, 2014; Prod Info VoSpire ER(R) oral extended-release tablets, 2012; Prod Info albuterol sulfate oral syrup, 2011). In another study, enlargement of the frontal portion of the fetal fontanelles was reported in rabbits administered inhaled doses approximately one-third the MRHDID (Prod Info VENTOLIN(R) HFA inhalation aerosol, 2014).

2) LEVALBUTEROL

a) MICE, RABBITS: Racemic albuterol sulfate exposures during gestation of 2 and 20 times the maximum recommended daily inhalation (MRDI) dose of levalbuterol tartrate for adults led to a respective 4.5% and 9.3% increase in cleft palate in mice. An increased incidence of cranioschisis was seen in rabbit offspring following racemic albuterol sulfate exposures during gestation of about 1500 times the MRDI dose of levalbuterol tartrate for adults on a mg/m(2) basis (Prod Info XOPENEX HFA(R) oral inhalation aerosol, 2015).
b) LACK OF EFFECT: There was no evidence of teratogenicity in rabbits following maternal oral administration of levalbuterol hydrochloride at doses approximately 108 to 750 times the maximum recommended daily inhalation dose for adults on a mg/m(2) basis (Prod Info XOPENEX(R) oral inhalation solution, 2015; Prod Info XOPENEX HFA(R) oral inhalation aerosol, 2015).

3.20.3)

A) PREGNANCY CATEGORY

1) Albuterol, albuterol sulfate/ipratropium bromide, and levalbuterol are classified as FDA Pregnancy Category C by the manufacturer (Prod Info XOPENEX HFA(R) oral inhalation aerosol, 2015; Prod Info XOPENEX(R) oral inhalation solution, 2015; Prod Info albuterol sulfate 0.083% inhalation solution, 2014; Prod Info albuterol sulfate oral tablets, 2014; Prod Info COMBIVENT(R) RESPIMAT(R) oral inhalation spray, 2014; Prod Info ipratropium bromide albuterol sulfate inhalation solution, 2014; Prod Info VENTOLIN(R) HFA oral inhalation aerosol, 2014; Prod Info VoSpire ER(R) oral extended-release tablets, 2012; Prod Info albuterol sulfate oral syrup, 2011; Briggs et al, 1998).
2) Albuterol should only be used in pregnant women if the potential benefit justifies the risk to the fetus. Patients should be advised to contact their physician if they become pregnant while taking this drug (Prod Info VENTOLIN(R) HFA oral inhalation aerosol, 2014).

B) LABOR ABNORMAL

1) In the United States, bronchodilators are approved only for the indication of asthma but their clinical use as tocolytic agents in preterm labor has been well documented (Edmonds & Letchworth, 1982; Addis, 1981; Gummerus, 1981; Pincus, 1981; Lind et al, 1980). Long-term adverse neonatal effects from tocolysis with albuterol have not been identified (Ryden, 1977). No differences in pregnancy outcome were observed in a placebo controlled study involving 144 women, half of whom received albuterol; however, fewer neonates in the active treatment group experienced respiratory distress (Ashworth et al, 1990). Albuterol and levalbuterol tartrate have not been approved for the management of preterm labor. Serious adverse reactions, including pulmonary edema, have been reported following administration of albuterol to women in labor (Prod Info XOPENEX HFA(R) oral inhalation aerosol, 2015; Prod Info AccuNeb(R) inhalation solution, 2011). Use levalbuterol for the treatment of bronchospasm during labor only when the potential benefit to the mother exceeds the potential risk to her fetus, as beta-adrenergic agonists can interfere with uterine contractility (Prod Info XOPENEX HFA(R) oral inhalation aerosol, 2015).

C) PLACENTAL BARRIER

1) The biochemical status of neonates whose mothers received albuterol for premature labor was compared with that of 15 controls . Initial results demonstrated no significant difference between the 2 groups. However, when only proven cases of fetal distress (pH less than 7.25) in the 2 groups were compared, a significant improvement in the pO2, pH, and base deficit values in the umbilical vein and the pO2 and pH values in the umbilical artery were noted in the group which had been given albuterol. No major maternal side effects were noted (Visser et al, 1979).
2) No significant differences in cord blood concentrations of insulin, T3, T4, or TSH were found when comparing 20 deliveries of patients treated with oral albuterol to 18 deliveries without beta mimetic therapy.

a) Although growth hormone (GH) levels in cord blood samples were significantly elevated in the treatment group (36.14 ng/mL vs 17.4 ng/mL), no correlations were found with length of therapy, time between cessation of therapy and delivery, or length of labor.
b) Elevations in GH were thought to be due to either fluctuating fetal blood glucose levels from beta mimetic therapy or direct fetal pituitary production from the beta mimetic therapy (Desgranges et al, 1987).

D) HYPOTENSION

1) CASE REPORT: Crowhurst (1980) reported development of a hypotensive and tachycardic episode in a 27-year-old woman following albuterol infusion 20 mcg/min with anesthesia. Blood pressure decreased from 130/70 to 80 mmHg, heart rate increased from 140 to 190 beats/minute. The authors suggest that use of albuterol to inhibit labor may be hazardous when combined with general anesthesia (Crowhurst, 1980).

E) TACHYCARDIA

1) When albuterol is used to arrest premature labor, fetal and maternal tachycardia can occur and are generally the dose-limiting side effects (Tambyraja, 1979; Liggins & Vaughan, 1973).
2) CASE REPORT: A 34-year-old woman pregnant at 33 weeks gestation received albuterol 2.5 mg by nebulizer every 4 hours for wheezing. Three hours after the fifth dose in 24 hours fetal tachycardia greater than 200 beats/minute was detected and echocardiogram detected atrial flutter at 420 beats/minute with predominantly 2:1 conduction. Albuterol was discontinued and the rhythm converted to normal 8 hours later (Baker & Flanagan, 1997).

F) PERINATAL DISORDER

1) A prospective study reported that the use of inhaled beta-agonist bronchodilators for the therapy of asthma during pregnancy was not associated with an increased frequency of adverse maternal or infant perinatal outcomes (Schatz et al, 1988).

a) In this study, perinatal outcomes were prospectively compared in 259 pregnant asthmatics who used bronchodilators during pregnancy, 101 pregnant asthmatics who did not use bronchodilators, and 295 pregnant control patients with no history of asthma. The most frequently used bronchodilator was metaproterenol (83% of patients); this was followed by isoetharine (27%), epinephrine (13%), albuterol (8%), and isoproterenol (4%) (Schatz et al, 1988)
b) Of the 259 subjects using bronchodilators, 30% administered them regularly throughout pregnancy with an average of 1 or more puffs daily, and 69% used them intermittently with an average of less than 1 puff/day; the dose was uncertain in 1% of patients (Schatz et al, 1988).
c) No differences were observed between the asthmatic patients who used inhaled bronchodilators and the patients who did not use bronchodilators with regard to perinatal mortality, congenital malformations, preterm births, numbers of low-birth-weight infants, mean birth weight, numbers of infants who were small for gestational age or had a low ponderal index, Apgar scores, labor and delivery complications, or postpartum bleeding (Schatz et al, 1988).
d) Although an increased incidence of maternal chronic hypertension, pregnancy-induced hypertension, and transient tachypnea of the newborn were observed in the patients with asthma who used bronchodilators, logistic regression analysis within the sample of patients with asthma did not reveal a significant association between the use of bronchodilators and these complications (Schatz et al, 1988).
e) Inhaled bronchodilators should be considered as part of the management of asthma during pregnancy for patients with severe or uncontrolled disease (Schatz et al, 1988). Poor oxygenation due to uncontrolled asthma represents a greater danger to the fetus than any potential harm associated with the drugs used to treat the disease (Anon, 2005; Schatz et al, 1988; Weinberger & Weiss, 1995).

G) LACK OF EFFECT

1) When maximum inhaled doses of albuterol were administered in the third trimester of pregnancy, no adverse effect on fetal heart rate or aortic blood flow velocity was observed (Rayburn et al, 1994).

H) ANIMAL STUDIES

1) RATS: Drug related material was transferred from maternal to fetal circulation in pregnant rats given radiolabeled albuterol sulfate (Prod Info VENTOLIN(R) HFA oral inhalation aerosol, 2014; Prod Info ipratropium bromide albuterol sulfate inhalation solution, 2014).

3.20.4)

A) LACK OF INFORMATION

1) It is not known whether albuterol or levalbuterol are excreted into human breast milk. The plasma concentrations of levalbuterol are very low following inhalation at therapeutic doses. Because many drugs are excreted into human milk and animal studies suggest a potential for tumorigenicity, exercise caution when administering albuterol or levalbuterol to a nursing mother (Prod Info XOPENEX(R) oral inhalation solution, 2015; Prod Info XOPENEX HFA(R) oral inhalation aerosol, 2015; Prod Info albuterol sulfate 0.083% inhalation solution, 2014; Prod Info albuterol sulfate oral tablets, 2014; Prod Info VENTOLIN(R) HFA oral inhalation aerosol, 2014; Prod Info VoSpire ER(R) oral extended-release tablets, 2012; Prod Info albuterol sulfate oral syrup, 2011).

3.20.5)

A) ANIMAL STUDIES

1) RATS: No impaired fertility was noted in rats following exposure to racemic albuterol sulfate at doses approximately 750 times the maximum recommended daily inhalation dose of levalbuterol tartrate for adults (Prod Info XOPENEX HFA(R) oral inhalation aerosol, 2015).
2) RATS: Impaired fertility was not observed when rats were administered oral doses up to 50 mg/kg (approximately 140 to 340 times the maximum recommended daily inhalation dose, 15 times the maximum recommended daily oral dose, and 250 times the maximum recommended daily nebulization dose, on a mg/m(2) basis) (Prod Info albuterol sulfate 0.083% inhalation solution, 2014; Prod Info albuterol sulfate oral tablets, 2014; Prod Info COMBIVENT(R) RESPIMAT(R) oral inhalation spray, 2014; Prod Info ipratropium bromide albuterol sulfate inhalation solution, 2014; Prod Info VENTOLIN(R) HFA inhalation aerosol, 2014; Prod Info VoSpire ER(R) oral extended-release tablets, 2012; Prod Info albuterol sulfate oral syrup, 2011).

Carcinogenicity

3.21.2)

A) RATS given 20 mg/kg doses for over 2 years developed benign smooth muscle tumors. No such tumors have been seen in humans.

3.21.3)

A) NEOPLASM

1) RATS given 20 mg/kg doses for over 2 years developed benign smooth muscle tumors (Breeden & Safirstein, 1990). No such tumors have been seen in humans.

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs and mental status.
B) Specific levels are generally not available and not helpful.
C) Obtain serum chemistries to monitor serum potassium concentrations in severely poisoned patients.
D) Monitor ECG in patients with chest pain or severe tachycardia.
E) Consider obtaining creatine kinase in severely agitated patients.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Specific levels are generally not available and not helpful.
2) Monitor blood glucose, especially in diabetics. Serum potassium should also be followed closely.
3) Albuterol appears to increase both renin and aldosterone serum levels. In 32 adult females treated for premature labor with albuterol 8 mg PO 3 times daily over 21 days, plasma renin activity and urinary aldosterone excretion were noted to significantly increase (Lammintausta & Erkkola, 1979).
4) Consider obtaining creatine kinase in severely agitated patients.

4.1.4)

A) OTHER

1) MONITORING

a) Monitor vital signs and mental status.
b) Monitor ECG in patients with chest pain or severe tachycardia.

2) BREATH ANALYSIS

a) Albuterol was found NOT to effect blood; breath alcohol ratios when used by asthmatics prior to a breath alcohol test (Gomm et al, 1991).

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with significant hypotension or dysrhythmias should be admitted.

6.3.1.2) HOME CRITERIA/ORAL

A) Children with unintentional ingestions of less than 1 mg/kg with mild symptoms can be observed at home (Wiley et al, 1994). Adults with unintentional overdose and mild symptoms may be observed at home.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist for assistance in managing severe poisonings.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with deliberate ingestions or children with ingestions greater than 1 mg/kg should be evaluated in a health care facility and observed for 4 to 8 hours for the onset of symptoms.

Monitoring

A)

B)

C)

D)

E)

Oral Exposure

6.5.1)

A) There is no role for prehospital gastrointestinal decontamination.

6.5.2)

A) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

B) GASTRIC LAVAGE

1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

2) PRECAUTIONS:

a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

3) LAVAGE FLUID:

a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

4) COMPLICATIONS:

a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

5) CONTRAINDICATIONS:

a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

6.5.3)

A) MONITORING OF PATIENT

1) Monitor vital signs and mental status.
2) Specific levels are generally not available and not helpful.
3) Obtain serum chemistries to monitor serum potassium concentrations in severely poisoned patients.
4) Monitor ECG in patients with chest pain or severe tachycardia.
5) Consider obtaining creatine kinase in severely agitated patients.

B) TACHYARRHYTHMIA

1) Propranolol may be useful to relieve palpitations and associated anxiety following ephedrine, pseudoephedrine, metaproterenol, phenylpropanolamine, albuterol or terbutaline ingestion.

a) WARNING: Propranolol is contraindicated in patients with bronchial asthma, cardiogenic shock, sinus bradycardia, or congestive heart failure, unless the failure is secondary to a tachyarrhythmia treatable with propranolol. In general, patients with a history of bronchospastic diseases should not receive beta blockers. Propranolol should be administered with caution because it may block bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta receptors (Prod Info INDERIDE(R) oral tablets, 2011)

2) DOSE: ADULT: 0.025 to 0.1 mg/kg intravenously slowly over 2 to 3 minutes; CHILDREN: 0.01 to 0.1 mg/kg intravenously slowly not to exceed an initial dose of 2 mg.
3) ATRIAL FIBRILLATION: A case of albuterol and spacer-induced atrial fibrillation has been reported (Breeden & Safirstein, 1990).

a) A 26-year-old asthmatic man who was on no other medications developed repeated episodes of atrial fibrillation after inhaling albuterol via a metered-dose inhaler with a spacer device. He was treated with propranolol and a repeat ECG showed normal sinus rhythm. The atrial fibrillation stopped after the patient stopped using the spacer device, while continuing to use the albuterol metered dose inhaler.

4) Concomitant use of albuterol and beta-blockers result in an antagonism of their effects (Prod Info VENTOLIN(R) oral tablets, 1998). Propranolol 40 mg was more effective than atenolol 100 mg in reversing the metabolic effects (hypokalemia, hyperglycemia) of albuterol 8 mg orally in 6 healthy volunteers (Minton et al, 1989).

C) VENTRICULAR ARRHYTHMIA

1) UNIFOCAL VENTRICULAR ECTOPIC BEATS: Occurred 12 hours after initiation of albuterol 0.6 mcg/min IV infusion (increased to 20 mcg/min) in a 24-year-old woman being treated for premature labor. Premature ectopics responded to lidocaine and decrease in dosage with subsequent delivery of a viable infant (Chew & Lew, 1979).

a) VENTRICULAR DYSRHYTHMIAS SUMMARY

1) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.

2) LIDOCAINE

a) LIDOCAINE/INDICATIONS

1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).

b) LIDOCAINE/DOSE

1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.

a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).

2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).

c) LIDOCAINE/MAJOR ADVERSE REACTIONS

1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).

d) LIDOCAINE/MONITORING PARAMETERS

1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).

3) AMIODARONE

a) AMIODARONE/INDICATIONS

1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).

b) AMIODARONE/ADULT DOSE

1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).

c) AMIODARONE/PEDIATRIC DOSE

1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).

d) ADVERSE EFFECTS

1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).

D) HYPOKALEMIA

1) Treat hypokalemia with oral or intravenous potassium as clinically indicated.
2) Use of a non-specific beta-blocker (propranolol) has reversed the hypokalemia during treatment for overdose (Connell et al, 1982).
3) Infusions of isoprenaline, albuterol, and prenalterol (a beta-1 specific agonist) were compared before and after beta-1 or beta-2 specific antagonist pretreatment.

a) Infusions were titrated to end-points of increased heart rates (+40 for isoprenaline; +20 for albuterol, and prenalterol); sequential changes in serum potassium were monitored. The beta-2 agonists both resulted in dose-related drops in serum potassium of 0.4 millimole/liter, about twice that induced by prenalterol.
b) Pretreatment with propranolol almost completely attenuated the potassium changes, while atenolol resulted in a drop of 0.6 millimole/liter. Infusion of 120 nanograms/kilogram/minute albuterol resulted in 0.48 millimole/liter reductions in potassium (Vincent et al, 1985).

E) FLUID/ELECTROLYTE BALANCE REGULATION

1) MONITOR URINARY OUTPUT and serum electrolytes in symptomatic patients. Fluid replacement may be necessary.

F) PSYCHOMOTOR AGITATION

1) INDICATION

a) If patient is severely agitated, sedate with IV benzodiazepines.

2) DIAZEPAM DOSE

a) ADULT: 5 to 10 mg IV initially, repeat every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).

3) LORAZEPAM DOSE

a) ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed (Manno, 2003).
b) CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).

4) Extremely large doses of benzodiazepines may be required in patients with severe intoxication in order to obtain adequate sedation. Titrate dose to clinical response and monitor for hypotension, CNS and respiratory depression, and the need for endotracheal intubation.

Inhalation Exposure

6.7.1)

A) Symptoms may occur after inhalation, but seem to be less common and less serious than when significant amounts have been ingested.
B) Some decontamination may be accomplished by mouth rinsing to remove materials left on the oral surfaces after use of an inhaler.

6.7.2)

A) GENERAL TREATMENT

1) Material absorbed via inhalation should be treated like an oral exposure.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

6.8.1)

A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

6.9.1)

A) DERMAL DECONTAMINATION

1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

A)

1) Hemodialysis is not considered appropriate treatment for overdose cases with this agent (Prod Info Proventil(R), albuterol, 1990).

Abstracts

Case Reports

A)

1) A 22-month-old child took up to 30 mg of a sibling's albuterol tablets. Within 1 to 2 hours he became agitated and was taken to an emergency department. No vomiting or diarrhea were seen; pulse was 180 beats/min, temperature 98.9 degrees F, respirations 29 per minute, and blood pressure 96/40 mmHg. Laboratory values were 321 mg/dL for glucose, 3.5 mEq/L for potassium, and a bicarbonate level of 14 mEq/L.

a) Base levels were not stated. The patient improved on supportive care above (King et al, 1991).

B)

1) A 26-year-old man with asthma developed albuterol and spacer-induced atrial fibrillation. He was on no other medications when he developed repeated episodes of atrial fibrillation after inhaling albuterol via a metered-dose inhaler with a spacer device. Fibrillation was recorded on an ECG within 30 minutes of inhalation.

a) He was treated with propranolol and a repeat ECG showed normal sinus rhythm. The atrial fibrillation stopped after the patient stopped using the spacer device, while continuing to use the albuterol metered dose inhaler. The spacer increases the amount of albuterol delivered to the lungs which apparently increased the adverse effects in this patient (Breeden & Safirstein, 1990).

C)

1) A 3-year-old child developed ataxia, loss of consciousness, and tonic-clonic seizures 16 hours after ingesting 60 mg (4 mg/kg) of albuterol syrup. Hypoglycemia was confirmed by assay as 0.9 mmol/L. After administering IV glucose 0.5 gm/kg she promptly regained consciousness. No further episodes of seizures were observed (Wasserman & Amitai, 1992).

Range Of Toxicity

Summary

A)

B)

C)

Therapeutic Dose

7.2.1)

A) ALBUTEROL

1) ACUTE BRONCHOSPASM

a) DRY POWDER INHALER

1) As a breath-actuated dry powder inhaler, the recommended dose is 2 inhalations every 4 to 6 hours; however, 1 inhalation every 4 hours may be sufficient in some patients. Each actuation delivers 108 mcg of albuterol sulfate (equivalent to 90 mcg of albuterol base) (Prod Info PROAIR(R) RESPICLICK(R) oral inhalation powder, 2016).

b) METERED-DOSE INHALER

1) The recommended dose of albuterol sulfate is 2 inhalations by metered-dose inhaler every 4 to 6 hours as needed. One inhalation every 4 hours may be sufficient in some patients. Each actuation delivers 108 micrograms of albuterol sulfate, equivalent to 90 micrograms of albuterol base (Prod Info PROVENTIL(R) HFA oral inhalation aerosol, 2007; Prod Info VENTOLIN(R) HFA inhalation aerosol, 2008; Prod Info PROAIR(R) HFA oral inhalation aerosol, 2006).
2) In patients with acute asthma exacerbation, the National Heart, Lung and Blood Institute asthma guidelines recommend 4 to 8 inhalations every 20 minutes up to 4 hours, then every 1 to 4 hours as needed (National Heart,Lung,and Blood Institute, 2007).

c) NEBULIZATION FOR INHALATION

1) Albuterol sulfate inhalation solution 0.083% is administered at a dose of 2.5 milligrams (3 milliliters) by inhalation over 5 to 15 minutes, 3 to 4 times daily as needed by nebulization (Prod Info PROVENTIL(R) oral inhalation solution, 2002; Prod Info VENTOLIN NEBULES(R) inhalation solution, 0.083%, 1998).
2) Albuterol sulfate inhalation solution 0.5% is administered at a dose of 2.5 milligrams (0.5 milliliters diluted in 2.5 milliliters of normal saline) by inhalation over 5 to 15 minutes, 3 to 4 times daily as needed by nebulization (Prod Info VENTOLIN(R) inhalation solution, 0.5%, 1998).
3) In patients with acute asthma exacerbation, the National Heart, Lung and Blood Institute asthma guidelines recommend 2.5 to 5 milligrams every 20 minutes for 3 doses, then 2.5 to 10 milligrams every 1 to 4 hours as needed, or 10 to 15 milligrams/hour by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).

d) ORAL

1) IMMEDIATE-RELEASE TABLETS AND SYRUP: The recommended initial dose of albuterol sulfate is 2 or 4 milligrams orally 3 or 4 times daily. If a patient does not respond to the 4 milligram dose, it may be carefully increased stepwise as tolerated, not to exceed 8 milligrams orally 4 times a day (32 milligrams total daily dose) (Prod Info VENTOLIN(R) oral syrup, USP, 1997; Prod Info VENTOLIN(R) oral tablet, USP, 1998).
2) EXTENDED-RELEASE TABLETS: The recommended dose of extended-release albuterol sulfate tablets is 8 milligrams orally every 12 hours. In some patients, including those with low body weight, a dose of 4 milligrams orally every 12 hours may be started and increased to 8 milligrams every 12 hours according to response. If control is not achieved, the dose may be carefully increased stepwise to a maximum dose of 32 milligrams per day in divided doses (16 milligrams every 12 hours) (Prod Info VOSPIRE ER(TM) oral extended-release tablet, 2002).

2) PROPHYLAXIS OF EXERCISE-INDUCED BRONCHOSPASM

a) DRY POWDER INHALER: As a breath-actuated dry powder inhaler, the recommended dose is 2 inhalations 15 to 30 minutes prior to exercise. Each actuation delivers 108 mcg of albuterol sulfate (equivalent to 90 mcg of albuterol base) (Prod Info PROAIR(R) RESPICLICK(R) oral inhalation powder, 2016).
b) METERED-DOSE INHALER: For prophylaxis of exercise-induced bronchospasm, the recommended dose of albuterol sulfate is 2 inhalations by metered-dose inhaler 15 to 30 minutes prior to exercise. Each actuation delivers 108 micrograms of albuterol sulfate, equivalent to 90 micrograms of albuterol base (Prod Info PROAIR HFA(R) inhalation aerosol, 2008; Prod Info PROVENTIL(R) HFA oral inhalation aerosol, 2007; Prod Info VENTOLIN(R) HFA inhalation aerosol, 2008).

3) DOSAGE IN OTHER DISEASE STATES

a) THYROID DISORDERS: An inverse relation between thyroid function and response to inhaled albuterol was demonstrated in an observational study (Harrison & Tattersfield, 1984).
b) CORONARY ARTERY DISEASE: Two case reports described angina that was induced by 5 to 10 milligrams albuterol by nebulization. Therefore, initial doses of no more than 1 milligram are recommended in patients with known or suspected coronary artery disease (Neville et al, 1982).

B) LEVALBUTEROL

1) METERED DOSE INHALER

a) TREATMENT AND PREVENTION OF BRONCHOSPASM: One to two inhalations (45 to 90 mcg levalbuterol base) every 4 to 6 hours (Prod Info XOPENEX HFA(R) oral inhalation aerosol, 2015).

2) NEBULIZATION FOR INHALATION

a) TREATMENT AND PREVENTION OF BRONCHOSPASM: Starting dose is 0.63 mg three times daily, every 6 to 8 hours, by nebulization. The dose may be increased to 1.25 mg three times daily in patients who either have more severe asthma or are not responding adequately to the lower dose (Prod Info XOPENEX(R) oral inhalation solution, 2015).

7.2.2)

A) ALBUTEROL

1) ACUTE BRONCHOSPASM

a) DRY POWDER INHALER

1) 4 YEARS AND OLDER: As a breath-actuated dry powder inhaler, the recommended dose of albuterol sulfate for children 4 years and older is 2 inhalations every 4 to 6 hours. One inhalation every 4 hours may be sufficient in some patients. Each actuation delivers 108 micrograms of albuterol sulfate, equivalent to 90 micrograms of albuterol base (Prod Info PROAIR(R) RESPICLICK(R) oral inhalation powder, 2016).

b) METERED DOSE INHALER

1) 4 YEARS AND OLDER: The recommended dose of albuterol sulfate for children 4 years and older is 2 inhalations by metered-dose inhaler every 4 to 6 hours as needed. One inhalation every 4 hours may be sufficient in some patients. Each actuation delivers 108 micrograms of albuterol sulfate, equivalent to 90 micrograms of albuterol base (Prod Info PROVENTIL(R) HFA oral inhalation aerosol, 2007; Prod Info VENTOLIN(R) HFA inhalation aerosol, 2008; Prod Info PROAIR HFA(R) inhalation aerosol, 2008).
2) In patients with acute asthma exacerbation, the National Heart, Lung and Blood Institute asthma guidelines recommend 4 to 8 inhalations every 20 minutes for 3 doses, then every 1 to 4 hours as needed. A mask should be added for children less than 4 years of age (National Heart,Lung,and Blood Institute, 2007).

c) NEBULIZATION FOR INHALATION

1) 12 YEARS AND OLDER: Albuterol sulfate inhalation solution 0.083% (Proventil(R) oral inhalation solution) is administered to children, 12 years of age and older, at a dose of 2.5 milligrams (3 milliliters) by inhalation over 5 to 15 minutes, 3 to 4 times daily as needed by nebulization (Prod Info PROVENTIL(R) oral inhalation solution, 2002).
2) 2 YEARS OR OLDER (WEIGHING AT LEAST 15 KG): Albuterol sulfate inhalation solution 0.083% (Ventolin Nebules (R) inhalation solution) is administered to children, 2 years of age and older who weigh at least 15 kilograms, at a dose of 2.5 milligrams (3 milliliters) by inhalation over 5 to 15 minutes, 3 to 4 times daily as needed by nebulization. For children who weigh less than 15 kilograms and require less than a 2.5 milligram dose, Ventolin Nebules (R) inhalation solution is not recommended (Prod Info VENTOLIN NEBULES(R) inhalation solution, 0.083%, 1998).
3) Albuterol sulfate inhalation solution 0.5% is administered at a dose of 0.1 to 0.15 milligrams/kilogram per dose by nebulization. The maximum dose is 2.5 milligrams 3 to 4 times daily by nebulization. The appropriate dose should be diluted in sterile normal saline to a total volume of 3 milliliters (Prod Info VENTOLIN(R) inhalation solution, 0.5%, 1998).
4) AccuNeb(TM) nebulized solution is administered to patients 2 to 12 years of age at 1.25 milligrams in 3 milliliters or 0.63 milligram in 3 milliliters by INHALATION over 5 to 15 minutes, 3 or 4 times daily by nebulizer, as needed. AccuNeb(TM) inhalation solution does not require dilution. Patients 6 to 12 years of age with more severe asthma, weight of greater than 40 kilograms, or patients 11 to 12 years of age may benefit more from an initial dose of 1.25 milligrams. AccuNeb(TM) has not been studied in the setting of acute asthma attacks; a higher concentration product (2.5 milligrams albuterol per 3 milliliters) may be more appropriate in treating acute exacerbations (Prod Info ACCUNEB(TM) inhalation solution, 2001).
5) In patients with acute asthma exacerbation, the National Heart, Lung and Blood Institute asthma guidelines recommend 0.15 milligrams/kilogram (minimum dose 2.5 milligrams) every 20 minutes for 3 doses then 0.15 to 0.3 milligram/kilogram up to 10 milligrams every 1 to 4 hours as needed, or 0.5 milligram/kilogram/hour by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).

d) ORAL

1) IMMEDIATE-RELEASE TABLETS AND SYRUP

a) 2 TO 6 YEARS: For children 2 to 6 years of age, the initial dose of albuterol sulfate syrup is 0.1 milligram/kilogram/dose, given three times a day; the starting dose should not exceed 2 milligrams/dose. If the child does not respond, the dose may be slowly increased to 0.2 milligram/kilogram/dose given 3 times/day, up to a maximum of 4 milligrams 3 times a day (maximum total daily dose of 12 milligrams) (Prod Info VENTOLIN(R) oral syrup, USP, 1997).
b) 6 TO 12 YEARS: The usual starting dose is 2 milligrams given 3 or 4 times daily; if the child does not respond, the dose may be slowly increased up to a maximum of 6 milligrams four times a day (maximum total daily dose of 24 milligrams) (Prod Info VENTOLIN(R) oral syrup, USP, 1997; Prod Info VENTOLIN(R) oral tablet, USP, 1998).
c) OVER 12 YEARS: The usual starting dose is 2 or 4 milligrams given 3 or 4 times a day. If the child does not respond to doses of 4 milligrams 4 times daily, the dose may be increased slowly to a maximum of 8 milligrams 4 times a day (maximum total daily dose of 32 milligrams) (Prod Info VENTOLIN(R) oral syrup, USP, 1997; Prod Info VENTOLIN(R) oral tablet, USP, 1998).

2) EXTENDED-RELEASE TABLETS

a) 6 TO 12 YEARS: The recommended starting dose of Vospire ER(TM) is 4 milligrams every 12 hours; may be increased cautiously to a maximum of 12 milligrams twice a day according to response (maximum total daily dose 24 milligrams) (Prod Info VOSPIRE ER(TM) oral extended-release tablet, 2002).
b) OVER 12 YEARS: The recommended starting dose is 4 milligrams or 8 milligrams every 12 hours; may be increased cautiously to a maximum of 16 milligrams twice a day according to response (maximum total daily dose 32 milligrams) (Prod Info VOSPIRE ER(TM) oral extended-release tablet, 2002).

2) PROPHYLAXIS OF EXERCISE-INDUCED BRONCHOSPASM

a) DRY POWDER INHALER (CHILDREN 4 YEARS OR OLDER): As a breath-actuated dry powder inhaler, the recommended dose of albuterol sulfate for children 4 years of age and older is 2 inhalations 15 to 30 minutes prior to exercise. Each actuation delivers 108 micrograms of albuterol sulfate, equivalent to 90 micrograms of albuterol base (Prod Info PROAIR(R) RESPICLICK(R) oral inhalation powder, 2016).
b) METERED-DOSE INHALER (CHILDREN 4 YEARS OR OLDER): For prophylaxis of exercise-induced bronchospasm, the recommended dose of albuterol sulfate for children 4 years of age and older is 2 inhalations by metered-dose inhaler 15 to 30 minutes prior to exercise. Each actuation delivers 108 micrograms of albuterol sulfate, equivalent to 90 micrograms of albuterol base (Prod Info PROAIR HFA(R) inhalation aerosol, 2008; Prod Info PROVENTIL(R) HFA oral inhalation aerosol, 2007; Prod Info VENTOLIN(R) HFA inhalation aerosol, 2008).

B) LEVALBUTEROL

1) METERED DOSE INHALER

a) 4 YEARS AND OLDER: One to two inhalations (45 to 90 mcg levalbuterol base) every 4 to 6 hours (Prod Info XOPENEX HFA(R) oral inhalation aerosol, 2015).
b) LESS THAN 4 YEARS: Safety and efficacy have not been established in children less than 4 years of age (Prod Info XOPENEX HFA(R) oral inhalation aerosol, 2015).

2) NEBULIZATION FOR INHALATION

a) 12 YEARS AND OLDER: Starting dose is 0.63 mg three times daily, every 6 to 8 hours, by nebulization. The dose may be increased to 1.25 mg three times daily in patients who either have more severe asthma or are not responding adequately to the lower dose (Prod Info XOPENEX(R) oral inhalation solution, 2015).
b) 6 TO 11 YEARS: Recommended dose is 0.31 mg three times daily, administered via nebulization. MAX dose is 0.63 mg three times daily (Prod Info XOPENEX(R) oral inhalation solution, 2015).
c) LESS THAN 6 YEARS: Safety and efficacy have not been established in children less than 6 years of age (Prod Info XOPENEX(R) oral inhalation solution, 2015).

Maximum Tolerated Exposure

A)

1) Schuh et al (1989) have documented that a relatively high-dose of aerosolized albuterol can be given frequently - 0.15 milligram/kilogram every 20 minutes (seven treatments in a 2 hour period); these high and frequent doses were not associated with any more side effects than lower more conventional doses, and high-dose therapy was more effective (Schuh et al, 1989).

B)

1) A prospective study was conducted to determine the threshold dose for toxicity following unintentional albuterol ingestion in children. Over a period of 18 months, 78 pediatric patients, who ingested albuterol and subsequently underwent medical evaluation, were identified. The mean ingested albuterol dose was 2 mg/kg (range from 0.2 to 8.8 mg/kg). The most commonly reported toxic effects included tachycardia (57%, 44/78), widened pulse pressure (50%, 27/54), hyperglycemia (50%, 12/24), agitation (45%, 35/78), low serum carbon dioxide (42%, 10/24), vomiting (26%, 20/78), and hypokalemia (26%, 9/35). Fifty-six patients (72%) were discharged from medical observation six hours post-ingestion. Twelve of 15 patients were hospitalized for 24 hours or less, with persistent symptoms of tachycardia and agitation, lasting more than 4 to 6 hours post-ingestion, being the most common reason for admission. All but one of the hospitalized patients had ingested more than 1 mg/kg of albuterol, indicating that the threshold dose for toxicity following albuterol ingestion in children is 1 mg/kg, based on the results of this study (Wiley et al, 1994).

C)

1) CHILD: A 3-year-old boy presented to the emergency department with a mild fever (37.9 degrees C) and tachycardia (144 bpm) approximately 30 minutes after inadvertently ingesting 53 mg of albuterol (4.8 mg/kg). With supportive care, the patient recovered and was discharged 3 days post-ingestion (Aktar et al, 2013).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) SPECIFIC SUBSTANCE

a) THERAPEUTIC ALBUTEROL CONCENTRATIONS

1) Uterine contractions are inhibited by plasma albuterol levels in the range of 8 to 33 nanograms/milliliter (Hutchings et al, 1987).
2) Peak serum levels after oral administration of 4 milligrams were seen at 240 minutes in a series of non-pregnant control patients and 120 minutes in 4 pregnant patients. Following 3 days of oral dosing (4 milligrams 5 times daily), pre-dose mean serum levels were 8 nanograms/milliliter and the 4-hour post-dose level was 12 nanograms/milliliter (Haukkamaa et al, 1985).

b) TOXIC ALBUTEROL CONCENTRATIONS

1) Whyte & Addis (1983) reported a fatal overdose with unknown amounts of albuterol and sustained release aminophylline. Initial albuterol plasma levels taken approximately 6 hours postingestion were 160 micrograms/liter. Serial levels taken until death at 36 hours indicated a half-life of 6.5 hours (Whyte & Addis, 1983).

Toxicity Information

7.7.1)

A) LD50- (ORAL)MOUSE:

1) > 2000 mg/kg (Prod Info Proventil(R), albuterol, 1990)

B) LD50- (ORAL)RAT:

1) > 2000 mg/kg (Prod Info Proventil(R), albuterol, 1990)

Pharmacology Toxicology

Pharmacologic Mechanism

A)

1) The prime action of beta-adrenergic drugs is to stimulate adenyl cylase, the enzyme which catalyzes the formation of cyclic-3, 5-adenosine monophosphate (cyclic AMP) from adenosine triphosphate (ATP) (Prenner, 1976).
2) Albuterol relaxes the smooth muscle of the bronchi, uterus, and skeletal muscle vascular bed. Significant decreases in gastrointestinal motility have also been documented with albuterol (Molline et al, 1972).
3) In the treatment of reversible obstructive airway disease, albuterol may also reduce chemical mediator release from pulmonary mast cells and improve mucociliary transport mechanisms (Middleton, 1981; Butchers et al, 1979; Howarth et al, 1985).
4) REVIEW ARTICLES: A complete review of the pharmacology, toxicology, and clinical uses of albuterol has been provided (Anon, 1981; Ahrens & Smith, 1984).

Toxicologic Mechanism

A)

B)

1) The stimulation of the beta-2 receptor will increase the ATPase enzyme, which results in elevated intracellular potassium concentrations. Theoretically, this is the basis for the production of hypokalemia with beta-2 specific agonists.
2) Other mechanisms contributing to the influx of potassium may include respiratory alkalosis secondary to respiratory stimulation from beta-adrenergic therapy and the influence of increased insulin secretion (Kung, 1986).

C)

Physicochemical

Physical Characteristics

A)

Molecular Weight

A)

Animal Toxicology

References

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ALBUTEROL AND RELATED AGENTS

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Genitourinary

Acid-Base

Hematologic

Dermatologic

Endocrine

Immunologic

Reproductive

Carcinogenicity

Monitoring Parameters Levels

Life Support

Patient Disposition

Monitoring

Oral Exposure

Inhalation Exposure

Eye Exposure

Dermal Exposure

Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Toxicity Information

Pharmacologic Mechanism

Toxicologic Mechanism

Physical Characteristics

Molecular Weight

General Bibliography