SYMPATHOMIMETIC AEROSOLS

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) NON-SELECTIVE BETA AGONISTS

a) Epinephrine (synonym)
b) Isoproterenol (synonym)

2) SELECTIVE BETA AGONISTS (B2 > B1)

a) Arformoterol tartrate (synonym)
b) Bitolterol (synonym)
c) Fenoterol (synonym)
d) Fenoterol hydrobromide (synonym)
e) Isoetharine (synonym)
f) Metaproterenol (synonym)
g) Pirbuterol (synonym)
h) Reproterol hydrochloride (synonym)
i) Terbutaline (synonym)

3) AMPHETAMINE-LIKE SYMPATHOMIMETIC AEROSOLS

a) Levo-desoxyephedrine (synonym)

1.2.1) MOLECULAR FORMULA
1) EPINEPHRINE: C9H13NO3
2) FORMOTEROL FUMARATE DIHYDRATE: (C19H24N2O4)2.C4H4O4.2H2O
3) INDACATEROL MALEATE: C24H28N2O3.C4H4O4
4) METAPROTERENOL SULFATE: (C11H17NO3)2.H2SO4
5) OLODATEROL HYDROCHLORIDE: C21H26N2O5.HCl
6) PIRBUTEROL ACETATE: C12H20N2O3.C2H4O2
7) SALMETEROL XINAFOATE: C25H37NO4.C11H8O3
8) VILANTEROL TRIFENATATE: C24H33Cl2NO5.C20H16O2

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Sympathomimetic aerosols are most commonly used for bronchodilation in patients with asthma or chronic obstructive pulmonary disease. They also may be used to treat patients with lung irritation, allergic reactions, croup, and hyperkalemia. These medications may also be used for tocolysis during pregnancy. These medications include nonselective beta agonists (epinephrine, isoproterenol), selective beta agonists that stimulate beta-2 or beta-1 receptors (albuterol, levalbuterol, arfomoterol tartrate, bitolterol, iseoetharine, metaproterenol, pirbuterol, reproterol hydrochloride, terbutaline), and amphetamine-like sympathomimetic aerosols (eg, levo-deoxyephedrine). These agents are rarely abused (injected) for their stimulant effects.
B) PHARMACOLOGY: These medications achieve their effect via agonist activity on beta adrenergic receptors. Depending on the medication, some are more selective for beta-2 receptors while others have equal efficacy on beta-1 and beta-2 adrenergic receptors.
C) TOXICOLOGY: These medications exert their toxic effects via sympathetic activation via beta adrenergic receptors.
D) EPIDEMIOLOGY: Mild toxicity is common with the use of these medications. More severe effects are rare, especially if these medications are used correctly.
E) WITH THERAPEUTIC USE

1) Adverse effects are common with the use of these drugs, and include elevations in blood pressure, tachycardia, anxiety, agitation, insomnia, tremor, anorexia, nausea, vomiting, bronchodilation, premature ventricular contractions, nausea, mydriasis, hyperglycemia, hypokalemia, and hyperventilation. PREGNANCY: These drugs do cross the placenta and may have negative effects on the fetus including heart rate and rhythm disturbances. In addition, interventricular septal thickness changes have been documented in fetuses exposed to these agents in utero. However, these complications are uncommon.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Tachycardia, mild hypertension, tremors, anxiety, nausea and vomiting, mild hypokalemia and hyperglycemia, and premature ventricular contractions. DERMAL exposures would not be expected to cause significant toxicity. OCULAR exposures may cause mydriasis and mild systemic toxicity. ORAL ingestion of sympathomimetic aerosol preparations is unlikely to cause systemic toxicity as most of these agents are poorly absorbed via ingestion.
2) SEVERE TOXICITY: More severe hypertension and tachycardia, persistent vomiting, muscle pain, rhabdomyolysis, acute lung injury, life-threatening cardiac dysrhythmias such as ventricular fibrillation, and myocardial infarction. PARENTERAL EXPOSURE: Systemic toxicity from injections of sympathomimetic inhalants has occurred and can cause severe toxicity and death.

0.2.5)

A) Small doses of epinephrine may cause transient decreases in blood pressure, but larger amounts will increase blood pressure.

1) When alpha adrenergic agonism results in increased blood pressure, beta-2 agonism causes decreased blood pressure, so hypertension or hypotension is possible.

B) All the drugs result in cardiac stimulation and have the potential for causing ventricular dysrhythmias including ventricular extrasystoles (PVC's), tachycardia, myocardial infarction, and even fibrillation.

0.2.6)

A) Sympathomimetics may cause hyperventilation. Bronchodilation may occur. Acute lung injury may occur in massive overdoses.

0.2.7)

A) WITH THERAPEUTIC USE

1) Anxiety and insomnia may be noted. Tremors, believed to be peripherally or non-centrally mediated, have been particularly marked with terbutaline.

0.2.8)

A) WITH POISONING/EXPOSURE

1) Signs and symptoms include anorexia, nausea, and vomiting.

0.2.12)

A) WITH POISONING/EXPOSURE

1) Hypokalemia may result from overdose.

0.2.15)

A) WITH POISONING/EXPOSURE

1) Massive overdose or abuse has resulted in muscle pain and rhabdomyolysis.

0.2.16)

A) Hyperglycemia may result from overdosage. Reactive hypoglycemia may result.

0.2.20)

A) The following agents have been classified as FDA pregnancy category C: albuterol, epinephrine, fluticasone furoate/vilanterol, glycopyrrolate/formoterol fumarate, isoetharine, indacaterol/glycopyrrolate, isoproterenol, metaproterenol, olodaterol, olodaterol/tiotropium bromide, salmeterol, and vilanterol/umeclidinium. Terbutaline has been classified as FDA pregnancy category B. Beta sympathomimetic drugs freely cross the placenta. When used during pregnancy for tocolysis, they were associated with adverse effects on the fetus. Fetal skeletal variations, including decreased or absent ossification in the cervical vertebral centrum and metacarpals, were observed in rabbits administered vilanterol at high inhaled doses.

0.2.21)

A) At the time of this review, the manufacturer does not report any carcinogenic potential of indacaterol/glycopyrrolate or glycopyrrolate/formoterol in humans.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) Systemic toxicity from oral ingestion of poorly absorbed sympathomimetic aerosol preparations is unlikely. Orally absorbable products (eg, phenylephrine, propylhexedrine, metaproterenol, albuterol) may produce toxicity, if ingested.
B) Follow recommendations under INHALATION EXPOSURE as appropriate.

0.4.3)

A) MILD TO MODERATE TOXICITY

1) Many patients require no treatment beyond the discontinuation of the offending drug. Benzodiazepines may be used to treat agitation, tremors, mild hypertension and/or tachycardia. Premature ventricular contractions usually do not require treatment. However, for patients with frequent or symptomatic premature ventricular contractions, checking and optimizing electrolytes is reasonable. Antiemetics may be used for patients with persistent nausea and vomiting.

B) SEVERE TOXICITY

1) Control agitation with benzodiazepines. For severe overdoses, the greatest concerns are cardiovascular and respiratory toxicities. For patients with cardiac dysrhythmias, correct electrolyte disorders (eg, hypokalemia, hypocalcemia, and hypomagnesemia). Treat unstable ventricular dysrhythmias with cardioversion, and antidysrhythmics like lidocaine and amiodarone. Hypertension and tachycardia typically improve with benzodiazepine sedation. For severe hypertension, nitroprusside is the preferred agent, but other alternatives include labetalol, nitroglycerin, and phentolamine. Tachycardia may be treated with esmolol, but beta adrenergic antagonists should be used cautiously in patients with reactive airway disease or congestive heart failure, in addition, use of beta blockers may cause unopposed alpha effects (primarily hypertension), if the agent involved in the overdose has both alpha and beta agonist effects. In patients with severe respiratory distress, treatment includes orotracheal intubation and assisted mechanical ventilation.

C) INHALATION EXPOSURE

1) Most of the treatment options discussed in this management refer to inhalational exposure, as this is the most common mode of exposure for these medications.

D) PARENTERAL EXPOSURE

1) Though not an intended mode of delivery, parenteral exposures with significant toxicity have been reported and should be managed similar to inhalational or oral toxicity, as appropriate. Inadvertent delivery of terbutaline subcutaneously has caused tachycardia, hypertension, and even ECG changes consistent with ischemia. There have been other reports of these agents being used intravenously for abuse, that caused agitation, tremor, hallucinations, amnesia, sweating, hypertension, tachycardia, and even hypotension, bradycardia and asystole.

E) DERMAL EXPOSURE

1) Significant toxicity is not expected from a dermal exposure, but simple decontamination with water or soap would be reasonable.

F) EYE EXPOSURE

1) Significant toxicity is not expected from an eye exposure, but simple irrigation of the eyes with water would be reasonable.

G) DECONTAMINATION

1) PREHOSPITAL: In general, there is no role for activated charcoal for oral ingestions of sympathomimetic aerosols due to their limited absorption via the gut. There is no role for dilution in any forms, and though likely not needed, it would not be unreasonable to wash skin for dermal exposures or irrigate eyes from ocular exposures.
2) HOSPITAL: There is little to no role for activated charcoal for oral ingestions as these agents have limited absorption. There is definitely no role for gastric lavage, whole bowel irrigation or multiple doses of charcoal.

H) AIRWAY MANAGEMENT

1) Though it is possible that sympathomimetic stimulants may cause acute lung injury due to massive catecholamine discharge in overdoses, airway management is usually not an issue in these patients.

I) ANTIDOTE

1) There is no specific antidote for these exposures.

J) ENHANCED ELIMINATION

1) There is no specific evidence to support the use of dialysis, hemoperfusion, urinary alkalinization, or multiple dose charcoal.

K) PATIENT DISPOSITION

1) HOME CRITERIA: Patients who are asymptomatic or who rapidly improve with cessation of the sympathomimetic aerosol(s) should be safe to manage at home.
2) OBSERVATION CRITERIA: Patients who do not improve with cessation of the sympathomimetic aerosol or who experience worsening symptoms should be sent to a healthcare facility for further observation until they improve. Patients may be discharged to home after they show clear and consistent improvement of their symptoms.
3) ADMISSION CRITERIA: Patients who do not demonstrate improvement after a period of observation of several hours or who require continuing treatment with medications should be admitted to the hospital. Those with severe symptoms that require intubation or management of dysrhythmias or severe hypertension should be admitted to the ICU. Patients may be discharged once all medications have been stopped and their symptoms are clearly improving.
4) CONSULT CRITERIA: Patients who are admitted to the ICU should receive critical care consultation. Consult a medical toxicologist or poison center for patients with severe toxicity or in whom the diagnosis is unclear.

L) PITFALLS

1) Potential errors in managing these patients include not recognizing signs of toxicity from the use of these medications or overlooking other possible causes for symptoms.

M) PHARMACOKINETICS

1) In general, the onset of action of these medications when inhaled is fairly quick, within a few minutes, and the duration of action depends on the particular medication, but can last for hours. Distribution can range widely depending on the medication, but in general these medications are intended to have maximal effect on the pulmonary system. Protein binding also ranges widely depending on the medication. Elimination half-life of these medications ranges from a few minutes for isoproterenol to up to a day for terbutaline. These parameters may vary depending on the patient's age and comorbid diseases.

N) TOXICOKINETICS

1) The half-life and duration of action of these medications may be increased in the overdose setting. Absorption kinetics should remain similar.

O) PREDISPOSING CONDITIONS

1) Extremes of age may be more sensitive to adverse effects from these medications. Patients with cardiac comorbid conditions may be more likely to develop cardiac-related complications.

P) DIFFERENTIAL DIAGNOSIS

1) The differential diagnosis includes inhalant abuse, methamphetamine abuse, cocaine use, and other medications or substances that can cause a sympathomimetic response and thyrotoxicosis.

0.4.6)

A) Systemic toxicity from injections of sympathomimetic inhalants has occurred and has resulted in death. Follow recommendations under INHALATION EXPOSURE when appropriate.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Heent

3.4.2)

A) WITH POISONING/EXPOSURE

1) SIALADENOSIS: Bilateral swelling of the parotid glands has been reported following excessive use of inhaled isoproterenol (Borsanyi & Blanchard, 1961) or epinephrine (Loria & Wedner, 1989).

3.4.3)

A) WITH POISONING/EXPOSURE

1) MYDRIASIS: Overdoses or abuse, as well as therapeutic use, may result in dilated pupils (Grant & Schuman, 1993; Scalzo et al, 1995).

Cardiovascular

3.5.1)

A) Small doses of epinephrine may cause transient decreases in blood pressure, but larger amounts will increase blood pressure.

1) When alpha adrenergic agonism results in increased blood pressure, beta-2 agonism causes decreased blood pressure, so hypertension or hypotension is possible.

3.5.2)

A) HYPERTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Small doses of epinephrine can cause transient decreases in blood pressure, but larger doses increase blood pressure sometimes to dangerous degrees.
b) Intravenous abuse of naphazoline inhalant has resulted in an increased blood pressure (van Montfrans et al, 1981). Naphazoline has a predominant alpha-adrenergic component which can cause prolonged hypertension with peripheral vasoconstriction.
c) CASE REPORT: Intravenous abuse of epinephrine (82.5 mg) nasal inhalant resulted in refractory hypertension and tachycardia. This was followed by a marked period of hypotension, bradycardia, and asystole, which required continuous pressor infusions and invasive monitoring. The patient remained in a persistent vegetative state until his death 26 days after exposure (Scalzo et al, 1995).
d) Overdosage with albuterol inhalation aerosol may result in hypertension (Prod Info PROVENTIL(R) inhalation solution, 2002).

B) CONDUCTION DISORDER OF THE HEART

1) WITH POISONING/EXPOSURE

a) These agents can result in cardiac stimulation and have the potential to alter rhythm function of the ventricle with ventricular extrasystoles, tachycardia, angina and even fibrillation. As a result, patients with angina can have clinical exacerbations. Abuse of these agents may be associated with cardiac arrest (Prod Info PROVENTIL(R) inhalation solution, 2002). Sinus tachycardia is the most common rhythm disturbance.
b) CASE REPORT: Sinus tachycardia was reported in a 22-year-old pregnant woman following administration of 200 mg ritodrine infusion over 12 hours. Acute pulmonary edema with severe hypoxia developed after caesarean section was completed. On the following 2 days, she had a myocardial ischemia, which spontaneously improved by the fourth day (Brosset et al, 1982).
c) CASE REPORT: Intravenous abuse of epinephrine (82.5 mg) inhalant (OTC asthma inhaler) in a 37-year-old man resulted in ventricular fibrillation requiring intensive supportive care. The patient developed refractory tachycardia (150 bpm) and hypertension prior to becoming markedly hypotensive with bradycardia followed by asystole. Following a persistent vegetative state, the patient died 26 days postexposure (Scalzo et al, 1995).
d) CASE SERIES: Four abusers of intravenous propylhexedrine were hospitalized with ECG evidence of severe left ventricular failure with 3 developing evidence of right ventricular dilatation (Croft et al, 1982).
e) CASE REPORT: Bradycardia (45/min), with many premature ventricular beats, was reported in an adult drug addict following the intravenous injection of naphazoline. A 29-year-old woman was also reported to have sinus bradycardia (36/min), with many ectopic ventricular beats, following naphazoline IV injection (van Montfrans et al, 1981).

C) MYOCARDIAL INFARCTION

1) WITH POISONING/EXPOSURE

a) These drugs all have the potential for cardiac stimulation; overdose or abuse of sympathomimetic aerosols may result in myocardial infarction (Scalzo et al, 1995).
b) CASE REPORT: Intravenous abuse of an epinephrine (82.5 mg) inhalant in a 37-year-old man resulted in ventricular fibrillation requiring aggressive life support measures. Initial CK-MB was 40.3 ng/mL (nl 0.0-7.5) with ST elevation in anterior ECG leads. Following a persistent vegetative state, the patient died 26 days postexposure (Scalzo et al, 1995).

D) CARDIOMEGALY

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Cardiomegaly was reported in a patient following many years of overusing an epinephrine-containing inhaler (Stewart et al, 1992).

Respiratory

3.6.1)

A) Sympathomimetics may cause hyperventilation. Bronchodilation may occur. Acute lung injury may occur in massive overdoses.

3.6.2)

A) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) Sympathomimetic stimulants may cause acute lung injury due to massive catecholamine discharge in overdoses (Curry et al, 1998; Nuchpuckdee et al, 1986; Hermansen & Johnson, 1984; Brosset et al, 1982).

B) HYPERVENTILATION

1) WITH THERAPEUTIC USE

a) Sympathomimetics may cause an increase in respiratory drive, an increase in oxygen consumption, and thus hyperventilation (Curry et al, 1998).

C) BRONCHIECTASIS

1) WITH THERAPEUTIC USE

a) Ephedrine, and possibly pseudoephedrine, have enough beta-2 effect to cause bronchodilation.

Neurologic

3.7.1)

A) WITH THERAPEUTIC USE

1) Anxiety and insomnia may be noted. Tremors, believed to be peripherally or non-centrally mediated, have been particularly marked with terbutaline.

3.7.2)

A) FEELING NERVOUS

1) WITH THERAPEUTIC USE

a) Anxiety is a common side effect of these agents.
b) Insomnia is also frequently reported.

B) TREMOR

1) WITH POISONING/EXPOSURE

a) Tremors, which are believed to be due to a peripheral and not a central effect, have been particularly marked with terbutaline.
b) CASE REPORT: A 29-year-old man presented to the ED with agitation, anxiety, and coarse hand tremors following the intentional ingestion of the contents of a Benzedrex(R) (propylhexedrine) nasal inhaler (Liggett, 1982).

C) HALLUCINATIONS

1) WITH POISONING/EXPOSURE

a) Hallucinations and aggressive behavior changes have been reported with salbutamol (Khanna & Davies, 1986; O'Callaghan & Milner, 1988; Thompson et al, 1983).
b) CASE REPORT: Chronic inhalation of sympathomimetics (L-ephedrine, phenylephrine HCl, and oxymetazoline) resulting in auditory and visual hallucinations led to the ED admission of a 61-year-old man. After discontinuation of the inhalers, the hallucinations gradually resolved(Escobar & Karno, 1982).

Gastrointestinal

3.8.1)

A) WITH POISONING/EXPOSURE

1) Signs and symptoms include anorexia, nausea, and vomiting.

3.8.2)

A) GASTRITIS

1) WITH POISONING/EXPOSURE

a) Signs and symptoms may include anorexia, nausea, and vomiting. A patient developed vomiting after experiencing a myocardial infarction and ventricular fibrillation following intravenous abuse of epinephrine (82.5 mg) (Scalzo et al, 1995).

Acid-Base

3.11.2)

A) LACTIC ACIDOSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 16-year-old girl, with a history of asthma, intentionally inhaled 60 puffs of a combination salmeterol xinafoate 25 mcg and fluticasone propionate 50 mcg and became anxious with complaints of chest pain and palpitations while living at an adolescent treatment center. Upon admission, she was alert and oriented with sinus tachycardia (heart rate 131 beats/min). Laboratory studies showed signs of lactic acidosis (pH 7.34, lactate 8.3 mmol/L), hypokalemia and hypophosphatemia. She was treated supportively with IV fluids and potassium repletion. Although the patient was stable, lactic acidosis (pH 7.30, bicarbonate 13 mmol/L) persisted for about 4.5 hours after presentation. A toxicology screen was negative and other laboratory studies were within normal limits. At 14 hours, she had no further signs or symptoms and was discharged after 18 hours of observation and a psychiatric evaluation (Manara et al, 2012).

Hematologic

3.13.2)

A) LEUKOCYTOSIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: A leukemoid reaction (WBC 38,200/mm(3); 92% neutrophils; 6% bands; 1% lymphocytes, 1% monocytes) caused by a nasal sympathomimetic (phenylephrine) has been reported. When phenylephrine was stopped, the WBC count dropped to 7500/mm(3) with a normal differential cell count, within 48 hours (Huyck et al, 1992).

Musculoskeletal

3.15.1)

A) WITH POISONING/EXPOSURE

1) Massive overdose or abuse has resulted in muscle pain and rhabdomyolysis.

3.15.2)

A) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) Increased serum CPK has been associated with the use or abuse of several sympathomimetic aerosols, including albuterol, terbutaline and epinephrine.
b) CASE REPORT: Intravenous abuse of epinephrine (82.5 mg) inhalant resulted in rhabdomyolysis (peak CK of 9,646 IU/L; creatinine of 3.6 mg/dL) in a 37-year-old man. The patient expired 26 days postexposure (Scalzo et al, 1995).

Endocrine

3.16.1)

A) Hyperglycemia may result from overdosage. Reactive hypoglycemia may result.

Reproductive

3.20.1)

3.20.2)

A) LACK OF INFORMATION

1) SALMETEROL

a) There are no adequate or well controlled studies of salmeterol use during human pregnancy (Prod Info SEREVENT(R) DISKUS(R) inhalation powder, 2014).

B) ANIMAL STUDIES

1) FORMOTEROL FUMARATE

a) Formoterol fumarate demonstrated teratogenic and embryocidal effects, increased pup loss at birth and during lactation, and decreased pup weights at approximately 1,500 and 61,000 times the maximum recommended human daily inhalation dose (MRHDID) on a body surface area basis. Umbilical hernia was noted at a dose of 1,500 times the MRHDID, while prolonged pregnancy and fetal brachygnathia were observed at doses 7,600 times the MRHDID. In another study, no teratogenic effects were seen at doses 600 times the MRHD. Subscapular liver cysts were seen on fetuses after exposure to an oral dose 61,000 times the MHRDID, whereas no teratogenic effects were observed at doses 3,600 times the MHRDID (Prod Info BEVESPI AEROSPHERE(TM) inhalation aerosol powder, 2016).

2) INDACATEROL/GLYCOPYRROLATE

a) During animal studies, no effects on perinatal or postnatal development were reported with indacaterol doses up to 110 times the maximum recommended human dose (MRHD) or with glycopyrrolate at doses up to 1100 times the MRHD. There were also no reports of teratogenicity with indacaterol at doses up to 770 times the MRHD or glycopyrrolate at doses up to 1400 times the MRHD (Prod Info UTIBRON(TM) NEOHALER(R) oral inhalation powder, 2015).

3) OLODATEROL

a) RABBITS: Studies in rabbits at inhaled doses of 2489 mcg/kg/day (approximately 7130 times the maximum recommended human daily inhalation dose (MRHDID) in adults on an AUC basis) showed fetal toxicities in the forms of enlarged or small heart atria or ventricles, eye abnormalities, and split or distorted sternum (Prod Info STRIVERDI(R) RESPIMAT(R) oral inhalation spray, 2014).
b) RATS: Studies in rats at inhaled doses of 1054 mcg/kg/day (approximately 2,731 times the maximum recommended human daily inhalation dose on an AUC basis) showed no teratogenic effects but showed placental transfer (Prod Info STRIVERDI(R) RESPIMAT(R) oral inhalation spray, 2014).

4) SALMETEROL

a) Salmeterol is known to cross the placental barrier following oral administration in both mice and rats. During animal studies, administration of salmeterol at doses approximately 160 times the maximum recommended daily inhalation dose (MRHDID) in rats did not result in any teratogenic effects. Fetal toxic effects as a result of beta-adrenoreceptor stimulation was reported in pregnant Dutch rabbits administered salmeterol at doses approximately 50 times the MRHDID. The effects included precocious eyelid openings, sternebral fusion, limb and paw flexures, cleft palate, and delayed ossification of frontal cranial bones. Fetal toxic effects were not reported at doses approximately 20 times the MRHDID. Administration of salmeterol at doses approximately 1600 times the MRHDID in New Zealand White rabbits only resulted in delayed ossification of the frontal cranial bones (Prod Info SEREVENT(R) DISKUS(R) inhalation powder, 2014).

5) VILANTEROL/FLUTICASONE FUROATE

a) There are no adequate or well controlled studies of fluticasone furoate/vilanterol use in human pregnancy. During animal studies, administration of fluticasone furoate and vilanterol in rats at doses approximately 9 and 40 times the maximum recommended human daily inhalation dose (MRHDID), respectively, revealed no evidence of teratogenicity. Teratogenic effects were not observed in rabbits administered fluticasone furoate or vilanterol at doses approximately 2 and 160 times the MRHDID, respectively. Fetal skeletal variations, including decreased or absent ossification in cervical vertebral centrum and metacarpals, were observed in rabbits administered vilanterol at approximately 1000 times the MRHDID. There were no observed effects on peri- or postnatal development in rats administered fluticasone furoate or vilanterol at doses approximately 3 and 3900 times the MRHDID, respectively (Prod Info BREO(TM) ELLIPTA(TM) oral inhalation powder, 2013).

6) VILANTEROL/UMECLIDINIUM

a) RABBITS: Fetal skeletal variations, including decreased or absent ossification in cervical vertebral centrum and metacarpals, were observed in rabbits administered vilanterol at inhaled doses of 5740 mcg/kg/day or subQ doses of 300 mcg/kg/day (approximately 450 times the maximum recommended human daily inhalation dose (MRHDID) in adults on an AUC basis) (Prod Info ANORO(TM) ELLIPTA(TM) oral inhalation powder, 2013).
b) LACK OF EFFECT: RABBITS: Teratogenic effects were not observed in rabbits administered vilanterol at inhaled doses up to 591 mcg/kg/day (approximately 70 times the MRHDID on an AUC basis) (Prod Info ANORO(TM) ELLIPTA(TM) oral inhalation powder, 2013).
c) LACK OF EFFECT: RATS: Administration in rats of the single agent vilanterol at inhaled doses up to 33,700 mcg/kg/day (approximately 13,000 times the MRHDID on a mcg/m(2) basis) revealed no evidence of teratogenicity (Prod Info ANORO(TM) ELLIPTA(TM) oral inhalation powder, 2013).

3.20.3)

A) LACK OF INFORMATION

1) GLYCOPYRROLATE/FORMOTEROL FUMARATE

a) There are no adequate and well-controlled studies of glycopyrrolate/formoterol fumarate or its individual components in pregnant women. The drug should be used during pregnancy only if the benefits to the mother outweigh the potential risks to the fetus(Prod Info BEVESPI AEROSPHERE(TM) inhalation aerosol powder, 2016).

B) INDACATEROL/GLYCOPYRROLATE

1) Use during pregnancy only if the potential maternal benefit outweighs the potential fetal risk (Prod Info UTIBRON(TM) NEOHALER(R) oral inhalation powder, 2015).

C) LABOR OR DELIVERY

1) Beta-adrenergic agonists can have the potential to interfere with uterine contractility (Prod Info STIOLTO(TM) RESPIMAT(R) oral inhalation spray, 2015; Prod Info STRIVERDI(R) RESPIMAT(R) oral inhalation spray, 2014).
2) Restrict use during labor to only those cases where the benefit clearly outweighs the risk (Prod Info STIOLTO(TM) RESPIMAT(R) oral inhalation spray, 2015).

D) MYOCARDIAL ISCHEMIA

1) Maternal effects following the use of beta sympathomimetics for tocolysis during pregnancy have included: hypertension, dysrhythmias, myocardial ischemia and damage, and electrolyte/fluid imbalances (Bendetti, 1983; Katz & Seeds, 1989).

E) OLODATEROL/TIOTROPIUM BROMIDE

1) Administer during pregnancy only if the benefit justifies the risk to the fetus (Prod Info STIOLTO(TM) RESPIMAT(R) oral inhalation spray, 2015).

F) PLACENTAL BARRIER

1) Beta sympathomimetic drugs freely cross the placenta. When used during pregnancy for tocolysis, they have been implicated in causing adverse effects on the fetus including (Katz & Seeds, 1989a; Brosset et al, 1982; Hermansen & Johnson, 1984; Lenke & Trupin, 1984; Nuchpuckdee et al, 1986):

a) Heart rate and rhythm disturbances, stillbirth, hydrops, myocardial ischemia and infarction, neonatal cardiac failure, and neonatal death.
b) Interventricular septal thickness changes have been documented in fetuses exposed to these agents in utero.
c) While these complications are not common, they add enough potential risk such that the therapeutic use of these agents during pregnancy should be carefully weighed.

G) PREGNANCY CATEGORY

1) The manufacturers have classified albuterol, epinephrine, fluticasone furoate/vilanterol, glycopyrrolate/formoterol fumarate, indacaterol/glycopyrrolate, isoetharine, isoproterenol, metaproterenol, olodaterol, olodaterol/tiotropium bromide, salmeterol, and vilanterol/umeclidinium as FDA pregnancy category C (Prod Info STIOLTO(TM) RESPIMAT(R) oral inhalation spray, 2015; Prod Info UTIBRON(TM) NEOHALER(R) oral inhalation powder, 2015; Prod Info SEREVENT(R) DISKUS(R) inhalation powder, 2014; Prod Info STRIVERDI(R) RESPIMAT(R) oral inhalation spray, 2014; Prod Info BREO(TM) ELLIPTA(TM) oral inhalation powder, 2013; Prod Info ANORO(TM) ELLIPTA(TM) oral inhalation powder, 2013; Prod Info AccuNeb(R) inhalation solution, 2011; Prod Info metaproterenol sulfate oral tablets, 2010; Prod Info Adrenalin(R), 1999; Prod Info Isuprel(R), 1999).
2) Terbutaline has been classified as pregnancy category B (Prod Info terbutaline sulfate injection, 2004).

H) ANIMAL STUDIES

1) INDACATEROL/GLYCOPYRROLATE

2) VILANTEROL/UMECLIDINIUM

a) LACK OF EFFECT: RATS: There were no observed effects on peri- or postnatal development in rats administered vilanterol at oral doses up to 10,000 mcg/kg/day (approximately 3900 times the maximum recommended human daily inhalation dose (MRHDID) in adults) (Prod Info ANORO(TM) ELLIPTA(TM) oral inhalation powder, 2013).

3.20.4)

A) BREAST MILK

1) GLYCOPYRROLATE/FORMOTEROL FUMARATE: It is not known whether glycopyrrolate/formoterol fumarate is excreted in human milk, although it has been detected in the milk of lactating rats. Therefore, caution should be exercised when glycopyrrolate/formoterol fumarate is administered to lactating women (Prod Info BEVESPI AEROSPHERE(TM) inhalation aerosol powder, 2016).
2) INDACATEROL/GLYCOPYRROLATE: It is unknown whether glycopyrrolate/indacaterol or the individual components are excreted into human breast milk. Discontinue treatment or discontinue nursing, taking into account the importance of the drug to the mother (Prod Info UTIBRON(TM) NEOHALER(R) oral inhalation powder, 2015).
3) OLODATEROL: It is unknown whether olodaterol is excreted in human breast milk. Because of the potential for serious adverse reactions in the nursing infant, exercise caution when administering to nursing women (Prod Info STRIVERDI(R) RESPIMAT(R) oral inhalation spray, 2014).
4) OLODATEROL/TIOTROPIUM BROMIDE: It is not known whether olodaterol/tiotropium bromide or the individual components are excreted in human breast milk. Olodaterol, the active metabolites of olodaterol, and tiotropium are known to be excreted in the milk of lactating animals. Use caution when administering to lactating women (Prod Info STIOLTO(TM) RESPIMAT(R) oral inhalation spray, 2015).
5) SALMETEROL: Lactation studies with salmeterol have not been conducted. Because many drugs are excreted in human milk and the potential for serious adverse reactions may exist in nursing infants, use caution when considering the use of salmeterol in lactating women (Prod Info SEREVENT(R) DISKUS(R) inhalation powder, 2014).
6) VILANTEROL/FLUTICASONE FUROATE: Lactation studies have not been conducted with fluticasone furoate/vilanterol. It is unknown whether fluticasone furoate/vilanterol is excreted into human breast milk, although other corticosteroids and beta-2 agonists have been detected in human milk. Due to the lack of information regarding the combination product and because many drugs are excreted in human milk, the manufacturer recommends using caution when administering fluticasone furoate/vilanterol to lactating women (Prod Info BREO(TM) ELLIPTA(TM) oral inhalation powder, 2013).
7) VILANTEROL/UMECLIDINIUM: Lactation studies have not been conducted with the umeclidinium and vilanterol combination or with the individual components. It is unknown whether umeclidinium or vilanterol are excreted into human breast milk (Prod Info ANORO(TM) ELLIPTA(TM) oral inhalation powder, 2013).

B) ANIMAL STUDIES

1) INDACATEROL/GLYCOPYRROLATE

a) During animal studies, indacaterol was detected in the milk of lactating animals. Glycopyrrolate was also detected in the milk of lactating animals with concentrations reaching up to 10-fold higher in the milk than that of the mother (Prod Info UTIBRON(TM) NEOHALER(R) oral inhalation powder, 2015).

2) OLODATEROL

a) Lactation studies in rats showed that olodaterol and its metabolites are excreted into the milk of lactating rats (Prod Info BEVESPI AEROSPHERE(TM) inhalation aerosol powder, 2016).

3) SALMETEROL

a) Salmeterol is excreted into the milk of lactating rats (Prod Info SEREVENT(R) DISKUS(R) inhalation powder, 2014).

3.20.5)

A) ANIMAL STUDIES

1) INDACATEROL/GLYCOPYRROLATE

a) Fertility was impaired (eg, decreased corpora lutea, decreased implantation sties, decreased live fetuses) in male and female animals administered subQ glycopyrrolate at doses up to 1900 times the maximum recommended human dose (MRHD). There were no adverse effects on fertility or reproductive performance with doses approximately 350 times the MRHD (Prod Info UTIBRON(TM) NEOHALER(R) oral inhalation powder, 2015).

2) OLODATEROL

a) RATS: In animal studies, olodaterol inhalation doses up to approximately 2322 times the maximum recommended human daily inhalation dose (RHDID) did not impair male or female fertility in rats (Prod Info STIOLTO(TM) RESPIMAT(R) oral inhalation spray, 2015; Prod Info STRIVERDI(R) RESPIMAT(R) oral inhalation spray, 2014).

3) VILANTEROL/UMECLIDINIUM AND VILANTEROL

a) RATS: No fertility studies were conducted with the umeclidinium and vilanterol combination; however, in animal reproductive studies, there was no evidence of impaired fertility in male and female rats administered single-agent vilanterol at inhaled doses up to 31,500 and 37,100 mcg/kg/day (approximately 12,000 and 14,500 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) in adults on a mcg/m(2) basis) (Prod Info ANORO(TM) ELLIPTA(TM) oral inhalation powder, 2013).

Carcinogenicity

3.21.2)

A) At the time of this review, the manufacturer does not report any carcinogenic potential of indacaterol/glycopyrrolate or glycopyrrolate/formoterol in humans.

3.21.4)

A) LACK OF INFORMATION

1) INDACATEROL/GLYCOPYRROLATE

a) No treatment related increases in tumors were reported during a 2-year inhalation study of indacaterol in Wistar rats at doses up to 110 times the maximum recommended human dose (MHRD). There was no evidence of tumorigenicity with doses up to 600 mg/kg/day(Prod Info UTIBRON(TM) NEOHALER(R) oral inhalation powder, 2015).

2) GLYCOPYRROLATE/FORMOTEROL FUMARATE

a) No long-term studies have been conducted in animals with the glycopyrrolate and formoterol fumarate combination or with glycopyrrolate alone (Prod Info BEVESPI AEROSPHERE(TM) inhalation aerosol powder, 2016)

B) GLYCOPYRROLATE/FORMOTEROL FUMARATE

1) In a 24-month carcinogenicity study in mice, a dose-related increase in the incidence of uterine leiomyomas were reported following formoterol fumarate oral doses of 0.1 mg/kg (approximately 25 times the maximum recommended human daily inhalation dose (MRHDID) on a mg/m(2) basis) or more. In a 24-month carcinogenicity study in Sprague-Dawley rats, an increased incidence of mesovarian leiomyoma and uterine leiomyosarcoma were reported with inhaled doses of formoterol fumarate 130 mcg/kg (approximately 65 times the MRHDID on a mcg/m(2) basis) (Prod Info BEVESPI AEROSPHERE(TM) inhalation aerosol powder, 2016).

Genotoxicity

1) There was no evidence of genotoxicity or mutagenicity with indacaterol in the following tests: In vitro Ames test, in vitro chromosome aberration test in V79 Chinese hamster cells, and in vivo rat bone marrow micronucleus test (Prod Info UTIBRON(TM) NEOHALER(R) oral inhalation powder, 2015).

1) There was no evidence of genotoxicity or mutagenicity with glycopyrrolate in the following tests: bacterial reverse mutation assay, in vitro mammalian cell micronucleus assay in TK6 cells, or the in vivo micronucleus assay in rats. There was no evidence of genotoxicity or mutagenicity with formoterol fumarate in the following tests: Ames Salmonella/microsome plate test, mouse lymphoma test, chromosome aberration test in human lymphocytes, and rat micronucleus test (Prod Info BEVESPI AEROSPHERE(TM) inhalation aerosol powder, 2016).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) If the patient is asymptomatic, laboratory evaluation is not indicated.
B) Patients who experience cardiac manifestations such as tachycardia, hypertension, hypotension, or dysrhythmias should be placed on a cardiac monitor and get an ECG, laboratory studies such as electrolytes, and potentially a troponin level if they are having chest pain.
C) Obtain a chest x-ray for patients with respiratory symptoms.
D) Obtain a total creatine kinase and monitor for rhabdomyolysis in patients with severe muscle pain.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Monitor serum electrolytes for possible hypokalemia.
2) Blood glucose monitoring is recommended.
3) Obtain a tropin level in a patient with chest pain.

4.1.4)

A) OTHER

1) MONITORING

a) Monitor ECG and blood pressure.
b) Monitor chest x-ray and arterial blood gases in patients with respiratory symptoms.

Methods

1) Levo-methamphetamine (l-desoxyephedrine) cannot be distinguished from dextro-methamphetamine in commonly used screening and confirmation urine assays.

a) The Syva EMIT test and RIA Abuscreen Kit give similar responses to both isomers, while the Abbott TDX assay is somewhat more sensitive to the d-isomer.
b) D/l differentiation assays using GC/MS are not routinely done, but are available (Fretthold, 1989).

Treatment

Life Support

Patient Disposition

6.3.3)

6.3.3.1) ADMISSION CRITERIA/INHALATION

A) Patients who do not demonstrate improvement after a period of observation of several hours or who require continuing treatment with medications should be admitted to the hospital. Those with severe symptoms that require intubation or management of dysrhythmias or severe hypertension should be admitted to the ICU. Patients may be discharged once all medications have been stopped and their symptoms are clearly improving.

6.3.3.2) HOME CRITERIA/INHALATION

A) Patients who are asymptomatic or who rapidly improve with cessation of the sympathomimetic aerosol(s) should be safe to manage at home.

6.3.3.3) CONSULT CRITERIA/INHALATION

A) Patients who are admitted to the ICU should receive critical care consultation. Consult a medical toxicologist or poison center for patients with severe toxicity or in whom the diagnosis is unclear.

6.3.3.5) OBSERVATION CRITERIA/INHALATION

A) Patients who do not improve with cessation of the sympathomimetic aerosol or who experience worsening symptoms should be sent to a healthcare facility for further observation until they improve. Patients may be discharged to home after they show clear and consistent improvement of their symptoms.

Monitoring

Oral Exposure

6.5.1)

A) In general, there is no role for activated charcoal for oral ingestions of sympathomimetic aerosols due to their limited absorption via the gut. There is no role for dilution in any forms, and though likely not needed, it would not be unreasonable to wash skin for dermal exposures or irrigate eyes from ocular exposures.

6.5.2)

A) SUMMARY

1) In general, there is no role for activated charcoal for oral ingestions of sympathomimetic aerosols due to their limited absorption via the gut. There is no role for dilution in any forms.

a) Orally absorbable products (eg, phenylephrine, propylhexedrine, metaproterenol, albuterol) may produce toxicity, if ingested. For example, a child weighing 10 kg ingesting more than 0.5 mL of metaproterenol nebulizer solution 5% would exceed the maximum recommended daily oral dose of 2.6 mg/kg/day.

B) 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).

6.5.3)

A) SUPPORT

1) Follow recommendations under INHALATION EXPOSURE when appropriate.

Inhalation Exposure

6.7.2)

A) SUPPORT

1) Many patients require no treatment beyond cessation of the offending drug. Discontinue all sympathomimetic agents. Benzodiazepines may be used to treat agitation, tremors, mild hypertension and/or tachycardia.
2) Premature ventricular contractions usually do not require treatment. However, for patients with frequent or symptomatic premature ventricular contractions, checking and optimizing electrolytes is reasonable. Antiemetics may be used for patients with persistent nausea and vomiting.

B) MONITORING OF PATIENT

1) Asymptomatic patients do not need laboratory evaluation.
2) Patients who experience cardiac manifestations such as tachycardia, hypertension, hypotension, or dysrhythmias should be placed on a cardiac monitor and obtain an ECG, and evaluate electrolytes. Obtain a troponin level, if the patient is having chest pain.
3) Perform a chest x-ray if the patient is experiencing respiratory symptoms.
4) Patients with severe muscle pain should have a total CK checked to monitor for rhabdomyolysis.

C) TACHYARRHYTHMIA

1) Tachycardia may be treated with esmolol, but beta adrenergic antagonists should be used cautiously in patients with reactive airway disease or congestive heart failure, in addition, use of beta blockers may cause unopposed alpha effects (primarily hypertension), if the agent involved in the overdose has both alpha and beta agonist effects.
2) TACHYCARDIA SUMMARY

a) Evaluate patient to be sure that tachycardia is not a physiologic response to dehydration, anemia, hypotension, fever, sepsis, or hypoxia. Sinus tachycardia does not generally require treatment unless hemodynamic compromise develops.
b) If therapy is required, a short acting, cardioselective agent such as esmolol is generally preferred (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
c) ESMOLOL/ADULT LOADING DOSE

1) Infuse 500 micrograms/kilogram (0.5 mg/kg) IV over 1 minute (Neumar et al, 2010).

d) ESMOLOL/ADULT MAINTENANCE DOSE

1) Follow loading dose with infusion of 50 mcg/kg per minute (0.05 mg/kg per minute) (Neumar et al, 2010).
2) EVALUATION OF RESPONSE: If response is inadequate, infuse second loading bolus of 0.5 mg/kg over 1 minute and increase the maintenance infusion to 100 mcg/kg (0.1 mg/kg) per minute. Reevaluate therapeutic effect, increase in the same manner if required to a maximum infusion rate of 300 mcg/kg (0.3 mg/kg) per minute (Neumar et al, 2010).
3) The manufacturer recommends that a maximum of 3 loading doses be used (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
4) END POINT OF THERAPY: As the desired heart rate or blood pressure is approached, omit loading dose and adjust maintenance infusion as required (Prod Info BREVIBLOC(TM) intravenous injection, 2012).

e) CAUTION

1) Esmolol is a short acting beta-adrenergic blocking agent with negative inotropic effects. Esmolol should be avoided in patients with asthma, obstructive airway disease, decompensated heart failure and pre-excited atrial fibrillation (wide complex irregular tachycardia) or atrial flutter (Neumar et al, 2010).

D) VENTRICULAR ARRHYTHMIA

1) For patients with cardiac dysrhythmias, correct electrolyte disorders (eg, hypokalemia, hypocalcemia, and hypomagnesemia). Treat unstable ventricular dysrhythmias with cardioversion, and antidysrhythmics like lidocaine and amiodarone.
2) VENTRICULAR DYSRHYTHMIAS SUMMARY

a) 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.

3) 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).

4) 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).

5) PROPRANOLOL

a) PROPRANOLOL/ADULT DOSE

1) INTRAVENOUS: 0.5 mg to 1 mg per dose IV over 1 minute. May repeat dose up to a total of 0.1 mg/kg, if needed (Neumar et al, 2010a). A second dose may be repeated in 2 minutes, if necessary; however, any additional drug administration should be given at least 4 hours later (Prod Info propranolol HCl IV injection, 2008).
2) The maximum dose is 3 mg; the rate should not exceed 1 mg/min (Prod Info propranolol HCl IV injection, 2008).

b) PROPRANOLOL/PEDIATRIC DOSE

1) INTRAVENOUS: 0.01 to 0.15 mg/kg IV every 6 to 8 hours (Luedtke et al, 1997).

c) MONITORING

1) The drug should be administered with cardiac monitoring or central venous pressure monitoring. Monitor for bradycardia, hypotension and congestive heart failure (Prod Info propranolol HCl IV injection, 2008).

6) PROCAINAMIDE

a) PROCAINAMIDE/ADULT LOADING DOSE

1) 20 to 50 milligrams/minute IV until dysrhythmia is suppressed or toxicity develops from procainamide (hypotension develops or the QRS is widened by 50%), or a total dose of 17 milligrams/kilogram is given (1.2 grams for a 70 kilogram person) (Neumar et al, 2010).
2) ALTERNATIVE DOSING: 100 mg every 5 minutes until dysrhythmia is controlled, or toxicity develops from procainamide (hypotension develops or the QRS is widened by 50%) or 17 mg/kg have been given (Neumar et al, 2010).
3) MAXIMUM DOSE: 17 milligrams/kilogram (Neumar et al, 2010).

b) PROCAINAMIDE/CONTROLLED INFUSION

1) In conscious patients, procainamide should be administered as a controlled infusion (20 milligrams/minute) because of the risk of QT prolongation and its hypotensive effects (Link et al, 2015)

c) PROCAINAMIDE/ADULT MAINTENANCE DOSE

1) 1 to 4 milligrams/minute via an intravenous infusion (Neumar et al, 2010).

d) PROCAINAMIDE/PEDIATRIC LOADING DOSE

1) 15 milligrams/kilogram IV/Intraosseously over 30 to 60 minutes; discontinue if hypotension develops or the QRS widens by 50% (Kleinman et al, 2010).

e) PROCAINAMIDE/PEDIATRIC MAINTENANCE DOSE

1) Initiate at 20 mcg/kg/minute and increase in 10 mcg/kg/minute increments every 15 to 30 minutes until desired effect is achieved; up to 80 mcg/kg/minute (Bouhouch et al, 2008; Ratnasamy et al, 2008; Mandapati et al, 2000; Luedtke et al, 1997; Walsh et al, 1997).

f) PROCAINAMIDE/PEDIATRIC MAXIMUM DOSE

1) 2 grams/day (Bouhouch et al, 2008; Ratnasamy et al, 2008; Mandapati et al, 2000; Luedtke et al, 1997; Walsh et al, 1997).

g) MONITORING PARAMETERS

1) ECG, blood pressure, and blood concentrations (Prod Info procainamide HCl IV, IM injection solution, 2011). Procainamide can produce hypotension and QT prolongation (Link et al, 2015).

h) AVOID

1) Avoid in patients with QT prolongation and CHF (Neumar et al, 2010).

E) BRADYCARDIA

1) Extreme caution should be used when treating bradycardia secondary to hypertension or AV block. Atropine could aggravate hypertension.
2) Bradycardia has been observed following phenylpropanolamine ingestion, but could occur following intoxication with other sympathomimetics.
3) ATROPINE

a) ATROPINE/DOSE

1) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
2) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.

a) There is no minimum dose (de Caen et al, 2015).
b) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).

F) HYPERTENSIVE EPISODE

1) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
2) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
3) SODIUM NITROPRUSSIDE/INDICATIONS

a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.

4) SODIUM NITROPRUSSIDE/DOSE

a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).

5) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION

a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

6) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS

a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

7) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS

a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

8) NITROGLYCERIN/INDICATIONS

a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).

9) NITROGLYCERIN/ADULT DOSE

a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).

10) NITROGLYCERIN/PEDIATRIC DOSE

a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).

11) PHENTOLAMINE/INDICATIONS

a) Useful for severe hypertension, particularly if caused by agents with alpha adrenergic agonist effects usually induced by catecholamine excess (Rhoney & Peacock, 2009).

12) PHENTOLAMINE/ADULT DOSE

a) BOLUS DOSE: 5 to 15 mg IV bolus repeated as needed (U.S. Departement of Health and Human Services, National Institutes of Health, and National Heart, Lung, and Blood Institute, 2004). Onset of action is 1 to 2 minutes with a duration of 10 to 30 minutes (Rhoney & Peacock, 2009).
b) CONTINUOUS INFUSION: 1 mg/hr, adjusted hourly to stabilize blood pressure. Prepared by adding 60 mg of phentolamine mesylate to 100 mL of 0.9% sodium chloride injection; continuous infusion ranging from 12 to 52 mg/hr over 4 days has been used in case reports (McMillian et al, 2011).

13) PHENTOLAMINE/PEDIATRIC DOSE

a) 0.05 to 0.1 mg/kg/dose (maximum of 5 mg per dose) intravenously every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed (Singh et al, 2012; Koch-Weser, 1974).

14) PHENTOLAMINE/ADVERSE EFFECTS

a) Adverse events can include orthostatic or prolonged hypotension, tachycardia, dysrhythmias, angina, flushing, headache, nasal congestion, nausea, vomiting, abdominal pain and diarrhea (Rhoney & Peacock, 2009; Prod Info Phentolamine Mesylate IM, IV injection Sandoz Standard, 2005).

15) CAUTION

a) Phentolamine should be used with caution in patients with coronary artery disease because it may induce angina or myocardial infarction (Rhoney & Peacock, 2009).

16) LABETALOL

a) INTRAVENOUS INDICATIONS

1) Consider if severe hypertension is unresponsive to short acting titratable agents such as sodium nitroprusside. Although labetalol has mixed alpha and beta adrenergic effects (Pearce & Wallin, 1994), it should be used cautiously if sympathomimetic agents are involved in the poisoning, as worsening hypertension may develop from alpha adrenergic effects.

b) ADULT DOSE

1) INTRAVENOUS BOLUS: Initial dose of 20 mg by slow IV injection over 2 minutes. Repeat with 40 to 80 mg at 10 minute intervals. Maximum total dose: 300 mg. Maximum effects on blood pressure usually occur within 5 minutes (Prod Info Trandate(R) IV injection, 2010).
2) INTRAVENOUS INFUSION: Administer infusion after initial bolus, until desired blood pressure is reached. Administer IV at 2 mg/min of diluted labetalol solution (1 mg/mL or 2 mg/3 mL concentrations); adjust as indicated and continue until adequate response is achieved; usual effective IV dose range is 50 to 200 mg total dose; maximum dose: 300 mg. Prepare 1 mg/mL concentration by adding 200 mg labetalol (40 mL) to 160 mL of a compatible solution and administered at a rate of 2 mL/min (2 mg/min); also can be mixed as an approximate 2 mg/3 mL concentration by adding 200 mg labetalol (40 mL) to 250 mL of solution and administered at a rate of 3 mL/min (2 mg/min) (Prod Info Trandate(R) IV injection, 2010). Use of an infusion pump is recommended (Prod Info Trandate(R) IV injection, 2010).

c) PEDIATRIC DOSE

1) INTRAVENOUS: LOADING DOSE: 0.2 to 1 mg/kg, may repeat every 5 to 10 minutes (Hari & Sinha, 2011; Flynn & Tullus, 2009; Temple & Nahata, 2000; Fivush et al, 1997; Fivush et al, 1997; Bunchman et al, 1992). Maximum dose: 40 mg/dose (Hari & Sinha, 2011; Flynn & Tullus, 2009). CONTINUOUS INFUSION: 0.25 to 3 mg/kg/hour IV (Hari & Sinha, 2011; Flynn & Tullus, 2009; Temple & Nahata, 2000; Fivush et al, 1997; Miller, 1994; Deal et al, 1992; Bunchman et al, 1992).

d) ADVERSE REACTIONS

1) Common adverse events include postural hypotension, dizziness; fatigue; nausea; vomiting, sweating, and flushing (Pearce & Wallin, 1994).

e) PRECAUTIONS

1) Contraindicated in patients with bronchial asthma, congestive heart failure, greater than first degree heart block, cardiogenic shock, or severe bradycardia or other conditions associated with prolonged or severe hypotension. In patients with pheochromocytoma, labetalol should be used with caution because it has produced a paradoxical hypertensive response in some patients with this tumor (Prod Info Trandate(R) IV injection, 2010).
2) Use caution in hepatic disease or intermittent claudication; effects of halothane may be enhanced by labetalol (Prod Info Trandate(R) IV injection, 2010). Labetalol should be stopped if there is laboratory evidence of liver injury or jaundice (Prod Info Trandate(R) IV injection, 2010).

f) MONITORING PARAMETER

1) Monitor blood pressure frequently during initial dosing and infusion (Prod Info Trandate(R) IV injection, 2010).

17) Propranolol, 1 mg IV, was used successfully to treat hypertension in a pseudoephedrine overdose and an ephedrine overdose (Burkhart, 1992).

G) ACUTE LUNG INJURY

1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

H) CHRONIC POISONING

1) Withdraw the aerosol medication, even if this requires hospitalization and full control of medication. Treat asthmatic symptoms vigorously, using a short course of high doses of corticosteroids, if necessary.

a) Use subQ injected epinephrine for acute symptoms until corticosteroids are effective.

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

Abstracts

Case Reports

1) Two similar reports also involved inadvertent 2.5 mg subQ doses with tachycardia (150 beats/minute) and elevated systolic pressures (130 to 150 mmHg) persisting for 6 to 8 hours with subsequent untreated recovery (Kaul & Stubblefield, 1980).

1) TERBUTALINE: Inadvertent subcutaneous administration of 2.5 mg terbutaline in a 35-year-old woman, 21 weeks pregnant, was followed in 10 minutes by substernal pressure, tachycardia, ST segment depressions, and inverted T waves consistent with ischemia. Cardiac effects resolved without specific treatment in 10 hours (Brandstetter & Gotz, 1980).

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) SPECIFIC SUBSTANCE

1) ALBUTEROL

a) The recommended dose is 1 to 2 oral inhalations every 4 to 6 hours. Each inhalation contains 108 mcg of albuterol sulfate (Prod Info PROAIR(R) HFA oral inhalation aerosol, 2010).

2) EPINEPHRINE

a) The recommended dose is 1 inhalation (0.22 mg). If symptoms are not relieved after at least 1 minute, may use once more. Do not exceed 2 doses in 3 hours (Prod Info PRIMATENE(R) inhalation mist, 2007).

3) FENOTEROL HYDROBROMIDE/IPRATROPIUM BROMIDE

a) ACUTE ASTHMA

1) METERED DOSE INHALER (Not available in US): 2 actuations (21 mcg ipratoropium bromide + 50 mcg fenoterol hydrobromide) are usually adequate for relief of symptoms in many cases. If breathing has not noticeably improved after 5 minutes, 2 further actuations may be used. If symptoms have not been relieved by 4 actuations, patients should be advised to consult with a physician or seek medical assistance immediately (Prod Info BERODUAL(R) inhalation solution, 2015).
2) NEBULIZED SOLUTION (Not available in US): Depending the severity of the acute episode, the recommended doses range between 261 mcg ipratropium bromide/500 mcg fenoterol hydrobromide and 652.5 mcg ipratropium bromide/1250 mcg fenoterol hydrobromide for inhalation. In severe cases, up to 1044 mcg ipratropium bromide/2000 mcg fenoterol hydrobromide may be used (Prod Info BERODUAL(R) inhalation solution, 2015).

b) INTERMITTENT AND LONG-TERM THERAPY

1) Metered Dose inhaler (Not available in US): 1 to 2 actuations (21 mcg ipratoropium bromide + 50 mcg fenoterol hydrobromide) for each administration; up to a maximum of 8 actuations per day (average of 1 to 2 actuations 3 times daily) (Prod Info BERODUAL(R) inhalation solution, 2015).

4) FLUTICASONE/VILANTEROL

a) ASTHMA

1) INHALATION: The recommended dose is fluticasone furoate 100 mcg/vilanterol 25 mcg or fluticasone furoate 200 mcg/vilanterol 25 mcg inhalation once daily; MAX: fluticasone furoate 200 mcg/vilanterol 25 mcg inhalation once daily (Prod Info BREO(R) ELLIPTA(R) oral inhalation powder, 2015).

b) COPD

1) INHALATION: The recommended dose is fluticasone furoate 100 mcg/vilanterol 25 mcg inhalation once daily; MAX: 1 inhalation daily of fluticasone furoate 100 mcg/vilanterol 25 mcg (Prod Info BREO(R) ELLIPTA(R) oral inhalation powder, 2015).

5) FORMOTEROL FUMARATE

a) POWDER FOR INHALATION:

1) ASTHMA/COPD: The recommended dose is inhalation of 1 12 mcg capsule every 12 hours. MAXIMUM dose: 24 mcg/day (Prod Info FORADIL(R) AEROLIZER(R) oral inhalation powder, 2011).
2) EXERCISE-INDUCED BRONCHOSPASM: The recommended dose is inhalation of 1 12 mcg capsule at least 15 minutes before exercise. MAXIMUM dose: 12 mcg every 12 hours (Prod Info FORADIL(R) AEROLIZER(R) oral inhalation powder, 2011).

6) GLYCOPYRROLATE/FORMOTEROL FUMARATE

a) The recommended dose is 2 inhalations twice daily, once in the morning and again in the evening. Each inhalation delivers glycopyrrolate 9 mcg and formoterol fumarate 4.8 mcg (Prod Info BEVESPI AEROSPHERE(TM) inhalation aerosol powder, 2016).

7) INDACATEROL/GLYCOPYRROLATE

a) The recommended dose is 1 capsule (indacaterol 27.5 mcg/glycopyrrolate 15.6 mcg) via oral inhalation twice daily at the same time each day (Prod Info UTIBRON(TM) NEOHALER(R) oral inhalation powder, 2015).

8) METAPROTERENOL

a) The recommended dose is 2 to 3 inhalations every 3 to 4 hours; each inhalation contains 0.65 mg. MAXIMUM dose: 12 inhalations/day (Prod Info ALUPENT(R) inhalation aerosol, 1999).

9) OLODATEROL/TIOTROPIUM BROMIDE

a) Usual dose: 2 oral inhalations once daily at same time each day. MAXIMUM: 2 inhalations in 24 hours (Prod Info STIOLTO(TM) RESPIMAT(R) oral inhalation spray, 2015).

10) PIRBUTEROL ACETATE

a) The recommended dose is 1 to 2 inhalations (200 to 400 mcg) every 4 to 6 hours. MAXIMUM dose: 12 inhalations/day (Prod Info MAXAIR(R) AUTOHALER(R) oral inhalation aerosol, 2008).

11) SALMETEROL XINAFOATE

a) ASTHMA/COPD

1) The recommended dose is 1 inhalation (50 mcg) twice daily (morning and evening, approximately 12 hours apart). Long-acting beta agonists should be used in combination with inhaled corticosteroids (Prod Info SEREVENT(R) DISKUS(R) oral inhalation powder, 2011).

b) EXERCISE-INDUCED BRONCHOSPASM

1) The recommended usual dose is 1 inhalation (50 mcg) at least 30 minutes before exercise. Wait at least 12 hours between doses (Prod Info SEREVENT(R) DISKUS(R) oral inhalation powder, 2011).

12) UMECLIDINIUM VILANTEROL

a) The recommended dose is one oral inhalation once daily. Each inhalation contains 62.5 mcg of umeclidinium and 25 mcg of vilanterol. MAXIMUM DOSE: one inhalation every 24 hours (Prod Info ANORO(TM) ELLIPTA(TM) oral inhalation powder, 2013).

7.2.2)

A) SPECIFIC SUBSTANCE

1) ALBUTEROL

a) ASTHMA

1) METERED-DOSE INHALER

a) 4 to 18 YEARS OF AGE: The recommended dose is 1 to 2 inhalations every 4 to 6 hours. Each inhalation contains 108 mcg of albuterol sulfate (Prod Info PROAIR(R) HFA oral inhalation aerosol, 2010).

2) NEBULIZED SOLUTION

a) 2 TO 12 YEARS OF AGE: The recommended starting dose is 1.25 mg or 0.63 mg administered 3 or 4 times daily (Prod Info AccuNeb(R) inhalation solution, 2011).

b) EXERCISE-INDUCED BRONCHOSPASM

1) 4 to 18 YEARS OF AGE: The recommended dose is 2 inhalations 15 to 30 minutes before exercise. Each inhalation contains 108 mcg of albuterol sulfate (Prod Info PROAIR(R) HFA oral inhalation aerosol, 2010).

2) EPINEPHRINE

a) LESS THAN 4 YEARS OF AGE: Recommended dosage has not been established (Prod Info PRIMATENE(R) inhalation mist, 2007).
b) 4 TO 18 YEARS OF AGE: The recommended dose is 1 inhalation (0.22 mg). If symptoms not relieved after at least 1 minute, may use once more. Do not exceed 2 doses in 3 hours (Prod Info PRIMATENE(R) inhalation mist, 2007).

3) FENOTEROL HYDROBROMIDE/IPRATROPIUM BROMIDE

a) METERED DOSE INHALER

1) ACUTE ASTHMA EPISODES

a) CHILDREN GREATER THAN 6 YEARS: Metered Dose inhaler (Not available in US): 2 actuations (21 mcg ipratoropium bromide + 50 mcg fenoterol hydrobromide) are usually adequate for relief of symptoms in many cases. If breathing has not noticeably improved after 5 minutes, 2 further actuations may be used. If symptoms have not been relieved by 4 actuations, patients should be advised to consult with a physician or seek medical assistance immediately (Prod Info BERODUAL(R) inhalation solution, 2015).
b) NOTE: In children, the metered dose aerosol should only be used with medical advice and under adult supervision (Prod Info BERODUAL(R) inhalation solution, 2015).

2) INTERMITTENT AND LONG-TERM THERAPY

a) CHILDREN GREATER THAN 6 YEARS: Metered Dose inhaler (Not available in US): 1 to 2 actuations (21 mcg ipratoropium bromide + 50 mcg fenoterol hydrobromide) for each administration; up to a maximum of 8 actuations per day (average of 1 to 2 actuations 3 times daily) (Prod Info BERODUAL(R) inhalation solution, 2015).
b) NOTE: In children, the metered dose aerosol should only be used with medical advice and under adult supervision (Prod Info BERODUAL(R) inhalation solution, 2015).

b) NEBULIZED SOLUTION

1) ACUTE EPISODE OF BRONCHOSPASM

a) CHILDREN 12 YEARS OF AGE OR OLDER (Not available in US): Depending the severity of the acute episode, the recommended doses range between 261 mcg ipratropium bromide/500 mcg fenoterol hydrobromide and 652.5 mcg ipratropium bromide/1250 mcg fenoterol hydrobromide for inhalation. In severe cases, up to 1044 mcg ipratropium bromide/2000 mcg fenoterol hydrobromide may be used (Prod Info BERODUAL(R) inhalation solution, 2015).

2) ACUTE ASTHMA EPISODES

a) CHILDREN 6 TO 12 YEARS (Not available in US): Depending on the severity of the acute episode the recommended doses range between 130.5 mcg ipratropium bromide/250 mcg fenoterol hydrobromide and 522 mcg ipratropium bromide/1000 mcg fenoterol hydrobromide for inhalation may be used (Prod Info BERODUAL(R) inhalation solution, 2015).
b) CHILDREN LESS THAN 6 YEARS OF AGE (Below 22 kg Body Weight) (Not available in US): Due to limited data in this age group the following dose is recommended under medical supervision only: Approximately 26.1 mcg ipratropium bromide/50 mcg fenoterol hydrobromide per kg body weight (ie, 0.1 mL = 2 drops) up to a maximum of 0.5 mL (10 drops) for inhalation (Prod Info BERODUAL(R) inhalation solution, 2015).

4) FLUTICASONE/VILANTEROL

a) Safety and effectiveness have not been established (Prod Info BREO(R) ELLIPTA(R) oral inhalation powder, 2015).

5) FORMOTEROL FUMARATE

a) POWDER FOR INHALATION

1) LESS THAN 5 YEARS OF AGE: Safety and effectiveness have not been established (Prod Info FORADIL(R) AEROLIZER(R) oral inhalation powder, 2011).
2) 5 TO 18 YEARS OF AGE:

a) ASTHMA: The recommended dose is inhalation of one 12 mcg capsule every 12 hours. MAXIMUM dose: 24 mcg/day (Prod Info FORADIL(R) AEROLIZER(R) oral inhalation powder, 2011).
b) EXERCISE-INDUCED BRONCHOSPASM: The recommended dose is inhalation of one 12 mcg capsule at least 15 minutes before exercise. MAXIMUM dose: 12 mcg every 12 hours (Prod Info FORADIL(R) AEROLIZER(R) oral inhalation powder, 2011).

6) GLYCOPYRROLATE/FORMOTEROL FUMARATE

a) Safety and effectiveness have not been established in pediatric patients (Prod Info BEVESPI AEROSPHERE(TM) inhalation aerosol powder, 2016).

7) INDACATEROL/GLYCOPYRROLATE

a) Safety and effectiveness have not been established in pediatric patients (Prod Info UTIBRON(TM) NEOHALER(R) oral inhalation powder, 2015).

8) METAPROTERENOL

a) METERED-DOSE INHALER

1) UP TO 12 YEARS OF AGE: Safety and efficacy have not been established (Prod Info ALUPENT(R) inhalation aerosol, 1999).
2) 12 TO 18 YEARS OF AGE: The recommended dose is 2 to 3 inhalations every 3 to 4 hours; each inhalation contains 0.65 mg. MAXIMUM dose: 12 inhalations per day (Prod Info ALUPENT(R) inhalation aerosol, 1999).

9) OLODATEROL/TIOTROPIUM BROMIDE

a) Safety and efficacy have not been established (Prod Info STIOLTO(TM) RESPIMAT(R) oral inhalation spray, 2015).

10) PIRBUTEROL ACETATE

a) UP TO 12 YEARS OF AGE: Safety and efficacy have not been established (Prod Info MAXAIR(R) AUTOHALER(R) oral inhalation aerosol, 2008).
b) 12 TO 18 YEARS OF AGE: The recommended dose is 1 to 2 inhalations (200 to 400 mcg) every 4 to 6 hours. MAXIMUM dose: 12 inhalations/day (Prod Info MAXAIR(R) AUTOHALER(R) oral inhalation aerosol, 2008).

11) SALMETEROL XINAFOATE

a) ASTHMA

1) 4 TO 18 YEARS OF AGE: The recommended dose is 1 inhalation (50 mcg) twice daily (morning and evening, approximately 12 hours apart). Long-acting beta agonists should be used in combination with inhaled corticosteroids (Prod Info SEREVENT(R) DISKUS(R) oral inhalation powder, 2011).

b) EXERCISE-INDUCED BRONCHOSPASM

1) 4 TO 18 YEARS OF AGE: The recommended usual dose is 1 inhalation (50 mcg) at least 30 minutes before exercise. Wait at least 12 hours between doses (Prod Info SEREVENT(R) DISKUS(R) oral inhalation powder, 2011).

12) UMECLIDINIUM VILANTEROL

a) Safety and effectiveness have not been established in pediatric patients (Prod Info ANORO(TM) ELLIPTA(TM) oral inhalation powder, 2013).

Minimum Lethal Exposure

1) CASE REPORT: Intravenous abuse of the contents of an epinephrine inhalant (82.5 mg) in a 37-year-old man has resulted in ventricular fibrillation, refractory hypertension and tachycardia, followed by hypotension, bradycardia and asystole. The patient died 26 days after exposure following a persistent vegetative state (Scalzo et al, 1995).

1) SUDDEN DEATH

a) The widespread use of inhaled bronchodilators has been associated with an increase in asthma-related deaths.
b) This was noted initially in the 1960s after introduction of high-dose isoproterenol metered-dose inhalers in the UK, and in the 1970s after introduction of a high-potency, long-acting bronchodilator aerosol, fenoterol, in New Zealand.
c) A Canadian retrospective case-control study found a doubling of the risk of death or near death from asthma in patients who regularly used either albuterol or fenoterol when adjusted for the available dosage forms of these 2 products. Marked elevation in risk occurred when the number of canisters exceeded 2 per month. No increased risk was found for the use of inhaled cromolyn or corticosteroids. Although further controlled studies are needed, the most likely explanation for these findings is that over use of bronchodilators delays the use of anti-inflammatory drugs (Spitzer et al, 1992).
d) Inhaled beta-agonists reverse only acute bronchial constriction and are ineffective for late phase reactions, while steroids and cromolyn are effective in preventing both reactions.
e) It is recommended that beta-agonists be used on an "as needed" basis rather than a regular scheduled dosage regimen. Increasing use should prompt evaluation of the need for prophylactic inhaled anti-inflammatory therapy (Burrows & Lebowitz, 1992).

Maximum Tolerated Exposure

1) Metabolism of isoproterenol and epinephrine are sufficiently rapid that acute toxicity is probably only associated with massive overuse.
2) FENOTEROL: Metabolic acidosis and hypokalemia have been observed when given in doses higher than recommended (Prod Info Duovent(R) UDV inhalation solution, 2015).

1) PROPYLHEXEDRINE: A 29-year-old man developed hand tremors, agitation, increased blood pressure and increased pulse rate following the ingestion of 250 mg propylhexedrine extracted from a nasal inhaler (Liggett, 1982).
2) SALMETEROL/FLUTICASONE: A 16-year-old girl, with a history of asthma, intentionally inhaled 60 puffs of a combination salmeterol xinafoate 25 mcg and fluticasone propionate 50 mcg and became anxious with complaints of chest pain and palpitations while living at an adolescent treatment center. Upon admission, she was alert and oriented with sinus tachycardia (heart rate 131 beats/min). Laboratory studies showed signs of lactic acidosis (pH 7.34, lactate 8.3 mmol/L), hypokalemia and hypophosphatemia. She was treated supportively with IV fluids and potassium repletion. Although the patient was stable, lactic acidosis (pH 7.30, bicarbonate 13 mmol/L) persisted for about 4.5 hours after presentation. A toxicology screen was negative and other laboratory studies were within normal limits. At 14 hours, she had no further signs or symptoms and was discharged after 18 hours of observation and a psychiatric evaluation (Manara et al, 2012).

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) SPECIFIC SUBSTANCE

a) TERBUTALINE: The normal therapeutic concentration is 2 to 6 micrograms/liter (Heath & Hulten, 1987).

Pharmacology Toxicology

Pharmacologic Mechanism

DRUG	ALPHA	BETA 1	BETA 2
Albuterol	-	+	++
Bitolterol	-	+	++
Isoetharine	-	+	++
Isoproterenol	-	+	+
Metaproterenol	-	+	++
Pirbuterol	-	+	++
Terbutaline	-	+	++
Epinephrine	+	+	+
Propylhexedrine	+	+	+
L-Desoxyephedrine	+	+	+
Fenoterol	-	+	++
Procaterol	-	+	++

Toxicologic Mechanism

Physicochemical

Physical Characteristics

Ph

Molecular Weight

Animal Toxicology

References

General Bibliography

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SYMPATHOMIMETIC AEROSOLS

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Acid-Base

Hematologic

Musculoskeletal

Endocrine

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Inhalation Exposure

Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Pharmacologic Mechanism

Toxicologic Mechanism

Physical Characteristics

Ph

Molecular Weight

General Bibliography