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DROXIDOPA

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Droxidopa is a synthetic amino acid precursor of norepinephrine. After conversion to norepinephrine, it may increase blood pressure by causing vasoconstriction of peripheral arteries and veins.

Specific Substances

    1) L-threo-3,4-Dihydroxyphenylserine
    2) DOPS
    3) L-DOPS
    4) L-threo-DOPS
    5) CAS 23651-95-8
    1.2.1) MOLECULAR FORMULA
    1) C9-H11-N-O5 (Prod Info NORTHERA(TM) oral capsules, 2014)

Available Forms Sources

    A) FORMS
    1) Droxidopa is available as 100 mg, 200 mg, and 300 mg capsules (Prod Info NORTHERA(TM) oral capsules, 2014).
    B) USES
    1) Droxidopa is approved for the treatment of symptomatic neurogenic orthostatic hypotension in patients with Parkinson's disease, multiple system atrophy, dopamine beta-hydroxylase deficiency, and non-diabetic autonomic neuropathy, and in patients with pure autonomic failure (Prod Info NORTHERA(TM) oral capsules, 2014).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Droxidopa is approved for the treatment of symptomatic neurogenic orthostatic hypotension in patients with Parkinson's disease, multiple system atrophy, dopamine beta-hydroxylase deficiency, and non-diabetic autonomic neuropathy, and in patients with pure autonomic failure.
    B) PHARMACOLOGY: Droxidopa, a synthetic amino acid analog which is metabolized to norepinephrine for pharmacologic effect, may increase blood pressure by causing vasoconstriction of peripheral arteries and veins. Minor, temporary increases in plasma norepinephrine levels have been observed following administration of droxidopa.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse reactions following therapeutic administration, with an incidence rate greater than 5% and at least a 3% greater incidence than placebo, include headache, dizziness, nausea, and hypertension.
    2) LESS FREQUENT: Symptoms resembling neuroleptic malignant syndrome (ie, hyperthermia, muscle rigidity, involuntary movements, mental status changes, altered consciousness) have been reported during post-marketing surveillance with droxidopa therapy.
    3) RARE: Hypersensitivity reactions (eg, bronchial asthma) may occur due to the tartrazine component of specific droxidopa products. Exacerbation of pre-existing ischemic heart disease, dysrhythmia, and congestive heart failure may occur with administration of droxidopa.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Signs and symptoms of an acute overdose are anticipated to be similar to excessive pharmacologic adverse events. During post-marketing surveillance, a patient ingested 7700 mg droxidopa and developed hypertensive crisis. The patient recovered with treatment.
    0.2.20) REPRODUCTIVE
    A) Droxidopa is classified as FDA pregnancy category C. Although there are no adequate or well-controlled studies of droxidopa use in pregnant women, decreased fetal body weight and increased incidences of undulant rib in fetuses have been reported following maternal administration of droxidopa during animal studies.

Laboratory Monitoring

    A) No specific laboratory tests are necessary unless otherwise clinically indicated.
    B) Monitor vital signs and mental status.
    C) Droxidopa plasma concentrations are not readily available or clinically useful in the management of overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. For severe hypertension, nitroprusside is preferred. Nitroglycerin and phentolamine are alternatives. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. CAUTION: Droxidopa may cause high blood pressure. If the patient demonstrates signs and symptoms of an acute allergic reaction that requires epinephrine, monitor blood pressure closely because increased blood pressure is possible with epinephrine. Although rare, treat neuroleptic malignant syndrome with oral bromocriptine, IV benzodiazepines in conjunction with cooling and other supportive measures. Consider dantrolene in severe cases.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe allergic reactions.
    E) ANTIDOTE
    1) None
    F) HYPERTENSIVE EPISODE
    1) Mild/moderate asymptomatic hypertension does not usually require treatment. For severe hypertension, nitroprusside is preferred, with nitroglycerin and phentolamine as alternatives.
    G) NEUROLEPTIC MALIGNANT SYNDROME
    1) Oral bromocriptine, IV benzodiazepines in conjunction with cooling and other supportive measures. Consider dantrolene in severe cases.
    H) HYPERSENSITIVITY REACTION
    1) MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids, or epinephrine. CAUTION: Droxidopa may cause high blood pressure. If the patient demonstrates signs and symptoms of an acute allergic reaction that requires epinephrine, monitor blood pressure closely because increased blood pressure is possible with epinephrine. SEVERE: Administer oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    I) ENHANCED ELIMINATION
    1) It is unknown if hemodialysis would be effective in overdose.
    J) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with a small inadvertent exposure, that remains asymptomatic, can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic should be observed with frequent monitoring of vital signs. Patients that remain asymptomatic can be discharged medically.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    K) PITFALLS
    1) When managing a suspected overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose are similar to reported side effects of the medication.
    L) PHARMACOKINETICS
    1) Protein binding is inversely related to droxidopa plasma concentration, ranging from 26% bound at 10,000 ng/mL to 75% bound at 100 ng/mL. Volume of distribution is approximately 200 L Droxidopa is metabolized to norepinephrine, an active metabolite, by DOPA decarboxylase (DDC). Following oral administration, approximately 75% of a radiolabeled dose is excreted in urine within 24 hours. Elimination half-life is approximately 2.5 hours.
    M) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause hypertension (eg, amphetamine) or neuroleptic malignant syndrome (eg, antipsychotics, neuroleptics).

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. During post-marketing surveillance, hypertensive crisis was reported in a patient who ingested 7700 mg droxidopa. The patient recovered with treatment.
    B) THERAPEUTIC DOSE: Initially, the recommended dose is 100 mg three times daily. The dose can be titrated up to a maximum daily dose of 1800 mg (600 mg three times daily).

Clinical Effects

Summary Of Exposure

    A) USES: Droxidopa is approved for the treatment of symptomatic neurogenic orthostatic hypotension in patients with Parkinson's disease, multiple system atrophy, dopamine beta-hydroxylase deficiency, and non-diabetic autonomic neuropathy, and in patients with pure autonomic failure.
    B) PHARMACOLOGY: Droxidopa, a synthetic amino acid analog which is metabolized to norepinephrine for pharmacologic effect, may increase blood pressure by causing vasoconstriction of peripheral arteries and veins. Minor, temporary increases in plasma norepinephrine levels have been observed following administration of droxidopa.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most common adverse reactions following therapeutic administration, with an incidence rate greater than 5% and at least a 3% greater incidence than placebo, include headache, dizziness, nausea, and hypertension.
    2) LESS FREQUENT: Symptoms resembling neuroleptic malignant syndrome (ie, hyperthermia, muscle rigidity, involuntary movements, mental status changes, altered consciousness) have been reported during post-marketing surveillance with droxidopa therapy.
    3) RARE: Hypersensitivity reactions (eg, bronchial asthma) may occur due to the tartrazine component of specific droxidopa products. Exacerbation of pre-existing ischemic heart disease, dysrhythmia, and congestive heart failure may occur with administration of droxidopa.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Signs and symptoms of an acute overdose are anticipated to be similar to excessive pharmacologic adverse events. During post-marketing surveillance, a patient ingested 7700 mg droxidopa and developed hypertensive crisis. The patient recovered with treatment.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE DISORDER
    1) WITH THERAPEUTIC USE
    a) Hypertension or increased blood pressure was one of the most common adverse reactions reported in droxidopa clinical trials. Hypertension occurred in 1.5% of patients treated for up to 2 weeks with droxidopa (n=131) compared with 0% of placebo-treated patients (n=132) and in 7% in patients treated for up to 10 weeks with droxidopa (n=114) compared with 0.9% of placebo-treated patients (n=108). Hypertension was also cited as a leading cause of treatment discontinuation in droxidopa clinical trials with no further information provided (Prod Info NORTHERA(TM) oral capsules, 2014).
    2) WITH POISONING/EXPOSURE
    a) During post-marketing surveillance, hypertensive crisis was reported in a patient who ingested 7700 mg droxidopa. The patient recovered with treatment (Prod Info NORTHERA(TM) oral capsules, 2014).
    B) HEART DISEASE
    1) WITH THERAPEUTIC USE
    a) Exacerbation of pre-existing ischemic heart disease, dysrhythmia, and congestive heart failure may occur with administration of droxidopa (Prod Info NORTHERA(TM) oral capsules, 2014).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) NEUROLEPTIC MALIGNANT SYNDROME
    1) WITH THERAPEUTIC USE
    a) Symptoms resembling neuroleptic malignant syndrome (ie, hyperthermia, muscle rigidity, involuntary movements, mental status changes, altered consciousness) have been reported in postmarketing surveillance with droxidopa therapy (Prod Info NORTHERA(TM) oral capsules, 2014).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache was one of the most common adverse reactions in droxidopa clinical trials, occurring in 6.1% of patients treated for up to 2 weeks with droxidopa (n=131) compared with 3% of placebo-treated patients (n=132) and in 13.2% in patients treated for up to 10 weeks with droxidopa (n=114) compared with 7.4% of placebo-treated patients (n=108). Headache also occurred in 13% of patients (mean age, 65 years) with a mean droxidopa exposure of approximately 1 year in open-label extension studies (n=422) (Prod Info NORTHERA(TM) oral capsules, 2014).
    C) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness was one of the most common adverse reactions in droxidopa clinical trials, occurring in 3.8% of patients treated for up to 2 weeks with droxidopa (n=131) compared with 1.5% of placebo-treated patients (n=132) and in 9.6% in patients treated for up to 10 weeks with droxidopa (n=114) compared with 4.6% of placebo-treated patients (n=108). Dizziness also occurred in 10% of patients (mean age, 65 years) with a mean droxidopa exposure of approximately 1 year in open-label extension studies (n=422) (Prod Info NORTHERA(TM) oral capsules, 2014).
    D) SYNCOPE
    1) WITH THERAPEUTIC USE
    a) Syncope occurred in 13% of patients (mean age, 65 years) with a mean droxidopa exposure of approximately 1 year in open-label extension studies (n=422) (Prod Info NORTHERA(TM) oral capsules, 2014).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) Nausea was one of the most common adverse reactions in droxidopa clinical trials. Nausea occurred in 1.5% of patients treated for up to 2 weeks with droxidopa (n=131) compared with 1.5% of placebo-treated patients (n=132) and in 8.8% in patients treated for up to 10 weeks with droxidopa (n=114) compared with 4.6% of placebo-treated patients (n=108). Nausea was also cited as a leading cause of treatment discontinuation in droxidopa clinical trials with no further information provided (Prod Info NORTHERA(TM) oral capsules, 2014).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) URINARY TRACT INFECTIOUS DISEASE
    1) WITH THERAPEUTIC USE
    a) Urinary tract infections occurred in 15% of patients (mean age, 65 years) with a mean droxidopa exposure of approximately 1 year in open-label extension studies (n=422) (Prod Info NORTHERA(TM) oral capsules, 2014).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) The tartrazine component of specific droxidopa products may cause hypersensitivity reactions (eg, bronchial asthma) in susceptible patients. Tartrazine sensitivity is common in patients with known aspirin hypersensitivity (Prod Info NORTHERA(TM) oral capsules, 2014).

Reproductive

    3.20.1) SUMMARY
    A) Droxidopa is classified as FDA pregnancy category C. Although there are no adequate or well-controlled studies of droxidopa use in pregnant women, decreased fetal body weight and increased incidences of undulant rib in fetuses have been reported following maternal administration of droxidopa during animal studies.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) During animal studies, oral administration of droxidopa 60, 200, and 600 mg/kg/day (approximately 0.3, 1, and 3 times, respectively, the maximum recommended human total daily dose of 1800 mg in a 60 kg patient) to pregnant Sprague Dawley rats resulted in the occurrence of fetal undulant ribs that were slight and spontaneously reversed after birth (Prod Info NORTHERA(TM) oral capsules, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Droxidopa is classified as FDA pregnancy category C (Prod Info NORTHERA(TM) oral capsules, 2014).
    B) ANIMAL STUDIES
    1) During animal studies, oral administration of droxidopa 60, 200, and 600 mg/kg/day (approximately 0.3, 1, and 3 times, respectively, the maximum recommended human total daily dose of 1800 mg in a 60 kg patient) to pregnant Sprague Dawley rats resulted in lowered fetal body weights (Prod Info NORTHERA(TM) oral capsules, 2014).
    2) Shortening of the gestation period was noted in rats following maternal administration of droxidopa at 600 mg/kg/day (Prod Info NORTHERA(TM) oral capsules, 2014).
    3) Low incidences of renal lesions (cysts, indentations or renal pelvic dilation) on the surface of the kidney were reported in female rats administered droxidopa during organogenesis (Prod Info NORTHERA(TM) oral capsules, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) ANIMAL STUDIES
    1) Droxidopa is excreted in rat breast milk and administration during the period of lactation has resulted in reduced weight gain and reduced survival in offspring (Prod Info NORTHERA(TM) oral capsules, 2014)
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) LACK OF EFFECT: Studies in rats indicate no evidence of fertility impairment with droxidopa use (Prod Info NORTHERA(TM) oral capsules, 2014).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) There was no evidence of carcinogenicity in mice and rats following long-term administration of droxidopa at doses up to 1000 mg/kg/day and 100 mg/kg/day, respectively. These doses correspond to approximately 3 and 0.5 times, respectively (based on the dose per unit of body surface area), the maximum recommended total daily dose of 1800 mg in a 60 kg patient (Prod Info NORTHERA(TM) oral capsules, 2014).

Genotoxicity

    A) Droxidopa was not mutagenic or clastogenic in the Ames assay or in the mouse micronucleus assay, respectively; however, it was clastogenic during the chromosome aberration assay involving Chinese hamster ovary cells (Prod Info NORTHERA(TM) oral capsules, 2014).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No specific laboratory tests are necessary unless otherwise clinically indicated.
    B) Monitor vital signs and mental status.
    C) Droxidopa plasma concentrations are not readily available or clinically useful in the management of overdose.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who remain symptomatic despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with a small inadvertent exposure, that remains asymptomatic, can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic should be observed with frequent monitoring of vital signs. Patients that remain asymptomatic can be discharged medically.

Monitoring

    A) No specific laboratory tests are necessary unless otherwise clinically indicated.
    B) Monitor vital signs and mental status.
    C) Droxidopa plasma concentrations are not readily available or clinically useful in the management of overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    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).
    6.5.2) PREVENTION OF ABSORPTION
    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).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. For severe hypertension, nitroprusside is preferred. Nitroglycerin and phentolamine are alternatives. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. CAUTION: Droxidopa may cause high blood pressure. If the patient demonstrates signs and symptoms of an acute allergic reaction that requires epinephrine, monitor blood pressure closely because increased blood pressure is possible with epinephrine. Although rare, treat neuroleptic malignant syndrome with oral bromocriptine, IV benzodiazepines in conjunction with cooling and other supportive measures. Consider dantrolene in severe cases.
    B) MONITORING OF PATIENT
    1) No specific laboratory tests are necessary unless otherwise clinically indicated.
    2) Monitor vital signs and mental status.
    3) Droxidopa plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) 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).
    D) NEUROLEPTIC MALIGNANT SYNDROME
    1) May be successfully managed with diphenhydramine, oral bromocriptine, benzodiazepines, or intravenous or oral dantrolene sodium in conjunction with cooling and other supportive care (May et al, 1983; Mueller et al, 1983; Leikin et al, 1987; Schneider, 1991) .
    a) BENZODIAZEPINES: In conjunction with cooling measures and supportive care, initial management of NMS should include administration of intravenous benzodiazepines for muscle relaxation (Goldfrank et al, 2002). Benzodiazepines may also be helpful in controlling agitation or reversal of catatonia (Caroff & Mann, 1993; Gratz et al, 1992).
    1) DOSE: Diazepam: 10 mg IV; Lorazepam: 1.5 to 2 mg IV (Gratz et al, 1992).
    b) BROMOCRIPTINE DOSE: 5 mg 3 times a day orally (Mueller et al, 1983).
    c) DANTROLENE LOADING DOSE: 2.5 mg/kg, to a maximum of 10 mg/kg IV (Barkin, 1992).
    d) DANTROLENE MAINTENANCE DOSE: 2.5 mg/kg IV every 6 hours (Barkin, 1992); 1 mg/kg orally every 12 hours, up to 50 mg/dose has also been successful (May et al, 1983).
    1) EFFICACY: Variable; often ineffective as sole agent. Most efficacious in reducing rigidity and the fever that may be produced at a muscular level; will not always resolve mental status changes or psychotic symptoms that probably are more central in origin. Efficacy may be improved if given with a dopamine agonist (Granato et al, 1983; Blue et al, 1986; May et al, 1983).
    2) Some studies report NO beneficial effects and suggest that dantrolene might even worsen the course of NMS (Rosebush & Stewart, 1989).
    e) NON-PHARMACOLOGIC METHODS: Rapid cooling, hydration, and serial assessment of respiratory, cardiovascular, renal and neurologic function, and fluid status are used in conjunction with drug therapy and discontinuation of the antipsychotic agent (Knight & Roberts, 1986).
    2) In a review of 67 case reports of neuroleptic malignant syndrome, the onset of clinical response was shorter after treatment with dantrolene (mean 1.15 days) or bromocriptine (1.03 days) than with supportive measures alone (6.8 days). The time to complete resolution was also shorter with these therapeutic interventions (Rosenberg & Green, 1989).
    3) RETROSPECTIVE STUDY: A study comparing 438 untreated patients with neuroleptic malignant syndrome and 196 treated cases found that administration of dantrolene, bromocriptine, or amantadine significantly reduced the death rate in these cases. Death rate of untreated cases was 21%; administration of dantrolene alone (no dosage reported) decreased death rate to 8.6% (n=58); with bromocriptine alone death rate was 7.8% (n=51); and with amantadine alone death rate was 5.9% (n=17). In combination with other drugs, each of these drugs significantly decreased the NMS-related death rate, although the decrease was slightly less than for single administrations (Sakkas et al, 1991).
    E) ACUTE ALLERGIC REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TLet al,null).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TLet al,null).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TLet al,null). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TLet al,null).
    13) CAUTION: Droxidopa may cause high blood pressure. If the patient demonstrates signs and symptoms of an acute allergic reaction that requires epinephrine, monitor blood pressure closely because increased blood pressure is possible with epinephrine.

Enhanced Elimination

    A) HEMODIALYSIS
    1) It is unknown if hemodialysis would be effective in overdose.

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. During post-marketing surveillance, hypertensive crisis was reported in a patient who ingested 7700 mg droxidopa. The patient recovered with treatment.
    B) THERAPEUTIC DOSE: Initially, the recommended dose is 100 mg three times daily. The dose can be titrated up to a maximum daily dose of 1800 mg (600 mg three times daily).

Therapeutic Dose

    7.2.1) ADULT
    A) Initially, the recommended dose is 100 mg three times daily, with the last dose taken at least 3 hours prior to bedtime. The dose can be titrated in increments of 100 mg three times daily every 24 to 48 hours, up to a maximum daily dose of 1800 mg (600 mg three times daily) (Prod Info NORTHERA(TM) oral capsules, 2014).
    7.2.2) PEDIATRIC
    A) Safety and efficacy in pediatric patients has not been established (Prod Info NORTHERA(TM) oral capsules, 2014).

Maximum Tolerated Exposure

    A) During post-marketing surveillance, hypertensive crisis was reported in a patient who ingested 7700 mg droxidopa. The patient recovered with treatment (Prod Info NORTHERA(TM) oral capsules, 2014).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Droxidopa, a synthetic amino acid analog which is metabolized to norepinephrine for pharmacologic effect, may increase blood pressure by causing vasoconstriction of peripheral arteries and veins. Minor, temporary increases in plasma norepinephrine levels have been observed following administration of droxidopa (Prod Info NORTHERA(TM) oral capsules, 2014).

Physicochemical

Physical Characteristics

    A) Droxidopa is white to off-white in the form of crystals or crystalline powder that is odorless and tasteless. It is soluble in dilute hydrochloric acid and is slightly soluble in water (Prod Info NORTHERA(TM) oral capsules, 2014).

Molecular Weight

    A) 213.19 (Prod Info NORTHERA(TM) oral capsules, 2014)

References

General Bibliography

    1) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    2) American Heart Association: 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2005; 112(24 Suppl):IV 1-203. Available from URL: http://circ.ahajournals.org/content/vol112/24_suppl/. As accessed 12/14/2005.
    3) Barkin RM: Pediatric Emergency Medicine, Mosby YearBook, St Louis, MO, 1992, pp 500.
    4) Blue MG, Schneider SM, & Noro S: Successful treatment of neuroleptic malignant syndrome with sodium nitroprusside. Ann Intern Med 1986; 104:56-57.
    5) Caroff SN & Mann SC: Neuroleptic malignant syndrome. Med Clin North Am 1993; 77:185-203.
    6) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    7) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    8) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    9) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    10) Friedman WF & George BL : Treatment of congestive heart failure by altering loading conditions of the heart. J Pediatr 1985; 106(5):697-706.
    11) Goldfrank L, Flomenbaum N, Lewin N, et al (Eds): Goldfrank's Toxicologic Emergencies, 7th ed. McGraw-Hill, New York, NY, 2002.
    12) Goldstein DS, Holmes C, Kaufmann H, et al: Clinical pharmacokinetics of the norepinephrine precursor L-threo-DOPS in primary chronic autonomic failure. Clin Auton Res 2004; 14(6):363-368.
    13) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    14) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    15) Granato JE, Stern BJ, & Ringel A: Neuroleptic malignant syndrome: successful treatment with dantrolene and bromocriptine. Ann Neurol 1983; 14:89-90.
    16) Gratz SS, Levinson DF, & Simpson GM: The treatment and management of neuroleptic malignant syndrome. Prog Neuro-Psychopharmacol Biol Psychiat 1992; 16:425-443.
    17) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    18) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    19) Ilbawi MN, Idriss FS, DeLeon SY, et al: Hemodynamic effects of intravenous nitroglycerin in pediatric patients after heart surgery. Circulation 1985; 72(3 Pt 2):II101-II107.
    20) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    21) Knight ME & Roberts RJ: Phenothiazine and butyrophenone intoxication in children. Pediatr Clin North Am 1986; 33:299-309.
    22) Koch-Weser J: Hypertensive emergencies. N Engl J Med 1974; 290:211.
    23) Laitinen P, Happonen JM, Sairanen H, et al: Amrinone versus dopamine-nitroglycerin after reconstructive surgery for complete atrioventricular septal defect. J Cardiothorac Vasc Anesth 1997; 11(7):870-874.
    24) Leikin JB, Baron S, & Engle J: Treatment of neuroleptic malignant syndrome with diphenhydramine (abstract). Vet Hum Toxicol 1987; 29:480.
    25) Lieberman P, Nicklas R, Randolph C, et al: Anaphylaxis-a practice parameter update 2015. Ann Allergy Asthma Immunol 2015; 115(5):341-384.
    26) Lieberman P, Nicklas RA, Oppenheimer J, et al: The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010; 126(3):477-480.
    27) May DC, Morris SW, & Stewart RW: Neuroleptic malignant syndrome: response to dantrolene sodium. Ann Intern Med 1983; 98:183-184.
    28) McMillian WD, Trombley BJ, Charash WE, et al: Phentolamine continuous infusion in a patient with pheochromocytoma. Am J Health Syst Pharm 2011; 68(2):130-134.
    29) Mueller PS, Vester JW, & Fermaglich J: Neuroleptic malignant syndrome: successful treatment with bromocriptine. JAMA 1983; 249:386-388.
    30) Nam YT, Shin T, & Yoshitake J: Induced hypotension for surgical repair of congenital dislocation of the hip in children. J Anesth 1989; 3(1):58-64.
    31) National Heart,Lung,and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma. National Heart,Lung,and Blood Institute. Bethesda, MD. 2007. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
    32) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    33) Nowak RM & Macias CG : Anaphylaxis on the other front line: perspectives from the emergency department. Am J Med 2014; 127(1 Suppl):S34-S44.
    34) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    35) Product Information: NITROPRESS(R) injection for IV infusion, Sodium Nitroprusside injection for IV infusion. Hospira, Inc., Lake Forest, IL, 2007.
    36) Product Information: NITROPRESS(R) injection, sodium nitroprusside injection. Hospira,Inc, Lake Forest, IL, 2004.
    37) Product Information: NORTHERA(TM) oral capsules, droxidopa oral capsules. Chelsea Therapeutics, Inc. (per manufacturer), Charlotte, NC, 2014.
    38) Product Information: Phentolamine Mesylate IM, IV injection Sandoz Standard, phentolamine mesylate IM, IV injection Sandoz Standard. Sandoz Canada (per manufacturer), Boucherville, QC, 2005.
    39) Product Information: diphenhydramine HCl intravenous injection solution, intramuscular injection solution, diphenhydramine HCl intravenous injection solution, intramuscular injection solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2013.
    40) Rasch DK & Lancaster L: Successful use of nitroglycerin to treat postoperative pulmonary hypertension. Crit Care Med 1987; 15(6):616-617.
    41) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    42) Rhoney D & Peacock WF: Intravenous therapy for hypertensive emergencies, part 1. Am J Health Syst Pharm 2009; 66(15):1343-1352.
    43) Rosebush P & Stewart T: A prospective analysis of 24 episodes of neuroleptic malignant syndrome. Am J Psychiatry 1989; 146:717-725.
    44) Rosenberg MR & Green M: Neuroleptic malignant syndrome: Review of response to therapy. Arch Intern Med 1989; 149:1927-1931.
    45) Sakkas P, Davis JM, & Janicak PG: Drug treatment of the neuroleptic malignant syndrome. Psychopharmacol Bull 1991; 27:381-384.
    46) Schneider SM: Neuroleptic malignant syndrome: controversies in treatment. Am J Emerg Med 1991; 9:360-362.
    47) Singh D, Akingbola O, Yosypiv I, et al: Emergency management of hypertension in children. Int J Nephrol 2012; 2012:420247.
    48) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    49) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.
    50) U.S. Department of Health and Human Services; National Institutes of Health; and National Heart, Lung, and Blood Institute: The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. U.S. Department of Health and Human Services. Washington, DC. 2004. Available from URL: http://www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.pdf. As accessed 2012-06-20.
    51) Vanden Hoek,TL; Morrison LJ; Shuster M et al: Part 12: Cardiac Arrest in Special Situations 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. American Heart Association. Dallas, TX. 2010. Available from URL: http://circ.ahajournals.org/cgi/reprint/122/18_suppl_3/S829. As accessed 2010-10-21.