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ALPROSTADIL

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Alprostadil is the naturally occurring form of prostaglandin E (PGE1), produced endogenously to relax vascular smooth muscle and cause vasodilation.

Specific Substances

    1) (11(alpha), 13E, 15S)-11,15-dihydroxy-9-oxoprost-13-en-1-oic acid
    2) (E)-(8R,11R,-12R,15S)-11,15--Dihydroxy-9- oxoprost-13-enoic acid
    3) 7((1R,2R,-3R)-3-Hydroxy-2-[(E)--(3S)--3-hydroxyoct-1-enyl]-5-oxocyclopentyl}heptanoic acid
    4) PGE(1)
    5) Prostaglandin E(1)
    6) U-10136
    7) LIP-PGE1
    8) Liposomal PGE1
    9) TLC C-53
    10) CAS 745-65-3
    11) PROSTAGLANDIN E1
    1.2.1) MOLECULAR FORMULA
    1) C20H34O5

Available Forms Sources

    A) FORMS
    1) Alprostadil is available in the United States as:
    a) Intravenous solution: 0.5 mg/mL (Prod Info PROSTIN VR PEDIATRIC(R) intravenous infusion solution, 2009; Prod Info alprostadil injection, 2005)
    b) Intracavernosal powder for solution: 10 mcg, 20 mcg, 40 mcg (Prod Info CAVERJECT(R) intracavernosal injection, 2009; Prod Info CAVERJECT IMPULSE(R) intracavernosal injection lyophilized powder for solution, 2009)
    c) Intracavernosal solution: 0.02 mg/mL (Prod Info CAVERJECT(R) intracavernosal injection, 2009)
    d) Kit: 10 mcg, 20 mcg, 40 mcg (Prod Info EDEX(R) intracavernous injection, 2006)
    e) Intraurethral suppository: 125 mcg, 250 mcg, 500 mcg, 1000 mcg (Prod Info MUSE(R) transurethral suppository, 2011)
    B) USES
    1) Alprostadil is used to maintain the patency of the ductus arteriosus until corrective surgery can be performed in neonates with congenital heart defects (eg, pulmonary atresia, pulmonary stenosis, tricuspid atresia, tetralogy of Fallot, interruption of the aortic arch, coarctation of the aorta) who are dependent on the patent ductus for survival (Prod Info PROSTIN VR PEDIATRIC(R) intravenous infusion solution, 2009; Prod Info alprostadil injection, 2005).
    2) In adults, alprostadil is indicated for the treatment of neurogenic, vasculogenic, psychogenic, or mixed etiology erectile dysfunction. Intracavernosal alprostadil may be used as an adjunct to other diagnostic tests in the diagnosis of erectile dysfunction (Prod Info CAVERJECT(R) intracavernosal injection, 2009; Prod Info CAVERJECT IMPULSE(R) intracavernosal injection lyophilized powder for solution, 2009).

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: Alprostadil is used to maintain the patency of the ductus arteriosus until corrective surgery can be performed in neonates with congenital heart defects (eg, pulmonary atresia, pulmonary stenosis, tricuspid atresia, tetralogy of Fallot, interruption of the aortic arch, coarctation of the aorta) who are dependent on the patent ductus for survival. In adults, alprostadil is indicated for the treatment of neurogenic, vasculogenic, psychogenic, or mixed etiology erectile dysfunction. Intracavernosal alprostadil may be used as an adjunct to other diagnostic tests in the diagnosis of erectile dysfunction.
    B) PHARMACOLOGY: Alprostadil, prostaglandin E1, is a naturally occurring acidic lipid with a variety of pharmacologic effects, including vasodilation, inhibition of platelet aggregation, and stimulation of intestinal and uterine smooth muscle.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) NEONATES: COMMON: Apnea (most often in neonates under 2 kg), fever, flushing, hypotension, bradycardia, and seizures. INFREQUENT: Hyperextension of the neck, tachycardia, diarrhea, edema, infection, and urticaria. Hematological disorders (eg, disseminated intravascular coagulation, anemia and thrombocytopenia) have been reported infrequently in neonates. Supraventricular tachycardia, ventricular fibrillation, and second degree heart block have been reported in less than 1% of infants with congenital heart disease treated with alprostadil.
    2) ADULTS: COMMON: Penile pain, urethral burning, minor urethral bleeding/spotting, testicular pain. OTHER EFFECTS: Priapism, penile fibrosis, fibrotic nodules, flushing, dizziness, headache, nausea, abdominal cramps, diarrhea, tachycardia, hypotension, myocardial infarction (rare), edema, and injection site reaction.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Overdoses in infants may cause apnea, bradycardia, fever, hypotension, and flushing. Overdoses in adults may result in hypotension, persistent penile pain, and priapism. Profound hypotension, disseminated intravascular coagulation and ventricular tachycardia were reported in a woman with placenta accreta who inadvertently received alprostadil instead of dinoprost.
    0.2.20) REPRODUCTIVE
    A) Alprostadil is in Pregnancy Category C. Alprostadil urethral suppositories and intracavernosal injection are not indicated for use in women, newborns, or children. Alprostadil IV solution is only indicated for use in neonates and infants.

Laboratory Monitoring

    A) Monitor vital signs following significant overdose.
    B) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) Monitor arterial blood gases and pulse oximetry in any patient with respiratory symptoms.
    D) Obtain an ECG, and institute continuous cardiac monitoring.
    E) Monitor for priapism. Prolonged erection or priapism (lasting more than 6 hours) should be treated to prevent tissue hypoxia and possible necrosis.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Bradycardia usually does not require treatment. If unresponsive, treat bradycardia with atropine. Treat hypotension with IV fluids, dopamine, or norepinephrine. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Prolonged erection or priapism (lasting more than 6 hours) should be treated to prevent tissue hypoxia and possible necrosis.
    C) DECONTAMINATION
    1) Gastrointestinal decontamination is not required; administered via the intravenous, intracavernosal, or intraurethral administration routes.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with serious toxicity or life-threatening respiratory depression. Apnea has been reported in about 10% to 12% of neonates.
    E) ANTIDOTE
    1) None.
    F) PRIAPISM
    1) An immediate urological consult is necessary. Clinical history should include the use of other agents (ie, antihypertensives, antidepressants, illegal agents) that may also be contributing to priapism. In a patient with ischemic priapism the corpora cavernosa are often completely rigid and the patient complains of pain, while nonischemic priapism the corpora are typically tumescent, but not completely rigid and pain is not typical. Aspirate blood from the corpus cavernosum with a fine needle. Blood gas testing of the aspirated blood may be used to distinguish ischemic (typically PO2 less than 30 mmHg, PCO2 greater than 60 mmHg, and pH less than 7.25) and nonischemic priapism. Color duplex ultrasonography may also be useful. If priapism persists after aspiration, inject a sympathomimetic. PHENYLEPHRINE: Dose: Adult: For intracavernous injection, dilute phenylephrine with normal saline for a concentration of 100 to 500 mcg/mL and give 1 mL injections every 3 to 5 minutes for approximately 1 hour (before deciding that treatment is not successful). For children and patients with cardiovascular disease: Use lower concentrations in smaller volumes. NOTE: Treatment is less likely to be effective if done more than 48 hours after the development of priapism. Distal shunting (NOT first-line therapy) should only be considered after a trial of intracavernous injection of sympathomimetics.
    G) VENTRICULAR DYSRHYTHMIAS
    1) Institute continuous cardiac monitoring, obtain an ECG, and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders. Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Unstable rhythms require immediate cardioversion.
    H) ENHANCED ELIMINATION
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: Men with inadvertent intracavernosal or transurethral overdose who are asymptomatic and do not have priapism can be managed at home.
    2) OBSERVATION CRITERIA: Symptomatic patients or those with inadvertent parenteral injection should be referred to a healthcare facility to be monitored for several hours to assess cardiac function. Low-flow priapism is a urologic emergency and should be treated promptly to prevent complications (eg, impotence). Patients that remain asymptomatic after 6 hours can be discharged.
    3) ADMISSION CRITERIA: Patients with persistent cardiac dysrhythmias, seizures, and respiratory depression should be admitted to an ICU setting.
    4) CONSULT CRITERIA: A medical toxicologist or poison control center should be consulted in cases that involve cardiac toxicity, or in whom the diagnosis is not clear.
    J) PITFALLS
    1) When managing a suspected alprostadil overdose, the possibility of multidrug involvement should be considered.
    K) PHARMACOKINETICS
    1) Intraurethral administration: Approximately 80% of a dose is absorbed within 10 minutes and is rapidly cleared from the systemic circulation by the lungs, leaving barely detectable systemic blood levels. Protein binding: 81% bound to albumin and to a lesser extent (55%) bound to (alpha)-globulin IV-4 fraction. After intravenous administration, about 90% of circulating alprostadil is metabolized in one pass through the lungs, mainly by beta- and omega-oxidation. Excretion: Renal: Almost 90% of an administered intravenous dose excreted in urine within 24 hours.
    L) DIFFERENTIAL DIAGNOSIS
    1) Includes overdose ingestions of cardiac agents or substances that may produce significant bradycardia, heart block or dysrhythmias, or priapism.

Range Of Toxicity

    A) TOXICITY: Overdose data is limited. Single IV doses of alprostadil from 1 to 120 mcg is usually well tolerated. Hypotension, disseminated intravascular coagulation, and ventricular tachycardia developed in a woman with placenta accreta who was given 500 mcg alprostadil.
    B) THERAPEUTIC DOSES: ADULTS: Erectile dysfunction - 125 to 1000 mcg intraurethrally; no more than 2 doses in 24 hours OR 1.5 to 60 mcg intracavernosal injection; no more than 3 doses weekly with at least 24 hours between doses. NEONATES: Patency of ductus arteriosus - initial, 0.05 to 0.1 mcg/kg/min continuous IV, maintenance 0.01 to 0.4 mcg/kg/min.

Clinical Effects

Summary Of Exposure

    A) USES: Alprostadil is used to maintain the patency of the ductus arteriosus until corrective surgery can be performed in neonates with congenital heart defects (eg, pulmonary atresia, pulmonary stenosis, tricuspid atresia, tetralogy of Fallot, interruption of the aortic arch, coarctation of the aorta) who are dependent on the patent ductus for survival. In adults, alprostadil is indicated for the treatment of neurogenic, vasculogenic, psychogenic, or mixed etiology erectile dysfunction. Intracavernosal alprostadil may be used as an adjunct to other diagnostic tests in the diagnosis of erectile dysfunction.
    B) PHARMACOLOGY: Alprostadil, prostaglandin E1, is a naturally occurring acidic lipid with a variety of pharmacologic effects, including vasodilation, inhibition of platelet aggregation, and stimulation of intestinal and uterine smooth muscle.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) NEONATES: COMMON: Apnea (most often in neonates under 2 kg), fever, flushing, hypotension, bradycardia, and seizures. INFREQUENT: Hyperextension of the neck, tachycardia, diarrhea, edema, infection, and urticaria. Hematological disorders (eg, disseminated intravascular coagulation, anemia and thrombocytopenia) have been reported infrequently in neonates. Supraventricular tachycardia, ventricular fibrillation, and second degree heart block have been reported in less than 1% of infants with congenital heart disease treated with alprostadil.
    2) ADULTS: COMMON: Penile pain, urethral burning, minor urethral bleeding/spotting, testicular pain. OTHER EFFECTS: Priapism, penile fibrosis, fibrotic nodules, flushing, dizziness, headache, nausea, abdominal cramps, diarrhea, tachycardia, hypotension, myocardial infarction (rare), edema, and injection site reaction.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. Overdoses in infants may cause apnea, bradycardia, fever, hypotension, and flushing. Overdoses in adults may result in hypotension, persistent penile pain, and priapism. Profound hypotension, disseminated intravascular coagulation and ventricular tachycardia were reported in a woman with placenta accreta who inadvertently received alprostadil instead of dinoprost.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Fever has been reported in approximately 14% of patients treated with alprostadil (Prod Info PROSTIN VR PEDIATRIC(R) intravenous infusion solution, 2009; Heymann & Clyman, 1982).
    B) WITH POISONING/EXPOSURE
    1) Overdoses in infants may cause fever (Prod Info PROSTIN VR PEDIATRIC(R) intravenous infusion solution, 2009).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) MYOCARDIAL INFARCTION
    1) WITH THERAPEUTIC USE
    a) In clinical trials, myocardial infarction was reported in 1% patients treated with alprostadil (Prod Info EDEX(R) intracavernous injection, 2006).
    b) CASE REPORT: Myocardial infarction was reported after intracavernosal administration of alprostadil in a patient with spinal cord injury and paraplegia . The 50-year-old patient was taking a calcium-channel blocker for hypertension and was a smoker. Twenty minutes after intracavernosal administration, the patient developed chest pain and tests were suggestive of myocardial infarction. A direct relationship was not established; however, it appears that the cardiovascular side effects of alprostadil may be more pronounced in those patients already having risk factors (Vaidyanathan & Krishnan, 1996).
    B) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) Bradycardia has been reported in 7% of neonates treated with alprostadil pediatric injection (Prod Info PROSTIN VR PEDIATRIC(R) intravenous infusion solution, 2009).
    2) WITH POISONING/EXPOSURE
    a) Overdoses in infants may cause bradycardia (Prod Info PROSTIN VR PEDIATRIC(R) intravenous infusion solution, 2009).
    C) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia has been reported in 3% of neonates treated with alprostadil pediatric injection (Prod Info PROSTIN VR PEDIATRIC(R) intravenous infusion solution, 2009).
    b) Supraventricular tachycardia has occurred in less than 1% of patients (Prod Info PROSTIN VR PEDIATRIC(R) intravenous infusion solution, 2009).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Profound hypotension, disseminated intravascular coagulation and ventricular tachycardia were reported in a 39-year-old woman with placenta accreta who inadvertently received alprostadil 500 mcg instead of dinoprost (Reedy et al, 1992).
    D) CARDIAC ARREST
    1) WITH THERAPEUTIC USE
    a) Cardiac arrest has been reported in 1% of infants with congenital heart disease treated with alprostadil (Prod Info PROSTIN VR PEDIATRIC(R) intravenous infusion solution, 2009).
    E) CONGESTIVE HEART FAILURE
    1) WITH THERAPEUTIC USE
    a) Congestive heart failure has been reported in less than 1% of infants with congenital heart disease treated with alprostadil (Prod Info PROSTIN VR PEDIATRIC(R) intravenous infusion solution, 2009).
    F) HEART BLOCK
    1) WITH THERAPEUTIC USE
    a) Second degree heart block has been reported in less than 1% of infants with congenital heart disease treated with alprostadil (Prod Info PROSTIN VR PEDIATRIC(R) intravenous infusion solution, 2009).
    G) VENTRICULAR FIBRILLATION
    1) WITH THERAPEUTIC USE
    a) Ventricular fibrillation has been reported in less than 1% of infants with congenital heart disease treated with alprostadil (Prod Info PROSTIN VR PEDIATRIC(R) intravenous infusion solution, 2009).
    H) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension has been reported in approximately 4% of infants with congenital heart disease treated with alprostadil (Prod Info PROSTIN VR PEDIATRIC(R) intravenous infusion solution, 2009; Heymann & Clyman, 1982).
    2) WITH POISONING/EXPOSURE
    a) Overdoses in infants may cause hypotension (Prod Info PROSTIN VR PEDIATRIC(R) intravenous infusion solution, 2009).
    b) Overdoses in adults may result in hypotension (Prod Info MUSE(R) transurethral suppository, 2011).
    c) CASE REPORT: Profound hypotension, disseminated intravascular coagulation, and ventricular tachycardia were reported in a 39-year-old woman with placenta accreta who inadvertently received alprostadil 500 mcg instead of dinoprost (Reedy et al, 1992).
    I) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypertension has been reported in approximately 2% of adults with erectile dysfunction treated with alprostadil (Prod Info EDEX(R) intracavernous injection, 2006).
    J) EDEMA
    1) WITH THERAPEUTIC USE
    a) Edema has been reported in approximately 1% of infants with congenital heart disease treated with alprostadil (Prod Info PROSTIN VR PEDIATRIC(R) intravenous infusion solution, 2009).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DISORDER OF RESPIRATORY SYSTEM
    1) WITH THERAPEUTIC USE
    a) Respiratory depression and distress, tachypnea, hypercapnia, bradypnea, and wheezing have been reported in less than 1% of infants with congenital heart disease treated with alprostadil (Prod Info PROSTIN VR PEDIATRIC(R) intravenous infusion solution, 2009).
    b) Apnea has been reported to occur in about 10 to 12% of neonates with congenital heart defects treated with alprostadil. Apnea is most common in neonates weighing less than 2 kg at birth and generally appears during the first hour of drug infusion (Prod Info PROSTIN VR PEDIATRIC(R) intravenous infusion solution, 2009; Heymann & Clyman, 1982).
    c) UPPER RESPIRATORY TRACT INFECTION: Has been reported in 5% of patients receiving alprostadil (Prod Info EDEX(R) intracavernous injection, 2006).
    2) WITH POISONING/EXPOSURE
    a) Overdoses in infants may cause apnea (Prod Info PROSTIN VR PEDIATRIC(R) intravenous infusion solution, 2009).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness has been reported in 2% to 4% of patients receiving alprostadil (Prod Info CAVERJECT(R) intracavernosal injection, 2009; Prod Info MUSE(R) transurethral suppository, 2011).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Five of 26 patients receiving 0.5 mg alprostadil for the treatment of Raynaud's disease reported a headache during administration (Clifford et al, 1980).
    C) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Approximately 4% of infants with congenital heart disease treated with alprostadil have experienced seizures (Prod Info PROSTIN VR PEDIATRIC(R) intravenous infusion solution, 2009).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea has been reported to occur in about 2% of patients treated with alprostadil (Prod Info PROSTIN VR PEDIATRIC(R) intravenous infusion solution, 2009).
    b) Diarrhea occurred in one of 26 patients receiving alprostadil 0.5 mg (total dose) for the treatment of severe Raynaud's disease (Clifford et al, 1980).
    c) Intestinal colic and diarrhea occurred in two neonates treated with intravenous infusion of alprostadil (Sankaran et al, 1981). Both infants experienced loose stools, abdominal discomfort, and irritability.
    B) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) WITH THERAPEUTIC USE
    a) Gastric outlet obstruction secondary to antral hyperplasia has been linked to alprostadil use in neonates. The duration of alprostadil therapy and cumulative dose may be related to this effect (Prod Info PROSTIN VR PEDIATRIC(R) intravenous infusion solution, 2009).
    b) GASTRIC REGURGITATION has been reported in less than 1% of patients (Prod Info PROSTIN VR PEDIATRIC(R) intravenous infusion solution, 2009).
    c) CASE REPORT: A 2-day-old infant developed gastric outlet obstruction during treatment with prostaglandin E1 infusion (total dose 2100 mg/kg). The infant received the infusion for 20 days. Regression in mucosal thickening was 40% at 3 weeks and had virtually disappeared after 8 weeks (Merkus et al, 1993).
    d) Gastric outlet obstruction was reported in 5 of 74 neonates receiving intravenous infusions of alprostadil for patency of the ductus arteriosus. Postmortem examination of the stomach in these victims revealed marked hyperplasia of the gastric pits. Occurrence of this adverse effect was correlated to cumulative dose; the authors recommended that patients receiving infusions of alprostadil at recommended doses for greater than 120 hours should be closely monitored (Peled et al, 1992).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) FUNCTIONAL DISORDER OF PENIS
    1) WITH THERAPEUTIC USE
    a) The following adverse effects have been reported with MUSE(R): penile pain (32%), urethral burning (12%), minor urethral bleeding/spotting (5%), and testicular pain (5%) (Prod Info MUSE(R) transurethral suppository, 2011).
    b) The following adverse effects have been reported with Caverject(R): penile pain (37%), prolonged erection (4%), penile fibrosis (3%), and hematoma (3%) (Prod Info CAVERJECT(R) intracavernosal injection, 2009).
    c) CASE REPORT: Tunica albuginea induration, penile curvature deformity, and a Peyronie's-like plaque were noted in a 66-year-old man after intracorporeal injection of prostaglandin E1. It was recommended that surgical excision be performed (Chen et al, 1994).
    2) WITH POISONING/EXPOSURE
    a) Overdoses in adults may result in persistent penile pain and priapism (Prod Info MUSE(R) transurethral suppository, 2011; Prod Info EDEX(R) intracavernous injection, 2006).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) DISSEMINATED INTRAVASCULAR COAGULATION
    1) WITH THERAPEUTIC USE
    a) Disseminated intravascular coagulation has been reported infrequently (1%) in neonates receiving alprostadil therapy (Prod Info PROSTIN VR PEDIATRIC(R) intravenous infusion solution, 2009).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Profound hypotension, disseminated intravascular coagulation, and ventricular tachycardia were reported in a 39-year-old woman with placenta accreta who inadvertently received alprostadil 500 mcg instead of dinoprost (Reedy et al, 1992).
    B) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Anemia has been reported infrequently in neonates receiving alprostadil therapy (Prod Info PROSTIN VR PEDIATRIC(R) intravenous infusion solution, 2009).
    C) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia has been reported infrequently in neonates receiving alprostadil therapy (Prod Info PROSTIN VR PEDIATRIC(R) intravenous infusion solution, 2009).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) LOCAL INFECTION OF WOUND
    1) WITH THERAPEUTIC USE
    a) SUPERINFECTIONS: In newborns (median age 2 days) who required the use of alprostadil for congenital heart disease, there was a reported trend (P=0.13) to develop a wound infection, when compared to controls. Pathogenic Staphylococcus epidermis was recovered from all infected sites (Fleming et al, 1984).
    B) FLUSHING
    1) WITH THERAPEUTIC USE
    a) Flushing has been reported in about 10% of patients and is more common after intra-arterial dosing (Prod Info PROSTIN VR PEDIATRIC(R) intravenous infusion solution, 2009; Carter & Garzon, 2000).
    b) Eight of 26 patients with severe Raynaud's disease experienced flushing following alprostadil infusion at a rate of 6 ng/kg/min for 12 hours increasing to 10 ng/kg/min (Clifford et al, 1980).
    2) WITH POISONING/EXPOSURE
    a) Overdoses in infants may cause flushing (Prod Info PROSTIN VR PEDIATRIC(R) intravenous infusion solution, 2009).
    C) URTICARIA
    1) WITH THERAPEUTIC USE
    a) A neonate with transposition of the great vessels developed an eruption of polycyclic and iridial patches of blanching erythema over the scalp, neck, chest, and left ankle during treatment with prostaglandin E1. A biopsy specimen revealed a very sparse mononuclear infiltrate in the dermis, consistent with urticaria (Carter & Garzon, 2000).
    D) INJECTION SITE REACTION
    1) WITH THERAPEUTIC USE
    a) Local reactions reported by patients receiving alprostadil intracavernosal injection during controlled and uncontrolled studies of up to 18 months in duration included injection site hematomas (3%) and ecchymosis (2%), penile rash (1%), and penile edema (1%). Hematoma and ecchymosis appeared to be a complication of faulty injection technique. No significant local adverse reactions were reported by patients who received 1 to 3 injections of placebo, other than penile pain (Prod Info CAVERJECT(R) intracavernosal injection, 2009; Prod Info CAVERJECT IMPULSE(R) intracavernosal injection lyophilized powder for solution, 2009).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCULOSKELETAL FINDING
    1) WITH THERAPEUTIC USE
    a) Less than 1% of patients have developed stiffness with alprostadil. Neck hyperextension has also been reported very infrequently (Prod Info Prostin VR Pediatric(R), alprostadil, 1997).
    b) Cortical hyperostosis has been observed in infants during long-term treatment with alprostadil (Prod Info Prostin VR Pediatric(R), alprostadil, 1997; Ueda et al, 1980; Abe et al, 1982; Teixeira et al, 1984) Benz-Bohn et al, 1984; (Dekel & Francis, 1981; Hst et al, 1988). Cortical proliferation regresses after drug discontinuation (Ueda et al, 1980; Alpert et al, 1984).
    c) CHRONIC: Cortical hyperostosis apparent from chest x-rays was reported in 53 of 86 infants (62%) receiving prolonged prostaglandin E1 infusion awaiting heart transplantation. There was an association with the duration of alprostadil infusion; infants (n=14) who received prostaglandin E1 more than 60 days were all affected, compared to 42% of infants who received therapy for less than 30 days and 82% of infants who received alprostadil for 30 to 60 days (Woo et al, 1994).
    d) The use of alprostadil has been reported to cause swelling of the extremities, digital swelling, and clubbing. In most cases this is both dose and duration related (Sharp & Robertson, 1987).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Severe hyperglycemia with apparent ketoacidosis was reported in the infant of a diabetic mother during infusion with alprostadil postoperatively (Cohen & Nihill, 1983).

Reproductive

    3.20.1) SUMMARY
    A) Alprostadil is in Pregnancy Category C. Alprostadil urethral suppositories and intracavernosal injection are not indicated for use in women, newborns, or children. Alprostadil IV solution is only indicated for use in neonates and infants.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) EMBRYOTOXICITY
    a) Increased incidences of visceral and skeletal variations, primarily left umbilical artery and generalized reduction in ossification of the entire skeleton, and gross visceral and skeletal malformations, primarily edema, hydrocephaly, anophthalmia or microphthalmia, and skeletal anomalies, occurred with maternally toxic doses of 2000 mcg/kg/day, which produced ataxia, lethargy, diarrhea, and retarded weight gain in the pregnant rats (Prod Info MUSE(R) urethral suppositories, 2012).
    2) LACK OF EFFECT
    a) RABBITS: Alprostadil administered intravaginally in pregnant rabbits resulted in no evidence of fetal harm at doses up to 1100 mcg/kg/day (about 12.5 times the maximum recommended daily dose based on body surface area) (Prod Info MUSE(R) urethral suppositories, 2012).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Pregnancy category C (Prod Info MUSE(R) urethral suppositories, 2012).
    2) Alprostadil urethral suppositories and intracavernosal injection are not for use in women (Prod Info Caverject(R) intracavernosal injection, 2014) and the suppositories should not be used for sexual intercourse with a pregnant woman unless a condom barrier is used (Prod Info MUSE(R) urethral suppositories, 2012).
    3) Alprostadil IV solution is only indicated for use in neonates and infants (Prod Info Prostin VR Pediatric(R) intravenous injection solution, 2013).
    B) ANIMAL STUDIES
    1) EMBRYOTOXICITY
    a) Alprostadil administered as a subQ bolus in pregnant rats showed evidence of embryotoxicity (ie, decreased fetal weight) at doses as low as 500 mcg/kg/day (Prod Info MUSE(R) urethral suppositories, 2012).
    b) Alprostadil administered as a subQ bolus at maternally toxic doses of 2000 mcg/kg/day in pregnant rats was associated with increased resorptions and reduced numbers of live fetuses (Prod Info MUSE(R) urethral suppositories, 2012).
    c) Continuous IV infusion also resulted in embryotoxicity, including decreased fetal weight gain and increased incidence of hydroureter, at a maternally toxic dose of 2000 mcg/kg/day, which also was associated with decreased maternal weight gain (Prod Info MUSE(R) urethral suppositories, 2012).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) SUMMARY
    1) Alprostadil urethral suppositories and intracavernosal injection are not indicated for use in women, newborns, or children (Prod Info Caverject(R) intracavernosal injection, 2014; Prod Info MUSE(R) urethral suppositories, 2012).
    2) Alprostadil IV solution is only indicated for use in neonates and infants (Prod Info Prostin VR Pediatric(R) intravenous injection solution, 2013).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the effects of this agent used IV on fertility in humans (Prod Info Prostin VR Pediatric(R) intravenous injection solution, 2013).
    B) LACK OF EFFECT
    1) No effect on human sperm motility or viability were reported with alprostadil concentrations of 400 mcg/mL studied in vitro (Prod Info MUSE(R) urethral suppositories, 2012).
    C) ANIMAL STUDIES
    1) Intraurethral administration of 3000 mcg/day for 13 weeks or 200 mcg/kg/day (about 3.5 times the maximum recommended daily dose based on body surface area) in dogs resulted in no effects on sperm concentration, morphology, or motility (Prod Info MUSE(R) urethral suppositories, 2012).
    2) Alprostadil doses of up to 0.2 mg/kg/day (200-fold the usual human doses) in rats did not adversely affect or alter spermatogenesis (Prod Info Caverject(R) intracavernosal injection, 2014).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs following significant overdose.
    B) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) Monitor arterial blood gases and pulse oximetry in any patient with respiratory symptoms.
    D) Obtain an ECG, and institute continuous cardiac monitoring.
    E) Monitor for priapism. Prolonged erection or priapism (lasting more than 6 hours) should be treated to prevent tissue hypoxia and possible necrosis.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    4.1.4) OTHER
    A) OTHER
    1) OTHER
    a) Obtain an ECG, and institute continuous cardiac monitoring.
    b) Monitor for priapism. Prolonged erection or priapism (lasting more than 6 hours) should be treated to prevent tissue hypoxia and possible necrosis (Prod Info EDEX(R) intracavernous injection, 2006).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients with persistent cardiac dysrhythmias, seizures, and respiratory depression should be admitted to an ICU setting.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) Men with inadvertent intracavernosal or transurethral overdose who are asymptomatic and do not have priapism can be managed at home.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) A medical toxicologist or poison control center should be consulted in cases that involve cardiac toxicity, or in whom the diagnosis is not clear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Symptomatic patients or those with inadvertent parenteral injection should be referred to a healthcare facility to be monitored for several hours to assess cardiac function. Low-flow priapism is a urologic emergency and should be treated promptly to prevent complications (eg, impotence). Patients that remain asymptomatic after 6 hours can be discharged.

Monitoring

    A) Monitor vital signs following significant overdose.
    B) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) Monitor arterial blood gases and pulse oximetry in any patient with respiratory symptoms.
    D) Obtain an ECG, and institute continuous cardiac monitoring.
    E) Monitor for priapism. Prolonged erection or priapism (lasting more than 6 hours) should be treated to prevent tissue hypoxia and possible necrosis.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not required; administered via the intravenous, intracavernosal, or intraurethral administration routes.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Refer to PARENTERAL SECTIONS for treatment information.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding.

Range Of Toxicity

Summary

    A) TOXICITY: Overdose data is limited. Single IV doses of alprostadil from 1 to 120 mcg is usually well tolerated. Hypotension, disseminated intravascular coagulation, and ventricular tachycardia developed in a woman with placenta accreta who was given 500 mcg alprostadil.
    B) THERAPEUTIC DOSES: ADULTS: Erectile dysfunction - 125 to 1000 mcg intraurethrally; no more than 2 doses in 24 hours OR 1.5 to 60 mcg intracavernosal injection; no more than 3 doses weekly with at least 24 hours between doses. NEONATES: Patency of ductus arteriosus - initial, 0.05 to 0.1 mcg/kg/min continuous IV, maintenance 0.01 to 0.4 mcg/kg/min.

Therapeutic Dose

    7.2.1) ADULT
    A) INTRACAVERNOSAL INJECTION
    1) ERECTILE DYSFUNCTION OF VASCULOGENIC, PSYCHOGENIC, OR MIXED ETIOLOGY: The recommended initial dose is 2.5 mcg administered INTRACAVERNOSALLY. The dose may be increased by 2.5 mcg (5 mcg total) within one hour if there is a partial response or by 5 mcg (7.5 mcg total) within one hour if there is no response. If additional dose increases are required, the dose may be increased in increments of 5 to 10 mcg administered at least 24 hours apart (Prod Info Caverject(R) intracavernosal injection, 2014).
    2) ERECTILE DYSFUNCTION OF PURE NEUROGENIC ETIOLOGY: The recommended initial dose is 1.25 mcg administered INTRACAVERNOSALLY. The dose may be increased to 2.5 mcg within one hour. If additional dose increases are required, the dose may be increased in increments of 5 mcg administered at least 24 hours apart (Prod Info Caverject(R) intracavernosal injection, 2014).
    B) TRANSURETHRAL
    1) The dose range is 125 mcg to 1000 mcg administered INTRAURETHRALLY as needed; no more than 2 doses in a 24-hour period (Prod Info MUSE(R) transurethral suppository, 2011).
    7.2.2) PEDIATRIC
    A) INTRACAVERNOSAL INJECTION
    1) Safety and effectiveness have not been established in pediatric patients (Prod Info CaverJect Impulse(R) Dual Chamber System intracavernosal injection powder, 2013).
    B) INTRAVENOUS INJECTION
    1) PATENCY OF DUCTUS ARTERIOSUS: The recommended dose is 0.05 to 0.1 mcg/kg/min administered as a continuous IV infusion or through an umbilical artery catheter. MAX DOSE: 0.4 mcg/kg/min. Reduce the infusion rate to the lowest possible dosage after therapeutic response is achieved (Prod Info Prostin VR Pediatric(R) intravenous injection solution, 2013).
    C) TRANSURETHRAL
    1) Safety and effectiveness have not been established in pediatric patients (Prod Info MUSE(R) transurethral suppository, 2011).

Maximum Tolerated Exposure

    A) In a single dose rising tolerance study in healthy volunteers, single intravenous doses of alprostadil from 1 to 120 mcg were usually well-tolerated. Beginning with a 40 mcg intravenous bolus dose, the incidence of drug-related systemic adverse events increased in a dose-dependent manner, mainly resulting in facial flushing (Prod Info EDEX(R) intracavernous injection, 2006).
    B) CASE REPORT: Profound hypotension, disseminated intravascular coagulation and ventricular tachycardia were reported in a 39-year-old woman with placenta accreta who inadvertently received alprostadil 500 mcg instead of dinoprost (Reedy et al, 1992).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 19800 mcg/kg (RTECS , 2002)
    2) LD50- (ORAL)MOUSE:
    a) 186 mg/kg (RTECS , 2002)
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 26400 mcg/kg (RTECS , 2002)
    4) LD50- (INTRAPERITONEAL)RAT:
    a) 24900 mcg/kg (RTECS , 2002)
    5) LD50- (ORAL)RAT:
    a) 228 mg/kg (RTECS , 2002)
    6) LD50- (SUBCUTANEOUS)RAT:
    a) 18600 mcg/kg (RTECS , 2002)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Alprostadil (Prostaglandin E1) is one of a family of naturally occurring acidic lipids with a wide variety of pharmacological actions (e.g.; vasodilation, inhibition of platelet aggregation, stimulation of intestinal and uterine smooth muscle). In animal studies, alprostadil relaxed retractor penis and corpus cavernosum urethrae in vitro. In addition, alprostadil relaxed isolated preparations of human corpus cavernosum and spongiosum, as well as cavernous arterial segments contracted by either noradrenaline or PGF 2(alpha) in vitro. In pigtail monkeys (Macaca nemestrina), dose-dependent increases in cavernous arterial blood flow were observed (Prod Info Caverject(R) Sterile powder, alprostadil, 1999; Prod Info MUSE(R) Urethral Suppository, alprostadil, 1998; Prod Info Prostin VR Pediatric(R), alprostadil, 1997).
    B) It promotes erection by relaxation of trabecular smooth muscle and by dilation of cavernosal arteries. This will lead to expansion of lacunar spaces and entrapment of blood by compressing the venules against the tunica albuginea. This process is called the corporal veno-occlusive mechanism (Prod Info Caverject(R) Sterile powder, alprostadil, 1999; Prod Info MUSE(R) Urethral Suppository, alprostadil, 1998).
    C) In animal studies, smooth muscle of the ductus arteriosus was especially sensitive to alprostadil. Alprostadil is used temporarily to maintain the patency of the ductus arteriosus until corrective or palliative surgery can be performed in neonates who have congenital heart defects (e.g.; pulmonary atresia, pulmonary stenosis, tricuspid atresia, tetralogy of Fallot, interruption of the aortic arch, coarctation of the aorta, or transposition of the great vessels with or without other defects) (Prod Info Prostin VR Pediatric(R), alprostadil, 1997).

Physicochemical

Physical Characteristics

    A) Alprostadil is a white to off-white crystalline powder with a solubility of 8000 mcg per 100 mL double distilled water at 35 degrees C (Prod Info CAVERJECT IMPULSE(R) intracavernosal injection, 2015).

Molecular Weight

    A) 354.49 (Prod Info CAVERJECT IMPULSE(R) intracavernosal injection, 2015)

References

General Bibliography

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    28) Product Information: CAVERJECT IMPULSE(R) intracavernosal injection lyophilized powder for solution, alprostadil intracavernosal injection lyophilized powder for solution. Pharmacia and Upjohn Company (per DailyMed), New York, NY, 2009.
    29) Product Information: CAVERJECT IMPULSE(R) intracavernosal injection, alprostadil intracavernosal injection. Pharmacia & Upjohn Company (per FDA), New York, NY, 2015.
    30) Product Information: CAVERJECT(R) intracavernosal injection, alprostadil intracavernosal injection. Pharmacia and Upjohn Company (per DailyMed), New York, NY, 2009.
    31) Product Information: CaverJect Impulse(R) Dual Chamber System intracavernosal injection powder, alprostadil intracavernosal injection powder. Pfizer (per FDA), New York, NY, 2013.
    32) Product Information: Caverject(R) Sterile powder, alprostadil. Pharmacia & Upjohn Co, Kalamazoo, MI, 1999.
    33) Product Information: Caverject(R) intracavernosal injection, alprostadil intracavernosal injection. Pharmacia & Upjohn Company (per FDA), New York, NY, 2014.
    34) Product Information: Cordarone(R) oral tablets, amiodarone HCl oral tablets. Wyeth Pharmaceuticals Inc (per FDA), Philadelphia, PA, 2015.
    35) Product Information: EDEX(R) intracavernous injection, alprostadil intracavernous injection. Schwarz Pharma, Milwaukee, WI, 2006.
    36) Product Information: Lidocaine HCl intravenous injection solution, lidocaine HCl intravenous injection solution. Hospira (per manufacturer), Lake Forest, IL, 2006.
    37) Product Information: MUSE(R) Urethral Suppository, alprostadil. VIVUS, Inc, Mountain View, CA, 1998.
    38) Product Information: MUSE(R) transurethral suppository, alprostadil transurethral suppository. Meda Pharmaceuticals Inc. (Per Daily Med), Somerset, NJ, 2011.
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    40) Product Information: PROSTIN VR PEDIATRIC(R) intravenous infusion solution, alprostadil intravenous infusion solution. Pharmacia and Upjohn Company (Per Daily Med), New York, NY, 2009.
    41) Product Information: Prostin VR Pediatric(R) intravenous injection solution, alprostadil intravenous injection solution. Pharmacia & Upjohn Co (per DailyMed), New York, NY, 2013.
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