Substances Included Synonyms

Therapeutic Toxic Class

A)

B)

Specific Substances

A)

1) 4-Amino-5-chloro-N-(2-diethylaminoethyl)-2-methoxybenzamine hydrochloride monohydrate
2) AHR-3070-C
3) MK 745
4) CAS 364-62-5 (metoclopramide)
5) CAS 7232-21-5 (Metoclopramide hydrochloride, anhydrous)
6) CAS 54143-57-6 (Metoclopramide hydrochloride, monohydrate)

1) Bromopridum

1) 2H-Benzimidazol-2-one, 5-chloro-1-(1-(1-(3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl)-4-piperidinyl)-1,3-dihdr)-
2) 5-chloro-1-(1-(3-(2-oxo-1-benzimidazolinyl)propyl)-4-piperidyl)-2-benzimidazolinone
3) CAS 57808-66-9

Available Forms Sources

A)

1) Metoclopramide is available in the following formulations:

a) 5 mg/5 mL oral solution (Prod Info metoclopramide oral solution, 2005)
b) 5 mg and 10 mg oral disintegrating tablets (Prod Info METOZOLV ODT orally disintegrating tablets, 2009)
c) 5 mg and 10 mg oral tablets (Prod Info REGLAN(R) oral tablets, 2009)
d) 5 mg/mL intravenous solution (Prod Info REGLAN(R) intravenous, intramuscular injection, 2009)
e) 5 mg/5 mL and 1 mg/mL oral syrup (Prod Info metoclopramide oral solution, 2005)

B)

1) Metoclopramide is used in the treatment of diabetic gastroparesis, prevention of postoperative or chemotherapy-induced nausea and vomiting, gastroesophageal reflux, small bowl intubation, and radiological examination of the gastrointestinal tract (Prod Info METOZOLV ODT orally disintegrating tablets, 2009; Prod Info REGLAN(R) oral tablets, 2009; Prod Info REGLAN(R) intravenous, intramuscular injection, 2009).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Metoclopramide is an antiemetic and a prokinetic gastrointestinal agent. It is used in the treatment of diabetic gastroparesis, prevention of postoperative or chemotherapy-induced nausea and vomiting, gastroesophageal reflux, small bowl intubation, and radiological examination of the gastrointestinal tract.
B) PHARMACOLOGY: Metoclopramide blocks dopamine receptors, and in higher doses also blocks serotonin receptors in the chemoreceptor trigger zone of the central nervous system. It enhances the response to acetylcholine of tissue in the upper gastrointestinal tract, causing enhanced motility and accelerated gastric emptying, and increases lower esophageal sphincter tone. It does not increase stimulation of gastric, biliary, or pancreatic secretions.
C) TOXICOLOGY: Its mechanism of toxicity is likely secondary to its mechanism of action, especially its dopamine antagonism.
D) EPIDEMIOLOGY: There are adverse reactions/unintentional exposures reported every year. Intentional overdose does occur, but is relatively rare, and toxicity is generally mild.
E) WITH THERAPEUTIC USE

1) There are many different adverse reactions that can occur with therapeutic dosing of metoclopramide.
2) CARDIOVASCULAR: AV block, bradycardia, edema, flushing (especially after high IV dosing), hypertension, hypotension, and supraventricular tachycardia may occur. Angioneurotic edema is rare.
3) CENTRAL NERVOUS SYSTEM: The most commonly observed (in up to 70% of patients) adverse effects. These effects are dose and age-related. They include acute dystonic reactions (in up to 25% of patients) and about 10% of patients exhibit fatigue, lassitude, or restlessness. Patients also exhibit akathisia, confusion, depression, dizziness, headache, insomnia, Parkinsonian-like symptoms, suicidal ideation, seizure, and tardive dyskinesia. Rarely, they exhibit hallucinations and neuroleptic malignant syndrome.
4) DERMATOLOGIC: Rash and urticaria may occur.
5) ENDOCRINE AND METABOLIC: Amenorrhea, galactorrhea, gynecomastia, and hyperprolactinemia may occur with chronic therapy.
6) GASTROINTESTINAL: Diarrhea and nausea may occur.
7) GENITOURINARY: Incontinence and urinary frequency may occur. Impotence may occur with chronic therapy.
8) HEMATOLOGIC: Agranulocytosis, leukopenia, neutropenia, porphyria, methemoglobinemia, and sulfhemoglobinemia have occurred.
9) IMMUNOLOGIC: Allergic reactions may occur.
10) EYES: Visual disturbances have also been reported.
11) RESPIRATORY: The most common respiratory adverse reaction is bronchospasm, however, laryngeal edema and laryngospasm have rarely occurred. Parenteral formulations that contain sulfite preservatives may precipitate bronchospasm in susceptible individuals.

F) WITH POISONING/EXPOSURE

1) TOXICITY: Inadvertent overdose in newborns and infants has resulted in severe methemoglobinemia and opisthotonic posturing. Common toxic effects include restlessness, drowsiness, insomnia, headache, confusion, dizziness and acute dystonic reactions. Acute dystonic reactions are more common in children and young adults, whereas prolonged reactions are more common in elderly patients. Most dystonic reactions resolve within 12 to 48 hours but may last for months after discontinuation of chronic therapy. Neuroleptic malignant syndrome is an idiosyncratic reaction that may develop after a single dose of medication but also can occur after overdose or prolonged therapy.

0.2.3)

A) Fever, hypothermia, hypotension, and hypertension have been reported.

0.2.20)

A) Metoclopramide is classified as FDA pregnancy category B. Metoclopramide crosses the placenta and is excreted in breast milk. In one study, metoclopramide use during the first trimester of pregnancy was not significantly associated with increased risks of major congenital malformations, low birth weight, preterm delivery, or perinatal death.

Laboratory Monitoring

A)

B)

C)

D)

E)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Routine decontamination is not recommended as most toxicity is mild. Dystonic reactions in adults can be treated with benztropine 1 to 4 mg IV (max 6 mg/day) and/or diphenhydramine 25 to 50 mg/dose IV over 2 minutes (maximum 100 mg/dose, 400 mg/day) in adults. Dosing of diphenhydramine in children is 1.25 mg/kg/dose IV over 2 minutes with a maximum daily dosing of 300 mg/day. Patients may require treatment for several days to avoid recurrence of dystonic reactions.

B) MANAGEMENT OF SEVERE TOXICITY

1) Severe toxicity, though rare, includes cardiovascular and CNS effects such as bradycardia, hypotension, hypertension, seizures, and cardiac arrest. Standard treatment is indicated such as atropine for bradycardia and fluids and pressors for hypotension. Seizures should be managed with benzodiazepines (eg, diazepam 5 to 10 mg or lorazepam 2 to 4 mg every 10 to 15 minutes for adults as needed; for children, 0.2 to 0.5 mg/kg diazepam or lorazepam 0.05 to 0.1 mg/kg every 5 minutes as needed). Consider giving phenobarbital or propofol if seizures continue to occur despite benzodiazepine therapy. Neuroleptic malignant syndrome can be treated with good supportive care and intravenous benzodiazepines; consider bromocriptine, amantadine or dantrolene if not responding to benzodiazepines. Methemoglobinemia can be treated with methylene blue in symptomatic patients.

C) DECONTAMINATION

1) PREHOSPITAL: Decontamination is generally not indicated as toxicity is usually not severe.
2) HOSPITAL: In general, decontamination is not indicated for this overdose, but may be considered for massive overdoses that present early. Activated charcoal should be considered if the patient is awake and cooperative and if the ingestion was relatively recent. Gastric lavage, whole bowel irrigation, or multiple doses of charcoal are not indicated.

D) AIRWAY MANAGEMENT

1) Endotracheal intubation and mechanical ventilation may be necessary if the patient develops respiratory distress or fails to protect his or her airway secondary to altered mental status.

E) ANTIDOTE

1) None.

F) METHEMOGLOBINEMIA

1) Initiate oxygen therapy. Treat with methylene blue if patient is symptomatic (usually at methemoglobin concentrations greater than 20% to 30% or at lower concentrations in patients with anemia, underlying pulmonary or cardiovascular disease). METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.

G) ENHANCED ELIMINATION

1) There is no role for dialysis, hemoperfusion, urinary alkalinization, or multiple dose charcoal.

H) PATIENT DISPOSITION

1) HOME CRITERIA: Asymptomatic patients with inadvertent exposures may be monitored at home. All other patients may require observation.
2) OBSERVATION CRITERIA: Intentional overdoses or patients with symptoms should be observed for 4 to 6 hours, and may be discharged if only mild symptoms persist.
3) ADMISSION CRITERIA: Patients with continued/worsening symptoms after observation for several hours should be admitted for further monitoring, and depending on the severity of their symptoms, may merit an ICU bed. Criteria for discharge should be resolution of symptoms.
4) CONSULT CRITERIA: Contact your local poison center or toxicologist for any concerns. The mainstay of treatment is good symptomatic and supportive care.

I) PITFALLS

1) Pitfalls in managing these patients include missing alternative diagnoses or not recognizing iatrogenic overdoses. Adverse events may occur even at therapeutic dosing. Dystonic reactions that resolve with intravenous benztropine or diphenhydramine often recur; patients may require several days of oral treatment to avoid recurrence.

J) PHARMACOKINETICS

1) Onset of action varies depending on the route of administration; typically, 1 to 3 minutes after IV administration, 10 to 15 minutes after an IM injection, and 30 to 60 minutes after oral dosing. Duration of action is approximately 1 to 2 hours, regardless of the route. Tmax after oral dosing is also 1 to 2 hours. Metoclopramide has a relatively high volume of distribution (3.5 L/kg). It is approximately 30% protein bound and the half-life of elimination is approximately 4 hours in children and 5 to 6 hours in adults, but is somewhat dose dependent. It is primarily excreted in urine (85%). There is some hepatic metabolism, including sulfonation and glucuronidation.

K) TOXICOKINETICS

1) In a fatality report of a 25-year-old woman who overdosed on both diltiazem and metoclopramide, there was a biphasic elimination curve for metoclopramide with an initial half-life of 1.3 hours and a terminal half-life of 20 hours.

L) PREDISPOSING CONDITIONS

1) The risk of developing tardive dyskinesia appears increased in the elderly, women, and diabetics. The majority of reports of tardive dyskinesia were in those taking higher doses, long-term use (more than 3 months), and in the elderly (particularly older women). Extrapyramidal symptoms occur most often in pediatric patients and adults less than 30 years of age. Metoclopramide should be used with caution or avoided in patients with Parkinson’s disease due to the increased risk of extrapyramidal symptoms. Patients with NADH-cytochrome b5 reductase deficiency (eg, neonates) are at increased risk of developing methemoglobinemia and/or sulfhemoglobinemia. Dosage adjustment may be needed for those with renal impairment.

M) DIFFERENTIAL DIAGNOSIS

1) Differential diagnosis should include other drugs and conditions that can cause altered mental status, dystonic reactions, and neuromuscular findings.

Range Of Toxicity

A)

B)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

E)

1) There are many different adverse reactions that can occur with therapeutic dosing of metoclopramide.
2) CARDIOVASCULAR: AV block, bradycardia, edema, flushing (especially after high IV dosing), hypertension, hypotension, and supraventricular tachycardia may occur. Angioneurotic edema is rare.
3) CENTRAL NERVOUS SYSTEM: The most commonly observed (in up to 70% of patients) adverse effects. These effects are dose and age-related. They include acute dystonic reactions (in up to 25% of patients) and about 10% of patients exhibit fatigue, lassitude, or restlessness. Patients also exhibit akathisia, confusion, depression, dizziness, headache, insomnia, Parkinsonian-like symptoms, suicidal ideation, seizure, and tardive dyskinesia. Rarely, they exhibit hallucinations and neuroleptic malignant syndrome.
4) DERMATOLOGIC: Rash and urticaria may occur.
5) ENDOCRINE AND METABOLIC: Amenorrhea, galactorrhea, gynecomastia, and hyperprolactinemia may occur with chronic therapy.
6) GASTROINTESTINAL: Diarrhea and nausea may occur.
7) GENITOURINARY: Incontinence and urinary frequency may occur. Impotence may occur with chronic therapy.
8) HEMATOLOGIC: Agranulocytosis, leukopenia, neutropenia, porphyria, methemoglobinemia, and sulfhemoglobinemia have occurred.
9) IMMUNOLOGIC: Allergic reactions may occur.
10) EYES: Visual disturbances have also been reported.
11) RESPIRATORY: The most common respiratory adverse reaction is bronchospasm, however, laryngeal edema and laryngospasm have rarely occurred. Parenteral formulations that contain sulfite preservatives may precipitate bronchospasm in susceptible individuals.

F)

1) TOXICITY: Inadvertent overdose in newborns and infants has resulted in severe methemoglobinemia and opisthotonic posturing. Common toxic effects include restlessness, drowsiness, insomnia, headache, confusion, dizziness and acute dystonic reactions. Acute dystonic reactions are more common in children and young adults, whereas prolonged reactions are more common in elderly patients. Most dystonic reactions resolve within 12 to 48 hours but may last for months after discontinuation of chronic therapy. Neuroleptic malignant syndrome is an idiosyncratic reaction that may develop after a single dose of medication but also can occur after overdose or prolonged therapy.

Vital Signs

3.3.1)

A) Fever, hypothermia, hypotension, and hypertension have been reported.

3.3.3)

A) FEVER may accompany dystonic reactions (Wandless et al, 1980). Fever without dystonia was described in a 46-year-old woman after high dose metoclopramide therapy (150 to 200 mg/dose intravenously for 4 doses) for prevention of cisplatin-induced vomiting (Thies & Zafar, 1986).
B) HYPOTHERMIA with a core temperature of 29 degrees C was reported in a 25-year-old female following an overdose of metoclopramide and diltiazem (Beno & Nemeth, 1991).

3.3.4)

A) HYPERTENSION has been reported following low-dose and high-dose use (Plouin, 1976; Rampton, 1977; Sheridan et al, 1982; Filibeck et al, 1984; USPDI, 1999).
B) HYPOTENSION: Mild to severe hypotension has been observed in patients following therapeutic use (Park, 1978; Park, 1981; Hughes, 1984).

Heent

3.4.3)

A) VISUAL DISTURBANCES have been reported in patients receiving metoclopramide (Prod Info REGLAN(R) intravenous, intramuscular injection, 2009).
B) OCULOGYRIC CRISIS has been reported in children receiving metoclopramide or domperidone (Sanklecha & Charde, 2013; Tait et al, 1990); has been reported in an adult (Edwards et al, 1989).

Cardiovascular

3.5.2)

A) CONDUCTION DISORDER OF THE HEART

1) WITH THERAPEUTIC USE

a) SUMMARY

1) In postmarketing experience, supraventricular tachycardia, bradycardia, and possible atrioventricular block were reported with the use of metoclopramide tablets. A causal relationship to drug exposure has not been established (Prod Info METOZOLV ODT orally disintegrating tablets, 2009).
2) METOCLOPRAMIDE: Dysrhythmias have been reported rarely, with isolated cases of supraventricular extrasystoles, supraventricular tachycardia, and bigeminy associated with hypotension (Hughes, 1984; Shaklai, 1974; Bevacqua, 1988).
3) DOMPERIDONE: Dysrhythmias (ventricular fibrillation, cardiac arrest) have been described following intravenous administration of domperidone (Joss et al, 1982) Roussak & Carey, 1984, Osborne et al, 1985). Death from ventricular fibrillation occurred in a 69-year-old man following 200 mg IV (Joss et al, 1982). Four patients sustained cardiac arrest following IV administration of 20 to 50 mg. All patients were successfully resuscitated (Roussak & Carey, 1984).

a) WITHDRAWAL FROM MARKET: Clinical trials with intravenous domperidone were discontinued in the US by Janssen. The company voluntarily withdrew the intravenous preparation from worldwide markets following reports of cardiovascular adverse effects.

b) CASE REPORTS

1) METOCLOPRAMIDE

a) Multifocal supraventricular extrasystoles were reported in a 55-year-old woman following a single intramuscular 10 mg dose (Shaklai, 1974).
b) Supraventricular tachycardia developed following a 10 mg intravenous dose of metoclopramide in a stable postpartum woman (Bevacqua, 1988).
c) Bradydysrhythmias and sinus arrest occurred in a 51-year-old female following metoclopramide administration on several occasions, and occurred on rechallenge (Malkoff et al, 1995).

2) DOMPERIDONE

a) Death from ventricular fibrillation occurred in a 69-year-old man following 200 mg IV (Joss et al, 1982).

c) Four patients sustained cardiac arrest following IV administration of 20 to 50 mg. All patients were successfully resuscitated (Roussak & Carey, 1984).
d) Significant ventricular dysrhythmias occurred in two of four patients following intravenous administration of domperidone. Both patients had hypokalemia, which might have contributed to the ventricular excitability (Osborne et al, 1985).

2) WITH POISONING/EXPOSURE

a) DOMPERIDONE (CASE REPORT): A 3-month-old infant presented with intense irritability, excessive crying, intermittent opisthotonus with upward deviation of the eyes (a classic oculogyric crises) and dystonic cycling movements of the upper and lower limbs several hours after receiving a large dose of domperidone (25 mg 2 times in 4 hours; total dose: 50 mg or more than 10 mg/kg in 4 hours instead of the prescribed 0.5 mg/kg/dose; a dose of 2.5 mL equals to 2.5 mg of domperidone). On presentation, the child had persistent tachycardia (200 to 240 beats/min), elevated serum prolactin (45.9 ng/mL; normal level up to 30) and serum potassium (6.2 mEq/mL; normal up to 5.3). An ECG showed supraventricular tachycardia. Following supportive care, including IV promethazine treatment, the child's symptoms gradually resolved over 36 hours (Sanklecha & Charde, 2013).

B) HEART BLOCK

1) WITH THERAPEUTIC USE

a) CASE REPORT: Sinus bradycardia progressing to complete heart block and transient asystole was reported immediately following 10 mg intravenously in a 54-year-old man with jaundice (Withington, 1986). Two other patients experienced extreme bradycardia, leading to complete heart block in one, within minutes of receiving an injection of metoclopramide (Midttun & Oberg, 1994).

C) HEART FAILURE

1) CASE REPORT: Congestive heart failure was reported in a 54-year-old female 3 days following initiation of metoclopramide therapy. The patient had predisposing factors of diabetes, coronary artery occlusion and a previous myocardial infarction. The CHF resolved after discontinuation of metoclopramide and therapy with enalapril and bumetanide. The author speculates that metoclopramide caused increased plasma aldosterone with increased salt retention thereby leading to cardiac decompensation (Ahmad, 1991).

D) HYPOTENSIVE EPISODE

1) Mild hypotension (decrease in systolic/diastolic of 5 to 15/0 to 10 mmHg, respectively) has been observed in normal subjects receiving 10 mg IV (Park, 1981).
2) Severe hypotension has resulted when anesthetized patients have been given metoclopramide, presumably due to additive effects with halothane or other anesthetics (Park, 1978; Hughes, 1984).

E) HYPERTENSIVE EPISODE

1) Hypertensive crisis has been reported following low dose (10 mg) intravenous use in a patient with pheochromocytoma (Plouin, 1976), high-dose use in prevention of cisplatin-induced nausea (Sheridan et al, 1982; Filibeck et al, 1984), and following oral therapy for parkinsonism (Rampton, 1977).
2) The hypertension was uncontrollable by nitroprusside in the pheochromocytoma patient (Plouin, 1976).

F) ANGIOEDEMA

1) WITH THERAPEUTIC USE

a) In postmarketing experience, angioneurotic edema was reported with the use of metoclopramide tablets. A causal relationship to drug exposure has not been established (Prod Info METOZOLV ODT orally disintegrating tablets, 2009).

Respiratory

3.6.2)

A) CYANOSIS

1) Cyanosis and respiratory distress may occur in patients with methemoglobinemia (Kearns & Fiser, 1988) and rare reports of sulfhemoglobinemia (Van Veldhuizen & Wyatt, 1995; Langford & Sheikh, 1999).

B) BRONCHOSPASM

1) CASE REPORT

a) Metoclopramide was implicated in precipitating two asthmatic episodes in a 58-year-old man with asthma (Chung et al, 1985).

C) RESPIRATORY FAILURE

1) CASE REPORT

a) A 32-year-old woman with a history of severe asthma and short-bowel syndrome received an oral dose of metoclopramide (10 mg) and developed transient dyspnea; respiratory failure occurred after the second dose requiring mechanical ventilation (MacLaren & Shields, 1998).

1) The authors speculated that bronchoconstriction from metoclopramide-induced cholinergic activity of the vagus nerve or anaphylaxis may have contributed to respiratory failure.

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM FINDING

1) WITH THERAPEUTIC USE

a) In postmarketing experience, restlessness, drowsiness, fatigue, and lassitude were reported in approximately 10% of patients receiving the most commonly prescribed oral metoclopramide dosage of 10 mg 4 times per day (Prod Info METOZOLV ODT orally disintegrating tablets, 2009; Prod Info REGLAN(R) oral tablets, 2009).
b) CASE REPORT: Hypersomnia associated with increased prolactin levels and amenorrhea, probably due to metoclopramide therapy, are reported in a female with previous menstrual-associated sleep disorder (Bamford, 1993).

B) HEADACHE

1) WITH THERAPEUTIC USE

a) During clinical trials involving 74 subjects, headache was reported in 5.2% of patients receiving metoclopramide orally disintegrating tablets and in 4.2% of patients receiving metoclopramide tablets (Prod Info METOZOLV ODT orally disintegrating tablets, 2009).

C) PSYCHOMOTOR AGITATION

1) Agitation, hyperexcitability, akathisia, and irritability may occur (Hamilton, 1987).

D) EXTRAPYRAMIDAL SIGN

1) SUMMARY

a) PEDIATRIC

1) The characteristic symptom of toxicity in children is muscle hypertonia. Other effects in children include muscular contractions of the face and neck, ataxia, dystonia, and opisthotonus.
2) TYPES: Consist mainly of several types of extrapyramidal symptoms: acute dystonia, akathisia, tardive dyskinesia, parkinsonism, tardive myoclonus, tardive tremor, and asterixis (Miller & Jankowitz, 1989; Lu & Chu, 1988).
3) ONSET: Symptoms in many cases occur after at least one year of continuous therapy and can persist after therapy is discontinued (USPDI, 1999).
4) INCIDENCE: According to the original manufacturer "extrapyramidal reactions" occur in 1 of 500 patients treated with metoclopramide (Prod Info, 1989). The overall reported rate is 28.6/million prescriptions and is highest in the age group 12 to 19 years; a substantial number received doses higher than recommended by the manufacturer (Bateman et al, 1985). In a prospective study 12 of 2557 (0.5%) had dystonic-dyskinetic events from metoclopramide (Bateman et al, 1989).
5) In postmarketing experience, akathisia (motor restlessness) was reported with the use of metoclopramide tablets (Prod Info METOZOLV ODT orally disintegrating tablets, 2009).
6) DOMPERIDONE (CASE REPORT): A 3-month-old infant presented with intense irritability, excessive crying, intermittent opisthotonus with upward deviation of the eyes (a classic oculogyric crises) and dystonic cycling movements of the upper and lower limbs several hours after receiving a large dose of domperidone (25 mg 2 times in 4 hours; total dose: 50 mg or more than 10 mg/kg in 4 hours instead of the prescribed 0.5 mg/kg/dose; a dose of 2.5 mL equals to 2.5 mg of domperidone). On presentation, the child had persistent tachycardia (200 to 240 beats/min), elevated serum prolactin (45.9 ng/mL; normal level up to 30) and serum potassium (6.2 mEq/mL; normal up to 5.3). An ECG showed supraventricular tachycardia. Following supportive care, including IV promethazine treatment, the child's symptoms gradually resolved over 36 hours (Sanklecha & Charde, 2013).

b) ADULT

1) Long term use of metoclopramide has resulted in irreversible tardive dyskinesia; symptoms are reported in 1 in 1000 patients over the age of 70 (Wiholm et al, 1984; Patel & Louis, 1986; Breitbart, 1986).
2) ROUTE OF ADMINISTRATION: In a review of 33 series of metoclopramide induced movement disorders involving a total of 1031 patients, 603 involved oral therapy and 428 involved IV administration (Miller & Jankowitz, 1989).
3) ONSET: Of 479 reports of extrapyramidal reactions to metoclopramide reported in Great Britain between 1967-1982, 455 were dystonic-dyskinetic reactions, 20 were parkinsonism and four were tardive dyskinesia (Bateman et al, 1985). In this series dystonic-dyskinetic reactions often developed within 24 hours of starting treatment and 94% occurred within 72 hours.

a) Dystonic reactions have been reported within minutes after starting intravenous therapy and generally disappear 24 hours after drug cessation (USPDI, 1999).

4) DURATION: Prolonged dystonic or dyskinetic reactions, lasting 42 to 53 days after drug discontinuation, have been described (Leopold, 1984; Walsh, 1982).
5) DOSE RELATIONSHIP: Extrapyramidal symptoms occurred in up to 27% of patients treated with high-dose intravenous metoclopramide (Kris et al, 1983). Extrapyramidal symptoms can occur with low doses in patients with renal disease (Sirota et al, 1986).
6) PROGNOSIS: Fatalities after acute dystonic reactions to metoclopramide have been reported in two patients.

c) CASE SERIES

1) ADULT

a) A retrospective case series of patients with a mean age of 63.9 years was examined for the prevalence of metoclopramide-induced tardive dyskinesias. A relative risk of 1.67 for tardive dyskinesia and 4.0 for parkinsonism was found. Diabetics had significantly greater severity of dyskinetic reactions (Ganzini et al, 1993). Sewell et al (1994) also report a higher incidence of dyskinesia among metoclopramide-treated diabetics in another case series.
b) Parkinsonism has been reported in 6 patients with chronic use (3 to 9 months) of metoclopramide, 40 mg/day. Five of the patients had renal failure. Symptoms decreased in all patients after discontinuation of the drug (Sethi et al, 1989).

d) CASE REPORTS

1) ADULT

a) (FATALITY): A 49-year-old woman with ovarian carcinoma treated with chemotherapy sustained 3 episodes of dystonic reactions several hours after intravenous administration of 60 mg metoclopramide and died five hours after onset of the dystonic reaction (Pollera et al, 1984).
b) (FATALITY): Another patient died on the way to the hospital, while suffering a dystonic reaction (Bateman et al, 1985).
c) A 76-year-old male diabetic experienced an abrupt onset of extrapyramidal symptoms shortly after beginning therapy with metoclopramide. 36 hours after discontinuing his metoclopramide his symptoms improved (Robinson et al, 1994).
d) A tetanus-like dystonia was reported in a 50-year-old woman receiving 0.5 mg/kg intravenously biweekly, after the 15th dose (DellaValle et al, 1985).
e) Dystonia and akathisia was reported in a 32-year-old female after metoclopramide, 10 mg IV over 1 min, was administered (Cory, 1994).
f) (WITHDRAWAL): A withdrawal syndrome of alternating extrapyramidal symptoms with dystonic symptoms is reported in 41-year-old female after a gradual reduction in metoclopramide dosing. The two set of symptoms followed a diurnal pattern. She gradually improved over 2 months (Noll & Pinsky, 1991).
g) ASTERIXIS and MYOCLONUS were reported in a 65-year-old man after two 5 mg oral doses of metoclopramide. Symptoms resolved within 12 hours of discontinuation of the drug (Lu & Chu, 1988).

2) PEDIATRIC

a) TARDIVE DYSKINESIA is reported in an 8-year-old boy following a single 10 mg dose. He had previously been on metoclopramide with no dystonic reaction. His reaction consisted of torticollis, oculogyric spasms, and facial grimacing. Following dose reduction to 5 mg, his reactions abated, but he continued to have involuntary facial movements (Putnam et al, 1992).
b) SUPRAGLOTTIC DYSTONIC REACTION: A 10-year-old boy (weight, 28 kg) presented with progressive inspiratory stridor and moderate respiratory distress several hours after receiving 3 oral doses of 10 mg metoclopramide over a 24-hour period (about 1 mg/kg per 24 hours). Initially, he was diagnosed with type I drug hypersensitivity reaction; however, treatment with oral prednisolone, promethazine and nebulized epinephrine did not improve his symptoms. Further therapy with salbutamol, and ipratropium bromide had no effect, but breathing improved rapidly after 0.25 mg of intramuscular benztropine; he recovered completely (Tait, 2001).

3) INFANT

a) OPISTHOTONOS: A non-responsive, 6-month-old child presented to the ED with a rigid, opisthotonic body posture and eyes open in a fixed stare following the accidental overdose of 24 mg (3 mg/kg) metoclopramide within a 9 hr period of time. The infant fully recovered (Batts & Munter, 1998).
b) A 4.5-month-old infant (weight, 7.5 kg) developed extrapyramidal symptoms (stiffness of upper extremities, fixed gaze, trismus, hyperextension of head, opisthotonus) after receiving 15 mg of metoclopramide (2 mg/kg) within 12 hours. Following supportive therapy, she recovered completely without further sequelae (Sahin et al, 2001).

E) NEUROLEPTIC MALIGNANT SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 58-year-old man with severe dehydration from C. difficile diarrhea, presented with altered mental status, confusion, delusions, restlessness, and seizures after ingesting 5 or more metoclopramide 10 mg tablets daily for about 3 days. He had a medical history of gastroparesis, Crohn's disease, recent tooth extraction, depression, and alcohol use, and was taking metoclopramide (10 mg orally twice daily), sertraline, venlafaxine, nebivolol, mesalamine, rabeprazole, and valsartan. Physical examination revealed confusion, dysarthria, lethargy, mild generalized rigidity, neck stiffness, diffuse abdominal tension, hypotension, and tachycardia. Laboratory results revealed acute metabolic acidosis, acute renal failure, and a CK of 160 Units/L. Brain MRI revealed incidental telangiectasia and few scattered microvascular ischemic changes. An EEG showed diffuse cerebral dysfunction. Sinus tachycardia with left axis deviation and left bundle branch block were also noted in an ECG. Despite supportive therapy, including antibiotics for C. difficile, his condition deteriorated and he developed fever (101.2 degrees F) and elevated CK 13,000 Units/L. At this time, he was diagnosed with fulminant neuroleptic malignant syndrome. He gradually recovered following supportive therapy, including dantrolene, bromocriptine, cyproheptadine, lorazepam, and hemodialysis (Supariwala et al, 2011).

2) SUMMARY

a) Several cases of metoclopramide-induced neuroleptic malignant syndrome have been reported (Prod Info METOZOLV ODT orally disintegrating tablets, 2009; Prod Info REGLAN(R) oral tablets, 2009; Prod Info REGLAN(R) intravenous, intramuscular injection, 2009; Donnett et al, 1991; Nonino, 1999).

3) CASE SERIES

a) A syndrome consisting of hyperpyrexia, muscular rigidity, autonomic dysfunction, altered consciousness, and elevated serum creatinine kinase has been described in 3 adult patients receiving a single 20 mg intramuscular dose and 40 mg/day for 10 days, and 30 mg/day for 4 days, respectively (Samie, 1987; Robinson et al, 1985; Patterson, 1988).

4) CASE REPORTS

a) Eight hours after the first dose of IV metoclopramide (10 mg every 6 hours) mild generalized rigidity was noted in a 70-year-old man; 18 hours after the first dose, hyperpyrexia, board-like muscle rigidity, and complete akinesis was reported. Fulminant neuroleptic malignant syndrome was diagnosed (Henderson & Longdon, 1991).
b) A 77-year-old active male was admitted to the ED with a diagnosis of neuroleptic malignant syndrome following one month therapy with cisapride and metoclopramide for gastroparesis. Concurrently with NMS, the patient experienced alternating hyperventilation with apnea. Eight days after discontinuing the two drugs, his symptoms improved. Death occurred 45 days later as a result of asphyxiation from vomiting. Necropsy revealed an almost normal CNS (Shintani et al, 1995).
c) A 50-year-old female was diagnosed with NMS following several doses of metoclopramide. Symptoms included generalized stiffness, tachycardia, confusion, fever, and hyperventilation. Abnormal laboratory findings included leukocytosis, increased CPK, liver enzymes and creatinine. Recovery was complete following therapy with dantrolene and bromocriptine (Bakri et al, 1992).

F) SEIZURE

1) WITH THERAPEUTIC USE

a) Seizures preceded by myoclonus were reported in a 75-year-old man after receiving metoclopramide 75 mg in divided doses over 48 hours for postoperative ileus. Oral phenytoin was started, but response was not satisfactory. Clonazepam was instituted, and the patient responded favorably (Eisele, 1988).

2) WITH POISONING/EXPOSURE

a) Seizures may occur in overdose (USPDI, 1999).

Gastrointestinal

3.8.2)

A) ABDOMINAL PAIN

1) WITH THERAPEUTIC USE

a) Abdominal pain with abdominal muscle rigidity has been observed with therapeutic use of metoclopramide (Khan & Razzak, 2006).

B) DIARRHEA

1) WITH THERAPEUTIC USE

a) Diarrhea has been reported with metoclopramide therapy (Prod Info METOZOLV ODT orally disintegrating tablets, 2009).

C) NAUSEA

1) WITH THERAPEUTIC USE

a) During clinical trials involving 74 subjects, nausea was reported in 4.2% of patients receiving metoclopramide orally disintegrating tablets and in 5.6% of patients receiving metoclopramide tablets (Prod Info METOZOLV ODT orally disintegrating tablets, 2009).

Genitourinary

3.10.2)

A) PRIAPISM

1) Priapism was observed in a patient taking thioridazine concurrently with metoclopramide (Velek et al, 1987).

B) IMPOTENCE

1) Impotence has been described in two patients treated with metoclopramide 40 and 60 mg/day for several months. These patients had elevated serum prolactin levels. Both patients resumed normal sexual function and had normal prolactin levels after cessation of metoclopramide (Berlin, 1986).

C) RETENTION OF URINE

1) CASE REPORT: Urinary retention, a dystonic reaction, is reported on three separate occasions following a continuous metoclopramide infusion in a 2-year-old boy. On one occasion it was accompanied by priapism and slurred speech. Procyclidine reversed the symptoms of urinary retention (Kohli-Kumar et al, 1991).

D) URINARY INCONTINENCE

1) WITH THERAPEUTIC USE

a) In postmarketing experience, urinary frequency and incontinence were reported with the use of metoclopramide tablets. A causal relationship to drug exposure has not been established (Prod Info METOZOLV ODT orally disintegrating tablets, 2009).

Hematologic

3.13.2)

A) METHEMOGLOBINEMIA

1) SUMMARY

a) Infants are prone to methemoglobinemia following high dose metoclopramide therapy probably due to their relatively low levels of NADH methemoglobin reductase and low renal clearance of metoclopramide.
b) In postmarketing experience, methemoglobinemia has occurred in adults and especially with overdosage in neonates (Prod Info METOZOLV ODT orally disintegrating tablets, 2009).
c) An age-dependent increase in methemoglobin was seen when urine or plasma from patients treated with metoclopramide was incubated with erythrocytes. Adult (10 years or greater) plasma produced insignificant elevations (0.5 to 1.5%). A urinary metabolite is suspected to be responsible (Zanesco & Carli, 1970).

2) CASE REPORTS

a) INFANT

1) Methemoglobinemia was reported in a 17-day-old infant following accidental overdose (Galletti et al, 1974).
2) Chiossi et al (1992) reported methemoglobinemia in a 17-day-old infant given 11.6 mg/kg/day.
3) An 18-day-old male developed a methemoglobin level of 23.2% after receiving a total of 1 mg/kg of metoclopramide over 3 days for decreased gastric motility (Wilson et al, 1987).
4) A 3-week-old infant developed a methemoglobin level of 20.5% after receiving 1 mg/kg metoclopramide every 6 hours for 36 hours (Kearns & Fiser, 1988).
5) A 3-week-old infant inadvertently received 1 mg/kg every 6 hours due to a 10-fold dosing error. Within 24 hours a methemoglobin level of 20.5% was obtained and respiratory distress was present (Kearns & Fiser, 1988).

b) ADULT

1) A methemoglobin level of 12% was reported in a 23-year-old female following 2 months of oral metoclopramide therapy. Cyanosis and methemoglobin levels resolved following discontinuation of the metoclopramide (Grant et al, 1994).

3) CASE SERIES

a) INFANT

1) Intramuscular administration of 1 mg/kg/day to 16 premature and 2 mg/kg/day to 16 full-term infants resulted in methemoglobinemia after 3 days (Zanesco & Agosti, 1967).

B) SULFHEMOGLOBINEMIA

1) CASE REPORTS

a) Sulfhemoglobinemia was reported in a 54-year-old male following chronic therapy with metoclopramide and a history of cigarette smoking. He was concurrently taking a number of other medications, including benztropine, loxapine, ranitidine, fluphenazine, clorazepam and magaldrate. The authors speculated that the sulfhemoglobinemia could have occurred with metoclopramide, an oxidizing agent, in the presence of sulfur-containing medications (ranitidine, fluphenazine and magaldrate) (Van Veldhuizen & Wyatt, 1995).
b) Sulfhemoglobinemia occurred in a 15-year-old female after an acetaminophen overdose for which she was treated with N-acetylcysteine and metoclopramide (Langford & Sheikh, 1999). After receiving 12 doses of intravenous metoclopramide (1 mg/kg), cyanosis developed without respiratory involvement. A sulfhemoglobin level of 16% was determined after cyanosis persisted following methylene blue administration. Symptoms resolved over 48 hours with supportive care.

C) AGRANULOCYTOSIS

1) WITH THERAPEUTIC USE

a) SUMMARY

1) Agranulocytosis has been reported during postmarketing experience with metoclopramide tablets. A causal relationship to drug exposure has not been established (Prod Info METOZOLV ODT orally disintegrating tablets, 2009).
2) Isolated cases of agranulocytosis have been reported. One was confirmed with rechallenge (Harvey & Luzar, 1988; Manoharan, 1988).

b) CASE REPORTS

1) Agranulocytosis was seen in a patient receiving 10 mg orally every six hours for 6 days (Manoharan, 1988).
2) Reversible agranulocytosis occurred during a two week treatment with metoclopramide 40 mg/day in a 61-year-old woman. She was also treated with other drugs so a rechallenge with metoclopramide was done, resulting in a second episode of agranulocytosis (Harvey & Luzar, 1988).

D) NEUTROPENIA

1) WITH THERAPEUTIC USE

a) Neutropenia has rarely been reported during postmarketing experience with metoclopramide tablets. A causal relationship to drug exposure has not been established (Prod Info METOZOLV ODT orally disintegrating tablets, 2009).

E) LEUKOPENIA

1) WITH THERAPEUTIC USE

a) Leukopenia has rarely been reported during postmarketing experience with metoclopramide tablets. A causal relationship to drug exposure has not been established (Prod Info METOZOLV ODT orally disintegrating tablets, 2009).

Dermatologic

3.14.2)

A) ERUPTION

1) WITH THERAPEUTIC USE

a) In postmarketing experience, rash and urticaria were reported with the use of metoclopramide tablets. A causal relationship to drug exposure has not been established (Prod Info METOZOLV ODT orally disintegrating tablets, 2009)

B) PURPURA

1) CASE REPORT: Nonthromobocytopenic palpable purpura was associated with metoclopramide (10 mg three times daily) use in a 72-year-old male who began therapy 2 days prior to admission (Goad, 1999). Platelet count remained normal and symptoms improved significantly with drug cessation; rechallenge was not conducted.

Musculoskeletal

3.15.2)

A) INCREASED MUSCLE TONE

1) Hypertonia has been reported in adults. The characteristic symptom of toxicity in children is muscle hypertonia.
2) Abdominal rigidity, resembling acute abdomen, has been noted with therapeutic use of metoclopramide (Khan & Razzak, 2006).

B) DYSTONIA

1) Toxic symptoms in infants and children include muscular contractions of the face and neck, ataxia, dystonia, and opisthotonus.

Endocrine

3.16.2)

A) HYPERALDOSTERONISM

1) Metoclopramide has been reported to cause hyperaldosteronism (Mazzacca et al, 1983; Sommers et al, 1989).
2) The metoclopramide-induced aldosterone response was attenuated by prior administration of neostigmine (Sommers et al, 1989).
3) CASE REPORT: Edema was reported in an 82-year-old man who was treated with metoclopramide 40 mg/day for two weeks, probably due to hyperaldosteronism (Zumoff, 1983).
4) CASE REPORT (INFANT): Possible hyperaldosteronism with excessive weight gain and fluid and electrolyte disturbances was reported in a 3.5 month-old-infant following therapy with metoclopramide (Fanning et al, 1995).

B) HYPERPROLACTINEMIA

1) Increased serum prolactin levels with corresponding amenorrhea is a well-known adverse effect of metoclopramide (Noll & Pinsky, 1991).
2) Walsh et al (1994) described a 40-year-old woman with a previous hysterectomy presenting with a prolactin level of 5840 mU/L and galactorrhea following use of metoclopramide, meperidine, and diazepam (Walsh et al, 1994).
3) Galactorrhea/hyperprolactinemia has been reported with domperidone (Sanklecha & Charde, 2013; Cann et al, 1983; Maddern, 1983) and metoclopramide (Noll & Pinsky, 1991; Walsh et al, 1994) and was associated with hyperprolactinemia (Meddern, 1983).

Immunologic

3.19.2)

A) ACUTE ALLERGIC REACTION

1) WITH THERAPEUTIC USE

a) Allergic reactions, manifesting as rash, urticaria, bronchospasm (especially in patients with asthma), or angioneurotic edema, including glossal or laryngeal edema, have rarely occurred with the use of metoclopramide tablets (Prod Info METOZOLV ODT orally disintegrating tablets, 2009).

Reproductive

3.20.1)

A) Metoclopramide is classified as FDA pregnancy category B. Metoclopramide crosses the placenta and is excreted in breast milk. In one study, metoclopramide use during the first trimester of pregnancy was not significantly associated with increased risks of major congenital malformations, low birth weight, preterm delivery, or perinatal death.

3.20.2)

A) LACK OF EFFECT

1) DOMPERIDONE: The odds of congenital malformations among infants with prenatal domperidone exposure were nonsignificant compared with infants with no exposure to teratogenic agents in a prospective cohort study. Three infants were born with congenital malformations among pregnant women treated with domperidone 10 to 30 mg/day at a median 5 weeks' gestation (n=120; cumulative dose, 10 to 1500 mg) compared with 3 infants with malformations born in the control group (n=212). Domperidone treatment was not linked to the malformations seen in this study, due to the malformation types and duration of exposure (Choi et al, 2013).
2) METOCLOPRAMIDE: A cohort study of 1,222,503 pregnancies found that metoclopramide use during pregnancy was not associated with increased risk of major congenital malformations overall, any of the 20 individually assessed malformation categories, spontaneous abortion, or stillbirth. Women were matched using a 1:4 ratio for metoclopramide-exposed to unexposed on the basis of age, calendar year, and propensity scores. Of 28,486 live-born infants exposed to metoclopramide in the first trimester, 721 had a major malformation during the first year of life (25.3 cases per 1000 births; 95% CI, 23.5 to 27.1) compared with 3024 of 113,698 unexposed infants (26.6 cases per 1000 births; 95% CI, 25.7 to 27.5), resulting in an adjusted prevalence odds ratio (OR) of 0.93 (95% CI, 0.86 to 1.02). There were also no significant associations between metoclopramide use during the first trimesters and any of the 20 individual malformation categories analyzed (eg, neural tube defects, ventricular septal defect, cleft palate, limb reduction), with the upper limit of the 95% CI for adjusted prevalence ORs below 2 in 17 of 20 categories and below 2.6 in the remaining 3 categories. For spontaneous abortion, 757 cases among 37,946 exposed women (20 cases per 1000 pregnancies; 95% CI, 18.5 to 21.4) compared with 9414 cases among 151,661 unexposed women (62.1 cases per 1000 pregnancies; 95% CI, 60.9 to 63.3) resulted in an adjusted hazard ratio (HR) of 0.35 (95% CI, 0.33 to 0.38). For stillbirth, 142 cases among 40,306 metoclopramide-exposed pregnancies (3.5 per 1000 pregnancies; 95% CI, 2.9 to 4.1) compared with 634 cases among 161,098 unexposed pregnancies (3.9 per 1000 pregnancies; 95% CI, 3.6 to 4.2) resulted in an adjusted HR of 0.9 (95% CI, 0.74 to 1.08) (Pasternak et al, 2013).
3) METOCLOPRAMIDE: In a large retrospective, population-based, cohort study involving 81,703 births, 3458 infants (4.2%) were exposed to metoclopramide during the first trimester of pregnancy (usual dose, 10 mg three times daily for 7 days) compared with 78,245 infants who were not exposed. The study found that metoclopramide use during the first trimester of pregnancy is not significantly associated with increased risks of major congenital malformations (5.3% exposed vs 4.9% not exposed; odds ratio OR 1.04; (95% confidence interval (CI), 0.89 to 1.21)), low birth weight (8.5% vs 8.3%; OR 1.01; 95% CI, 0.89 to 1.14), preterm delivery (6.3% vs 5.9%; OR 1.15; 95% CI, 0.99 to 1.34), or perinatal death 1.5% vs 2.2% ; OR 0.87; 95% CI, 0.55 to 1.38) (Matok et al, 2009).

3.20.3)

A) PREGNANCY CATEGORY

1) Metoclopramide is classified as FDA pregnancy category B (Australian Drug Evaluation Committee, 1999).
2) METOCLOPRAMIDE: There are no adequate and well-controlled studies of metoclopramide in pregnant women. The use of metoclopramide during the first trimester of pregnancy did not result in significant fetal malformations in a review of three separate studies (Magee et al, 2002). Metoclopramide has not been found to increase the incidence of abnormalities in infants born to mothers who received the drug at various times up to the 28th week of pregnancy (Singh & Lean, 1970). In one study, metoclopramide use during the first trimester of pregnancy was not significantly associated with increased risks of major congenital malformations, low birth weight, preterm delivery, or perinatal death (Matok et al, 2009). A cohort study of 1,222,503 pregnancies found that metoclopramide use during pregnancy was not associated with increased risk of major congenital malformations overall, any of the 20 individually assessed malformation categories, spontaneous abortion, or stillbirth (Pasternak et al, 2013). Metoclopramide should only be used in pregnant women if only clearly needed (Prod Info reglan(R) oral tablets, 2011).
3) DOMPERIDONE: There are no adequate and well-controlled studies of domperidone in pregnant women. In a prospective cohort study, the odds of congenital malformations among infants with prenatal domperidone exposure were nonsignificant compared with infants with no exposure to teratogenic agents (Choi et al, 2013). Until more human data becomes available, domperidone should only be used if the benefit outweighs the potential risk to the fetus.

B) PLACENTAL BARRIER

1) Metoclopramide does cross the placenta at term; cord:maternal plasma ratios of 0.57 to 0.84 have been reported after IV doses immediately prior to caesarean section. No adverse effects on the fetus have been observed (Briggs et al, 1998).

C) PREGNANCY OUTCOME

1) In a database review of 309 pregnant women that had taken metoclopramide during pregnancy, no documented association between the use of metoclopramide and adverse outcome (i.e., risk of malformation, preterm delivery or low birth weight were among the factors analyzed) were reported. The authors noted that further research was needed (Sorensen et al, 2000).
2) In a prospective study, 126 pregnant women had taken metoclopramide during the first trimester of pregnancy with a mean daily dose of 23 mg (+/-10 mg) (range, 10 to 40), for an average of 10 (+/- 10) days (range, 1 to 35). The women were then matched with a control group for age and lifestyle issues. NO association was found for an increased risk of fetal malformations, spontaneous abortions, or decreased birth weight of the infants (Berkovitch et al, 2000).

D) LACK OF EFFECT

1) METOCLOPRAMIDE: A cohort study of 1,222,503 pregnancies found that metoclopramide use during pregnancy was not associated with increased risk of major congenital malformations overall, any of the 20 individually assessed malformation categories, spontaneous abortion, or stillbirth. Women were matched using a 1:4 ratio for metoclopramide-exposed to unexposed on the basis of age, calendar year, and propensity scores. Of 28,486 live-born infants exposed to metoclopramide in the first trimester, 721 had a major malformation during the first year of life (25.3 cases per 1000 births; 95% CI, 23.5 to 27.1) compared with 3024 of 113,698 unexposed infants (26.6 cases per 1000 births; 95% CI, 25.7 to 27.5), resulting in an adjusted prevalence odds ratio (OR) of 0.93 (95% CI, 0.86 to 1.02). There were also no significant associations between metoclopramide use during the first trimesters and any of the 20 individual malformation categories analyzed (eg, neural tube defects, ventricular septal defect, cleft palate, limb reduction), with the upper limit of the 95% CI for adjusted prevalence ORs below 2 in 17 of 20 categories and below 2.6 in the remaining 3 categories. For spontaneous abortion, 757 cases among 37,946 exposed women (20 cases per 1000 pregnancies; 95% CI, 18.5 to 21.4) compared with 9414 cases among 151,661 unexposed women (62.1 cases per 1000 pregnancies; 95% CI, 60.9 to 63.3) resulted in an adjusted hazard ratio (HR) of 0.35 (95% CI, 0.33 to 0.38). For stillbirth, 142 cases among 40,306 metoclopramide-exposed pregnancies (3.5 per 1000 pregnancies; 95% CI, 2.9 to 4.1) compared with 634 cases among 161,098 unexposed pregnancies (3.9 per 1000 pregnancies; 95% CI, 3.6 to 4.2) resulted in an adjusted HR of 0.9 (95% CI, 0.74 to 1.08) (Pasternak et al, 2013).
2) METOCLOPRAMIDE: In a large retrospective, population-based, cohort study involving 81,703 births, 3458 infants (4.2%) were exposed to metoclopramide during the first trimester of pregnancy (usual dose, 10 mg three times daily for 7 days) compared with 78,245 infants who were not exposed. The study found that metoclopramide use during the first trimester of pregnancy is not significantly associated with increased risks of major congenital malformations (5.3% exposed vs 4.9% not exposed; odds ratio OR 1.04; (95% confidence interval (CI), 0.89 to 1.21)), low birth weight (8.5% vs 8.3%; OR 1.01; 95% CI, 0.89 to 1.14), preterm delivery (6.3% vs 5.9%; OR 1.15; 95% CI, 0.99 to 1.34), or perinatal death 1.5% vs 2.2% ; OR 0.87; 95% CI, 0.55 to 1.38) (Matok et al, 2009).

3.20.4)

A) BREAST MILK

1) DOMPERIDONE

a) Domperidone has been used to temporarily increase breast milk production in women with a low milk supply. A randomized, double blind, placebo-controlled trial involving 16 women (7 in the treatment group, 9 in the placebo group), demonstrated that short-term use of domperidone is safe and effective. Small concentrations of the drug (1.2 ng/mL) were detected in the breast milk samples obtained after five days of treatment with domperidone, 10 mg three times per day. The daily dose to the infant was estimated to be less than 0.2 mcg/kg. There were no reported side effects in the infants attributable to domperidone (da Silva et al, 2001). However, daily doses greater than 30 mg/day have been associated with an increased risk of serious ventricular arrhythmia and sudden cardiac death in adults. Therefore, domperidone treatment should be initiated at the lowest possible dose and titrated upwards with caution (Teva Canada Limited, 2012).

2) METOCLOPRAMIDE

a) Metoclopramide is excreted into breast milk. Milk:plasma ratios of 1.8 to 1.9 have been reported in humans (Briggs et al, 1998).
b) The daily dose ingested by a nursing infant during maternal use of 30 mg/day has been estimated as 1 to 45 mcg/kg/day, less than the 500 mcg/kg/day recommended in infants (Harrington et al, 1983) or the 100 mcg/kg/day that has been given to premature infants (Sankaran et al, 1982a).
c) Metoclopramide appears to be safe during breast-feeding in doses of 45 mg/day or less (Briggs et al, 1998).

Genotoxicity

A)

B)

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) No specific laboratory studies are needed in most patients.
B) Metoclopramide levels are not readily available and not useful in managing toxicity.
C) Monitor vital signs, mental status, and for the development of dystonic reactions.
D) Monitor CBC with differential, CPK, and liver enzymes in symptomatic patients.
E) Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Monitor CPK and liver function tests when signs and symptoms suggestive of NMS are present.

B) ENDOCRINE

1) Measure serum prolactin levels in patients with amenorrhea or galactorrhea.

C) HEMATOLOGIC

1) Obtain methemoglobin levels in patients with cyanosis.
2) Monitor CBC when signs and symptoms suggestive of NMS are present.

4.1.4)

A) OTHER

1) ECG

a) Monitor ECG in overdoses for bradycardias and possible ventricular arrhythmias.

Methods

A)

1) Metoclopramide serum concentrations were measured using a high-performance liquid chromatographic method (Anthony et al, 1986).

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with continued/worsening symptoms after observation for several hours should be admitted for further monitoring, and depending on the severity of their symptoms, may merit an ICU bed. Criteria for discharge should be resolution of symptoms.

6.3.1.2) HOME CRITERIA/ORAL

A) Asymptomatic patients with inadvertent exposures may be monitored at home. All other patients may require observation.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Contact your local poison center or toxicologist for any concerns. The mainstay of treatment is good symptomatic and supportive care.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Intentional overdoses or patients with symptoms should be observed for 4 to 6 hours, and may be discharged if only mild symptoms persist.

Monitoring

A)

B)

C)

D)

E)

Oral Exposure

6.5.1)

A) PREHOSPITAL: Decontamination is generally not indicated as toxicity is usually not severe.

6.5.2)

A) SUMMARY: In general, decontamination is not indicated for this overdose, but may be considered for massive overdoses that present early. Activated charcoal should be considered if the patient is awake and cooperative and if the ingestion was relatively recent. Gastric lavage, whole bowel irrigation, or multiple doses of charcoal are not indicated.
B) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

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

2) CHARCOAL DOSE

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

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

b) ADVERSE EFFECTS/CONTRAINDICATIONS

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

6.5.3)

A) SUPPORT

1) MANAGEMENT OF MILD TO MODERATE TOXICITY

a) Routine decontamination is not recommended as most toxicity is mild. Dystonic reactions in adults can be treated with benztropine 1 to 4 mg IV (max 6 mg/day) and/or diphenhydramine 25 to 50 mg/dose IV over 2 minutes (maximum 100 mg/dose, 400 mg/day) in adults. Dosing of diphenhydramine in children is 1.25 mg/kg/dose IV over 2 minutes with a maximum daily dosing of 300 mg/day. Patients may require treatment for several days to avoid recurrence of dystonic reactions.

2) MANAGEMENT OF SEVERE TOXICITY

a) Severe toxicity, though rare, includes cardiovascular and CNS effects such as bradycardia, hypotension, hypertension, seizures, and cardiac arrest. Standard treatment is indicated such as atropine for bradycardia and fluids and pressors for hypotension. Seizures should be managed with benzodiazepines (eg, diazepam 5 to 10 mg or lorazepam 2 to 4 mg every 10 to 15 minutes for adults as needed; for children, 0.2 to 0.5 mg/kg diazepam or lorazepam 0.05 to 0.1 mg/kg every 5 minutes as needed). Consider giving phenobarbital or propofol if seizures continue to occur despite benzodiazepine therapy. Neuroleptic malignant syndrome can be treated with good supportive care and intravenous benzodiazepines; consider bromocriptine, amantadine or dantrolene if not responding to benzodiazepines. Methemoglobinemia can be treated with methylene blue in symptomatic patients.

B) MONITORING OF PATIENT

1) No specific laboratory studies are needed in most patients.
2) Metoclopramide levels are not readily available and not useful in managing toxicity.
3) Monitor vital signs, mental status, and for the development of dystonic reactions.
4) Monitor CBC with differential, CPK, and liver enzymes in symptomatic patients.
5) Obtain an ECG and institute continuous cardiac monitoring in symptomatic patients.

C) DRUG-INDUCED DYSTONIA

1) ADULT

a) BENZTROPINE: 1 to 4 mg once or twice daily intravenously or intramuscularly; maximum dose: 6 mg/day; 1 to 2 mg of the injection will usually provide quick relief in emergency situations (Prod Info benztropine mesylate IV, IM injection, 2009).
b) DIPHENHYDRAMINE: 10 to 50 mg intravenously at a rate not exceeding 25 mg/minute or deep intramuscularly; maximum dose: 100 mg/dose; 400 mg/day (Prod Info diphenhydramine hcl injection, 2006).

2) CHILDREN

a) DIPHENHYDRAMINE: 5 mg/kg/day or 150 mg/m(2)/day intravenously divided into 4 doses at a rate not to exceed 25 mg/min, or deep intramuscularly; maximum dose: 300 mg/day. Not recommended in premature infants and neonates (Prod Info diphenhydramine hcl injection, 2006).

3) If the patient does not respond administer diazepam 5 mg intravenously.

a) Since dystonias may recur, additional doses (oral or intravenous) may be needed following initial therapy. Symptoms are usually self-limited and disappear within 24 hours.
b) However, prolonged reactions lasting 6 to 7 weeks have been reported, requiring prolonged therapy.

D) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

E) BRADYCARDIA

1) ATROPINE/DOSE

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

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

F) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

2) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

3) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

G) 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).

H) NEUROLEPTIC MALIGNANT SYNDROME

1) CONCLUSION - Treatment with either bromocriptine, amantadine, or dantrolene, even when they must be used in conjunction with other agents, will decrease the death rate due to neuroleptic malignant syndrome.
2) Intravenous dantrolene and oral bromocriptine have been used successfully to treat metoclopramide-induced neuroleptic malignant syndrome (Patterson, 1988).

a) DANTROLENE - Administer 0.25 to 3 milligrams/kilogram intravenously four times daily until the patient is able to swallow oral medication (Granato et al, 1983).

1) Fulminant neuroleptic malignant syndrome (NMS) unresponsive to 2 milligrams intravenous benztropine resolved within 1 hour following a slow intravenous bolus of dantrolene 2 milligrams/kilogram. Four hours later a partial relapse was treated with the same dose of dantrolene which resulted in the permanent resolution of NMS (Henderson & Longdon, 1991).

b) BROMOCRIPTINE - 5 milligrams three times daily up to 20 milligrams four times daily in adults. Pediatric dosing guidelines have not been established (Granato et al, 1983; Mueller, 1985).

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 (Sakkas et al, 1991).

a) Death rate of untreated cases was 21 percent; 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).
b) 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.

I) METHEMOGLOBINEMIA

1) SUMMARY

a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.

2) METHYLENE BLUE

a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).

3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)

a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.

4) Methylene blue (1 to 2 milligrams/kilogram of a 1% solution given intravenously over 5 minutes) has been used successfully to reverse methemoglobinemia in premature and full term infants who had received metoclopramide (USPDI, 1999).

Enhanced Elimination

A)

1) There is no role for dialysis, hemoperfusion, urinary alkalinization, or multiple dose charcoal.

Abstracts

Case Reports

A)

1) Bar (1966) described an overdose with metoclopramide in a 32-year-old male who ingested 36 tablets (total dose unknown) and developed symptoms of somnolence, confusion, and traces of albumin in the urine. No extrapyramidal symptoms were observed. The patient recovered following gastric lavage.

B)

1) A 3-week-old infant was inadvertently administered a 10-fold overdose of metoclopramide for treatment of gastroesophageal reflux.

a) The dose given was 1 mg/kg orally every 6 hours. Irritability, lethargy, poor feeding, mild diarrhea, respiratory distress, and cyanosis were noted on the following day. A methemoglobin level of 20.5% was obtained.
b) Administration of 3 mg of methylene blue IV resulted in dramatic improvement in cyanosis and respiratory symptoms (Kearns & Fiser, 1988).

Range Of Toxicity

Summary

A)

B)

Therapeutic Dose

7.2.1)

A) ORAL: 10 to 15 mg up to 4 times daily (Prod Info METOZOLV ODT orally disintegrating tablets, 2009; Prod Info REGLAN(R) oral tablets, 2009).
B) IV or IM: Varies by indication: 10 to 20 mg as a single dose or slowly over 1 to 2 minutes OR for chemotherapy-induced nausea and vomiting: 1 to 2 mg/kg/dose IV over 15 min administered 30 min prior to chemotherapy and then every 2 hours for 2 doses, then every 3 hours for 3 doses (Prod Info REGLAN(R) intravenous, intramuscular injection, 2009).

7.2.2)

A) GASTROESOPHAGEAL REFLUX: The safety and efficacy of oral metoclopramide in pediatric patients have not been established by the manufacturer (Prod Info METOZOLV ODT orally disintegrating tablets, 2009; Prod Info REGLAN(R) oral tablets, 2009). However, the following doses have been used:

1) (infants) 0.1 mg/kg orally 3 to 4 times daily 10 to 30 min before meals and at bedtime (maximum dose 0.3 to 0.75 mg/kg/day for 2 wks to 6 months) (Leung & Lai, 1984; Sankaran et al, 1982; Bodensteiner & Grunos, 1984; Hitch et al, 1982)
2) (neonates) 0.15 mg/kg orally every 6 hours (Kearns et al, 1998)

B) INTESTINAL INTUBATION: (14 years and older) a single 10 mg IV dose over 1 to 2 minutes (Prod Info metoclopramide injection, 2005)
C) INTESTINAL INTUBATION: (6 to 14 years of age) a single 2.5 mg to 5 mg IV dose over 1 to 2 minutes (Prod Info metoclopramide injection, 2005)
D) INTESTINAL INTUBATION: (under 6 years of age) a single 0.1 mg/kg IV dose over 1 to 2 minutes (Prod Info metoclopramide injection, 2005)

Maximum Tolerated Exposure

A)

1) EXCESSIVE METOCLOPRAMIDE THERAPEUTIC DOSE

a) Adults who ingested 360 milligrams and 800 milligrams developed symptoms of somnolence, confusion, and traces of albumin in the urine; but no extrapyramidal symptoms were reported (Bar, 1966).
b) It is recommended that the total daily dosage of metoclopramide not exceed 500 micrograms/kilogram, except when used for chemotherapy-associated nausea and vomiting (S Sweetman , 2000).
c) A 4.5-month-old infant (weight, 7.5 kg) developed extrapyramidal symptoms (stiffness of upper extremities, fixed gaze, trismus, hyperextension of head, opisthotonus) after receiving 15 mg of metoclopramide (2 mg/kg) within 12 hours. Following supportive therapy, she recovered completely without further sequelae (Sahin et al, 2001).
d) SUPRAGLOTTIC DYSTONIC REACTION - A 10-year-old boy (weight, 28 kg) presented with progressive inspiratory stridor and moderate respiratory distress secondary to a supraglottic dystonic reaction several hours after receiving 3 oral doses of 10 mg metoclopramide over a 24-hour period (about 1 mg/kg per 24 hours). Following treatment with 0.25 mg of intramuscular benztropine, he recovered completely (Tait, 2001).

2) TOXIC METOCLOPRAMIDE DOSE

a) A 58-year-old man with severe dehydration from C. difficile diarrhea, developed fulminant neuroleptic malignant syndrome complicated by acute renal failure, metabolic acidosis, and rhabdomyolysis, after ingesting 5 or more metoclopramide 10 mg tablets daily for about 3 days. He recovered following supportive therapy, including dantrolene, bromocriptine, cyproheptadine, lorazepam, and hemodialysis (Supariwala et al, 2011).
b) Ingestion of 3.3 to 7.7 milligrams/kilogram in children and 4.6 to 6.6 milligrams/kilogram in adults has resulted in neurological symptoms with recovery (Giger, 1975).
c) Accidental ingestion of 24 mg (3 mg/kg) metoclopramide over a 9 hr period in a 6-month-old infant resulted in toxic extrapyramidal symptoms of opisthotonic body posture, with full recovery (Batts & Munter, 1998).

3) DOMPERIDONE

a) CASE REPORT: A 3-month-old infant presented with intense irritability, excessive crying, intermittent opisthotonus with upward deviation of the eyes (a classic oculogyric crises) and dystonic cycling movements of the upper and lower limbs several hours after receiving a large dose of domperidone (25 mg 2 times in 4 hours; total dose: 50 mg or more than 10 mg/kg in 4 hours instead of the prescribed 0.5 mg/kg/dose; a dose of 2.5 mL equals to 2.5 mg of domperidone). On presentation, the child had persistent tachycardia (200 to 240 beats/min), elevated serum prolactin (45.9 ng/mL; normal level up to 30) and serum potassium (6.2 mEq/mL; normal up to 5.3). An ECG showed supraventricular tachycardia. Following supportive care, including IV promethazine treatment, the child's symptoms gradually resolved over 36 hours (Sanklecha & Charde, 2013).

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) METOCLOPRAMIDE

a) The mean metoclopramide concentration following the second dose of oral metoclopramide 2 milligrams/kilogram given every two hours was 1,171 nanograms/milliliter (Anthony et al, 1986).
b) The mean metoclopramide concentration following the second dose of intravenous metoclopramide 2 milligrams/kilogram given every two hours was 1,030 nanograms/milliliter (Anthony et al, 1986).
c) Blood concentrations following an oral dose of metoclopramide 10 milligrams reached a peak of about 40 nanograms/milliliter within the first two hours (Teng et al, 1977). Following a dose of metoclopramide 10 milligrams, the mean plasma concentration was 68.5 nanograms/milliliter (Lewis et al, 1980).

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) INFANT

a) A metoclopramide serum level of 0.15 mcg/mL, taken approximately 4 hours after the last dose of metoclopramide (24 mg given accidentally over a 9 hr period), is reported in a 6-month-old infant (Batts & Munter, 1998).

Toxicity Information

7.7.1)

A) ANIMAL DATA

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 96 mg/kg ((RTECS, 2000))

2) LD50- (ORAL)MOUSE:

a) 270 mg/kg ((RTECS, 2000))

3) LD50- (SUBCUTANEOUS)MOUSE:

a) 190 mg/kg ((RTECS, 2000))

4) LD50- (INTRAPERITONEAL)RAT:

a) 114 mg/kg ((RTECS, 2000))

5) LD50- (ORAL)RAT:

a) 750 mg/kg ((RTECS, 2000))

6) LD50- (SUBCUTANEOUS)RAT:

a) 340 mg/kg ((RTECS, 2000))

Pharmacology Toxicology

Pharmacologic Mechanism

A)

Toxicologic Mechanism

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Physicochemical

Physical Characteristics

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Molecular Weight

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Animal Toxicology

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METOCLOPRAMIDE AND RELATED AGENTS

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Genitourinary

Hematologic

Dermatologic

Musculoskeletal

Endocrine

Immunologic

Reproductive

Genotoxicity

Monitoring Parameters Levels

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Toxicity Information

Pharmacologic Mechanism

Toxicologic Mechanism

Physical Characteristics

Molecular Weight

General Bibliography