Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

A)

1) Ondansetron hydrochloride (synonym)
2) Ondansetron hydrochloride dihydrate (synonym)
3) Molecular Formula: C18-H19-N3-O-HCL-2H2O
4) ONDANSETRON (5HT3-ANTAGONIST)

1) MDL-73147
2) Dolasetron mesylate (synonym)
3) Molecular Formula: C19-H20-N2-O3-CH3-H.H20

1) BRL-43694
2) Molecular Formula: C18-H24-N4-O
3) CAS 109889-09-0

1) CAS 135720-56-5 (palonosetron)
2) CAS 137729-55-4 (palonosetron hydrochloride)
3) Molecular Formula: C19-H24-N2-O,HCl

1) Tropisetron hydrochloride (synonym)
2) ICS-205-930
3) Molecular formula: C17-H20-N2-O2, HCl
4) CAS 89565-68-4 (tropisetron)
5) CAS 105826-92-4 (tropisetron hydrochloride)

1) GR68755

1.2.1) MOLECULAR FORMULA
1) DOLASETRON MESYLATE: C19H20N2O3-CH3SO3H-H2O
2) GRANISETRON HYDROCHLORIDE: C18H24N4O-HCl
3) ONDANSETRON: C18H19N3O
4) ONDANSETRON HYDROCHLORIDE DIHYDRATE: C18H19N3O-HCl-2H2O

Available Forms Sources

A)

1) ONDANSETRON

a) ORAL SOLUBLE FILM: 4 mg and 8 mg (Prod Info ZUPLENZ(R) oral soluble film, 2010)
b) ORALLY DISINTEGRATING TABLET (ODT): 4 mg and 8 mg (Prod Info ZOFRAN(R), ZOFRAN ODT(R) oral disintegrating tablets, oral tablets, solution, 2009)
c) ORAL SOLUTION: 4 mg/5 mL in 50 mL bottle (Prod Info ZOFRAN(R) oral tablets, oral solution, ZOFRAN ODT(R) orally disintegrating tablets, 2006)
d) ONDANSETRON HYDROCHLORIDE INJECTION: 2 mg/mL, 32 mg/50 mL 5% dextrose solution premixed for intravenous infusion over 15 minutes (Prod Info ZOFRAN(R) IV, IM injection, 2009)
e) ONDANSETRON HYDROCHLORIDE TABLETS: 4 mg, 8 mg, and 24 mg tablets (Prod Info ondansetron hcl oral tablets, 2006)

2) DOLASETRON

a) ORAL TABLETS: 50 mg and 100 mg (Prod Info ANZEMET(R) oral tablets, 2009)
b) INJECTION: 12.5 mg/0.625 mL single use ampules and 100 mg/5 mL single use vials and 500 mg/25 mL multidose vial (Prod Info ANZEMET(R) intravenous injection, 2009)

3) GRANISETRON

a) ORAL TABLET: 1 mg (Prod Info KYTRIL(R) oral tablets, solution, 2009)
b) ORAL SOLUTION: 2 mg/10 mL in a 30 mL bottle (Prod Info KYTRIL(R) oral tablets, solution, 2009)
c) INJECTION: 1 mg/mL for single use and 4 mL multidose vial (Prod Info KYTRIL(R) IV injection, 2009)
d) TRANSDERMAL PATCH: 52 cm(2) patch that contains 34.3 mg of granisetron delivering 3.1 mg/24 hours (Prod Info SANCUSO transdermal system, 2008)

4) PALONOSETRON

a) INJECTION: 0.25 mg/5 mL in single use vials for intravenous use only (Prod Info ALOXI(R) IV injection, 2007)

5) ALOSETRON/LIMITED AVAILABILITY

a) ALOSETRON: Glaxo Wellcome voluntarily withdrew alosetron from the United States market on November 28, 2000. Several deaths and many cases of serious adverse events, including ischemic colitis and severely obstructed or ruptured bowels due to complications of severe constipation, were reported in patients taking alosetron (Anon, 2000). In June 2002, the US Food and Drug Administration decided to allow alosetron back on to the US market under heavy restrictions for use only in women with refractory, diarrhea-predominant irritable bowel syndrome ((Anon, 2002)).
b) ORAL TABLETS: 0.5 mg and 1 mg tablets (Prod Info LOTRONEX(R) oral tablets, 2008).

B)

1) Ondansetron related agents are indicated for the prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy (Prod Info ZUPLENZ(R) oral soluble film, 2010; Prod Info ZOFRAN(R), ZOFRAN ODT(R) oral disintegrating tablets, oral tablets, solution, 2009)
2) Ondansetron and dolasetron are indicated also for the treatment or prevention of postoperative nausea and vomiting (Prod Info ZOFRAN(R), ZOFRAN ODT(R) oral disintegrating tablets, oral tablets, solution, 2009).
3) Ondansetron and granisetron tablets are indicated for the initial and repeat courses of moderately emetogenic cancer chemotherapy (Prod Info ZUPLENZ(R) oral soluble film, 2010; Prod Info ZOFRAN(R), ZOFRAN ODT(R) oral disintegrating tablets, oral tablets, solution, 2009).
4) ALOSETRON: Alosetron is indicated for women with severe diarrhea-predominant irritable bowel syndrome (Prod Info LOTRONEX(R) oral tablets, 2008).
5) Glaxo Wellcome voluntarily withdrew alosetron from the United States market on November 28, 2000. Several deaths and many cases of serious adverse events, including ischemic colitis and severely obstructed or ruptured bowels due to complications of severe constipation, were reported in patients taking alosetron (Anon, 2000). In June 2002, the US Food and Drug Administration decided to allow alosetron back on to the US market under heavy restrictions for use only in women with refractory, diarrhea-predominant irritable bowel syndrome ((Anon, 2002)).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: These agents are used to treat or prevent postoperative and chemotherapy-induced nausea and vomiting. Alosetron is indicated for women with severe diarrhea-predominant irritable bowel syndrome.
B) PHARMACOLOGY: These agents are selective serotonin 5-HT3-type receptor antagonists.
C) EPIDEMIOLOGY: Overdose is rare.
D) WITH THERAPEUTIC USE

1) Adverse effects after therapeutic doses include: constipation or diarrhea, dry mouth, fever, musculoskeletal pain, rash, injection site reactions, burning sensations, hot flashes, hypokalemia, transient blurred vision and loss of vision, transient elevations of liver enzymes, seizures, headache, drowsiness, dizziness, sedation, extrapyramidal reactions, tachycardia, chest pain, hypotension, and anaphylaxis. ECG abnormalities, including QT prolongation, ST segment depression, and second degree atrioventricular block have been reported with ondansetron IV injection. A child with known susceptibility to malignant hyperthermia (MH) developed an MH-like syndrome 3 hours after receiving ondansetron and died.

E) WITH POISONING/EXPOSURE

1) DOLASETRON: An intentional ingestion of 2 g of dolasetron produced severe hypotension, first degree AV block, QRS widening and a prolonged QTc interval in an adult. Overdose of IV dolasetron has resulted in hypotension, dizziness, and abnormal ECG. GRANISETRON: No symptoms or only the occurrence of a slight headache have been reported with overdosage of up to 38.5 mg of granisetron hydrochloride injection. ONDANSETRON: Overdose has caused fever, rashes, pruritus, restlessness, CNS depression, self-limited seizures, tachycardia, mild elevations in liver enzymes, hypotension, temporary blindness (2 to 3 minutes duration) and a constellation of findings consistent with serotonin syndrome. A toddler developed somnolence, tachycardia, hyperreflexia, seizure activity, airway obstruction, rash, transiently elevated liver enzymes, and a prolonged QTc interval after inadvertently ingesting 7 to 8 tablets of 8-mg ondansetron (an estimated 5.6 to 6.4 mg/kg).

0.2.20)

A) Ondansetron, granisetron, dolasetron, and palonosetron are classified as FDA pregnancy category B. The netupitant and palonosetron combination is FDA pregnancy category C. Ondansetron crosses the placental barrier during the first trimester of pregnancy, with an average fetal tissue concentration of 41% of the corresponding maternal plasma concentration. Ondansetron and palonosetron did not result in fetal harm or impairment of fertility in rats and rabbits. Ondansetron is excreted in the breast milk of lactating rats. It is not known whether palonosetron is excreted in breast milk.

0.2.21)

A) No human data exist. Animal studies did not indicate carcinogenic potential.

Laboratory Monitoring

A)

B)

C)

Treatment Overview

0.4.2)

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. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Treat severe hypotension IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Therapeutic doses of ondansetron may cause prolongation of the QT interval. Concomitant use of ondansetron and other drugs that prolong the QT interval may increase the risk of torsades de pointes. Treat torsades de pointes with IV magnesium sulfate, and correct electrolyte abnormalities, overdrive pacing may be necessary.

C) DECONTAMINATION

1) PREHOSPITAL: Prehospital gastrointestinal decontamination is not recommended because of the potential for CNS depression and subsequent aspiration.
2) HOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.

D) AIRWAY MANAGEMENT

1) Ensure adequate ventilation and perform endotracheal intubation early in patients with life-threatening cardiac dysrhythmias, severe allergic reactions, or persistent seizures.

E) ANTIDOTE

1) None.

F) TORSADES DE POINTES

1) Therapeutic doses of ondansetron may cause prolongation of the QT interval. Concomitant use of ondansetron and other drugs that prolong the QT interval may increase the risk of torsades de pointes. Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Hemodynamically unstable patients require electrical cardioversion. Treat stable patients with magnesium, atrial overdrive pacing may be necessary. Correct electrolyte abnormalities (hypomagnesemia, hypokalemia, hypocalcemia). MAGNESIUM SULFATE/DOSE: ADULTS: 1 to 2 g IV (mixed in 50 to 100 mL D5W) infused over 5 min, repeat 2 g bolus and begin infusion of 0.5 to 1 g/hr if dysrhythmias recur. CHILDREN: 25 to 50 mg/kg diluted to 10 mg/mL; infuse IV over 5 to 15 min. OVERDRIVE PACING: Begin at 130 to 150 beats/min, decrease as tolerated. Rates of 100 to 120 beats/min may terminate torsades. Avoid class Ia (quinidine, disopyramide, procainamide), class Ic (flecainide, encainide, propafenone) and most class III antidysrhythmics (N-acetylprocainamide, sotalol).

G) ENHANCED ELIMINATION

1) Hemodialysis and hemoperfusion are not expected to be of benefit because of the large volumes of distribution of ondansetron and hydrodolasetron (active metabolite of dolasetron).

H) PATIENT DISPOSITION

1) HOME CRITERIA: A child with an inadvertent exposure to 1 or 2 tablets, that remains asymptomatic can be managed at home.
2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours. Patients that remain asymptomatic can be discharged.
3) ADMISSION CRITERIA: Patients with unstable vital signs, persistent cardiac dysrhythmias, mental status changes, and persistent seizures should be admitted.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.

I) PITFALLS

1) When managing a suspected overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose are similar to reported side effects of the medication.

J) PHARMACOKINETICS

1) ABSORPTION: ondansetron: rapid oral absorption; oral bioavailability is about 56%. dolasetron: well absorbed; oral bioavailability is about 75%. PROTEIN BINDING: ondansetron: 70% to 76%; hydrodolasetron (the major metabolite of dolasetron): 69% to 77%; palonosetron: about 62%. Vd: ondansetron: about 160 L; hydrodolasetron (the major metabolite of dolasetron): 5.8 L/kg in adults; palonosetron: 8.3 +/- 2.5 L/kg. METABOLISM: ondansetron: metabolized by hepatic cytochrome p450 enzymes via hydroxylation followed by glucuronidation or sulphate conjugation, with less than 5% of the drug appearing unchanged in the urine. Dolasetron: the reduction of dolasetron to hydrodolasetron is mediated by carbonyl reductase. Cytochrome P450 and flavin monooxygenase are responsible for the subsequent hydroxylation and n-oxidation of hydrodolasetron, respectively. EXCRETION: ondansetron: 44% to 60% of a dose is recovered in the urine within 24 hours, with only 5% to 10% being recovered as unchanged drug; dolasetron: 61% of a dose of hydrodolasetron is excreted in the urine as unchanged drug. ELIMINATION HALF-LIFE: ondansetron: approximately 3 hours; palonosetron: approximately 40 hours.

K) DIFFERENTIAL DIAGNOSIS

1) Includes other agents that cause hypotension (eg, vasodilators, beta blockers, calcium channel blockers) or QT interval prolongation.

Range Of Toxicity

A)

B)

C)

D)

E)

F)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

1) Adverse effects after therapeutic doses include: constipation or diarrhea, dry mouth, fever, musculoskeletal pain, rash, injection site reactions, burning sensations, hot flashes, hypokalemia, transient blurred vision and loss of vision, transient elevations of liver enzymes, seizures, headache, drowsiness, dizziness, sedation, extrapyramidal reactions, tachycardia, chest pain, hypotension, and anaphylaxis. ECG abnormalities, including QT prolongation, ST segment depression, and second degree atrioventricular block have been reported with ondansetron IV injection. A child with known susceptibility to malignant hyperthermia (MH) developed an MH-like syndrome 3 hours after receiving ondansetron and died.

E)

1) DOLASETRON: An intentional ingestion of 2 g of dolasetron produced severe hypotension, first degree AV block, QRS widening and a prolonged QTc interval in an adult. Overdose of IV dolasetron has resulted in hypotension, dizziness, and abnormal ECG. GRANISETRON: No symptoms or only the occurrence of a slight headache have been reported with overdosage of up to 38.5 mg of granisetron hydrochloride injection. ONDANSETRON: Overdose has caused fever, rashes, pruritus, restlessness, CNS depression, self-limited seizures, tachycardia, mild elevations in liver enzymes, hypotension, temporary blindness (2 to 3 minutes duration) and a constellation of findings consistent with serotonin syndrome. A toddler developed somnolence, tachycardia, hyperreflexia, seizure activity, airway obstruction, rash, transiently elevated liver enzymes, and a prolonged QTc interval after inadvertently ingesting 7 to 8 tablets of 8-mg ondansetron (an estimated 5.6 to 6.4 mg/kg).

Heent

3.4.3)

A) WITH THERAPEUTIC USE

1) BLURRED VISION: Cases of transient blurred vision and altered accommodation with intravenous administration have been reported (Prod Info ondansetron hcl injection, 2006a).
2) BLINDNESS: CASE REPORT: One patient who received 72 mg of ondansetron as a single intravenous dose developed sudden blindness of 2 to 3 minutes duration (Prod Info ondansetron hcl injection, 2006a).
3) OCULOGYRIC CRISIS: CASE REPORT: Oculogyric crisis developed in a 3-year-old boy who received ondansetron (2 mg; 0.11 mg/kg IV) for nausea and intermittent vomiting. Physical examination revealed intermittent prolonged deviation of his eyes upward and periods of convergence alternating with rapid beats of horizontal nystagmus. He also appeared very anxious and unaware of his surroundings but no other dystonic movements were observed. Following supportive care, including IV diphenhydramine (1.1 mg/kg), his symptoms resolved within 20 minutes (Plumb et al, 2015).

Cardiovascular

3.5.2)

A) WIDE QRS COMPLEX

1) WITH POISONING/EXPOSURE

a) CASE REPORT (DOLASETRON): A 21-year-old woman presented to the hospital 3 hours after intentionally ingesting 2 g of dolasetron and had an initial ECG which showed first degree AV block (72 beats per minute) with a wide QRS complex and a prolonged QTc interval of 611 ms (normal 470 ms in women). Blood pressure was 64/30 mm Hg. The patient was drowsy, but neurologically intact. Labs were within normal limits except for a calcium concentration of 2.09 mmol/L (normal 2.25 to 2.58 mmol/L). Supportive care included fluid resuscitation and norepinephrine. QTc gradually improved with a normal interval within 12 hours; the patient was discharged to home after 36 hours of observation (Rochford et al, 2007).
b) CASE REPORT (DOLASETRON): Prolongation of PR, QRS, and QTc intervals were reported in a 59-year-old man 2 hours after an intravenous infusion of 1000 mg dolasetron given over 15 minutes. The patient's ECG intervals returned to baseline following treatment with a plasma expander, dopamine, and atropine (Prod Info ANZEMET(R) oral tablets, 2006).

B) TACHYARRHYTHMIA

1) WITH THERAPEUTIC USE

a) Of 67 courses of ondansetron administered, one case of tachycardia occurred (Nicolai et al, 1993).
b) Intravenous ondansetron has been associated with tachycardia, angina, and electrocardiographic alterations but the incidence is rare (Prod Info ondansetron hcl injection, 2006a).

2) WITH POISONING/EXPOSURE

a) CASE REPORT (ONDANSETRON): A 12-month-old boy, weighing 10 kg, ingested 7 to 8 tablets of 8 mg ondansetron (an estimated 5.6-6.4 mg/kg) and developed somnolence within 20 minutes of exposure. Upon admission, his heart rate was 175 beats/min (normal for age 89-115 beats/min). Following supportive care including mechanical ventilation, pulse rate normalized to 110 beats/minute. The patient recovered and was discharged to home after 48 hours (George et al, 2008).

C) HEART BLOCK

1) WITH THERAPEUTIC USE

a) Electrocardiogram abnormalities, including QT prolongation, ST segment depression, and second degree atrioventricular block, have been reported with ondansetron IV injection (Prod Info Ondansetron IV injection, 2010).
b) CASE REPORT (ONDANSETRON): Infusion of 32 mg of ondansetron intravenously over 4 minutes resulted in a vasovagal episode with transient second degree heart block (Prod Info ondansetron hcl injection, 2006a).
c) CASE REPORT (DOLASETRON): A 61-year-old woman developed complete heart block after receiving 200 mg dolasetron for the prevention of postoperative nausea and vomiting. The patient was also taking verapamil (Prod Info ANZEMET(R) oral tablets, 2006).

2) WITH POISONING/EXPOSURE

a) CASE REPORT (DOLASETRON): A 21-year-old woman presented to the hospital 3 hours after intentionally ingesting 10 200-mg dolasetron tablets and had an initial ECG which showed first degree AV block (72 beats per minute) with a wide QRS complex and a prolonged QTc interval of 611 ms (normal 470 ms in women). Blood pressure was 64/30 mm Hg. Labs were within normal limits except for a calcium concentration of 2.09 mmol/L (normal 2.25 to 2.58 mmol/L) (Rochford et al, 2007).
b) CASE REPORT (DOLASETRON): Prolongation of PR, QRS, and QTc intervals were reported in a 59-year-old man 2 hours after an intravenous infusion of 1000 mg dolasetron given over 15 minutes. The patient's ECG intervals returned to baseline following treatment with a plasma expander, dopamine, and atropine (Prod Info ANZEMET(R) oral tablets, 2006).

D) CHEST PAIN

1) WITH THERAPEUTIC USE

a) The manufacturer reports chest pain as a rare side effect of ondansetron (Prod Info Zofran(R), ondansetron hydrochloride, 2000).
b) Several cases of chest pain associated with therapeutic use of ondansetron have been reported (Ballard et al, 1992).

E) HYPOTENSIVE EPISODE

1) WITH THERAPEUTIC USE

a) CASE REPORT (ONDANSETRON): Hypotension occurred in one patient who ingested 48 mg of ondansetron tablets (Prod Info ZOFRAN(R) oral tablets, oral solution, ZOFRAN ODT(R) orally disintegrating tablets, 2006).

2) WITH POISONING/EXPOSURE

a) CASE REPORT (DOLASETRON): A 21-year-old woman presented to the hospital 3 hours after intentionally ingesting 10 200-mg dolasetron tablets and had an initial blood pressure of 64/30 mm Hg and a prolonged QTc interval. The patient was drowsy, but neurologically intact. Supportive care included fluid resuscitation and norepinephrine. QTc gradually improved within 12 hours, and the patient was discharged to home after 36 hours of observation (Rochford et al, 2007).
b) CASE REPORT (DOLASETRON): Severe hypotension and dizziness occurred in a 59-year-old man 40 minutes after receiving an intravenous infusion of dolasetron 1000 mg (13 mg/kg) given over 15 minutes. The patient's blood pressure returned to normal 3 hours later following treatment (Prod Info ANZEMET(R) oral tablets, 2006).
c) CASE REPORT (ONDANSETRON): An 8-year-old boy with a history of precursor B-cell lymphoblastic lymphoma, presented 1 hour after ingesting 15 ondansetron 4-mg oral tablets (1.25 mg/kg). He vomited once before presentation. He developed hypotension (BP 87/31 mm Hg) about 6 hours postingestion and recovered after receiving intravenous fluids and norepinephrine (0.1 mcg/kg/min) for about 12 hours (Ghafouri et al, 2012).

F) SUDDEN CARDIAC DEATH

1) WITH THERAPEUTIC USE

a) CASE REPORT (DOLASETRON): A 66-year-old man, with stage IV non-Hodgkins lymphoma, suddenly died six hours after receiving an intravenous injection of dolasetron, 1.8 mg/kg. The patient was also receiving doxorubicin and concomitant cyclophosphamide (Prod Info ANZEMET(R) oral tablets, 2006).

G) PROLONGED QT INTERVAL

1) WITH POISONING/EXPOSURE

a) Rare cases of transient ECG changes, including QT prolongation, predominantly with the intravenous form, have been reported with ondansetron (Prod Info ZOFRAN(R) IV injection, 2011; Prod Info ZOFRAN(R) oral tablets, solution, 2011; Prod Info ZOFRAN ODT(R) oral disintegrating tablets, 2011).
b) CASE REPORT (ONDANSETRON): A 12-month-old boy, weighing 10 kg, ingested 7 to 8 tablets of 8 mg ondansetron (an estimated 5.6 to 6.4 mg/kg) and developed somnolence within 20 minutes of exposure and evidence of seizure activity. An initial ECG showed sinus tachycardia with a manually calculated QTc of 461 ms (normal for age less than 440 ms). Approximately 20 hours after exposure his heart rate stabilized and a repeat ECG showed a QTc of 390 ms. The patient fully recovered and was discharged to home after 48 hours (George et al, 2008).

Respiratory

3.6.2)

A) BRONCHOSPASM

1) Bronchospasm occurs rarely with intravenous infusion (Prod Info ondansetron hcl injection, 2006a).

Neurologic

3.7.2)

A) SEIZURE

1) WITH THERAPEUTIC USE

a) During clinical trials less than 1% of patients developed seizures. Patients at greatest risk include those with neurologic predisposition, including brain metastases, severe metabolic and electrolyte abnormalities, or antineoplastic therapy (Prod Info ZOFRAN(R) oral tablets, oral solution, ZOFRAN ODT(R) orally disintegrating tablets, 2006).
b) One case of ondansetron-associated seizure in a patient without neurologic predisposition has been reported (Sargent et al, 1993).

2) WITH POISONING/EXPOSURE

a) CASE REPORT (ONDANSETRON): A 12-month-old boy, weighing 10 kg, ingested 7 to 8 tablets of 8 mg ondansetron (an estimated 5.6-6.4 mg/kg), and developed somnolence within 20 minutes of exposure and intermittent jerking movements. Shortly after admission, horizontal nystagmus and persistent myoclonic movements of the extremities occurred. After initial stabilization including intubation, the patient had a brief tonic-clonic seizure with significant oxygen desaturation, which resolved with lorazepam. Following supportive care the patient fully recovered and was discharged to home at 48 hours(George et al, 2008).

B) HEADACHE

1) WITH THERAPEUTIC USE

a) Headache is a common adverse event reported with therapeutic use of ondansetron (Prod Info ZUPLENZ(R) oral soluble film, 2010).
b) INCIDENCE: Headache occurred in 17% to 26% of ondansetron patients in Phase III clinical trials (Bryson, 1992).

1) Among 30 patients receiving oral ondansetron and placebo in a controlled study, 12 reported headache, one described as severe (Herrstedt et al, 1993).
2) In a randomized controlled trial of antiemetics for chemotherapy-induced nausea, the ondansetron group had a 39% rate of headache but this rate was not statistically different than other groups (Abali & Celik, 2007).

c) DOLASETRON: Headache occurred in 18% to 23% of chemotherapy patients given dolasetron during clinical trials (Prod Info Anzemet(R), dolasetron, 1999).
d) GRANISETRON: The most prevalent adverse effect is headache (10% to 21% of patients). No symptoms or only the occurrence of a slight headache have been reported with overdose of up to 38.5 mg of granisetron hydrochloride injection (Prod Info Kytril(R), 2000).
e) PALONOSETRON: Headache was the most frequently reported adverse event associated with therapeutic use (Prod Info ALOXI(R) IV injection, 2007).

2) WITH POISONING/EXPOSURE

a) No symptoms or only the occurrence of a slight headache have been reported with overdosage of up to 38.5 mg of granisetron hydrochloride injection (Prod Info KYTRIL(R) IV injection, 2011).

C) DIZZINESS

1) WITH THERAPEUTIC USE

a) Among 30 patients receiving oral ondansetron and placebo in a controlled study, five reported episodes of dizziness, one described as severe (Herrstedt et al, 1993).
b) CASE REPORT (DOLASETRON): A 59-year-old man experienced dizziness 40 minutes after receiving an intravenous infusion of dolasetron 1000 mg given over 15 minutes (Prod Info ANZEMET(R) oral tablets, 2006).
c) In a randomized controlled trial of antiemetics for chemotherapy-induced nausea, the ondansetron group had a 17% rate of dizziness (Abali & Celik, 2007).

D) DROWSY

1) WITH THERAPEUTIC USE

a) Among 30 patients receiving oral ondansetron and placebo in a controlled study, one reported mild sedation (Herrstedt et al, 1993).
b) Sedation occurred in 6% to 8% of patients in a controlled study; the incidence was similar to that of placebo (DuPen et al, 1992).

E) SEROTONIN SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORT (ONDANSETRON): A 12-month-old boy, weighing 10 kg, ingested 7 to 8 tablets of 8 mg ondansetron (an estimated 5.6 to 6.4 mg/kg) and developed somnolence within 20 minutes of exposure and intermittent jerking movements. Shortly after admission, horizontal nystagmus and persistent myoclonic movements of the extremities occurred. After initial stabilization including intubation, the patient had a brief tonic-clonic seizure with significant oxygen desaturation. Other manifestations included: tachycardia, facial flushing, mydriasis, transiently elevated liver enzymes, and temperature (maximum temperature 38.4 degrees C) and blood pressure fluctuations. Following intensive care, the patient clinically improved within 24 hours and was discharged to home at 48 hours (George et al, 2008). The authors suggested that the signs and symptoms observed were consistent with serotonin syndrome.

F) EXTRAPYRAMIDAL DISEASE

1) WITH THERAPEUTIC USE

a) Several case reports indicate a rare occurrence of extrapyramidal effects with ondansetron treatment.

1) CASE REPORT: A 65-year-old woman being treated for recurrent pelvic sarcoma received ondansetron injection 10 mg daily for 3 days. She appeared confused on the third night, with tremulousness of the lower jaw and cogwheel rigidity of both wrists. Diphenhydramine administration and discontinuation of ondansetron resulted in dramatic improvement with no further episodes of dystonic reactions (Dobrow et al, 1991).
2) CASE REPORT: A 58-year-old man complained of shoulder and back pain with opisthotonos and difficulty moving because of stiffness and mild shortness of breath fifteen minutes following intravenous ondansetron 0.15 mg/kg. The symptoms gradually resolved over 10 minutes without treatment. One month later an identical episode of extrapyramidal symptoms occurred following ondansetron 7.5 mg with diphenhydramine pretreatment. Further treatment with ondansetron at 50% reduced doses produced no neurologic symptoms (Halperin & Murphy, 1992).
3) CASE REPORT: A 65-year-old woman experienced dystonia of the jaw, stiffness of limbs, inability to speak, anxiety, and a burning sensation on face and hands immediately following injection of her seventh dosage of ondansetron. Subsequent dosages of ondansetron were administered diluted and over a 15 minute intravenous infusion and no further episodes of neurologic effects occurred (Garcia-del- Muro et al, 1993).

G) MALIGNANT HYPERTHERMIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 5-year-old boy, with a history of an RYR-1 related congenital neuromuscular disorder (multiminicore disease) and known susceptibility to malignant hyperthermia (MH), developed malignant hyperthermia after administration of ondansetron (2 mg orally). Hyperthermia (temperature 41 degrees Celsius) developed 3 hours after administration. Upon readmission, the patient was asystolic. Despite aggressive resuscitation efforts, the child died. There was laboratory evidence of severe hyperkalemia (15.3 mEq/L) and an elevated creatine kinase (3297 Units/L). Postmortem findings of bronchopneumonia, intrahepatic thrombus, and mesenteric lymphadenopathy were determined to be noncontributory to the development of MH. This case did suggest probable MH secondary to ondansetron based on the child's history of susceptibility, along with findings of severe hyperkalemia, rhabdomyolysis and muscle rigidity. In addition, the application of the Naranjo algorithm (score of 5/10) was consistent with a probable-association (Gener et al, 2010).

Gastrointestinal

3.8.2)

A) CONSTIPATION

1) WITH THERAPEUTIC USE

a) ONDANSETRON

1) Of 67 courses of ondansetron administered, ten cases of constipation occurred (Nicolai et al, 1993).
2) Among 30 patients receiving oral ondansetron and placebo in a controlled study, nine developed constipation (Herrstedt et al, 1993).
3) Constipation occurred in 3% to 11% of patients treated with ondansetron who also received highly emetogenic regimens (Prod Info ZOFRAN(R) oral tablets, oral solution, ZOFRAN ODT(R) orally disintegrating tablets, 2006; Smith, 1989) .
4) In patients treated with non-cisplatin chemotherapy, the incidence of constipation with ondansetron has been approximately 2% (Schmoll, 1989).
5) The incidence of constipation appears to be greater than that observed with metoclopramide therapy (Smith, 1989; Schmoll, 1989).
6) CASE SERIES/PREGNANT WOMEN: In a study of 1193 pregnant women exposed to ondansetron, severe constipation was reported in 36 (3%) pregnancies (Fejzo et al, 2015).

b) GRANISETRON

1) In clinical trials, constipation was reported in 18% of patients treated with granisetron (Prod Info Kytril(R), 2000).

B) INTESTINAL OBSTRUCTION

1) WITH THERAPEUTIC USE

a) Intestinal obstruction has been reported infrequently among pregnant women receiving ondansetron. Of the 1193 ondansetron exposures, there were 3 reported cases of hospitalization for intestinal obstruction. Two of the patients took ondansetron during all 3 trimesters every 6 hours at doses up to 32 mg/day. The third patient took ondansetron for only 3 weeks during her first trimester only at 16 mg/day. In addition, delayed gastric emptying occurred in 107 (8.9%) pregnancies administered ondansetron (Fejzo et al, 2015).

C) DIARRHEA

1) WITH THERAPEUTIC USE

a) Diarrhea was a common adverse event reported with the therapeutic use of ondansetron (Prod Info ZUPLENZ(R) oral soluble film, 2010).

1) In a randomized controlled trial of antiemetics for chemotherapy-induced nausea, diarrhea was reported in less than 5% of patients treated with ondansetron (Abali & Celik, 2007).

b) Diarrhea has been reported in approximately 7% of patients treated with ondansetron for cisplatin-induced vomiting (Hesketh et al, 1989; Marty, 1989; Smith, 1989). The incidence of diarrhea with ondansetron has been lower in patients receiving non-cisplatin based chemotherapy (Schmoll, 1989).
c) In clinical trials, diarrhea was reported in 9% of patients treated with granisetron (Prod Info Kytril(R), 2000).

D) APTYALISM

1) WITH THERAPEUTIC USE

a) Dry mouth has been reported in approximately 5% of patients treated with ondansetron for cisplatin-induced emesis (Hesketh et al, 1989; Marty, 1989). The incidence of dry mouth has been lower in patients receiving less emetogenic regimens (Schmoll, 1989).

E) HICCOUGHS

1) WITH THERAPEUTIC USE

a) Of 67 courses of ondansetron administered, one case of singultus was reported (Nicolai et al, 1993).

F) PANCREATITIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: Acute pancreatitis (amylase 505 IU/L; lipase 550 IU/L) has been reported in a patient treated with granisetron followed by ondansetron (Rodier et al, 1996).

Hepatic

3.9.2)

A) LIVER ENZYMES ABNORMAL

1) WITH THERAPEUTIC USE

a) Transient elevations in aminotransferases and serum bilirubin have occurred during ondansetron and dolasetron therapy (Prod Info ZOFRAN(R) oral tablets, oral solution, ZOFRAN ODT(R) orally disintegrating tablets, 2006; Prod Info ANZEMET(R) oral tablets, 2006; Marty et al, 1989; Marty, 1989; Smith, 1989). In a study involving patients treated with cisplatin, transient elevations in liver enzymes of at least 2 times baseline values and outside the upper limits of normal range were reported in 17% of patients during intermittent intravenous ondansetron therapy (Hesketh et al, 1989). These changes may be attributable to cancer chemotherapy and not ondansetron (Marty et al, 1989; Smith, 1989; Hesketh et al, 1989).
b) Of 67 courses of ondansetron administered, four cases of ALT/AST elevation occurred (Nicolai et al, 1993).
c) A toddler developed transient elevations of AST (93 Units/L (normal age range: 20-65 Units/L)) and ALT (127 Units/L (normal age range: less than 54 Units/L)) concentrations following an inadvertent oral ingestion of 7 to 8 tablets of 8 mg ondansetron (an estimated 5.6 to 6.4 mg/kg). Upon discharge at 48 hours, the concentrations had normalized (George et al, 2008).

B) ACUTE HEPATITIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 39-year-old woman with a history of gastroesophageal reflux disease developed mild elevation of transaminases 28 days after starting alosetron. An MRI revealed an enlarged and edematous liver with diffuse homogeneous increased T2 signal consistent with acute hepatitis. Following the discontinuation of alosetron, she recovered without further sequelae (Turgeon et al, 2005).

C) HEPATIC FAILURE

1) WITH THERAPEUTIC USE

a) CASE REPORT: Hepatic failure developed after a second course of ondansetron and cyclophosphamide in a 76-year-old patient with lymphoma, who was a carrier of hepatitis. The patient subsequently died; the etiology of hepatic failure unknown (Prod Info ZOFRAN(R) oral tablets, oral solution, ZOFRAN ODT(R) orally disintegrating tablets, 2006).

Genitourinary

3.10.2)

A) DYSURIA

1) WITH THERAPEUTIC USE

a) DuPen et al (1992) reported the development of dysuria among patients in an oral ondansetron study with doses of 1, 4 or 8 mg. The incidence was not significantly different from that of placebo (DuPen et al, 1992).

Dermatologic

3.14.2)

A) ERUPTION

1) WITH THERAPEUTIC USE

a) Approximately 1% of the patients administered intravenous ondansetron developed a rash (Prod Info ZOFRAN(R) oral tablets, oral solution, ZOFRAN ODT(R) orally disintegrating tablets, 2006).

2) WITH POISONING/EXPOSURE

a) Rash has occurred with suspected overdose (Prod Info Zofran(R), ondansetron hydrochloride, 2000).
b) CASE REPORT (ONDANSETRON): A 12-month-old boy, weighing 10 kg, ingested 7 to 8 tablets of 8 mg ondansetron (an estimated 5.6 to 6.4 mg/kg) and developed somnolence. Shortly after admission, an erythematous rash, which was more pronounced on the extremities, along with facial flushing were observed. Following supportive care the patient was discharged to home after 48 hours (George et al, 2008).

B) INJECTION SITE REACTION

1) WITH THERAPEUTIC USE

a) Injection site reactions (redness, swelling, burning) occurred in 4% to 6% of 544 women receiving ondansetron orally following ambulatory gynecologic surgery. Frequency of site reactions with placebo was similar (McKenzie et al, 1993).

C) FLUSHING

1) WITH POISONING/EXPOSURE

a) CASE REPORT: One patient who had received an unintentional intravenous overdose of 145 mg ondansetron complained of hot flashes and a burning sensation when her skin touched the bed linens (Bryson, 1992). Facial flushing was also observed in a toddler (10 kg) following an inadvertent oral ingestion of 7 to 8 tablets of 8 mg ondansetron an estimated dose of 5.6 to 6.4 mg/kg (George et al, 2008).

D) LACK OF EFFECT

1) Mouse studies failed to produce evidence of vesicant activity of ondansetron with intradermal injection. Five mice received intradermal application of 0.1 mL ondansetron injection in concentrations of 100, 200, and 300 mcg/mL. No reactions were observed (Loughner et al, 1993).

Musculoskeletal

3.15.2)

A) MUSCLE PAIN

1) WITH THERAPEUTIC USE

a) Among ambulatory patients taking oral ondansetron in doses of 1, 4 or 8 mg, 9 to 14% complained of musculoskeletal pain. Sixteen percent of those receiving placebo complained of musculoskeletal pain (DuPen et al, 1992).

B) ASTHENIA

1) WITH THERAPEUTIC USE

a) Asthenia has been reported in up to 18% of patients on oral granisetron and in 5% of patients on intravenous granisetron (Prod Info Kytril(R), 2000).

Immunologic

3.19.2)

A) ANAPHYLACTOID REACTION

1) WITH THERAPEUTIC USE

a) Twenty-four cases of anaphylactoid-anaphylactic reactions have been reported. Reactions consisted of urticaria, angioedema, hypotension, bronchospasm, and dyspnea. One patient developed shock with cardiac arrest and apnea ten minutes following ondansetron injection (Chen et al, 1993).
b) CASE REPORT (ONDANSETRON): A 12-month-old boy, weighing 10 kg, ingested 7 to 8 tablets of 8 mg ondansetron (an estimated 5.6 to 6.4 mg/kg) and developed somnolence within 20 minutes of exposure and evidence of stridor shortly after admission. An erythematous rash, which was more pronounced on the extremities, along with facial flushing were also observed. Supportive care included intubation and mechanical ventilation for approximately 20 hours; the patient was discharged to home after 48 hours (George et al, 2008). The authors suggested that these initial symptoms may have been related to a hypersensitivity reaction.

Reproductive

3.20.1)

A) Ondansetron, granisetron, dolasetron, and palonosetron are classified as FDA pregnancy category B. The netupitant and palonosetron combination is FDA pregnancy category C. Ondansetron crosses the placental barrier during the first trimester of pregnancy, with an average fetal tissue concentration of 41% of the corresponding maternal plasma concentration. Ondansetron and palonosetron did not result in fetal harm or impairment of fertility in rats and rabbits. Ondansetron is excreted in the breast milk of lactating rats. It is not known whether palonosetron is excreted in breast milk.

3.20.2)

A) LACK OF INFORMATION

1) GRANISETRON

a) There are no adequate and well-controlled studies of granisetron use in pregnant women (Prod Info SANCUSO transdermal system, 2008).

2) PALONOSETRON

a) There are no adequate and well-controlled studies of palonosetron use in pregnant women.

B) ONDANSETRON

1) Data from the Swedish Medical Birth Register combined with the Swedish Register of Prescribed drugs found that ondansetron use during early pregnancy was not associated with a high risk of congenital malformation; however, an increased risk of cardiovascular malformations was observed. Of the 1349 infants exposed to ondansetron during early pregnancy, malformations of any kind were reported in 49 infants. Of these 49 congenital malformations, 38 were considered relatively severe, 19 were cardiovascular defects, and 17 were septum defects. Of the 17 septum defects that occurred after exposure to ondansetron, 13 had ventricular septum defects, 1 had an atrium septum defect, and 3 had both ventricular and atrium septum defects. It was suggested that the teratogenic effect may be related to ondansetron's potential to cause QT prolongation and cardiac arrhythmias. There were also no reports of cleft palate; however, one case of cleft lip/palate was reported. Hypospadias was reported in 3 of the exposed infants (expected number 3.7) (Danielsson et al, 2014).
2) A cohort study of 608,385 pregnancies in Denmark showed that ondansetron use during pregnancy was not associated with a significantly increased risk of adverse fetal outcomes. Women who were exposed to ondansetron during pregnancy were matched to unexposed women in a 1:4 ratio in propensity-score-matched analyses of spontaneous abortion (exposed, n=1849 vs unexposed, n=7396), stillbirth (n=1915 vs n=7660), any major birth defect (n=1233 vs n=4392), and infants with low birth weight and small for gestational age (n=1784 vs n=7136). Pregnant women who were exposed to ondansetron were not at increased risk for spontaneous abortion, which occurred in 1.1% of exposed women and 3.7% of unexposed women during gestational weeks 7 to 12 (hazard ratio [HR], 0.49; 95% CI, 0.27 to 0.91) and 1% and 1.8% of exposed and unexposed women, respectively, during weeks 13 to 22 (HR, 0.6; 95% CI, 0.29 to 1.21). Ondansetron exposure during pregnancy was also not associated with a significantly increased risk of stillbirth (0.3% vs 0.4% for exposed vs unexposed women; HR, 0.42; 95% CI, 0.1 to 1.73), any major birth defect (2.9% vs 2.9%, respectively; adjusted prevalence odds ratio [OR], 1.12; 95% CI, 0.69 to 1.82), preterm delivery (6.2% vs 5.2%; prevalence OR, 0.9; 95% CI, 0.66 to 1.25), delivery of a low-birth-weight infant (4.1% vs 3.7%; prevalence OR, 0.76; 95% CI, 0.51 to 1.13), or delivery of a small-for-gestational-age infant (10.4% vs 9.2%; prevalence OR, 1.13; 95% CI, 0.89 to 1.44). A potential confounder for this study is the fact that nausea and vomiting, rather than treatment with ondansetron, are associated with a lower risk of spontaneous abortion or other fetal toxicity (Pasternak et al, 2013).
3) Based on a prospective cohort study of 176 women who took ondansetron during the first trimester of pregnancy, there does not seem to be an increase in the rates of major malformations in the infants above baseline. In this group of women, there were 169 live births, 5 miscarriages, 2 therapeutic abortions, 6 major malformations, and the mean birthweight was 3362 g. None of these parameters differed significantly from results found in two comparison groups (n=175 each); the first group comprised of women similarly exposed to other antiemetics and the second group comprised of women similarly exposed to non-teratogens. The small sample of the study, however, has an 80% power to detect only a 3.5-fold increase in the rate of major malformation (Einarson et al, 2004).

C) LACK OF EFFECT

1) ONDANSETRON

a) In a randomized, controlled trial of 15 pregnant women treated with intravenous ondansetron (another serotonin subtype (5-HT3) receptor antagonist) for severe nausea and vomiting of pregnancy during the first trimester of pregnancy, no fetal malformations were observed (Magee et al, 2002).

D) ANIMAL STUDIES

1) GRANISETRON

a) Pregnant rats given intravenous granisetron at doses of up to 9 mg/kg/day and oral doses up to 125 mg/kg/day (about 24 times and 326 times the recommended human dose, respectively) and pregnant rabbits given intravenous granisetron at doses of up to 3 mg/kg/day and oral doses up to 32 mg/kg/day (about 16 times and 167 times the recommended human dose, respectively) did not result in fetal harm (Prod Info SANCUSO transdermal system, 2008).

2) ONDANSETRON

a) Rats and rabbits receiving 10 to 30 mg/kg during pregnancy did not exhibit harm to the fetus due to ondansetron (Prod Info Zofran(R), ondansetron hydrochloride, 2000).

3) PALONOSETRON

a) Pregnant rats and rabbits given palonosetron at doses of up to 60 mg/kg/day, 1894 and 3789 times the recommended human intravenous dose, respectively, did not result in fetal harm (Prod Info ALOXI(R) IV injection, 2008). In another animal study, rats and rabbits exposed to ondansetron doses of 70 times that given to humans also revealed no developmental toxicity (Magee et al, 2002).

3.20.3)

A) PREGNANCY CATEGORY

1) The manufacturers have classified ONDANSETRON, GRANISETRON, DOLASETRON, and PALONOSETRON as FDA pregnancy category B (Prod Info ALOXI(R) IV injection, 2008; Prod Info ZOFRAN(R) oral tablets, oral solution, ZOFRAN ODT(R) orally disintegrating tablets, 2006; Prod Info ANZEMET(R) injection, 2006; Prod Info SANCUSO transdermal system, 2008) and the netupitant and palonosetron combination as FDA pregnancy category C (Prod Info AKYNZEO(R) oral capsules, 2014).
2) Ondansetron was shown to cross the placental barrier in a prospective, observational study involving 41 women during the first trimester of pregnancy (median gestation age 10.6 (9.3 - 12.1) weeks. Three oral doses of ondansetron 8 mg were administered at 1400 and 2200 hours the day prior and 4 hours prior to elective, surgical termination of pregnancy. Immediately before induction of anesthesia samples of maternal venous blood were drawn. After anesthesia, coelomic and amniotic fluid, and fetal tissue samples were obtained. Ondansetron was detected in all samples, with a median fetal tissue/maternal plasma ratio of 0.41 (0.31 - 0.52) (Siu et al, 2006).

3.20.4)

A) BREAST MILK

1) GRANISETRON

a) It is unknown whether granisetron is excreted in human breast milk (Prod Info SANCUSO transdermal system, 2008).

2) ONDANSETRON

a) Ondansetron is excreted in the breast milk of rats. The excretion of ondansetron in human milk has not been established. Caution is recommended when administering ondansetron to nursing mothers (Prod Info Zofran(R), ondansetron hydrochloride, 2000; Briggs et al, 1998).

3) PALONOSETRON

a) It is unknown whether palonosetron is excreted in breast milk (Prod Info ALOXI(R) IV injection, 2008).

3.20.5)

A) ANIMAL STUDIES

1) GRANISETRON

a) Pregnant rats given intravenous granisetron at doses of up to 9 mg/kg/day and oral doses up to 125 mg/kg/day (about 24 times and 326 times the recommended human dose, respectively, delivered by the patch) and pregnant rabbits given intravenous granisetron at doses of up to 3 mg/kg/day and oral doses up to 32 mg/kg/day (about 16 times and 167 times the recommended human dose, respectively, delivered by the patch) did not result in impaired fertility (Prod Info SANCUSO transdermal system, 2008).

2) ONDANSETRON

a) Rats and rabbits receiving 10 to 30 mg/kg during pregnancy did not exhibit impaired fertility due to ondansetron (Prod Info Zofran(R), ondansetron hydrochloride, 2000).

3) PALONOSETRON

a) Pregnant rats and rabbits given palonosetron at doses of up to 60 mg/kg/day, 1894 and 3789 times the recommended human intravenous dose, respectively, and 921 and 1841 times the recommended human oral dose, respectively, did not exhibit impaired fertility (Prod Info ALOXI(R) IV injection, 2008).

Carcinogenicity

3.21.2)

A) No human data exist. Animal studies did not indicate carcinogenic potential.

3.21.3)

A) LACK OF INFORMATION

1) HUMANS

a) No human data exist. Animal studies did not indicate carcinogenic potential.

3.21.4)

A) MICE

1) DOLASETRON - Male mice receiving at least 150 mg/kg/day dolasetron over 2 years showed a significant increase in the incidence of combined hepatocellular adenomas and carcinomas (Prod Info Anzemet(R), dolasetron, 1999).

B) LACK OF EFFECT

1) RATS AND MICE

a) ONDANSETRON - Rats and mice receiving oral doses up to 10 and 30 mg/kg/day, respectively (approximately 3.6 and 5.4 times the recommended human dose based on body surface area of 0.15 mg/kg given IV 3 times/day) of ondansetron over 2 years did not exhibit carcinogenic effects (Prod Info ZOFRAN(R) intravenous injection, 2012).

Genotoxicity

A)

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs, mental status, and liver enzymes following a significant overdose.
B) Obtain a baseline ECG and institute continuous cardiac monitoring after significant overdose. Based on limited data, AV block, QRS widening and QTc prolongation have developed in overdose.
C) Serum concentrations of these agents are not widely available or clinically useful in guiding management.

Methods

A)

1) High-performance liquid chromatography has been used to determine ondansetron concentration in plasma (Colthup & Palmer, 1989).

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with unstable vital signs, persistent cardiac dysrhythmias, mental status changes, and persistent seizures should be admitted.

6.3.1.2) HOME CRITERIA/ORAL

A) A child with an inadvertent exposure to 1 or 2 tablets, that remains asymptomatic can be managed at home.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for several hours. Patients that remain asymptomatic can be discharged.

Monitoring

A)

B)

C)

Oral Exposure

6.5.1)

A) Prehospital gastrointestinal decontamination is not recommended because of the potential for CNS depression and subsequent aspiration.

6.5.2)

A) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

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

2) CHARCOAL DOSE

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

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

b) ADVERSE EFFECTS/CONTRAINDICATIONS

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

6.5.3)

A) MONITORING OF PATIENT

1) Monitor vital signs, mental status, and liver enzymes following an overdose.
2) Obtain a baseline ECG and institute continuous cardiac monitoring after significant overdose. Based on limited data, AV block, QRS widening and QTc prolongation have developed in overdose.

B) SODIUM BICARBONATE

1) Sodium bicarbonate should not be routinely administered, and there is no evidence that bicarbonate improves prolonged QRS from ondansetron exposure. The only human case reported documenting use of sodium bicarbonate (two 100 mmol boluses over 2 hours and an additional 200 ml over the next 10 hours) was in a woman with hypotension, first degree AV block, QRS widening and QTc prolongation. There was no evident effect on the ECG (Rochford et al, 2007). WARNING: Sodium bicarbonate is contraindicated in patients with significant QT prolongation due to potassium shifts and subsequent worsening of QT prolongation.

C) 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).

D) TORSADES DE POINTES

1) Therapeutic doses of ondansetron may cause prolongation of the QT interval. Concomitant use of ondansetron and other drugs that prolong the QT interval may increase the risk of torsade de pointes.
2) SUMMARY

a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).

3) MAGNESIUM SULFATE

a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).

4) OVERDRIVE PACING

a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).

5) POTASSIUM REPLETION

a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).

6) ISOPROTERENOL

a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

7) OTHER DRUGS

a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).

8) AVOID

a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.

E) DYSTONIA

1) Diphenhydramine has been used to manage adverse effects of therapeutic use including fever, rashes, pruritus, and restlessness.
2) CASE REPORT/ADULT: A 65-year-old woman being treated for recurrent pelvic sarcoma received ondansetron injection 10 mg daily for 3 days. She appeared confused on the third night, with tremulousness of the lower jaw and cogwheel rigidity of both wrists. Diphenhydramine administration and discontinuation of ondansetron resulted in dramatic improvement with no further episodes of dystonic reactions (Dobrow et al, 1991).
3) CASE REPORT/ADULT: A 58-year-old man complained of shoulder and back pain with opisthotonos and difficulty moving because of stiffness and mild shortness of breath fifteen minutes following intravenous ondansetron 0.15 mg/kg. The symptoms gradually resolved over 10 minutes without treatment. One month later an identical episode of extrapyramidal symptoms occurred following ondansetron 7.5 mg with diphenhydramine pretreatment. Further treatment with ondansetron at 50% reduced doses produced no neurologic symptoms (Halperin & Murphy, 1992).
4) OCULOGYRIC CRISIS/PEDIATRIC: Oculogyric crisis developed in a 3-year-old boy who received ondansetron (2 mg; 0.11 mg/kg IV) for nausea and intermittent vomiting. Physical examination revealed intermittent prolonged deviation of his eyes upward and periods of convergence alternating with rapid beats of horizontal nystagmus. He also appeared very anxious and unaware of his surroundings but no other dystonic movements were observed. Following supportive care, including IV diphenhydramine (1.1 mg/kg), his symptoms resolved within 20 minutes (Plumb et al, 2015).

Enhanced Elimination

A)

1) Hemodialysis and hemoperfusion are not expected to be of benefit because of the large volumes of distribution of ondansetron and hydrodolasetron (active metabolite of dolasetron) and high protein binding (greater than 70%).

Abstracts

Case Reports

A)

1) OVERDOSE: Seven patients received ondansetron injection in unintentional overdose due to miscalculation of weight-based dose. The largest single dose was 150 mg and the largest cumulative daily dose was 252 mg in 3 doses of 84 mg every 2 hours. Adverse effects were mild and transient, consisting of hot flashes, elevation of liver enzymes, itchy nose, and vague restlessness (Prod Info Zofran(R), ondansetron, 1994).
2) CLINICAL TRIALS: The following adverse effects occurred among 215 adults receiving 4 mg ondansetron orally 3 times a day for 3 days: headache (49), constipation (10), abdominal pain (7), weakness (5), and xerostomia (3) (Prod Info Zofran(R), ondansetron, 1994).

a) The following adverse effects occurred among 215 adults receiving 8 mg ondansetron orally 3 times a day for 3 days: headache (46), constipation (15), abdominal pain (11), weakness (7), and xerostomia (4) (Prod Info Zofran(R), ondansetron, 1994).

3) Thirty-six patients receiving cisplatin-containing chemotherapies of urological cancers were evaluated for efficacy and tolerability of antiemetic therapy. Sixty-seven courses of ondansetron were administered, in combination with dexamethasone. Adverse effects included constipation (10), headache (8), ALT/AST elevation (4), tachycardia (1), and singultus (1) (Nicolai et al, 1993).

Range Of Toxicity

Summary

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Therapeutic Dose

7.2.1)

A) SPECIFIC SUBSTANCE

1) ALOSETRON

a) The recommended oral dose is 0.5 mg twice daily for 4 weeks for severe diarrhea-predominant irritable bowel syndrome (IBS). The dose may be increased to 1 mg twice daily (Prod Info LOTRONEX(R) oral tablets, 2008).

2) DOLASETRON

a) PREVENTION OF CANCER CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING

1) ORAL: The recommended dose is 100 mg given within an hour of chemotherapy; recommended dose should not be exceeded (Prod Info ANZEMET(R) oral tablets, 2013).

b) PREVENTION OR TREATMENT OF POSTOPERATIVE NAUSEA AND VOMITING

1) INTRAVENOUS: The recommended dose is 12.5 mg given as a single dose 15 minutes before the cessation of anesthesia (prevention) or as soon as nausea or vomiting develops (treatment). A repeat dose should not be initiated as rescue therapy if prophylaxis has failed (Prod Info ANZEMET(R) intravenous injection, 2013).

3) ONDANSETRON

a) ORAL: Dosing varies by indication and formulation; it is generally 8 to 24 mg orally; MAX: 24 mg daily (Prod Info ZUPLENZ(R) oral soluble film, 2010; Prod Info ZOFRAN(R), ZOFRAN ODT(R) oral disintegrating tablets, oral tablets, solution, 2009).
b) PARENTERAL/CHEMOTHERAPY: 3 doses of 0.15 mg/kg IV starting 30 min prior to chemotherapy; subsequent doses (0.15 mg/kg) may be repeated 4 and 8 hours after the first dose; MAX single IV dose, 16 mg (Prod Info ZOFRAN(R) intravenous injection, 2012).
c) PARENTERAL/PREVENTION OF POSTOPERATIVE NAUSEA: 4 mg IV/IM immediately prior to anesthesia induction or postoperatively in patients not receiving prophylactic antiemetics if nausea and/or vomiting occurs within 2 hours of surgery; administering a second dose does not provide additional benefit (Prod Info ZOFRAN(R) intravenous injection, 2012).

4) PALONOSETRON

a) POSTOPERATIVE NAUSEA AND VOMITING: A single 0.075 mg IV dose administered over 10 seconds. Administer immediately before induction of anesthesia (Prod Info ALOXI(R) intravenous injection, 2014).
b) PREVENTION OF CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING: A single 0.25 mg IV dose administered over 30 seconds. Administer 30 minutes prior to the start of chemotherapy (Prod Info ALOXI(R) intravenous injection, 2014).

5) PALONOSETRON AND NETUPITANT

a) With highly emetogenic chemotherapy (including cisplatin-based regimens), the recommended dose is 1 capsule of netupitant 300 mg/palonosetron 0.5 mg orally 1 hour prior to chemotherapy on day 1; administer with dexamethasone 12 mg orally 30 minutes prior to chemotherapy on day 1, and 8 mg orally on days 2 to 4 (Prod Info AKYNZEO(R) oral capsules, 2014).
b) With anthracycline and cyclophosphamide-based regimens and not highly emetogenic regimens, the recommended dose is 1 capsule of netupitant 300 mg/palonosetron 0.5 mg orally 1 hour prior to chemotherapy on day 1; administer with dexamethasone 12 mg orally 30 minutes before chemotherapy on day 1 (Prod Info AKYNZEO(R) oral capsules, 2014).

7.2.2)

A) DOLASETRON

1) PREVENTION OF CANCER CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING

a) CHILDREN 2 TO 16 YEARS OF AGE: 1.8 mg/kg given 1 hour prior to chemotherapy, up to a maximum of 100 mg orally; recommended dose should not be exceeded (Prod Info ANZEMET(R) oral tablets, 2013).
b) CHILDREN 2 YEARS OF AGE AND LESS: The safety and efficacy of dolasetron has not been established (Prod Info ANZEMET(R) oral tablets, 2013).

2) PREVENTION OR TREATMENT OF POSTOPERATIVE NAUSEA AND VOMITING

a) CHILDREN 2 TO 16 YEARS OF AGE: 1.2 mg/kg of IV formulation given orally within 2 hours of surgery, up to a maximum of 100 mg (Prod Info ANZEMET(R) intravenous injection, 2013).
b) CHILDREN 2 TO 16 YEARS OF AGE: 0.35 mg/kg, with a maximum dose of 12.5 mg, given IV as a single dose 15 minutes before the cessation of anesthesia or as soon as nausea or vomiting appears; recommended dose should not be exceeded (Prod Info ANZEMET(R) intravenous injection, 2013).
c) CHILDREN 2 YEARS OF AGE AND LESS: The safety and efficacy of dolasetron has not been established (Prod Info ANZEMET(R) intravenous injection, 2013).

B) ONDANSETRON

1) INTRAVENOUS

a) EMETOGENIC CHEMOTHERAPY

1) CHILDREN 6 MONTHS AND OLDER: 0.15 mg/kg administered over 15 minutes, 30 minutes before the start of chemotherapy. Two additional doses should be given 4 and 8 hours after the first ondansetron dose; MAX single IV dose, 16 mg (Prod Info ZOFRAN(R) intravenous injection, 2012). The ASHP Commission on Therapeutics have provided guidelines for the use of ondansetron in the prevention of chemotherapy-induced nausea and vomiting (Anon, 1999).

b) POSTOPERATIVE NAUSEA AND VOMITING

1) CHILDREN 1 MONTH TO 12 YEARS OF AGE: 0.1 mg/kg IV for children weighing 40 kg or less OR ondansetron 4 mg for children weighing more than 40 kg. The recommended infusion time is 2 to 5 minutes, but no less than 30 seconds immediately prior to or following induction of anesthesia, or postoperatively if patient experiences nausea and/or vomiting shortly after surgery and did not receive prophylactic antiemetics (Prod Info ZOFRAN(R) intravenous injection, 2012).

2) ORAL

a) CHILDREN 12 YEARS AND OLDER: 8 mg orally disintegrating tablet, tablet, or solution OR the administration of a 4 mg soluble film 30 minutes prior to chemotherapy, then repeated 8 hours later. Continue twice daily ondansetron (ie, every 12 hours) 1 to 2 days after the completion of chemotherapy (Prod Info ZUPLENZ(R) oral soluble film, 2010; Prod Info ZOFRAN(R), ZOFRAN ODT(R) oral disintegrating tablets, oral tablets, solution, 2009).
b) CHILDREN 4 TO 11 YEARS OF AGE: 4 mg orally disintegrating tablet, tablet, or solution OR the administration of a 4 mg soluble film 3 times daily. The first dose should be administered 30 minutes prior to chemotherapy, then repeated 4 to 8 hours after the initial dose. Continue ondansetron, administered every 8 hours, for 1 to 2 days after the completion of chemotherapy (Prod Info ZUPLENZ(R) oral soluble film, 2010; Prod Info ZOFRAN(R), ZOFRAN ODT(R) oral disintegrating tablets, oral tablets, solution, 2009).

C) PALONOSETRON

1) PREVENTION OF CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING: A single 20 mcg/kg IV dose administered over 15 minutes. Administer 30 minutes prior to the start of chemotherapy. MAX dose: 1.5 mg (Prod Info ALOXI(R) intravenous injection, 2014).

Minimum Lethal Exposure

A)

1) The minimum lethal human dose to these agents has not been delineated.

Maximum Tolerated Exposure

A)

1) In clinical trials, individual alosetron doses as large as 16 mg orally (8 times higher than the recommended total daily dose) did not result in significant adverse effects (Prod Info LOTRONEX(R) oral tablets, 2010).

B)

1) Individual doses of 145 mg and a total daily dose of 252 mg in 3 divided doses have been administered intravenously without significant adverse effects. These doses are more than 10 times the recommended daily dose. Severe blindness for 2 to 3 minutes and constipation developed in a patient following a single 72 mg intravenous dose of ondansetron. Hypotension occurred in an adult after taking 48 mg of ondansetron orally (Prod Info ZUPLENZ(R) oral soluble film, 2010; Prod Info ZOFRAN(R) oral tablets, oral solution, ZOFRAN ODT(R) orally disintegrating tablets, 2006).
2) CASE REPORT: A toddler developed somnolence, tachycardia, hyperreflexia, seizure activity, airway obstruction, rash, transiently elevated liver enzymes and a prolonged QTc interval after inadvertently ingesting 7 to 8 tablets of 8-mg ondansetron (an estimated 5.6 to 6.4 mg/kg). The patient was intubated for approximately 20 hr with clinical improvement and discharged to home at 48 hr (George et al, 2008).
3) CASE REPORT (ONDANSETRON): An 8-year-old boy with a history of precursor B-cell lymphoblastic lymphoma, presented 1 hour after ingesting 15 ondansetron 4-mg oral tablets (1.25 mg/kg). He vomited once before presentation. He developed hypotension (BP 87/31 mm Hg) about 6 hours postingestion and recovered after receiving intravenous fluids and norepinephrine (0.1 mcg/kg/min) for about 12 hours (Ghafouri et al, 2012).

C)

1) Individual doses as large as 5 mg/kg intravenously or 400 mg orally have been safely given to healthy volunteers or cancer patients (Prod Info ANZEMET(R) oral tablets, 2006).
2) CASE REPORT: A 21-year-old woman intentionally ingested 10 200-mg (2000 mg) dolasetron tablets and developed a first degree AV block, a wide QRS complex and prolonged QTc interval of 611 ms (normal 470 ms in women) and severe hypotension (64/30 mm Hg). Clinical effects resolved with supportive care which included fluid resuscitation and norepinephrine (Rochford et al, 2007).
3) CASE REPORT: Severe hypotension, dizziness, and prolongation of PR, QRS, and QTc intervals developed in a 59-year-old man after receiving an intravenous infusion of dolasetron 1000 mg (13 mg/kg) given over 15 minutes. He recovered following supportive care (Prod Info ANZEMET(R) oral tablets, 2011).
4) CASE REPORT: A 7-year-old boy did not develop any symptoms after receiving dolasetron 6 mg/kg orally (Prod Info ANZEMET(R) oral tablets, 2011).

D)

1) No symptoms or only the occurrence of a slight headache have been reported with overdosage of up to 38.5 mg of granisetron hydrochloride injection (Prod Info KYTRIL(R) IV injection, 2011).

E)

1) CASE SERIES: In a dose ranging study, 50 adults were given palonosetron at a dose of 90 mcg/kg, which is approximately 25 times the recommended dose of 0.25 mg. Adverse events were similar to those reported with therapeutic use, and no dose response effect was observed (Prod Info ALOXI(R) IV injection, 2007).

Pharmacology Toxicology

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Animal Toxicology

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FeedBack

ONDANSETRON AND RELATED DRUGS

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

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Dermatologic

Musculoskeletal

Immunologic

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Pharmacologic Mechanism

Physical Characteristics

Ph

Molecular Weight

General Bibliography