Zofran

Generic Name: Ondansetron Hydrochloride
Class: 5-HT3 Receptor Antagonists
VA Class: GA700
Chemical Name: 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one monohydrochloride dihydrate
Molecular Formula: C₁₈H₁₉N₃O•ClH• 2H₂O
CAS Number: 103639-04-9

Special Alerts:

[Posted 09/15/2011] ISSUE: FDA notified healthcare professionals and patients of an ongoing safety review and labeling changes for the anti-nausea drug Zofran (ondansetron, ondansetron hydrochloride and generics). Ondansetron may increase the risk of developing prolongation of the QT interval of the electrocardiogram, which can lead to an abnormal and potentially fatal heart rhythm, including Torsade de Pointes. Patients at particular risk for developing Torsade de Pointes include those with underlying heart conditions, such as congenital long QT syndrome, those who are predisposed to low levels of potassium and magnesium in the blood, and those taking other medications that lead to QT prolongation.

BACKGROUND: Ondansetron (Zofran) is in a class of medications called 5-HT3 receptor antagonists. It is used to prevent nausea and vomiting caused by cancer chemotherapy, radiation therapy and surgery. FDA is requiring GlaxoSmithKline to conduct a thorough QT study to determine the degree to which ondansetron may cause QT interval prolongation.

RECOMMENDATION: The labels are being revised to include a warning to avoid use in patients with congenital long QT syndrome because these patients are at particular risk for Torsade. Recommendations for ECG monitoring in patients with electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), congestive heart failure, bradyarrhythmias, or in patients taking other medications that can lead to QT prolongation, are being included in the labels. For more information visit the FDA website at: and .

Introduction

Antiemetic; selective inhibitor of type 3 serotonergic (5-HT₃) receptors.^{1 33}

Uses for Zofran

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Cancer Chemotherapy-induced Nausea and Vomiting

Prevention of nausea and vomiting associated with emetogenic cancer chemotherapy; may use orally with highly emetogenic chemotherapy (i.e., cisplatin ≥50 mg/m²) or initial and repeat courses of moderately emetogenic chemotherapy, or IV with initial and repeat courses of emetogenic chemotherapy, including high-dose cisplatin.^{1 3 6 8 10 27 28 29 30 31 33 36 37 38 39 40 41}

Postoperative Nausea and Vomiting

Prevention or treatment of postoperative nausea and vomiting.^{1 4 11 12 32 33 76}

Routine prophylaxis not recommended in patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively.^{1 33}

Recommended for patients who, in the clinician’s judgement, must avoid nausea and/or vomiting postoperatively, even when anticipated incidence is low.^{1 33}

Radiation-induced Nausea and Vomiting

Prevention of nausea and vomiting associated with radiation, either total body irradiation or single high-dose fraction or daily fractionated radiation to the abdomen.³³

Zofran Dosage and Administration

Administration

Administer orally, by IV infusion, or by IV or IM injection.^{1 33}

Oral Administration

Administer orally as conventional tablet, orally disintegrating tablet, or oral solution.³³

Commercially available oral solution and orally disintegrating tablets may be used interchangeably.³³

Do not remove orally disintegrating tablet from blister until just prior to dosing; do not push through foil.³³ With dry hands, peel open blister package, and gently remove the tablet; place tablet on tongue to dissolve, and swallow with saliva.³³

Administration of orally disintegrating tablet with liquid is not necessary.³³

IV Administration

For prevention of cancer chemotherapy-induced nausea/vomiting, administer by IV infusion using diluted injection or premixed injection.¹

Administer premixed injection by IV infusion only; do not use flexible plastic container in series connections.¹ For preparation and administration instructions for premixed injection, consult manufacturer’s labeling.¹

For prevention of postoperative nausea and vomiting, administer undiluted by IV injection.¹

Dilution

For IV infusion, dilute ondansetron hydrochloride injection in 50 mL of 5% dextrose injection or 0.9% sodium chloride injection; the premixed injection does not require further dilution.¹

For IV injection, no dilution required.¹

Rate of Administration

IV infusion: Infuse over 15 minutes.¹

IV injection: Inject over a period of ≥30 seconds, preferably over 2–5 minutes.¹

IM Administration

For prevention of postoperative nausea and vomiting in adults, may administer undiluted by IM injection as an alternative to IV injection.¹ (See Postoperative Nausea and Vomiting under Dosage and Administration.)

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as ondansetron hydrochloride dihydrate (for oral or IV use) and as ondansetron base (orally disintegrating tablets); dosage expressed in terms of ondansetron.^{1 33}

Pediatric Patients

Cancer Chemotherapy-induced Nausea and Vomiting

Prevention

Oral

Children 4–11 years of age: Initially, 4 mg given 30 minutes before administration of moderately emetogenic chemotherapy, followed by subsequent 4-mg doses given 4 and 8 hours after first dose.³³ Continue with 4 mg every 8 hours for 1–2 days after completion of chemotherapy.³³

Children ≥12 years of age: Initially, 8 mg given 30 minutes before administration of moderately emetogenic chemotherapy, followed by a subsequent 8-mg dose given 8 hours after first dose.³³ Continue with 8 mg every 12 hours for 1–2 days after completion of chemotherapy.³³

IV

Pediatric patients 6 months to 18 years of age: 0.15 mg/kg by IV infusion beginning 30 minutes before start of emetogenic chemotherapy, followed by subsequent 0.15-mg/kg doses given 4 and 8 hours after first dose.¹

Postoperative Nausea and Vomiting

Prevention

IV

Infants and children 1 month to 12 years of age weighing ≤40 kg: 0.1 mg/kg as a single dose by IV injection immediately before or after induction of anesthesia.¹

Children ≤12 years of age weighing >40 kg: 4 mg as a single dose by IV injection immediately before or after induction of anesthesia.¹

Treatment

IV

Infants and children 1 month to 12 years of age weighing ≤40 kg: 0.1 mg/kg as a single dose by IV injection postoperatively, if nausea and/or vomiting occur shortly after surgery.¹

Children ≤12 years of age weighing >40 kg: 4 mg as a single dose by IV injection postoperatively, if nausea and/or vomiting occur shortly after surgery.¹

Efficacy of a second dose administered postoperatively after a single, prophylactic, preinduction IV dose has failed to achieve adequate control of postoperative nausea and vomiting has not been evaluated in children; such repeat doses are not effective in adults.¹

Adults

Cancer Chemotherapy-induced Nausea and Vomiting

Prevention

Oral

Initially, 8 mg given 30 minutes before administration of moderately emetogenic chemotherapy, followed by a subsequent 8-mg dose given 8 hours after first dose.³³ Continue with 8 mg every 12 hours for 1–2 days after completion of chemotherapy.³³

24 mg as a single dose given 30 minutes before administration of single-day highly emetogenic chemotherapy.³³

IV

0.15 mg/kg by IV infusion beginning 30 minutes before administration of emetogenic chemotherapy, followed by 0.15 mg/kg infused 4 and 8 hours after first dose.¹

Alternatively, 32 mg as a single dose by IV infusion beginning 30 minutes before administration of emetogenic chemotherapy.¹

Postoperative Nausea and Vomiting

Prevention

Oral

16 mg as a single dose given 1 hour before induction of anesthesia.³³

IV

4 mg as a single dose by IV injection (undiluted) immediately before induction of anesthesia.¹

Limited information available regarding dosage in patients weighing >80 kg.¹

IM

4 mg as a single dose by IM injection (undiluted) as an alternative to IV administration.¹

Limited information available regarding dosage in patients weighing >80 kg.¹

Treatment

IV

4 mg as a single dose by IV injection (undiluted) postoperatively, if nausea and/or vomiting occur shortly after surgery.¹

If adequate control of postoperative nausea and vomiting is not achieved after a single, prophylactic, preinduction IV dose, a second IV dose postoperatively does not provide additional control of nausea and vomiting.¹

Radiation-induced Nausea and Vomiting

Prevention, Usual Dosage

Oral

Usually, 8 mg 3 times daily.³³

Prevention, for Total Body Irradiation

Oral

8 mg 1–2 hours before each fraction of radiotherapy administered each day.³³

Prevention, for Single High-dose Fraction Radiation to Abdomen

Oral

8 mg 1–2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for 1–2 days after completion of radiotherapy.³³

Prevention, for Daily Fractionated Radiation to Abdomen

Oral

8 mg 1–2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for each day radiotherapy is given.³³

Special Populations

Hepatic Impairment

Do not exceed total daily dosage of 8 mg (parenteral or oral) in patients with severe hepatic impairment (Child-Pugh score ≥10); ^{1 33} no experience to date with continuation beyond the first day of IV therapy.¹

Renal Impairment

No dosage adjustment required, but no experience to date with continuation beyond the first day of therapy.³³

Geriatric Patients

No dosage adjustment required.^{1 33}

Cautions for Zofran

Contraindications

• 
  

  Known hypersensitivity to ondansetron.^{1 33}

  
  

Warnings/Precautions

Sensitivity Reactions

Sensitivity reactions, including anaphylactic reaction, angioedema, bronchospasm, cardiopulmonary arrest, hypotension, laryngeal edema, laryngospasm, shock, shortness of breath, and stridor, reported rarely.^{1 5 16 33 39}

Possible hypersensitivity reactions in patients who have exhibited hypersensitivity to other selective 5-HT₃ receptor antagonists.^{1 33}

General Precautions

GI Precautions

Does not stimulate gastric or intestinal peristalsis; do not use as a substitute for nasogastric suction.^{1 33}

May mask progressive ileus and/or gastric distention in patients undergoing abdominal surgery or in those with chemotherapy-induced nausea and vomiting.^{1 33}

Cardiac Effects

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Transient ECG alterations (e.g., QT interval prolongation) reported rarely, generally in patients receiving ondansetron IV.^{1 33}

Phenylketonuria

Each 4- or 8-mg Zofran ODT orally disintegrating tablet contains aspartame (Nutrasweet), which is metabolized in the GI tract to provide <0.03 mg of phenylalanine per tablet.³³

Specific Populations

Pregnancy

Category B.^{1 33}

Lactation

Distributed into milk in rats; not known whether distributed into human milk.^{1 33} Caution advised if used in nursing women.^{1 33}

Pediatric Use

Safety and efficacy of oral or IV ondansetron for prevention of chemotherapy-induced emesis generally comparable to that in adults.^{1 33}

Little information available on IV use for prevention of postoperative nausea and vomiting in pediatric patients <1 month of age or for prevention of chemotherapy-induced nausea and vomiting in pediatric patients <6 months of age.^{1 33} Little information available on oral dosage in children ≤4 years of age.³³

Because clearance is reduced in infants 1–4 months of age compared with those >4 to 24 months of age, closely monitor infants <4 months of age.¹ (See Half-life under Pharmacokinetics.)

Efficacy of single 24-mg oral dose for prevention of nausea and vomiting induced by highly emetogenic chemotherapy or oral therapy for prevention of radiation-induced or postoperative nausea and vomiting not established in children <18 years of age.³³

Geriatric Use

No substantial differences in safety or efficacy in patients >65 years of age relative to younger adults, but increased sensitivity cannot be ruled out.^{1 16 33}

Hepatic Impairment

Clearance is decreased and half-life increased in patients with hepatic impairment.^{1 33} Use with caution and at reduced dosage in patients with severe hepatic impairment.^{1 15 33} (See Special Populations under Dosage and Administration.)

Common Adverse Effects

Headache, diarrhea, dizziness, constipation, fever, drowsiness/sedation, shivers, malaise/fatigue, hypoxia, pyrexia, urinary retention, pruritus.^{1 33}

Interactions for Zofran

Substrate of CYP1A2, CYP2D6, and CYP3A4 in vitro; does not appear to induce or inhibit CYP isoenzymes.^{1 33}

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors or inducers of CYP1A2, CYP2D6, or CYP3A4; potential pharmacokinetic interaction (altered ondansetron metabolism).^{1 33} Based on available data, no dosage adjustment recommended for patients on these drugs.^{1 33}

Specific Drugs

Drug	Interaction	Comments
Alfentanil	No change in respiratory depressant effects of alfentanil1 33
Antacids	No effect on ondansetron bioavailability33
Atracurium	No change in degree of neuromuscular blockade produced by atracurium1 33
Carbamazepine	Substantial increase in ondansetron clearance (decreased AUC, peak plasma concentrations, and half-life)1 33	On basis of available data, no dosage adjustment recommended1 33
Carmustine	No effect on ondansetron pharmacokinetics1 33
Cisplatin	No effect on ondansetron pharmacokinetics1 33
Etoposide	No effect on ondansetron pharmacokinetics1 33
Methotrexate	IV ondansetron did not increase blood levels of high-dose methotrexate in pediatric patients1 33
Phenytoin	Substantial increase in ondansetron clearance (decreased AUC, peak plasma concentrations, and half-life)1 33	On basis of available data, no dosage adjustment recommended1 33
Rifampin	Decreased blood concentrations of ondansetron1 33	On basis of available data, no dosage adjustment recommended1 33
Temazepam	No effect on temazepam pharmacokinetics or pharmacodynamics1 33
Tramadol	No pharmacokinetic interaction observed, but possible increased tramadol dosage requirements for patient-controlled analgesia1 33

Zofran Pharmacokinetics

Absorption

Bioavailability

Well absorbed from GI tract after oral administration.³³ Mean bioavailability after administration of single 8-mg tablet is approximately 56%; increased bioavailability expected with dosages >8 mg.^{33 c}

Peak plasma concentrations are attained approximately 1.5–2.2 hours after oral administration, approximately 25 minutes after IV infusion, or 41 minutes after IM injection.^{1 33 c}

Commercially available oral solution and orally disintegrating tablets (4- or 8-mg doses) are bioequivalent to corresponding doses of conventional tablets.³³

Food

Food slightly increases bioavailability.³³

Special Populations

Extent and rate of absorption are increased in women compared with men; not known whether differences are clinically important.³³

Distribution

Extent

Circulating drug distributes into erythrocytes.³³

Distributed into milk in rats; not known whether distributed into human milk.³³

Plasma Protein Binding

70–76%.³³

Elimination

Metabolism

Extensively metabolized in the liver via hydroxylation followed by subsequent glucuronide or sulfate conjugation.³³ CYP isoenzymes 1A2, 2D6, and 3A4 are involved.^{1 33}

Exibits nonlinear pharmacokinetics, possibly due to saturation of hepatic metabolism.^c

Elimination Route

<5% of a dose is excreted unchanged in urine.¹

Half-life

Adults: Approximately 3–3.5 hours after single 8-mg oral dose; approximately 4 hours after IV administration.^{1 33 c}

Children and adolescents 3–18 years of age: 2.4–3 hours after IV administration.^{1 c}

Infants 5–24 months of age: 2.9 hours after IV administration.¹

Infants 1–4 months of age: 6.7 hours after IV administration.¹

Special Populations

In patients with mild to moderate hepatic impairment, clearance is decreased 2-fold and half-life increased to 11.6 hours.^{1 33} In patients with severe hepatic impairment (Child-Pugh score ≥10), clearance is decreased 2- to 3-fold and half-life increased to 20 hours.^{1 33}

Although renal clearance contributes minimally to overall clearance, mean plasma clearance is reduced by about 50% in patients with severe renal impairment (Cl_cr <30 mL/minute); reduction in clearance is variable and not consistent with an increase in half-life.^{1 33}

In geriatric patients >75 years of age, clearance is decreased and half-life is increased to 4.5–6.2 hours.^{1 33}

Stability

Storage

Oral

Conventional Tablets

Tight, light resistant containers at 2–30°C; protect from light.³³

Orally Disintegrating Tablets

2–30°C.³³

Solution

15–30°C; store bottles upright and protect from light.³³

Parenteral

Injection

2–30°C; protect from light.¹

Occasionally precipitates at the stopper/vial interface in vials stored upright; potency and safety not affected.¹ If precipitate is found, vigorously shake vial to resolubilize.¹

Premixed Injection

2–30°C. Protect from light; do not freeze; avoid excessive heat.¹

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Do not mix with solutions for which physical and chemical compatibility have not been established, particularly alkaline solutions, as precipitate may form.¹

Solution Compatibility

Compatible
Dextrose 5% in water1 d
Dextrose 5% in water with potassium chloride 0.3%d
Dextrose 5% in sodium chloride 0.45 of 0.9%1
Mannitol 10%d
Ringer’s injectiond
Ringer’s injection, lactatedd
Sodium chloride 0.9%1 d
Sodium chloride 0.9% with potassium chloride 0.3%d

Drug Compatibility

Admixture Compatibilityd

Compatible
Cisplatin
Cyclophosphamide
Cytarabine
Dacarbazine
Doxorubicin HCl
Doxorubicin HCl with vincristine sulfate
Etoposide
Fluconazole with ranitidine HCl
Hydromorphone HCl
Meperidine HCl
Methotrexate sodium
Morphine sulfate
Variable
Dacarbazine with doxorubicin HCl
Dexamethasone sodium phosphate
Meropenem

Y-Site Compatibilityd

Compatible
Aldesleukin
Amifostine
Amikacin sulfate
Azithromycin
Aztreonam
Bleomycin sulfate
Carboplatin
Carmustine
Cefazolin sodium
Cefotaxime sodium
Cefoxitin sodium
Ceftazidime
Ceftizoxime sodium
Cefuroxime sodium
Chlorpromazine HCl
Cimetidine HCl
Cisplatin
Cladribine
Clindamycin phosphate
Cyclophosphamide
Cytarabine
Dacarbazine
Dactinomycin
Daunorubicin HCl
Dexamethasone sodium phosphate
Dexmedetomidine HCl
Diphenhydramine HCl
Docetaxel
Dopamine HCl
Doxorubicin HCl
Doxorubicin HCl liposome injection
Doxycycline hyclate
Droperidol
Etoposide
Etoposide phosphate
Famotidine
Fenoldopam mesylate
Filgrastim
Floxuridine
Fluconazole
Fludarabine phosphate
Gallium nitrate
Gemcitabine HCl
Gentamicin sulfate
Haloperidol lactate
Heparin sodium
Hetastarch in lactated electrolyte injection (Hextend)
Hydrocortisone sodium phosphate
Hydrocortisone sodium succinate
Hydromorphone HCl
Hydroxyzine HCl
Ifosfamide
Imipenem–cilastatin sodium
Linezolid
Magnesium sulfate
Mannitol
Mechlorethamine HCl
Melphalan HCl
Meperidine HCl
Mesna
Methotrexate sodium
Metoclopramide HCl
Mitomycin
Mitoxantrone HCl
Morphine sulfate
Oxaliplatin
Paclitaxel
Paclitaxel with ranitidine HCl
Pentostatin
Piperacillin sodium–tazobactam sodium
Potassium chloride
Prochlorperazine edisylate
Promethazine HCl
Ranitidine HCl
Remifentanil HCl
Sodium acetate
Streptozocin
Teniposide
Thiotepa
Ticarcillin disodium
Ticarcillin disodium–clavulanate potassium
Topotecan HCl
Vancomycin HCl
Vinblastine sulfate
Vincristine sulfate
Vinorelbine tartrate
Zidovudine
Incompatible
Acyclovir sodium
Allopurinol sodium
Aminophylline
Amphotericin B
Amphotericin B cholesteryl sulfate complex
Ampicillin sodium
Ampicillin sodium–sulbactam sodium
Amsacrine
Cefepime HCl
Furosemide
Ganciclovir sodium
Lansoprazole
Lorazepam
Methylprednisolone sodium succinate
Pemetrexed disodium
Sargramostim
Sodium bicarbonate
Variable
Fluorouracil
Meropenem

Actions

• 
  

  Antiemetic activity appears to be mediated both centrally (in medullary chemoreceptor trigger zone) and peripherally (in GI tract) via inhibition of 5-HT₃ receptors.^{27 43 44 45 47 50 51 67 68}

  
  

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

  For patients taking orally disintegrating tablets, importance of not removing tablet from blister until just before administering dose and of not pushing tablet through foil; importance of opening blister pack with dry hands and of placing tablet on tongue to dissolve and be swallowed with saliva.³³

  
  


• 
  

  Importance of informing patients with phenylketonuria that orally disintegrating tablets contain aspartame.³³

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 33}

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.^{1 33}

  
  


• 
  

  Importance of advising patients of other important precautionary information.^{1 33} (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Ondansetron

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, orally disintegrating	4 mg	ZofranODT (with aspartame and paraben)	GlaxoSmithKline
		8 mg	ZofranODT (with aspartame and paraben)	GlaxoSmithKline

Ondansetron Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Solution	4 mg (of ondansetron) per 5 mL	Zofran	GlaxoSmithKline
	Tablets, film-coated	4 mg (of ondansetron)	Zofran	GlaxoSmithKline
		8 mg (of ondansetron)	Zofran	GlaxoSmithKline
Parenteral	Injection, for IV use	2 mg (of ondansetron) per mL	Zofran	GlaxoSmithKline

Ondansetron Hydrochloride in Dextrose 5%

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection, for IV infusion only	0.64 mg/mL of ondansetron (32 mg) in Dextrose 5%	Zofran Injection Premixed	GlaxoSmithKline

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Ondansetron 4MG Dispersible Tablets (MYLAN): 30/$52.99 or 90/$138.97

Ondansetron 8MG Dispersible Tablets (SANDOZ): 30/$40.99 or 90/$99.99

Ondansetron HCl 4MG Tablets (SANDOZ): 30/$70.99 or 90/$186.97

Ondansetron HCl 8MG Tablets (ACTAVIS TOTOWA): 30/$39.99 or 90/$99.97

Zofran 4MG Tablets (GLAXO SMITH KLINE): 10/$245.00 or 30/$702.93

Zofran 8MG Tablets (GLAXO SMITH KLINE): 30/$1,169.91 or 90/$3,403.36

Zofran ODT 4MG Dispersible Tablets (GLAXO SMITH KLINE): 30/$659.95 or 90/$1,909.91

Zofran ODT 8MG Dispersible Tablets (GLAXO SMITH KLINE): 10/$415.97 or 30/$1,209.95

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions September 15, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. GlaxoSmithKline. Zofran (ondansetron hydrochloride) injection and injection premixed prescribing information. Research Triangle Park, NC; 2006 Feb.

2. Glaxo, Research Triangle Park, NC: Personal communication.

3. Milne RJ, Heel RC. Ondansetron: therapeutic use as an antiemetic. Drugs. 1991; 41:574-95. [PubMed 1711961]

4. Dershwitz M, Rosow CE, Di Biase PM et al. Ondansetron is effective in decreasing postoperative nausea and vomiting. Clin Pharmacol Ther. 1992; 52:96-101. [IDIS 299623] [PubMed 1385567]

5. Chen M, Tanner A, Gallo-Torres H. Anaphylactoid-anaphylactic reactions associated with ondansetron. Ann Intern Med. 1993; 119:862. [IDIS 320846] [PubMed 8379613]

6. Beck TM, Ciociola AA, Jones SE et al. Efficacy of oral ondansetron in the prevention of emesis in outpatients receiving cyclophosphamide-based chemotherapy. Ann Intern Med. 1993; 118:407-13. [IDIS 311537] [PubMed 8439113]

7. Sargent AI, Deppe SA, Chan FA. Seizure associated with ondansetron. Clin Pharm. 1993; 12:613-5. [IDIS 317861] [PubMed 8222528]

8. Herrstedt J, Sigsgaard T, Boesgaard M et al. Ondansetron plus metopimazine compared with ondansetron alone in patients receiving moderately emetogenic chemotherapy. N Engl J Med. 1993; 328:1076-80. [IDIS 312366] [PubMed 8455664]

9. Pritchard JF, Bryson JC, Kernodle AE et al. Age and gender effects on ondansetron pharmacokinetics: evaluation of healthy aged volunteers. Clin Pharmacol Ther. 1992; 41:51-5.

10. Jones AL, Hill AS, Soukop M et al. Comparison of dexamethasone and ondansetron in the prophylaxis of emesis induced by moderately emetogenic chemotherapy. Lancet. 1991; 338:483-7. [IDIS 284480] [PubMed 1678453]

11. Scuderi P, Wetchler B, Sung YF et al. Treatment of postoperative nausea and vomiting after outpatient surgery with the 5-HT₃ antagonist ondansetron. Anesthesiology. 1993; 78:15-20. [IDIS 309383] [PubMed 8424548]

12. McKenzie R, Kovac A, O’Connor T et al. Comparison of ondansetron versus placebo to prevent postoperative nausea and vomiting in women undergoing ambulatory gynecologic surgery. Anesthesiology. 1993; 78:21-8. [IDIS 309384] [PubMed 8424561]

13. Ballard HS, Bottino G, Bottino J. Ondansetron and chest pain. Lancet. 1992; 340:1107. [IDIS 304614] [PubMed 1357506]

14. Bryson JC. Clinical safety of ondansetron. Semin Oncol. 1992; 19(Suppl 15):26-32. [PubMed 1485179]

15. Castle WM, Jukes AJ, Griffiths CJ et al. Safety of ondansetron. Eur J Anaesthesiol. 1992; 9(Suppl 6):63-6. [PubMed 1735399]

16. Finn AL. Toxicity and side effects of ondansetron. Semin Oncol. 1992; 19(Suppl 10):53-60. [PubMed 1387251]

17. Smith RN. Safety of ondansetron. Eur J Cancer Clin Oncol. 1989; 25(Suppl 1):S47-50. [PubMed 2533899]

18. Krstenansky PM, Petree J, Long G. Extrapyramidal reaction caused by ondansetron. Ann Pharmacother. 1994; 28:280. [IDIS 325871] [PubMed 8173151]

19. Halperin JR, Murphy B. Extrapyramidal reaction to ondansetron. Cancer. 1992; 69:1275. [IDIS 292533] [PubMed 1531444]

20. Dobrow RB, Coppock MA, Hosenpud JR. Extrapyramidal reaction caused by ondansetron. J Clin Oncol. 1991; 9:1921. [PubMed 1833512]

21. Garcia-del-Muro X, Cardenal F, Ferrer P. Extrapyramidal reaction associated with ondansetron. Eur J Cancer. 1993; 29A:288. [PubMed 8422300]

22. Siderov J, Zalcberg J, Chambers B et al. Migraine following the use of a 5-hydroxytryptamine antagonist. Aust N Z J Med. 1993; 23:527-8. [PubMed 8297291]

23. Mitchell KE, Popkin MK, Trick W et al. Psychiatric complications associated with ondansetron. Psychosomatics. 1994; 35:161-3. [PubMed 8171176]

24. Tsidonis O. Ondansetron-induced jaundice. ASHP Midyear Clinical Meeting. Dec 6-10, 1992. Abstract No. P-411D.

25. McQueen KD, Milton JD. Multicenter postmarketing surveillance of ondansetron therapy in pediatric patients. Ann Pharmacother. 1994; 28:85-92. [IDIS 324489] [PubMed 8123969]

26. Stevens RF. The role of ondansetron in paediatric patients: a review of three studies. Eur J Cancer. 1991; 27(Suppl 1):S20-2. [PubMed 1831631]

27. De Mulder PHM, Seynaeve C, Vermorken JB et al. Ondansetron compared with high-dose metoclopramide in prophylaxis of acute and delayed cisplatin-induced nausea and vomiting: a multicenter, randomized, double-blind, crossover study. Ann Intern Med. 1990; 113:834-40. [IDIS 274419] [PubMed 2146911]

28. Sledge GW Jr, Einhorn L, Nagy C et al. Phase III double-blind comparison of intravenous ondansetron and metoclopramide as antiemetic therapy for patients receiving multiple-day cisplatin-based chemotherapy. Cancer. 1992; 70:2524-8. [IDIS 305314] [PubMed 1423181]

29. Grunberg SM, Lane M, Lester EP et al. Randomized double-blind comparison of three dose levels of intravenous ondansetron in the prevention of cisplatin-induced emesis. Cancer Chemother Pharmacol. 1993; 32:268-72. [PubMed 8324868]

30. Hesketh PJ, Harvey WH, Harker WG et al. A randomized, double-blind comparison of intravenous ondansetron alone and in combination with intravenous dexamethasone in the prevention of high-dose cisplatin-induced emesis. J Clin Oncol. 1994; 12:596-600. [IDIS 327016] [PubMed 8120559]

31. Cubeddu LX, Pendergrass K, Ryan T et al. Efficacy of oral ondansetron, a selective antagonist of 5-HT₃ receptors, in the treatment of nausea and vomiting associated with cyclophosphamide-based chemotherapies. Am J Clin Oncol. 1994; 17:137-46. [IDIS 329907] [PubMed 8141105]

32. Pearman MH. Single dose intravenous ondansetron in the prevention of postoperative nausea and vomiting. Anaesthesia. 1994; 49(Suppl):11-5. [IDIS 325312] [PubMed 8129156]

33. GlaxoSmithKline. Zofran (ondansetron hydrochloride) tablets, Zofran ODT (ondansetron) orally disintegrating tablets, and Zofran (ondansetron hydrochloride) oral solution prescribing information. Research Triangle Park, NC; 2006 Feb.

34. Rust M, Cohen LA. Single oral dose ondansetron in the prevention of postoperative nausea and emesis. Anaesthesia. 1994; 49(Suppl):16-23. [IDIS 325313] [PubMed 8129157]

35. Kris MG, Gralla RJ, Clark RA et al. Dose-ranging evaluation of the serotonin antagonist GR-C507/75 (GR38032F) when used as an antiemetic in patients receiving anticancer chemotherapy. J Clin Oncol. 1988; 6:659-62. [PubMed 2965755]

36. Rosso R, Campora E, Cetto G et al. Oral ondansetron (GR 38032F) for the control of acute and delayed cyclophosphamide-induced emesis. Anticancer Res. 1991; 11:937-40. [PubMed 1829602]

37. Smith DB, Newlands ES, Rustin GJS et al. A phase I/II study of the 5-HT3 antagonist GR38032F in the anti-emetic prophylaxis of patients receiving high-dose cisplatin chemotherapy. Cancer Chemother Pharmacol. 1990; 25:291-4. [PubMed 1688516]

38. Kaasa S, KvalQy S, Dicato MA et al. A comparison of ondansetron with metoclopramide in the prophylaxis of chemotherapy-induced nausea and vomiting: a randomized, double-blind study. Eur J Cancer. 1990; 26:311-4. [PubMed 2141487]

39. Grunberg SM, Stevenson LL, Russell CA et al. Dose ranging phase I study of the serotonin antagonist GR38032F for prevention of cisplatin-induced nausea and vomiting. J Clin Oncol. 1989; 7:1137-41. [PubMed 2526864]

40. Hesketh PJ, Murphy WK, Lester EP et al. GR 38032F (GR-C507/75): a novel compound effective in the prevention of acute cisplatin-induced emesis. J Clin Oncol. 1989; 7:700-5. [PubMed 2523957]

41. Einhorn LH, Nagy C, Werner K et al. Ondansetron: a new antiemetic for patients receiving cisplatin chemotherapy. J Clin Oncol. 1990; 8:731-5. [PubMed 2138214]

42. Baltzer L, Kris MG, Hinkley L et al. Reversible electrocardiographic interval prolongations following the specific serotonin antagonists ondansetron (OND) and dolasetron mesylate (DM): a pos