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Special Alerts

The Food and Drug Administration (FDA) is notifying healthcare providers that ondansetron hydrochloride (Zofran®) 32 mg single premixed intravenous doses in a sodium chloride or dextrose solution will no longer be marketed because of the potential for QT prolongation, which can lead to torsade de pointes, a potentially fatal abnormal heart rhythm. The I.V. 32 mg dose has been removed from GlaxoSmithKline's ondansetron (Zofran®) labeling. The FDA is working with the manufacturers of all ondansetron 32 mg, premixed single-dose injectable products to voluntarily recall them from the market. The FDA anticipates these products will be removed from the market through early 2013 and does not expect this recall to contribute to a drug shortage.

The approved labeling continues to recommend I.V. ondansetron for the prevention of chemotherapy induced nausea and vomiting at 0.15 mg/kg every 4 hours for 3 doses. No single I.V. dose should exceed 16 mg. Oral dosing labeling for ondansetron is unchanged.

Further information may be found at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm330772.htm.

Previously, in September 2011, the U.S. Food and Drug Administration (FDA) notified healthcare professionals about an ongoing safety review of the risk of QT prolongation with ondansetron. At that time, the FDA required GlaxoSmithKline (manufacturer of Zofran®) to conduct an in-depth study on the effects of ondansetron on the QT interval. Recent preliminary study results suggest that a single intravenous dose of ondansetron (Zofran®) 32 mg may prolong the QT interval, which could predispose patients to development of torsade de pointes. Those most at risk include patients with congenital long QT syndrome, heart failure, bradyarrhythmias, electrolyte abnormalities (ie, hypokalemia, hypomagnesemia), and concomitant use of other QT-prolonging medications. GlaxoSmithKline has announced changes to ondansetron labeling to remove the 32 mg single intravenous dose. Updated labeling will also state that ondansetron 0.15 mg/kg can be administered to patients with chemotherapy-induced nausea and vomiting every 4 hours for 3 doses, but no single intravenous dose should exceed 16 mg. The labeling for oral ondansetron will not be changed.

Further information may be found at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm310219.htm?source=govdelivery

Drug Shortages

One or more forms of this drug may be in short supply or unavailable. Refer to the following for additional information:

ASHP: http://www.ashp.org/menu/DrugShortages

FDA: http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm314742.htm#ondansetron or http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm314742.htm#ondansetron32

Pronunciation

(on DAN se tron)

Brand Names: U.S.

• Zofran®
• Zofran® ODT
• Zuplenz®

Brand Names: Canada

• Apo-Ondansetron®
• CO Ondansetron
• Dom-Ondansetron
• JAMP-Ondansetron
• Mint-Ondansetron
• Mylan-Ondansetron
• Ondansetron Injection
• Ondansetron Injection USP
• Ondansetron-Odan
• Ondansetron-Omega
• PHL-Ondansetron
• PMS-Ondansetron
• RAN™-Ondansetron
• ratio-Ondansetron
• Sandoz-Ondansetron
• Teva-Ondansetron
• Zofran®
• Zofran® ODT
• ZYM-Ondansetron

Pharmacologic Category

• Antiemetic
• Selective 5-HT₃ Receptor Antagonist

Dosing: Adult

Prevention of nausea and vomiting associated with emetogenic chemotherapy:

Manufacturer's labeling:

I.V.: 0.15 mg/kg/dose (maximum: 16 mg/dose) over 15 minutes for 3 doses, beginning 30 minutes prior to chemotherapy, followed by subsequent doses 4 and 8 hours after the first dose

Highly-emetogenic agents/single-day therapy: Oral: 24 mg given as three 8 mg tablets 30 minutes prior to the start of therapy

Moderately-emetogenic agents: Oral: 8 mg beginning 30 minutes before chemotherapy; repeat dose 8 hours after initial dose, then 8 mg every 12 hours for 1-2 days after chemotherapy completed

American Society of Clinical Oncology Antiemetic Guideline recommendations (Basch, 2011): High emetic risk: Day(s) chemotherapy is administered:

I.V.: 8 mg or 0.15 mg/kg. Note: Single I.V. doses >16 mg are no longer recommended by the manufacturer due to the potential for QT prolongation.

Oral: 8 mg twice daily

Prevention of nausea and vomiting associated with radiation therapy:

Manufacturer's labeling:

Total body irradiation: Oral: 8 mg 1-2 hours before each daily fraction of radiotherapy

Single high-dose fraction radiotherapy to abdomen: Oral: 8 mg 1-2 hours before irradiation, then 8 mg every 8 hours after first dose for 1-2 days after completion of radiotherapy

Daily fractionated radiotherapy to abdomen: Oral: 8 mg 1-2 hours before irradiation, then 8 mg every 8 hours after first dose for each day of radiotherapy

American Society of Clinical Oncology Antiemetic Guideline recommendations (Basch, 2011): Give before each fraction throughout radiation therapy for high emetic risk (continue for at least 24 hours after completion) and for moderate emetic risk; for low emetic risk, may give either as prevention or rescue; for minimal emetic risk, give as rescue (if rescue used for either low or minimal emetic risk, then prophylaxis should be given until the end of radiation therapy):

I.V. (unlabeled route/dosing): 8 mg or 0.15 mg/kg. Note: Single I.V. doses >16 mg are no longer recommended by the manufacturer due to the potential for QT prolongation.

Oral: 8 mg twice daily

Postoperative nausea and vomiting (PONV):

Oral: 16 mg given 1 hour prior to induction of anesthesia

I.M., I.V.: 4 mg as a single dose (over 2-5 minutes if giving I.V.) administered ~30 minutes before the end of anesthesia (see Note below) or as treatment if vomiting occurs after surgery (Gan, 2007).

Note: The manufacturer recommends administration immediately before induction of anesthesia; however, this has been shown not to be as effective as administration at the end of surgery (Sun, 1997). Repeat doses given in response to inadequate control of nausea/vomiting from preoperative doses are generally ineffective.

Treatment of severe or refractory hyperemesis gravidum (unlabeled use):

Oral: 8 mg every 12 hours (Levichek, 2002)

I.V.: 8 mg administered over 15 minutes every 12 hours (ACOG, 2004)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Prevention of nausea and vomiting associated with emetogenic chemotherapy: I.V.: Children 6 months to 18 years: 0.15 mg/kg/dose (maximum: 16 mg/dose) over 15 minutes for 3 doses, beginning with the first dose administered 30 minutes prior to chemotherapy, followed by subsequent doses administered 4 and 8 hours after the first dose

Prevention of nausea and vomiting associated with moderately-emetogenic chemotherapy: Oral:

4-11 years: 4 mg 30 minutes before chemotherapy; repeat 4 and 8 hours after initial dose, then 4 mg every 8 hours for 1-2 days after chemotherapy completed

≥12 years: Refer to adult dosing.

Prevention of postoperative nausea and vomiting (PONV): I.V.: Children 1 month to 12 years:

≤40 kg: 0.1 mg/kg as a single dose over 2-5 minutes

>40 kg: 4 mg as a single dose over 2-5 minutes

Dosing: Renal Impairment

No dosage adjustment necessary (there is no experience for oral ondansetron beyond day 1)

Dosing: Hepatic Impairment

Severe impairment (Child-Pugh C):

I.V.: Day 1: Maximum dose: 8 mg (there is no experience beyond day 1)

Oral: Maximum daily dose: 8 mg

Use: Labeled Indications

I.V.: Prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy (including high-dose cisplatin); prevention of postoperative nausea and/or vomiting (PONV); treatment of PONV if no prophylactic dose of ondansetron received

Oral: Prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy (including high-dose cisplatin); prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy; prevention of nausea and vomiting associated with radiotherapy (either total body irradiation, single high-dose fraction to the abdomen, or daily fractions to the abdomen); prevention of PONV

Use: Unlabeled

Hyperemesis gravidarum (severe or refractory); breakthrough treatment of nausea and vomiting associated with chemotherapy

Clinical Practice Guidelines

Antiemetics:

American Society of Clinical Oncology Clinical Practice Guideline Update, 2011

Multinational Association of Supportive Care in Cancer (MASCC)/European Society for Medical Oncology (ESMO), “Antiemetic Guidelines,” Updated 2011

National Comprehensive Cancer Network® (NCCN), Clinical Practice Guidelines in Oncology™, Antiemesis

Administration: I.M.

Should be given undiluted.

Administration: I.V.

IVPB: Infuse diluted solution over 15-30 minutes; 24-hour continuous infusions have been reported, but are rarely used.

Chemotherapy-induced nausea and vomiting: Give first dose 30 minutes prior to beginning chemotherapy.

I.V. push: Prevention of postoperative nausea and vomiting: Single doses may be administered I.V. injection over 2-5 minutes as undiluted solution.

Administration: I.V. Detail

pH: 3-4

Administration: Oral

Oral dosage forms should be given 30 minutes prior to chemotherapy; 1-2 hours before radiotherapy; 1 hour prior to the induction of anesthesia

Orally-disintegrating tablets: Do not remove from blister until needed. Peel backing off the blister, do not push tablet through. Using dry hands, place tablet on tongue and allow to dissolve. Swallow with saliva.

Oral soluble film: Do not remove from pouch until immediately before use. Using dry hands, place film on top of tongue and allow to dissolve (4-20 seconds). Swallow with or without liquid. If using more than one film, each film should be allowed to dissolve completely before administering the next film.

Dietary Considerations

Take without regard to meals. Some products may contain phenylalanine.

Storage

Oral soluble film: Store between 20°C and 25°C (68°F and 77°F). Store pouches in cartons; keep film in individual pouch until ready to use.

Oral solution: Store between 15°C and 30°C (59°F and 86°F). Protect from light.

Tablet: Store between 2°C and 30°C (36°F and 86°F).

Vial: Store between 2°C and 30°C (36°F and 86°F). Protect from light. Stable when mixed in D₅W or NS for 48 hours at room temperature.

Reconstitution

Prior to I.V. infusion, dilute in 50 mL D₅W or NS.

Compatibility

Stable in D₅ ¹/₂NS, D₅NS, D₅W, mannitol 10%, LR, NS; do not mix injection with alkaline solutions.

Y-site administration: Compatible: Aldesleukin, amifostine, amikacin, azithromycin, aztreonam, bleomycin, carboplatin, carmustine, caspofungin, cefazolin, cefotaxime, cefoxitin, ceftazidime, cefuroxime, chlorpromazine, cimetidine, cisatracurium, cisplatin, cladribine, clindamycin, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, dexamethasone sodium phosphate, dexmedetomidine, diphenhydramine, docetaxel, dopamine, doripenem, doxorubicin, doxorubicin liposome, doxycycline, droperidol, etoposide, etoposide phosphate, famotidine, fenoldopam, filgrastim, floxuridine, fluconazole, fludarabine, gallium nitrate, gemcitabine, gentamicin, haloperidol, heparin, hetastarch in lactate electrolyte injection (Hextend®), hydrocortisone sodium phosphate, hydrocortisone sodium succinate, hydromorphone, hydroxyzine, ifosfamide, imipenem/cilastatin, linezolid, magnesium sulfate, mannitol, mechlorethamine, melphalan, meperidine, mesna, methotrexate, metoclopramide, mitomycin, mitoxantrone, morphine, oxaliplatin, paclitaxel, paclitaxel with ranitidine, pentostatin, piperacillin/tazobactam, potassium chloride, prochlorperazine edisylate, promethazine, ranitidine, remifentanil, sodium acetate, streptozocin, telavancin, teniposide, thiotepa, ticarcillin/clavulanate, topotecan, vancomycin, vinblastine, vincristine, vinorelbine, zidovudine. Incompatible: Acyclovir, allopurinol, aminophylline, amphotericin B, amphotericin B cholesteryl sulfate complex, ampicillin, ampicillin/sulbactam, amsacrine, cefepime, furosemide, ganciclovir, lorazepam, methylprednisolone sodium succinate, micafungin, pemetrexed, sargramostim, sodium bicarbonate. Variable (consult detailed reference): Cyclosporine, fluorouracil, fosaprepitant, meropenem, piperacillin.

Compatibility in syringe: Compatible: Alfentanil, atropine, fentanyl, glycopyrrolate, meperidine, metoclopramide, midazolam, morphine, naloxone, neostigmine, propofol. Incompatible: Phenytoin. Variable (consult detailed reference): Dexamethasone sodium phosphate, droperidol.

Extemporaneously Prepared

Note: Commercial oral solution is available (0.8 mg/mL)

If commercial oral solution is unavailable, a 0.8 mg/mL syrup may be made with ondansetron tablets, Ora-Plus® (Paddock), and any of the the following syrups: Cherry syrup USP, Syrpalta® (HUMCO), Ora-Sweet® (Paddock), or Ora-Sweet® Sugar-Free (Paddock). Crush ten 8 mg tablets in a mortar and reduce to a fine powder (flaking of the tablet coating occurs). Add 50 mL Ora-Plus® in 5 mL increments, mixing thoroughly; mix while adding the chosen syrup in incremental proportions to almost 100 mL; transfer to a calibrated bottle, rinse mortar with syrup, and add sufficient quantity of syrup to make 100 mL. Label "shake well" and "refrigerate". Stable for 42 days refrigerated (Trissel, 1996).

Rectal suppositories: Calibrate a suppository mold for the base being used. Determine the displacement factor (DF) for ondansetron for the base being used (Fattibase® = 1.1; Polybase® = 0.6). Weigh the ondansetron tablet(s). Divide the tablet weight by the DF; this result is the weight of base displaced by the drug. Subtract the weight of base displaced from the calculated weight of base required for each suppository. Grind the ondansetron tablets in a mortar and reduce to a fine powder. Weigh out the appropriate weight of suppository base. Melt the base over a water bath (<55°C). Add the ondansetron powder to the suppository base and mix well. Pour the mixture into the suppository mold and cool. Stable for at least 30 days refrigerated (Tenjarla, 1998).

Medication Safety Issues

Ondansetron may be confused with dolasetron, granisetron, palonosetron

Zofran® may be confused with Zantac®, Zosyn®

Contraindications

Hypersensitivity to ondansetron or any component of the formulation; concomitant use of apomorphine

Warnings/Precautions

Concerns related to adverse effects:

• Allergic reactions: Use with caution in patients allergic to other 5-HT₃ receptor antagonists; cross-reactivity has been reported.

• QT prolongation: Dose-dependent QT interval prolongation occurs with ondansetron use. Cases of torsade de pointes have also been reported to the manufacturer. Selective 5-HT₃ antagonists, including ondansetron, have been associated with a number of dose-dependent increases in ECG intervals (eg, PR, QRS duration, QT/QT_c, JT), usually occurring 1-2 hours after I.V. administration. Single doses >16 mg ondansetron I.V. are no longer recommended due to the potential for an increased risk of QT prolongation. In most patients, these changes are not clinically relevant; however, when used in conjunction with other agents that prolong these intervals or in those at risk for QT prolongation, arrhythmia may occur. When used with agents that prolong the QT interval (eg, Class I and III antiarrhythmics) or in patients with cardiovascular disease, clinically relevant QT interval prolongation may occur resulting in torsade de pointes. A number of trials have shown that 5-HT₃ antagonists produce QT interval prolongation to variable degrees. Avoid ondansetron use in patients with congenital long QT syndrome. Use caution and monitor ECG in patients with other risk factors for QT prolongation (eg, medications known to prolong QT interval, electrolyte abnormalities [hypokalemia or hypomagnesemia], heart failure, bradyarrhythmias, and cumulative high-dose anthracycline therapy). Reduction in heart rate may also occur with the 5-HT₃ antagonists. I.V. formulations of 5-HT₃ antagonists have more association with ECG interval changes, compared to oral formulations.

Disease-related concerns:

• Hepatic impairment: Dose limitations are recommended for patients with severe hepatic impairment (Child-Pugh class C); use with caution in mild-moderate hepatic impairment; clearance is decreased and half-life increased in hepatic impairment.

Dosage form specific issues:

• Phenylalanine: Orally-disintegrating tablets contain phenylalanine.

Other warnings/precautions:

• Chemotherapy-associated emesis: For chemotherapy, should be used on a scheduled basis, not on an “as needed” (PRN) basis, since data support the use of this drug only in the prevention of nausea and vomiting (due to antineoplastic therapy) and not in the rescue of nausea and vomiting. Should only be used in the first 24-48 hours of chemotherapy. Data does not support any increased efficacy in delayed nausea and vomiting.

• Ileus or gastric distention: Does not stimulate gastric or intestinal peristalsis; may mask progressive ileus and/or gastric distension.

Geriatric Considerations

Elderly have a slightly decreased hepatic clearance rate. This does not, however, require a dose adjustment.

Pregnancy Risk Factor

B

Pregnancy Considerations

Teratogenic effects were not observed in animal reproduction studies. Ondansetron readily crosses the human placenta in the first trimester of pregnancy and can be detected in fetal tissue (Siu, 2006). The use of ondansetron for the treatment of nausea and vomiting of pregnancy (NVP) has been evaluated. Although a significant increase in birth defects has not been described in case reports and some studies (Ferreira, 2012; Pasternak, 2013), other studies have shown a possible association with ondansetron exposure and adverse fetal events (Anderka, 2012; Einarson, 2004). Additional studies are needed to determine safety to the fetus, particularly during the first trimester. Based on available data, use is generally reserved for severe NVP (hyperemesis gravidarum) or when conventional treatments are not effective (ACOG, 2004; Koren, 2012; Levicheck, 2002; Tan, 2011). Because a dose-dependent QT-interval prolongation occurs with use, the manufacturer recommends ECG monitoring in patients with electrolyte abnormalities (which can be associated with some cases of NVP; Koren, 2012).

Lactation

Excretion in breast milk unknown/use caution

Breast-Feeding Considerations

It is not known if ondansetron is excreted into breast milk. The manufacturer recommends caution be used if administered to nursing women.

Adverse Reactions

Note: Percentages reported in adult patients.

>10%:

Central nervous system: Headache (9% to 27%), malaise/fatigue (9% to 13%)

Gastrointestinal: Constipation (6% to 11%)

1% to 10%:

Central nervous system: Drowsiness (8%), fever (2% to 8%), dizziness (7%), anxiety (6%), cold sensation (2%)

Dermatologic: Pruritus (2% to 5%), rash (1%)

Gastrointestinal: Diarrhea (2% to 7%)

Genitourinary: Gynecological disorder (7%), urinary retention (5%)

Hepatic: ALT increased (>2 times ULN: 1% to 5%), AST increased (>2 times ULN: 1% to 5%)

Local: Injection site reaction (4%; pain, redness, burning)

Neuromuscular & skeletal: Paresthesia (2%)

Respiratory: Hypoxia (9%)

<1%, postmarketing, and/or case reports: Abnormal hepatic function, anaphylactoid reactions, anaphylaxis, angina, angioedema, arrhythmia, arthralgia, atrial fibrillation, AV block, blindness (transient/following infusion; lasting ≤48 hours), blurred vision (transient/following infusion), bradycardia, bronchospasm, cardiopulmonary arrest, chest discomfort, chills, dyspnea, dystonic reaction, electrocardiographic alterations (second-degree heart block and ST-segment depression), extrapyramidal symptoms, flushing, hepatic failure, hepatic necrosis, hepatitis, hiccups, hyperhidrosis, hypersensitivity reaction, hypokalemia, hypotension, jaundice, laryngeal edema, laryngospasm, lethargy, oculogyric crisis, palpitation, premature ventricular contractions (PVC), QT interval increased, seizure, shock, stridor, supraventricular tachycardia, syncope, tachycardia, torsade de pointes, urticaria, vascular occlusive events, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia

Allergy and Idiosyncratic Reactions

Serotonin 5-HT₃ Antagonist Allergy

Metabolism/Transport Effects

Substrate of CYP1A2 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP2E1 (minor), CYP3A4 (major), P-glycoprotein; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP1A2 (weak), CYP2C9 (weak), CYP2D6 (weak)

Drug Interactions

Apomorphine: Antiemetics (5HT3 Antagonists) may enhance the hypotensive effect of Apomorphine. Risk X: Avoid combination

ARIPiprazole: CYP2D6 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Risk D: Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Management: Consider avoiding CYP3A4 inducing herbs in order to avoid therapeutic failure of the substrate. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Risk D: Consider therapy modification

Highest Risk QTc-Prolonging Agents: Moderate Risk QTc-Prolonging Agents may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Risk X: Avoid combination

Ivabradine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Risk X: Avoid combination

Mifepristone: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Risk X: Avoid combination

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Moderate Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Risk D: Consider therapy modification

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Risk C: Monitor therapy

Rifamycin Derivatives: May increase the metabolism of Antiemetics (5HT3 Antagonists). Risk C: Monitor therapy

Tapentadol: Antiemetics (5HT3 Antagonists) may diminish the analgesic effect of Tapentadol. Risk C: Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

TraMADol: Antiemetics (5HT3 Antagonists) may diminish the analgesic effect of TraMADol. Risk C: Monitor therapy

Ethanol/Nutrition/Herb Interactions

Food: Tablet: Food slightly increases the extent of absorption.

Herb/Nutraceutical: St John's wort may decrease ondansetron levels.

Monitoring Parameters

ECG (if applicable in high risk patients); potassium, magnesium

Nursing: Physical Assessment/Monitoring

Assess allergy history (selective 5-HT₃ receptor antagonists) prior to administering. Avoid use in presence of, or potential for, cardiac conduction abnormalities (eg, QT prolongation, medication known to prolong QT interval, electrolyte abnormalities). Oral and I.V. doses have different schedules and should not be administered on "PRN" basis.

Patient Education

Discuss specific use of drug and side effects with patient as it relates to treatment. Patient may experience headache, asthenia, constipation, dizziness, presyncope, fatigue, blurred vision, or illogical thinking. Have patient report immediately to prescriber tachycardia or rash. Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Film, soluble, oral:

Zuplenz®: 4 mg (10s); 8 mg (10s) [peppermint flavor]

Infusion, premixed in D₅W [preservative free]: 32 mg (50 mL [DSC])

Zofran®: 32 mg (50 mL [DSC])

Infusion, premixed in NS [preservative free]: 32 mg (50 mL)

Injection, solution: 2 mg/mL (2 mL, 20 mL)

Zofran®: 2 mg/mL (20 mL)

Injection, solution [preservative free]: 2 mg/mL (2 mL)

Solution, oral: 4 mg/5 mL (5 mL, 50 mL)

Zofran®: 4 mg/5 mL (50 mL) [contains sodium benzoate; strawberry flavor]

Tablet, oral: 4 mg, 8 mg

Zofran®: 4 mg, 8 mg

Tablet, orally disintegrating, oral: 4 mg, 8 mg

Zofran® ODT: 4 mg, 8 mg [contains phenylalanine <0.03 mg/tablet; strawberry flavor]

Anatomic Therapeutic Chemical (ATC) Classification

Generic Available (U.S.)

Yes: Excludes oral soluble film

Pricing: U.S. (Medi-Span®)

Film (Zuplenz Oral)

4 mg (1): $15.63

8 mg (1): $15.63

Solution (Ondansetron HCl Injection)

4 mg/2 mL (2 mL): $1.14

40 mg/20 mL (20 mL): $24.30

Solution (Ondansetron HCl Oral)

4 mg/5 mL (50 mL): $239.82

Solution (Ondansetron HCl-NaCl Intravenous)

32 mg/50 mL (50 mL): $43.20

Solution (Zofran Injection)

40 mg/20 mL (20 mL): $256.40

Solution (Zofran Oral)

4 mg/5 mL (50 mL): $269.74

Tablet, orally-disintegrating (Ondansetron Oral)

4 mg (30): $668.78

8 mg (30): $1113.95

Tablet, orally-disintegrating (Zofran ODT Oral)

4 mg (30): $752.17

8 mg (30): $1252.86

Tablets (Ondansetron HCl Oral)

4 mg (30): $735.05

8 mg (30): $1217.42

24 mg (1): $105.50

Tablets (Zofran Oral)

4 mg (3): $79.73

8 mg (30): $1328.09

Mechanism of Action

Selective 5-HT₃-receptor antagonist, blocking serotonin, both peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone

Pharmacodynamics/Kinetics

Onset of action: ~30 minutes

Absorption: Oral: Well absorbed from GI tract

Distribution: V_d: Children: 1.7-3.7 L/kg; Adults: 2.2-2.5 L/kg

Protein binding, plasma: 70% to 76%

Metabolism: Extensively hepatic via hydroxylation, followed by glucuronide or sulfate conjugation; CYP1A2, CYP2D6, and CYP3A4 substrate; some demethylation occurs

Bioavailability: Oral: 56% to 71% (some first pass metabolism); Rectal: 58% to 74%

Half-life elimination: Children <15 years: 2-7 hours; Adults: 3-6 hours

Mild-to-moderate hepatic impairment (Child-Pugh classes A and B): Adults: 12 hours

Severe hepatic impairment (Child-Pugh class C): Adults: 20 hours

Time to peak: Oral: ~2 hours; Oral soluble film: ~1 hour

Excretion: Urine (44% to 60% as metabolites, ~5% as unchanged drug); feces (~25%)

Pharmacogenomic Genes of Interest

Cytochrome P450, Family 3, Subfamily A, Polypeptide 4

Local Anesthetic/Vasoconstrictor Precautions

Ondansetron is one of the drugs confirmed to prolong the QT interval and is accepted as having a risk of causing torsade de pointes. The risk of drug-induced torsade de pointes is extremely low when a single QT interval prolonging drug is prescribed. In terms of epinephrine, it is not known what effect vasoconstrictors in the local anesthetic regimen will have in patients with a known history of congenital prolonged QT interval or in patients taking any medication that prolongs the QT interval. Until more information is obtained, it is suggested that the clinician consult with the physician prior to the use of a vasoconstrictor in suspected patients, and that the vasoconstrictor (epinephrine, mepivacaine and levonordefrin [Carbocaine® 2% with Neo-Cobefrin®]) be used with caution.

Dental Health Professional Considerations

Ondansetron is a safer alternative than phenothiazines (ie, promethazine) for the treatment of moderate-to-severe postoperative nausea and vomiting. The cost can be a limitation.

Ondansetron is known to prolong the QT interval. The QT interval is measured as the time and distance between the Q point of the QRS complex and the end of the T wave in the ECG tracing. After adjustment for heart rate, the QT interval is defined as prolonged if it is more than 450 msec in men and 460 msec in women. A long QT syndrome was first described in the 1950s and 60s as a congenital syndrome involving QT interval prolongation and syncope and sudden death. Some of the congenital long QT syndromes were characterized by a peculiar electrocardiographic appearance of the QRS complex involving a premature atria beat followed by a pause, then a subsequent sinus beat showing marked QT prolongation and deformity. This type of cardiac arrhythmia was originally termed “torsade de pointes” (translated from the French as “twisting of the points”). Ondansetron is considered as having a risk of causing torsade de pointes. Since it is not known what effect vasoconstrictors in the local anesthetic regimen will have in patients with a known history of congenital prolonged QT interval or in patients taking any medication that prolongs the QT interval, a medical consult is suggested.

Effects on Dental Treatment

Ondansetron is an alternative to phenothiazines (ie, promethazine) for the treatment of moderate-to-severe postoperative nausea and vomiting. Ondansetron prolongs the QT interval in a dose-dependent manner. Avoid ondansetron in patients with congenital long QT syndrome.

Effects on Bleeding

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause dizziness

Mental Health: Effects on Psychiatric Treatment

Barbiturates and carbamazepine may increase the metabolism of ondansetron; monitor for diminished effects

Index Terms

• GR38032R
• Ondansetron Hydrochloride
• Zuplenz®

References

International Brand Names

• Avessa (LU)
• Cedantron (ID)
• Cetron (AR)
• Danac (MX)
• Dantron (TH, ZA)
• Danzetron (AU)
• Emeset (IN)
• Emetron (HU)
• Emistop (PH)
• Emodan (PH)
• Frazon (ID)
• Glotron (ID)
• Invomit (ID)
• Izofran (CN, UY)
• Lartron (MX)
• Modifical (CO)
• Narfoz (ID)
• Nausedron (BR)
• Ondak (CO)
• Ondant (KP)
• Ondavell (ID)
• Ondaz (AU)
• Onetic (ID)
• Onset-8 (PH)
• Onsetron (KP)
• Onsia (TH)
• Onzod (TW)
• Osetron (AU)
• Setronax (HK, MY, SG)
• Vomceran (ID)
• Vometron (ID)
• Vomiof (IN)
• Vomiz (TW)
• Zetron (TH)
• Zofran (AE, AR, AT, AU, BB, BE, BF, BG, BH, BJ, BM, BR, BS, BZ, CH, CI, CL, CY, CZ, DE, DK, EC, EE, EG, ES, ET, FI, GB, GH, GM, GN, GY, HK, HN, HR, HU, ID, IE, IL, IQ, IR, IT, JM, JO, JP, KE, KP, KW, LB, LR, LU, LY, MA, ML, MR, MT, MU, MW, MX, MY, NE, NG, NL, NO, NZ, OM, PE, PH, PK, PL, PT, PY, QA, RU, SA, SC, SD, SE, SK, SL, SN, SR, SY, TH, TN, TR, TT, TW, TZ, UG, VE, YE, ZM, ZW)
• Zofran Zydis (CR, DO, GT, KP, NI, NZ, PA, SV, TH)
• Zofron (GR)
• Zophren (FR)

Lexi-Comp.com

Last full review/revision April 2013