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Ondansetron

Pronunciation

(on DAN se tron)

Index Terms

  • GR38032R
  • Ondansetron HCl
  • Ondansetron Hydrochloride

Dosage Forms

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

Film, Oral:

Zuplenz: 4 mg (1 ea, 10 ea, 30 ea); 8 mg (1 ea, 10 ea, 30 ea)

Solution, Injection, as hydrochloride [strength expressed as base]:

Zofran: 40 mg/20 mL (20 mL [DSC]) [contains methylparaben, propylparaben]

Generic: 4 mg/2 mL (2 mL); 40 mg/20 mL (20 mL)

Solution, Injection, as hydrochloride [strength expressed as base, preservative free]:

Generic: 4 mg/2 mL (2 mL)

Solution, Intravenous, as hydrochloride [strength expressed as base]:

Generic: 12 mg/50 mL in NaCl 0.9% (50 mL); 16 mg/50 mL in NaCl 0.9% (50 mL); 8 mg/50 mL in NaCl 0.9% (50 mL)

Solution, Oral, as hydrochloride [strength expressed as base]:

Zofran: 4 mg/5 mL (50 mL) [strawberry flavor]

Generic: 4 mg/5 mL (50 mL)

Tablet, Oral:

Generic: 24 mg

Tablet, Oral, as hydrochloride [strength expressed as base]:

Zofran: 4 mg, 8 mg

Generic: 4 mg, 8 mg

Tablet Disintegrating, Oral:

Zofran ODT: 4 mg, 8 mg [contains aspartame, methylparaben sodium, propylparaben sodium; strawberry flavor]

Generic: 4 mg, 8 mg

Brand Names: U.S.

  • Zofran
  • Zofran ODT
  • Zuplenz

Pharmacologic Category

  • Antiemetic
  • Selective 5-HT3 Receptor Antagonist

Pharmacology

Ondansetron is a selective 5-HT3-receptor antagonist which blocks serotonin, both peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone

Absorption

Oral: 100%; nonlinear absorption occurs with increasing oral doses; Zofran ODT tablets are bioequivalent to Zofran tablets; absorption does not occur via oral mucosa

Distribution

Vd:

Infants and Children: Surgical patients:

1 to 4 months: 3.5 L/kg

5 to 24 months: 2.3 L/kg

3 to 12 years: 1.65 L/kg

Children and Adolescents: Cancer patients: 4 to 18 years: 1.9 L/kg

Adults: 1.9 L/kg

Metabolism

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

Excretion

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

Clearance:

Cancer patients: Children and Adolescents 4 to 18 years: 0.599 L/kg/hour

Surgical patients: Infants and Children: 1 to 4 months: 0.401 L/kg/hour; 5 to 24 months: 0.581 L/kg/hour; 3 to 12 years: 0.439 L/kg/hour

Adult (normal): 19 to 40 years: 0.381 L/kg/hour; 61 to 74 years: 0.319 L/kg/hour; >75 years: 0.262 L/kg/hour

Onset of Action

~30 minutes

Time to Peak

Oral: ~2 hours; Oral soluble film: ~1 hour

Half-Life Elimination

Children:

Cancer patients: Children and Adolescents: 4 to 18 years: 2.8 hours

Surgical patients: Infants 1 to 4 months: 6.7 hours; Infants and Children 5 months to 12 years: 2.9 hours

Adults: 3 to 6 hours; Mild-to-moderate hepatic impairment (Child-Pugh classes A and B): 12 hours; Severe hepatic impairment (Child-Pugh class C): 20 hours

Protein Binding

Plasma: 70% to 76%

Special Populations: Renal Function Impairment

Mean plasma Cl is reduced by 41% (IV) and 50% (oral) in patients with severe renal impairment (CrCl less than 30 mL/min).

Special Populations: Hepatic Function Impairment

Cl is reduced 2- to 3-fold and the volume of distribution is increased. The half-life is increased to 20 h in patients with severe hepatic impairment.

Special Populations: Elderly

In elderly older than 75 y of age, there is a reduction in Cl and an increase in elimination half-life.

Special Populations: Gender

The extent and rate of absorption is greater in women than in men. There is slower Cl, a smaller volume of distribution, and higher bioavailability in women.

Use: Labeled Indications

Cancer chemotherapy-induced nausea and vomiting:

IV: Prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy (including high-dose cisplatin)

Oral:

Prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy (including cisplatin ≥50 mg/m2).

Prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy.

Radiotherapy-associated nausea and vomiting: Oral: Prevention of nausea and vomiting associated with radiotherapy in patients receiving either total body irradiation, single high-dose fraction to the abdomen, or daily fractions to the abdomen.

Postoperative nausea and/or vomiting: IV and Oral: Prevention of postoperative nausea and/or vomiting (PONV). If nausea/vomiting occur in a patient who had not received prophylactic ondansetron, IV ondansetron may be administered to prevent further episodes.

Limitations of use: Routine prophylaxis for PONV in patients with minimal expectation of nausea and/or vomiting is not recommended, although use is recommended in patients when nausea and vomiting must be avoided in the postoperative period, even if the incidence of PONV is low.

Off Label Uses

Nausea and vomiting of pregnancy (severe or refractory)

Based on the Society of Obstetricians and Gynaecologists of Canada Nausea and Vomiting in Pregnancy guidelines, the use of ondansetron may be considered in the treatment of severe or refractory hyperemesis gravidarum when preferred agents have failed [Arsenault 2002].

Postoperative nausea and vomiting (treatment)

Based on the Society for Ambulatory Anesthesia guidelines, it is reasonable to administer a 5-HT3 receptor antagonist for treatment of postoperative nausea and vomiting when a prophylactic agent was not utilized or for failure when an agent from a different class was utilized [Gan 2007].

Contraindications

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

Dosing: Adult

Note: Single IV doses >16 mg are no longer recommended due to the potential for QT prolongation.

Prevention of chemotherapy-induced nausea and vomiting:

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

Prevention of nausea and vomiting associated with highly emetogenic chemotherapy: Oral: 24 mg 30 minutes prior to the start of single-day chemotherapy

Prevention of nausea and vomiting associated with moderately emetogenic chemotherapy: Oral: 8 mg beginning 30 minutes before chemotherapy; repeat dose 8 hours after initial dose, then 8 mg every 12 hours for 1 to 2 days after chemotherapy completed

Guideline recommendations: Prevention of chemotherapy-induced nausea and vomiting:

American Society of Clinical Oncology (ASCO [Hesketh 2017]):

High emetic risk, including most anthracyclines combined with cyclophosphamide regimens: Day(s) chemotherapy is administered (antiemetic regimen also includes dexamethasone, an NK1 receptor antagonist, and olanzapine):

IV: 8 mg or 0.15 mg/kg (maximum: 16 mg/dose)

Oral: 8 mg twice daily or three 8 mg oral soluble films (total dose 24 mg) once

Moderate emetic risk: Day(s) chemotherapy is administered (antiemetic regimen also includes dexamethasone [and an NK1 receptor antagonist for carboplatin AUC ≥4]):

IV: 8 mg or 0.15 mg/kg (maximum: 16 mg/dose)

Oral: 8 mg twice daily

Low emetic risk:

IV: 8 mg or 0.15 mg/kg (maximum: 16 mg/dose) prior to chemotherapy

Oral: 8 mg prior to chemotherapy

Multinational Association of Supportive Care in Cancer (MASCC) and European Society of Medical Oncology (ESMO) (Roila 2016):

Highly emetic chemotherapy, (antiemetic regimen includes dexamethasone and aprepitant/fosaprepitant):

IV: 8 mg or 0.15 mg/kg (maximum: 16 mg/dose) as a single dose prior to chemotherapy

Oral: 16 mg as a single dose prior to chemotherapy (8 mg twice daily has also been used)

Moderately emetic chemotherapy (antiemetic regimen includes dexamethasone [and aprepitant/fosaprepitant for AC chemotherapy regimen]):

IV: 8 mg or 0.15 mg/kg (maximum: 16 mg/dose) as a single dose prior to chemotherapy

Oral: 16 mg (as 8 mg twice daily)

Low emetic risk: Ondansetron (dose not specified) prior to chemotherapy on day 1

Prevention of radiation therapy-induced nausea and vomiting:

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

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

Daily fractionated radiotherapy to abdomen: Oral: 8 mg administered 1 to 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 (ASCO [Hesketh 2017]): Give before each fraction throughout radiation therapy for high emetic risk (with dexamethasone; continue for at least 24 hours after completion) and for moderate emetic risk (with or without dexamethasone before the first 5 fractions). 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).

IV (off-label route/dosing): 8 mg or 0.15 mg/kg (maximum: 16 mg/dose) once or twice daily

Oral: 8 mg once or twice daily

Prevention of postoperative nausea and vomiting (PONV):

IM, IV: 4 mg as a single dose (over 2 to 5 minutes if giving IV) administered ~30 minutes before the end of anesthesia (see Note below).

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.

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

Treatment of postoperative nausea and vomiting (off-label): IV: 4 mg as a single dose for failure when an agent from a different class was utilized as prophylaxis or 1 mg may be effective when a prophylactic agent was not utilized (Gan 2007)

Nausea and vomiting of pregnancy (severe or refractory) (off-label use):

IV: 8 mg administered over 15 minutes every 12 hours (Arsenault 2002)

Oral: 8 mg every 12 hours (Arsenault 2002)

Dosing: Geriatric

Oral, IV: No dosing adjustment required; refer to adult dosing.

Dosing: Pediatric

Prevention of chemotherapy-induced nausea and vomiting:

Prevention of nausea and vomiting associated with emetogenic chemotherapy: Infants ≥6 months, Children, and Adolescents: IV: 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 administered 4 and 8 hours after the first dose

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

Children 4 to 11 years: 4 mg 30 minutes before chemotherapy; repeat 4 and 8 hours after initial dose, then 4 mg 3 times a day for 1 to 2 days after chemotherapy completed

Children ≥12 years:

Tablet: 8 mg 30 minutes before chemotherapy; repeat 8 hours after initial dose, then 8 mg twice daily (every 12 hours) for 1 to 2 days after chemotherapy completed.

Soluble film: 8 mg orally twice a day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the first dose, then 8 mg twice a day (every 12 hours) for 1 to 2 days after completion of chemotherapy.

Guideline recommendations: Prevention of chemotherapy-induced nausea and vomiting:

Pediatric Oncology Group of Ontario (POGO)(off-label dosing; Dupuis 2013; Patel 2017):

Highly emetogenic chemotherapy: Infants ≥1 month and Children <12 years: IV, Oral: 0.15 mg/kg/dose (5 mg/m2/dose) prior to chemotherapy and then every 8 hours; maximum recommended IV dose: 16 mg. Antiemetic regimen also includes dexamethasone

Highly emetogenic chemotherapy: Children ≥12 years and Adolescents: IV, Oral: 0.15 mg/kg/dose (5 mg/m2/dose) prior to chemotherapy and then every 8 hours; maximum recommended IV dose: 16 mg. Antiemetic regimen includes dexamethasone and if no known or suspected drug interactions, aprepitant.

Moderately emetogenic chemotherapy: Infants ≥1 month, Children, and Adolescents: IV, Oral: 0.15 mg/kg/dose (5 mg/m2/dose; maximum: 8 mg dose); prior to chemotherapy and then every 12 hours. Antiemetic regimen also includes dexamethasone.

Low emetogenicity chemotherapy: Infants ≥1 month, Children, and Adolescents: IV, Oral: 0.3 mg/kg/dose (10 mg/m2/dose; maximum IV dose: 16 mg) prior to chemotherapy

Prevention of postoperative nausea and vomiting (PONV):

Infants ≥1 month and Children ≤12 years: IV:

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

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

Adolescents >12 years: IV, IM: Refer to adult dosing.

Dosing: Renal Impairment

IV: No dosage adjustment is necessary.

Oral: No dosage adjustment necessary; however, according to the manufacturer, there is no experience for oral ondansetron in renal impairment beyond first-day administration (has not been studied beyond day 1).

Dosing: Hepatic Impairment

Mild to moderate impairment: No dosage adjustment necessary.

Severe impairment (Child-Pugh class C):

IV: Day 1: Maximum daily dose: 8 mg; however, according to the manufacturer, (there is no experience beyond first-day administration (has not been studied beyond day 1)

Oral: Maximum daily dose: 8 mg

Reconstitution

Vial:

Prevention of chemotherapy-induced nausea and vomiting: Dilution is required prior to IV infusion. Dilute in 50 mL D5W or NS. In pediatric patients between 6 months and 1 year of age and/or ≤10 kg, may dilute in 10 to 50 mL D5W or NS, depending on fluid needs of the patient. Use diluted solutions within 24 hours of preparation.

Prevention of postoperative nausea and vomiting: No dilution is required.

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).

Tenjarla SN, Ward ES, and Fox JL, "Ondansetron Suppositories: Extemporaneous Preparation, Drug Release, Stability and Flux Through Rabbit Rectal Membrane," Int J Pharm Compound, 1998, 2(1):83-8. Trissel LA, Trissel's Stability of Compounded Formulations, Washington, DC: American Pharmaceutical Association, 1996.

Administration

Oral: Oral dosage forms should be administered 30 minutes prior to chemotherapy; 1 to 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 attempt to push tablet through the foil. Using dry hands, place tablet on tongue and allow to dissolve. Swallow with saliva (no need to administer with liquids).

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 to 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.

IM: Should be administered undiluted.

IV:

IVPB: Infuse diluted solution over 15 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.

IV push: Prevention of postoperative nausea and vomiting: Single doses may be administered IV injection as undiluted solution over at least 30 seconds but preferably over 2 to 5 minutes

Dietary Considerations

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. Chemically and physically stable when mixed in D5W or NS for 48 hours at room temperature; however, diluents generally do not contain a preservative and sterile precautions should be observed. After dilution, do not use beyond 24 hours.

Premixed bag in D5W: Store at 20°C to 25°C (68°F to 77°F), excursions permitted from 15°C to 30°C (59°F to 86°F); may refrigerate; avoid freezing and excessive heat; protect from light.

Drug Interactions

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

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

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

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Hydroxychloroquine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Avoid combination

MetFORMIN: Ondansetron may increase the serum concentration of MetFORMIN. Monitor therapy

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Avoid combination

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Panobinostat: Ondansetron may enhance the arrhythmogenic effect of Panobinostat. 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.). Monitor therapy

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification

Probucol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Avoid combination

Promazine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Avoid combination

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

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

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

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Serotonin Modulators: Antiemetics (5HT3 Antagonists) may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Exceptions: Nicergoline. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

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

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

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

Vinflunine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Avoid combination

Xipamide: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Moderate Risk). Monitor therapy

Adverse Reactions

Note: Percentages reported in adult patients unless otherwise specified.

>10%:

Central nervous system: Headache (oral: 9% to 27%; IV: 17%), fatigue (oral: ≤9% to 13%), malaise (oral: ≤9% to 13%)

Gastrointestinal: Constipation (6% to 11%)

1% to 10%:

Central nervous system: Drowsiness (IV: ≤8%), sedation (IV: ≤8%), (dizziness (7%), agitation (oral: ≤6%), anxiety (oral: ≤6%), paresthesia (IV: 2%), sensation of cold (IV: 2%)

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

Gastrointestinal: Diarrhea (oral: 6% to 7%; IV: Children 1 to 24 months of age: 2%)

Genitourinary: Gynecologic disease (oral: 7%), urinary retention (oral: 5%)

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

Local: Injection site reaction (IV: 4%; includes burning sensation at injection site, erythema at injection site, injection site pain)

Respiratory: Hypoxia (oral: 9%)

Miscellaneous: Fever (2% to 8%)

<1% (Limited to important or life-threatening): Abdominal pain, accommodation disturbance, atrial fibrillation, cardiorespiratory arrest (IV), depression of ST segment on ECG, dyspnea, extrapyramidal reaction (IV), flushing, hepatic failure (when used with other hepatotoxic medications), hiccups, hypersensitivity reaction, hypokalemia, hypotension, laryngospasm (IV), liver enzyme disorder, mucosal tissue reaction, myocardial infarction, neuroleptic malignant syndrome, positive lymphocyte transformation test, prolonged Q-T interval on ECG (dose dependent), second-degree atrioventricular block, serotonin syndrome, shock (IV), Stevens-Johnson syndrome, supraventricular tachycardia, syncope, tachycardia, tonic-clonic seizures, torsades de pointes, transient blindness (lasted ≤48 hours), transient blurred vision (following infusion), vascular occlusive events, ventricular premature contractions, ventricular tachycardia, weakness

Warnings/Precautions

Concerns related to adverse effects:

• Hypersensitivity: Hypersensitivity reactions (including anaphylaxis and bronchospasm) have been reported; discontinue if hypersensitivity occurs. Use with caution in patients allergic to other 5-HT3 receptor antagonists; cross-reactivity has been reported.

• QT prolongation: ECG changes, including dose-dependent QT interval prolongation, have been observed with ondansetron use. Cases of torsade de pointes have also been reported. Selective 5-HT3 antagonists, including ondansetron, have been associated with a number of dose-dependent increases in ECG intervals (eg, PR, QRS duration, QT/QTc, JT), usually occurring 1 to 2 hours after IV administration. Single doses >16 mg ondansetron IV 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 torsades 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. IV formulations of 5-HT3 antagonists have more association with ECG interval changes, compared to oral formulations.

• Serotonin syndrome: Serotonin syndrome has been reported with 5-HT3 receptor antagonists, predominantly when used in combination with other serotonergic agents (eg, SSRIs, SNRIs, MAOIs, mirtazapine, fentanyl, lithium, tramadol, and/or methylene blue). Some of the cases have been fatal. The majority of serotonin syndrome reports due to 5-HT3 receptor antagonist have occurred in a postanesthesia setting or in an infusion center. Serotonin syndrome has also been reported following overdose of ondansetron. Monitor patients for signs of serotonin syndrome, including mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile blood pressure, diaphoresis, dizziness, flushing, hyperthermia); neuromuscular changes (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination); gastrointestinal symptoms (eg, nausea, vomiting, diarrhea); and/or seizures. If serotonin syndrome occurs, discontinue 5-HT3 receptor antagonist treatment and begin supportive management.

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.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer’s labeling.

• Phenylalanine: Orally-disintegrating tablets contain phenylalanine.

Other warnings/precautions:

• Chemotherapy-associated emesis: Antiemetics are most effective when used prophylactically (Roila 2016). If emesis occurs despite optimal antiemetic prophylaxis, re-evaluate emetic risk, disease, concurrent morbidities and medications to assure antiemetic regimen is optimized (ASCO [Hesketh 2016]).

• Ileus or gastric distention: Ondansetron does not stimulate gastric or intestinal peristalsis (do not use in place of nasogastric suction). Ondansetron may mask progressive ileus and/or gastric distension; monitor for decreased bowel activity.

Monitoring Parameters

ECG (if applicable in high-risk or elderly patients); potassium, magnesium. Monitor for signs of serotonin syndrome; monitor for decreased bowel activity.

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events 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). Due to pregnancy-induced physiologic changes, clearance of ondansetron may increase as pregnancy progresses (Lemon 2016).

Although ondansetron has been evaluated for the treatment of nausea and vomiting of pregnancy, current guidelines note data related to fetal safety is conflicting (ACOG 2015); ondansetron is generally reserved for use when other agents have failed (Arsenault 2002). 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). An international consensus panel recommends that 5-HT3 antagonists (including ondansetron) should not be withheld in pregnant patients receiving chemotherapy for the treatment of gynecologic cancers, when chemotherapy is given according to general recommendations for chemotherapy use during pregnancy (Amant 2010).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, loss of strength and energy, constipation, diarrhea, anxiety, or injection site irritation. Have patient report immediately to prescriber angina, passing out, bradycardia, tachycardia, abnormal heartbeat, numbness or tingling, severe fatigue, abdominal pain, difficult urination, abnormal movements, vision changes, seizures, dizziness, chills, or signs of serotonin syndrome (dizziness, severe headache, agitation, hallucinations, tachycardia, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea) (HCAHPS).

• 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.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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