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Ondansetron

Pronunciation

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); 8 mg (1 ea, 10 ea)

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

Zofran: 40 mg/20 mL (20 mL) [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, preservative free]:

Generic: 32 mg/50 mL (50 mL [DSC])

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 Dispersible, 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

Selective 5-HT3-receptor antagonist, blocking 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.

Canadian labeling: Additional use (not in US labeling): IV: Treatment of PONV

Use: Unlabeled

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

Contraindications

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

Dosing: Adult

Prevention of chemotherapy-induced nausea and vomiting:

US labeling:

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

Canadian labeling:

Prevention of nausea and vomiting associated with highly emetogenic chemotherapy:

IV: 8 to 16 mg (maximum: 16 mg/dose) administered over 15 minutes at least 30 minutes prior to chemotherapy; may administer an additional 8 mg dose at 4 and 8 hours after the initial dose. May convert to oral therapy after the first 24 hours.

Oral: 8 mg every 8 hours for up to 5 days following chemotherapy; oral therapy is initiated after receiving 24 hours of IV ondansetron.

Prevention of nausea and vomiting associated with less emetogenic chemotherapy:

IV: 8 mg administered over 15 minutes at least 30 minutes prior to chemotherapy; may convert to oral therapy twice daily

Oral: 8 mg administered 1 to 2 hours prior to chemotherapy, followed by 8 mg orally twice daily for up to 5 days following chemotherapy

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

American Society of Clinical Oncology (ASCO; Basch 2011):

High emetic risk: Day(s) chemotherapy is administered (antiemetic regimen also includes dexamethasone and aprepitant or fosaprepitant):

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

Oral: 8 mg twice daily

Multinational Association of Supportive Care in Cancer (MASCC) and European Society of Medical Oncology (ESMO) (Roila 2010):

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

IV: 8 mg or 0.15 mg/kg as a single dose prior to chemotherapy. Note: Single IV doses >16 mg are no longer recommended by the manufacturer due to the potential for QT prolongation

Oral: 24 mg as a single dose prior to chemotherapy

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

IV: 8 mg or 0.15 mg/kg as a single dose prior to chemotherapy. Note: Single IV doses >16 mg are no longer recommended by the manufacturer due to the potential for QT prolongation.

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:

US labeling:

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

Canadian labeling: Oral: 8 mg 1 to 2 hours prior to radiation followed by 8 mg every 8 hours for up to 5 days after a course of treatment

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).

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

Prevention of postoperative nausea and vomiting (PONV):

IM, IV (US labeling) or IV (Canadian labeling): 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) 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.

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

Treatment of postoperative nausea and vomiting (Canadian labeling): IV: 4 mg as a single dose (preferably over 2 to 5 minutes, but not less than 30 seconds)

Treatment of severe or refractory hyperemesis gravidum (off-label use):

IV: 8 mg administered over 15 minutes every 12 hours (ACOG 2004)

Oral: 8 mg every 12 hours (Levichek 2002)

Dosing: Geriatric

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

Canadian labeling:

IV: Refer to adult dosing. Note: Not approved for post operative nausea/vomiting in elderly patients. In the prevention of nausea and vomiting associated with emetogenic chemotherapy, ECG monitoring should be considered in patients 65 to 74 years receiving higher initial dosing (eg, 16 mg); in patients ≥75 years, the initial dose should not exceed 8 mg; per usual adult dosing, may give 2 additional IV doses of 8 mg at least 4 hours apart (if third dose is needed, consider ECG monitoring).

Oral: No dosage adjustment required; refer to adult dosing.

Dosing: Pediatric

Prevention of chemotherapy-induced nausea and vomiting:

US labeling:

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 every 8 hours for 1 to 2 days after chemotherapy completed

Children ≥12 years: Refer to adult dosing.

Canadian labeling:

Prevention of nausea and vomiting associated with emetogenic chemotherapy: Children 4 to 12 years:

IV: 3 to 5 mg/m2 over 15 minutes at least 30 minutes prior to chemotherapy, then convert to oral therapy; continue for up to 5 days following chemotherapy

Oral: 4 mg every 8 hours for up to 5 days following chemotherapy; oral therapy is started after an IV dose is given prior to chemotherapy

Pediatric guideline recommendations:

Prevention of chemotherapy-induced nausea and vomiting (off-label dosing; Dupuis 2013):

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): US labeling: 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

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

U.S. labeling:

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

Canadian labeling:

Mild impairment: No dosage adjustment necessary.

Moderate to severe impairment: Maximum daily dose: 8 mg

Reconstitution

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

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 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 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 to 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.

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.

Compatibility

Stable in D51/2NS, D5NS, D5W, mannitol 10%, LR, NS; do not mix injection with alkaline solutions.

Y-site administration: Incompatible with 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.

Compatibility in syringe: Incompatible with phenytoin.

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.

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. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. 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. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. 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. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. 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

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

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

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

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

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

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. Consider therapy modification

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

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

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

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. 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

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

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

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

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

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:

• 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/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, 2010). If emesis occurs despite optimal antiemetic prophylaxis, re-evaluate emetic risk, disease, concurrent morbidities and medications to assure antiemetic regimen is optimized (Basch, 2011).

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

Monitoring Parameters

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

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). 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, or injection site irritation. Have patient report immediately to prescriber angina, passing out, bradycardia, tachycardia, arrhythmia, numbness or tingling, severe fatigue, abdominal pain, difficult urination, abnormal movements, vision changes, seizures, or signs of serotonin syndrome (dizziness, severe headache, agitation, hallucinations, tachycardia, arrhythmia, 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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