Clinical Guidelines

Guide to Ondansetron Use in Oncology Settings

Drug Use Evaluation Subcommittee, Pharmacy and Therapeutics Subcommittee,
University of Iowa Hospitals and Clinics
Peer Review Status:

I. Indication for Use

A. Ondansetron (Zofran^®), I.V., is approved for

1. Prevention of acute-onset nausea and vomiting (N/V) due to highly/very highly emetogenic chemotherapy (see Table 1).
2. Prevention or treatment of chemotherapy or radiation therapy associated N/V in patients (pts) refractory to or intolerant of alternative antiemetic therapy.
3. Use in pts for whom oral ondansetron is indicated, but not feasible.

B. Ondansetron, oral, is approved for

1. Prevention of N/V due to moderately emetogenic chemotherapy (see Table 1).
2. Use as an alternative to I.V. ondansetron, including use highly to very highly emetogenic chemotherapy.
3. Prevention or treatment of chemotherapy or radiation-therapy associated N/V in pts refractory to or intolerant of alternative antiemetic therapy.
4. Prevention of delayed onset N/V (e.g., following cisplatin) in pts refractory to or intolerant of standard antiemetic therapy (e.g., oral metoclopramide/dexamethasone x 3-5 days).

C. Ondansetron should not be used to prevent or treat N/V due to chemotherapy with low emetic potential, unless:

1. Pts are refractory to or intolerant of appropriate doses of alternative antiemetics.
2. Vomiting or retching would pose serious medical risks (e.g., risk of cerebellar herniation due to increased intracranial pressure) and alternative antiemetics are felt to be inappropriate.

II. Dosage and Administration

A. I.V. Ondansetron, Multiple-Dose

1. Doses should be standardized (see Table 2). The dose is 0.15 mg/kg actual body wt for children under 20 kg.
2. Give 1st dose 30 minutes before emetogenic chemotherapy, and repeat the dose 4 and 8 hours later.
3. Doses are diluted in 50 ml D5W or NS and infused over 15 minutes. Pediatric pts may receive dose in a syringe, for infusion over 15 minutes, as per pediatric protocols.
4. For prolonged continuous infusions of emetogenic chemotherapy, a dose is given 30 minutes prior to the infusion, and repeat doses every 8 hours until the infusion and emetic risk period is complete. Oral ondansetron should be strongly considered in this setting.

B. I.V. Ondansetron, Single-Dose

1. Single pre-chemotherapy ondansetron doses of 8 mg or 32 mg have shown good efficacy in high dose cisplatin-based chemotherapy.^{(1, 2)} Other doses have not been evaluated. The 32 mg doses have not been evaluated in pediatric pts.
2. The recommended dose is 8 mg or 32 mg, diluted in 50 ml D5W or NS, administered over 15 minutes.
3. No repeat doses are given with this strategy. alternative antiemetics may be considered for PRN purposes.

C. Oral Ondansetron

1. Doses are standardized. An 8 mg tablet is used in adults and children 12 years or older. A 4 mg tablet may be used in children 4-11 years of age.
2. A single tablet is given 30 minutes before chemotherapy, then repeated 4 and 8 hours later. The same dose is then scheduled two⁽³⁾ or three times daily for an additional 1-2 days. A maximum duration of 3 days following completion of chemotherapy is recommended.

III. Ondansetron - PRN Dosing

1. Avoid PRN dosing with ondansetron. Give appropriate scheduled doses to cover the emetic risk period, and employ alternative antiemetics to provide additional "as needed" protection.
2. This strategy is not only cost-effective, but is also based on sound pharmacologic principles. Single-dose studies (8 mg or 32 mg) suggest prolonged duration of effect regardless of the short half-life. The use of additional alternative antiemetics with different mechanisms/sites of action is a highly rational prescribing approach with proven benefit.
3. Only when additional alternative PRN antiemetics fail (e.g., metoclopramide, prochlorperazine, lorazepam) should PRN ondansetron be considered.
4. The role of ondansetron in cisplatin-associated delayed-onset N/V is unclear.⁽⁴⁾ If ondansetron is employed, scheduled doses (oral preferably) are suggested, not PRN. Metoclopramide with/without dexamethasone shows a more consistent favorable response.

IV. Patient Monitoring

1. Effectiveness: document episodes of vomiting and retching, and severity of nausea.
2. Adverse Reactions: document headache, sedation, diarrhea, constipation, altered liver function studies, and any other drug-associated adverse events.

V. Cost of Antiemetic Therapy

1. Effective antiemetic therapy provides pt comfort, may prevent complications, may reduce length of stay in clinic and inpatient settings, and may reduce unnecessary readmissions. These outcomes can carry both direct and indirect financial benefit.
2. Selection of specific antiemetic regimens must take into account efficacy, but must clearly include a cost comparison between regimens providing comparable efficacy, and acceptable side effect profiles.
3. Ondansetron acquisition costs are very high. When ondansetron is felt to be appropriate, the following cost saving strategies should be considered.
    
   1. Avoid PRN ondansetron. The financial ramifications for the patient are high. Alternative PRN antiemetics are more appropriate and may be more rational as an adjunct to appropriately scheduled ondansetron.
   2. Use single dose ondansetron, instead of multiple doses. Efficacy is similar, and the concurrent use of scheduled or PRN alternative antiemetics is reasonable. The use of 8 mg IV X 1 may be equivalent in efficacy to 32 mg IV x 1.
   3. When appropriate, oral ondansetron may be an effective and less expensive substitute for IV ondansetron.

Table 1. Emetogenic Potential of Cancer Chemotherapy Agents*
Very Highly Emetogenic
Cisplatin	Mechlorethamine
Cytarabine (> or = 500 mg/m2)	Melphalan IV
Dacarbazine	Streptozocin
Ifosfamide
Highly Emetogenic
Carmustine	Etoposide (> or = 500 mg/m2)
Carboplatin	Lomustine
Cyclophosphamide	Methotrexate (> or = 200 mg/m2)
Dactinomycin	Thiotepa (> or = 15 mg/m2)
Moderately Emetogenic
Cytarabine (200-500 mg/m2	Mitomycin
Daunorubicin	Plicamycin
Doxorubicin	Vinblastine
Idarubicin
Low Emetogenic Risk
Azathioprine	L-Asparaginase
BCG Vaccine	Leuprolide acetate
Bleomycin	Levamisole
Busulfan	Megestrol
Chlorambucil	Melphalan (oral)
Cladribine (2-CDA)	Mercaptopurine
Cytarabine (< 200 mg/m2)	Methotrexate (< 200 mg/m2)
Etoposide	Mitotane
Floxuridine	Mitoxantrone
Fludarabine	Paclitaxel
Fluorouracil	Tamoxifen
Fluoxymesterone	Teniposide
Flutamide	Thioguanine
Hydroxyurea	Thiotepa (< 15 mg/m2)
Interferon, Alfa-2	Vincristine
*The specific dose, duration of infusion, the concurrent use of other emetogenic agents, among other factors, will influence this predicted risk.

Table 2. Intravenous Ondansetron Standardized Doses
Patient Weight	Standard Dose
< 20 kg	see belowa
20 - 21 kg	3 mg
22 - 28 kg	4 mg
29 - 35 kg	5 mg
36 - 43 kg	6 mg
44 - 49 kg	7 mg
50 - 60 kg	8 mg
61 - 72 kg	10 mg
73 - 86 kg	12 mg
87 - 100 kg	14 mg
> 100 kg	0.15 mg/kg rounded to nearest 2 mg
aCalculate dose, based on body weight, as 0.15 mg/kg
NOTE: In patients with severe hepatic insufficiency, the manufacturer recommends that the total daily dose should not exceed 8 mg. Repeated doses have not been studied in patients with hepatic insufficiency.

References

1. Beck TM, Hesketh PJ, Madajewicz S, et al. Stratified, randomized, double-blind comparison of intravenous ondansetron administered as a multiple-dose regimen versus two single-dose regimens in the prevention of cisplatin-induced nausea and vomiting. J Clin Oncol 1992;10:1969-75.
2. Seynaeve C, Schuller J, Buser K, et al. Comparison of the anti-emetic efficacy of different doses of ondansetron, given as either a continuous infusion or a single intravenous dose, in acute cisplatin-induced emesis. A multicenter, double-blind, randomized, parallel group study. Br J Cancer 1992;66:192-7.
3. Dicato MA. Oral treatment with ondansetron in an outpatient setting. Eur J Cancer 1991;27(Suppl 1):S18-S19.
4. Kris MG, Tyson LB, Clark RA, et al. Oral ondansetron for the control of delayed emesis after cisplatin. Report of a Phase II study and a review of completed trials to manage delayed emesis. Cancer 1992;70(Suppl 8/15):1012-16.

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Last Modified: January 15, 1997