Ondansetron (Page 5 of 8)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenic effects were not seen in 2-year studies in rats and mice with oral ondansetron doses up to 10 and 30 mg/kg per day, respectively (approximately 3.6 and 5.4 times the recommended human intravenous dose of 0.15 mg/kg given three times a day, based on BSA). Ondansetron was not mutagenic in standard tests for mutagenicity.

Oral administration of ondansetron up to 15 mg/kg per day (approximately 3.8 times the recommended human intravenous dose, based on BSA) did not affect fertility or general reproductive performance of male and female rats.

14 CLINICAL STUDIES

The clinical efficacy of ondansetron hydrochloride, the active ingredient of Ondansetron Injection, was assessed in clinical trials as described below.

14.1 Chemotherapy-Induced Nausea and Vomiting

Adu lts

In a double-blind trial of three different dosing regimens of Ondansetron Injection, 0.015 mg/kg, 0.15 mg/kg, and 0.30 mg/kg, each given three times during the course of cancer chemotherapy, the 0.15-mg/kg dosing regimen was more effective than the 0.015-mg/kg dosing regimen. The 0.30-mg/kg dosing regimen was not shown to be more effective than the 0.15-mg/kg dosing regimen.

Cisplatin-Based Chemotherapy: In a double-blind trial in 28 patients, Ondansetron Injection (three 0.15-mg/kg doses) was significantly more effective than placebo in preventing nausea and vomiting induced by cisplatin-based chemotherapy. Therapeutic response was as shown in Table 7.

T able 7. Therapeutic Response in Prevention of Chemotherapy-Induced Nausea and Vomiting in Single-day Cisplatin Therapy a i n Adults

Ondansetron Injection(0.15 mg/kg x 3)

Placebo P -Valueb
Number of patients 14 14
Treatment response
0 Emetic episodes 2 (14%) 0 (0%)
1-2 Emetic episodes 8 (57%) 0 (0%)
3-5 Emetic episodes 2 (14%) 1 (7%)
More than 5 emetic episodes/rescued 2 (14%) 13 (93%) 0.001
Median number of emetic episodes 1.5 Undefinedc
Median time to first emetic episode (h) 11.6 2.8 0.001
Median nausea scores (0-100)d 3 59 0.034
Global satisfaction with control of nausea and vomiting (0-100)e 96 10.5 0.009

a Chemotherapy was high dose (100 and 120 mg/m2 ; Ondansetron Injection n = 6, placebo n = 5) or moderate dose (50 and 80 mg/m2 ; Ondansetron Injection n = 8, placebo n = 9). Other chemotherapeutic agents included fluorouracil, doxorubicin, and cyclophosphamide. There was no difference between treatments in the types of chemotherapy that would account for differences in response.
b Efficacy based on “all-patients-treated” analysis.
c Median undefined since at least 50% of the patients were rescued or had more than five emetic episodes.
d Visual analog scale assessment of nausea: 0 = no nausea, 100 = nausea as bad as it can be.e Visual analog scale assessment of satisfaction: 0 = not at all satisfied, 100 = totally satisfied.

Ondansetron injection (0.15-mg/kg x 3 doses) was compared with metoclopramide (2 mg/kg x 6 doses) in a single-blind trial in 307 patients receiving cisplatin ≥100 mg/m2 with or without other chemotherapeutic agents. Patients received the first dose of ondansetron or metoclopramide 30 minutes before cisplatin. Two additional ondansetron doses were administered 4 and 8 hours later, or five additional metoclopramide doses were administered 2, 4, 7, 10, and 13 hours later. Cisplatin was administered over a period of 3 hours or less. Episodes of vomiting and retching were tabulated over the period of 24 hours after cisplatin. The results of this trial are summarized in Table 8.

T able 8. Therapeutic Response in Prevention of Vomiting Induced by Cisplatin (100 mg/m 2 ) Single-day Therapya i n Adults

Ondansetron Injection 0.15 mg/kg x 3

Metoclopramide 2 mg/kg x 6

P- Value

Number of patients in efficacy population

136

138

Treatment response 0 Emetic episodes 1-2 Emetic episodes 3-5 Emetic episodes More than 5 emetic episodes/rescued

54 (40%)34 (25%)19 (14%)29 (21%)

41 (30%)30 (22%)18 (13%)49 (36%)

Comparison of treatments with respect to 0 Emetic episodes More than 5 emetic episodes/rescued

54/13629/136

41/13849/138

0.0830.009

Median number of emetic episodes

1

2

0.005

Median time to first emetic episode (h)

20.5

4.3

< 0.001

Global satisfaction with control of nausea and vomiting (0-100)b

85

63

0.001

Acute dystonic reactions

0

8

0.005

Akathisia

0

10

0.002

a In addition to cisplatin, 68% of patients received other chemotherapeutic agents, including cyclophosphamide, etoposide, and fluorouracil. There was no difference between treatments in the types of chemotherapy that would account for differences in response.b Visual analog scale assessment: 0 = not at all satisfied, 100 = totally satisfied.

Cyclophosphamide-Based Chemotherapy: In a double-blind, placebo-controlled trial of Ondansetron Injection (three 0.15-mg/kg doses) in 20 patients receiving cyclophosphamide (500 to 600 mg/m2) chemotherapy, Ondansetron Injection was significantly more effective than placebo in preventing nausea and vomiting. The results are summarized in Table 9.

T able 9. Therapeutic Response in Prevention of Chemotherapy-Induced Nausea and Vomiting in Single-day Cyclophosphamide Therapya in Adults

Ondansetron Injection(0.15 mg/kg x 3)

Placebo P- Valueb

Number of patients

10

10

Treatment response

0 Emetic episodes

7 (70%)

0 (0%)

0.001

1-2 Emetic episodes

0 (0%)

2 (20%)

3-5 Emetic episodes

2 (20%)

4 (40%)

More than 5 emetic episodes/rescued

1 (10%)

4 (40%)

0.131

Median number of emetic episodes

0

4

0.008

Median time to first emetic episode (h)

Undefinedc

8.79

Median nausea scores (0-100) d

0

60

0.001

Global satisfaction with control of nausea and vomiting (0-100) e

100

52

0.008

a Chemotherapy consisted of cyclophosphamide in all patients, plus other agents, including fluorouracil, doxorubicin, methotrexate, and vincristine. There was no difference between treatments in the type of chemotherapy that would account for differences in response.
b Efficacy based on “all-patients-treated” analysis.
c Median undefined since at least 50% of patients did not have any emetic episodes.
d Visual analog scale assessment of nausea: 0 = no nausea, 100 = nausea as bad as it can be.e Visual analog scale assessment of satisfaction: 0 = not at all satisfied, 100 = totally satisfied.

Re-treatment: In uncontrolled trials, 127 patients receiving cisplatin (median dose, 100 mg/m2) and ondansetron who had two or fewer emetic episodes were re-treated with ondansetron and chemotherapy, mainly cisplatin, for a total of 269 re-treatment courses (median: 2; range: 1 to 10). No emetic episodes occurred in 160 (59%), and two or fewer emetic episodes occurred in 217 (81%) re-treatment courses.

Ped iatrics

Four open-label, noncomparative (one US, three foreign) trials have been performed with 209 pediatric cancer patients aged 4 to 18 years given a variety of cisplatin or noncisplatin regimens. In the three foreign trials, the initial dose of Ondansetron Injection ranged from 0.04 to 0.87 mg/kg for a total dose of 2.16 to 12 mg. This was followed by the oral administration of ondansetron ranging from 4 to 24 mg daily for 3 days. In the US trial, Ondansetron Injection was administered intravenously (only) in three doses of 0.15 mg/kg each for a total daily dose of 7.2 to 39 mg. In these trials, 58% of the 196 evaluable patients had a complete response (no emetic episodes) on Day 1. Thus, prevention of vomiting in these pediatric patients was essentially the same as for patients older than 18 years.

An open-label, multicenter, noncomparative trial has been performed in 75 pediatric cancer patients aged 6 to 48 months receiving at least one moderately or highly emetogenic chemotherapeutic agent. Fifty-seven percent (57%) were females; 67% were white, 18% were American Hispanic, and 15% were black patients. Ondansetron Injection was administered intravenously over 15 minutes in three doses of 0.15 mg/kg. The first dose was administered 30 minutes before the start of chemotherapy; the second and third doses were administered 4 and 8 hours after the first dose, respectively. Eighteen patients (25%) received routine prophylactic dexamethasone (i.e., not given as rescue). Of the 75 evaluable patients, 56% had a complete response (no emetic episodes) on Day 1. Thus, prevention of vomiting in these pediatric patients was comparable to the prevention of vomiting in patients aged 4 years and older.

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