ONDANSETRON (Page 5 of 6)

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 mg/kg per day and 30 mg/kg per day, respectively (approximately 4 and 6 times the maximum recommended human oral dose of 24 mg per day, based on body surface area).

Ondansetron was not mutagenic in standard tests for mutagenicity.

Oral administration of ondansetron up to 15 mg/kg per day (approximately 6 times the maximum recommended human oral dose of 24 mg per day, based on body surface area) did not affect fertility or general reproductive performance of male and female rats.

14 CLINICAL STUDIES

14.1 Prevention of Chemotherapy-Induced Nausea and Vomiting

Highly Emetogenic Chemotherapy

In 2 randomized, double-blind, monotherapy trials, a single 24 mg oral dose of ondansetron tablets was superior to a relevant historical placebo control in the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin greater than or equal to 50 mg/m2. Steroid administration was excluded from these clinical trials. More than 90% of patients receiving a cisplatin dose greater than or equal to 50 mg/m2 in the historical-placebo comparator, experienced vomiting in the absence of antiemetic therapy.

The first trial compared oral doses of ondansetron 24 mg as a single dose, 8 mg every 8 hours for 2 doses, and 32 mg as a single dose in 357 adult cancer patients receiving chemotherapy regimens containing cisplatin greater than or equal to 50 mg/m2. The first or single dose was administered 30 minutes prior to chemotherapy. A total of 66% of patients in the ondansetron 24-mg once-a-day group, 55% in the ondansetron 8-mg twice-a-day group, and 55% in the ondansetron 32-mg once-a-day group, completed the 24-hour trial period with 0 emetic episodes and no rescue antiemetic medications, the primary endpoint of efficacy. Each of the 3 treatment groups was shown to be statistically significantly superior to a historical placebo control.

In the same trial, 56% of patients receiving a single 24 mg oral dose of ondansetron experienced no nausea during the 24-hour trial period, compared with 36% of patients in the oral ondansetron 8-mg twice-a-day group (P = 0.001) and 50% in the oral ondansetron 32-mg once-a-day group. Dosage regimens of ondansetron tablets 8 mg twice daily and 32 mg once daily are not recommended for the prevention of nausea and vomiting associated with highly emetogenic chemotherapy [see Dosage and Administration (2.1)].

In a second trial, efficacy of a single 24 mg oral dose of ondansetron tablets for the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin greater than or equal to 50 mg/m2 , was confirmed.

Moderately Emetogenic Chemotherapy

A randomized, placebo-controlled, double-blind trial was conducted in the US in 67 patients receiving a cyclophosphamide-based chemotherapy regimen containing doxorubicin. The first 8 mg dose of ondansetron tablets was administered 30 minutes before the start of chemotherapy, with a subsequent dose 8 hours after the first dose, followed by 8 mg of ondansetron tablets twice a day for 2 days after the completion of chemotherapy.

Ondansetron tablets were significantly more effective than placebo in preventing vomiting. Treatment response was based on the total number of emetic episodes over the 3-day trial period. The results of this trial are summarized in Table 7:

Table 7: Emetic Episodes — Treatment Response in Patients Receiving Moderately Emetogenic Chemotherapy (Cyclophosphamide-based Regimen Containing Doxorubicin)

Ondansetron

Tablets

(n = 33)

Placebo

(n = 34)

P Value

Treatment response

0 Emetic episodes

1 to 2 Emetic episodes

More than 2 emetic episodes/withdrawn

20 (61%)

6 (18%)

7 (21%)

2 (6%)

8 (24%)

24 (71%)

<0.001

<0.001

Median number of emetic episodes

0.0

Undefineda

Median time to first emetic episode (hours)

Undefinedb

6.5

a Median undefined since at least 50% of the patients were withdrawn or had more than 2 emetic episodes.

b Median undefined since at least 50% of patients did not have any emetic episodes.

In a double-blind US trial in 336 patients receiving a cyclophosphamide-based chemotherapy regimen containing either methotrexate or doxorubicin, ondansetron tablets 8 mg administered twice a day, was as effective as ondansetron tablets 8 mg administered 3 times a day in preventing nausea and vomiting. Ondansetron Tablets 8 mg three times daily is not a recommended regimen for the treatment of moderately emetogenic chemotherapy [see Dosage and Administration (2.1)].

Treatment response was based on the total number of emetic episodes over the 3-day trial period. See Table 8 for the details of the dosage regimens studied and results of this trial.

Table 8: Emetic Episodes — Treatment Response after Ondansetron Tablets Administered Twice a Day and Three Times a Day

Ondansetron Tablets

8 mg Twice Dailya

(n = 165)

8 mg Three Times a Dayb

(n = 171)

Treatment response

0 Emetic episodes

1-2 Emetic episodes

More than 2 emetic episodes/withdrawn

101 (61%)

16 (10%)

48 (29%)

99 (58%)

17 (10%)

55 (32%)

Median number of emetic episodes

0.0

0.0

Median time to first emetic episode (h)

Undefinedc

Undefinedc

Median nausea scores (0-100)d

6

6

a The first 8 mg dose was administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent 8 mg dose 8 hours after the first dose, followed by 8 mg administered twice a day for 2 days after the completion of chemotherapy.

b The first 8 mg dose was administered 30 minutes before the start of emetogenic chemotherapy, with subsequent 8 mg doses at 4 hours and 8 hours after the first dose, followed by 8 mg administered 3 times a day for 2 days after the completion of chemotherapy.

c Median undefined since at least 50% of patients did not have any emetic episodes.

d Visual analog scale assessment: 0 = no nausea, 100 = nausea as bad as it can be.

Re-treatment

In single-arm trials, 148 patients receiving cyclophosphamide-based chemotherapy were re-treated with ondansetron tablets 8 mg three times daily during subsequent chemotherapy for a total of 396 re-treatment courses. No emetic episodes occurred in 314 (79%) of the re-treatment courses, and only 1 to 2 emetic episodes occurred in 43 (11%) of the re-treatment courses.

Pediatric Trials

Three open-label, single-arm, non-US trials have been performed with 182 pediatric patients aged 4 to 18 years with cancer who were given a variety of cisplatin or noncisplatin regimens. The initial dose of ondansetron tablets injection ranged from 0.04 to 0.87 mg per kg (total dose of 2.16 mg to 12 mg) followed by the administration of oral doses of ondansetron tablets ranging from 4 to 24 mg daily for 3 days. In these trials, 58% of the 170 evaluable patients had a complete response (no emetic episodes) on Day 1. In 2 trials the response rates to ondansetron tablets 4 mg three times a day in patients younger than 12 years was similar to ondansetron tablets 8 mg three times daily in patients 12 to 18 years. Prevention of emesis in these pediatric patients was essentially the same as for adults.

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