ONDANSETRON HYDROCHLORIDE (Page 2 of 6)

CLINICAL TRIALS

Chemotherapy-Induced Nausea and Vomiting

Highly Emetogenic Chemotherapy: In 2 randomized, double-blind, monotherapy trials, a single 24 mg ondansetron hydrochloride tablet was superior to a relevant historical placebo control in the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin ≥50 mg/m². Steroid administration was excluded from these clinical trials. More than 90% of patients receiving a cisplatin dose ≥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 once a day, 8 mg twice a day, and 32 mg once a day in 357 adult cancer patients receiving chemotherapy regimens containing cisplatin ≥50 mg/m². 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 study 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 oral ondansetron 24 mg once a day experienced no nausea during the 24 hour study 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.

In a second trial, efficacy of the oral ondansetron 24 mg once a day regimen in the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin ≥50 mg/m² , was confirmed.

Moderately Emetogenic Chemotherapy: In one double-blind US study in 67 patients, ondansetron tablets 8 mg administered twice a day were significantly more effective than placebo in preventing vomiting induced by cyclophosphamide-based chemotherapy containing doxorubicin. Treatment response is based on the total number of emetic episodes over the 3-day study period. The results of this study are summarized in Table 3:

Table 3: Emetic Episodes: Treatment Response

* The first dose was administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the first dose. An 8 mg ondansetron tablet was administered twice a day for 2 days after completion of chemotherapy. † Median undefined since at least 50% of the patients were withdrawn or had more than two emetic episodes. ‡ Median undefined since at least 50% of patients did not have any emetic episodes.
	Ondansetron
	8 mg b.i.d. tablets *	Placebo	p Value
Number of patients	33	34
Treatment response 0 Emetic episodes 1-2 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	Undefined †
Median time to first emetic episode (h)	Undefined ‡	6.5

In one double-blind US study in 336 patients, ondansetron tablets 8 mg administered twice a day were as effective as ondansetron tablets 8 mg administered three times a day in preventing nausea and vomiting induced by cyclophosphamide-based chemotherapy containing either methotrexate or doxorubicin. Treatment response is based on the total number of emetic episodes over the 3-day study period. The results of this study are summarized in Table 4:

Table 4: Emetic Episodes: Treatment Response

* The first dose was administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the first dose. An 8 mg ondansetron tablet was administered twice a day for 2 days after completion of chemotherapy. † The first dose was administered 30 minutes before the start of emetogenic chemotherapy, with subsequent doses 4 and 8 hours after the first dose. An 8 mg ondansetron tablet was administered three times a day for 2 days after completion of chemotherapy. ‡ Median undefined since at least 50% of patients did not have any emetic episodes. § Visual analog scale assessment: 0 = no nausea, 100 = nausea as bad as it can be.
	Ondansetron
	8 mg b.i.d. ondansetron tablets *	8 mg t.i.d. ondansetron tablets †
Number of Patients	165	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)	Undefined ‡	Undefined ‡
Median nausea scores (0-100)§	6	6

Re-treatment: In uncontrolled 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 one to two emetic episodes occurred in 43 (11%) of the re-treatment courses.

Pediatric Studies: Three open-label, uncontrolled, foreign trials have been performed with 182 pediatric patients 4 to 18 years old with cancer who were given a variety of cisplatin or noncisplatin regimens. In these foreign trials, 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 administration of ondansetron tablets ranging from 4 to 24 mg daily for 3 days. In these studies, 58% of the 170 evaluable patients had a complete response (no emetic episodes) on day 1. Two studies showed the response rates for patients less than 12 years of age who received ondansetron tablets 4 mg three times a day to be similar to those in patients 12 to 18 years of age who received ondansetron tablets 8 mg three times daily. Thus, prevention of emesis in these pediatric patients was essentially the same as for patients older than 18 years of age. Overall, ondansetron tablets were well tolerated in these pediatric patients.