Chemotherapy-Induced Nausea and Vomiting:

Adults Studies: In a double-blind study of three different dosing regimens of Ondanselron Injection, USP, 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 study in 28 patients, Ondansetron Injection, USP (three 0.15 mg/kg doses) was significantly more effective than placebo in preventing nausea and vomiting induced by cisplatin-based chemotherapy. Treatment response was as shown in Table 4.

* Chemotherapy was high dose (100 and 120mg/m2; Ondansetron Injection, USP n=6, placebo n=5) or moderate dose (50 and 80 mg/m2; Ondansetron Injection, USP 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.

† Efficacy based on "all patients treated" analysis.

‡ Median undefined since at least 50% of the patients were rescued or had more than five emetic episodes. § Visual analog scale assessment of nausea: 0 = no nausea, 100 = nausea as bad as it can be.

II Visual analog scale assessment of satisfaction: 0 = not at all satisfied, 100 = totally satisfied.

  


Ondanselron was compared with metoclopramide 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 study are summarized in Table 5.

* 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.

† Visual analog scale assessment: 0 = not at all satisfied, 100 = totally satisfied.

  


In a stratified, randomized, double-blind, parallel-group, multicenter study, a single 32 mg dose of ondansetron was compared with three 0.15-mg/kg doses in patients receiving cisplatin doses of either 50 to 70 mg/m2 or >100 mg/m2. Patients received the first ondansetron dose 30 minutes before cisplatin. Two additional ondansetron doses were administered 4 and 8 hours later to the group receiving three 0.15-mg/kg doses. In both strata, significantly fewer patients on the single 32-mg dose than those receiving the three-dose regimen failed.

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

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

  


Cyclophosphamide-Based Chemotherapy: In a double-blind, placebo-controlled study of Ondansetron Injection, USP (three 0.15-mg/kg doses) in 20 patients receiving cyclophosphamide (500 to 600 mg/m2) chemotherapy, Ondansetron Injection, USP was significantly more effective than placebo in preventing nausea and vomiting. The results are summarized in Table 7.

* 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.

† Efficacy based on "all patients treated" analysis.

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

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

Pediatric Studies: 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 Ondansetron Injection, USP dose 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, USP 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 studies, 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 of age.

An open-label, multicenter, noncomparative trial has been performed in 75 pediatric cancer patients 6 to 48 months of age 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, USP was administered intravenously over 15 minutes in three doses of 0.15 mg/kg. The first dosewas 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 4 years of age and older.

Clinical trial information in pediatric cancer patients 6 months to 48 months of age is approved for GlaxoSmithKline Corporation's ondansetron injection. However, due to GlaxoSmithKline's marketing exclusivity rights, this drug product is not labeled for use in this subpopulation of pediatric patients.

Postoperative Nausea and Vomiting: Prevention of Postoperative Nausea and Vomiting: Adult Studies: Adult surgical patients who received ondansetron immediately before the induction of general balanced anesthesia (barbiturate: thiopental, methohexital, or thiamylal; opioid: alfentanil or fentanyl; nitrous oxide; neuromuscular blockade: succinylcholine/curare and/or vecuronium or atracurium; and supplemental isoflurane) were evaluated in two double blind US studies involving 554 patients. Ondansetron Injection, USP (4 mg) I.V. given over 2 to 5 minutes was significantly more effective than placebo. The results of these studies are summarized in Table 8.

The study populations in Table 8 consisted mainly of females undergoing laparoscopic procedures.

In a placebo-controlled study conducted in 468 males undergoing outpatient procedures, a single 4-mg I.V. ondansetron dose prevented postoperative vomiting over a 24-hour study period in 79% of males receiving drug compared to 63% of males receiving placebo (P<001).

Two other placebo-controlled studies were conducted in 2,792 patients undergoing major abdominal or gynecological surgeries to evaluate a single 4-mg or 8-mg I.V ondansetron dose for prevention of postoperative nausea and vomiting over a 24-hour study period. At the 4-mg dosage, 59% of patients receiving ondansetron versus 45% receiving placebo in the firt study (P<0.001) and 41% of patients receiving ondansetron versus 30% receiving placebo in the second study (P=0.001) experienced no emetic episodes. No additional benefit was observed in patients who received I.V. ondansetron 8 mg compared to patients who received I.V. ondansetron 4 mg.

Pediatric Studies: Three double-blind, placebo-controlled studies have been performed (one US, two foreign) in 1,049 male and female patients (2 to 12 years of age) undergoing general anesthesia with nitrous oxide. The surgical procedures included tonsillectomy with or without adenoidectomy, strabismus surgery, herniorrhaphy, and orchidopexy. Patients were randomized to either single I.V. doses of ondansetron (0.1 mg/kg for pediatric patients weighing 40 kg or less, 4 mg for pediatric patients weighing more than 40 kg) or placebo. Study drug was administered over at least 30 seconds, immediately prior to or following anesthesia induction. Ondansetron was significantly more effective than placebo in preventing nausea and vomiting. The results of these studies are summarized in Table 9.

* Failure was one or more emetic episodes, rescued, or withdrawn.

† Nausea measured as none mild, or severe.

  


A double-blind, multicenter, placebo-controlled study was conducted in 670 pediatric patients 1 month to 24 months of age who were undergoing routine surgery under general anesthesia. Seventy-five percent (75%) were males; 64% were white, 15% were black, 13% were American Hispanic, 2% were Asian, and 6% were "other race" patients. A single 0.1-mg/kg I.V. dose of ondansetron administered within 5 minutes following induction of anesthesia was statistically significantly more effective than placebo in preventing vomiting. In the placebo group, 28% of patients experienced vomiting compared to 11% of subjects who received ondansetron (P<0.01). Overall, 32 (10%) of placebo patients and 18 (5%) of patients who received ondansetron received antiemetic rescue medication(s) or prematurely withdrew from the study.

Clinical trial information in pediatric surgical patients 1 month to 24 months of age is approved for GlaxoSmithKline Corporation's ondansetron injection. However, due to GlaxoSmithKline's marketing exclusivity rights, this drug product is not labeled for use in this subpopulation of pediatric patients.

Prevention of Further Postoperative Nausea and Vomiting:

Adult Studies: Adult surgical patients receiving general balanced anesthesia (barbiturate: thiopental, methohexital, or thiamylal; opioid: alfentanil or fentanyl; nitrous oxide; neuromuscular blockade: succinylcholine/curare and/or vecuronium or atracurium; and supplemental isoflurane) who received no prophylactic antiemetics and who experienced nausea and/or vomiting within 2 hours postoperatively were evaluated in two doudle-blind US studies involving 441 patients.

Patients who experienced an episode of postoperative nausea and/or vomiting were given Ondansetron Injection, USP (4 mg) I.V. over 2 to 5 minutes, and this was significantly more effective than placebo. The results of these studies are summarized in Table 10.

* After administration of study drug.

† Nausea measured on a scale of 0-10 with 0 = no nausea, 10 = nausea as bad as it can be.

  


The study populations in Table 10 consisted mainly of women undergoing laparoscopic procedures.

Repeat Dosing in Adults: In patients who do not achieve adequate control of postoperative nausea and vomiting following a single, prophylatic, preinduction, I.V. dose of ondansetron 4 mg, administration of a second I.V. dose of ondansetron 4 mg postoperatively does not provide additional control of nausea and vomiting.

Pediatric Study: One double-blind, placebo-controlled, US study was performed in 351 male and female outpatients (2 to 12 years of age) who received general anesthesia with nitrous oxide and no prophylactic antiemetics. Surgical procedures were unrestricted. Patients who experienced two or more emetic episodes within 2 hours following discontinuation of nitrous oxide were randomized to either single I.V. doses of ondansetron (0.1 mg/kg for pediatric patients weighing 40 kg or less, 4 mg for pediatric patients weighing more than 40 kg) or placebo administered over at least 30 seconds. Ondansetron was significantly more effective than placebo in preventing further episodes of nausea and vomiting. The results of the study are summarized in Table 11.

*Failure was one or more emetic episodes, rescued, or withdrawn.