14.1 Chemotherapy-Induced Nausea and Vomiting
Single-Day Chemotherapy
Cisplatin-Based Chemotherapy
In a double-blind, placebo-controlled study in 28 cancer patients, granisetron hydrochloride injection, administered as a single intravenous infusion of 40 mcg/kg, was significantly more effective than placebo in preventing nausea and vomiting induced by cisplatin chemotherapy (see Table 3).
Table 3 Prevention of Chemotherapy-Induced Nausea and Vomiting-Single-Day Cisplatin Therapy1
| Granisetron Hydrochloride Injection | Placebo | P-Value |
Number of Patients | 14 | 14 | |
Response Over 24 Hours | | | |
Complete Response2 | 93% | 7% | <0.001 |
No Vomiting | 93% | 14% | <0.001 |
No More Than Mild Nausea | 93% | 7% | <0.001 |
1Cisplatin administration began within 10 minutes of granisetron hydrochloride injection infusion and continued for 1.5 to 3.0 hours. Mean cisplatin dose was 86 mg/m
2 in the granisetron hydrochloride injection group and 80 mg/m
2 in the placebo group.
2No vomiting and no moderate or severe nausea.
Granisetron hydrochloride injection was also evaluated in a randomized dose response study of cancer patients receiving cisplatin ≥75 mg/m
2. Additional chemotherapeutic agents included: anthracyclines, carboplatin, cytostatic antibiotics, folic acid derivatives, methylhydrazine, nitrogen mustard analogs, podophyllotoxin derivatives, pyrimidine analogs, and vinca alkaloids. Granisetron hydrochloride injection doses of 10 and 40 mcg/kg were superior to 2 mcg/kg in preventing cisplatin-induced nausea and vomiting, but 40 mcg/kg was not significantly superior to 10 mcg/kg (see Table 4).
Table 4 Prevention of Chemotherapy-Induced Nausea and Vomiting-Single-Day High-Dose Cisplatin Therapy1
| Granisetron Hydrochloride Injection (mcg/kg) | P-Value (vs. 2 mcg/kg) |
| 2 | 10 | 40 | 10 | 40 |
Number of Patients | 52 | 52 | 53 | | |
Response Over 24 Hours | | | | | |
Complete Response2 | 31% | 62% | 68% | <0.002 | <0.001 |
No Vomiting | 38% | 65% | 74% | <0.001 | <0.001 |
No More Than Mild Nausea | 58% | 75% | 79% | NS | 0.007 |
1Cisplatin administration began within 10 minutes of granisetron hydrochloride injection infusion and continued for 2.6 hours (mean). Mean cisplatin doses were 96 to 99 mg/m
2.
2No vomiting and no moderate or severe nausea.
Granisetron hydrochloride injection was also evaluated in a double-blind, randomized dose response study of 353 patients stratified for high (≥80 to 120 mg/m
2) or low (50 to 79 mg/m
2) cisplatin dose. Response rates of patients for both cisplatin strata are given in Table 5.
Table 5 Prevention of Chemotherapy-Induced Nausea and Vomiting-Single-Day High-Dose and Low-Dose Cisplatin Therapy1
| Granisetron Hydrochloride Injection (mcg/kg) | P-Value (vs. 5 mcg/kg) |
| 5 | 10 | 20 | 40 | 10 | 20 | 40 |
High-Dose Cisplatin | | | | | | | |
Number of Patients | 40 | 49 | 48 | 47 | | | |
Response Over 24 Hours | | | | | | | |
Complete Response2 | 18% | 41% | 40% | 47% | 0.018 | 0.025 | 0.004 |
No Vomiting | 28% | 47% | 44% | 53% | NS | NS | 0.016 |
No Nausea | 15% | 35% | 38% | 43% | 0.036 | 0.019 | 0.005 |
Low-Dose Cisplatin | | | | | | | |
Number of Patients | 42 | 41 | 40 | 46 | | | |
Response Over 24 Hours | | | | | | | |
Complete Response2 | 29% | 56% | 58% | 41% | 0.012 | 0.009 | NS |
No Vomiting | 36% | 63% | 65% | 43% | 0.012 | 0.008 | NS |
No Nausea | 29% | 56% | 38% | 33% | 0.012 | NS | NS |
1Cisplatin administration began within 10 minutes of granisetron hydrochloride injection infusion and continued for 2 hours (mean). Mean cisplatin doses were 64 and 98 mg/m
2 for low and high strata.
2No vomiting and no use of rescue antiemetic.
For both the low and high cisplatin strata, the 10, 20, and 40 mcg/kg doses were more effective than the 5 mcg/kg dose in preventing nausea and vomiting within 24 hours of chemotherapy administration. The 10 mcg/kg dose was at least as effective as the higher doses.
Moderately Emetogenic Chemotherapy
Granisetron hydrochloride injection, 40 mcg/kg, was compared with the combination of chlorpromazine (50 to 200 mg/24 hours) and dexamethasone (12 mg) in patients treated with moderately emetogenic chemotherapy, including primarily carboplatin >300 mg/m
2, cisplatin 20 to 50 mg/m
2 and cyclophosphamide >600 mg/m
2. Granisetron hydrochloride injection was superior to the chlorpromazine regimen in preventing nausea and vomiting (see Table 6).
Table 6 Prevention of Chemotherapy-Induced Nausea and Vomiting-Single-Day Moderately Emetogenic Chemotherapy
| Granisetron Hydrochloride Injection | Chlorpromazine1 | P-Value |
Number of Patients | 133 | 133 | |
Response Over 24 Hours | | | |
Complete Response2 | 68% | 47% | <0.001 |
No Vomiting | 73% | 53% | <0.001 |
No More Than Mild Nausea | 77% | 59% | <0.001 |
1Patients also received dexamethasone, 12 mg.
2No vomiting and no moderate or severe nausea.
In other studies of moderately emetogenic chemotherapy, no significant difference in efficacy was found between granisetron hydrochloride injection doses of 40 mcg/kg and 160 mcg/kg.
Repeat-Cycle Chemotherapy
In an uncontrolled trial, 512 cancer patients received granisetron hydrochloride injection, 40 mcg/kg, prophylactically, for two cycles of chemotherapy, 224 patients received it for at least four cycles, and 108 patients received it for at least six cycles. Granisetron hydrochloride injection efficacy remained relatively constant over the first six repeat cycles, with complete response rates (no vomiting and no moderate or severe nausea in 24 hours) of 60% to 69%. No patients were studied for more than 15 cycles.
Pediatric Studies
A randomized double-blind study evaluated the 24-hour response of 80 pediatric cancer patients (age 2 to 16 years) to granisetron hydrochloride injection 10, 20 or 40 mcg/kg. Patients were treated with cisplatin ≥60 mg/m
2, cytarabine ≥3 g/m
2, cyclophosphamide ≥1 g/m
2 or nitrogen mustard ≥6 mg/m
2 (see Table 7).
Table 7 Prevention of Chemotherapy-Induced Nausea and Vomiting in Pediatric Patients
| Granisetron Hydrochloride Injection Dose (mcg/kg) |
| 10 | 20 | 40 |
Number of Patients | 29 | 26 | 25 |
Median Number of Vomiting Episodes | 2 | 3 | 1 |
Complete Response Over 24 Hours1 | 21% | 31% | 32% |
1No vomiting and no moderate or severe nausea.
A second pediatric study compared granisetron hydrochloride injection 20 mcg/kg to chlorpromazine plus dexamethasone in 88 patients treated with ifosfamide ≥3 g/m
2/day for two or three days. Granisetron hydrochloride injection was administered on each day of ifosfamide treatment. At 24 hours, 22% of granisetron hydrochloride injection patients achieved complete response (no vomiting and no moderate or severe nausea in 24 hours) compared with 10% on the chlorpromazine regimen. The median number of vomiting episodes with granisetron hydrochloride injection was 1.5; with chlorpromazine it was 7.0.