Granisetron Hydrochloride Injection - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Granisetron Hydrochloride Injection - Scientific Information

Manufacture: Fresenius Kabi USA, LLC
Country: United States
Condition: Nausea/Vomiting, Chemotherapy Induced, Nausea/Vomiting, Postoperative, Nausea/Vomiting, Radiation Induced
Class: 5HT3 receptor antagonists
Form: Liquid solution, Intravenous (IV)
Ingredients: Granisetron Hydrochloride, Sodium Chloride, Citric Acid Monohydrate, Sodium Citrate, Phenol

Description

Granisetron Hydrochloride Injection, USP is a serotonin-3 (5-HT3) receptor antagonist. Chemically it is endo-N-(9-methyl-9-azabicyclo [3.3.1] non-3-yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride.

Its chemical structure is:

Granisetron hydrochloride is a white to off-white solid that is readily soluble in water and normal saline at 20°C. Granisetron hydrochloride injection, USP is a clear, colorless, sterile, nonpyrogenic, aqueous solution for intravenous administration.

Granisetron hydrochloride injection, USP 1 mg/mL is available in 1 mL single-use and 4 mL multipleuse vials. Granisetron hydrochloride injection, USP 0.1 mg/mL is available in a 1 mL single-use vial.

1 mg/mL (preservative-free): Each 1 mL contains 1.12 mg granisetron hydrochloride equivalent to granisetron, 1 mg; sodium chloride, 9 mg; citric acid, monohydrate 0.67 mg (equivalent to 0.61 mg citric acid); sodium citrate dihydrate, 2.12 mg (equivalent to 1.86 mg sodium citrate); and Water for Injection, USP, q.s. The solution’s pH ranges from 4.0 to 6.0.

0.1 mg/mL (preservative-free): Each 1 mL contains 0.112 mg granisetron hydrochloride equivalent to granisetron, 0.1 mg; sodium chloride, 9 mg; citric acid, monohydrate 0.67 mg (equivalent to 0.61 mg citric acid); sodium citrate dihydrate, 2.12 mg (equivalent to 1.86 mg sodium citrate); and Water for Injection, USP, q.s. The solution’s pH ranges from 4.0 to 6.0.

1 mg/mL (preserved): Each 1 mL contains 1.12 mg granisetron hydrochloride equivalent to granisetron, 1 mg; sodium chloride, 9 mg; citric acid, monohydrate 0.67 mg (equivalent to 0.61 mg citric acid); sodium citrate dihydrate, 2.12 mg (equivalent to 1.86 mg sodium citrate); phenol, 5 mg, as a preservative and Water for Injection, USP, q.s. The solution’s pH ranges from 4.0 to 6.0.

Clinical Pharmacology

Mechanism of Action

Granisetron is a selective 5-hydroxytryptamine (5-HT3) receptor antagonist with little or no affinity for other serotonin receptors, including 5-HT1; 5-HT1A; 5-HT1B/C; 5-HT2; for alpha1-, alpha2- or betaadrenoreceptors; for dopamine-D2; or for histamine-H1; benzodiazepine; picrotoxin or opioid receptors.

Serotonin receptors of the 5-HT3 type are located peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. During chemotherapy-induced vomiting, mucosal enterochromaffin cells release serotonin, which stimulates 5-HT3 receptors. This evokes vagal afferent discharge and may induce vomiting. Animal studies demonstrate that, in binding to 5-HT3 receptors, granisetron blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli such as cisplatin. In the ferret animal model, a single granisetron injection prevented vomiting due to high-dose cisplatin or arrested vomiting within 5 to 30 seconds.

In most human studies, granisetron has had little effect on blood pressure, heart rate or ECG. No evidence of an effect on plasma prolactin or aldosterone concentrations has been found in other studies.

Granisetron hydrochloride injection exhibited no effect on oro-cecal transit time in normal volunteers given a single intravenous infusion of 50 mcg/kg or 200 mcg/kg. Single and multiple oral doses slowed colonic transit in normal volunteers.

Pharmacokinetics

Chemotherapy-Induced Nausea and Vomiting

In adult cancer patients undergoing chemotherapy and in volunteers, mean pharmacokinetic data obtained from an infusion of a single 40 mcg/kg dose of granisetron hydrochloride injection are shown in Table 1.

Table 1: Pharmacokinetic Parameters in Adult Cancer Patients Undergoing Chemotherapy and in Volunteers , Following a Single Intravenous 40 mcg/kg Dos e of Granis etron Hydrochloride Injection
Peak Plas ma
Concentration
(ng/mL)
Terminal Phas e
Plas ma Half-Life
(h)
Total
Clearance
(L/h/kg)
Volume of
Dis tribution
(L/kg)
Cancer Patients
 Mean 63.8* 8.95* 0.38* 3.07*
 Range 18 to 176 0.9 to 31.1 0.14 to 1.54 0.85 to 10.4
Volunteers
 21 to 42 years
 Mean 64.3 4.91 0.79 3.04
 Range 11.2 to 182 0.88 to 15.2 0.2 to 2.56 1.68 to 6.13
 65 to 81 years
 Mean 57 7.69 0.44 3.97
 Range 14.6 to 153 2.65 to 17.7 0.17 to 1.06 1.75 to 7.01

*5-minute infusion.

3-minute infusion.

Distribution

Plasma protein binding is approximately 65% and granisetron distributes freely between plasma and red blood cells.

Metabolism

Granisetron metabolism involves N-demethylation and aromatic ring oxidation followed by conjugation.

In vitro liver microsomal studies show that granisetron’s major route of metabolism is inhibited by ketoconazole, suggestive of metabolism mediated by the cytochrome P-450 3A subfamily. Animal studies suggest that some of the metabolites may also have 5-HT3 receptor antagonist activity.

Elimination

Clearance is predominantly by hepatic metabolism. In normal volunteers, approximately 12% of the administered dose is eliminated unchanged in the urine in 48 hours. The remainder of the dose is excreted as metabolites, 49% in the urine, and 34% in the feces.

Subpopulations
Gender

There was high inter- and intra-subject variability noted in these studies. No difference in mean AUC was found between males and females, although males had a higher Cmax generally.

Elderly

The ranges of the pharmacokinetic parameters in elderly volunteers (mean age 71 years), given a single 40 mcg/kg intravenous dose of granisetron hydrochloride injection, were generally similar to those in younger healthy volunteers; mean values were lower for clearance and longer for half-life in the elderly patients (see Table 1).

Pediatric Patients

A pharmacokinetic study in pediatric cancer patients (2 to 16 years of age), given a single 40 mcg/kg intravenous dose of granisetron hydrochloride injection, showed that volume

of distribution and total clearance increased with age. No relationship with age was observed for peak plasma concentration or terminal phase plasma half-life. When volume of distribution and total clearance are adjusted for body weight, the pharmacokinetics of granisetron are similar in pediatric and adult cancer patients.

Renal Failure Patients

Total clearance of granisetron was not affected in patients with severe renal failure who received a single 40 mcg/kg intravenous dose of granisetron hydrochloride injection.

Hepatically Impaired Patients

A pharmacokinetic study in patients with hepatic impairment due to neoplastic liver involvement showed that total clearance was approximately halved compared to patients without hepatic impairment. Given the wide variability in pharmacokinetic parameters noted in patients, dosage adjustment in patients with hepatic functional impairment is not necessary.

Postoperative Nausea and Vomiting

In adult patients (age range, 18 to 64 years) recovering from elective surgery and receiving general balanced anesthesia, mean pharmacokinetic data obtained from a single 1 mg dose of granisetron hydrochloride injection administered intravenously over 30 seconds are shown in Table 2.

Table 2: Pharmacokinetic Parameters in 16 Adult Surgical Patients Following a Single Intravenous 1 mg Dose of Granis etron Hydrochloride Injection
Terminal Phase Plas ma Half-Life
(h)
Total Clearance (L/h/kg) Volume of Dis tribution (L/kg)
Mean 8.63 0.28 2.42
Range 1.77 to 17.73 0.07 to 0.71 0.71 to 4.13

The pharmacokinetics of granisetron in patients undergoing surgery were similar to those seen in cancer patients undergoing chemotherapy.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 24-month carcinogenicity study, rats were treated orally with granisetron 1, 5 or 50 mg/kg/day (6, 30 or 300 mg/m2/day). The 50 mg/kg/day dose was reduced to 25 mg/kg/day (150 mg/m2/day) during week 59 due to toxicity. For a 50 kg person of average height (1.46 m2 body surface area), these doses represent 16, 81 and 405 times the recommended clinical dose (0.37 mg/m2, IV) on a body surface area basis. There was a statistically significant increase in the incidence of hepatocellular carcinomas and adenomas in males treated with 5 mg/kg/day (30 mg/m2/day, 81 times the recommended human dose based on body surface area) and above, and in females treated with 25 mg/kg/day (150 mg/m2/day, 405 times the recommended human dose based on body surface area). No increase in liver tumors was observed at a dose of 1 mg/kg/day (6 mg/m2/day, 16 times the recommended human dose based on body surface area) in males and 5 mg/kg/day (30 mg/m2/day, 81 times the recommended human dose based on body surface area) in females. In a 12-month oral toxicity study, treatment with granisetron 100 mg/kg/day (600 mg/m2/day, 1,622 times the recommended human dose based on body surface area) produced hepatocellular adenomas in male and female rats while no such tumors were found in the control rats. A 24-month mouse carcinogenicity study of granisetron did not show a statistically significant increase in tumor incidence, but the study was not conclusive.

Because of the tumor findings in rat studies, granisetron hydrochloride injection should be prescribed only at the dose and for the indication recommended [see Indications and Usage and Dosage and Administration].

Granisetron was not mutagenic in an in vitro Ames test and mouse lymphoma cell forward mutation assay, and in vivo mouse micronucleus test and in vitro and ex vivo rat hepatocyte UDS assays. It, however, produced a significant increase in UDS in HeLa cells in vitro and a significant increased incidence of cells with polyploidy in an in vitro human lymphocyte chromosomal aberration test.

Granisetron at subcutaneous doses up to 6 mg/kg/day (36 mg/m2/day, 97 times the recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.

Clinical Studies

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 asa 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

1 Cisplatin administration began within 10 minutes of granisetron hydrochloride injection infusion and continued for 1.5 to 3 hours. Mean cisplatin dose was 86 mg/m2 in the granisetron hydrochloride injection group and 80 mg/m2 in the placebo group.

2 No 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/m2. 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

1 Cisplatin 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/m2.

2 No 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/m2) or low (50 to 79 mg/m2) 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

1 Cisplatin administration began within 10 minutes of granisetron hydrochloride injection infusion and continued for 2 hours (mean). Mean cisplatin doses were 64 and 98 mg/m2 for low and high strata.

2 No 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/m2, cisplatin 20 to 50 mg/m2 and cyclophosphamide >600 mg/m2. 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
Granis etron 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

1 Patients also received dexamethasone, 12 mg.

2 No vomiting and no moderate or severe nausea.

In other studies of moderately emetogenic chemotherapy, no significant difference in efficacy was found between granisetron hydrochloride 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/m2, cytarabine ≥3 g/m2, cyclophosphamide ≥ 1 g/m2 or nitrogen mustard ≥6 mg/m2 (see Table 7).

Table 7: Prevention of Chemotherapy-Induced Nausea and Vomiting in Pediatric Patients
Granis etron 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%

1 No 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/m2/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.

Postoperative Nausea and Vomiting

Prevention of Postoperative Nausea and Vomiting

The efficacy of granisetron hydrochloride injection for prevention of postoperative nausea and vomiting was evaluated in 868 patients, of which 833 were women, 35 men, 484 Caucasians, 348 Asians, 18 Blacks, 18 Other, with 61 patients 65 years or older. Granisetron hydrochloride injection was evaluated in two randomized, double-blind, placebo-controlled studies in patients who underwent elective gynecological surgery or cholecystectomy and received general anesthesia. Patients received a single intravenous dose of granisetron hydrochloride injection (0.1 mg, 1 mg or 3 mg) or placebo either 5 minutes before induction of anesthesia or immediately before reversal of anesthesia. The primary endpoint was the proportion of patients with no vomiting for 24 hours after surgery. Episodes of nausea and vomiting and use of rescue antiemetic therapy were recorded for 24 hours after surgery. In both studies, granisetron hydrochloride injection (1 mg) was more effective than placebo in preventing postoperative nausea and vomiting (see Table 8). No additional benefit was seen in patients who received the 3 mg dose.

Table 8: Prevention of Pos toperative Nausea and Vomiting in Adult Patients
Study and Efficacy
Endpoint
Placebo Granisetron
Hydrochloride
Injection
0.1 mg
Granisetron
Hydrochloride
Injection
1 mg
Granisetron
Hydrochloride
Injection
3 mg
Study 1
Number of
Patients
133 132 134 128
No Vomiting
0 to 24 hours 34% 45% 63%** 62%**
No Nausea
0 to 24 hours 22% 28% 50%** 42%**
No Nausea or
Vomiting
0 to 24 hours 18% 27% 49%** 42%**
No Use of Rescue
Antiemetic
Therapy
0 to 24 hours 60% 67% 75%** 77%**
Study 2
Number of
Patients
117 - 110 114
No Vomiting
0 to 24 hours 56% - 77%** 75%**
No Nausea
0 to 24 hours 37% - 59% 56%

*P<0.05

**P<0.001 versus placebo

Note: No Vomiting = no vomiting and no use of rescue antiemetic therapy; No Nausea = no nausea and no use of rescue antiemetic therapy

Gender/Race

There were too few male and Black patients to adequately assess differences in effect in either population.

Treatment of Postoperative Nausea and Vomiting

The efficacy of granisetron hydrochloride injection for treatment of postoperative nausea and vomiting was evaluated in 844 patients, of which 731 were women, 113 men, 777 Caucasians, 6 Asians, 41 Blacks, 20 Other, with 107 patients 65 years or older. Granisetron hydrochloride injection was evaluated in two randomized, double-blind, placebo-controlled studies of adult surgical patients who received general anesthesia with no prophylactic antiemetic agent, and who experienced nausea or vomiting within 4 hours postoperatively. Patients received a single intravenous dose of granisetron hydrochloride injection (0.1 mg, 1 mg or 3 mg) or placebo after experiencing postoperative nausea or vomiting. Episodes of nausea and vomiting and use of rescue antiemetic therapy were recorded for 24 hours after administration of study medication. Granisetron hydrochloride injection was more effective than placebo in treating postoperative nausea and vomiting (see Table 9). No additional benefit was seen in patients who received the 3 mg dose.

Table 9: Treatment of Postoperative Nausea and Vomiting in Adult Patients
Study and
Efficacy
Endpoint
Placebo Granis etron
Hydrochloride
Injection
0.1 mg
Granis etron
Hydrochloride
Injection
1 mg
Granis etron
Hydrochloride
Injection
3 mg
Study 3
Number of
Patients
133 128 133 125
No Vomiting
 0 to 6 hours 26% 53%*** 58%*** 60%***
 0 to 24 hours 20% 38%*** 46%*** 49%***
No Nausea
 0 to 6 hours 17% 40%*** 41%*** 42%***
 0 to 24 hours 13% 27%** 30%** 37%***
No Use of
Rescue
Antiemetic
Therapy
 0 to 6 hours
 0 to 24 hours 33% 51%** 61%*** 61%***
Study 4
Number of
Patients
(All Patients)
162 163
No Vomiting
 0 to 6 hours 20% 32%*
 0 to 24 hours 14% 23%*
No Nausea
 0 to 6 hours 13% 18%
 0 to 24 hours 9% 14%
No Nausea or
Vomiting
 0 to 6 hours 13% 18%
 0 to 24 hours 9% 14%
No Use of
Rescue
Antiemetic
Therapy
 0 to 6 hours
 0 to 24 hours 24% 34%
Number of
Patients
(Treated for
Vomiting)1
86 103
No Vomiting
 0 to 6 hours 21% 27%
 0 to 24 hours 14% 20%

*P<0.05

**P<0.01

***P<0.001 versus placebo

1 Protocol Specified Analysis: Patients who had vomiting prior to treatment

Note: No vomiting = no vomiting and no use of rescue antiemetic therapy; No nausea = no nausea and no use of rescue antiemetic therapy

Gender/Race

There were too few male and Black patients to adequately assess differences in effect in either population.