Granisol.net

Package Insert
Metabolism
Table 3 Prevention of Nausea and Vomiting 24 Hours Post-Chemotherapy1
Granisetron metabolism involves N-demethylation and aromatic ring oxidation followed by conjuga- PediatRx, Inc.
Percentages of Patients
tion. In vitro liver microsomal studies show that granisetron’s major route of metabolism is inhibitedby ketoconazole, suggestive of metabolism mediated by the cytochrome P-450 3A subfamily. Animal Efficacy Measures
Granisetron HCl
Granisetron HCl
Prochlorperazine2
Granisol™ (granisetron HCl) Oral Solution
studies suggest that some of the metabolites may also have 5-HT receptor antagonist activity.
10 mg twice daily
1 mg twice a day
2 mg once a day
Elimination
DESCRIPTION
Clearance is predominantly by hepatic metabolism. In normal volunteers, approximately 11% of the Granisol™ Oral Solution contains granisetron hydrochloride, an antinauseant and antiemetic agent.
orally administered dose is eliminated unchanged in the urine in 48 hours. The remainder of the Chemically it is endo-N-(9-methyl-9-azabicyclo [3.3.1] non-3-yl)-1-methyl-1H-indazole-3- dose is excreted as metabolites, 48% in the urine and 38% in the feces.
carboxamide hydrochloride with a molecular weight of 348.9 (312.4 free base). Its empirical for- Subpopulations
mula is C H N O•HCl, while its chemical structure is: The effects of gender on the pharmacokinetics of granisetron HCl tablets have not been studied.
However, after intravenous infusion of granisetron, no difference in mean AUC was found between Moderately emetogenic chemotherapeutic agents included cisplatin (20 mg/m2 to 50 mg/m2), males and females, although males had a higher C oral and intravenous cyclophosphamide, carboplatin, dacarbazine, doxorubicin.
2 Historical control from a previous double-blind granisetron trial.
In elderly and pediatric patients and in patients with renal failure or hepatic impairment, the phar- 3 No vomiting, no moderate or severe nausea, no rescue medication.
macokinetics of granisetron was determined following administration of intravenous granisetron.
4 No vomiting, no nausea, no rescue medication.
* Statistically significant (P < 0.05) vs. prochlorperazine historical control.
Granisetron hydrochloride is a white to off-white solid that is readily soluble in water and normal The ranges of the pharmacokinetic parameters in elderly volunteers (mean age 71 years), given a sin - Results from a granisetron HCl tablets 2 mg daily alone treatment arm in a third double-blind, ran- gle 40-mcg/kg intravenous dose of granisetron HCl injection, were generally similar to those in younger domized trial, were compared to prochlorperazine (PCPZ), 10 mg bid, derived from a historical con- healthy volunteers; mean values were lower for clearance and longer for half-life in the elderly.
Oral Solution
trol. The 24-hour results for granisetron HCl tablets 2 mg daily were statistically superior to PCPZ Each 10 mL of clear, orange-colored, orange-flavored Granisol™ Oral Solution contains 2.24 mg of Renal Failure Patients
for all efficacy parameters: complete response (58%), no vomiting (79%), no nausea (51%), total granisetron hydrochloride equivalent to 2 mg granisetron. Inactive ingredients: citric acid anhy- Total clearance of granisetron was not affected in patients with severe renal failure who received control (49%). The PCPZ rates are shown in Table 3.
drous, FD&C Yellow No. 6, orange flavor, purified water, sodium benzoate, and sorbitol.
a single 40 mcg/kg intravenous dose of granisetron HCl injection.
Cisplatin-Based Chemotherapy
Hepatically Impaired Patients
CLINICAL PHARMACOLOGY
The first double-blind trial compared granisetron HCl tablets 1 mg bid, relative to placebo (historical A pharmacokinetic study with intravenous granisetron in patients with hepatic impairment due to Granisetron is a selective 5-hydroxytryptamine (5-HT ) receptor antagonist with little or no affin - control), in 119 cancer patients receiving high-dose cisplatin (mean dose 80 mg/m2). At 24 hours, neoplastic liver involvement showed that total clearance was approximately halved compared to ity for other serotonin receptors, including 5-HT ; 5-HT ; 5-HT granisetron HCl tablets 1 mg bid was significantly (P < 0.001) superior to placebo (historical con- patients without hepatic impairment. Given the wide variability in pharmacokinetic parameters beta-adrenoreceptors; for dopamine-D ; or for histamine-H ; benzodiazepine; picrotoxin or opioid trol) in all efficacy parameters: complete response (52%), no vomiting (56%) and no nausea (45%).
noted in patients, dosage adjustment in patients with hepatic functional impairment is not The placebo rates were 7%, 14%, and 7%, respectively, for the three efficacy parameters.
Serotonin receptors of the 5-HT type are located peripherally on vagal nerve terminals and cen- Results from a granisetron HCl tablets 2 mg once a day alone treatment arm in a second double- Pediatric Patients
trally in the chemoreceptor trigger zone of the area postrema. During chemotherapy that induces blind, randomized trial, were compared to both granisetron HCl tablets 1 mg twice a day and place- A pharmacokinetic study in pediatric cancer patients (2 to 16 years of age), given a single vomiting, mucosal enterochromaffin cells release serotonin, which stimulates 5-HT receptors. This bo historical controls. The 24-hour results for granisetron HCl tablets 2 mg once a day were: com- 40 mcg/kg intravenous dose of granisetron HCl injection, showed that volume of distribution and evokes vagal afferent discharge, inducing vomiting. Animal studies demonstrate that, in binding to plete response (44%), no vomiting (58%), no nausea (46%), total control (40%). The efficacy of total clearance increased with age. No relationship with age was observed for peak plasma con- 5-HT receptors, granisetron blocks serotonin stimulation and subsequent vomiting after emeto- granisetron HCl tablets 2 mg once a day was comparable to granisetron HCl tablets 1 mg twice centration or terminal phase plasma half-life. When volume of distribution and total clearance are genic stimuli such as cisplatin. In the ferret animal model, a single granisetron injection prevented aday and statistically superior to placebo. The placebo rates were 7%, 14%, 7%, and 7%, respec- adjusted for body weight, the pharmacokinetics of granisetron are similar in pediatric and adult 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 No controlled study comparing granisetron injection with the oral formulation to prevent evidence of an effect on plasma prolactin or aldosterone concentrations has been found in other CLINICAL TRIALS
chemotherapy-induced nausea and vomiting has been performed.
Chemotherapy-Induced Nausea and Vomiting
Radiation-Induced Nausea and Vomiting
Following single and multiple oral doses, granisetron HCl tablets slowed colonic transit in normal Granisetron HCl tablets prevent nausea and vomiting associated with initial and repeat courses of Total Body Irradiation
volunteers. However, granisetron had no effect on oro-cecal transit time in normal volunteers when emetogenic cancer therapy, as shown by 24-hour efficacy data from studies using both moderately- In a double-blind randomized study, 18 patients receiving granisetron HCl tablets, 2 mg daily, expe- given as a single intravenous (IV) infusion of 50 mcg/kg or 200 mcg/kg.
rienced significantly greater antiemetic protection compared to patients in a historical negative Pharmacokinetics
Moderately Emetogenic Chemotherapy
control group who received conventional (non-5-HT antagonist) antiemetics. Total body irradiation In healthy volunteers and adult cancer patients undergoing chemotherapy, administration of The first trial compared granisetron HCl tablets doses of 0.25 mg to 2 mg twice a day, in 930 can- consisted of 11 fractions of 120 cGy administered over 4 days, with three fractions on each of the granisetron HCl tablets produced mean pharmacokinetic data shown in Table 1.
cer patients receiving, principally, cyclophosphamide, carboplatin, and cisplatin (20 mg/m2 to first 3 days, and two fractions on the fourth day. Granisetron HCl tablets were given one hour before 50 mg/m2). Efficacy was based on complete response (i.e., no vomiting, no moderate or severe the first radiation fraction of each day.
Table 1 Pharmacokinetic Parameters (Median [range]) Following Granisetron HCl Tablets
nausea, no rescue medication), no vomiting, and no nausea. Table 2 summarizes the results of this
Twenty-two percent (22%) of patients treated with granisetron HCl tablets did not experience vom- Peak Plasma
Terminal Phase
Volume of
Total Clearance
iting or receive rescue antiemetics over the entire 4-day dosing period, compared to 0% of patients Concentration
Plasma Half-Life
Distribution
(L/h/kg)
Table 2 Prevention of Nausea and Vomiting 24 Hours Post-Chemotherapy1
in the historical negative control group (P < 0.01).
Percentages of Patients
In addition, patients who received granisetron HCl tablets also experienced significantly fewer Cancer Patients
Granisetron HCl Tablet Dose
emetic episodes during the first day of radiation and over the 4-day treatment period, compared to patients in the historical negative control group. The median time to the first emetic episode was Efficacy Measures
0.25 mg bid
0.5 mg bid
36 hours for patients who received granisetron HCl tablets.
Volunteers
Fractionated Abdominal Radiation
single 1 mg dose
The efficacy of granisetron HCl tablets, 2 mg daily, was evaluated in a double-blind, placebo- controlled randomized trial of 260 patients. Granisetron HCl tablets were given 1 hour before radi- Not determined after oral administration; following a single intravenous dose of 40 mcg/kg, ation, composed of up to 20 daily fractions of 180 to 300 cGy each. The exceptions were patients terminal phase half-life was determined to be 8.95 hours.
with seminoma or those receiving whole abdomen irradiation who initially received 150 cGy per Chemotherapy included oral and injectable cyclophosphamide, carboplatin, cisplatin (20 mg/m2 fraction. Radiation was administered to the upper abdomen with a field size of at least 100 cm2.
to 50 mg/m2), dacarbazine, doxorubicin, epirubicin. A 2 mg dose of Granisol Oral Solution is bioequivalent to the corresponding dose of granisetron 2 No vomiting, no moderate or severe nausea, no rescue medication.
The proportion of patients without emesis and those without nausea for granisetron HCl tablets, HCl tablets (1 mg x 2) and may be used interchangeably.
* Statistically significant (P < 0.01) vs. 0.25 mg bid. compared to placebo, was statistically significant (P < 0.0001) at 24 hours after radiation, irrespec- Absorption
† Statistically significant (P < 0.01) vs. 0.5 mg bid. tive of the radiation dose. Granisetron was superior to placebo in patients receiving up to 10 daily When granisetron HCl tablets were administered with food, AUC was decreased by 5% and C fractions of radiation, but was not superior to placebo in patients receiving 20 fractions.
Results from a second double-blind, randomized trial evaluating granisetron HCl tablets 2 mg once increased by 30% in non-fasted healthy volunteers who received a single dose of 10 mg.
a day and granisetron HCl tablets 1 mg twice a day were compared to prochlorperazine 10 mg Patients treated with granisetron HCl tablets (n=134) had a significantly longer time to the first Distribution
twice a day derived from a historical control. At 24 hours, there was no statistically significant dif- episode of vomiting (35 days vs. 9 days, P < 0.001) relative to those patients who received placebo Plasma protein binding is approximately 65% and granisetron distributes freely between plasma ference in efficacy between the two granisetron HCl tablet regimens. Both regimens were statisti- (n=126), and a significantly longer time to the first episode of nausea (11 days vs. 1 day, P < 0.001).
cally superior to the prochlorperazine control regimen (see Table 3).
Granisetron provided significantly greater protection from nausea and vomiting than placebo.
INDICATIONS AND USAGE
Pregnancy
Table 5 Principal Adverse Events in Clinical Trials — Single-Day Chemotherapy
Granisetron is indicated for the prevention of: Teratogenic Effects
Percent of Patients with Event
ț Nausea and vomiting associated with initial and repeat courses of emetogenic cancer therapy, Pregnancy Category B
Granisetron HCl Injection1
Comparator2
Reproduction studies have been performed in pregnant rats at oral doses up to 125 mg/kg/day 40 mcg/kg
Nausea and vomiting associated with radiation, including total body irradiation and fractionated (750 mg/m2/day, 507 times the recommended human dose based on body surface area) and preg- (n=1268)
nant rabbits at oral doses up to 32 mg/kg/day (378 mg/m2/day, 255 times the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or CONTRAINDICATIONS
harm to the fetus due to granisetron. There are, however, no adequate and well-controlled studies Granisetron is contraindicated in patients with known hypersensitivity to the drug or any of its com- in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
PRECAUTIONS
Nursing Mothers
1 Adverse events were generally recorded over 7 days post-granisetron HCl injection administration.
Granisetron is not a drug that stimulates gastric or intestinal peristalsis. It should not be used It is not known whether granisetron is excreted in human milk. Because many drugs are excreted 2 Metoclopramide/dexamethasone and phenothiazines/dexamethasone.
instead of nasogastric suction. The use of granisetron in patients following abdominal surgery or in in human milk, caution should be exercised when granisetron is administered to a nursing woman.
In the absence of a placebo group, there is uncertainty as to how many of these events should be patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or Pediatric Use
attributed to granisetron, except for headache, which was clearly more frequent than in compari- Safety and effectiveness in pediatric patients have not been established.
An adequate QT assessment has not been conducted, but QT prolongation has been reported with Geriatric Use
Radiation-Induced Nausea and Vomiting
granisetron. Therefore, Granisol Oral Solution should be used with caution in patients with pre- During clinical trials, 325 patients 65 years of age or older received granisetron HCl tablets; 298 In controlled clinical trials, the adverse events reported by patients receiving granisetron HCl tablets existing arrhythmias or cardiac conduction disorders, as this might lead to clinical consequences.
were 65 to 74 years of age, and 27 were 75 years of age or older. Efficacy and safety were main- and concurrent radiation were similar to those reported by patients receiving granisetron Patients with cardiac disease, on cardio-toxic chemotherapy, with concomitant electrolyte abnor- HCl tablets prior to chemotherapy. The most frequently reported adverse events were diarrhea, malities and/or on concomitant medications that prolong the QT interval are particularly at risk.
asthenia, and constipation. Headache, however, was less prevalent in this patient population.
Drug Interactions
ADVERSE REACTIONS
Postmarketing Experience
Granisetron does not induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system in QT prolongation has been reported with granisetron (see PRECAUTIONS and Drug Interactions).
QT prolongation has been reported with granisetron (see PRECAUTIONS and Drug Interactions).
vitro. There have been no definitive drug-drug interaction studies to examine pharmacokinetic or Chemotherapy-Induced Nausea and Vomiting
OVERDOSAGE
pharmacodynamic interaction with other drugs; however, in humans, granisetron HCl injection has Over 3700 patients have received granisetron HCl tablets in clinical trials with emetogenic cancer There is no specific treatment for granisetron hydrochloride overdosage. In case of overdosage, been safely administered with drugs representing benzodiazepines, neuroleptics, and anti-ulcer therapies consisting primarily of cyclophosphamide or cisplatin regimens.
symptomatic treatment should be given. Overdosage of up to 38.5 mg of granisetron hydrochloride medications commonly prescribed with antiemetic treatments. Granisetron HCl injection also does In patients receiving granisetron HCl tablets 1 mg bid for 1, 7 or 14 days, or 2 mg daily for 1 day, injection has been reported without symptoms or only the occurrence of a slight headache.
not appear to interact with emetogenic cancer chemotherapies. Because granisetron is metabo- adverse experiences reported in more than 5% of the patients with comparator and placebo inci- lized by hepatic cytochrome P-450 drug-metabolizing enzymes, inducers or inhibitors of these dences are listed in Table 4.
DOSAGE AND ADMINISTRATION
enzymes may change the clearance and, hence, the half-life of granisetron. No specific interaction Emetogenic Chemotherapy
Table 4 Principal Adverse Events in Clinical Trials
studies have been conducted in anesthetized patients. In addition, the activity of the cytochrome The recommended adult dosage of oral granisetron hydrochloride is 2 mg once daily or 1 mg twice P-450 subfamily 3A4 (involved in the metabolism of some of the main narcotic analgesic agents) Percent of Patients With Event
daily. In the 2 mg once-daily regimen, 10 mL of Granisol Oral Solution (2 teaspoonfuls, equivalent is not modified by granisetron in vitro.
GranisetronHCl1
GranisetronHCl 1
Comparator2
to 2 mg of granisetron) are given up to 1 hour before chemotherapy. In the 1 mg twice-daily regi-men, the first teaspoonful (5 mL) of Granisol Oral Solution is given up to 1 hour before chemother- In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of granisetron.
apy, and the second teaspoonful (5 mL) of Granisol Oral Solution, 12 hours after the first. Either reg- However, the clinical significance of in vivo pharmacokinetic interactions with ketoconazole is not 1 mg twice a day
2 mg once a day
imen is administered only on the day(s) chemotherapy is given. Continued treatment, while not on known. In a human pharmacokinetic study, hepatic enzyme induction with phenobarbital resulted (n=1450)
chemotherapy, has not been found to be useful.
in a 25% increase in total plasma clearance of intravenous granisetron. The clinical significance of Use in the Elderly, Renal Failure Patients or Hepatically Impaired Patients
No dosage adjustment is recommended (see CLINICAL PHARMACOLOGY: Pharmacokinetics).
QT prolongation has been reported with granisetron. Use of Granisol Oral Solution in patients con- Pediatric Use
currently treated with drugs known to prolong the QT interval and/or are arrhythmogenic may result Safety and effectiveness in pediatric patients have not been established.
Radiation (Either Total Body Irradiation or Fractionated Abdominal Radiation)
Carcinogenesis, Mutagenesis, Impairment of Fertility
The recommended adult dosage of oral granisetron hydrochloride is 2 mg once daily. Ten milliliters In a 24-month carcinogenicity study, rats were treated orally with granisetron 1, 5 or 50 mg/kg/day Adverse events were recorded for 7 days when granisetron HCl tablets were given on a single of Granisol Oral Solution (2 teaspoonfuls, equivalent to 2 mg of granisetron) are taken within 1 hour (6, 30 or 300 mg/m2/day). The 50 mg/kg/day dose was reduced to 25 mg/kg/day (150 mg/m2/day) day and for up to 28 days when granisetron HCl tablets were administered for 7 or 14 days.
during week 59 due to toxicity. For a 50 kg person of average height (1.46 m2 body surface area), Metoclopramide/dexamethasone; phenothiazines/dexamethasone; dexamethasone alone; Pediatric Use
these doses represent 4, 20, and 101 times the recommended clinical dose (1.48 mg/m2, oral) on Safety and effectiveness in pediatric patients have not been established.
a body surface area basis. There was a statistically significant increase in the incidence of hepa- Other adverse events reported in clinical trials were: Use in the Elderly
tocellular carcinomas and adenomas in males treated with 5 mg/kg/day (30 mg/m2/day, 20 times Gastrointestinal: In single-day dosing studies in which adverse events were collected for 7 days, No dosage adjustment is recommended.
the recommended human dose based on body surface area) and above, and in females treated with nausea (20%) and vomiting (12%) were recorded as adverse events after the 24-hour efficacy 25 mg/kg/day (150 mg/m2/day, 101 times the recommended human dose based on body surface HOW SUPPLIED
area). No increase in liver tumors was observed at a dose of 1 mg/kg/day (6 mg/m2/day, 4 times Hepatic: In comparative trials, elevation of AST and ALT (> 2 times the upper limit of normal) following Oral Solution
the recommended human dose based on body surface area) in males and 5 mg/kg/day the administration of granisetron HCl tablets occurred in 5% and 6% of patients, respectively. These Clear, orange-colored, orange-flavored, 2 mg/10 mL, in 30 mL amber glass bottles with child- (30 mg/m2/day, 20 times the recommended human dose based on body surface area) in females.
frequencies were not significantly different from those seen with comparators (AST: 2%; ALT: 9%).
In a 12-month oral toxicity study, treatment with granisetron 100 mg/kg/day (600 mg/m2/day, Cardiovascular: Hypertension (1%); hypotension, angina pectoris, atrial fibrillation, and syncope Storage
405 times the recommended human dose based on body surface area) produced hepatocellular Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).
adenomas in male and female rats while no such tumors were found in the control rats. A 24-month [See USP Controlled Room Temperature]. Keep bottle closed tightly and stored in an upright posi- mouse carcinogenicity study of granisetron did not show a statistically significant increase in tumor Central Nervous System: Dizziness (5%), insomnia (5%), anxiety (2%), somnolence (1%). One case incidence, but the study was not conclusive.
compatible with, but not diagnostic of, extrapyramidal symptoms has been reported in a patient treated with granisetron HCl tablets.
Because of the tumor findings in rat studies, granisetron should be prescribed only at the dose and for the indication recommended (see INDICATIONS AND USAGE, and DOSAGE AND ADMINIS-
Hypersensitivity: Rare cases of hypersensitivity reactions, sometimes severe (eg, anaphylaxis, TRATION).
shortness of breath, hypotension, urticaria) have been reported.
Granisetron was not mutagenic in the in vitro Ames test and mouse lymphoma cell forward muta- Other: Fever (5%). Events often associated with chemotherapy also have been reported: leukope- Therapex
tion assay, and in vivo mouse micronucleus test and in vitro and ex vivo rat hepatocyte UDS assays.
nia (9%), decreased appetite (6%), anemia (4%), alopecia (3%), thrombocytopenia (2%).
It, however, produced a significant increase in UDS in HeLa cells in vitro and a significant increased Over 5000 patients have received injectable granisetron in clinical trials.
incidence of cells with polyploidy in an in vitro human lymphocyte chromosomal aberration test.
Table 5 gives the comparative frequencies of the five commonly reported adverse events (≥ 3%)
Granisetron at oral doses up to 100 mg/kg/day (600 mg/m2/day, 405 times the recommended in patients receiving granisetron HCl injection, 40 mcg/kg, in single-day chemotherapy trials. These human dose based on body surface area) was found to have no effect on fertility and reproductive patients received chemotherapy, primarily cisplatin, and intravenous fluids during the 24-hour peri- performance of male and female rats.
od following granisetron HCl injection administration.

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