SANCUSO

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

Intravenous Administration
Granisetron hydrochloride injection solution
-For intravenous use only.
-Administer 30 minutes before the administration of chemotherapy.

IV Push
-May be given undiluted over 30 seconds via Y-site.

Intermittent IV infusion
-Prepare IV infusion at the time of administration. Dilute dose in 5% Dextrose or 0.9% Sodium Chloride Injection.
-Infuse IV over 5 minutes.
-Storage: When diluted as directed, granisetron has been shown to be stable for at least 24 hours and stored at room temperature under normal lighting conditions.



Topical Administration
Transdermal Patch Formulations
Granisetron transdermal patch (Sancuso) (NOTE: Not FDA-approved for use in pediatric patients)

-Each patch releases 3.1 mg of granisetron per 24 hours for up to 7 days.
-The patch should be applied directly after the pouch has been opened.
-Only one patch should be worn at any time.
-Do not cut the patch.
-Open the pouch and apply the patch to clean, dry, nearly hairless, intact healthy skin on the upper outer arm. Do not place the patch on skin that is red, irritated, or damaged.
-After the patch is applied, wash hands thoroughly.
-Do not apply a heat pad or heat lamp over or in the vicinity of the patch and avoid extended exposure to heat.
-Cover the application site of the patch with clothing, if there is a risk of exposure to direct natural or artificial sunlight throughout the period of wear and for 10 days following its removal.
-Remove the patch by peeling off gently from the skin.
-Upon removal, fold the patch in half with the sticky side together, and discard in the household trash in a manner that prevents accidental contact or ingestion by children, pets or others.

Gastrointestinal effects are relatively frequent with granisetron use. Constipation is one of the most commonly occurring adverse events, reported by approximately 3-18% of adult patients in clinical trials. Interestingly, diarrhea may also occur (reported by 3-9% of adults in controlled trials). In a dose finding study of granisetron in pediatric patients receiving high-dose cisplatin chemotherapy, constipation (2 mcg/kg, 5.8%; 10 mcg/kg, 3.8%; 40 mcg/kg, 0%) and diarrhea (2 mcg/kg, 3.8%; 10 mcg/kg, 5.8%; 40 mcg/kg, 5.7%) were reported. Abdominal pain (4-6%) and dyspepsia (4-6%) occurred at a rate similar to the comparator and placebo groups in clinical trials involving adult patients. Nausea and vomiting were reported after the 24-hour efficacy period in single-day dosing studies with oral granisetron. Additionally, decreased appetite or anorexia occurred in 6% of patients who received oral granisetron and dysgeusia (taste disorder) was reported in 2% of patients who received granisetron IV (2-160 mcg/kg over single or multiple days) in clinical trials.

Headache is a common adverse reaction to injectable and oral granisetron therapy and has been reported in up to 21% of adult patients. In a dose-finding study of granisetron in pediatric patients receiving high-dose cisplatin chemotherapy, headache occurred in 7 to 11.5% of patients. Other central nervous system adverse effects that occurred with IV or oral granisetron in adult clinical trials include headache (transdermal, 1%), insomnia (IV, less than 2%; oral, 5%), anxiety (IV, less than 2%; oral, 2%), drowsiness (IV, 4%; oral, 1%), dizziness (IV, 4%; oral, 5%), agitation (IV, less than 2%), and CNS excitability (IV, less than 2%). There has been one case report of extrapyramidal symptoms (EPS) with oral granisetron; rare cases of extrapyramidal syndrome with IV granisetron (in patients who also received other EPS-causing drugs) have been reported.

Asthenia was reported commonly with the use of granisetron 1 mg PO twice daily for 1, 7, or 14 days (14%) and 2 mg PO daily for 1 day (18%), and 40 mcg/kg IV once (5%) prior to emetogenic chemotherapy in adult patients in clinical trials. Asthenia also occurred commonly with the use of oral granisetron prior to radiation therapy in clinical trials.

In comparative clinical trials, elevated hepatic enzymes have been reported with granisetron given to prevent chemotherapy-induced nausea and vomiting. AST and ALT level elevations of greater than 2 times the upper limit of normal were reported in 5% and 6% of adult patients, respectively, who received oral tablets, in 2.8% and 3.3% of patients, respectively, who received IV (2-160 mcg/kg over single or multiple days), and in 5.6% of adult patients who received granisetron 1 mg IV for postoperative nausea and vomiting. The incidence of elevated transaminase concentrations was not significantly increased with oral or IV use compared with comparator agents in clinical studies.

QT prolongation has been reported with granisetron in post-marketing surveillance. Use with caution in patients with pre-existing arrhythmias or cardiac conduction disorders; other risk factors for QT prolongation include patients with cardiac disease or electrolyte abnormalities and patients receiving concomitant cardio-toxic chemotherapy or medications that also cause QT-interval prolongation. In a prospective crossover randomized dose comparison trial in pediatric patients (median 8.7 years of age) not using cardiotoxic chemotherapeutic agents, granisetron 40 mcg/kg/dose caused bradycardia; no other cardiac side effects were reported. In a study of 22 children and adolescents (2 to 16 years old) receiving granisetron 40 mcg/kg IV or ondansetron 0.1 mg/kg IV, granisetron transiently affected cardiac repolarization, but ondansetron did not. Hypertension was reported in 2% of adult patients who received granisetron IV (2 to 160 mcg/kg over single or multiple days) and 1% of patients who received oral tablets prior to emetogenic chemotherapy in clinical trials. In a dose finding study of granisetron in pediatric patients receiving high-dose cisplatin chemotherapy, hypertension occurred in more than 5% of patients (2 mcg/kg, 5.8%; 10 mcg/kg, 3.8%; 40 mcg/kg, 5.7%). Hypotension and atrial fibrillation were reported rarely with IV and oral use. Other cardiovascular adverse effects that occurred rarely with IV granisetron in clinical trials include ECG abnormalities and other arrhythmias (e.g., bradycardia, AV block, ventricular ectopy including non-sustained tachycardia). Angina pectoris and syncope were reported rarely with oral granisetron in clinical trials. Bradycardia, chest pain (unspecified), palpitations, and sick sinus syndrome have been reported with post-marketing use of the transdermal patch.

Hypersensitivity reactions, some cases severe (e.g., anaphylactoid reactions, dyspnea, hypotension, urticaria), have been reported with parenteral, oral, and transdermal granisetron. Granisetron should be used cautiously in patients with a history of hypersensitivity reactions to other 5HT3 receptor antagonists; cross-sensitivity may be seen between these agents. Furthermore, it has been hypothesized that antagonism at serotonin (5HT) receptors, and increased concentrations of serotonin, increase the risk of developing bronchospasm. In a case report, a 1-year-old girl with cancer experienced an anaphylactic reaction to the 4th dose of ondansetron. After 2 weeks, the patient was given granisetron and did not experience a reaction. Prior to granisetron administration, a granisetron prick, intradermal, and oral provocation test was performed. Additionally, the dose was divided into 3 smaller doses that were given at 30-minute intervals.

Leukopenia (9%), anemia (4%), and thrombocytopenia (2%) were reported in adult patients who received oral granisetron to prevent chemotherapy-induced nausea and vomiting in clinical trials. These events may have been associated with concomitant chemotherapy use.

In clinical trials that studied granisetron to prevent chemotherapy-induced nausea and vomiting, alopecia was reported in 3% of adult patients who received oral granisetron and rash (unspecified) was reported in 1% of adult patients who received IV granisetron (2 to 160 mcg/kg over single or multiple days). Alopecia may have been associated with concomitant chemotherapy use. Application site reactions (e.g., skin irritation) have occurred with granisetron transdermal patch use in clinical trials; however, the incidence of this adverse effect was similar to placebo. Patch non-adhesion and other application site reactions including pain, pruritus, erythema, rash, vesicles (vesicular rash), burn, skin discoloration, and urticaria have been reported postmarketing. Remove the patch if a severe or generalized skin reaction (e.g., allergic rash, erythematous, macular, papular rash, or pruritus) occurs.

Fever was reported in 3% of patients who received IV granisetron (2-160 mcg/kg over single or multiple days) and 7.9% of adult patients who received a single dose of 1 mg IV for postoperative nausea and vomiting. In clinical trials, 5% of adult patients who received oral granisetron to prevent chemotherapy-induced nausea and vomiting reported fever. Fever occurred more often with IV granisetron compared with comparator arms (8.6% vs 3.4%; p < 0.014) in multiple-day dosing studies; most comparator arms contained dexamethasone.

Serotonin syndrome has been reported with 5-HT3 receptor antagonists, such as granisetron, during concurrent use of other medications known to increase CNS or peripheral serotonin concentrations or during overdose. Some of the reported cases were fatal; most occurred in a post-anesthesia care unit or infusion center. If serotonin syndrome becomes evident during treatment, discontinue granisetron and any other serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome includes a range of signs and symptoms that can include mental status changes (e.g., agitation, hallucinations, delirium, coma), gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), and/or seizures. Cases consistent with serotonin syndrome have been reported in pediatric patients after inadvertent overdose of another 5-HT3 receptor antagonist (oral ondansetron at an estimated ingestion > 5 mg/kg). Symptoms reported in these cases included somnolence, agitation, tachycardia, tachypnea, hypertension, flushing, mydriasis, diaphoresis, myoclonic movements, horizontal nystagmus, hyperreflexia, and seizures. Patients required supportive care, including intubation in some cases, with complete recovery in 1-2 days.

Granisetron should be avoided in patients with known or suspected granisetron hypersensitivity or to any inactive ingredients of the product. Granisetron should be used with caution in patients with ondansetron hypersensitivity, palonosetron hypersensitivity, dolasetron hypersensitivity, or hypersensitivity to similar drugs; cross sensitivity may be seen between these agents. Furthermore, it has been hypothesized that antagonism at serotonin (5HT) receptors, and the subsequent increased concentrations of serotonin, increase the risk of developing bronchospasm and/or vasoconstriction. In a case report, a 1-year-old girl with cancer experienced an anaphylactic reaction to the 4th dose of ondansetron. After 2 weeks, the patient was given granisetron and did not experience a reaction. Prior to granisetron administration, a granisetron prick, intradermal, and oral provocation test was performed. Additionally, the dose was divided into 3 smaller doses that were given at 30 minute intervals.

QT prolongation has been reported with granisetron use. Use granisetron with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, cardiac disease, cardiac arrhythmias, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.

The use of granisetron may mask the symptoms of progressive ileus, GI obstruction, and/or gastric distension. Patients with pre-existing GI conditions or risk factors for GI obstruction should be monitored carefully.

Although the manufacturer does not recommend dosage adjustments for patients with hepatic disease, significant hepatic impairment has been shown to decrease granisetron's elimination, which could theoretically increase the risk of concentration-related adverse events in susceptible patients.

Some parenteral formulations of granisetron contain benzyl alcohol and should not be used in neonates. There have been reports of fatal 'gasping syndrome' in neonates (< 1 month of age) after the administration of parenteral solutions containing the preservative benzyl alcohol at dosages > 99 mg/kg/day. The minimum amount of benzyl alcohol to cause toxicity is unknown. Although granisetron is not commonly used in neonates, if there were an extenuating circumstance and use was necessary, a preservative-free product would be preferred.

Granisetron transdermal patches are not FDA-approved for use in pediatric patients; however, if they are used off-label, precautions should be taken when exposure to sunlight or heat is expected. Granisetron may be degraded by direct natural or artificial sunlight. Due to a potential photosensitive skin reaction, if there is a risk of sunlight (UV) exposure, patients should cover the patch with clothing during the period of wear and for 10 days after its removal. In addition, patients should avoid prolonged exposure to heat near the application site (e.g., a heating pad, ambient temperature increase, electric blanket, hot baths, etc.), as systemic plasma concentrations will increase during heat exposure.

Description: Granisetron is a serotonin (5-HT3) receptor antagonist generally used for the prevention and treatment of radiation or chemotherapy-induced nausea/vomiting (CINV) and for post-operative nausea/vomiting (PONV). Granisetron is generally considered to be similar to other agents in the class in terms of efficacy and adverse reactions. Although only the parenteral formulation is FDA-approved for use in pediatric patients, oral formulations are also recommended in clinical practice guidelines for the prevention of chemotherapy-induced nausea/vomiting in pediatric patients. ASCO guidelines recommend that children receiving moderate to high-emetic-risk chemotherapy agents should be offered a 2-drug combination of a 5-HT3 receptor antagonist and dexamethasone; aprepitant is also added to the 2-drug combination with high-emetic-risk agents. The safety and effectiveness of granisetron IV injection have not been established in pediatric patients for the prevention or treatment of post-operative nausea or vomiting (PONV); however, the drug has been used off-label for this indication. Intravenous granisetron is FDA-approved for use in pediatric patients 2 years and older. Other formulations of granisetron (oral, transdermal, and extended-release subcutaneous injection) are not FDA-approved for pediatric patients.

For chemotherapy-induced nausea/vomiting (CINV) and chemotherapy-induced nausea/vomiting prophylaxis:
Intravenous dosage:
Children and Adolescents 2 years and older: 10 mcg/kg, 20 mcg/kg, or 40 mcg/kg IV within 30 to 60 minutes before beginning emetogenic chemotherapy. 10 mcg/kg IV is the FDA-approved dose and has been established in clinical practice ; however, 20 mcg/kg and 40 mcg/kg doses have also been used in clinical practice. The Pediatric Oncology Group of Ontario (POGO) recommends granisetron 40 mcg/kg IV as a single daily dose.
Oral dosage:
Children and Adolescents 2 years and older*: 40 mcg/kg/dose PO every 12 hours is recommended by the Pediatric Oncology Group of Ontario (POGO) for children receiving moderate or low emetogenic risk chemotherapy.

For post-operative nausea/vomiting (PONV) prophylaxis*:
NOTE: The FDA-approved product label recommends against granisetron for postoperative nausea/vomiting (PONV) due to lack of efficacy and risk of QT prolongation.
Oral dosage:
Children and Adolescents: 20 mcg/kg or 40 mcg/kg (Max: 1 mg) PO 20 minutes before induction of anesthesia was effective in children undergoing strabismus surgery. In a randomized, double-blind, placebo-controlled trial, 73 pediatric patients received granisetron 20 mcg/kg, 40 mcg/kg, or placebo 20 minutes prior to strabismus repair surgery. Granisetron 20 and 40 mcg/kg were more effective than placebo in decreasing the incidence of PONV in the first 24 hours (29% in granisetron groups vs. 84% in placebo group, p less than 0.05) and the number of children experiencing severe vomiting was reduced in the granisetron 20 mcg/kg and 40 mcg/kg groups compared to placebo (4%, 8%, and 48%, respectively, p less than 0.05).

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Children
Younger than 2 years: Safety and efficacy have not been established.
2 years and older: 10 mcg/kg/dose IV is the FDA-approved dosage; up to 40 mcg/kg/dose IV is used off-label. Safety and efficacy have not been established for oral, subcutaneous, or transdermal formulations; however, up to 40 mcg/kg/dose PO every 12 hours has been used off-label for chemotherapy-induced nausea/vomiting.
-Adolescents
10 mcg/kg/dose IV is the FDA-approved dosage; up to 40 mcg/kg/dose IV is used off-label. Safety and efficacy have not been established for oral, subcutaneous, or transdermal formulations; however, up to 40 mcg/kg/dose PO every 12 hours has been used off-label for chemotherapy-induced nausea/vomiting.

Patients with Hepatic Impairment Dosing
No dosage adjustment is recommended for hepatic impairment.

Patients with Renal Impairment Dosing
Granisetron Injection, Tablet or oral solution, and Transdermal Patch: No dosage adjustment is recommended.

Granisetron Extended-Release Subcutaneous Injection: (NOTE: This dosage form is not FDA-approved in pediatric patients)
-Moderate renal impairment (CrCL 30 to 59 mL/minute): Do not administer more frequently than once every 14 days.
-Severe renal impairment (CrCL less than 30 mL/minute): Avoid use.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Granisetron is a 5-HT3 receptor antagonist. 5-HT3 receptors are found centrally in the chemoreceptor trigger zone and peripherally at vagal nerve terminals in the intestines. Whether the action of granisetron is mediated centrally, peripherally, or a combination of both remains to be determined. Its affinity for 5-HT3 receptors is 4000-40,000 times higher than for other serotonin receptors. Emesis during chemotherapy appears to be associated with the release of serotonin from enterochromaffin cells in the small intestine. Blocking these nerve endings in the intestines prevents signals to the central nervous system. Granisetron may antagonize the effects of serotonin on the cholinergic neurons of the colon, slowing colonic transit time.

Much like chemotherapy-induced nausea and vomiting (CINV), postoperative nausea and vomiting (PONV) is not controlled by a single neurotransmitter, but serotonin is believed to play a major role. The process of postoperative nausea and vomiting is coordinated by the vomiting center in the central nervous system. Stimulation can be initiated centrally in areas such as the cerebral cortex and otic or vestibular nerves, or peripherally in areas such as the oropharynx, mediastinum, gastrointestinal tract, renal pelvis, peritoneum, or genitalia. Stretching and inflammation that occur during or after surgery may trigger chemical stimulation that lead to nausea and vomiting. Centrally, granisetron blocks the 5-HT3 receptor site at the chemoreceptor trigger zone, stopping the vomiting reflex produced by the vomiting center. Because of multiple neurochemical receptor sites involved during surgery, combination antiemetic therapy with drugs of different mechanisms is often necessary.

Pharmacokinetics: Granisetron is FDA-approved for parenteral administration in pediatric patients. Oral formulations, a transdermal patch, and extended-release subcutaneous injection are also available but approved only for adult use. Granisetron is approximately 65% protein bound; it distributes freely between plasma and erythrocytes. Granisetron undergoes N-demethylation and oxidation in the liver. Animal studies indicate that the metabolites may have pharmacologic activity. In healthy volunteers, approximately 12% of a dose was eliminated unchanged in the urine within 48 hours; the remainder of the dose was excreted as metabolites in the urine (49%) and the feces (34%). There is significant interpatient variability in drug clearance; terminal plasma half-lives of 4.9 to 9 hours have been reported in various adult populations.

Affected cytochrome P450 isoenzymes: CYP1A1, CYP3A4
Granisetron is metabolized by CYP1A1 and CYP3A4. Granisetron metabolism involves N-demethylation and aromatic ring oxidation followed by conjugation. Animal studies indicate that the metabolites may have pharmacologic activity. Granisetron does not induce or inhibit the cytochrome P450 enzyme system.


-Route-Specific Pharmacokinetics
Oral Route
Coadministration of granisetron tablets with food decreases the AUC by about 5% and increases the Cmax by about 30% in healthy volunteers. After a single 1 mg oral dose given to 39 adult volunteers, the terminal half-life was 6.23 hours (range, 0.96 to 19.9) and the volume of distribution was 3.94 L/kg (range, 1.89 to 39.4).

Intravenous Route
After a 5-minute IV infusion of granisetron 40 mcg/kg in adults, the mean peak plasma concentration was approximately 64 ng/mL (range, 11.2 to 182). The terminal half-life was 8.95 hours (range, 0.9 to 31.1) in cancer patients and 4.91 hours (range, 0.88 to 15.2) in adult volunteers ages 21 to 42 years. The volume of distribution was 3.07 L/kg (range, 0.85 to 10.4) in cancer patients and 3.04 L/kg (1.68 to 6.13) in adult volunteers. After adjustments for body weight, the volume of distribution and total clearance of IV granisetron in pediatric patients are similar to those of adults receiving similar doses.


-Special Populations
Pediatrics
Children and Adolescents
The pharmacokinetics of granisetron are similar in pediatric and adult patients with cancer when the volume of distribution and total clearance are adjusted for body weight. However, there is significant interpatient variability.

In a pharmacokinetic study of a single dose of IV granisetron 1 to 3 mg (41.7 to 56.1 mcg/kg) in 7 pediatric patients with cancer (2 to 14 years of age), the following parameters were calculated :
Cmax (mcg/L) = 60.1 +/- 26.6
Vd (L/kg) = 2.57 +/- 1.87
CL (L/h/kg) = 0.121 +/- 0.076
t1/2 (hours) = 20.9 +/- 20.8

In another pharmacokinetic study of 40 pediatric patients with cancer given a single 40 mcg/kg IV dose, PK parameters were compared between 3 groups: group 1 = ages 2 to 6 years (n = 20), group 2 = ages 7 to 11 years (n = 11), and group 3 = ages 12 to 16 years (n = 9).
group 1 group 2 group 3
Vd (L/kg) 1.36 1.7 1.24
CL (L/h/kg) 0.145 0.241 0.303
t1/2 (hours) 6.13 5.03 3.86

Hepatic Impairment
In a pharmacokinetic study, the total clearance of granisetron was approximately 50% less in adult patients with hepatic impairment secondary to neoplastic liver involvement compared to patients without hepatic impairment. However, due to pharmacokinetic variances noted among patients as well as good tolerance of doses well above the recommended 10 mcg/kg dose, dosage adjustment in patients with hepatic impairment is not recommended.

Renal Impairment
In a pharmacokinetic study, severe renal failure did not affect the total clearance of a single 40 mcg/kg IV dose of granisetron hydrochloride injection.