Granisetron Hydrochloride

GRANISETRON HYDROCHLORIDE- granisetron hydrochloride injection
Hikma Pharmaceuticals USA Inc.

1 INDICATIONS AND USAGE

Granisetron Hydrochloride Injection, USP is a serotonin-3 (5-HT₃ ) receptor antagonist indicated for:

• The prevention of nausea and/or vomiting associated with initial and repeat courses of emetogenic cancer therapy, including high-dose cisplatin.

2 DOSAGE AND ADMINISTRATION

2.1 Prevention of Chemotherapy-Induced Nausea and Vomiting

Adult Patients
The recommended dosage for Granisetron Hydrochloride Injection is 10 mcg/kg administered intravenously within 30 minutes before initiation of chemotherapy, and only on the day(s) chemotherapy is given.

Infusion Preparation
Granisetron Hydrochloride Injection may be administered intravenously either undiluted over 30 seconds or diluted with 0.9% Sodium Chloride or 5% Dextrose and infused over 5 minutes.

Stability
Intravenous infusion of Granisetron Hydrochloride Injection should be prepared at the time of administration. However, Granisetron Hydrochloride Injection has been shown to be stable for at least 24 hours when diluted in 0.9% Sodium Chloride or 5% Dextrose and stored at room temperature under normal lighting conditions.

As a general precaution, Granisetron Hydrochloride Injection should not be mixed in solution with other drugs. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit.

Pediatric Patients
The recommended dose in pediatric patients 2 to 16 years of age is 10 mcg/kg [see Clinical Studies (14)]. Pediatric patients under 2 years of age have not been studied.

3 DOSAGE FORMS AND STRENGTHS

Single Dose Vials for Injection: 1 mg/mL
Multiple Dose Vials for Injection: 4 mg/4 mL (1 mg/mL)

4 CONTRAINDICATIONS

Granisetron Hydrochloride Injection is contraindicated in patients with known hypersensitivity (e.g. anaphylaxis, shortness of breath, hypotension, urticaria) to the drug or to any of its components.

5 WARNINGS AND PRECAUTIONS

5.1 Gastric or Intestinal Peristalsis

Granisetron hydrochloride is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction. The use of granisetron hydrochloride in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distention.

5.2 Cardiovascular Events

An adequate QT assessment has not been conducted, but QT prolongation has been reported with granisetron hydrochloride. Therefore, granisetron hydrochloride should be used with caution in patients with pre-existing arrhythmias or cardiac conduction disorders, as this might lead to clinical consequences. Patients with cardiac disease, on cardio-toxic chemotherapy, with concomitant electrolyte abnormalities and/or on concomitant medications that prolong the QT interval are particularly at risk.

5.3 Hypersensitivity Reactions

Hypersensitivity reactions (e.g. anaphylaxis, shortness of breath, hypotension, urticaria) may occur in patients who have exhibited hypersensitivity to other selective 5-HT₃ receptor antagonists

5.4 Benzyl Alcohol

Granisetron Hydrochloride Injection 1 mg/mL contains benzyl alcohol. Benzyl alcohol, a component of Granisetron Hydrochloride Injection 1 mg/mL, has been associated with serious adverse reactions and death, particularly in neonates. The “gasping syndrome,” characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and metabolites in blood and urine, has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome,” the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.

5.5 Serotonin Syndrome

The development of serotonin syndrome has been reported with 5-HT₃ receptor antagonists. Most reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and intravenous methylene blue). Some of the reported cases were fatal. Serotonin syndrome occurring with overdose of another 5-HT₃ receptor antagonist alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT₃ receptor antagonist use occurred in a post-anesthesia care unit or an infusion center.

Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of granisetron and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue granisetron and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if granisetron is used concomitantly with other serotonergic drugs [see Drug Interactions (7), Patient Counseling Information (17)].

6 ADVERSE REACTIONS

QT prolongation has been reported with granisetron hydrochloride [see Warnings and Precautions (5.2) and Drug Interactions (7)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in patients.

Chemotherapy-Induced Nausea and VomitingThe following have been reported during controlled clinical trials or in the routine management of patients. The percentage figures are based on clinical trial experience only. Table 1 gives the comparative frequencies of the two most commonly reported adverse reactions (≥3%) in patients receiving Granisetron Hydrochloride Injection, in single-day chemotherapy trials. These patients received chemotherapy, primarily cisplatin, and intravenous fluids during the 24-hour period following Granisetron Hydrochloride Injection administration. Reactions were generally recorded over seven days post-Granisetron Hydrochloride Injection administration.

Table 1. Principal Adverse Reactions in Clinical Trials — Single-Day Chemotherapy

* Metoclopramide/dexamethasone and phenothiazines/dexamethasone.
Percent of Patients With Reaction
	Granisetron Hydrochloride Injection 40 mcg/kg (n=1268)	Comparator * (n=422)
Headache	14%	6%
Constipation	3%	3%

Additional adverse events reported in clinical trials were asthenia, somnolence and diarrhea.

In over 3,000 patients receiving Granisetron Hydrochloride Injection (2 to 160 mcg/kg) in single-day and multiple-day clinical trials with emetogenic cancer therapies, adverse events, other than those adverse reactions listed in Table 1, were observed; attribution of many of these events to granisetron hydrochloride is uncertain.

Hepatic: In comparative trials, mainly with cisplatin regimens, elevations of AST and ALT (>2 times the upper limit of normal) following administration of Granisetron Hydrochloride Injection occurred in 2.8% and 3.3% of patients, respectively. These frequencies were not significantly different from those seen with comparators (AST: 2.1%; ALT: 2.4%).

Cardiovascular: Hypertension (2%); hypotension, arrhythmias such as sinus bradycardia, atrial fibrillation, varying degrees of A-V block, ventricular ectopy including non-sustained tachycardia, and ECG abnormalities have been observed rarely.

Central Nervous System: Agitation, anxiety, CNS stimulation and insomnia were seen in less than 2% of patients. Extrapyramidal syndrome occurred rarely and only in the presence of other drugs associated with this syndrome.

Hypersensitivity: Rare cases of hypersensitivity reactions, sometimes severe (eg, anaphylaxis, shortness of breath, hypotension, urticaria) have been reported.

Other: Fever (3%), taste disorder (2%), skin rashes (1%). In multiple-day comparative studies, fever occurred more frequently with Granisetron Hydrochloride Injection (8.6%) than with comparative drugs (3.4%, P<0.014), which usually included dexamethasone.