Palonosetron Hydrochloride: Package Insert and Label Information

PALONOSETRON HYDROCHLORIDE — palonosetron hydrochloride injection
Cipla USA Inc.

1 INDICATIONS AND USAGE

1.1 Chemotherapy-Induced Nausea and Vomiting in Adults

Palonosetron Hydrochloride Injection is indicated for:

• Moderately emetogenic cancer chemotherapy — prevention of acute and delayed nausea and vomiting associated with initial and repeat courses
• Highly emetogenic cancer chemotherapy — prevention of acute nausea and vomiting associated with initial and repeat courses

1.2 Chemotherapy-Induced Nausea and Vomiting in Pediatric Patients Aged 1 Month to Less than 17 Years

Palonosetron Hydrochloride Injection is indicated for prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy.

1.3 Postoperative Nausea and Vomiting in Adults

Palonosetron Hydrochloride Injection is indicated for prevention of postoperative nausea and vomiting (PONV) for up to 24 hours following surgery. Efficacy beyond 24 hours has not been demonstrated.

As with other antiemetics, routine prophylaxis is not recommended in patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. In patients where nausea and vomiting must be avoided during the postoperative period, Palonosetron Hydrochloride Injection is recommended even where the incidence of postoperative nausea and/or vomiting is low.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

Chemotherapy-Induced Nausea and Vomiting

*Note different dosing units in pediatrics
Age	Dose*	Infusion Time
Adults	0 . 2 5 mg x 1	Infuse over 30 seconds beginning approx. 30 min before the start of chemo
Pediatrics (1 month to less than 17 years)	2 0 micrograms per kilogram (max 1.5 mg) x 1	Infuse over 15 minutes beginning approx. 30 min before the start of chemo

Postoperative Nausea and Vomiting

Dosage for Adults — a single 0.075 mg intravenous dose administered over 10 seconds immediately before the induction of anesthesia.

2.2 Instructions for Intravenous Administration

Palonosetron Hydrochloride Injection is supplied ready for intravenous administration at a concentration of 0.05 mg/mL (50 mcg/ mL). Palonosetron Hydrochloride Injection should not be mixed with other drugs. The infusion line should be flushed with normal saline before and after administration of Palonosetron Hydrochloride Injection. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit.

3 DOSAGE FORM AND STRENGTHS

Palonosetron Hydrochloride Injection is supplied as a single-use sterile, clear, colorless solution in glass vials that provide:

• 0.25 mg (free base) per 5 mL (concentration: 0.05 mg/mL, 50 mcg/mL)

4 CONTRAINDICATIONS

Palonosetron Hydrochloride Injection is contraindicated in patients known to have hypersensitivity to the drug or any of its components. [see Adverse Reactions (6.2) ].

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity

Hypersensitivity reactions, including anaphylaxis, have been reported with or without known hypersensitivity to other 5-HT₃ receptor antagonists.

5.2 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 Palonosetron Hydrochloride Injection and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue Palonosetron Hydrochloride Injection and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if Palonosetron Hydrochloride Injection is used concomitantly with other serotonergic drugs [see Drug Interactions (7), Patient Counseling Information (17) ].

6 ADVERSE REACTIONS

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 practice.

6.1 Chemotherapy-Induced Nausea and Vomiting

Adults

In clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic chemotherapy, 1374 adult patients received palonosetron. Adverse reactions were similar in frequency and severity with Palonosetron Hydrochloride Injection and ondansetron or dolasetron. Following is a listing of all adverse reactions reported by 2% of patients in these trials (Table 1).

Table 1: Adverse Reactions from Chemotherapy-Induced Nausea and Vomiting Studies ≥ 2% in any Treatment Group

Event	Palonosetron Hydrochloride Injection 0.25 mg (N=633)	Ondansetron 32 mg I.V. (N=410)	Dolasetron 100 mg I.V. (N=194)
Headache	60 (9%)	34 (8%)	32 (16%)
Constipation	29 (5%)	8 (2%)	12 (6%)
Diarrhea	8 (1%)	7 (2%)	4 (2%)
Dizziness	8 (1%)	9 (2%)	4 (2%)
Fatigue	3 (< 1%)	4 (1%)	4 (2%)
Abdominal Pain	1 (< 1%)	2 (< 1%)	3 (2%)
Insomnia	1 (< 1%)	3 (1%)	3 (2%)

In other studies, 2 subjects experienced severe constipation following a single palonosetron dose of approximately 0.75 mg, three times the recommended dose. One patient received a 10 mcg/kg oral dose in a post-operative nausea and vomiting study and one healthy subject received a 0.75 mg I.V. dose in a pharmacokinetic study.

In clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of Palonosetron Hydrochloride Injection to adult patients receiving concomitant cancer chemotherapy:

Cardiovascular: 1%: non-sustained tachycardia, bradycardia, hypotension, < 1%: hypertension, myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles and QT prolongation. In many cases, the relationship to Palonosetron Hydrochloride Injection was unclear.

Dermatological: < 1%: allergic dermatitis, rash.

Hearing and Vision: < 1%: motion sickness, tinnitus, eye irritation and amblyopia.

Gastrointestinal System: 1%: diarrhea, < 1%: dyspepsia, abdominal pain, dry mouth, hiccups and flatulence.

General: 1%: weakness, < 1%: fatigue, fever, hot flash, flu-like syndrome.

Liver: < 1%: transient, asymptomatic increases in AST and/or ALT and bilirubin. These changes occurred predominantly in patients receiving highly emetogenic chemotherapy.

Metabolic: 1%: hyperkalemia, < 1%: electrolyte fluctuations, hyperglycemia, metabolic acidosis, glycosuria, appetite decrease, anorexia.

Musculoskeletal: < 1%: arthralgia.

Nervous System: 1%: dizziness, < 1%: somnolence, insomnia, hypersomnia, paresthesia.

Psychiatric: 1%: anxiety, < 1%: euphoric mood.

Urinary System: < 1%: urinary retention.

Vascular: < 1%: vein discoloration, vein distention.

Pediatrics

In a pediatric clinical trial for the prevention of chemotherapy-induced nausea and vomiting 163 cancer patients received a single 20 mcg/kg (maximum 1.5 mg) intravenous infusion of palonosetron 30 minutes before beginning the first cycle of emetogenic chemotherapy. Patients had a mean age of 8.4 years (range 2 months to 16.9 years) and were 46% male; and 93% white.

The following adverse reactions were reported for palonosetron:

Nervous System: <1%: headache, dizziness, dyskinesia.

General: <1%: infusion site pain.

Dermatological: <1%: allergic dermatitis, skin disorder.

In the trial, adverse reactions were evaluated in pediatric patients receiving palonosetron for up to 4 chemotherapy cycles.

6.2 Postoperative Nausea and Vomiting

The adverse reactions cited in Table 2 were reported in ≥ 2% of adults receiving I.V. Palonosetron Hydrochloride Injection 0.075 mg immediately before induction of anesthesia in one phase 2 and two phase 3 randomized placebo-controlled trials. Rates of events between palonosetron and placebo groups were similar. Some events are known to be associated with, or may be exacerbated by concomitant perioperative and intraoperative medications administered in this surgical population. Please refer to Section 12.2, thorough QT/QTc study results, for data demonstrating the lack of palonosetron effect on QT/QTc.

Table 2: Adverse Reactions from Postoperative Nausea and Vomiting Studies ≥ 2% in any Treatment Group

Event	Palonosetron Hydrochloride Injection 0.075 mg (N=336)	Placebo (N=369)
Electrocardiogram QT prolongation	16 (5%)	11 (3%)
Bradycardia	13 (4%)	16 (4%)
Headache	11 (3%)	14 (4%)
Constipation	8 (2%)	11(3%)

In these clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of Palonosetron Hydrochloride Injection to adult patients receiving concomitant perioperative and intraoperative medications including those associated with anesthesia:

Cardiovascular: 1%: electrocardiogram QTc prolongation, sinus bradycardia, tachycardia, < 1%: blood pressure decreased, hypotension, hypertension, arrhythmia, ventricular extrasystoles, generalized edema, ECG T wave amplitude decreased, platelet count decreased. The frequency of these adverse effects did not appear to be different from placebo.

Dermatological: 1%: pruritus.

Gastrointestinal System: 1%: flatulence, < 1%: dry mouth, upper abdominal pain, salivary hypersecretion, dyspepsia, diarrhea, intestinal hypomotility, anorexia.

General: < 1%: chills.

Liver: 1%: increases in AST and/or ALT, < 1%: hepatic enzyme increased.

Metabolic: < 1%: hypokalemia, anorexia.

Nervous System: < 1%: dizziness.

Respiratory: < 1%: hypoventilation, laryngospasm.

Urinary System: 1%: urinary retention.

6.3 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Palonosetron Hydrochloride Injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Very rare cases (<1/10,000) of hypersensitivity reactions including anaphylaxis and anaphylactic shock and injection site reactions (burning, induration, discomfort and pain) were reported from postmarketing experience of Palonosetron Hydrochloride Injection 0.25 mg in the prevention of chemotherapy-induced nausea and vomiting.

7 DRUG INTERACTIONS

Palonosetron is eliminated from the body through both renal excretion and metabolic pathways with the latter mediated via multiple CYP enzymes. Further in vitro studies indicated that palonosetron is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4/5 (CYP2C19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5. Therefore, the potential for clinically significant drug interactions with palonosetron appears to be low.

Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT₃ receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) [see Warnings and Precautions (5.2) ].

Coadministration of 0.25 mg I.V. palonosetron and 20 mg I.V. dexamethasone in healthy subjects revealed no pharmacokinetic drug-interactions between palonosetron and dexamethasone.

In an interaction study in healthy subjects where palonosetron 0.25 mg (I.V. bolus) was administered on day 1 and oral aprepitant for 3 days (125 mg/80 mg/80 mg), the pharmacokinetics of palonosetron were not significantly altered (AUC: no change, C_max : 15% increase).

A study in healthy volunteers involving single-dose I.V. palonosetron (0.75 mg) and steady state oral metoclopramide (10 mg four times daily) demonstrated no significant pharmacokinetic interaction.

In controlled clinical trials, Palonosetron Hydrochloride Injection has been safely administered with corticosteroids, analgesics, antiemetics /antinauseants, antispasmodics and anticholinergic agents.

Palonosetron did not inhibit the antitumor activity of the five chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C) in murine tumor models.