Palonosetron

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous:

Aloxi: 0.25 mg/5 mL (5 mL) [contains edetate disodium dihydrate]

Generic: 0.25 mg/5 mL (5 mL)

Solution, Intravenous [preservative free]:

Aloxi: 0.25 mg/5 mL (5 mL) [contains edetate disodium]

Generic: 0.25 mg/2 mL (2 mL); 0.25 mg/5 mL (5 mL)

Solution Prefilled Syringe, Intravenous:

Generic: 0.25 mg/5 mL (5 mL)

Pharmacology

Mechanism of Action

Palonosetron is a selective 5-HT₃ receptor antagonist, blocking serotonin, both on vagal nerve terminals in the periphery and centrally in the chemoreceptor trigger zone

Pharmacokinetics/Pharmacodynamics

Absorption

Capsules [Canadian product]: Well absorbed

Distribution

V_d:Children 1 month to 17 years: Mean range: 5.3 to 6.3 L/kg; Adults: 8.3 ± 2.5 L/kg

Metabolism

~50% metabolized via CYP enzymes (and likely other pathways) to relatively inactive metabolites (N-oxide-palonosetron and 6-S-hydroxy-palonosetron); CYP1A2, 2D6, and 3A4 contribute to its metabolism

Excretion

Urine (80%; 40% as unchanged drug)

Clearance:

Infants and children <2 years: 0.31 L/hour/kg

Children 2 to <12 years: Mean range: 0.19 to 0.23 L/hour/kg

Children ≥12 years, Adolescents, and Adults: 0.16 L/hour/kg

Time to Peak

Plasma: Capsules [Canadian product]: 5.1 ± 5.9 hours

Half-Life Elimination

IV: Children 1 month to 17 years: Median: 29.5 hours (range: 20 to 30 hours); Adults: ~40 hours

Protein Binding

~62%

Use: Labeled Indications

Chemotherapy-induced nausea and vomiting: Prevention of acute and delayed nausea and vomiting associated with initial and repeat courses in patients treated with moderately emetogenic cancer chemotherapy in adults; prevention of acute nausea and vomiting associated with initial and repeat courses in patients treated with highly emetogenic cancer chemotherapy in adults; prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy (including highly emetogenic chemotherapy) in pediatric patients 1 month to <17 years.

Capsules [Canadian product]: Prevention of acute nausea and vomiting associated with moderately emetogenic cancer chemotherapy in adults.

Postoperative nausea and vomiting: Prevention of postoperative nausea and vomiting (PONV) for up to 24 hours following surgery in adults.

Limitations of use: Routine prophylaxis for PONV in patients with minimal expectation of nausea and/or vomiting is not recommended, although use is recommended in patients when nausea and vomiting must be avoided in the postoperative period, even if the incidence of PONV is low.

Contraindications

Known hypersensitivity to palonosetron or any component of the formulation

Dosage and Administration

Dosing: Adult

Prevention of chemotherapy-induced nausea and vomiting (moderately and highly emetogenic chemotherapy): IV: 0.25 mg beginning ~30 minutes prior to the start of chemotherapy

Capsule [Canadian product]: Moderately emetogenic chemotherapy: Oral: 0.5 mg ~1 hour prior to the start of chemotherapy.

Guideline recommendations: Prevention of chemotherapy-induced nausea and vomiting:

American Society of Clinical Oncology (ASCO [Hesketh 2017]):

High emetic risk, including most anthracyclines combined with cyclophosphamide regimens; antiemetic regimen also includes dexamethasone (days 1 to 4), an NK₁ receptor antagonist, and olanzapine (days 1 to 4):

IV: 0.25 mg on day 1 prior to chemotherapy

Oral: 0.5 mg [Canadian product] on day 1 prior to chemotherapy

Moderate emetic risk; antiemetic regimen also includes dexamethasone (days 1 to 3) [and an NK₁ receptor antagonist for carboplatin AUC ≥4]:

IV: 0.25 mg on day 1 prior to chemotherapy

Oral: 0.5 mg [Canadian product] on day 1 prior to chemotherapy

Low emetic risk:

IV: 0.25 mg prior to chemotherapy

Oral: 0.5 mg [Canadian product] prior to chemotherapy

Multinational Association of Supportive Care in Cancer (MASCC) and European Society of Medical Oncology (ESMO) (Roila 2016):

Highly emetic chemotherapy, (antiemetic regimen includes dexamethasone and aprepitant/fosaprepitant/rolapitant):

IV: 0.25 mg on day 1 prior to chemotherapy

Oral: 0.5 mg [Canadian product] on day 1 prior to chemotherapy

Moderately emetic chemotherapy (antiemetic regimen includes dexamethasone [and aprepitant/fosaprepitant/rolapitant for AC chemotherapy regimen]):

IV: 0.25 mg on day 1 prior to chemotherapy

Oral: 0.5 mg [Canadian product] on day 1 prior to chemotherapy

Low emetic risk: 0.25 mg IV or 0.5 mg orally [Canadian product] prior to chemotherapy on day 1 may be considered

Prevention of postoperative nausea and vomiting: IV: 0.075 mg immediately prior to anesthesia induction

Dosing: Geriatric

No dosage adjustment necessary. Refer to adult dosing.

Dosing: Pediatric

Note: Dosing presented in both mcg and mg; use extra caution to verify correct units

Chemotherapy-induced nausea and vomiting; prevention: Note: Use in combination with or without dexamethasone and aprepitant depending upon patient age, chemotherapy emetogenic potential, and drug-interaction profile (refer to specific protocols or guidelines) (POGO [Patel 2017]).

Infants, Children, and Adolescents <17 years: IV: 20 mcg/kg as a single dose administered ~30 minutes prior to the start of chemotherapy; maximum dose: 1,500 mcg/dose (1.5 mg/dose)

Adolescents ≥17 years:

IV: 0.25 mg as a single dose administered ~30 minutes before chemotherapy

Oral [Canadian product]: Limited data available: 0.5 mg as a single dose administered prior to chemotherapy (POGO [Patel 2017])

Postoperative nausea and vomiting (PONV); prevention: Note: Expert recommendations for PONV management do not include palonosetron as a therapeutic option for the prevention or treatment of PONV in pediatric patients (SAA [Gan 2014]).

Infants, Children, and Adolescents <17 years: Limited data available; efficacy results variable: IV: 1 mcg/kg as a single dose; maximum dose: 75 mcg/dose (0.075 mg/dose) immediately prior to anesthesia induction; dosing based on a double-blind randomized comparative trial with ondansetron which showed complete response in 78.2% of the palonosetron group and 82.7% of the ondansetron; however, palonosetron efficacy data did not meet noninferiority margin; safety analysis showed no unexpected adverse effects, similar data as adult patients.

Adolescents ≥17 years: Limited data available in 17 years of age: IV: 0.075 mg immediately prior to anesthesia induction

Administration

IV: Flush IV line with NS prior to and following administration.

Prevention of chemotherapy-induced nausea and vomiting: Infuse over 30 seconds, beginning ~30 minutes prior to the start of chemotherapy

Capsule [Canadian product]: May be administered with or without food.

Prevention of postoperative nausea and vomiting: Infuse over 10 seconds immediately prior to anesthesia induction

Storage

Prefilled syringe: Store at 20°C to 25°C (68°F to 77°F); protect from light. Do not freeze. Discard unused portion.

Vials: Store intact vials at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Do not freeze. Protect from light. Solutions of 5 mcg/mL and 30 mcg/mL in NS, D5W, D5¹/₂NS, and D5LR injection are stable for 48 hours at room temperature and 14 days under refrigeration (Trissel 2004).

Capsules [Canadian product]: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Apomorphine: Antiemetics (5HT3 Antagonists) may enhance the hypotensive effect of Apomorphine. Avoid combination

Serotonergic Agents (High Risk): Antiemetics (5HT3 Antagonists) may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Exceptions: TraMADol. Monitor therapy

Tapentadol: Antiemetics (5HT3 Antagonists) may diminish the analgesic effect of Tapentadol. Monitor therapy

TraMADol: Antiemetics (5HT3 Antagonists) may enhance the serotonergic effect of TraMADol. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Adverse Reactions

Frequencies reported for both indications (chemotherapy-associated nausea and vomiting and postoperative nausea and vomiting) and in adults unless otherwise noted.

1% to 10%:

Cardiovascular: Prolonged Q-T interval on ECG (PONV 1% to 5%; chemotherapy-associated <1%), bradycardia (chemotherapy-associated 1%), sinus bradycardia (PONV: 1%), tachycardia (may be nonsustained; 1%), hypotension (≤1%)

Central nervous system: Headache (chemotherapy-associated: Adults 9%; infants, children, and adolescents <1%), anxiety (chemotherapy-associated: 1%), dizziness (infants, children, adolescents, and adults ≤1%)

Dermatologic: Pruritus (PONV: 1%)

Endocrine & metabolic: Hyperkalemia (chemotherapy-associated: 1%)

Gastrointestinal: Constipation (chemotherapy-associated: 5%), diarrhea (≤1%), flatulence (≤1%)

Genitourinary: Urinary retention (≤1%)

Hepatic: Increased serum ALT (≤1%; may be transient), increased serum AST (≤1%; may be transient)

Neuromuscular & skeletal: Weakness (chemotherapy-associated: 1%)

<1%, postmarketing, and/or case reports: Abdominal pain, allergic dermatitis, amblyopia, anaphylactic shock (very rare), anaphylaxis (very rare), anasarca, anemia, anorexia, arthralgia, cardiac arrhythmia, chills, decreased appetite, decreased blood pressure, decreased gastrointestinal motility, decreased platelet count, dermatological disease (infants, children, and adolescents), distended vein, drowsiness, dyskinesia (infants, children, and adolescents), dyspepsia, electrolyte disturbance, epistaxis, erythema, euphoria, extrasystoles, eye irritation, fatigue, fever, flattened T wave on ECG, flu-like symptoms, glycosuria, hiccups, hot flash, hyperglycemia, hypersensitivity (very rare), hypersomnia, hypertension, hypokalemia, hypoventilation, increased bilirubin (transient), increased liver enzymes, infusion site pain (infants, children, and adolescents), injection site reaction (very rare; includes burning sensation at injection site, discomfort at injection site, induration at injection site, pain at injection site), insomnia, ischemic heart disease, laryngospasm, limb pain, metabolic acidosis, motion sickness, paresthesia, serotonin syndrome, sialorrhea, sinus arrhythmia, sinus tachycardia, skin rash, supraventricular extrasystole, tinnitus, vein discoloration, ventricular premature contractions, xerostomia

Warnings/Precautions

Concerns related to adverse effects:

• ECG effects: Selective 5-HT₃ receptor antagonists have been associated with dose-dependent increases in ECG intervals (eg, PR, QRS duration, QT/QTc, JT). A thorough QT/QTc study evaluating the effect of palonosetron on QT/QTc demonstrated a magnitude of effect less than the threshold for regulatory concern (Morganroth 2016). Reduction in heart rate may occur with the 5-HT₃ antagonists, including palonosetron (Gonullu 2012).
• Hypersensitivity reactions: Hypersensitivity (including anaphylaxis) has been reported in patients with or without known hypersensitivity to other 5-HT₃ receptor antagonists.
• Serotonin syndrome: Serotonin syndrome has been reported with 5-HT₃ receptor antagonists, predominantly when used in combination with other serotonergic agents (eg, SSRIs, SNRIs, MAOIs, mirtazapine, fentanyl, lithium, tramadol, and/or methylene blue). Some of the cases have been fatal. The majority of serotonin syndrome reports due to 5-HT₃ receptor antagonists have occurred in a post-anesthesia setting or in an infusion center. Serotonin syndrome has also been reported following overdose of another 5-HT₃ receptor antagonist. Monitor patients for signs of serotonin syndrome, including mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile blood pressure, diaphoresis, dizziness, flushing, hyperthermia); neuromuscular changes (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination); gastrointestinal symptoms (eg, nausea, vomiting, diarrhea); and/or seizures. If serotonin syndrome occurs, discontinue 5-HT₃ receptor antagonist treatment and begin supportive management.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Chemotherapy-associated emesis: Antiemetics are most effective when used prophylactically (Roila 2016). If emesis occurs despite optimal antiemetic prophylaxis, re-evaluate emetic risk, disease, concurrent morbidities and medications to assure antiemetic regimen is optimized (Hesketh 2017).
• Postoperative nausea and vomiting: Use is not recommended if there is little expectation of postoperative nausea and vomiting (PONV); may use for low expectation of PONV if it is essential to avoid nausea and vomiting in the postoperative period.

Pregnancy

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies. Use during pregnancy only if clearly needed.

Patient Education

What is this drug used for?

• It is used to prevent upset stomach and throwing up.

Frequently reported side effects of this drug

• Headache
• Constipation

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Injection site pain or irritation
• Chest pain
• Passing out
• Abnormal heartbeat
• Fast heartbeat
• Serotonin syndrome like dizziness, severe headache, agitation, sensing things that seem real but are not, fast heartbeat, arrhythmia, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea.
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.