Palonosetron (Monograph)

Brand name: Aloxi
Drug class: 5-HT3 Receptor Antagonists
ATC class: A04AA
VA class: GA605
Chemical name: (S)-2-[(3S)-Quinuclidin-3-yl]-2,3,3a,4,5,6-hexahydro-1H-benzo[de]isoquinolin-1-one hydrochloride
Molecular formula: C₁₉H₂₄N₂O•HCl
CAS number: 135729-62-3

Medically reviewed by Drugs.com on Feb 23, 2024. Written by ASHP.

Introduction

Antiemetic; selective, second-generation inhibitor of type 3 serotonergic (5-HT₃) receptors.

Uses for Palonosetron

Cancer Chemotherapy-induced Nausea and Vomiting

Palonosetron is used IV for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy.

Palonosetron also is used IV for the prevention of acute nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy.

For prevention of nausea and vomiting associated with highly emetogenic chemotherapy regimens (including an anthracycline plus cyclophosphamide), ASCO recommends a 3-drug antiemetic regimen consisting of an NK₁ receptor antagonist (e.g., either oral aprepitant or IV fosaprepitant), a 5-HT₃ receptor antagonist (e.g., dolasetron, granisetron, ondansetron, palonosetron), and dexamethasone. ASCO states that fixed-combination netupitant and palonosetron plus dexamethasone is an additional treatment option.

For moderately emetogenic chemotherapy regimens, ASCO recommends a 2-drug antiemetic regimen preferably consisting of palonosetron and dexamethasone. If palonosetron is not available, a first-generation 5-HT₃ receptor antagonist (preferably granisetron or ondansetron) may be substituted. Limited evidence suggests that aprepitant may be added to this regimen; in such cases, use of any 5-HT₃ receptor antagonist is appropriate.

For chemotherapy regimens with a low emetogenic risk, ASCO recommends administration of a single dose of dexamethasone prior to chemotherapy.

For chemotherapy regimens with minimal emetogenic risk, ASCO states that routine antiemetic administration is not necessary.

Postoperative Nausea and Vomiting

Palonosetron is used IV for the prevention of postoperative nausea and vomiting for up to 24 hours following surgery. Efficacy of the drug beyond 24 hours not demonstrated.

Routine prophylaxis not recommended in patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively.

Recommended for patients in whom nausea and/or vomiting must be avoided postoperatively, even when anticipated incidence is low.

Palonosetron Dosage and Administration

Administration

IV Administration

Administer IV. Visually inspect solution for particulate matter and discoloration prior to administration.

Do not mix with other drugs; flush tubing with 0.9% sodium chloride injection before and after administration.

Rate of Administration

For prevention of cancer chemotherapy-induced nausea and vomiting in adults, administer IV over a period of 30 seconds.

For prevention of cancer chemotherapy-induced nausea and vomiting in pediatric patients 1 month to <17 years of age, administer IV over 15 minutes.

For prevention of postoperative nausea and vomiting in adults, administer IV over a period of 10 seconds.

Dosage

Available as palonosetron hydrochloride; dosage expressed in terms of palonosetron.

Pediatric Patients

Cancer Chemotherapy-induced Nausea and Vomiting

Prevention

IV

Pediatric patients 1 month to <17 years of age: 20 mcg/kg (up to a maximum of 1.5 mg) as a single dose administered by IV infusion approximately 30 minutes before administration of chemotherapy.

Manufacturer states that a clinical study demonstrated that pediatric patients require a higher dose of palonosetron to prevent cancer chemotherapy-induced nausea and vomiting compared with adults.

Adults

Cancer Chemotherapy-induced Nausea and Vomiting

Prevention

IV

0.25 mg as a single dose administered IV approximately 30 minutes before administration of chemotherapy.

Postoperative Nausea and Vomiting

Prevention

IV

0.075 mg as a single dose administered IV immediately before induction of anesthesia.

Prescribing Limits

Pediatric Patients

Cancer Chemotherapy-induced Nausea and Vomiting

Prevention

IV

Pediatric patients 1 month to <17 years of age: Maximum of one 1.5-mg dose.

Adults

Cancer Chemotherapy-induced Nausea and Vomiting

Prevention

IV

Maximum of one 0.25-mg dose.

Postoperative Nausea and Vomiting

Prevention

IV

Maximum of one 0.075-mg dose.

Special Populations

Hepatic Impairment

No dosage adjustments required for any degree of hepatic impairment.

Renal Impairment

No dosage adjustments required for any degree of renal impairment.

Geriatric Patients

No dosage adjustments required.

Cautions for Palonosetron

Contraindications

• Known hypersensitivity to palonosetron or any ingredient in the formulation.

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, reported in palonosetron-treated patients with or without known hypersensitivity to other 5-HT₃ receptor antagonists. (See Advice to Patients.)

Serotonin Syndrome

Serotonin syndrome (in some cases fatal) reported in patients receiving 5-HT₃ receptor antagonists. Most cases were associated with concomitant use of other serotonergic drugs (e.g., SSRIs, SNRIs, MAO inhibitors, mirtazapine, fentanyl, lithium, tramadol, IV methylene blue). Serotonin syndrome occurring with overdosage of another 5-HT₃ receptor antagonist alone (ondansetron) also reported. The majority of reports of serotonin syndrome related to 5-HT₃ receptor antagonist use occurred in a post-anesthesia care unit or infusion center.

Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile BP, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), and seizures with or without GI symptoms (e.g., nausea, vomiting, diarrhea).

Monitor patients for emergence of serotonin syndrome, particularly with concomitant use of other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue palonosetron and initiate supportive treatment. (See Specific Drugs under Interactions.)

Specific Populations

Pregnancy

Category B.

Lactation

Not known whether palonosetron is distributed into milk. Discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established in neonates younger than 1 month of age for prevention of chemotherapy-induced nausea and vomiting.

Safety and efficacy not established in pediatric patients for prevention of postoperative nausea and vomiting.

Geriatric Use

In chemotherapy-induced nausea and vomiting clinical studies, no substantial differences in safety and efficacy relative to younger adult cancer patients, but increased sensitivity cannot be ruled out. No dosage adjustment or special monitoring is required. (See Special Populations under Pharmacokinetics.)

In postoperative nausea and vomiting clinical studies, no overall differences in safety compared with younger individuals, although possibility of increased sensitivity cannot be ruled out. No differences in efficacy observed in geriatric patients for the chemotherapy-induced nausea and vomiting indication and none are expected for geriatric postoperative nausea and vomiting patients. However, efficacy in geriatric patients not adequately evaluated to date.

Hepatic Impairment

No dosage adjustment necessary in patients with any degree of hepatic impairment. (See Special Populations under Pharmacokinetics.)

Renal Impairment

No dosage adjustment necessary in patients with any degree of renal impairment. (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Chemotherapy-induced nausea and vomiting in adults: Headache, constipation, diarrhea, dizziness, nonsustained tachycardia, bradycardia, hypotension, weakness, hyperkalemia, anxiety.

Postoperative nausea and vomiting in adults: QT-interval prolongation, bradycardia, headache, constipation.

Drug Interactions

Approximately 50% metabolized, principally by CYP2D6 and to a lesser extent by CYP3A and CYP1A2; however, pharmacokinetics not substantially different between poor and extensive CYP2D6 substrate metabolizers.

Does not inhibit activity of CYP isoenzymes 1A2, 2A6, 2B6, 2C9, 2D6, 2E1, or 3A4/5; effect on isoenzyme 2C19 activity undetermined. Does not induce activity of isoenzymes 1A2, 2D6, or 3A4/5.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Clinically important pharmacokinetic interactions are unlikely.

Drugs Associated with Serotonin Syndrome

Potentially serious, sometimes fatal, serotonin syndrome, particularly with concomitant use of other serotonergic agents. (See Serotonin Syndrome under Cautions.)

Monitor patients for serotonin syndrome. If serotonin syndrome occurs, immediately discontinue palonosetron and initiate supportive treatment.

Specific Drugs

Palonosetron has been administered safely with analgesics, anticholinergic agents, antiemetics, antispasmodics, and corticosteroids in clinical studies.

Palonosetron Pharmacokinetics

Distribution

Extent

Not known whether distributed into milk.

Plasma Protein Binding

Approximately 62%.

Elimination

Metabolism

Approximately 50% metabolized (principally by CYP2D6 and to a lesser extent by CYP3A and CYP1A2) to 2 metabolites with <1% of the 5-HT₃ receptor inhibitor activity of palonosetron. However, pharmacokinetics are not substantially different between poor and extensive CYP2D6 substrate metabolizers.

Elimination Route

Eliminated principally in urine (approximately 80% in 144 hours, about 40% as palonosetron).

Half-life

Approximately 40 hours.

Special Populations

Hepatic impairment: Total body clearance not substantially affected.

Mild to moderate renal impairment: Pharmacokinetics not substantially affected.

Severe renal impairment: Total systemic exposure increased by approximately 28%. Effect of dialysis on pharmacokinetics not studied, but unlikely to have clinically important effect.

Geriatric patients: In a population pharmacokinetic analysis, no differences in pharmacokinetics observed between cancer patients ≥65 years of age and younger cancer patients (18–64 years of age).

Stability

Storage

Parenteral

Injection

20–25°C (may be exposed to 15–30°C). Protect from light; do not freeze.

Actions

• Antiemetic activity for acute nausea and vomiting appears to be mediated via inhibition of serotonin activity both centrally (in area postrema and chemoreceptor trigger zone) and peripherally (in GI tract).

• Alternative mechanisms to peripheral and CNS stimulation by serotonin appear to be responsible for delayed nausea and vomiting. Risk of delayed nausea and vomiting may be decreased by effective prevention of acute nausea and vomiting in the same chemotherapy cycle. Palonosetron’s potency and long plasma half-life may contribute to its efficacy in delayed nausea and vomiting.

• Postoperative nausea and vomiting is influenced by a number of patient-, surgical-, and anesthesia-related factors and is triggered by a release of serotonin in a cascade of neuronal events involving both the CNS and the GI tract.

Advice to Patients

• Importance of reading the manufacturer's patient information before beginning therapy and rereading it each time palonosetron is given.

• Importance of informing patients that hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving palonosetron. Advise patients to seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction occur while receiving the drug.

• Importance of informing patients of the possibility of serotonin syndrome, particularly with concomitant use of palonosetron and another serotonergic agent (e.g., antidepressants, antimigraine agents). Advise patients to seek immediate medical attention should they experience symptoms of serotonin syndrome: alterations in mental status, autonomic instability, neuromuscular symptoms, or seizures (with or without GI symptoms).

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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