Palonosetron

A04A - Antiemetics and antinauseants ATC A04AA05 Small molecule approved 2003 Oral Parenteral Natural product

JFDA label: Aloxi 0.25mg/5ml

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

Indications

Approved

Capsules [Canadian product]
Chemotherapy-induced nausea and vomiting
Postoperative nausea and vomiting

Off-label

Chemotherapy-induced nausea and vomiting, moderately emetogenic chemotherapy (pediatrics)

Contraindications

Source: Lexicomp

Known hypersensitivity to palonosetron or any component of the formulation Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (1)

Common Prolonged Q-T interval on ECG

Hepatobiliary disorders (2)

Common Increased serum ALT · increased serum AST

Renal and urinary disorders (1)

Common Urinary retention

Metabolism and nutrition disorders (1)

Common Hyperkalemia

Gastrointestinal disorders (3)

Common Constipation · diarrhea · flatulence

Musculoskeletal and connective tissue disorders (1)

Common Weakness

Dosing

Source: Lexicomp

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

(For additional information see "Palonosetron: Pediatric drug information") Prevention of chemotherapy-induced nausea and vomiting (highly emetogenic chemotherapy): Infants ≥1 month, Children, and Adolescents mcg/kg (maximum dose: 1.5 mg) beginning ~30 minutes prior to the start of chemotherapy Pediatric guideline recommendations: Prevention of chemotherapy-induced nausea and vomiting for highly emetogenic chemotherapy (Patel 2017): Infants ≥1 month to 6 months: IV: 20 mcg/kg once prior to chemotherapy (maximum: 1.5 mg/dose). Antiemetic regimen also includes dexamethasone (if no contraindications to corticosteroids). Infants ≥6 months, Children and Adolescents mcg/kg once prior to chemotherapy (maximum: 1.5 mg/dose). Antiemetic regimen also includes aprepitant (if no potential drug interactions) and dexamethasone (if no contraindications to corticosteroids). Adolescents ≥17 years: IV: 0.25 mg once prior to chemotherapy. Antiemetic regimen also includes aprepitant (if no potential drug interactions) and dexamethasone (if no contraindications to corticosteroids). Oral [Canadian product]: 0.5 mg once prior to chemotherapy. Antiemetic regimen also includes aprepitant (if no potential drug interactions) and dexamethasone (if no contraindications to corticosteroids). Prevention of chemotherapy-induced nausea and vomiting for moderately emetogenic chemotherapy (off-label; Patel 2017): Infants ≥1 month to 6 months: IV: 20 mcg/kg once prior to chemotherapy (maximum: 1.5 mg/dose. Antiemetic regimen also includes dexamethasone (if no contraindications to corticosteroids). Infants ≥6 months, Children and Adolescents mcg/kg once prior to chemotherapy (maximum: 1.5 mg/dose). Antiemetic regimen also includes dexamethasone; if patient cannot receive corticosteroids, antiemetic regimen may include aprepitant (if no potential drug interactions). Adolescents ≥17 years: IV: 0.25 mg once prior to chemotherapy. Antiemetic regimen also includes dexamethasone; if patient cannot receive corticosteroids, antiemetic regimen may include aprepitant (if no potential drug interactions). Oral [Canadian product]: 0.5 mg once prior to chemotherapy. Antiemetic regimen also includes dexamethasone; if patient cannot receive corticosteroids, antiemetic regimen may include aprepitant (if no potential drug interactions).

No dosage adjustment necessary. Refer to adult dosing.

No dosage adjustment is necessary.

Warnings & Precautions

Source: Lexicomp

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 & Lactation

Pregnancy

FDA category B

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

Lactation

It is not known if palonosetron is present in breast milk. Due to the potential for adverse reactions in the breastfed infant, the manufacturer recommends a decision be made whether to discontinue breastfeeding or to discontinue palonosetron, taking into account the importance of treatment to the mother.

Chemistry & Properties

Formula	C19H24N2O
Molecular weight	296.41 g/mol
IUPAC name	(3aS)-2-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-3a,4,5,6-tetrahydro-3H-benzo[de]isoquinolin-1-one
CAS	135729-61-2
PubChem CID	6337614
InChIKey	`CPZBLNMUGSZIPR-NVXWUHKLSA-N`
logP	2.66 (XLogP 2.8)
Polar surface area	23.55 Å²
H-bond acceptors / donors	2 / 0
Drug-likeness (QED)	0.80
Lipinski violations	0

SMILES

O=C1c2cccc3c2[C@H](CCC3)CN1[C@@H]1CN2CCC1CC2

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	10.0%
Half-life	1.552 h
Volume of distribution	5.953 L/kg
Protein binding	66.4%
BBB penetrant	Yes

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—
CYP2B6	Inhibitor	—
CYP2C19	Substrate	—
CYP2D6	Substrate	—
CYP3A4	Substrate	—

Receptor binding (top 1)

Target	Action	Affinity
5-HT3A (HTR3A)	Antagonist	pKi 10.5

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Alfentanil	major
Almotriptan	major
Amiodarone	major
Amisulpride	major
Amitriptyline	major
Amoxapine	major
Anagrelide	major
Apomorphine	major
Arsenic trioxide	major
Bedaquiline	major
Bepridil	major
Bupropion	major
Buspirone	major
Cabozantinib	major
Ceritinib	major
Chloroquine	major
Cisapride	major
Citalopram	major
Clomipramine	major
Clozapine	major
Crizotinib	major
Desipramine	major
Desvenlafaxine	major
Dexfenfluramine	major
Dextromethorphan	major
Disopyramide	major
Dofetilide	major
Dolasetron	major
Doxepin	major
Doxepin (topical)	major
Dronedarone	major
Droperidol	major
Duloxetine	major
Efavirenz	major
Eletriptan	major
Escitalopram	major
Fenfluramine	major
Fentanyl	major
Fingolimod	major
Fluoxetine	major

Showing 40 of 100+.

Registered Products (3)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Akynzeo	Capsule 0.5 mg, 300 mg	1 cap	Sukhtian Group	62.160
Aloxi	Vial 0.25 mg/5 ml	1 vial	Sukhtian Group	—
Megatron	Vial 0.05 mg/ml	1 vial	MS PHARMA/JORDAN	—