Palonosetron (DB00377): A Comprehensive Monograph on a Second-Generation 5-HT3 Receptor Antagonist

1.0 Executive Summary

Palonosetron is a second-generation serotonin 5-HT3 receptor antagonist distinguished by a unique pharmacological profile and superior clinical efficacy in the prevention of nausea and vomiting, particularly those induced by chemotherapy (CINV) and surgery (PONV). Chemically defined as the pure (S,S)-stereoisomer of a complex isoquinoline derivative, its structure confers a significantly higher binding affinity for the 5-HT3 receptor and facilitates unique allosteric interactions, which are not observed with first-generation agents like ondansetron or granisetron. These pharmacodynamic properties, combined with its exceptionally long pharmacokinetic half-life of approximately 40 hours, provide the basis for its sustained antiemetic activity.

Clinically, Palonosetron is the only 5-HT3 receptor antagonist monotherapy approved by the U.S. Food and Drug Administration (FDA) for the prevention of delayed CINV associated with moderately emetogenic chemotherapy (MEC). Pivotal clinical trials have consistently demonstrated its superiority over first-generation antagonists in providing a complete response—defined as no emesis and no rescue medication—over a 120-hour period. Its efficacy is well-established for acute CINV following both MEC and highly emetogenic chemotherapy (HEC), for PONV prevention up to 24 hours, and in pediatric populations as young as one month of age. Palonosetron serves as a foundational component in modern antiemetic regimens, where its efficacy is enhanced by co-administration with corticosteroids and neurokinin-1 (NK-1) receptor antagonists. This has led to its inclusion in guideline-recommended triple-therapy regimens and its development as part of a fixed-dose combination product, Akynzeo (palonosetron/netupitant).

The safety profile of Palonosetron is well-characterized and favorable. The most common adverse events are mild-to-moderate headache and constipation. Critically, it exhibits a superior cardiac safety profile compared to older agents, with a clinically insignificant effect on the QTc interval at therapeutic doses, a key advantage in polymedicated oncology patients. Warnings and precautions are in line with the drug class and include the potential for hypersensitivity reactions and Serotonin Syndrome, particularly when co-administered with other serotonergic medications. Its single-dose administration for each indication simplifies treatment protocols and improves patient convenience. Developed by Helsinn Healthcare SA and marketed under brand names including Aloxi®, Palonosetron's successful regulatory journey and strategic lifecycle management have established it as a standard of care and a cornerstone of modern antiemetic therapy.

2.0 Identification and Chemical Profile

The precise and unambiguous identification of a pharmaceutical agent is fundamental to its study and clinical application. This section provides a definitive chemical and physical profile of Palonosetron, detailing its nomenclature, structural characteristics, and key identifiers used across scientific and regulatory domains.

2.1 Nomenclature and Identifiers

Palonosetron is known by a variety of chemical names, synonyms, and database identifiers that ensure its consistent recognition in global literature and regulatory filings.

• Primary Chemical Name (IUPAC): The systematic name according to the International Union of Pure and Applied Chemistry (IUPAC) is (3aS)-2-octan-3-yl]-2,3,3a,4,5,6-hexahydro-1H-benzo[de]isoquinolin-1-one.[1] This name precisely describes its complex heterocyclic structure and specific stereochemistry.
• Generic and International Names: The established generic name is Palonosetron. International nonproprietary names (INN) include Palonosétron (French), Palonosetrón (Spanish), and Palonosetronum (Latin).[1]
• Key Identifiers: Palonosetron is cataloged under several unique codes for regulatory and database purposes:
• DrugBank ID: DB00377 [1]
• CAS Number: 135729-56-5 for the free base.[4] The hydrochloride salt is associated with CAS number 135729-61-2.[2]
• UNII Code: 5D06587D6R.[2]
• Synonyms and Development Codes: The compound has been referred to by development codes such as RS-25259-197 and RS 25233-198.[3]
• Database Cross-references: It is extensively cross-referenced in major chemical and biological databases, including PubChem CID (148211), ChEMBL (ChEMBL1189679), KEGG (D07175), and ChemSpider (4892289).[2]

2.2 Molecular Structure and Physicochemical Properties

The therapeutic activity of Palonosetron is a direct consequence of its specific three-dimensional structure and its resulting physical and chemical properties.

• Molecular Formula and Weight: The chemical formula for Palonosetron is C19​H24​N2​O.[2] Its corresponding molar mass is approximately 296.41 g/mol.[2]
• Structural Representations: The molecule's structure can be represented using standardized chemical notations:
• InChI: InChI=1S/C19H24N2O/c22-19-16-6-2-4-14-3-1-5-15(18(14)16)11-21(19)17-12-20-9-7-13(17)8-10-20/h2,4,6,13,15,17H,1,3,5,7-12H2/t15-,17-/m1/s1 [2]
• InChIKey: CPZBLNMUGSZIPR-NVXWUHKLSA-N [2]
• Canonical SMILES: O=C5N([C@H]2C1CCN(CC1)C2)C[C@@H]4c3c5cccc3CCC4 [2]
• Stereochemistry: Palonosetron possesses two chiral centers, resulting in the potential for multiple stereoisomers. The clinically active and marketed form is the pure (S,S)-stereoisomer.[2] The use of a single, defined stereoisomer is a critical aspect of modern drug development, as different isomers can have vastly different pharmacological activities, metabolic fates, and toxicities. The selection of the (S,S)-isomer for clinical use implies that this specific three-dimensional configuration provides the optimal fit and interaction with the 5-HT3 receptor's binding site, which is the structural foundation for the drug's high potency and unique binding characteristics.
• Physical and Chemical Properties:
• Appearance: At room temperature, Palonosetron is a solid, typically described as an off-white powder.[2]
• Solubility: The hydrochloride salt, which is used in pharmaceutical formulations, is easily soluble in water, soluble in propylene glycol, and slightly soluble in ethanol and isopropyl alcohol.[2]
• Melting Point: The melting point is reported to be between 87 to 88 °C (189 to 190 °F).[2]
• Predicted Physicochemical Parameters: Computational models predict a boiling point of 511.0±50.0 °C and a pKa of 9.77±0.33, reflecting its basic nitrogen atom in the quinuclidine ring system.[4] The predicted partition coefficient (XLogP) is 2.69, indicating moderate lipophilicity, which is consistent with its ability to cross biological membranes and distribute widely in the body.[3]

2.3 Synthesis and Manufacturing

The chemical synthesis of Palonosetron is a multi-step process designed to produce the specific (S,S)-stereoisomer required for clinical activity. The manufacturing process must be stereoselective to avoid contamination with other, less active or potentially harmful isomers.

• Synthetic Pathway: The synthesis of Palonosetron has been described in the scientific literature, with key publications appearing in the Journal of Medicinal Chemistry (1993) and Synthesis (1996).[6] A common synthetic route starts from (S)-N-(1-Azabicyclo[2.2.2]oct-3-yl)-5,6,7,8-tetrahydro-1-naphthalenecarboxamide.[4]
• Key Raw Materials: The synthesis involves several key starting materials and intermediates, including (S)-quinuclidin-3-amine, which provides the chiral azabicyclic moiety, and various derivatives of tetrahydronaphthalene carboxylic acid, which form the tricyclic isoquinolinone core of the molecule.[4] The complexity of these materials and the need for stereocontrol highlight the sophisticated chemistry required for the drug's production.

The following table provides a consolidated summary of the key chemical and physical identifiers for Palonosetron.

Table 2.1: Chemical and Physical Identifiers for Palonosetron

Property	Value	Source(s)
IUPAC Name	(3aS)-2-octan-3-yl]-2,3,3a,4,5,6-hexahydro-1H-benzo[de]isoquinolin-1-one	1
DrugBank ID	DB00377	1
CAS Number	135729-56-5 (free base)	4
Molecular Formula	C19​H24​N2​O	2
Molecular Weight	296.41 g/mol	2
Stereochemistry	(S,S)-stereoisomer	2
Physical Form	Off-white powder	5
Melting Point	87 - 88 °C	2
InChIKey	CPZBLNMUGSZIPR-NVXWUHKLSA-N	2
Oral Bioavailability	97%	2

3.0 Comprehensive Pharmacological Profile

The clinical utility and superiority of Palonosetron are rooted in its distinct pharmacological properties. As a second-generation 5-HT3 receptor antagonist, it possesses unique pharmacodynamic and pharmacokinetic characteristics that differentiate it from older agents in its class. This section dissects its mechanism of action at the molecular level and describes its journey through the body.

3.1 Pharmacodynamics: Mechanism of Action

The pharmacodynamics of Palonosetron explain how it interacts with its biological target to produce its therapeutic antiemetic effect. Its mechanism is defined by high selectivity, potent affinity, and a unique mode of receptor interaction.

3.1.1 Primary Mechanism: Selective 5-HT3 Receptor Antagonism

The fundamental mechanism of Palonosetron is the selective blockade of the serotonin 5-HT3 receptor, a ligand-gated ion channel.[1] Emesis, particularly CINV, is initiated in large part by the release of serotonin from enterochromaffin cells in the gastrointestinal (GI) tract following damage from cytotoxic chemotherapy.[1] This released serotonin activates 5-HT3 receptors located on peripheral vagal afferent nerves, which transmit signals to the medullary vomiting center in the brainstem. Serotonin also acts centrally on 5-HT3 receptors in the chemoreceptor trigger zone (CTZ) of the area postrema, a region that detects emetogenic substances in the blood.[8]

Palonosetron exerts its antiemetic activity by competitively inhibiting the binding of serotonin to these 5-HT3 receptors at both peripheral and central sites.[1] By blocking these receptors, it interrupts the signaling cascade that leads to the sensation of nausea and the vomiting reflex.[8] A key feature of Palonosetron is its high specificity; it has little to no affinity for other neurotransmitter receptors, such as other serotonin receptor subtypes (5-HT1, 5-HT2, 5-HT4), dopamine, adrenergic, histamine, or opioid receptors.[1] This high selectivity is crucial for its favorable safety profile, as it avoids off-target effects that could lead to unwanted side effects like sedation or extrapyramidal symptoms.

3.1.2 Receptor Binding and Allosteric Properties: The Second-Generation Advantage

What elevates Palonosetron to a second-generation agent is not just its primary mechanism but the unique nature of its interaction with the 5-HT3 receptor. This interaction is characterized by two key features that contribute to its enhanced and prolonged efficacy.

First, Palonosetron exhibits a remarkably high binding affinity for the 5-HT3 receptor. This affinity is reported to be at least 30-fold greater than that of first-generation antagonists like ondansetron and granisetron.[9] This means that Palonosetron binds more tightly and effectively to the receptor, allowing for potent blockade at lower concentrations and contributing to its superior clinical efficacy observed in head-to-head trials.[8]

Second, and perhaps more significantly, Palonosetron demonstrates a unique molecular interaction with the receptor. Evidence suggests that it engages in allosteric interactions and exhibits positive cooperativity.[13] Unlike a simple competitive antagonist that just physically blocks the binding site, an allosteric modulator binds to a different site on the receptor and induces a conformational change. This change can alter the receptor's function, in this case, locking it in a prolonged, non-functional state that is resistant to activation by serotonin. This allosteric mechanism, which is not observed with first-generation agents, is thought to be a primary contributor to the drug's long duration of action, allowing it to suppress the emetic reflex long after peak plasma concentrations have passed.[13] This sophisticated binding mechanism provides a clear pharmacodynamic explanation for why Palonosetron is uniquely effective against delayed CINV.

3.2 Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of Palonosetron describes its absorption, distribution, metabolism, and excretion. Its most notable feature is an exceptionally long elimination half-life, which works in concert with its potent pharmacodynamics to provide sustained antiemetic coverage from a single dose.

3.2.1 Absorption and Bioavailability

Palonosetron is formulated for both intravenous and oral administration.[2] When taken orally, it is well absorbed from the gut and exhibits excellent bioavailability, with studies showing that 97% of the oral dose reaches systemic circulation.[2] Following oral administration, peak plasma concentrations (

Cmax​) are typically achieved in approximately 5.1 hours (Tmax​), and this absorption is not affected by the presence of food.[2]

3.2.2 Distribution

Once in the bloodstream, Palonosetron distributes extensively throughout the body. This is evidenced by its large apparent volume of distribution (Vd​), which is approximately 8.3 L/kg.[1] This large value indicates that the drug does not remain confined to the bloodstream but partitions widely into body tissues. Palonosetron exhibits moderate binding to plasma proteins, with approximately 62% of the drug being bound.[1] The remaining unbound fraction is free to distribute to target tissues and interact with 5-HT3 receptors.

3.2.3 Metabolism

Approximately half (50%) of an administered dose of Palonosetron is metabolized, primarily in the liver.[1] This metabolism is mediated by the cytochrome P450 (CYP) enzyme system. The primary isoenzyme involved is CYP2D6, with minor contributions from CYP3A4 and CYP1A2.[1] This involvement of multiple CYP pathways may contribute to a lower risk of clinically significant drug-drug interactions, as the inhibition of a single pathway would not completely block the drug's metabolism.

The metabolic process yields two main metabolites: an N-oxide derivative and a 6S-hydroxy derivative.[2] Crucially, both of these metabolites are pharmacologically insignificant, possessing less than 1% of the 5-HT3 receptor antagonist activity of the parent compound, Palonosetron.[2] This means that the therapeutic effect is almost entirely attributable to the unchanged drug.

3.2.4 Elimination and Extended Half-Life

Palonosetron and its inactive metabolites are eliminated from the body primarily through the kidneys.[2] Following a single intravenous dose, about 80% of the dose is recovered in the urine over 144 hours, with approximately 40% of this being the unchanged parent drug.[2] A smaller fraction is eliminated via the feces.[2]

The defining pharmacokinetic feature of Palonosetron is its exceptionally long terminal elimination half-life (t1/2​). In healthy individuals, the half-life is approximately 37 hours, and in cancer patients, it is even longer, averaging around 40 to 48 hours.[2] In some patients, the half-life can exceed 100 hours.[2] This is in stark contrast to first-generation 5-HT3 antagonists, whose half-lives are typically in the range of 2 to 15 hours.[2] This prolonged half-life ensures that therapeutically effective plasma concentrations of Palonosetron are maintained for several days following a single administration, providing the sustained coverage necessary to prevent both acute (0-24 hours) and delayed (24-120 hours) CINV.

The synergy between the drug's pharmacodynamics and pharmacokinetics is the core of its clinical success. The long half-life (a pharmacokinetic property) ensures the drug is present at the receptor for an extended period, while the high-affinity, allosteric binding (a pharmacodynamic property) ensures that its inhibitory effect on the receptor is profound and persistent. Together, these attributes provide a robust and prolonged antiemetic effect that is superior to that of older agents.

The following table compares the key pharmacological properties of Palonosetron with those of representative first-generation 5-HT3 antagonists.

Table 3.1: Comparative Pharmacological Profile of 5-HT3 Receptor Antagonists

Feature	Palonosetron	Ondansetron	Granisetron
Generation	Second	First	First
Receptor Binding Affinity	Very High (>30x higher than 1st gen)	High	High
Allosteric Interaction	Yes (Positive Cooperativity)	No	No
Elimination Half-Life (t1/2​)	~40 hours	~4-6 hours	~9 hours
Primary Metabolic Pathway	CYP2D6 (major), CYP3A4, CYP1A2	CYP3A4, CYP1A2, CYP2D6	CYP3A4
Key Differentiator	Prolonged half-life and unique allosteric binding leading to superior efficacy in delayed CINV	Standard for acute CINV, less effective for delayed CINV	Standard for acute CINV, less effective for delayed CINV
Source(s)	2	9	9

4.0 Clinical Efficacy and Therapeutic Applications

The clinical value of Palonosetron is defined by its proven efficacy in preventing nausea and vomiting across a range of challenging clinical scenarios. Its development and subsequent clinical trial program established a new benchmark for antiemetic therapy, particularly by demonstrating robust control over the delayed phase of CINV. This section details its approved indications and analyzes the pivotal clinical trial data that underpin its use.

4.1 Approved Indications and Clinical Use

Palonosetron is approved by major regulatory bodies, including the U.S. FDA and the European Medicines Agency (EMA), for several key indications in both adult and pediatric populations.

4.1.1 Chemotherapy-Induced Nausea and Vomiting (CINV) in Adults

Palonosetron is a cornerstone therapy for the prevention of CINV, with specific approvals based on the emetogenic potential of the chemotherapy regimen:

• Moderately Emetogenic Chemotherapy (MEC): It is indicated for the prevention of both acute (occurring within the first 24 hours) and delayed (occurring from 24 to 120 hours) nausea and vomiting associated with initial and repeat courses of MEC.[1] This dual approval for both phases is a key differentiator from first-generation agents.
• Highly Emetogenic Chemotherapy (HEC): It is indicated for the prevention of acute nausea and vomiting associated with initial and repeat courses of HEC.[1] While not approved as a monotherapy for delayed HEC, it is a critical component of combination regimens that are effective in this setting.

4.1.2 Postoperative Nausea and Vomiting (PONV) in Adults

Palonosetron is indicated for the prevention of PONV for up to 24 hours following surgery.[1] Its use is recommended in situations where PONV must be avoided, even if the baseline risk is low.[18] Efficacy beyond the initial 24-hour postoperative period has not been formally established.[16]

4.1.3 Pediatric Applications

The use of Palonosetron has been extended to younger patients based on dedicated clinical studies. It is approved for children aged 1 month to less than 17 years for the prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including HEC.[16] This approval provides a vital therapeutic option for one of the most vulnerable patient populations.

4.2 Analysis of Pivotal Clinical Trials

The approvals and guideline recommendations for Palonosetron are built on a foundation of rigorous, large-scale, randomized controlled trials. These studies not only established its efficacy but also demonstrated its superiority over the previous standard of care.

4.2.1 Superiority in Moderately Emetogenic Chemotherapy (MEC)

Two landmark Phase III, double-blind trials definitively established Palonosetron's superiority in the MEC setting.

• In one trial, 570 patients were randomized to receive a single intravenous dose of Palonosetron (0.25 mg) or ondansetron (32 mg) prior to MEC.[15] Palonosetron was statistically superior, with a Complete Response (CR: no emesis, no rescue medication) rate of 81.0% vs. 68.6% for ondansetron in the acute phase ( p=0.008) and 74.1% vs. 55.1% in the delayed phase (p<0.001).[15]
• In a second trial, 592 patients receiving MEC were randomized to Palonosetron (0.25 mg) or dolasetron (100 mg).[15] While the difference in the acute phase was not statistically significant in this trial, Palonosetron was again statistically superior in the delayed phase, with a CR rate of 54.0% vs. 38.7% for dolasetron ( p=0.004).[15]

These trials were groundbreaking because they were the first to show a clinically and statistically significant advantage of one 5-HT3 antagonist over others, particularly in the difficult-to-treat delayed phase.

4.2.2 Efficacy in Highly Emetogenic Chemotherapy (HEC)

In the HEC setting, where the risk of emesis is extremely high, a pivotal Phase III trial compared a single dose of Palonosetron (0.25 mg) with ondansetron (32 mg) in 667 patients, the majority of whom also received prophylactic dexamethasone.[15] The study found that Palonosetron was non-inferior to ondansetron in preventing acute CINV.[20] More importantly, in the subgroup of patients who received concomitant dexamethasone—which reflects modern clinical practice—Palonosetron demonstrated superior efficacy over ondansetron in controlling emesis throughout the entire 5-day post-chemotherapy period, with statistically significant advantages in the delayed and overall phases.[9]

4.2.3 Pooled Analysis Confirming Superiority

To provide a more robust estimate of its relative efficacy, a pooled analysis of patient-level data from four large Phase III trials was conducted.[21] This analysis included 1,787 patients treated with Palonosetron and 1,175 treated with an older 5-HT3 antagonist (ondansetron, dolasetron, or granisetron). The results overwhelmingly confirmed the findings of the individual trials. CR rates were significantly higher for Palonosetron in the delayed period (57% vs. 45%,

p<0.0001) and the overall 0-120 hour period (51% vs. 40%, p<0.0001).[21] This large-scale analysis solidified Palonosetron's position as the most effective single-agent 5-HT3 antagonist for comprehensive CINV prevention.

4.2.4 Efficacy in Combination Regimens

Modern CINV prevention relies on multi-modal therapy targeting different emetic pathways. Palonosetron is a preferred backbone for these regimens.

• Combination with Corticosteroids: As shown in the HEC trials, the efficacy of Palonosetron is significantly enhanced by co-administration with a corticosteroid like dexamethasone.[9] This combination is now standard of care for MEC and HEC.
• Combination with NK-1 Antagonists: Emesis is also mediated by substance P acting on neurokinin-1 (NK-1) receptors. Combining Palonosetron with an NK-1 antagonist (e.g., aprepitant, netupitant) provides dual-pathway blockade and is the recommended regimen for HEC. Clinical trials have demonstrated the high efficacy of these triple-therapy regimens.[9] This strategy culminated in the development of Akynzeo, a fixed-dose combination of Palonosetron and the NK-1 antagonist netupitant (or its prodrug, fosnetupitant), which simplifies treatment by providing two highly effective antiemetics in a single administration.[22]

4.2.5 Efficacy in PONV

The approval for PONV was based on Phase III trials comparing Palonosetron to placebo. In a pivotal study involving 574 patients undergoing gynecologic or abdominal laparoscopic surgery, a single 0.075 mg intravenous dose of Palonosetron given before anesthesia resulted in a significantly higher CR rate (no emesis, no rescue medication) in the first 24 hours compared to placebo (42.8% vs. 25.9%, p=0.0035).[15]

4.2.6 Pediatric Efficacy

The pediatric approval was supported by a study that demonstrated a single 20 mcg/kg dose of Palonosetron was as effective as a standard ondansetron-based regimen in preventing acute CINV in patients from 1 month to less than 17 years of age.[19] The CR rate in the first 24 hours was 59.4% for the Palonosetron group, meeting the study's primary endpoint of non-inferiority.[19]

The clinical trial program for Palonosetron was instrumental in shifting the paradigm of antiemetic research. By focusing on endpoints that captured the full 5-day period of risk, particularly the delayed phase, the studies established a new and higher standard for efficacy. This changed clinical expectations from simply controlling acute vomiting to maintaining a vomit-free and low-nausea state for patients throughout their most vulnerable period, significantly improving quality of life.[15]

The following table summarizes the key results from the pivotal Phase III trials that established the efficacy of Palonosetron in CINV.

Table 4.1: Summary of Pivotal Phase III Clinical Trials for Palonosetron in CINV

Trial Reference / Focus	Patient Population (Emetogenicity)	N	Intervention	Comparator	Primary Endpoint	Key Result (Complete Response: Palonosetron vs. Comparator)	Source(s)
Gralla et al. 2003	MEC	570	Palonosetron 0.25 mg IV	Ondansetron 32 mg IV	CR in Acute Phase	Acute (0-24h): 81.0% vs. 68.6% (p=0.008) Delayed (>24-120h): 74.1% vs. 55.1% (p<0.001)	15
Eisenberg et al. 2003	MEC	592	Palonosetron 0.25 mg IV	Dolasetron 100 mg IV	CR in Acute Phase	Acute (0-24h): 63.0% vs. 52.9% (p=0.049) Delayed (>24-120h): 54.0% vs. 38.7% (p=0.004)	15
Aapro et al. 2006	HEC (Cisplatin)	667	Palonosetron 0.25 mg IV	Ondansetron 32 mg IV	CR in Acute Phase	Acute (0-24h): 59.2% vs. 57.0% (Non-inferior) Delayed (>24-120h with Dexamethasone): 42.0% vs. 28.6% (p=0.021)	9
Boccia et al. 2013 (Pooled)	MEC/HEC	2,962	Palonosetron 0.25/0.75 mg IV	Ondansetron/Dolasetron/Granisetron	CR in Acute, Delayed, Overall	Delayed (>24-120h): 57% vs. 45% (p<0.0001) Overall (0-120h): 51% vs. 40% (p<0.0001)	21

5.0 Safety, Tolerability, and Risk Management

A thorough understanding of a drug's safety profile is paramount to its appropriate clinical use. Palonosetron is generally well-tolerated, with a safety profile that is comparable or superior to older agents in its class. This section provides a comprehensive overview of its adverse effects, critical warnings and precautions, and clinically significant drug interactions.

5.1 Comprehensive Adverse Event Profile

The adverse reactions associated with Palonosetron have been characterized through extensive clinical trials in both adult and pediatric populations for CINV and PONV indications.

• Common Adverse Reactions: The most frequently reported treatment-related adverse events are generally mild to moderate in intensity.
• In adult CINV trials, the most common side effects are headache (occurring in up to 9% of patients) and constipation (up to 5%).[2]
• In adult PONV trials, the most common events (≥2%) are QT prolongation (5%), bradycardia (slow heart rate, 4%), headache (3%), and constipation (2%).[16]
• Infrequent Adverse Reactions: A variety of less common side effects have been reported in less than 2% of patients. These include:
• Gastrointestinal: Diarrhea, dyspepsia, abdominal pain, dry mouth, and flatulence.[17]
• Nervous System: Dizziness, insomnia, somnolence, and dyskinesia (in pediatrics).[2]
• General: Fatigue, weakness, and infusion site pain.[26]
• Cardiovascular: Tachycardia, hypotension, and extrasystoles.[16]
• Hepatic: Transient, asymptomatic increases in liver enzymes (AST and/or ALT) have been observed, predominantly in patients receiving highly emetogenic chemotherapy.[16]
• Postmarketing Experience: Surveillance after the drug's approval has identified very rare but important adverse reactions. These include:
• Hypersensitivity Reactions: Anaphylaxis, anaphylactic shock, dyspnea (shortness of breath), bronchospasm, facial edema, erythema, rash, and urticaria (hives).[16]
• Injection Site Reactions: Burning, induration (hardening of tissue), discomfort, and pain at the site of intravenous administration.[26]

5.2 Warnings, Precautions, and Contraindications

The product labeling for Palonosetron includes several critical warnings and precautions to guide its safe use and mitigate potential risks.

• Contraindications: Palonosetron is strictly contraindicated in patients with a known hypersensitivity to the drug or any of its formulation components.[16]
• Warning - Hypersensitivity Reactions: Serious, life-threatening hypersensitivity reactions, including anaphylaxis, have been reported.[26] A crucial aspect of this warning is that these reactions can occur in patients with or without a known prior hypersensitivity to other 5-HT3 receptor antagonists. This unpredictability necessitates that healthcare providers be prepared to manage anaphylaxis whenever Palonosetron is administered. If a reaction occurs, the drug must be discontinued immediately, and appropriate medical treatment initiated. The drug should not be re-administered to any patient who has previously experienced a hypersensitivity reaction to it.[26]
• Warning - Serotonin Syndrome: The development of Serotonin Syndrome, a potentially fatal condition, has been reported with 5-HT3 receptor antagonists.[16] The risk is highest when Palonosetron is used concomitantly with other serotonergic drugs. This includes common medications such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), mirtazapine, and certain analgesics like fentanyl and tramadol.[16] The safe use of Palonosetron therefore depends not only on the drug itself but on a comprehensive review of the patient's entire medication profile. Clinicians must monitor patients for signs and symptoms, which include mental status changes (agitation, hallucinations), autonomic instability (tachycardia, labile blood pressure, hyperthermia), and neuromuscular symptoms (tremor, rigidity, hyperreflexia). If Serotonin Syndrome is suspected, Palonosetron and other serotonergic agents should be discontinued, and supportive care initiated.[26]
• Precaution - Cardiovascular Effects: While non-clinical studies showed that Palonosetron has the potential to block cardiac ion channels involved in ventricular repolarization, its clinical cardiac safety profile is a significant advantage.[20] At the approved 0.25 mg dose, its effect on the QTc interval is minimal and not considered clinically significant, with an average increase of only 1-3 milliseconds.[9] This compares favorably to the larger QTc increases observed with some first-generation agents.[20] This lack of a significant cardiac warning makes Palonosetron a particularly valuable option for oncology patients, who are often elderly, may have pre-existing cardiac conditions, are susceptible to electrolyte imbalances from vomiting or diarrhea, and may be receiving other cardiotoxic therapies. Nonetheless, caution is still advised when using the drug in patients with existing risk factors for QT prolongation, such as congenital QT syndrome or uncorrected electrolyte abnormalities.[14]
• Precaution - Gastrointestinal Effects: Palonosetron may decrease large bowel motility and increase transit time. Therefore, patients with a history of constipation or with signs of subacute intestinal obstruction should be monitored closely following its administration.[14]

5.3 Clinically Significant Drug Interactions

The potential for drug-drug interactions with Palonosetron is relatively low, which is a favorable characteristic for its use in polymedicated cancer patients.

• Serotonergic Agents: As detailed in the warning above, this is the most clinically important interaction. The concomitant use of Palonosetron with drugs that increase serotonin levels elevates the risk of Serotonin Syndrome.[16]
• Apomorphine: Co-administration of 5-HT3 antagonists with apomorphine (a dopamine agonist used for Parkinson's disease) is contraindicated. This combination has been reported to cause profound hypotension and loss of consciousness.[27]
• CYP450 System: Palonosetron is metabolized by CYP2D6, CYP3A4, and CYP1A2, but it does not significantly inhibit or induce these enzymes at clinical concentrations.[2] Clinical studies have shown no significant pharmacokinetic interactions when Palonosetron is co-administered with a CYP2D6 inhibitor (metoclopramide) or with common combination antiemetics like dexamethasone and aprepitant.[14] This low potential for metabolic interactions simplifies its use and reduces the need for dose adjustments based on concomitant medications.

6.0 Dosage, Administration, and Formulations

The practical application of Palonosetron in the clinical setting is guided by its available formulations and specific, evidence-based dosing regimens for each indication and patient population. The drug's long half-life is a key determinant of its simple, single-dose administration schedule, which represents a significant advantage in convenience and compliance.

6.1 Commercial Formulations

Palonosetron is commercially available in several ready-to-use formats, eliminating the need for complex reconstitution or dilution.

• Intravenous (IV) Solution: The most common formulation is a sterile, clear, colorless, isotonic buffered solution for intravenous administration.[11] It is supplied in single-dose vials and prefilled syringes at a standard concentration of 0.05 mg/mL (50 mcg/mL).[17] Common presentations for different indications include:
• 0.25 mg in 5 mL
• 0.075 mg in 1.5 mL [27]
• Oral Capsules: An oral formulation is also available under the brand name Aloxi®. It is supplied as a 0.5 mg soft gelatin capsule and is approved for the prevention of acute CINV associated with moderately emetogenic chemotherapy in adults.[2]
• Fixed-Dose Combination Products: Palonosetron is also a component of the fixed-dose combination product Akynzeo®, which combines it with the NK-1 receptor antagonist netupitant (oral capsule) or its intravenous prodrug, fosnetupitant.[24]

6.2 Dosing Regimens and Administration Guidelines

The dosing of Palonosetron is indication-specific and differs between adult and pediatric populations. The single-dose regimen for each therapeutic event (a cycle of chemotherapy or a surgical procedure) is a direct clinical benefit of its prolonged pharmacokinetic profile.

6.2.1 Adult Dosing

• Chemotherapy-Induced Nausea and Vomiting (CINV) Prevention: The recommended adult dose is a single 0.25 mg dose administered as an intravenous infusion over 30 seconds. It should be given approximately 30 minutes prior to the start of chemotherapy.[17]
• Postoperative Nausea and Vomiting (PONV) Prevention: The recommended adult dose is a single 0.075 mg dose administered as an intravenous injection over 10 seconds. It should be given immediately before the induction of anesthesia.[17]

6.2.2 Pediatric Dosing (CINV Prevention)

• For pediatric patients aged 1 month to less than 17 years, the recommended dose is a single 20 mcg/kg dose. This dose is administered as an intravenous infusion over 15 minutes, also beginning approximately 30 minutes before the start of chemotherapy.[17]
• The maximum dose in this pediatric population should not exceed 1.5 mg.[17]

6.2.3 Administration Instructions

To ensure safety and efficacy, specific administration procedures must be followed:

• Ready to Use: The intravenous solution is supplied ready for administration and should not be mixed with other drugs in the same infusion line.[17]
• Flush the Line: It is critical to flush the infusion line with 0.9% sodium chloride (normal saline) both before and after the administration of Palonosetron. This ensures that the full dose is delivered to the patient and prevents potential physicochemical incompatibilities with other drugs that may be administered through the same line.[17]
• Visual Inspection: Before administration, the solution should be visually inspected for any particulate matter or discoloration. Only clear, colorless solutions should be used.[17]
• Single-Dose: All vials and prefilled syringes are for single use only. Any unused portion should be discarded.[17]

The following table provides a consolidated clinical reference for the recommended dosing and administration of intravenous Palonosetron.

Table 6.1: Recommended Dosing and Administration for Intravenous Palonosetron

Indication	Patient Population	Dose	Route	Administration Details	Source(s)
CINV Prevention	Adults	0.25 mg	IV Infusion	Infuse over 30 seconds, ~30 minutes before chemotherapy.	17
CINV Prevention	Pediatrics (1 month to <17 years)	20 mcg/kg (Max 1.5 mg)	IV Infusion	Infuse over 15 minutes, ~30 minutes before chemotherapy.	17
PONV Prevention	Adults	0.075 mg	IV Injection	Inject over 10 seconds, immediately before induction of anesthesia.	17

7.0 Regulatory and Commercial Overview

The commercial success and widespread clinical adoption of Palonosetron are the result of a robust clinical development program and a strategic approach to lifecycle management. This section details the drug's key brand names, manufacturers, and its regulatory history, which illustrates its evolution from a novel standalone agent to a foundational component of next-generation antiemetic therapies.

7.1 Global Brand Names and Manufacturers

Palonosetron is marketed globally under several brand names, both as a single agent and as part of a combination product.

• Primary Brand Names: The most widely recognized brand name for Palonosetron as a single agent is Aloxi®. Other brand names include Posfrea® and Palonosetron Accord.[1]
• Combination Product Brand Name: Palonosetron is a key component of the fixed-dose combination product Akynzeo®, which pairs it with the NK-1 receptor antagonist netupitant (for oral administration) or its prodrug fosnetupitant (for intravenous administration).[1]
• Key Companies: The development and commercialization of Palonosetron involve a network of pharmaceutical companies:
• Originator and Licensor: Helsinn Healthcare SA, a Swiss pharmaceutical group, is the original developer and worldwide licensor of Palonosetron and Akynzeo.[24]
• Marketing and Manufacturing Partners: Helsinn has established partnerships with several major companies for marketing and distribution in various regions. These include Eisai, Pfizer, and Juniper Biologics.[33]
• Generic Manufacturers: Following patent expiry, several companies, including Accord Healthcare, Apotex Corp., and Fresenius Kabi, have introduced generic versions of Palonosetron injection, increasing market access.[14]

7.2 Regulatory History and Approval Milestones

The regulatory timeline of Palonosetron highlights a well-executed strategy of initial approval followed by indication expansions and formulation innovations to maximize its clinical utility and commercial longevity.

• July 25, 2003: The U.S. Food and Drug Administration (FDA) granted initial approval to Helsinn Healthcare for Aloxi® (palonosetron hydrochloride) injection for the prevention of CINV in adults.[8] This marked the entry of the first second-generation 5-HT3 antagonist into the market.
• February 29, 2008: The FDA approved a supplemental New Drug Application (sNDA) for Aloxi®, expanding its indication to include the prevention of PONV in adults at a lower dose of 0.075 mg.[25]
• August 22, 2008: The FDA approved Aloxi® oral capsules (0.5 mg) for the prevention of acute CINV with MEC, providing an alternative route of administration.[29]
• May 28, 2014: A significant milestone was achieved with the FDA approval of Aloxi® injection for the prevention of acute CINV in pediatric patients aged 1 month to less than 17 years, addressing a critical unmet need.[19]
• October 10, 2014: The FDA approved Akynzeo® (oral netupitant/palonosetron), the first fixed-dose oral combination of a 5-HT3 antagonist and an NK-1 antagonist. This approval represented a major evolution, simplifying guideline-recommended triple therapy into a more convenient regimen.[24]
• May 26, 2016: The European Medicines Agency (EMA) granted its first marketing authorisation for a generic version, Palonosetron Accord, signaling the drug's established role and the beginning of wider market competition.[14]
• April 19, 2018: The FDA approved an intravenous formulation, Akynzeo® for Injection (fosnetupitant/palonosetron), providing a parenteral option for the combination therapy.[31]

This regulatory pathway demonstrates a highly successful lifecycle management strategy. The initial approval established Palonosetron's superiority. Subsequent expansions into new indications (PONV), populations (pediatrics), and formulations (oral) broadened its clinical reach. The development of the Akynzeo® franchise was a pivotal strategic move. By leveraging Palonosetron's best-in-class profile as the backbone for a new, patented combination product, Helsinn effectively extended the commercial life of the franchise, addressed evolving clinical guidelines, and provided a more convenient therapeutic option for patients and providers.

The following table chronologically summarizes the key regulatory milestones in the history of Palonosetron and its related combination products.

Table 7.1: Key Regulatory Milestones for Palonosetron and Related Products

Date	Regulatory Body	Action	Product	Details of Action	Source(s)
July 25, 2003	U.S. FDA	Initial Approval	Aloxi® Injection	Prevention of CINV in adults.	39
Feb 29, 2008	U.S. FDA	Indication Expansion	Aloxi® Injection	Prevention of PONV in adults.	25
Aug 22, 2008	U.S. FDA	New Formulation Approval	Aloxi® Capsules	Oral formulation for CINV prevention.	29
May 28, 2014	U.S. FDA	Population Expansion	Aloxi® Injection	Prevention of acute CINV in pediatric patients (≥1 month old).	19
Oct 10, 2014	U.S. FDA	New Product Approval	Akynzeo® Capsules	Fixed-dose oral combination of netupitant/palonosetron for CINV.	24
May 26, 2016	EMA	Initial Authorization	Palonosetron Accord	First marketing authorisation for a generic version in the EU.	14
Apr 19, 2018	U.S. FDA	New Product Approval	Akynzeo® for Injection	Fixed-dose IV combination of fosnetupitant/palonosetron for CINV.	31

8.0 Conclusion and Expert Synthesis

Palonosetron represents a significant advancement in antiemetic pharmacotherapy and a paradigm of successful rational drug design. Its development and clinical validation have fundamentally altered the standards and expectations for managing chemotherapy-induced and postoperative nausea and vomiting. The comprehensive analysis of its chemical, pharmacological, clinical, and regulatory profile reveals a molecule whose superiority is not incidental but is deeply rooted in its unique scientific attributes.

The journey from its chemical structure to its clinical performance is a clear and logical progression. The specific (S,S)-stereochemistry of its complex isoquinoline backbone was engineered to optimize its interaction with the 5-HT3 receptor. This resulted in a pharmacodynamic profile characterized by exceptionally high binding affinity and a unique allosteric binding mechanism, features that confer a more profound and durable receptor blockade than that of its predecessors. This potent molecular action is complemented perfectly by its distinctive pharmacokinetic profile, most notably an extended elimination half-life of approximately 40 hours. This synergy—a drug that binds more tightly and for longer at its target, while also remaining in the body for a prolonged period—is the definitive explanation for its superior clinical efficacy.

The clinical trial evidence is unequivocal. Palonosetron was the first 5-HT3 antagonist to demonstrate statistically significant superiority over first-generation agents in preventing CINV, particularly in the challenging delayed phase. This achievement redefined the goals of antiemetic therapy, shifting the focus from merely controlling acute emesis to providing comprehensive protection over the entire 5-day period of risk, thereby substantially improving patient quality of life. Its well-documented efficacy, combined with a favorable safety profile highlighted by a lack of clinically significant cardiac effects at therapeutic doses, has established it as a preferred agent in numerous clinical guidelines.

Ultimately, Palonosetron is more than just another antiemetic. It is a foundational agent in modern supportive cancer care. Its successful lifecycle management, culminating in its role as the cornerstone of the fixed-dose combination product Akynzeo, showcases its evolution from a standalone drug to an integral component of guideline-directed, multi-modal antiemetic strategies. In conclusion, Palonosetron stands as a testament to how targeted improvements in pharmacology can translate directly into meaningful and superior clinical outcomes, solidifying its position as a standard of care for preventing some of the most distressing side effects of cancer treatment and surgery.

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