netupitant/palonosetron

Action and Spectrum

Actions and Spectrum: 

Action: 

netupitant (NK-1 Receptor Antagonist): netupitant acts as a selective antagonist of substance P, the ligand for the NK-1 receptor. Substance P is a neurotransmitter that plays a crucial role in the emetic reflex pathway within the central nervous system (CNS). By blocking the NK-1 receptor, netupitant inhibits the binding of substance P, thereby interrupting the signaling cascade that leads to nausea and vomiting. This action effectively suppresses the initial phase of CINV, which is particularly associated with acute and delayed emesis following chemotherapy. 

palonosetron (5-HT3 Receptor Antagonist): palonosetron is a potent and highly selective antagonist of the serotonin 5-HT3 receptor. This receptor is predominantly located in the gut and the CNS, modulating the release of serotonin, and influencing emetic pathways. By binding to the 5-HT3 receptor, palonosetron inhibits the activation of serotonin-induced emesis, thus effectively mitigating the occurrence of acute and delayed CINV. 

Spectrum: 

netupitant/palonosetron combination therapy offers a broad spectrum of action, targeting both the acute and delayed phases of CINV, making it an effective option for patients undergoing highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC).

Drug Interaction

Adverse Reaction

Frequency not defined  

constipation, stomach upset  

skin redness 

feeling weak or tired 

headache 

Black Box Warning

Black Box Warning:  

None

Contraindication / Caution

Contraindication/Caution:  

Hypersensitivity: netupitant/palonosetron is contraindicated in individuals with a known hypersensitivity or allergy to either netupitant or palonosetron or any of the components of the formulation. Hypersensitivity reactions may manifest as skin rashes, itching, facial swelling, or severe anaphylactic reactions, necessitating immediate medical attention. 

Use with Highly Emetogenic Chemotherapy (HEC): The combination of netupitant/palonosetron is not recommended for use with Highly Emetogenic Chemotherapy (HEC) regimens, as safety and efficacy data for this specific patient population are limited. Alternative antiemetic options should be considered in such cases. 

Use with Strong CYP3A4 Inducers: Co-administration of netupitant/palonosetron with strong cytochrome P450 3A4 (CYP3A4) inducers is contraindicated. Strong CYP3A4 inducers, such as rifampicin, phenytoin, carbamazepine, and St. John’s wort, can significantly reduce the plasma concentrations of netupitant, potentially leading to a loss of efficacy. If the concurrent use of a strong CYP3A4 inducer is unavoidable, alternative antiemetic therapies should be considered. 

Use with Pimozide: Concomitant administration of netupitant/palonosetron and pimozide is contraindicated due to the risk of QTc interval prolongation and torsades de pointes. Pimozide is an antipsychotic agent, and concurrent use with netupitant/palonosetron may lead to serious cardiac adverse events. 

Severe Hepatic Impairment: The administration of netupitant/palonosetron is not recommended for patients with severe hepatic impairment, as indicated by a Child-Pugh score of C. Limited data is available in this patient population, and the drug’s metabolism may be altered, leading to potential safety concerns. 

Pregnancy: netupitant/palonosetron may pose potential risks to the developing fetus during pregnancy. Hence, it is advisable to refrain from administering this combination medication to pregnant women unless the advantages clearly outweigh the potential risks. For reproductive-age women undergoing treatment with netupitant/palonosetron, it is crucial to employ suitable contraceptive precautions. 

Breastfeeding: It is unknown whether netupitant and palonosetron are excreted in human breast milk. Because of the possibility of harmful outcomes in breastfeeding infants, netupitant/palonosetron should not be used while breastfeeding. 

Pregnancy / Lactation

Pregnancy warnings:     

Pregnancy category: AU TGA pregnancy category: B3
US FDA pregnancy category: Not assigned. 

Lactation: Excreted into human milk is unknown 

Pregnancy Categories:         

Category A: Studies that were well-controlled and met expectations revealed no risk to the fetus in either the first or second trimester. 

Category B: There were a lack of studies on pregnant women and no evidence of risk to the fetus in animal experiments.   

Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    

Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.   

Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    

Category N: There is no data available for the drug under this category

Pharmacology

Pharmacology:  

netupitant/palonosetron is a fixed-dose combination of two potent antiemetic agents, netupitant and palonosetron, designed to prevent and alleviate chemotherapy-induced nausea and vomiting (CINV) in patients undergoing highly emetogenic or moderately emetogenic chemotherapy. 

Pharmacodynamics:  

netupitant: netupitant is a selective antagonist of the human neurokinin-1 (NK-1) receptor, a subtype of the tachykinin receptor family. The NK-1 receptor is predominantly found in the central nervous system (CNS), particularly in areas involved in emesis regulation, such as the vomiting center located in the medulla oblongata. By blocking the NK-1 receptor, netupitant inhibits the binding of substance P, a neurotransmitter responsible for triggering emetic signals.  

palonosetron: palonosetron is a highly selective 5-HT3 receptor antagonist, which targets the serotonin (5-HT3) receptors located both centrally in the CNS and peripherally in the gastrointestinal tract. Activation of 5-HT3 receptors in the gut and the brain can induce emesis through different pathways. palonosetron’s binding to these receptors competitively inhibits serotonin binding and subsequently blocks the emetic signals triggered by serotonin release during chemotherapy. 

Pharmacokinetics: 

Absorption 

netupitant exhibits good oral bioavailability and is absorbed rapidly after ingestion, reaching peak plasma concentrations within 4 to 6 hours. On the other hand, palonosetron also demonstrates good oral bioavailability, and its absorption occurs relatively quickly, with peak plasma concentrations observed at approximately 2 to 4 hours post-dose.  

Distribution 

Both netupitant and palonosetron have moderate to high plasma protein binding. netupitant primarily binds to albumin, while palonosetron binds to both albumin and alpha-1 acid glycoprotein. These protein-bound fractions influence the distribution of the drugs within the body and may also affect their interactions with other medications. 

Metabolism 

netupitant is primarily metabolized by the hepatic cytochrome P450 enzyme system, particularly CYP3A4, into several metabolites, which are subsequently eliminated via urine and feces. palonosetron is primarily metabolized through multiple pathways involving CYP2D6 and CYP3A4 enzymes, forming metabolites that are eventually excreted mainly in the urine. Co-administration of netupitant and palonosetron may lead to potential drug-drug interactions due to their involvement with common metabolic pathways. 

Excretion and Elimination 

following metabolism, the metabolites of netupitant and palonosetron, along with a portion of unchanged drug, are excreted via both renal and biliary routes. The elimination half-life of netupitant ranges from approximately 4 to 40 hours, while palonosetron exhibits a longer half-life of approximately 40 hours. The prolonged half-life of palonosetron may contribute to its sustained pharmacological effects and the need for a single-dose regimen. 

Adminstartion

Administration:  

The standard dosage of netupitant/palonosetron is one capsule taken orally, approximately one hour before the start of chemotherapy on the designated day of treatment. 

The treatment cycle can range from single-day chemotherapy to multiple-day chemotherapy, and the administration of netupitant/palonosetron should align with each chemotherapy session. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: netupitant/palonosetron 

Why do we use netupitant/palonosetron?  

netupitant/palonosetron is primarily beneficial in minimizing the risk of both acute and delayed Chemotherapy-induced Nausea vomiting.