fosnetupitant

Action and Spectrum

Actions and Spectrum: 

Actions: 

Neurokinin 1 (NK-1) receptors/ human substance P/ are selectively antagonistic by netupitant. The activation of neurokinin 1 (NK-1) receptors, which are widely dispersed throughout the central and peripheral neural systems, by substance P has been primarily linked to delayed emesis. Netupitant suppresses substance P-mediated reactions, as demonstrated by in vivo and in vitro investigations. 

Spectrum: 

A parenteral phosphorylated prodrug of netupitant is called fosnetupitant. Its active form, netupitant, has a longer elimination half-life than aprepitant and is distinguished by strong affinity and selectivity to the neurokinin-1 receptor.  

Intravenous netupitant-palonosetron, a fixed-dose blend of fosnetupitant and palonosetron, has been approved in the EU and the US to prevent CINV. Approaches in Japan have concentrated on the creation of fosnetupitant as a single agent. 

Drug Interaction

Adverse Reaction

Frequency not defined 

Pain at injection site 

Swelling at injection site 

Redness at injection site 

Waekness 

Headache 

Tiredness 

Constipation 

Decreased appetite 

Urticaria 

Malaise 

Hiccups 

Black Box Warning

Black Box Warning: 

The use of this medication carries the potential to increase serotonin levels, and in rare instances, it can cause serotonin toxicity or syndrome. The risk of encountering this condition is elevated when the medication is taken concurrently with other drugs that also augment serotonin levels. Therefore, it is crucial to communicate with your doctor or pharmacist, providing a comprehensive list of all the medications you are currently using.

Suppose you observe symptoms such as a rapid heartbeat, loss of coordination, hallucinations, severe dizziness, intense nausea, diarrhea or vomiting, unexplained fever, muscle twitching, or unusual restlessness/agitation. In that case, it is imperative to seek immediate medical attention. Heightened awareness and prompt reporting of such symptoms contribute to ensuring timely intervention and appropriate medical care. 

Contraindication / Caution

Contraindication/Caution: 

Contraindications 

• Hypersensitivity 

Cautions 

• Renal impairment 
• QT prolongation 
• Hepatic impairment 
• Serotonin syndrome 
• Drug interactions 
• Pregnancy  
• Breastfeeding 
• Geriatrics 

Pregnancy / Lactation

Pregnancy consideration:  

Pregnancy category D 

Breastfeeding warnings:  

No data is available regarding the excretion of drug in breast milk. 

Pregnancy category: D 

Category A: well-controlled and satisfactory studies show no risk to the fetus in the first or later trimester. 

Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 

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: No data is available for the drug under this category. 

Pharmacology

Pharmacology: 

When combined with palonosetron, fosnetupitant helps avoid both acute and delayed nausea and vomiting that come with first- and second-course highly emetogenic cancer chemotherapy, which includes high-dose cisplatin. Fosnetupitant, a neurokinin-1 (NK-1) receptor antagonist, works to prevent chemotherapy-induced nausea and vomiting by inhibiting the action of substance P, a neurotransmitter involved in the vomiting reflex. This combination is especially used with cancer patients receiving chemotherapy regimens that are known to have considerable side effects, such as nausea and vomiting. 

Pharmacodynamics: 

Chemotherapy-induced nausea and vomiting (CINV) is controlled by a substance called P and the activation of NK1 receptors or serotonin and the activation of its receptors, including 5-HT3 receptors. While substance P, the ligand for NK1 receptors, is thought to have a major influence on delayed-phase CINV, acute-phase CINV is principally linked to the stimulation of 5-HT3 receptors.

This delayed-phase CINV usually appears 24 hours to 5 days after therapy and is mostly caused by a substance called P bound to NK1 receptors in the brain’s central nervous system, especially in regions like the area postrema and nucleus tractus solitarius that are linked to the vomiting reflex. A new NK1 receptor antagonist with high affinity and selectivity for NK1 receptors, fosnetupitant is intended for intravenous delivery. 

Pharmacokinetics: 

Absorption 

Following a 30-minute infusion of AKYNZEO IV as a single dosage for cancer patients, the fosnetupitant rapidly vanished from the bloodstream with a notable terminal half-life of less than an hour and reached Cmax at the end of the administration. After the infusion was finished, the fosnetupitant concentration dropped to less than 1% of Cmax in just 30 minutes.  

Distribution 

Protein-bound is 92.14 – 94.86% 

The volume of distribution is 296+-535 L 

Metabolism 

Through metabolic hydrolysis, fosnetupitant is quickly transformed into netupitant in vivo. According to their AUC ratio, netupitant exposure in patients receiving AKYNZEO IV was 17 times more than fosnetupitant exposure. Rapid generation of netupitant metabolites M1, M2, and M3 was seen from the released netupitant. According to their AUC ratio, the metabolite M1, M2, and M3 exposures in patients were 32%, 21%, and 28% of netupitant exposure, respectively. For M1, M2, and M3, the median tmax was 12, 2, and 12 hours, respectively. 

Elimination and Excretion 

With a half-life of roughly 70 hours, netupitant is excreted gradually and is mostly broken down into three active metabolites in the liver by the enzyme cytochrome P450 (CYP) 3A, with minimal involvement from renal excretion. Because netupitant is a CYP3A inhibitor, interactions between it and other medications that the enzyme metabolizes have been documented in clinical settings. 

Fosnetupitant plasma concentrations decreased in a bi-exponential manner following AKYNZEO IV dosing. Within thirty minutes after the infusion stopped, the mean fosnetupitant plasma concentration was less than 1% of Cmax. 

Adminstartion

Administration: 

One vial of AKYNZEO IV (250 mcg palonosetron and 235 mg fosnetupitant) should be infused intravenously for 30 minutes at a time. The infusion should begin around 30 minutes prior to the start of each chemotherapy cycle.

To make sure the medication is administered completely, flush the IV line with the same carrier solution after the infusion. When used with AKYNZEO IV, the prescribed amount of oral dexamethasone needs to be lowered by roughly 50%.  

It’s important to remember that AKYNZEO IV should only be injected; intramuscular or subcutaneous injections are not appropriate. An ongoing IV infusion lasting 30 minutes should be used for the intravenous administration. Don’t give AKYNZEO IV as a bolus shot or as a concentrated solution. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: fosnetupitant 

Pronounced: fos-neh-TOO-pi-tant 

Why do we use fosnetupitant? 

With a favorable safety profile and a decreased incidence of injection site responses, the fosnetupitant showed no discernible inferiority to the fosaprepitant.  Therefore, fosnetupitant is effective in preventing chemotherapy-induced nausea and vomiting (CINV) in the acute phase, delayed phase, and beyond-delayed phase.

On November 18, 2021, Dr. Akito Hata of the Department of Thoracic Oncology at the Kobe Minimally Invasive Cancer Center in Kobe, Japan, and colleagues published the results of the CONSOLE phase III study in the  Clinical Oncology Journal. This was the first head-to-head comparison between two distinct neurokinin-1 receptor antagonists in combination with palonosetron and dexamethasone.