Netupitant And Palonosetron

Netupitant And Palonosetron Uses, Dosage, Side Effects, Food Interaction and all others data.

Netupitant is an antiemitic drug approved by the FDA in October 2014 for use in combination with palonosetron for the prevention of acute and delayed vomiting and nausea associated with cancer chemotherapy including highly emetogenic chemotherapy. Netupitant is a neurokinin 1 receptor antagonist. The combination drug is marketed by Eisai Inc. and Helsinn Therapeutics (U.S.) Inc. under the brand Akynzeo.

Nausea and Vomiting is usually produced by chemotherapeutic agents by releasing serotonin from the enterochromaffin cells of the small intestine.The released serotonin (5-HT) then activates 5-HT3 receptors located on vagal afferents to initiate the vomiting reflex. Postoperative nausea and vomiting is influenced by multiple patient, surgical and anesthesia related factors and is triggered by release of serotonin (5-HT) in a cascade of neuronal events involving both the central nervous system and the gastrointestinal tract. The 5-HT3 receptor has been demonstrated to selectively participate in the emetic response. Palonosetron is a 5-HT3 receptor antagonist with a strong binding affinity for this receptor and little or no affinity for other receptors. So by binding with this receptor palonosetron inhibits binding of serotonine to this receptor and also inhibits vomiting reflux.

Palonosetron is an antinauseant and antiemetic agent indicated for the prevention of nausea and vomiting associated with moderately-emetogenic cancer chemotherapy and for the prevention of postoperative nausea and vomiting. Palonosetron is a highly specific and selective serotonin 5-HT3 receptor antagonist that is pharmacologically related to other 5-HT3 receptor antagonists, but differs structurally. Palonosetron has a high affinity for 5-HT3 receptors, but has little to no affinity for other receptors. The serontonin 5-HT3 receptors are located on the nerve terminals of the vagus in the periphery, and centrally in the chemoreceptor trigger zone of the area postrema. It is suggested that chemotherapeutic agents release serotonin from the enterochromaffin cells of the small intestine by causing degenerative changes in the GI tract. The serotonin then stimulates the vagal and splanchnic nerve receptors that project to the medullary vomiting center, as well as the 5-HT3 receptors in the area postrema, thus initiating the vomiting reflex, causing nausea and vomiting.

Netupitant And Palonosetron
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Netupitant And Palonosetron
Generic	Netupitant + palonosetron
Weight	300mg + 0.5mg
Type	Oral capsule
Therapeutic Class
Manufacturer
Available Country	United States
Last Updated:	September 19, 2023 at 7:00 am

Uses

Netupitant is an antiemetic agent used in combination with palonosetron to prevent acute and delayed vomiting and nausea caused by chemotherapy.

Moderately emetogenic cancer chemotherapy- prevention of acute and delayed nausea and vomiting associated with initial and repeat courses

Highly emetogenic cancer chemotherapy- prevention of acute nausea and vomiting associated with initial and repeat courses

Prevention of postoperative nausea and vomiting (PONV) for up to 24 hours following surgery. Efficacy beyond 24 hours has not been demonstrated.

Netupitant And Palonosetron is also used to associated treatment for these conditions: Acute caused and vomiting caused by Chemotherapy, Delayed Nausea and Vomiting caused by ChemotherapyChemotherapy-Induced Nausea and Vomiting (CINV), Post Operative Nausea and Vomiting (PONV), Acute chemotherapy induced nausea and vomiting, Delayed chemotherapy induced nausea and vomiting

How Netupitant And Palonosetron works

Delayed emesis (vomiting) has been largely associated with the activation of tachykinin family neurokinin 1 (NK1) receptors (broadly distributed in the central and peripheral nervous systems) by substance P. As shown in in vitro and in vivo studies, netupitant inhibits substance P mediated responses.

Palonosetron is a selective serotonin 5-HT₃ receptor antagonist. The antiemetic activity of the drug is brought about through the inhibition of 5-HT₃ receptors present both centrally (medullary chemoreceptor zone) and peripherally (GI tract). This inhibition of 5-HT₃ receptors in turn inhibits the visceral afferent stimulation of the vomiting center, likely indirectly at the level of the area postrema, as well as through direct inhibition of serotonin activity within the area postrema and the chemoreceptor trigger zone. Alternative mechanisms appear to be primarily responsible for delayed nausea and vomiting induced by emetogenic chemotherapy, since similar temporal relationships between between serotonin and emesis beyond the first day after a dose have not been established, and 5-HT₃ receptor antagonists generally have not appeared to be effective alone in preventing or ameliorating delayed effects. It has been hypothesized that palonosetron's potency and long plasma half-life may contribute to its observed efficacy in preventing delayed nausea and vomiting caused by moderately emetogenic cancer chemotherapy.

Dosage

Netupitant And Palonosetron dosage

Chemotherapy-Induced Nausea and Vomiting: Dosage for Adults- a single 0.25 mg I.V. dose administered over 30 seconds. Dosing should occur 30 minutes before the start of chemotherapy. Alternatively 0.5 mg tablet approximately 1 hour before the start of chemotherapy.

Postoperative Nausea and Vomiting: Dosage for Adults- a single 0.075 mg I.V. dose administered over 10 seconds immediately before the induction of anesthesia. In case of 0.5 mg tablet, dose should be determined by the physician.

Instructions for I.V. Administration-

It should not be mixed with other drugs
Flush the infusion line with normal saline before and after administration
Parenteral drug products should be inspected visually for particulate matter and discoloration before administration

Intravenous:

Nausea and vomiting associated with cancer chemotherapy: Physically and chemically stable at concentrations of 5 and 30 mcg/ml in glucose 5%, sodium chloride 0.9%, glucose 5% in lactated Ringer's for at least 48 hr at room temperature, exposed to light and for 14 days under refridgeration.

Side Effects

The most common adverse reactions of Palonosetron in chemotherapy-induced nausea and vomiting are headache and constipation. The most common adverse reactions of Palonosetron in postoperative nausea and vomiting are QT prolongation, bradycardia, headache and constipation.

Toxicity

Daily oral administration of netupitant in rats at doses up to 30 mg/kg (1.9 times the human AUC in male rats and 3.7 times the human AUC in female rats at the recommended human dose) had no effects on fertility or reproductive performance.

A single intravenous dose of palonosetron at 30 mg/kg (947 and 474 times the human dose for rats and mice, respectively, based on body surface area) was lethal to rats and mice. The major signs of toxicity were convulsions, gasping, pallor, cyanosis and collapse.

Precaution

For IV administration only. Not for intradermal, subcutaneous, or IM administration.
Do not administer if particulate matter, cloudiness, or discoloration is noted.
Discard any unused solution. Do not save unused solution for later administration.
Do not mix with other medications.

Interaction

In vitro studies indicated that Palonosetron is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4/5 (CYP2C19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5. Therefore, drug interactions with Palonosetron appears to be low. In controlled clinical trials, Palonosetron injection has been safely administered with corticosteroids, analgesics, antiemetics/ antinauseants, antispasmodics and anticholinergic drugs. Palonosetron did not inhibit the antitumor activity of the five chemotherapeutic agents tested (cisplatin, cytarabine, doxorubicin and mitomycin C) in murine tumor models.

Volume of Distribution

In cancer patients, Vz/F: 1982 ± 906 L (mean ± SD).

8.3 ± 2.5 L/kg

Elimination Route

Upon oral administration of a single dose of netupitant, netupitant started to be measurable in plasma between 15 minutes and 3 hours after dosing. Plasma concentrations reached Cmax in approximately 5 hours. There was a greater than dose-proportional increase in the systemic exposure with the dose increase from 10 mg to 300 mg and a dose-proportional increase in systemic exposure with a dose increase from 300 mg to 450 mg.

Low oral bioavailability.

Half Life

96 hours with CV% of 61.

Approximately 40 hours

Clearance

Estimated systemic clearance of 20.3 ± 9.2 L/h (mean ± SD).

160 +/- 35 mL/h/kg

Elimination Route

Primarily fecal.

After a single intravenous dose of 10 mcg/kg [14C]-palonosetron, approximately 80% of the dose was recovered within 144 hours in the urine

Pregnancy & Breastfeeding use

US FDA Pregnancy category B. It is not known whether Paloxiron is excreted in human milk.

Contraindication

Palonosetron is contraindicated in patients known to have hypersensitivity to the drug or any of its components. Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists.

Special Warning

Pediatric Use: Safety and effectiveness in patients below the age of 18 years have not been established. However different clinical trial shows Palonosetron is well tolerated and effective from one month of age.

Geriatric Use: Pharmacokinetics analysis did not reveal any differences in Palonosetron pharmacokinetics between patients ≥ 65 years of age and younger patients (18 to 64 years)

Renal Function Impairment: No dosage adjustments are needed with any degree of renal function impairment.

Hepatic Function Impairment: No dosage adjustments are needed with any degree of hepatic function impairment.

Elderly: No dosage adjustments or special monitoring are needed in elderly patients.