Fosnetupitant/palonosetron
Fosnetupitant/palonosetron Uses, Dosage, Side Effects, Food Interaction and all others data.
In April 2018, the U.S. Food and Drug Administration (FDA) and the Swiss company Helsinn approved the intravenous formulation of AKYNZEO® (NEPA, a fixed antiemetic combination of fosnetupitant, 235mg, and palonosetron, 0.25mg) as an alternative treatment option for patients experiencing chemotherapy-induced nausea and vomiting . Fosnetupitant is the pro-drug form of netupitant .
Generally, 25% to 30% of patients with a diagnosis of cancer receive chemotherapy as a treatment modality and 70% to 80% of these patients undergoing chemotherapy treatment may experience nausea and vomiting as major side effects. Considered one of the most distressing side effects of chemotherapy, nausea and vomiting has an immense impact on the quality of life of patients receiving certain antineoplastic therapies .
In the combination drug, Akynzeo, palonosetron prevents nausea and vomiting during the acute phase and fosnetupitant prevents nausea and vomiting during both the acute and delayed phase after cancer chemotherapy .
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.
| Trade Name | Fosnetupitant/palonosetron |
| Generic | Fosnetupitant + palonosetron |
| Type | Intravenous |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Fosnetupitant is a medication used in combination with others to prevent chemotherapy associated nausea and vomiting.
Indicated in combination palonosetron (as the drug Akynzeo) and dexamethasone in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy .
The following are indications listed on the EMA label :
Prevention of acute and delayed nausea and vomiting associated with highly emetogenic cisplatin-based cancer chemotherapy .
Prevention of acute and delayed nausea and vomiting associated with moderately emetogenic cancer 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.
Fosnetupitant/palonosetron is also used to associated treatment for these conditions: Acute delayed Nausea caused by cancer chemotherapy, Acute delayed Nausea caused by highly emetogenic cancer chemotherapy, Acute delayed Vomiting caused by cancer chemotherapy, Acute delayed Vomiting caused by highly emetogenic cancer 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 Fosnetupitant/palonosetron works
The fosnetupitant in this drug combination is a selective P/neurokinin-1 (NK-1) receptor antagonist .
Netupitant, the active moiety of fosnetupitant, is a selective neurokinin 1 (NK1) receptor antagonist with antiemetic activity. Netupitant competitively binds to and blocks the activity of the human substance P/NK1 receptors in the central nervous system (CNS), inhibiting NK1-receptor binding of the endogenous tachykinin neuropeptide substance P (SP), which results in the prevention of chemotherapy-induced nausea and vomiting (CINV). Substance P is found in neurons of vagal afferent fibers innervating the brain-stem nucleus tractus solitarii and the area postrema, which contains the chemoreceptor trigger zone (CTZ), and may be present at high levels in response to chemotherapy. The NK-receptor is a G-protein receptor coupled to the inositol phosphate signal-transduction pathway and is found in both the nucleus tractus solitarii and the area postrema .
Netupitant demonstrated 92.5% NK1 receptor occupancy at 6 hours, with 76% occupancy at 96 hours .
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
Fosnetupitant/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
Most common adverse reactions (≥3%) for AKYNZEO capsules are headache, asthenia, dyspepsia, fatigue, constipation and erythema .
The safety profile of Akynzeo for injection is generally similar to that seen with Aynzeo capsules , .
Currently a repeated dose safety study is ongoing in patients receiving anthracycline plus cyclophosphamide to further establish the safety profile in this setting .
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
The mean SD volume of distribution of fosnetupitant in healthy subjects and in patients was 124 +/- 76 L and 296 +/- 535 L, respectively .
- 8.3 ± 2.5 L/kg
Elimination Route
Following single intravenous doses of Akynzeo for injection in patients (235 mg fosnetupitant and 0.25 mg palonosetron infused in 30 minutes) or fosnetupitant in healthy subjects (235 mg fosnetupitant infused in 30 minutes), maximum concentration of fosnetupitant was achieved at the end of the 30-minute infusion .
Oral bioavailability in each species varied substantially between animals, with 42-105%, 34-83% and 37-62% in rats, dogs, and monkeys. The large variation is most likely due to the low numbers of animals used in the studies .
Low oral bioavailability.
Half Life
Netupitant is eliminated from the body in a multi-exponential fashion, with an apparent elimination half-life in cancer patients of 80 ± 29 hours (mean ± SD) .
Approximately 40 hours
Clearance
Netupitant has a mean estimated systemic clearance of 0.3 ± 9.2 L/h (mean ± SD) after a single oral dose of Akynzeo .
- 160 +/- 35 mL/h/kg
Elimination Route
After one oral dose of [14C]netupitant, approximately one-half of the administered radioactivity was measured in the urine and feces within 120 hours of the dose. The total of 3.95% and 70.7% of the radioactive dose was measured in the urine and feces collected over 336 hours, respectively, and the average fraction of an oral dose of netupitant excreted unchanged in urine is under 1%, implying that renal clearance is not a significant route of elimination for the netupitant-related entities .
About 86.5% and 4.7% of administered radioactivity was estimated to be excreted via the feces and urine within 30 days post-dose .
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.
Storage Condition
Store at controlled temperature of 20-25°C (68°F-77°F). Protect from light and protect injectable from freezing.
Innovators Monograph
You find simplified version here Fosnetupitant/palonosetron
