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Netupitant and Palonosetron

Pronunciation

(net UE pi tant & pal oh NOE se tron)

Index Terms

  • NEPA
  • Netupitant/Palonosetron HCl
  • Palonosetron and Netupitant

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Akynzeo: Netupitant 300 mg and palonosetron 0.5 mg

Brand Names: U.S.

  • Akynzeo

Pharmacologic Category

  • Antiemetic
  • Selective 5-HT3 Receptor Antagonist
  • Substance P/Neurokinin 1 Receptor Antagonist

Pharmacology

Netupitant is a selective substance P/neurokinin (NK1) receptor antagonist, which augments the antiemetic activity of 5-HT3 receptor antagonists and corticosteroids to inhibit acute and delayed chemotherapy-induced emesis. Palonosetron is a selective 5-HT3 receptor antagonist, which blocks serotonin, both on vagal nerve terminals in the periphery and centrally in the chemoreceptor trigger zone. Palonosetron inhibits the cross-talk between the 5-HT3 and NK1 receptors. The combination of palonosetron and netupitant works synergistically to inhibit substance P response to a greater extent than either agent alone (Aapro, 2014).

Absorption

Netupitant: Within 15 minutes to 3 hours; Palonosetron: Well absorbed

Distribution

Netupitant: Vd: 1,982 ± 906 L; Palonosetron: Vd: 8.3 ± 2.5 L/kg

Metabolism

Netupitant: Extensively hepatic via CYP3A4 (major), CYP2C9 (minor) and CYP2D6 (minor); forms active metabolites M1, M2, and M3

Palonosetron: ~50% metabolized to relatively inactive metabolites (N-oxide-palonosetron and 6-S-hydroxy-palonosetron); CYP2D6, 3A4, and 1A2 contribute to metabolism

Excretion

Netupitant: Feces (~71%); urine (~4%)

Palonosetron: Feces (5% to 8%); urine (85% to 93%; 40% as unchanged drug)

Time to Peak

Netupitant and palonosetron: ~5 hours

Half-Life Elimination

Netupitant: 80 ± 29 hours; Palonosetron: 48 ± 19 hours

Protein Binding

Netupitant: >99.5% for netupitant; >97% for major metabolites

Palonosetron: ~62%

Special Populations: Hepatic Function Impairment

For netupitant, the mean AUC was 67% higher and the mean Cmax was 40% higher in patients with mild hepatic impairment. The mean AUC was 86% higher and the mean Cmax was 41% higher in patients with moderate impairment. For palonosetron, the AUC was 33% higher in patients with mild hepatic impairment and 62% higher in patients with moderate impairment.

Special Populations: Gender

For netupitant, Cmax was 35% higher in females than in males while the AUC was similar between males and females. For palonosetron, mean AUC was 35% higher and the mean Cmax was 26% higher in females than in males.

Use: Labeled Indications

Chemotherapy-induced nausea and vomiting: 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.

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Dosing: Adult

Highly-emetogenic chemotherapy (including cisplatin-based): Oral: One capsule ~1 hour prior to initiation of chemotherapy on day 1 (Gralla, 2014). Note: Antiemetic regimen also includes dexamethasone 12 mg orally ~30 minutes prior to initiation of chemotherapy on day 1, and 8 mg orally once daily on days 2 to 4.

Anthracycline and cyclophosphamide-based chemotherapy and chemotherapy not considered highly emetogenic: Oral: One capsule ~1 hour prior to initiation of chemotherapy on day 1 (Gralla, 2014). Note: Antiemetic regimen also includes dexamethasone 12 mg orally ~30 minutes prior to chemotherapy on day 1.

Dosing: Geriatric

No dosage adjustment necessary. Refer to adult dosing.

Dosing: Renal Impairment

Mild or moderate impairment: No dosage adjustment is necessary.

Severe impairment or ESRD: Avoid use.

Dosing: Hepatic Impairment

Mild or moderate impairment (Child-Pugh score 5 to 8): No dosage adjustment is necessary.

Severe impairment (Child-Pugh score >9): Avoid use.

Administration

Oral: May administer with or without food.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F)

Drug Interactions

AmLODIPine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of AmLODIPine. Monitor therapy

Apixaban: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Apixaban. Monitor therapy

Apomorphine: Antiemetics (5HT3 Antagonists) may enhance the hypotensive effect of Apomorphine. Avoid combination

Aprepitant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Aprepitant. Avoid combination

ARIPiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Asunaprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Asunaprevir. Avoid combination

Avanafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil. Management: The maximum avanafil adult dose is 50 mg per 24-hour period when used together with a moderate CYP3A4 inhibitor. Patients receiving such a combination should also be monitored more closely for evidence of adverse effects. Consider therapy modification

Blonanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Blonanserin. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Bosentan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Bosutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosutinib. Avoid combination

Brexpiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole. Management: The brexpiprazole dose should be reduced to 25% of usual if used together with both a moderate CYP3A4 inhibitor and a strong or moderate CYP2D6 inhibitor, or if a moderate CYP3A4 inhibitor is used in a CYP2D6 poor metabolizer. Monitor therapy

Bromocriptine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bromocriptine. Management: The bromocriptine dose should not exceed 1.6 mg daily with use of a moderate CYP3A4 inhibitor. The Cycloset brand specifically recommends this dose limitation, but other bromocriptine products do not make such specific recommendations. Consider therapy modification

Budesonide (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Systemic). Avoid combination

Budesonide (Topical): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Topical). Management: Per US prescribing information, avoid this combination. Canadian product labeling does not recommend strict avoidance. If combined, monitor for excessive glucocorticoid effects as budesonide exposure may be increased. Consider therapy modification

Cannabis: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased. Monitor therapy

Cilostazol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in adult patients who are also receiving moderate inhibitors of CYP3A4. Consider therapy modification

Cobimetinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cobimetinib. Management: Avoid the concomitant use of cobimetinib and moderate CYP3A4 inhibitors. If concurrent short term (14 days or less) use cannot be avoided, reduce the cobimetinib dose to 20 mg daily. Avoid combination

Colchicine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Colchicine. Management: Reduce colchicine dose as directed when using with a moderate CYP3A4 inhibitor, and increase monitoring for colchicine-related toxicity. Use extra caution in patients with impaired renal and/or hepatic function. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Netupitant. Avoid combination

CYP3A4 Substrates: Netupitant may increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dapoxetine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dapoxetine. Management: The dose of dapoxetine should be limited to 30 mg/day when used together with a moderate inhibitor of CYP3A4. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Dexamethasone (Systemic): Netupitant may increase the serum concentration of Dexamethasone (Systemic). Management: Decrease dexamethasone doses to 12 mg on day 1, and if needed based on the emetic potential of the regimen, 8 mg daily on days 2 to 4 of chemotherapy when administered with netupitant. Consider therapy modification

Dofetilide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dofetilide. Monitor therapy

Domperidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Domperidone. Avoid combination

DOXOrubicin (Conventional): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to moderate CYP3A4 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Dronabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. Monitor therapy

Eletriptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eletriptan. Management: The use of eletriptan within 72 hours of a moderate CYP3A4 inhibitor should be avoided. Consider therapy modification

Eliglustat: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eliglustat. Management: Use should be avoided under some circumstances. See full drug interaction monograph for details. Consider therapy modification

Eplerenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eplerenone. Management: When used concomitantly with moderate inhibitors of CYP3A4, eplerenone dosing recommendations vary by indication and international labeling. See full drug interaction monograph for details. Consider therapy modification

Everolimus: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

FentaNYL: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of FentaNYL. Management: Monitor patients closely for several days following initiation of this combination, and adjust fentanyl dose as necessary. Consider therapy modification

Flibanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Flibanserin. Avoid combination

GuanFACINE: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of GuanFACINE. Management: Reduce the guanfacine dose by 50% when initiating this combination. Consider therapy modification

Halofantrine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine. Consider therapy modification

HYDROcodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of HYDROcodone. Monitor therapy

Ibrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ibrutinib. Management: If a moderate CYP3A inhibitor must be used, consider reducing the dose of ibrutinib to 140mg daily and monitor closely for signs of toxicity. Avoid combination

Ifosfamide: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Imatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Imatinib. Monitor therapy

Ivabradine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivabradine. Avoid combination

Ivacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions are required; consult prescribing information for specific age- and weight-based recommendations. Consider therapy modification

Lomitapide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lomitapide. Avoid combination

Lurasidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurasidone. Management: U.S. labeling: start at 20 mg/day and limit to max of 80 mg/day with moderate CYP3A4 inhibitor. Canadian labeling: limit to max of 40 mg/day with moderate CYP3A4 inhibitor; avoid concomitant use of grapefruit products. Consider therapy modification

Mirodenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Mirodenafil. Monitor therapy

Naloxegol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naloxegol. Avoid combination

NiMODipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of NiMODipine. Monitor therapy

Olaparib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Olaparib. Management: Avoid use of moderate CYP3A4 inhibitors in patients being treated with olaparib. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 200 mg twice daily. Avoid combination

OxyCODONE: CYP3A4 Inhibitors (Moderate) may enhance the adverse/toxic effect of OxyCODONE. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite Oxymorphone may also be increased. Monitor therapy

Pimecrolimus: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of Pimecrolimus. Monitor therapy

Pimozide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pimozide. Avoid combination

Propafenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Propafenone. Monitor therapy

Ranolazine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ranolazine. Management: Limit the ranolazine adult dose to a maximum of 500 mg twice daily in patients concurrently receiving moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, erythromycin, etc.). Consider therapy modification

Salmeterol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Salmeterol. Monitor therapy

SAXagliptin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of SAXagliptin. Monitor therapy

Serotonin Modulators: Antiemetics (5HT3 Antagonists) may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Exceptions: Nicergoline. Monitor therapy

Sildenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sildenafil. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Simeprevir. Avoid combination

Sonidegib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sonidegib. Management: Avoid concomitant use of sonidegib and moderate CYP3A4 inhibitors when possible. When concomitant use cannot be avoided, limit CYP3A4 inhibitor use to less than 14 days and monitor for sonidegib toxicity (particularly musculoskeletal adverse reactions). Consider therapy modification

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Suvorexant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Suvorexant. Consider therapy modification

Tapentadol: Antiemetics (5HT3 Antagonists) may diminish the analgesic effect of Tapentadol. Monitor therapy

Telithromycin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Telithromycin. Monitor therapy

Tetrahydrocannabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Ticagrelor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ticagrelor. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tolvaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolvaptan. Avoid combination

Trabectedin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Trabectedin. Avoid combination

TraMADol: Antiemetics (5HT3 Antagonists) may diminish the analgesic effect of TraMADol. Monitor therapy

Udenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Udenafil. Monitor therapy

Ulipristal: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ulipristal. Management: This is specific for when ulipristal is being used for signs/symptoms of uterine fibroids (Canadian indication). When ulipristal is used as an emergency contraceptive, patients receiving this combination should be monitored for ulipristal toxicity. Avoid combination

Venetoclax: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

Vilazodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vilazodone. Monitor therapy

Vindesine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vindesine. Monitor therapy

Zopiclone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zopiclone. Management: The starting adult dose of zopiclone should not exceed 3.75 mg if combined with a moderate CYP3A4 inhibitor. Monitor patients for signs and symptoms of zopiclone toxicity if these agents are combined. Consider therapy modification

Zuclopenthixol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zuclopenthixol. Monitor therapy

Adverse Reactions

1% to 10%:

Central nervous system: Headache (9%), fatigue (4% to 7%)

Dermatologic: Erythema (3%)

Gastrointestinal: Dyspepsia (4%), constipation (3%)

Neuromuscular & skeletal: Weakness (8%)

Warnings/Precautions

Concerns related to adverse effects:

• Hypersensitivity: Hypersensitivity (including anaphylaxis) has been reported with or without known hypersensitivity to other 5-HT3 receptor antagonists.

• Serotonin syndrome: Serotonin syndrome has been reported with 5-HT3 receptor antagonists, predominantly when used in combination with other serotonergic agents (eg, SSRIs, SNRIs, MAOIs, mirtazapine, fentanyl, lithium, tramadol, and methylene blue). Some of the cases have been fatal. The majority of serotonin syndrome reports with 5-HT3 receptor antagonists occurred in a postanesthesia setting or in an infusion center. Serotonin syndrome has also been reported following overdose of another 5-HT3 receptor antagonist. Monitor patients for signs of serotonin syndrome, including mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile blood pressure, diaphoresis, dizziness, flushing, hyperthermia); neuromuscular changes (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination); gastrointestinal symptoms (eg, nausea, vomiting, diarrhea); and/or seizures. If serotonin syndrome occurs, discontinue 5-HT3 receptor antagonist treatment and begin supportive management.

Disease-related concerns:

• Hepatic impairment: Avoid use in severe hepatic impairment. Dosage adjustment not necessary in mild or moderate impairment.

• Renal impairment: Avoid use in severe renal impairment or end stage renal disease. Dosage adjustment not necessary in mild or moderate impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Use caution when dosing elderly patients due to a higher frequency of decreased hepatic, renal, cardiac function, and concomitant disease or drug therapy.

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies using the components of this combination product.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience constipation, headache, redness, loss of strength and energy, or nausea. Have patient report immediately to prescriber signs of serotonin syndrome (dizziness, severe headache, agitation, hallucinations, tachycardia, arrhythmia, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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