Can Akynzeo (netupitant and palonosetron) and ondansetron be taken together?

Can Akynzeo and Ondansetron Be Taken Together?

No, Akynzeo and ondansetron should not be taken together because Akynzeo already contains palonosetron (a 5-HT3 receptor antagonist in the same drug class as ondansetron), making the addition of ondansetron redundant and potentially increasing side effects without improving efficacy. 1

Why This Combination Is Not Recommended

Akynzeo Contains a 5-HT3 Antagonist Already

• Akynzeo is a fixed-dose combination containing netupitant (an NK1 receptor antagonist) and palonosetron (a 5-HT3 receptor antagonist) 1, 2
• Adding ondansetron would mean taking two 5-HT3 receptor antagonists simultaneously, which provides no additional antiemetic benefit 3
• When used in combination with an NK1 antagonist, there is no preferred 5-HT3 receptor antagonist, meaning palonosetron (in Akynzeo) is equally effective as ondansetron 3

Guideline Evidence Against Combining 5-HT3 Antagonists

• NCCN guidelines consistently recommend choosing ONE 5-HT3 receptor antagonist (either palonosetron, granisetron, ondansetron, or dolasetron) in antiemetic regimens, never combining them 3
• The recommended regimens for highly emetogenic chemotherapy include "a 5-HT3 RA (choose one)" followed by a list of options, explicitly indicating selection of a single agent 3
• ASCO guidelines similarly recommend single 5-HT3 antagonist selection, with palonosetron 0.25 mg IV or ondansetron 8 mg orally twice daily as alternatives, not additions 4

Palonosetron in Akynzeo Is Superior to Ondansetron

• Palonosetron has approximately 100-fold higher binding affinity for the 5-HT3 receptor compared to ondansetron and a significantly longer half-life of approximately 40 hours 5, 6
• Palonosetron demonstrates superiority over first-generation 5-HT3 antagonists (including ondansetron) particularly for delayed emesis (24-120 hours post-chemotherapy) 6, 7
• In pediatric patients receiving highly emetogenic chemotherapy, palonosetron provided superior antiemetic control in the delayed phase compared to ondansetron (complete response 53.5% vs 32.8%, P < 0.05) 7

What to Do If Breakthrough Nausea Occurs

Add a Different Drug Class, Not Another 5-HT3 Antagonist

• If breakthrough nausea or vomiting occurs despite taking Akynzeo as prescribed, rescue medications from different drug classes should be added rather than repeating or adding another 5-HT3 antagonist 8
• NCCN breakthrough treatment guidelines recommend adding one agent from a different drug class to the current regimen 3

Specific Breakthrough Treatment Options

• Olanzapine 5-10 mg orally daily (category 1 recommendation) 3
• Metoclopramide 10-20 mg orally/IV every 4-6 hours 3, 9
• Lorazepam 0.5-2 mg orally/sublingual/IV every 6 hours 3
• Prochlorperazine 10 mg orally/IV every 6 hours or 25 mg suppository rectally every 12 hours 3
• Haloperidol 0.5-2 mg orally/IV every 4-6 hours 3

Clinical Algorithm for Antiemetic Selection

For Highly Emetogenic Chemotherapy (Including Cisplatin)

• Day 1: Akynzeo (netupitant 300 mg/palonosetron 0.5 mg) one capsule 1 hour before chemotherapy PLUS dexamethasone 12 mg 30 minutes before chemotherapy 1
• Days 2-4: Dexamethasone 8 mg once daily only—no additional 5-HT3 antagonist needed 1
• The palonosetron in Akynzeo provides coverage for both acute and delayed phases, eliminating the need for additional antiemetic pills on days 2-5 8

For Anthracycline-Cyclophosphamide or Moderately Emetogenic Chemotherapy

• Day 1: Akynzeo one capsule 1 hour before chemotherapy PLUS dexamethasone 12 mg 30 minutes before chemotherapy 1
• Days 2-4: No further antiemetic therapy required 1

Important Safety Considerations

Cardiac Safety Profile

• Both ondansetron and palonosetron carry warnings about QT prolongation, so combining them would theoretically increase this risk 10
• However, pooled safety data from 3,280 patients showed NEPA (Akynzeo) was well-tolerated with cardiac adverse events rare: QT prolongation (1.6%), tachycardia (1.1%), and serious cardiac events were uncommon 11
• If ondansetron is contraindicated due to QT prolongation concerns, Akynzeo (which contains palonosetron, not ondansetron) is actually a safer alternative 9

Common Adverse Events

• The most frequently observed treatment-related adverse events with Akynzeo are headache and constipation, both typically mild 2, 11
• Adding ondansetron would increase the risk of these same side effects (headache, constipation) without improving efficacy 11

Bottom Line

Use Akynzeo alone with dexamethasone as directed—do not add ondansetron. If nausea control is inadequate, add olanzapine, metoclopramide, or another agent from a different drug class rather than stacking 5-HT3 antagonists. 3, 8, 1