netupitant/palonosetron (Akynzeo)
Classes: Antiemetic Agents; NK1 Receptor Antagonists; Antiemetics, Selective 5-HT3 Antagonist
Dosing and uses of Akynzeo (netupitant/palonosetron)
Adult dosage forms and strengths
netupitant/palonosetron
capsule
- 300mg/0.5mg
Chemotherapy-Induced Nausea & Vomiting
Indicated for prevention of acute and delayed nausea and vomiting (N/V) associated with cancer chemotherapy
Highly emetogenic chemotherapy
- Includes cisplatin-based chemotherapy
- 1 capsule (300 mg/0.5 mg) PO ~1 hr before starting chemotherapy PLUS
- Dexamethasone 12 mg PO 30 minutes prior to chemotherapy on day 1 and 8 mg PO qDay on days 2-4
Chemotherapy not considered highly emetogenic
- Includes anthracyclines and cyclophosphamide-based chemotherapy
- 1 capsule (300 mg/0.5 mg) PO ~1 hr before starting chemotherapy PLUS
- Dexamethasone 12 mg PO 30 minutes prior to chemotherapy on day 1
- Administration of dexamethasone on days 2-4 is not necessary
Dosage modifications
Renal impairment
- Mild or moderate: No dosage adjustment required
- Severe or ESRD: Avoid use
Hepatic impairment
- Mild or moderate (Child-Pugh 5-8): No dosage adjustment required
- Severe (Child-Pugh ≥9): Avoid use
Dosing Considerations
Indication includes, but is not limited to, highly emetogenic chemotherapy
Palonosetron prevents N/V during acute phase
Netupitant prevents N/V during both acute and delayed phase
Administration
May take with or without food
Pediatric dosage forms and strengths
<18 years: Safety and efficacy not established
Akynzeo (netupitant/palonosetron) adverse (side) effects
1-10%
Headache (9%)
Asthenia (8%)
Fatigue (4-7%)
Dyspepsia (4%)
Constipation (3%)
Erythema (3%)
<1%
Increased AST/ALT >3 x ULN and total bilirubin >ULN (0.3%)
Increased AST/ALT >3 x ULN and total bilirubin >2 x ULN (0.1%)
Increased AST/ALT >10 x ULN and total bilirubin >ULN (0%)
Warnings
Contraindications
None
Cautions
Hypersensitivity, including anaphylaxis, reported
Serotonin syndrome has been reported with 5-HT3 receptor antagonists (eg, palonosetron)
Netupitant is a CYP3A4 substrate and a moderate inhibitor of CYP3A4
Pregnancy and lactation
Pregnancy category: C
Lactation: Unknown if distributed in human breast milk
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Akynzeo (netupitant/palonosetron)
Mechanism of action
Netupitant: Tachykinin NK1 receptor (substance P) antagonist
Palonosetron: 5-hydroxytryptamine 3 (5-HT3) receptor antagonist; binds to 5-HT3 receptors both in peripheral and central nervous system, with primary effects in GI tract
Absorption
Peak plasma time
- netupitant: 5 hr
- palonosetron: 5 hr
Peak plasma concentration
- netupitant: 434 ng/mL
- palonosetron: 1.53 ng/mL
AUC
- netupitant: 14,401 ng•hr/mL
- palonosetron: 56.7 ng•hr/mL
Distribution
Protein bound
- netupitant: >99.5%
- palonosetron: 62%
Vd
- netupitant: 1982 L
- palonosetron: 8.3 L/kg
Metabolism
Netupitant
- Metabolized mainly by CYP3A4, and to a lesser degree by CYP2C9 and CYP2D6
- Extensively metabolized to form three major metabolites: desmethyl derivative, M1; N-oxide derivative, M2; and OH-methyl derivative, M3
- Metabolites M1, M2, and M3 were shown to bind to the substance P/neurokinin 1 (NK1) receptor
Palonosetron
- Metabolized mainly by CYP2D6, and to a lesser extent by CYP3A4 and CYP1A2
- 50% metabolized to form 2 primary metabolites: N-oxide-palonosetron and 6-S hydroxy-palonosetron
Elimination
Half-life
- netupitant: 96 hr; 80 hr (patients with cancer)
- palonosetron: 44 hr; 48 hr (patients with cancer)
Total body clearance
- netupitant: 20.3 L/hr
- palonosetron: 160 mL/hr/kg
Renal clearance
- palonosetron: 66.5 mL/hr/kg
Excretion
- netupitant: 70% feces; 4% urine
- palonosetron: 5-8% feces; 85-93% urine