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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