AKYNZEO
Clinical safety rating: caution
Comprehensive clinical and safety monograph for AKYNZEO (AKYNZEO).
Netupitant is a neurokinin-1 (NK1) receptor antagonist that blocks the action of substance P, thereby preventing chemotherapy-induced emesis. Palonosetron is a serotonin-3 (5-HT3) receptor antagonist that inhibits the emetic reflex by blocking serotonin binding at 5-HT3 receptors in the gastrointestinal tract and central nervous system.
| Metabolism | Netupitant: primarily metabolized by CYP3A4, with minor contributions from CYP2C9 and CYP2D6; forms active metabolite M1. Palonosetron: partially metabolized by CYP2D6, with about 40% of the drug excreted unchanged in urine. |
| Excretion | Netupitant: 70% excreted in feces (4% unchanged), 5% in urine (0.1% unchanged). Palonosetron: 80% excreted in urine (40% unchanged), 15% in feces. |
| Half-life | Netupitant: 80 hours (range 60-130) allowing single-dose coverage. Palonosetron: 40 hours (intravenous), 40-48 hours (oral). |
| Protein binding | Netupitant: >99% bound (albumin and α1-acid glycoprotein). Palonosetron: 62% bound (albumin). |
| Volume of Distribution | Netupitant: 1980 L (approx 30 L/kg in a 70 kg adult), extensive tissue distribution. Palonosetron: 6-9 L/kg, moderate distribution. |
| Bioavailability | Oral netupitant: 63% (absolute). Oral palonosetron: 97%. |
| Onset of Action | Oral capsule: antiemetic effect within 0.5-1 hour, maximal by 2-3 hours. |
| Duration of Action | Protects against acute and delayed CINV for up to 5 days post-chemotherapy. Netupitant provides sustained NK1 antagonism; palonosetron has long receptor binding. |
AKYNZEO (fosnetupitant 235 mg and palonosetron 0.25 mg) is administered as a single IV infusion over 30 minutes, completed 30 minutes before chemotherapy. The recommended adult dose is a fixed combination of 235 mg fosnetupitant and 0.25 mg palonosetron.
| Dosage form | SOLUTION |
| Renal impairment | No dose adjustment is required for patients with mild to moderate renal impairment (CrCl ≥30 mL/min). There is insufficient data for severe renal impairment (CrCl <30 mL/min) or end-stage renal disease; use with caution. |
| Liver impairment | No dose adjustment is necessary for mild hepatic impairment (Child-Pugh A). For moderate hepatic impairment (Child-Pugh B), no dose adjustment is recommended. Not studied in severe hepatic impairment (Child-Pugh C); avoid use. |
| Pediatric use | Safety and efficacy in pediatric patients have not been established; no pediatric dosing recommendations are available. |
| Geriatric use | No dose adjustment is required based on age. Clinical studies included patients ≥65 years; no overall differences in safety or efficacy were observed. However, greater sensitivity in some older individuals cannot be ruled out. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for AKYNZEO (AKYNZEO).
| Breastfeeding | Present in rat milk; unknown if excreted in human milk. M/P ratio not established. Caution advised due to potential for adverse effects in nursing infants (e.g., serotonin syndrome). Consider temporary discontinuation of breastfeeding during treatment. |
| Teratogenic Risk | Pregnancy Category C: Animal studies have shown teratogenic effects, but no adequate human studies. Risk cannot be ruled out. First trimester: Potential for major malformations; use only if benefit outweighs risk. Second and third trimesters: Limited data; may cause fetal adverse effects related to serotonin and substance P antagonism. |
■ FDA Black Box Warning
No FDA black box warnings.
| Common Effects | Fatigue Erythema skin redness Weakness Headache Constipation Indigestion |
| Serious Effects |
Hypersensitivity to any component of the formulation
| Precautions | Hypersensitivity reactions including anaphylaxis; serotonin syndrome when used in combination with other serotonergic agents; constipation; headache; asthenia; fatigue; dyspepsia; potential for QT prolongation with excessive use; not recommended for patients with severe hepatic impairment. |
| Food/Dietary | Grapefruit and grapefruit juice should be avoided as they may inhibit CYP3A4, leading to increased levels of netupitant and risk of adverse effects. No other specific food interactions are known. Take with or without food. |
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| Fetal Monitoring | Monitor maternal vital signs (heart rate, blood pressure) and ECG due to risk of QT prolongation. Assess for symptoms of serotonin syndrome (agitation, tremor, hyperthermia). Fetal monitoring: serial ultrasounds for growth and well-being if used in second/third trimester. |
| Fertility Effects | No specific human fertility studies. Animal studies showed no impairment of fertility at clinically relevant doses. Theoretical risk due to neurotransmitter modulation may affect reproductive hormone regulation; clinical significance unknown. |
| Clinical Pearls | AKYNZEO (netupitant + palonosetron) is a fixed-dose combination for prevention of chemotherapy-induced nausea and vomiting (CINV). Netupitant is a NK1 receptor antagonist; palonosetron is a 5-HT3 receptor antagonist. Use for highly emetogenic chemotherapy (e.g., cisplatin) and moderately emetogenic chemotherapy. Contraindicated in severe hepatic impairment (Child-Pugh C). Dose adjustment not required for renal impairment. Avoid use with strong CYP3A4 inhibitors (e.g., ketoconazole) as netupitant is a moderate CYP3A4 inhibitor and can increase levels of CYP3A4 substrates. Administer 1 capsule orally 1 hour before chemotherapy. The capsule should be swallowed whole; no need for concomitant dexamethasone when used with a corticosteroid-sparing regimen (however, dexamethasone is often still used per guidelines). |
| Patient Advice | Take one capsule exactly as prescribed, one hour before your chemotherapy infusion. · Swallow the capsule whole; do not crush, chew, or open it. · If you miss a dose, contact your healthcare provider; do not take two doses at once. · Common side effects include headache, fatigue, and constipation; report severe or persistent symptoms. · Avoid grapefruit and grapefruit juice while taking this medication as it may increase the risk of side effects. · Tell your doctor about all medications you are taking, including prescription, over-the-counter, and herbal supplements. · This medication may cause dizziness or drowsiness; avoid driving or operating heavy machinery until you know how it affects you. · If you are pregnant, planning to become pregnant, or breastfeeding, discuss this with your doctor. |