netupitant/palonosetron (Rx)

Brand and Other Names:Akynzeo, fosnetupitant
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

netupitant/palonosetron

capsule

  • 300mg/0.5mg

injection, lyophilized powder for reconstitution

  • (235mg/0.25mg)/vial
  • Note: Parenteral product contains fosnetupitant, a prodrug of netupitant

Chemotherapy-Induced Nausea & Vomiting

Capsules: Indicated for in combination with dexamethasone in adults prevention of acute and delayed nausea and vomiting (N/V) associated with cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy

Injection: Indicated in combination with dexamethasone in adults for prevention of acute and delayed N/V associated with initial and repeat courses of highly emetogenic chemotherapy

Highly emetogenic chemotherapy

  • Includes cisplatin-based chemotherapy
  • 1 capsule (300 mg/0.5 mg) PO ~1 hr before starting chemotherapy OR
  • 1 reconstituted vial (235mg/0.25mg) IV over 30 min starting 30 min before 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 (CrCl 30-60 mL/min): No dosage adjustment required
  • Severe (CrCl <30 mL/min) or end-stage renal disease (ESRD): Avoid use

Hepatic impairment

  • Mild or moderate (Child-Pugh 5-8): No dosage adjustment required
  • Severe (Child-Pugh ≥9): Avoid use

Dosing Considerations

Limitations of use

  • Injection: Not studied for prevention of N/V associated with anthracycline plus cyclophosphamide chemotherapy
  • Palonosetron prevents N/V during acute phase after chemotherapy
  • Netupitant prevents N/V during both the acute and delayed phase after chemotherapy

<18 years: Safety and efficacy not established

Use caution when dosing patients as they have a greater frequency of decreased hepatic, renal or cardiac function and concomitant disease or other drug therapy

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Interactions

Interaction Checker

and netupitant/palonosetron

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            Adverse 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%)

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            Warnings

            Contraindications

            None

            Cautions

            Hypersensitivity reactions (eg, anaphylaxis) reported in patients treated with palonosetron, with or without known hypersensitivity to other 5-HT3 receptor antagonists

            Serotonin syndrome has been reported with 5-HT3 receptor antagonists (eg, palonosetron); most reports have been associated with concomitant use of serotonergic drugs (eg, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and IV methylene blue); discontinue netupitant/palonosetron if symptoms occur

            Drug interactions overview

            • Netupitant is a CYP3A4 substrate and a moderate inhibitor of CYP3A4
            • Palonosetron is mainly metabolized by CYP2D6 and to a lesser extent by CYP3A4 and CYP1A2
            • Strong CYP3A4 inducers (eg, rifampin) can decrease netupitant/palonosetron efficacy by substantially reducing plasma concentrations of the netupitant component; avoid use
            • Concomitant use with a strong CYP3A4 inhibitor (eg, ketoconazole) can increase the systemic exposure to the netupitant component; no dosage adjustment is necessary for single dose administration
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            Pregnancy & Lactation

            Pregnancy

            Limited available data with its use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes

            Animal studies

            • Netupitant
              • An increased incidence of external and skeletal abnormalities in rabbit fetuses was observed following daily oral administration of netupitant in rabbits at 10 mg/kg/day and higher (0.2 times the human AUC at the recommended single dose to be given with each cycle of chemotherapy) during the period of organogenesis; abnormalities included positional abnormalities in the limbs and paws, and fused sternebrae
              • Reduction in fetal rabbit weight occurred at 30 mg/kg/day; maternal toxicity in rabbits (eg, loss of bodyweight during the treatment period) was also observed at 30 mg/kg/day; daily oral administration of up to 30 mg/kg netupitant (3.7 times the human AUC at the recommended dose) in rats during organogenesis through lactation produced no adverse effects in the offspring
            • Fosnetupitant
              • Daily IV administration of 39 mg/kg/day fosnetupitant in rats (3 times the human AUC for netupitant at the recommended single dose to be given with each cycle of chemotherapy) during the period of organogenesis produced delayed ossification of pubis
              • No effects on embryofetal development were observed with daily administration of up to 13 mg/kg fosnetupitant in rats (2 times the human AUC for netupitant at the recommended single dose to be given with each cycle of chemotherapy); due to limited systemic exposure to fosnetupitant in pregnant rats, it is not possible to provide an AUC-based comparison of fosnetupitant exposure in rats and humans

            Lactation

            No data on the presence of netupitant (or fosnetupitant) or palonosetron in human milk, the effects on the breastfed infant, or the effects on milk production

            Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for netupitant/palonosetron and any potential adverse effect on the breastfed child from netupitant/palonosetron or from the underlying maternal condition

            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.

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            Pharmacology

            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

            • Fosnetupitant: 0.5 hr (IV, healthy subjects and patients)
            • Netupitant: 5 hr (oral, healthy subjects); 4 hr (oral, patients); 0.5 hr (IV, healthy subjects); 0.6 hr (IV, patients)
            • Palonosetron: 5 hr (oral, healthy subjects and patients); 0.6 hr (IV patients)

            Peak plasma concentration

            • Fosnetupitant: 6,431 ng/mL (IV, healthy subjects); 3,478 ng/mL (IV, patients)
            • Netupitant: 434 ng/mL (oral, healthy subjects); 496 ng/mL (oral, patients); 841 ng/mL (IV, healthy subjects); 590 ng/mL (IV, patients)
            • Palonosetron: 1.53 ng/mL (oral, healthy subjects); 0.95 ng/mL (oral, patients); 0.8 ng/mL (IV, patients)

            AUC

            • Fosnetupitant: 2,938 ng•hr/mL (IV, healthy subjects); 1,401 ng•hr/mL (IV, patients)
            • Netupitant: 14,401 ng•hr/mL (oral, healthy subjects); 56.7 ng•hr/mL (oral, patients); 12,012 ng•hr/mL (IV, healthy subjects); 8,922 ng•hr/mL (IV, patients)
            • Palonosetron: 56.7 ng•hr/mL (oral, healthy subjects); 58.3 ng•hr/mL (oral, patients); 28 ng•hr/mL (IV, patients)

            Distribution

            Protein bound

            • Fosnetupitant: 92% at 1 micromolar; 95% at 10 micromolar (IV)
            • Netupitant: >99.5% (oral); >97% (major metabolites, oral)
            • Palonosetron: 62% (oral)

            Vd

            • Fosnetupitant: 124 L (IV)
            • Netupitant: 3,314 L (oral, healthy subjects); 1,982 L (oral, patients); 2,627 L (IV)
            • Palonosetron: 586 L (oral, healthy subjects); 663 L (oral, patients); 594 L (IV)

            Metabolism

            Fosnetupitant

            • Converted in vivo to netupitant by metabolic hydrolysis
            • Netupitant metabolites M1, M2 and M3 were generated from the released netupitant

            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

            • Fosnetupitant: 0.75 hr (IV)
            • Netupitant: 96 hr (oral, healthy subjects); 80 hr (oral, patients); 144 hr (IV)
            • Palonosetron: 44 hr (oral, healthy subjects); 48 hr (oral, patients); 58 hr (IV)

            Total body clearance

            • Fosnetupitant: 249 L/hr (IV)
            • Netupitant: 20.3 L/hr (oral); 14.1 L/hr (IV)
            • Palonosetron: 9.6 L/hr (oral, healthy subjects); 10 (oral, cancer); 7.6 L/hr (IV)

            Renal clearance

            • Palonosetron: 66.5 mL/hr/kg

            Excretion

            • Netupitant: 70% (feces); 4% (urine)
            • Palonosetron: 5-8% (feces); 85-93% (urine)
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            Administration

            IV Compatibilities

            D5W or 0.9% NaCl

            IV Incompatibilities

            Solutions containing divalent cations (eg, calcium, magnesium), including Lactated Ringer’s and Hartmann's Solution

            Limited data are available on the compatibility with other IV substances, additives or other medications, and should not be added to netupitant/palonosetron solution or infused simultaneously

            If the same IV line is used for sequential infusion of several different drugs, flush line before and after infusion with 0.9% NaCl

            IV Preparation

            Injection contains no antimicrobial preservatives

            Inject 20 mL D5W or 0.9% NaCl along the vial wall and not jetted in order to prevent foaming; swirl vial gently

            Prepare an infusion vial or bag filled with 30 mL of D5W or 0.9% NaCl

            Withdraw entire contents of the reconstituted vial and transfer it into the infusion vial or bag to yield a total volume of 50 mL

            Gently invert vial or bag until complete dissolution

            Before administration, inspect final diluted solution for particulate matter and discoloration; discard vial or bag if particulates and/or discoloration are observed

            IV Administration

            Infuse over 30 minutes

            At the end of the infusion, flush infusion line with the same carrier solution to ensure complete drug administration

            Oral Administration

            Capsules: Take with or without food

            Storage

            Capsules

            • Store at 20-25°C (68-77°F); excursions permitted from 15-30°C (59-86°F)

            Unused vials

            • Store at 2-8°C (35.6-46.4°F) in carton, protected from light

            Reconstituted vials and diluted solutions

            • Store at room temperature
            • Total time from reconstitution to start of the infusion should not exceed 3 hr
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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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