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
  • ready-to-dilute IV solution: (235mg/0.25mg)/20mL vial
  • Note: Parenteral products contain 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

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            Contraindicated (3)

            • apomorphine

              netupitant/palonosetron, apomorphine. Mechanism: unspecified interaction mechanism. Contraindicated. Profound hypotension and loss of consciousness reported when 5HT3 antagonists are coadministered with apomorphine. .

            • flibanserin

              netupitant/palonosetron will increase the level or effect of flibanserin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Coadministration of flibanserin with moderate or strong CYP3A4 inhibitors is contraindicated. Severe hypotension or syncope can occur.

            • lonafarnib

              netupitant/palonosetron will increase the level or effect of lonafarnib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Lonafarnib is a sensitive CYP3A4 substrate. Coadministration with strong or moderate CYP3A4 inhibitors is contraindicated.

            Serious - Use Alternative (84)

            • abametapir

              abametapir will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. For 2 weeks after abametapir application, avoid taking drugs that are CYP3A4 substrates. If not feasible, avoid use of abametapir.

            • almotriptan

              netupitant/palonosetron, almotriptan. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • amitriptyline

              netupitant/palonosetron, amitriptyline. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • amoxapine

              netupitant/palonosetron, amoxapine. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • apalutamide

              apalutamide will decrease the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of apalutamide, a strong CYP3A4 inducer, with drugs that are CYP3A4 substrates can result in lower exposure to these medications. Avoid or substitute another drug for these medications when possible. Evaluate for loss of therapeutic effect if medication must be coadministered. Adjust dose according to prescribing information if needed.

            • avapritinib

              netupitant/palonosetron will increase the level or effect of avapritinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of avapritinib with strong CYP3A4 inhibitors.

            • bosentan

              bosentan will decrease the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Netupitant is mainly metabolized by CYP3A4; avoid use in patients who are chronically using a strong CYP3A4 inducer

            • carbamazepine

              carbamazepine will decrease the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Netupitant is mainly metabolized by CYP3A4; avoid use in patients who are chronically using a strong CYP3A4 inducer

            • citalopram

              netupitant/palonosetron, citalopram. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • clomipramine

              netupitant/palonosetron, clomipramine. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • cobimetinib

              netupitant/palonosetron will increase the level or effect of cobimetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If concurrent short term (14 days or less) use of moderate CYP3A inhibitors is unavoidable for patients who are taking cobimetinib 60 mg, reduce the cobimetinib dose to 20 mg. After discontinuation of a moderate CYP3A inhibitor, resume cobimetinib 60 mg. Use an alternative to a moderate CYP3A inhibitor in patients who are taking a reduced dose of cobimetinib (40 or 20 mg daily).

            • dabrafenib

              dabrafenib will decrease the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Netupitant is mainly metabolized by CYP3A4; avoid use in patients who are chronically using a strong CYP3A4 inducer

            • desipramine

              netupitant/palonosetron, desipramine. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • desvenlafaxine

              netupitant/palonosetron, desvenlafaxine. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • dexamethasone

              dexamethasone will decrease the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Netupitant is mainly metabolized by CYP3A4; avoid use in patients who are chronically using a strong CYP3A4 inducer

            • doxepin

              netupitant/palonosetron, doxepin. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • duloxetine

              netupitant/palonosetron, duloxetine. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • efavirenz

              efavirenz will decrease the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Netupitant is mainly metabolized by CYP3A4; avoid use in patients who are chronically using a strong CYP3A4 inducer

            • eletriptan

              netupitant/palonosetron, eletriptan. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • encorafenib

              netupitant/palonosetron will increase the level or effect of encorafenib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If concomitant use of a moderate CYP3A4 inhibitor is unavoidable, reduce encorafenib dose to one-half of the dose (eg, reduce from 450 mg/day to 225 mg/day). After discontinuing the inhibitor for 3-5 elimination half-lives, resume previous encorafenib dose.

            • entrectinib

              netupitant/palonosetron will increase the level or effect of entrectinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of moderate CYP3A4 inhibitors with entrectinib, a CYP3A4 substrate. If coadministration unavoidable, reduce dose to 200 mg/day for patients aged 12 y or older with BSA >1.50m2. Resume previous entrectinib dose after discontinuing moderate CYP3A inhibitor for 3-5 elimination half-lives.

            • enzalutamide

              enzalutamide will decrease the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Netupitant is mainly metabolized by CYP3A4; avoid use in patients who are chronically using a strong CYP3A4 inducer

            • escitalopram

              netupitant/palonosetron, escitalopram. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • eslicarbazepine acetate

              eslicarbazepine acetate will decrease the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Netupitant is mainly metabolized by CYP3A4; avoid use in patients who are chronically using a strong CYP3A4 inducer

            • etravirine

              etravirine will decrease the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Netupitant is mainly metabolized by CYP3A4; avoid use in patients who are chronically using a strong CYP3A4 inducer

            • fentanyl

              netupitant/palonosetron will increase the level or effect of fentanyl by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration of CYP3A4 inhibitors with fentanyl is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider fentanyl dose adjustments until stable drug effects are achieved.

            • fentanyl intranasal

              netupitant/palonosetron will increase the level or effect of fentanyl intranasal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration of CYP3A4 inhibitors with fentanyl is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider fentanyl dose adjustments until stable drug effects are achieved.

            • fentanyl transdermal

              netupitant/palonosetron will increase the level or effect of fentanyl transdermal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration of CYP3A4 inhibitors with fentanyl is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider fentanyl dose adjustments until stable drug effects are achieved.

            • fentanyl transmucosal

              netupitant/palonosetron will increase the level or effect of fentanyl transmucosal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration of CYP3A4 inhibitors with fentanyl is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider fentanyl dose adjustments until stable drug effects are achieved.

            • fexinidazole

              fexinidazole will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Fexinidazole inhibits CYP3A4. Coadministration may increase risk for adverse effects of CYP3A4 substrates.

            • fluoxetine

              netupitant/palonosetron, fluoxetine. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • fluvoxamine

              fluvoxamine increases toxicity of netupitant/palonosetron by serotonin levels. Avoid or Use Alternate Drug.

            • fosphenytoin

              fosphenytoin will decrease the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Netupitant is mainly metabolized by CYP3A4; avoid use in patients who are chronically using a strong CYP3A4 inducer

            • frovatriptan

              netupitant/palonosetron, frovatriptan. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • imipramine

              netupitant/palonosetron, imipramine. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • infigratinib

              netupitant/palonosetron will increase the level or effect of infigratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • isocarboxazid

              netupitant/palonosetron, isocarboxazid. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • ivabradine

              netupitant/palonosetron will increase the level or effect of ivabradine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of ivabradine with moderate CYP3A4 inhibitors.

            • ivosidenib

              ivosidenib will decrease the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sensitive CYP3A4 substrates with ivosidenib or replace with alternative therapies. If coadministration is unavoidable, monitor patients for loss of therapeutic effect of these drugs.

            • lemborexant

              netupitant/palonosetron will increase the level or effect of lemborexant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of lemborexant with moderate or strong CYP3A inhibitors.

            • levomilnacipran

              netupitant/palonosetron, levomilnacipran. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • lurbinectedin

              netupitant/palonosetron will increase the level or effect of lurbinectedin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • midazolam intranasal

              netupitant/palonosetron will increase the level or effect of midazolam intranasal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of moderate CYP3A4 inhibitors with midazolam intranasal causes higher midazolam systemic exposure, which may prolong sedation.

            • milnacipran

              netupitant/palonosetron, milnacipran. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • mitotane

              mitotane will decrease the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Netupitant is mainly metabolized by CYP3A4; avoid use in patients who are chronically using a strong CYP3A4 inducer

            • mobocertinib

              netupitant/palonosetron will increase the level or effect of mobocertinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If use of moderate CYP3A4 inhibitor unavoidable, reduce mobocertinib dose by ~50% (eg, 160 to 80 mg); closely monitor QTc interval.

            • nafcillin

              nafcillin will decrease the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Netupitant is mainly metabolized by CYP3A4; avoid use in patients who are chronically using a strong CYP3A4 inducer

            • naratriptan

              netupitant/palonosetron, naratriptan. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • neratinib

              netupitant/palonosetron will increase the level or effect of neratinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of neratinib with strong/moderate CYP3A4 inhibitors.

            • nevirapine

              nevirapine will decrease the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Netupitant is mainly metabolized by CYP3A4; avoid use in patients who are chronically using a strong CYP3A4 inducer

            • nortriptyline

              netupitant/palonosetron, nortriptyline. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • olaparib

              netupitant/palonosetron will increase the level or effect of olaparib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with moderate CYP3A inhibitors cannot be avoided, reduce olaparib dose to 200 mg (capsule) or 150 mg (tablet) PO BID. Do not substitute tablets with capsules.

            • oxcarbazepine

              oxcarbazepine will decrease the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Netupitant is mainly metabolized by CYP3A4; avoid use in patients who are chronically using a strong CYP3A4 inducer

            • pacritinib

              netupitant/palonosetron will increase the level or effect of pacritinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • paroxetine

              netupitant/palonosetron, paroxetine. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • pemigatinib

              netupitant/palonosetron will increase the level or effect of pemigatinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors is unavoidable, reduce pemigatinib dose (refer to drug monograph dosage modifications). After discontinuing the CYP3A4 inhibitor for 3 elimination half-lives, may resume previous pemigatinib dose.

            • pentobarbital

              pentobarbital will decrease the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Netupitant is mainly metabolized by CYP3A4; avoid use in patients who are chronically using a strong CYP3A4 inducer

            • pexidartinib

              netupitant/palonosetron will increase the level or effect of pexidartinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors is unavoidable, reduce pexidartinib dose (refer to drug monograph dosage modifications). After discontinuing the CYP3A4 inhibitor for 3 elimination half-lives, may resume previous pexidartinib dose.

            • phenelzine

              netupitant/palonosetron, phenelzine. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • phenobarbital

              phenobarbital will decrease the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Netupitant is mainly metabolized by CYP3A4; avoid use in patients who are chronically using a strong CYP3A4 inducer

            • phenytoin

              phenytoin will decrease the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Netupitant is mainly metabolized by CYP3A4; avoid use in patients who are chronically using a strong CYP3A4 inducer

            • primidone

              primidone will decrease the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Netupitant is mainly metabolized by CYP3A4; avoid use in patients who are chronically using a strong CYP3A4 inducer

            • protriptyline

              netupitant/palonosetron, protriptyline. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • rasagiline

              netupitant/palonosetron, rasagiline. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • rifabutin

              rifabutin will decrease the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Netupitant is mainly metabolized by CYP3A4; avoid use in patients who are chronically using a strong CYP3A4 inducer

            • rifampin

              rifampin will decrease the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Netupitant is mainly metabolized by CYP3A4; avoid use in patients who are chronically using a strong CYP3A4 inducer

            • rifapentine

              rifapentine will decrease the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Netupitant is mainly metabolized by CYP3A4; avoid use in patients who are chronically using a strong CYP3A4 inducer

            • rizatriptan

              netupitant/palonosetron, rizatriptan. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • selegiline

              netupitant/palonosetron, selegiline. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • selegiline transdermal

              netupitant/palonosetron, selegiline transdermal. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • selumetinib

              netupitant/palonosetron will increase the level or effect of selumetinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration with strong or moderate CYP3A4 inhibitors cannot be avoided, reduce selumetinib dosage (refer to selumetinib monograph for further information). After discontinuation of the strong or moderate CYP3A4 inhibitor for 3 elimination half-lives, resume selumetinib dose that was taken before initiating the inhibitor.

            • sertraline

              netupitant/palonosetron, sertraline. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • siponimod

              netupitant/palonosetron will increase the level or effect of siponimod by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of siponimod with a moderate or strong CYP3A4 inhibitor PLUS a moderate or strong CYP2C9 inhibitor is not recommended.

            • St John's Wort

              St John's Wort will decrease the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Netupitant is mainly metabolized by CYP3A4; avoid use in patients who are chronically using a strong CYP3A4 inducer

            • sumatriptan

              netupitant/palonosetron, sumatriptan. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • sumatriptan intranasal

              netupitant/palonosetron, sumatriptan intranasal. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • tazemetostat

              netupitant/palonosetron will increase the level or effect of tazemetostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of tazemetostat with moderate CYP3A4 inhibitors. If coadministration is unavoidable, reduce tazemetostat current dose (see drug monograph Dosage Modifications).

            • tranylcypromine

              netupitant/palonosetron, tranylcypromine. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • trimipramine

              netupitant/palonosetron, trimipramine. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • tucatinib

              tucatinib will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid concomitant use of tucatinib with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If unavoidable, reduce CYP3A substrate dose according to product labeling.

            • venetoclax

              netupitant/palonosetron will increase the level or effect of venetoclax by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If a moderate CYP3A inhibitor must be used, reduce the venetoclax dose by at least 50%. Monitor more closely for signs of venetoclax toxicities.

            • venlafaxine

              netupitant/palonosetron, venlafaxine. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            • voxelotor

              voxelotor will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid.

            • zolmitriptan

              netupitant/palonosetron, zolmitriptan. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.

            Monitor Closely (67)

            • acalabrutinib

              netupitant/palonosetron will increase the level or effect of acalabrutinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Decrease acalabrutinib dose to 100 mg once daily if coadministered with a moderate CYP3A inhibitor.

            • atazanavir

              atazanavir will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Netupitant is mainly metabolized by CYP3A4; no dosage adjustment is required

            • atogepant

              netupitant/palonosetron will increase the level or effect of atogepant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • betrixaban

              netupitant/palonosetron increases levels of betrixaban by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Decrease betrixaban dose to 80 mg PO once, then 40 mg PO qDay if coadministered with a P-gp inhibitor.

            • brexpiprazole

              netupitant/palonosetron will increase the level or effect of brexpiprazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Administer a quarter of brexpiprazole dose if coadministered with a moderate CYP3A4 inhibitor PLUS a strong/moderate CYP2D6 inhibitor.

            • buprenorphine subdermal implant

              netupitant/palonosetron will increase the level or effect of buprenorphine subdermal implant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor patients already on buprenorphine subdermal implant who require newly-initiated treatment with CYP3A4 inhibitors for signs and symptoms of overmedication. If the dose of the concomitant CYP3A4 inhibitor cannot be reduced or discontinued, implant removal may be necessary and the patient should then be treated with a buprenorphine dosage form that permits dose adjustments. If a CYP3A4 inhibitor is discontinued in a patient who has been stabilized on buprenorphine, monitor the patient for withdrawal.

            • buprenorphine, long-acting injection

              netupitant/palonosetron will increase the level or effect of buprenorphine, long-acting injection by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Patients who transfer to buprenorphine long-acting injection from transmucosal buprenorphine coadministered with CYP3A4 inhibitors should be monitored to ensure buprenorphine plasma levels are adequate. Within 2 weeks, if signs and symptoms of buprenorphine toxicity or overdose occur and the concomitant CYP3A4 inhibitor cannot be reduced or discontinued, transition the patient back to a buprenorphine formulation that permits dose adjustments.

            • cannabidiol

              netupitant/palonosetron will increase the level or effect of cannabidiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Consider reducing the cannabidiol dose when coadministered with a moderate CYP3A4 inhibitor.

            • cenobamate

              cenobamate will decrease the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Increase dose of CYP3A4 substrate, as needed, when coadministered with cenobamate.

            • clarithromycin

              clarithromycin will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Netupitant is mainly metabolized by CYP3A4; no dosage adjustment is required

            • cobicistat

              cobicistat will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Netupitant is mainly metabolized by CYP3A4; no dosage adjustment is required

            • conivaptan

              conivaptan will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Netupitant is mainly metabolized by CYP3A4; no dosage adjustment is required

            • daridorexant

              netupitant/palonosetron will increase the level or effect of daridorexant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Daridorexant dose should not exceed 25 mg per night when coadministered with moderate CYP3A4 inhibitors.

            • darunavir

              darunavir will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Netupitant is mainly metabolized by CYP3A4; no dosage adjustment is required

            • deflazacort

              netupitant/palonosetron will increase the level or effect of deflazacort by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Decrease deflazacort dose to one-third of the recommended dose if coadministered with moderate or strong CYP3A4 inhibitors.

            • diazepam intranasal

              netupitant/palonosetron will increase the level or effect of diazepam intranasal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Strong or moderate CYP3A4 inhibitors may decrease rate of diazepam elimination, thereby increasing adverse reactions to diazepam.

            • elagolix

              elagolix decreases levels of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Elagolix is a weak-to-moderate CYP3A4 inducer. Monitor CYP3A substrates if coadministered. Consider increasing CYP3A substrate dose if needed.

            • encorafenib

              encorafenib, netupitant/palonosetron. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Encorafenib both inhibits and induces CYP3A4 at clinically relevant plasma concentrations. Coadministration of encorafenib with sensitive CYP3A4 substrates may result in increased toxicity or decreased efficacy of these agents.

            • fedratinib

              fedratinib will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Adjust dose of drugs that are CYP3A4 substrates as necessary.

            • fenfluramine

              netupitant/palonosetron decreases effects of fenfluramine by pharmacodynamic antagonism. Use Caution/Monitor. Potent serotonin receptor antagonists may decrease fenfluramine efficacy. If coadministered, monitor appropriately.

            • finerenone

              netupitant/palonosetron will increase the level or effect of finerenone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor serum potassium during initiation and dosage adjustment of either finererone or moderate CYP3A4 inhibitors. Adjust finererone dosage as needed.

            • fosamprenavir

              fosamprenavir will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Netupitant is mainly metabolized by CYP3A4; no dosage adjustment is required

            • grapefruit

              grapefruit will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Netupitant is mainly metabolized by CYP3A4; no dosage adjustment is required

            • guanfacine

              netupitant/palonosetron will increase the level or effect of guanfacine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Strong or moderate CYP3A4 inhibitors significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if coadministered, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available.

            • ibrutinib

              netupitant/palonosetron increases levels of ibrutinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Coadministration with moderate CYP3A4 inhibitors, reduce ibrutinib dose to 280 mg qDay (B-cell malignancies) or 420 mg qDay (graft versus host disease). After CYP3A inhibitor discontinuation, resume previous dose of ibrutinib.

            • idelalisib

              idelalisib will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Netupitant is mainly metabolized by CYP3A4; no dosage adjustment is required

            • ifosfamide

              netupitant/palonosetron decreases effects of ifosfamide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration .

            • imatinib

              imatinib will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Netupitant is mainly metabolized by CYP3A4; no dosage adjustment is required

            • indinavir

              indinavir will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Netupitant is mainly metabolized by CYP3A4; no dosage adjustment is required

            • isavuconazonium sulfate

              netupitant/palonosetron will increase the level or effect of isavuconazonium sulfate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • isoniazid

              isoniazid will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Netupitant is mainly metabolized by CYP3A4; no dosage adjustment is required

            • istradefylline

              istradefylline will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Istradefylline 40 mg/day increased peak levels and AUC of CYP3A4 substrates in clinical trials. This effect was not observed with istradefylline 20 mg/day. Consider dose reduction of sensitive CYP3A4 substrates.

            • itraconazole

              itraconazole will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Netupitant is mainly metabolized by CYP3A4; no dosage adjustment is required

            • ivacaftor

              netupitant/palonosetron will increase the level or effect of ivacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce ivacaftor dose if coadministered with moderate CYP3A4 inhibitors. See specific ivacaftor-containing product for precise dosage modification.

            • ivosidenib

              netupitant/palonosetron will increase the level or effect of ivosidenib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration with moderate CYP3A4 inhibitors may increase ivosidenib plasma concentrations, thus increasing the risk of QTc prolongation. Monitor for increased risk of QTc interval prolongation.

            • ketoconazole

              ketoconazole will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Netupitant is mainly metabolized by CYP3A4; no dosage adjustment is required

            • lefamulin

              netupitant/palonosetron will increase the level or effect of lefamulin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor for adverse effects if lefamulin is coadministered with moderate CYP3A inhibitors.

            • levamlodipine

              netupitant/palonosetron will increase the level or effect of levamlodipine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Coadministration with moderate and strong CYP3A inhibitors results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is coadministered with CYP3A inhibitors to determine the need for dose adjustment.

            • levoketoconazole

              levoketoconazole will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Netupitant is mainly metabolized by CYP3A4; no dosage adjustment is required

            • lopinavir

              lopinavir will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Netupitant is mainly metabolized by CYP3A4; no dosage adjustment is required

            • lorlatinib

              lorlatinib will decrease the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • lumateperone

              netupitant/palonosetron will increase the level or effect of lumateperone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce lumateperone dose to 21 mg/day if coadministered with moderate CYP3A4 inhibitors.

            • mavacamten

              netupitant/palonosetron will increase the level or effect of mavacamten by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Inititiation of moderate CYP3A4 inhibitors may require decreased mavacamten dose.

            • naldemedine

              netupitant/palonosetron increases levels of naldemedine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Monitor naldemedine for potential adverse effects if coadministered with strong or moderate CYP3A4 inhibitors.

            • nefazodone

              nefazodone will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Netupitant is mainly metabolized by CYP3A4; no dosage adjustment is required

            • nelfinavir

              nelfinavir will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Netupitant is mainly metabolized by CYP3A4; no dosage adjustment is required

            • nicardipine

              nicardipine will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Netupitant is mainly metabolized by CYP3A4; no dosage adjustment is required

            • palbociclib

              netupitant/palonosetron will increase the level or effect of palbociclib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • posaconazole

              posaconazole will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Netupitant is mainly metabolized by CYP3A4; no dosage adjustment is required

            • quinidine

              quinidine will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Netupitant is mainly metabolized by CYP3A4; no dosage adjustment is required

            • ribociclib

              ribociclib will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • rimegepant

              netupitant/palonosetron will increase the level or effect of rimegepant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid repeating rimegepant dose within 48 hr if coadministered with a moderate CYP3A4 inhibitor.

            • ritonavir

              ritonavir will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Netupitant is mainly metabolized by CYP3A4; no dosage adjustment is required

            • rucaparib

              rucaparib will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Adjust dosage of CYP3A4 substrates, if clinically indicated.

            • saquinavir

              saquinavir will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Netupitant is mainly metabolized by CYP3A4; no dosage adjustment is required

            • sonidegib

              netupitant/palonosetron will increase the level or effect of sonidegib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of sonidegib with moderate CYP3A4 inhibitors. If a moderate CYP3A inhibitor must be used, administer the moderate CYP3A inhibitor for <14 days and monitor closely for adverse reactions, particularly musculoskeletal adverse reactions.

            • stiripentol

              stiripentol, netupitant/palonosetron. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Stiripentol is a CYP3A4 inhibitor and inducer. Monitor CYP3A4 substrates coadministered with stiripentol for increased or decreased effects. CYP3A4 substrates may require dosage adjustment.

            • sufentanil SL

              netupitant/palonosetron will increase the level or effect of sufentanil SL by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration of sufentanil SL with any CYP3A4 inhibitor may increase sufentanil plasma concentration, and, thereby increase or prolonged adverse effects, including potentially fatal respiratory depression.

            • tazemetostat

              tazemetostat will decrease the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • tecovirimat

              tecovirimat will decrease the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Tecovirimat is a weak CYP3A4 inducer. Monitor sensitive CYP3A4 substrates for effectiveness if coadministered.

            • tezacaftor

              netupitant/palonosetron will increase the level or effect of tezacaftor by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Adjust tezacaftor dosage regimen if coadministered with a moderate CYP3A inhibitor.

            • tinidazole

              netupitant/palonosetron will increase the level or effect of tinidazole by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • tipranavir

              tipranavir will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Netupitant is mainly metabolized by CYP3A4; no dosage adjustment is required

            • trabectedin

              netupitant/palonosetron will increase the level or effect of trabectedin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • voclosporin

              netupitant/palonosetron will increase the level or effect of voclosporin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce voclosporin daily dosage to 15.8 mg PO in AM and 7.9 mg PO in PM.

            • voriconazole

              voriconazole will increase the level or effect of netupitant/palonosetron by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Netupitant is mainly metabolized by CYP3A4; no dosage adjustment is required

            • zanubrutinib

              netupitant/palonosetron will increase the level or effect of zanubrutinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce zanubrutinib dose when coadministered with a moderate CYP3A4 inhibitor. Interrupt dose as recommended for adverse reactions. After discontinuing the CYP3A4 inhibitor, resume previous dose of zanubrutinib. See zanubrutinib Dosage Modifications for precise recommendation.

            Minor (3)

            • estradiol vaginal

              netupitant/palonosetron will increase the level or effect of estradiol vaginal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • irinotecan

              netupitant/palonosetron will increase the level or effect of irinotecan by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • irinotecan liposomal

              netupitant/palonosetron will increase the level or effect of irinotecan liposomal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

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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

            Lyophilized powder

            • 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

            Final dilution

            • Withdraw entire contents of the reconstituted vial or ready-to-dilute solutin 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

            • Room temperature at 20-25ºC (68-77ºF); excursions permitted from 15-30ºC (59-86ºF)

            Unopened vials

            • Lyophilized powder for reconstitution: Refrigerate at 2-8ºC (35.6-46.4ºF)
            • Ready-to-dilute IV solution: Room temperature at 20-25ºC (68-77ºF)
            • Store in carton; protect from light

            Reconstituted vials and diluted solutions

            • Store at room temperature
            • Do not exceed 24 hr total time from reconstitution/dilution to start of infusion
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            Images

            BRAND FORM. UNIT PRICE PILL IMAGE
            Akynzeo (netupitant) oral
            -
            300-0.5 mg capsule

            Copyright © 2010 First DataBank, Inc.

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            Patient Handout

            Patient Education
            netupitant-palonosetron oral

            NETUPITANT/PALONOSETRON - ORAL

            (net-UE-pi-tant/PAL-oh-NOE-se-tron)

            COMMON BRAND NAME(S): Akynzeo

            USES: This product contains 2 medications: netupitant and palonosetron. It is used to prevent nausea and vomiting caused by cancer drug treatment (chemotherapy). Netupitant and palonosetron work by blocking natural substances in the body (such as substance P/neurokinin 1, serotonin) that cause vomiting.

            HOW TO USE: Read the Patient Information Leaflet if available from your pharmacist before you start taking netupitant/palonosetron and each time you get a refill. If you have any questions, ask your doctor or pharmacist.Take this medication by mouth with or without food as directed by your doctor, usually 1 hour before the start of chemotherapy.Tell your doctor if you vomit or feel nauseated.

            SIDE EFFECTS: Headache may occur. If this effect lasts or gets worse, tell your doctor or pharmacist promptly.Remember that this medication has been prescribed because your doctor has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.One of the medications in this product (palonosetron) may increase serotonin and rarely cause a very serious condition called serotonin syndrome/toxicity. The risk increases if you are also taking other drugs that increase serotonin, so tell your doctor or pharmacist of all the drugs you take (see Drug Interactions section). Get medical help right away if you develop some of the following symptoms: fast heartbeat, hallucinations, loss of coordination, severe dizziness, severe nausea/vomiting/diarrhea, twitching muscles, unexplained fever, unusual agitation/restlessness.A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.In the US -Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

            PRECAUTIONS: Before taking this product, tell your doctor or pharmacist if you are allergic to netupitant or to palonosetron; or to other anti-nausea serotonin blockers (such as ondansetron); or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney disease, liver disease.Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.It is unknown if this product passes into breast milk. Consult your doctor before breast-feeding.

            DRUG INTERACTIONS: Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.This medication can slow down the removal of other medications from your body, which may affect how they work. Examples of affected drugs include flibanserin, lomitapide, among others.Other medications can affect the removal of this product from your body, which may affect how it works. Examples include rifamycins (such as rifampin), St. John's wort, among others.The risk of serotonin syndrome/toxicity increases if you are also taking other drugs that increase serotonin. Examples include street drugs such as MDMA/"ecstasy," St. John's wort, certain antidepressants (including SSRIs such as fluoxetine/paroxetine, SNRIs such as duloxetine/venlafaxine), among others. The risk of serotonin syndrome/toxicity may be more likely when you start or increase the dose of these drugs.

            OVERDOSE: If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center.

            NOTES: Do not share this medication with others.

            MISSED DOSE: It is important to take each dose of this medication as scheduled. If you miss a dose, ask your doctor or pharmacist right away for a new dosing schedule. Do not double the dose to catch up.

            STORAGE: Store at room temperature away from light and moisture. Do not store in the bathroom. Keep all medications away from children and pets.Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

            Information last revised March 2022. Copyright(c) 2022 First Databank, Inc.

            IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

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            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

            To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

            Adding plans allows you to:

            • View the formulary and any restrictions for each plan.
            • Manage and view all your plans together – even plans in different states.
            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            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.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
            Additional Offers
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.