Akynzeo

Substance P/Neurokinin 1 (NK1) Antagonist and Serotonin (5HT3) Antagonist Antiemetic Combinations

Oral Administration

Take dose approximately 1 hour prior to beginning chemotherapy.
Capsules may be taken with or without food.

Injectable Administration

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Discard the vial or bag if particulates and/or discoloration are observed.

Intravenous Administration

Administer by intravenous infusion only.
Fosnetupitant; palonosetron is available as a powder in a single-dose vial for reconstitution, a solution for injection in a single-dose vial of solution (ready-to-use), and a single-dose vial of solution (to-be-diluted); all three products contain no antimicrobial preservatives, and are intended for single use only.
Do not mix or reconstitute fosnetupitant; palonosetron with any solution containing divalent cations (e.g., calcium or magnesium), including Lactated Ringer's Injection or Hartmann's Solution.
Limited data are available on the compatibility of fosnetupitant; palonosetron for injection with other intravenous substances, additives or other medications with the exception of intravenous dexamethasone sodium phosphate; they should not be added to the fosnetupitant; palonosetron solution or infused simultaneously. If the same intravenous line is used for sequential infusion of several different drugs, flush the line before and after infusion of fosnetupitant; palonosetron solution with 0.9% Sodium Chloride Injection, USP.
Akynzeo (fosnetupitant; palonosetron) powder for injection: Reconstitution
Use aseptic technique to prepare the infusion.
Inject 20 mL 5% Dextrose Injection, USP or 0.9% Sodium Chloride for Injection into the vial, directing the solvent towards the wall of the vial to prevent foaming. Avoid jetting the solvent into the vial. Swirl the vial gently; avoid shaking.
Prepare an infusion bag filled with 30 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride for Injection.
Withdraw the entire volume from the vial and transfer to the infusion bag (total volume = 50 mL). Gently invert the vial or bag until complete dissolution.
The powder for injection is compatible with intravenous dexamethasone sodium phosphate which can be added to the infusion bag containing Akynzeo solution or infused simultaneously.
Storage: The total time from dilution to the start of the infusion, with or without intravenous dexamethasone sodium phosphate, should not exceed 24 hours. Store the final diluted solution at room temperature.
Administration
Administer over 30 minutes. At the end of the infusion, flush the infusion line with the same carrier solution to ensure complete drug administration.
Akynzeo (fosnetupitant; palonosetron) solutions for injection:
Akynzeo (fosnetupitant; palonosetron) (To-be-Diluted) solution for injection
Preparation
Use aseptic technique to prepare the infusion.
Prepare an infusion bag filled with 30 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride for Injection.
Withdraw the entire volume from the vial (20mL) and transfer to the infusion bag (total volume = 50 mL). Gently invert the vial or bag until complete dissolution.
The to-be-diluted solution is compatible with intravenous dexamethasone sodium phosphate which can be added to the infusion bag containing Akynzeo solution or infused simultaneously.
Storage: The total time from dilution to the start of the infusion, with or without intravenous dexamethasone sodium phosphate, should not exceed 24 hours. Store the final diluted solution at room temperature.
Administration
Administer over 30 minutes. At the end of the infusion, flush the infusion line with the same carrier solution to ensure complete drug administration.
Akynzeo (fosnetupitant; palonosetron) (Ready-to-Use) solution for injection
Preparation
Use aseptic technique to prepare the infusion.
Insert a vented intravenous set through the septum of the vial.
Once the stopper is punctured, use immediately.
The ready-to-use solution for injection is compatible with intravenous dexamethasone sodium phosphate which can be infused simultaneously; however, do not add dexamethasone sodium phosphate to the ready-to-use vial.
Administration
Invert and hang the vial using the provided strap affixed to the bottom of the vial.
Administer over 30 minutes. At the end of the infusion, flush the infusion line 5% Dextrose Injection, USP or 0.9% Sodium Chloride, USP to ensure complete drug administration.

Severe

anaphylactoid reactions / Rapid / Incidence not known
anaphylactic shock / Rapid / Incidence not known
bradycardia / Rapid / Incidence not known
hyperkalemia / Delayed / Incidence not known
laryngospasm / Rapid / Incidence not known
serotonin syndrome / Delayed / Incidence not known

Moderate

constipation / Delayed / 3.0-3.0
erythema / Early / 3.0-3.0
elevated hepatic enzymes / Delayed / 0-1.0
dyskinesia / Delayed / Incidence not known
hypertension / Early / Incidence not known
QT prolongation / Rapid / Incidence not known
edema / Delayed / Incidence not known
hypotension / Rapid / Incidence not known
sinus tachycardia / Rapid / Incidence not known
amblyopia / Delayed / Incidence not known
euphoria / Early / Incidence not known
glycosuria / Early / Incidence not known
metabolic acidosis / Delayed / Incidence not known
hyperglycemia / Delayed / Incidence not known
hypokalemia / Delayed / Incidence not known
urinary retention / Early / Incidence not known
hyperbilirubinemia / Delayed / Incidence not known
hypoventilation / Rapid / Incidence not known
hot flashes / Early / Incidence not known
thrombocytopenia / Delayed / Incidence not known

Mild

headache / Early / 9.0-9.0
asthenia / Delayed / 8.0-8.0
fatigue / Early / 4.0-7.0
dyspepsia / Early / 4.0-4.0
paresthesias / Delayed / Incidence not known
dizziness / Early / Incidence not known
drowsiness / Early / Incidence not known
insomnia / Early / Incidence not known
flatulence / Early / Incidence not known
anorexia / Delayed / Incidence not known
hiccups / Early / Incidence not known
abdominal pain / Early / Incidence not known
hypersalivation / Early / Incidence not known
diarrhea / Early / Incidence not known
xerostomia / Early / Incidence not known
rash / Early / Incidence not known
pruritus / Rapid / Incidence not known
tinnitus / Delayed / Incidence not known
ocular irritation / Rapid / Incidence not known
arthralgia / Delayed / Incidence not known
anxiety / Delayed / Incidence not known
weakness / Early / Incidence not known
fever / Early / Incidence not known
chills / Rapid / Incidence not known

Akynzeo

Rx

Combination of a selective substance P neurokinin 1 (NK1) receptor antagonist and highly selective 5-HT3 receptor antagonist
Used with dexamethasone for prevention of CINV due to chemotherapy, including, but not limited to, highly emetogenic chemotherapy
Palonosetron prevents nausea and vomiting during the acute phase and netupitant/fosnetupitant prevents nausea and vomiting during both the acute and delayed phase after chemotherapy

For acute and delayed chemotherapy-induced nausea/vomiting prophylaxis (CINV prophylaxis) associated with initial and repeat courses of cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. For patients receiving highly emetogenic chemotherapy, including cisplatin-based chemotherapy. Oral dosage Adults

1 capsule (300 mg netupitant/0.5 mg palonosetron) PO as a single dose approximately 60 minutes prior to chemotherapy. The FDA-approved regimen is in combination with dexamethasone (12 mg PO 30 minutes prior to chemotherapy on day 1, then 8 mg PO once daily on days 2, 3, and 4).

Intravenous dosage Adults

1 vial (235 mg fosnetupitant/ 0.25 mg palonosetron) IV over 30 minutes, as a single dose approximately 30 minutes prior to chemotherapy. The FDA-approved regimen is in combination with dexamethasone (12 mg IV 30 minutes prior to chemotherapy on day 1, then 8 mg IV once daily on days 2, 3, and 4).

For patients receiving anthracycline- and cyclophoshamide-based chemotherapy and chemotherapy not considered highly emetogenic. Oral dosage Adults

1 capsule (300 mg netupitant/0.5 mg palonosetron) PO as a single dose approximately 60 minutes before chemotherapy. The FDA-approved regimen includes dexamethasone (12 mg PO 30 minutes before chemotherapy on day 1 only).

Hepatic Impairment

Mild hepatic impairment (Child-Pugh score 5 to 6): No adjustment needed.
Moderate hepatic impairment (Child-Pugh score 7 to 9 ): No adjustment needed.
Severe hepatic impairment (Child-Pugh score greater than 9): Limited data are available; avoid use in these patients.

Renal Impairment

CrCl 30 mL/min and greater: No dosage adjustment needed.
CrCl 30 mL/min and less: Avoid use of netupitant, fosnetupitant; palonosetron in patients with severe renal impairment or end-stage renal disease. The pharmacokinetics and safety of netupitant have not been studied in patients with severe renal impairment. Severe renal impairment does not substantially affect palonosetron.
 
Intermittent hemodialysis
Avoid use. Dialysis studies have not been performed; however, due to the large volume of distribution it is unlikely that netupitant, fosnetupitant; palonosetron clearance is affected by hemodialysis.
 
Continuous hemodialysis (CAVHD, CVVHD)
Avoid use. Dialysis studies have not been performed; however, due to the large volume of distribution it is unlikely that netupitant, fosnetupitant; palonosetron clearance is affected by continuous hemodialysis.

Abemaciclib: (Moderate) Monitor for an increase in abemaciclib-related adverse reactions if coadministration with netupitant is necessary; consider reducing the dose of abemaciclib in 50-mg decrements if toxicities occur. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. Abemaciclib is a CYP3A4 substrate and netupitant is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors is predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 1.6- to 2.4-fold.
Acalabrutinib: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with netupitant. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with netupitant may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of netupitant could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If netupitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Netupitant is a moderate inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with netupitant may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of netupitant could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If netupitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Netupitant is a moderate inhibitor of CYP3A4.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of netupitant is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like netupitant can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If netupitant is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of netupitant is necessary. If netupitant is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a moderate inhibitor like netupitant can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If netupitant is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Adagrasib: (Moderate) Monitor for an increase in netupitant-related adverse reactions if coadministration with adagrasib is necessary. Netupitant is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased netupitant exposure by 140%; however, no dosage adjustment is necessary.
Alfentanil: (Moderate) If concomitant use of alfentanil and palonosetron is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Alosetron: (Major) Theoretically, the coadministration of two potent and selective 5HT-3 antagonists, such as palonosetron and alosetron could lead to severe constipation. Constipation, reported individually with alosetron in roughly 25% of patients, could be worsened by the administration of palonosetron, which has a constipation rate of roughly 5% as well as a long half-life. Patients who are debilitated, elderly or taking medications that decrease GI motility may be at greater risk for constipation. Ischemic colitis has been reported in patients receiving alosetron during clinical trials and post-marketing. If a decision is made to co-prescribe palonosetron and alosetron, the patient should be informed of the potential for worsening constipation and should contact their health care provider immediately. If severe constipation or ischemic colitis develops while taking these two drugs, the alosetron should be discontinued immediately and not re-started.
Alprazolam: (Major) Avoid coadministration of alprazolam and netupitant (or fosnetupitant) due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with netupitant, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and netupitant is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors increased alprazolam exposure by 1.6- to 1.98-fold.
Amlodipine: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as netupitant, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine; valsartan may be required.
Amlodipine; Atorvastatin: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as netupitant, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine; valsartan may be required.
Amlodipine; Benazepril: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as netupitant, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine; valsartan may be required.
Amlodipine; Celecoxib: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as netupitant, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine; valsartan may be required.
Amlodipine; Olmesartan: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as netupitant, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine; valsartan may be required.
Amlodipine; Valsartan: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as netupitant, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine; valsartan may be required.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as netupitant, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine; valsartan may be required.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4; the inhibitory effect on CYP3A4 can last for multiple days. Clarithromycin is partially metabolized by CYP3A4, and increased concentrations may lead to an increased risk for side effects, including QT prolongation. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor such as clarithromycin can significantly increase the systemic exposure to netupitant. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron. Co-administration of single dose netupitant 600 mg and palonosetron 1.5 mg had no significant effects on the QTc interval.
Aprepitant, Fosaprepitant: (Major) Netupitant; palonosetron and aprepitant, fosaprepitant should not be used together, as they are a duplication of therapy. Additionally, netupitant is a moderate CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate; the manufacturer of aprepitant recommends avoiding administration with moderate CYP3A4 inhibitors due to substantially increased aprepitant exposure. Coadministration of daily oral aprepitant (230 mg, or 1.8 times the recommended single dose) with a moderate CYP3A4 inhibitor, diltiazem, increased the aprepitant AUC 2-fold with a concomitant 1.7-fold increase in the diltiazem AUC; clinically meaningful changes in ECG, heart rate, or blood pressure beyond those induced by diltiazem alone did not occur. Netupitant and palonosetron are also both CYP3A4 substrates. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer; substitution of fosaprepitant 115 mg IV on day 1 of the 3-day regimen may lessen the inhibitory effects of CYP3A4. The AUC of a single dose of another CYP3A4 substrate, midazolam, increased by 2.3-fold and 3.3-fold on days 1 and 5, respectively, when coadministered with a 5-day oral aprepitant regimen. After a 3-day oral aprepitant regimen, the AUC of midazolam increased by 25% on day 4, and decreased by 19% and 4% on days 8 and 15, respectively, when given on days 1, 4, 8, and 15. As a single 40-mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.2-fold; the midazolam AUC increased by 1.5-fold after a single 125-mg dose of oral aprepitant. After single doses of IV fosaprepitant, the midazolam AUC increased by 1.8-fold (150 mg) and 1.6-fold (100 mg); less than a 2-fold increase in the midazolam AUC is not considered clinically important. (Minor) Aprepitant, fosaprepitant is indicated for the prophylaxis of chemotherapy-induced nausea/vomiting in combination with a 5HT3 antagonist, one of which is palonosetron. Palonosetron is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and theoretically could increase plasma concentrations of palonosetron. The AUC of another CYP3A4 substrate, midazolam, was increased for several days after aprepitant dosing when the two drugs were coadministered; however, in clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or dolasetron. The effects of aprepitant on palonosetron pharmacokinetics has not been evaluated. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction.
Aripiprazole: (Moderate) Monitor for aripiprazole-related adverse reactions during concomitant use of netupitant. Patients receiving both a CYP2D6 inhibitor plus netupitant may require an aripiprazole dosage adjustment. Dosing recommendations vary based on aripiprazole dosage form, CYP2D6 inhibitor strength, and CYP2D6 metabolizer status. See prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is a CYP3A and CYP2D6 substrate; netupitant is a moderate CYP3A inhibitor.
Artemether; Lumefantrine: (Major) Artemether; lumefantrine should be used with caution with netupitant; palonosetron. Lumefantrine is an inhibitor of CYP2D6, and palonosetron is a substrate of the CYP2D6 isoenzyme. Coadministration may lead to increased palonosetron concentrations and serotonin-related side effects.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with netupitant may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of netupitant could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If netupitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Netupitant is a moderate inhibitor of CYP3A4.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of netupitant is necessary. If netupitant is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a moderate inhibitor like netupitant can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If netupitant is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Atazanavir: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4 since the plasma concentrations of the primary substrate can increase; the inhibitory effect on CYP3A4 can last for multiple days. Atazanavir is partially metabolized by CYP3A4. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor can significantly increase the systemic exposure to netupitant. Atazanavir is a strong CYP3A4 inhibitor. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron. (Moderate) The plasma concentrations of palonosetron may be elevated when administered concurrently with atazanavir. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Atazanavir is a CYP3A4 inhibitor; palonosetron is a substrate of CYP3A4.
Atazanavir; Cobicistat: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4 since the plasma concentrations of the primary substrate can increase; the inhibitory effect on CYP3A4 can last for multiple days. Atazanavir is partially metabolized by CYP3A4. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor can significantly increase the systemic exposure to netupitant. Atazanavir is a strong CYP3A4 inhibitor. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron. (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as cobicistat. The plasma concentrations of cobicistat can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days. In addition, netupitant is mainly metabolized by CYP3A4. Cobicistat has been shown to be a strong CYP3A4 inhibitor, and may increase netupitant exposure. Coadministration with another strong CYP3A4 inhibitor increased netupitant exposure by 140%. No dosage adjustment is necessary. (Moderate) The plasma concentrations of palonosetron may be elevated when administered concurrently with atazanavir. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Atazanavir is a CYP3A4 inhibitor; palonosetron is a substrate of CYP3A4. (Moderate) The plasma concentrations of palonosetron may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Cobicistat is an inhibitor of CYP3A4 and CYP2D6; palonosetron is a substrate of both CYP3A4 and CYP2D6.
Avapritinib: (Major) Avoid coadministration of avapritinib with netupitant due to the risk of increased avapritinib-related adverse reactions. If concurrent use is unavoidable, reduce the starting dose of avapritinib from 300 mg PO once daily to 100 mg PO once daily in patients with gastrointestinal stromal tumor or from 200 mg PO once daily to 50 mg PO once daily in patients with advanced systemic mastocytosis. Avapritinib is a CYP3A4 substrate and netupitant is a moderate CYP3A4 inhibitor. Coadministration of avapritinib 300 mg PO once daily with a moderate CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 210% at steady-state.
Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with netupitant may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of netupitant in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If netupitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4. Netupitant is an inhibitor of CYP3A4.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as methylene blue. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Bortezomib: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as bortezomib. The plasma concentrations of bortezomib can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
Bosutinib: (Major) Avoid concomitant use of bosutinib and netupitant; palonosetron; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and netupitant is a moderate CYP3A4 inhibitor. In a cross-over trial in 18 healthy volunteers, the Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
Brigatinib: (Major) Avoid coadministration of brigatinib with netupitant if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 40% without breaking tablets (i.e., from 180 mg to 120 mg; from 120 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of netupitant, resume the brigatinib dose that was tolerated prior to initiation of netupitant. Brigatinib is a CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase the AUC of brigatinib by approximately 40%.
Bromocriptine: (Major) When bromocriptine is used for diabetes, do not exceed a dose of 1.6 mg once daily during concomitant use of netupitant; palonosetron. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; netupitant is a moderate inhibitor of CYP3A4. Administration of bromocriptine with a moderate inhibitor of CYP3A4 increased the bromocriptine mean AUC and Cmax by 3.7-fold and 4.6-fold, respectively.
Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and netupitant may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; inhibition of CYP3A4 by netupitant can last for multiple days after a single dose.
Buprenorphine: (Moderate) If concomitant use of buprenorphine and palonosetron is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as buprenorphine. The plasma concentrations of buprenorphine can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
Buprenorphine; Naloxone: (Moderate) If concomitant use of buprenorphine and palonosetron is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as buprenorphine. The plasma concentrations of buprenorphine can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with netupitant may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of netupitant could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If netupitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Netupitant is a moderate inhibitor of CYP3A4.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Concomitant use of codeine with netupitant may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of netupitant could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If netupitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Netupitant is a moderate inhibitor of CYP3A4.
Carbamazepine: (Major) Netupitant is mainly metabolized by CYP3A4. Avoid coadministration of netupitant in patients who are chronically using a strong CYP3A4 inducer, such as carbamazepine. A strong CYP3A inducer can decrease the efficacy of netupitant by substantially reducing plasma concentrations of netupitant. In addition, netupitant is a moderate inhibitor of CYP3A4 and the plasma concentrations of medications that are primarily metabolized through CYP3A4, such as carbamazepine, can increase with coadministration; the inhibitory effect on CYP3A4 can last for multiple days.
Celecoxib; Tramadol: (Moderate) If concomitant use of tramadol and palonosetron is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Ceritinib: (Moderate) Monitor for netupitant-related adverse reactions if coadministration with ceritinib is necessary; however, a dosage adjustment is not necessary. Ceritinib is a strong CYP3A4 inhibitor and netupitant is primarily metabolized by CYP3A4. Coadministration with another strong CYP3A4 inhibitor increased the mean Cmax and AUC of netupitant by 25% and 140%, respectively.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with netupitant may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of netupitant could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If netupitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Netupitant is a moderate inhibitor of CYP3A4.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with netupitant may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of netupitant could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If netupitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Netupitant is a moderate inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of netupitant is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like netupitant can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If netupitant is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Citalopram: (Major) Because of the potential risk and severity of serotonin syndrome, use caution and monitor closely when administering palonosetron with other drugs that have serotonergic properties, such as citalopram. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Clarithromycin: (Major) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4; the inhibitory effect on CYP3A4 can last for multiple days. Clarithromycin is partially metabolized by CYP3A4, and increased concentrations may lead to an increased risk for side effects, including QT prolongation. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor such as clarithromycin can significantly increase the systemic exposure to netupitant. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron. Co-administration of single dose netupitant 600 mg and palonosetron 1.5 mg had no significant effects on the QTc interval.
Clomipramine: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as clomipramine. The plasma concentrations of clomipramine can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
Cobicistat: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as cobicistat. The plasma concentrations of cobicistat can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days. In addition, netupitant is mainly metabolized by CYP3A4. Cobicistat has been shown to be a strong CYP3A4 inhibitor, and may increase netupitant exposure. Coadministration with another strong CYP3A4 inhibitor increased netupitant exposure by 140%. No dosage adjustment is necessary. (Moderate) The plasma concentrations of palonosetron may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Cobicistat is an inhibitor of CYP3A4 and CYP2D6; palonosetron is a substrate of both CYP3A4 and CYP2D6.
Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with chronic netupitant; palonosetron therapy due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of netupitant; palonosetron is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of netupitant; palonosetron, resume cobimetinib at the previous dose. Use an alternative to netupitant; palonosetron in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a CYP3A substrate in vitro, and netupitant is a moderate inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Codeine: (Moderate) Concomitant use of codeine with netupitant may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of netupitant could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If netupitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Netupitant is a moderate inhibitor of CYP3A4.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with netupitant may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of netupitant could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If netupitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Netupitant is a moderate inhibitor of CYP3A4.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with netupitant may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of netupitant could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If netupitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Netupitant is a moderate inhibitor of CYP3A4.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with netupitant may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of netupitant could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If netupitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Netupitant is a moderate inhibitor of CYP3A4.
Codeine; Promethazine: (Moderate) Concomitant use of codeine with netupitant may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of netupitant could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If netupitant is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Netupitant is a moderate inhibitor of CYP3A4.
Colchicine: (Major) Avoid concomitant use of colchicine and netupitant due to the risk for increased colchicine exposure which may increase the risk for adverse effects. If concomitant use is necessary, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce a dose of 0.6 mg twice daily to 0.3 mg twice daily or 0.6 mg once daily; reduce a dose of 0.6 mg once daily to 0.3 mg once daily. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 1.2 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 1.2 mg. Colchicine is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors increased colchicine overall exposure by 1.4- to 1.9-fold.
Crizotinib: (Moderate) Monitor for an increase in crizotinib-related adverse reactions if coadministration with netupitant is necessary. Crizotinib is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor.
Dabrafenib: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and the plasma concentrations of medications that are primarily metabolized through CYP3A4, such as dabrafenib, can increase with coadministration. The inhibitory effect on CYP3A4 can last for multiple days. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant in patients who are chronically using a strong CYP3A4 inducer should be avoided since a strong CYP3A inducer can decrease the efficacy of netupitant by substantially reducing plasma concentrations of netupitant. Dabrafenib is a CYP3A4 inducer. If coadministration is necessary, no dosage adjustment is necessary for single dose administration of netupitant; palonosetron.
Daclatasvir: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with netupitant; palonosetron, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. If these drugs are administered together, monitor patients for daclatasvir-related adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
Daridorexant: (Major) Limit the daridorexant dose to 25 mg if coadministered with netupitant. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor. Concomitant use of another moderate CYP3A inhibitor increased daridorexant overall exposure 2.4-fold.
Darunavir: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4 since the plasma concentrations of the primary substrate can increase; the inhibitory effect on CYP3A4 can last for multiple days. Darunavir is partially metabolized by CYP3A4. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor can significantly increase the systemic exposure to netupitant. Darunavir is a strong CYP3A4 inhibitor. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron. (Moderate) The plasma concentrations of palonosetron may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Darunavir is an inhibitor of CYP3A4 and CYP2D6; palonosetron is a substrate of both CYP3A4 and CYP2D6.
Darunavir; Cobicistat: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4 since the plasma concentrations of the primary substrate can increase; the inhibitory effect on CYP3A4 can last for multiple days. Darunavir is partially metabolized by CYP3A4. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor can significantly increase the systemic exposure to netupitant. Darunavir is a strong CYP3A4 inhibitor. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron. (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as cobicistat. The plasma concentrations of cobicistat can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days. In addition, netupitant is mainly metabolized by CYP3A4. Cobicistat has been shown to be a strong CYP3A4 inhibitor, and may increase netupitant exposure. Coadministration with another strong CYP3A4 inhibitor increased netupitant exposure by 140%. No dosage adjustment is necessary. (Moderate) The plasma concentrations of palonosetron may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Cobicistat is an inhibitor of CYP3A4 and CYP2D6; palonosetron is a substrate of both CYP3A4 and CYP2D6. (Moderate) The plasma concentrations of palonosetron may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Darunavir is an inhibitor of CYP3A4 and CYP2D6; palonosetron is a substrate of both CYP3A4 and CYP2D6.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4 since the plasma concentrations of the primary substrate can increase; the inhibitory effect on CYP3A4 can last for multiple days. Darunavir is partially metabolized by CYP3A4. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor can significantly increase the systemic exposure to netupitant. Darunavir is a strong CYP3A4 inhibitor. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron. (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as cobicistat. The plasma concentrations of cobicistat can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days. In addition, netupitant is mainly metabolized by CYP3A4. Cobicistat has been shown to be a strong CYP3A4 inhibitor, and may increase netupitant exposure. Coadministration with another strong CYP3A4 inhibitor increased netupitant exposure by 140%. No dosage adjustment is necessary. (Moderate) The plasma concentrations of palonosetron may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Cobicistat is an inhibitor of CYP3A4 and CYP2D6; palonosetron is a substrate of both CYP3A4 and CYP2D6. (Moderate) The plasma concentrations of palonosetron may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Darunavir is an inhibitor of CYP3A4 and CYP2D6; palonosetron is a substrate of both CYP3A4 and CYP2D6.
Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with netupitant; palonosetron. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; netupitant is a moderate inhibitor of CYP3A4. Administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold.
Delavirdine: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4 since the plasma concentrations of the primary substrate can increase; the inhibitory effect on CYP3A4 can last for multiple days. Delavirdine is partially metabolized by CYP3A4. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor can significantly increase the systemic exposure to netupitant. Delavirdine is a strong CYP3A4 inhibitor. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron.
Desvenlafaxine: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as desvenlafaxine. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Although clinical studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 inhibition at doses of 100 mg/day, the manufacturer recommends the dose reduction of CYP2D6 substrates, such as palonosetron,by up to one-half if co-administered with desvenlafaxine 400 mg/day.
Dexamethasone: (Minor) When dexamethasone is used with netupitant; palonosetron, follow the approved dexamethasone dosage reduction: 12 mg on day 1 followed by 8 mg per day on days 2 to 4, if needed based on the emetogenic potential of the chemotherapy regimen. Dexamethasone is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor. Concomitant use of dexamethasone and netupitant increases the systemic exposure of dexamethasone by more than 2-fold.
Dextromethorphan; Quinidine: (Moderate) Coadminister with caution. Palonosetron is metabolized by CYP2D6, and quinidine is an inhibitor of this isoenzyme. Coadministration may result in elevated plasma concentrations of palonosetron, causing ain increased risk for serotonin-related adverse events.
Dichlorphenamide: (Moderate) Use dichlorphenamide and palonosetron together with caution as both drugs can cause metabolic acidosis. Concurrent use may increase the severity of metabolic acidosis. Measure sodium bicarbonate concentrations at baseline and periodically during dichlorphenamide treatment. If metabolic acidosis occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
Disulfiram: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as disulfiram. The plasma concentrations of disulfiram can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
Docetaxel: (Major) Netupitant; palonosetron is indicated for the prophylaxis of chemotherapy-induced nausea/vomiting; however, docetaxel-related adverse events may be increased. Netupitant is a moderate CYP3A4 inhibitor and docetaxel is a CYP3A4 substrate; the inhibitory effect of netupitant on CYP3A4 can last for multiple days. When coadministered with netupitant, palonosetron, the mean Cmax and AUC of docetaxel were increased by 49% and 35%, respectively, compared to when coadministered with palonosetron alone. The mean AUC of palonosetron was approximately 65% higher when netupitant; palonosetron was coadministered with docetaxel than with etoposide or cyclophosphamide, while the AUC of netupitant was similar among groups.
Donepezil: (Moderate) Use caution in administering donepezil with netupitant; palonosetron. Coadministration of donepezil with CYP3A4 inhibitors, such as netupitant, may increase donepezil concentrations, potentially resulting in dose-related toxicity. However, the clinical effect of such an interaction on the response to donepezil has not been determined.
Donepezil; Memantine: (Moderate) Use caution in administering donepezil with netupitant; palonosetron. Coadministration of donepezil with CYP3A4 inhibitors, such as netupitant, may increase donepezil concentrations, potentially resulting in dose-related toxicity. However, the clinical effect of such an interaction on the response to donepezil has not been determined.
Dronabinol: (Major) Use caution if coadministration of dronabinol with netupitant; palonosetron is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; netupitant is a moderate inhibitor of CYP3A4. Concomitant use may result in elevated plasma concentrations of dronabinol.
Dronedarone: (Moderate) Coadminister dronedarone and palonosetron together with caution. Dronedarone is an inhibitor of CYP2D6 and CYP3A4. Palonsetron is a substrate for CYP2D6 and CYP3A4. Coadministration of dronedarone and palonosetron may result in elevated plasma concentrations of palonsetron. (Moderate) Concomitant use of dronedarone and netupitant; palonosetron should be approached with caution due to a possible risk of QT prolongation and torsade de pointes (TdP) from dronedarone. Dronedarone is an inhibitor of CYP2D6 and CYP3A4, and a primary substrate for CYP3A4. Palonosetron is metabolized by CYP3A4. Netupitant is a substrate and moderate inhibitor of CYP3A4. Coadministration of dronedarone and netupitant; palonosetron may result in elevated plasma concentrations of palonsetron, netupitant, or dronedarone. Dronedarone is associated with dose-related increases in the QTc interval. Co-administration of single dose netupitant 600 mg and palonosetron 1.5 mg had no significant effects on the QTc interval.
Duloxetine: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as duloxetine. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Duvelisib: (Moderate) Monitor for increased toxicity of duvelisib if coadministered with netupitant. Coadministration may increase the exposure of duvelisib. Duvelisib is a CYP3A substrate; netupitant is a moderate CYP3A inhibitor.
Elacestrant: (Major) Avoid concomitant use of elacestrant and netupitant due to the risk of increased elacestrant exposure which may increase the risk for adverse effects. Elacestrant is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased elacestrant overall exposure by 2.3-fold.
Elbasvir; Grazoprevir: (Moderate) Administering elbasvir; grazoprevir with netupitant; palonosetron may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Netupitant; palonosetron is a substrate and moderate inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity. (Moderate) Administering palonosetron with elbasvir; grazoprevir may result in elevated palonosetron plasma concentrations. Palonosetron is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Eletriptan: (Moderate) Monitor for increased eletriptan-related adverse effects if coadministered with netupitant. Systemic concentrations of eletriptan may be increased. Additive serotonergic-related side effects might also occur. Eletriptan is a substrate for CYP3A4, and netupitant is a moderate CYP3A4 inhibitor. Coadministration of other moderate CYP3A4 inhibitors increased the eletriptan AUC by 2 to 4-fold.
Elexacaftor; tezacaftor; ivacaftor: (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with netupitant; palonosetron; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); netupitant is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure 3-fold. Simulation suggests a moderate inhibitor may increase tezacaftor exposure 2-fold. (Major) If netupitant and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold. (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor to every other day in the morning when coadministered with netupitant; omit the ivacaftor evening dose and administer in the morning every other day alternating with elexacaftor; tezacaftor; ivacaftor (i.e., recommended dose of elexacaftor; tezacaftor; ivacaftor on day 1 in the morning and recommended dose of ivacaftor on day 2 in the morning). Coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. Elexacaftor, tezacaftor, and ivacaftor are CYP3A substrates; netupitant is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure by 2.9-fold. Simulation suggests a moderate inhibitor may increase elexacaftor and tezacaftor exposure by 2.3-fold and 2.1-fold, respectively.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as cobicistat. The plasma concentrations of cobicistat can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days. In addition, netupitant is mainly metabolized by CYP3A4. Cobicistat has been shown to be a strong CYP3A4 inhibitor, and may increase netupitant exposure. Coadministration with another strong CYP3A4 inhibitor increased netupitant exposure by 140%. No dosage adjustment is necessary. (Moderate) The plasma concentrations of palonosetron may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Cobicistat is an inhibitor of CYP3A4 and CYP2D6; palonosetron is a substrate of both CYP3A4 and CYP2D6.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as cobicistat. The plasma concentrations of cobicistat can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days. In addition, netupitant is mainly metabolized by CYP3A4. Cobicistat has been shown to be a strong CYP3A4 inhibitor, and may increase netupitant exposure. Coadministration with another strong CYP3A4 inhibitor increased netupitant exposure by 140%. No dosage adjustment is necessary. (Moderate) The plasma concentrations of palonosetron may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Cobicistat is an inhibitor of CYP3A4 and CYP2D6; palonosetron is a substrate of both CYP3A4 and CYP2D6.
Encorafenib: (Major) Avoid coadministration of encorafenib and netupitant due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of netupitant. If netupitant is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of netupitant. Encorafenib is a CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
Entrectinib: (Major) Avoid coadministration of entrectinib with netupitant due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older

with BSA greater than 1.5 m2, reduce the entrectinib dose to 200 mg PO once daily. If netupitant is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of netupitant. Entrectinib is a CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
Enzalutamide: (Major) Avoid coadministration of netupitant with enzalutamide due to decreased plasma concentrations of netupitant. Netupitant is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased netupitant exposure by 82%.
Eplerenone: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Netupitant is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
Escitalopram: (Major) Because of the potential risk and severity of serotonin syndrome, use caution and monitor closely when administering palonosetron with other drugs that have serotonergic properties, such as escitalopram. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Ethosuximide: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as ethosuximide. The plasma concentrations of ethosuximide can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
Etonogestrel: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as netupitant may increase the serum concentration of etonogestrel.
Etonogestrel; Ethinyl Estradiol: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as netupitant may increase the serum concentration of etonogestrel.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with netupitant is necessary. The dose of everolimus may need to be reduced. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Netupitant is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4/P-gp inhibitors increased the AUC of everolimus by 3.5 to 4.4-fold.
Ezetimibe; Simvastatin: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as simvastatin. The plasma concentrations of simvastatin can increase when coadministered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of netupitant is necessary. If netupitant is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like netupitant can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If netupitant is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl. (Moderate) If concomitant use of fentanyl and palonosetron is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Finasteride; Tadalafil: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as tadalafil. The plasma concentrations of tadalafil can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or netupitant; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased overall exposure to finerenone by 248%.
Flibanserin: (Contraindicated) The concomitant use of flibanserin and moderate CYP3A4 inhibitors, such as netupitant; palonosetron, is contraindicated. Moderate CYP3A4 inhibitors can increase flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following use of a moderate CYP3A4 inhibitor, start flibanserin at least 2 weeks after the last dose of the CYP3A4 inhibitor. If initiating a moderate CYP3A4 inhibitor following flibanserin use, start the moderate CYP3A4 inhibitor at least 2 days after the last dose of flibanserin.
Fluconazole: (Moderate) Netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a CYP3A4 inhibitor, such as fluconazole, can increase the systemic exposure to netupitant. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron.
Fluoxetine: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as fluoxetine. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Fluticasone; Umeclidinium; Vilanterol: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as vilanterol. The plasma concentrations of vilanterol can increase when co-administered with netupitant, possibly increasing the risk of cardiovascular adverse effects. The inhibitory effect on CYP3A4 can last for multiple days.
Fluticasone; Vilanterol: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as vilanterol. The plasma concentrations of vilanterol can increase when co-administered with netupitant, possibly increasing the risk of cardiovascular adverse effects. The inhibitory effect on CYP3A4 can last for multiple days.
Fluvoxamine: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as fluvoxamine. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Fosamprenavir: (Moderate) Monitor for increased fosamprenavir toxicity if coadministered with netupitant. Concurrent use may increase the plasma concentrations of fosamprenavir. Fosamprenavir is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor.
Fosphenytoin: (Major) Netupitant is mainly metabolized by CYP3A4. Avoid coadministration of netupitant in patients who are chronically using a strong CYP3A4 inducer, such as fosphenytoin. A strong CYP3A inducer can decrease the efficacy of netupitant by substantially reducing plasma concentrations of netupitant. In addition, netupitant is a moderate inhibitor of CYP3A4 and the plasma concentrations of medications that are primarily metabolized through CYP3A4 can increase with coadministration; the inhibitory effect on CYP3A4 can last for multiple days. Fosphenytoin has been shown to be partially metabolized by CYP3A4. If coadministration is necessary, no dosage adjustment is necessary for single dose administration of netupitant; palonosetron.
Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of netupitant is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like netupitant can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If netupitant is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Guanfacine: (Major) Netupitant may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon netupitant; palonosetron discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and netupitant is a moderate CYP3A4 inhibitor. The inhibitory effect of netupitant can last for multiple days; monitor patients closely.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of netupitant is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like netupitant can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If netupitant is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of netupitant is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like netupitant can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If netupitant is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of netupitant is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like netupitant can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If netupitant is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of netupitant is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like netupitant can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If netupitant is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as methylene blue. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Ibrutinib: (Major) If ibrutinib is coadministered with netupitant, reduce the initial ibrutinib dosage to 280 mg/day PO in patients receiving ibrutinib for B-cell malignancy. Resume ibrutinib at the previous dosage if netupitant is discontinued. No initial ibrutinib dosage adjustment is necessary in patients receiving ibrutinib for chronic graft-versus-host disease. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); modify the ibrutinib dosage as recommended if toxicity occurs. Ibrutinib is a CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the AUC value of ibrutinib was increased by 3-fold.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of netupitant is necessary. If netupitant is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a moderate inhibitor like netupitant can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If netupitant is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Idelalisib: (Moderate) Netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor (e.g., idelalisib) can significantly increase the systemic exposure to netupitant. However, no dosage adjustment is necessary for single dose administration.
Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with netupitant is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Netupitant is a moderate CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
Imatinib: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as imatinib, STI-571. The plasma concentrations of CYP3A4 substrates can increase when co-administered with netupitant. The inhibitory effect on CYP3A4 can last for multiple days. If coadministration is necessary, use caution and monitor for chemotherapeutic related adverse reactions.
Indinavir: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4 since the plasma concentrations of the primary substrate can increase; the inhibitory effect on CYP3A4 can last for multiple days. Indinavir is partially metabolized by CYP3A4. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor can significantly increase the systemic exposure to netupitant. Indinavir is a strong CYP3A4 inhibitor. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron.
Infigratinib: (Major) Avoid concomitant use of infigratinib and netupitant. Coadministration may increase infigratinib exposure, increasing the risk of adverse effects. Infigratinib is a CYP3A4 substrate and netupitant is a moderate CYP3A4 inhibitor.
Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with netupitant; palonosetron may result in increased serum concentrations of all 3 drugs. Netupitant and palonosetron are substrates of the hepatic isoenzyme CYP3A4 while netupitant is also an inhibitor of CYP344; isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate and moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together. (Moderate) Concomitant use of isavuconazonium with palonosetron may result in increased serum concentrations of palonosetron. Palonosetron is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
Isocarboxazid: (Moderate) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as monoamine oxidase inhibitors (MAOIs). Serotonin syndrome has been described following the concomitant use of 5-HT3 receptor antagonists and other serotonergic drugs. Monitor for the emergence of serotonin syndrome. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Netupitant is mainly metabolized by CYP3A4. Avoid coadministration of netupitant in patients who are chronically using a strong CYP3A4 inducer, such as rifampin. A strong CYP3A inducer can decrease the efficacy of netupitant by substantially reducing plasma concentrations of netupitant. A Single dose of netupitant; palonosetron was administered with rifampicin, following once daily administration of 600 mg rifampicin for 17 days. Pharmacokinetics of netupitant and palonosetron were compared to that after administration of netupitant; palonosetron alone. Coadministration of rifampicin decreased the mean Cmax and AUC of netupitant by 62% and 82%, respectively, compared to those after netupitant; palonosetron alone. Coadministration of rifampicin decreased the mean Cmax and AUC for palonosetron by 15% and 19%, respectively.
Isoniazid, INH; Rifampin: (Major) Netupitant is mainly metabolized by CYP3A4. Avoid coadministration of netupitant in patients who are chronically using a strong CYP3A4 inducer, such as rifampin. A strong CYP3A inducer can decrease the efficacy of netupitant by substantially reducing plasma concentrations of netupitant. A Single dose of netupitant; palonosetron was administered with rifampicin, following once daily administration of 600 mg rifampicin for 17 days. Pharmacokinetics of netupitant and palonosetron were compared to that after administration of netupitant; palonosetron alone. Coadministration of rifampicin decreased the mean Cmax and AUC of netupitant by 62% and 82%, respectively, compared to those after netupitant; palonosetron alone. Coadministration of rifampicin decreased the mean Cmax and AUC for palonosetron by 15% and 19%, respectively.
Itraconazole: (Moderate) Monitor for increased netupitant and itraconazole adverse effects if coadminsitration is necessary. No dosage adjustment of netupitant is necessary for single dose administration of netupitant; palonosetron. Netupitant is a moderate CYP3A4 inhibitor and substrate; itraconazole is a strong CYP3A4 inhibitor and substrate.
Ivabradine: (Major) Avoid coadministration of ivabradine and netupitant; palonosetron as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; netupitant is a moderate CYP3A4 inhibitor. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
Ivacaftor: (Major) If netupitant and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with netupitant due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate and netupitant is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
Ixabepilone: (Moderate) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of netupitant is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor.
Ketoconazole: (Moderate) Monitor for an increase in netupitant-related adverse reactions if coadministration with ketoconazole is necessary. Netupitant is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased netupitant exposure by 140%; however, no dosage adjustment is necessary.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4; the inhibitory effect on CYP3A4 can last for multiple days. Clarithromycin is partially metabolized by CYP3A4, and increased concentrations may lead to an increased risk for side effects, including QT prolongation. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor such as clarithromycin can significantly increase the systemic exposure to netupitant. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron. Co-administration of single dose netupitant 600 mg and palonosetron 1.5 mg had no significant effects on the QTc interval.
Larotrectinib: (Moderate) Monitor for an increase in larotrectinib-related adverse reactions if concomitant use with netupitant is necessary. Concomitant use may increase larotrectinib exposure. Larotrectinib is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase larotrectinib exposure by 2.7-fold.
Lefamulin: (Moderate) Monitor for lefamulin-related adverse effects if oral lefamulin is administered with netupitant as concurrent use may increase exposure from lefamulin tablets; an interaction is not expected with intravenous lefamulin. Lefamulin is a CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor. The effect of moderate inhibitors on lefamulin has not been studied; however, use of a strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Lemborexant: (Major) Avoid coadministration of lemborexant and netupitant as concurrent use is expected to significantly increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor. Coadministration of lemborexant with another moderate CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold.
Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of netupitant; palonosetron; monitor for potential reduction in efficacy. Netupitant is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of netupitant; palonosetron; monitor for potential reduction in efficacy. Netupitant is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
Letermovir: (Moderate) An increase in the plasma concentration of netupitant may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. However, when these drugs are given together, no dosage adjustments are needed for a single dose of netupitant. Netupitant is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In a drug interaction study, administration with another strong CYP3A4 inhibitor increased the mean maximum plasma concentration and exposure of netupitant by 25% and 140%, respectively.
Levamlodipine: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as netupitant, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine; valsartan may be required.
Levoketoconazole: (Moderate) Monitor for an increase in netupitant-related adverse reactions if coadministration with ketoconazole is necessary. Netupitant is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased netupitant exposure by 140%; however, no dosage adjustment is necessary.
Levomilnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as levomilnacipran. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, discontinue palonosetron and levomilnacipran and initiate appropriate medical treatment.
Lidocaine: (Moderate) Concomitant use of systemic lidocaine and netupitant may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; inhibition of CYP3A4 by netupitant can last for multiple days after a single dose.
Lidocaine; Epinephrine: (Moderate) Concomitant use of systemic lidocaine and netupitant may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; inhibition of CYP3A4 by netupitant can last for multiple days after a single dose.
Lidocaine; Prilocaine: (Moderate) Concomitant use of systemic lidocaine and netupitant may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; inhibition of CYP3A4 by netupitant can last for multiple days after a single dose.
Linezolid: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as linezolid. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Lithium: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as lithium. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and netupitant is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; netupitant is a CYP3A4 substrate and moderate CYP3A4 inhibitor.
Lopinavir; Ritonavir: (Moderate) Coadministration may result in increased netupitant and ritonavir exposure. Netupitant is a CYP3A4 substrate and moderate inhibitor of CYP3A4; the inhibitory effect on CYP3A4 can last for multiple days. Ritonavir is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased netupitant exposure by 140%. No dosage adjustment is necessary. (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are metabolized through CYP3A4 such as lopinavir; the inhibitory effect on CYP3A4 can last for multiple days. Increased lopinavir concentrations may occur and may lead to side effects, including a possible risk for QT prolongation.
Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of netupitant; palonosetron in patients who are taking ivacaftor; lumacaftor. Lumacaftor; ivacaftor may reduce the antiemetic efficacy of netupitant; palonosetron by significantly decreasing the systemic exposure of netupitant. Netupitant is extensively metabolized primarily by CYP3A4, and lumacaftor is a strong CYP3A inducer. Palonosetron is also partially metabolized via CYP3A4, although in vitro studies suggest this is not its primary metabolic pathway. In addition, netupitant is a moderate inhibitor of CYP3A. Because ivacaftor is primarily metabolized by CYP3A, systemic exposure could theoretically increase when given with a CYP3A inhibitor; however, intermittent single-dose use of netupitant; palonosetron and the CYP3A induction effects of lumacaftor on ivacaftor make the clinical relevance of this interaction unlikely. Lumacaftor; ivacaftor dosage adjustments are not recommended with concomitant use of a moderate CYP3A inhibitor such as netupitant.
Lumacaftor; Ivacaftor: (Major) If netupitant and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Lumateperone: (Major) Reduce the dose of lumateperone to 21 mg once daily if concomitant use of netupitant is necessary. Concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased lumateperone exposure by approximately 2-fold.
Lurasidone: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as lurasidone. The plasma concentrations of lurasidone can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and netupitant due to the risk of increased lurbinectedin exposure which may increase the incidence of lurbinectedin-related adverse reactions. If concomitant use is unavoidable, consider reducing the dose of lurbinectedin if clinically indicated. Lurbinectedin is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor.
Maraviroc: (Moderate) Use caution if coadministration of maraviroc with netupitant is necessary, due to a possible increase in maraviroc exposure. Maraviroc is a CYP3A substrate and netupitant is a CYP3A4 inhibitor; the inhibitory effect on CYP3A4 can last for multiple days. Monitor for an increase in adverse effects with concomitant use.
Mavacamten: (Major) Reduce the mavacamten dose by 1 level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients receiving mavacamten and starting netupitant therapy. Avoid initiation of netupitant in patients who are on stable treatment with mavacamten 2.5 mg per day because a lower dose of mavacamten is not available. Initiate mavacamten at the recommended starting dose of 5 mg PO once daily in patients who are on stable netupitant therapy. Concomitant use increases mavacamten exposure, which may increase the risk of adverse drug reactions. Mavacamten is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor. The impact that a CYP3A inhibitor may have on mavacamten overall exposure varies based on the patient's CYP2C19 metabolizer status. Concomitant use of a moderate CYP3A inhibitor increased mavacamten overall exposure by 15% in CYP2C19 normal and intermediate metabolizers; concomitant use in poor metabolizers is predicted to increase mavacamten exposure by up to 55%.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as methylene blue. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Methylene Blue: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as methylene blue. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Midazolam: (Major) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as midazolam. The plasma concentrations of CYP3A4 substrates can increase when co-administered with netupitant. The inhibitory effect on CYP3A4 can last for multiple days. When administered with netupitant, the systemic exposure to midazolam was significantly increased. Increased midazolam exposure may lead to increased sedation or respiratory depression. Monitor patients closely who receive concurrent therapy.
Milnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as milnacipran. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as palonosetron may be increased when co-administered with mirabegron. Palonosetron is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
Mirtazapine: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as mirtazapine. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Mitapivat: (Moderate) Do not exceed mitapivat 20 mg PO twice daily during coadministration with netupitant and monitor hemoglobin and for adverse reactions from mitapivat. Coadministration increases mitapivat concentrations. Mitapivat is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased mitapivat overall exposure by 2.6-fold.
Mitotane: (Major) Avoid the concomitant use of mitotane with netupitant; palonosetron; if coadministration cannot be avoided, monitor for decreased efficacy of netupitant; palonosetron. Mitotane is a strong CYP3A4 inducer. Palonosetron is metabolized via multiple CYP isoenzymes, including CYP3A4, however, netupitant is primarily metabolized via CYP3A4; coadministration may result in decreased plasma concentrations of netupitant. (Minor) Use caution if mitotane and palonosetron are used concomitantly, and monitor for decreased efficacy of palonosetron and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer. Palonosetron is metabolized via multiple CYP isoenzymes, including CYP3A4; coadministration may theoretically result in decreased plasma concentrations of palonosetron, however, the potential for clinically significant drug interactions appears to be low.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and netupitant; reduce the dose of mobocertinib by approximately 50% and monitor the QT interval more frequently if use is necessary. Concomitant use may increase mobocertinib exposure and the risk for adverse reactions. Mobocertinib is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor. Use of a moderate CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 100% to 200%.
Monoamine oxidase inhibitors: (Moderate) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as monoamine oxidase inhibitors (MAOIs). Serotonin syndrome has been described following the concomitant use of 5-HT3 receptor antagonists and other serotonergic drugs. Monitor for the emergence of serotonin syndrome. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment.
Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with netupitant. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor.
Naloxegol: (Major) Avoid concomitant administration of naloxegol and netupitant due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with netupitant is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and netupitant is a moderate CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
Nanoparticle Albumin-Bound Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 during concomitant use of netupitant. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor.
Nefazodone: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4 since the plasma concentrations of the primary substrate can increase; the inhibitory effect on CYP3A4 can last for multiple days. Nefazodone is partially metabolized by CYP3A4. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor such as nefazodone can significantly increase the systemic exposure to netupitant. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron.
Nelfinavir: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4 since the plasma concentrations of the primary substrate can increase; the inhibitory effect on CYP3A4 can last for multiple days. Nelfinavir is partially metabolized by CYP3A4 in-vitro. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor such as nelfinavir can significantly increase the systemic exposure to netupitant. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron.
Neratinib: (Major) Avoid concomitant use of netupitant with neratinib due to an increased risk of neratinib-related toxicity; if possible, allow a washout period of one week after the last dose of netupitant prior to beginning therapy with neratinib. Neratinib is a CYP3A4 substrate; netupitant significantly inhibits CYP3A4 for at least 4 days after a single dose. The effect of moderate CYP3A4 inhibition on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inhibitor increased neratinib exposure by 481%. Because of the significant impact on neratinib exposure from strong CYP3A4 inhibition, the potential impact on neratinib safety from concomitant use with moderate CYP3A4 inhibitors should be considered as they may also significantly increase neratinib exposure.
Niacin; Simvastatin: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as simvastatin. The plasma concentrations of simvastatin can increase when coadministered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
Nirmatrelvir; Ritonavir: (Moderate) Coadministration may result in increased netupitant and ritonavir exposure. Netupitant is a CYP3A4 substrate and moderate inhibitor of CYP3A4; the inhibitory effect on CYP3A4 can last for multiple days. Ritonavir is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased netupitant exposure by 140%. No dosage adjustment is necessary.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with netupitant due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and netupitant is a CYP3A4 inhibitor.
Olanzapine; Fluoxetine: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as fluoxetine. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Olaparib: (Major) Avoid coadministration of olaparib with netupitant due to the risk of increased olaparib-related adverse reactions. If concomitant use is unavoidable, reduce the dose of olaparib to 150 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after netupitant is discontinued. Olaparib is a CYP3A substrate and netupitant is a moderate CYP3A4 inhibitor; concomitant use may increase olaparib exposure. Coadministration with a moderate CYP3A inhibitor is predicted to increase the olaparib Cmax by 14% and the AUC by 121%.
Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and netupitant is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and netupitant may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If netupitant is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A4 substrate and netupitant is a moderate CYP3A4 inhibitor.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as netupitant, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine; valsartan may be required.
Omaveloxolone: (Major) Avoid concomitant use of omaveloxolone and netupitant. If concomitant use is necessary, decrease omaveloxolone dose to 100 mg once daily; additional dosage reductions may be necessary. Concomitant use may increase omaveloxolone exposure and the risk for omaveloxolone-related adverse effects. Omaveloxolone is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased omaveloxolone overall exposure by 1.25-fold.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of netupitant is necessary. If netupitant is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a moderate inhibitor like netupitant can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If netupitant is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Ozanimod: (Major) Coadministration of ozanimod with palonosetron is not recommended due to the potential for hypertensive crisis. If coadministration is necessary, closely monitor patients for hypertension. An active metabolite of ozanimod inhibits MAO-B, which may increase the potential for hypertensive crisis. Palonosetron may increase blood pressure by increasing serotonin concentrations.
Paclitaxel: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as paclitaxel. The plasma concentrations of CYP3A4 substrates can increase when co-administered with netupitant. The inhibitory effect on CYP3A4 can last for multiple days. If coadministration is necessary, use caution and monitor for chemotherapeutic related adverse reactions.
Pacritinib: (Major) Avoid concurrent use of pacritinib with netupitant due to the risk of increased pacritinib exposure which increases the risk of adverse reactions. Pacritinib is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor.
Palovarotene: (Major) Avoid concomitant use of palovarotene and netupitant due to the risk for increased palovarotene exposure which may increase the risk for adverse effects. If concomitant use is necessary, decrease the palovarotene dose by half. Palovarotene is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased palovarotene overall exposure by 2.5-fold.
Paroxetine: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as paroxetine. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects associated with increased exposure to palonosetron if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP2D6 inhibitor, while palonosetron is a CYP2D6 substrate.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and netupitant due to the risk of increased pemigatinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of pemigatinib to 9 mg PO once daily if original dose was 13.5 mg per day and to 4.5 mg PO once daily if original dose was 9 mg per day. If netupitant is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of netupitant. Pemigatinib is a CYP3A4 substrate and netupitant is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase pemigatinib exposure by approximately 50% to 80%.
Perindopril; Amlodipine: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as netupitant, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine; valsartan may be required.
Pexidartinib: (Major) Avoid concomitant use of pexidartinib and netupitant due to the risk of increased pexidartinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pexidartinib dosage as follows: 500 mg/day or 375 mg/day of pexidartinib, reduce to 125 mg twice daily; 250 mg/day of pexidartinib, reduce to 125 mg once daily. If netupitant is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of netupitant. Pexidartinib is a CYP3A substrate; netupitant is a moderate CYP3A inhibitor. Coadministration of another moderate CYP3A inhibitor increased pexidartinib overall exposure by 67%.
Phenelzine: (Moderate) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as monoamine oxidase inhibitors (MAOIs). Serotonin syndrome has been described following the concomitant use of 5-HT3 receptor antagonists and other serotonergic drugs. Monitor for the emergence of serotonin syndrome. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment.
Phenobarbital: (Major) Netupitant is mainly metabolized by CYP3A4. Avoid coadministration of netupitant in patients who are chronically using a strong CYP3A4 inducer, such as phenobarbital. A strong CYP3A inducer can decrease the efficacy of netupitant by substantially reducing plasma concentrations of netupitant.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Netupitant is mainly metabolized by CYP3A4. Avoid coadministration of netupitant in patients who are chronically using a strong CYP3A4 inducer, such as phenobarbital. A strong CYP3A inducer can decrease the efficacy of netupitant by substantially reducing plasma concentrations of netupitant.
Phenytoin: (Major) Netupitant is mainly metabolized by CYP3A4. Avoid coadministration of netupitant in patients who are chronically using a strong CYP3A4 inducer, such as phenytoin. A strong CYP3A inducer can decrease the efficacy of netupitant by substantially reducing plasma concentrations of netupitant. In addition, netupitant is a moderate inhibitor of CYP3A4 and the plasma concentrations of medications that are primarily metabolized through CYP3A4 can increase with coadministration; the inhibitory effect on CYP3A4 can last for multiple days. Phenytoin has been shown to be partially metabolized by CYP3A4. If coadministration is necessary, no dosage adjustment is necessary for single dose administration of netupitant; palonosetron.
Pimozide: (Major) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as pimozide. The plasma concentrations of pimozide can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days, and this might raise the risk for QT prolongation and other side effects from pimozide.
Posaconazole: (Moderate) The concurrent use of posaconazole and netupitant should be approached with caution. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme involved in the metabolism of netupitant. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor (e.g., posaconazole) can significantly increase the systemic exposure to netupitant. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron.
Pralsetinib: (Major) Avoid concomitant use of netupitant with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the daily dose of pralsetinib by 100 mg. Pralsetinib is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor is predicted to increase the overall exposure of pralsetinib by 71%.
Primidone: (Major) Netupitant is mainly metabolized by CYP3A4. Avoid coadministration of netupitant in patients who are chronically using a strong CYP3A4 inducer, such as primidone. A strong CYP3A inducer can decrease the efficacy of netupitant by substantially reducing plasma concentrations of netupitant.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and netupitant due to the risk for increased colchicine exposure which may increase the risk for adverse effects. If concomitant use is necessary, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce a dose of 0.6 mg twice daily to 0.3 mg twice daily or 0.6 mg once daily; reduce a dose of 0.6 mg once daily to 0.3 mg once daily. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 1.2 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 1.2 mg. Colchicine is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor. Concomitant use with other moderate CYP3A inhibitors increased colchicine overall exposure by 1.4- to 1.9-fold.
Quazepam: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as quazepam. The plasma concentrations of quazepam can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
Quinidine: (Moderate) Coadminister with caution. Palonosetron is metabolized by CYP2D6, and quinidine is an inhibitor of this isoenzyme. Coadministration may result in elevated plasma concentrations of palonosetron, causing ain increased risk for serotonin-related adverse events.
Ranolazine: (Major) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as ranolazine. The plasma concentrations of ranolazine can increase when co-administered with netupitant, which is a moderate CYP3A4 inhibitor; the inhibitory effect on CYP3A4 can last for multiple days. This might increase the risk for ranolazine-related side effects, such as QT prolongation. Ranolazine is a mild CYP3A4 inhibitor and a CYP2D6 inhbitior, but should not have significant effect on netupitant or palonosetron. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron. Co-administration of single dose netupitant 600 mg and palonosetron 1.5 mg had no significant effects on the QTc interval.
Ribociclib: (Moderate) Monitor for an increase in netupitant-related adverse reactions if coadministration with ribociclib is necessary. Netupitant is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased netupitant exposure by 140%; however, no dosage adjustment is necessary.
Ribociclib; Letrozole: (Moderate) Monitor for an increase in netupitant-related adverse reactions if coadministration with ribociclib is necessary. Netupitant is a CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased netupitant exposure by 140%; however, no dosage adjustment is necessary.
Rifampin: (Major) Netupitant is mainly metabolized by CYP3A4. Avoid coadministration of netupitant in patients who are chronically using a strong CYP3A4 inducer, such as rifampin. A strong CYP3A inducer can decrease the efficacy of netupitant by substantially reducing plasma concentrations of netupitant. A Single dose of netupitant; palonosetron was adm inistered with rifampicin, following once daily administration of 600 mg rifampicin for 17 days. Pharmacokinetics of netupitant and palonosetron were compared to that after administration of netupitant; palonosetron alone. Coadministration of rifampicin decreased the mean Cmax and AUC of netupitant by 62% and 82%, respectively, compared to those after netupitant; palonosetron alone. Coadministration of rifampicin decreased the mean Cmax and AUC for palonosetron by 15% and 19%, respectively.
Rifapentine: (Major) Avoid coadministration of netupitant with chronic use of rifapentine; concurrent use may decrease netupitant exposure and lead to reduced efficacy. Netupitant is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased netupitant exposure by 62%.
Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with netupitant; concurrent use may increase rimegepant exposure. Rimegepant is a CYP3A4 substrate and netupitant is a moderate CYP3A4 inhibitor.
Ritonavir: (Moderate) Coadministration may result in increased netupitant and ritonavir exposure. Netupitant is a CYP3A4 substrate and moderate inhibitor of CYP3A4; the inhibitory effect on CYP3A4 can last for multiple days. Ritonavir is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased netupitant exposure by 140%. No dosage adjustment is necessary.
Ruxolitinib: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as ruxolitinib. The plasma concentrations of ruxolitinib can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
Saquinavir: (Major) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are metabolized through CYP3A4 such as saquinavir since the plasma concentrations can increase; the inhibitory effect on CYP3A4 can last for multiple days. Increased saquinavir concentrations may lead to an increased risk for side effects, including possible QT prolongation. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor such as saquinavir can significantly increase the systemic exposure to netupitant. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron.
Segesterone Acetate; Ethinyl Estradiol: (Minor) Coadministration of segesterone, a CYP3A4 substrate and netupitant, a moderate CYP3A4 inhibitor may increase the serum concentration of segesterone.
Selpercatinib: (Major) Avoid coadministration of selpercatinib and netupitant due to the risk of increased selpercatinib exposure which may increase the risk of adverse reactions, including QT prolongation. If coadministration is unavoidable, reduce the dose of selpercatinib to 80 mg PO twice daily if original dose was 120 mg twice daily, and to 120 mg PO twice daily if original dose was 160 mg twice daily. Monitor ECGs for QT prolongation more frequently. If netupitant is discontinued, resume the original selpercatinib dose after 3 to 5 elimination half-lives of netupitant. Selpercatinib is a CYP3A4 substrate and netupitant is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors is predicted to increase selpercatinib exposure by 60% to 99%.
Selumetinib: (Major) Avoid coadministration of selumetinib and netupitant due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If netupitant is discontinued, resume the original selumetinib dose after 3 elimination half-lives of netupitant. Selumetinib is a CYP3A4 substrate and netupitant is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor is predicted to increase selumetinib exposure by 41%.
Sertraline: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as sertraline. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Sildenafil: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with netupitant; palonosetron is necessary; a dose reduction of sildenafil may be necessary when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and netupitant is a moderate CYP3A4 inhibitor.
Simvastatin: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as simvastatin. The plasma concentrations of simvastatin can increase when coadministered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
Siponimod: (Moderate) Concomitant use of siponimod and netupitant may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of netupitant. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sirolimus overall exposure 1.6-fold.
Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with netupitant. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Netupitant is a CYP3A4 inhibitor; velpatasvir is a substrate of CYP3A4.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution when administering velpatasvir with netupitant. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Netupitant is a CYP3A4 inhibitor; velpatasvir is a substrate of CYP3A4.
Sonidegib: (Major) Avoid the concomitant use of sonidegib and netupitant; palonosetron as sonidegib levels may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. If concomitant use cannot be avoided, administer netupitant; palonosetron for less than 14 days; monitor patients closely for adverse reactions (e.g., elevated serum creatine kinase and serum creatinine levels). Sonidegib is a CYP3A4 substrate and netupitant is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
Sparsentan: (Moderate) Monitor for an increase in sparsentan-related adverse effects if concomitant use with netupitant is necessary. Concomitant use may increase sparsentan exposure. Sparsentan is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor. Concomitant use with another moderate CYP3A inhibitor increased sparsentan overall exposure by 70%.
St. John's Wort, Hypericum perforatum: (Major) Netupitant is mainly metabolized by CYP3A4. Avoid coadministration of netupitant in patients who are chronically using a strong CYP3A4 inducer, such as St. John's Wort, Hypericum perforatum. A strong CYP3A inducer can decrease the efficacy of netupitant by substantially reducing plasma concentrations of netupitant; however, the amount of individual constituents in various products may alter the inducing effects, making drug interactions unpredictable.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if netupitant must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of netupitant is necessary. If netupitant is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a moderate CYP3A4 inhibitor like netupitant can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If netupitant is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Suvorexant: (Major) A dose reduction to 5 mg of suvorexant is recommended during concurrent use with netupitant; palonosetron. The suvorexant dose may be increased to 10 mg if needed for efficacy. Suvorexant is a CYP3A4 substrate and netupitant is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased the suvorexant AUC by 2-fold.
Tadalafil: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as tadalafil. The plasma concentrations of tadalafil can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with netupitant as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. If concomitant use is unavoidable, decrease current tazemetostat daily dosage by 50% (e.g., decrease 800 mg PO twice daily to 400 mg PO twice daily; 600 mg PO twice daily to 400 mg PO for first dose and 200 mg PO for second dose; 400 mg PO twice daily to 200 mg PO twice daily). If netupitant is discontinued, wait at least 3 half-lives of netupitant before increasing the dose of tazemetostat to the previous tolerated dose. Tazemetostat is a CYP3A4 substrate and netupitant is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased tazemetostat exposure by 3.1-fold.
Telmisartan; Amlodipine: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as netupitant, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine; valsartan may be required.
Tezacaftor; Ivacaftor: (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with netupitant; palonosetron; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet every other day in the morning and 1 ivacaftor tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); netupitant is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure 3-fold. Simulation suggests a moderate inhibitor may increase tezacaftor exposure 2-fold. (Major) If netupitant and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to once daily. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and netupitant is a moderate CYP3A inhibitor. Coadministration with another moderate CYP3A inhibitor increased ivacaftor exposure by 3-fold.
Tiagabine: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as tiagabine. The plasma concentrations of tiagabine can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
Ticagrelor: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as ticagrelor. The plasma concentrations of ticagrelor can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
Tipranavir: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4 since the plasma concentrations of the primary substrate can increase; the inhibitory effect on CYP3A4 can last for multiple days. Tipranavir is partially metabolized by CYP3A4. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor such as tipranavir can significantly increase the systemic exposure to netupitant. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron.
Tolvaptan: (Major) Avoid coadministration of netupitant when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with netupitant. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Interrupt tolvaptan in ADPKD patients if the recommended reduced doses are not available in patients requiring short-term therapy of netupitant. Tolvaptan is a sensitive CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
Tramadol: (Moderate) If concomitant use of tramadol and palonosetron is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Tramadol; Acetaminophen: (Moderate) If concomitant use of tramadol and palonosetron is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Tranylcypromine: (Moderate) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as monoamine oxidase inhibitors (MAOIs). Serotonin syndrome has been described following the concomitant use of 5-HT3 receptor antagonists and other serotonergic drugs. Monitor for the emergence of serotonin syndrome. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment.
Trazodone: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as trazodone. The plasma concentrations of trazodone can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with netupitant and consider appropriate dose reduction of triazolam if clinically indicated. Coadministration may increase triazolam exposure. Triazolam is a sensitive CYP3A substrate and netupitant is a moderate CYP3A inhibitor.
Tucatinib: (Moderate) Monitor for an increase in netupitant-related adverse reactions if coadministration with tucatinib is necessary. Netupitant is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased netupitant exposure by 140%; however, no dosage adjustment is necessary.
Ubrogepant: (Major) Limit the initial dose of ubrogepant to 50 mg and avoid a second dose within 24 hours if coadministered with netupitant. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor resulted in a 3.5-fold increase in the exposure of ubrogepant.
Umeclidinium; Vilanterol: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as vilanterol. The plasma concentrations of vilanterol can increase when co-administered with netupitant, possibly increasing the risk of cardiovascular adverse effects. The inhibitory effect on CYP3A4 can last for multiple days.
Vardenafil: (Major) Do not use vardenafil orally disintegrating tablets with netupitant due to increased vardenafil exposure; do not exceed a single dose of 5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; netupitant is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased the AUC of vardenafil by 4-fold.
Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with netupitant; palonosetron due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of netupitant; palonosetron. Venetoclax is a CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor.
Venlafaxine: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as venlafaxine. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Vilazodone: (Major) Because of the potential risk and severity of serotonin syndrome, use caution and monitor closely when administering palonosetron with other drugs that have serotonergic properties, such as vilazodone. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as vilazodone. The plasma concentrations of vilazodone can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days. The manufacturer of vilazodone recommends a reduction in vilazodone dose to 20 mg/day in patients receiving a moderate CYP3A4 inhibitor who are experiencing intolerable side effects. When the inhibitor is discontinued, resume the previous vilazodone dose.
Vinblastine: (Moderate) Monitor for an earlier onset and/or increased severity of vinblastine-related adverse reactions, including myelosuppression, constipation, and peripheral neuropathy, if coadministration with netupitant is necessary. Vinblastine is a CYP3A4 substrate and netupitant is a moderate CYP3A4 inhibitor. Enhanced vinblastine toxicity was reported with coadministration of another moderate CYP3A4 inhibitor.
Vincristine Liposomal: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as vincristine. The plasma concentrations of CYP3A4 substrates can increase when co-administered with netupitant. The inhibitory effect on CYP3A4 can last for multiple days. If coadministration is necessary, use caution and monitor for chemotherapeutic related adverse reactions.
Vincristine: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as vincristine. The plasma concentrations of CYP3A4 substrates can increase when co-administered with netupitant. The inhibitory effect on CYP3A4 can last for multiple days. If coadministration is necessary, use caution and monitor for chemotherapeutic related adverse reactions.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with netupitant is necessary. Vinorelbine is a CYP3A4 substrate and netupitant is a moderate CYP3A4 inhibitor.
Voclosporin: (Major) Reduce the voclosporin dosage to 15.8 mg PO in the morning and 7.9 mg PO in the evening if coadministered with netupitant. Concomitant use may increase voclosporin exposure and the risk of voclosporin-related adverse effects such as nephrotoxicity, hypertension, and QT prolongation. Voclosporin is a sensitive CYP3A4 substrate and netupitant is a moderate CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors is predicted to increase voclosporin exposure by 3-fold.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4; the inhibitory effect on CYP3A4 can last for multiple days. Clarithromycin is partially metabolized by CYP3A4, and increased concentrations may lead to an increased risk for side effects, including QT prolongation. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor such as clarithromycin can significantly increase the systemic exposure to netupitant. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron. Co-administration of single dose netupitant 600 mg and palonosetron 1.5 mg had no significant effects on the QTc interval.
Voriconazole: (Moderate) Monitor for an increase in netupitant-related adverse reactions if coadministration with voriconazole is necessary. Netupitant is a CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased netupitant exposure by 140%; however, no dosage adjustment is necessary.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with netupitant is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Netupitant is a moderate CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO twice daily if coadministered with netupitant. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Further decrease the zanubrutinib dose as recommended if adverse reactions occur. After discontinuation of netupitant, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor. The AUC of zanubrutinib is predicted to increase by 157% to 317% when coadministered with other moderate CYP3A4 inhibitors.
Zolpidem: (Moderate) It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of netupitant, a moderate CYP3A4 inhibitor, since CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism. There is evidence of an increase in pharmacodynamics effects and systemic exposure of zolpidem during co-administration with some potent inhibitors of CYP3A4, such as azole antifungals.

Akynzeo Intravenous Inj Pwd: 235-0.25mg
Akynzeo Oral Cap: 300-0.5mg
Akynzeo/Fosnetupitant, Palonosetron Intravenous Inj Sol: 20mL, 235-0.25mg

Adults

1 capsule (netupitant 300 mg; palonosetron 0.5 mg) PO as a single dose; 1 vial (235 mg fosnetupitant/0.25 mg palonosetron) IV infusion.

Geriatric

1 capsule (netupitant 300 mg; palonosetron 0.5 mg) PO as a single dose; 1 vial (235 mg fosnetupitant/0.25 mg palonosetron) IV infusion.

Adolescents

Safety and efficacy have not been established.

Children

Safety and efficacy have not been established.

Infants

Not indicated.

Neonates

Not indicated.

Netupitant, fosnetupitant is a selective substance P neurokinin 1 (NK1) receptor antagonist that prevents nausea and vomiting during both the acute and delayed phase after chemotherapy. Fosnetupitant is a prodrug of netupitant. Palonosetron is a highly selective 5-HT3 receptor antagonist that prevents nausea and vomiting during the acute phase; when used together, the combination is more effective than palonosetron alone.
Netupitant, fosnetupitant: Netupitant, fosnetupitant is a selective antagonist of human substance P/neurokinin-1 (NK1) receptors. Substance P and the NK1 receptors are present in the brain stem (medulla) centers that control the emetic reflex. Substance P is a peptide that increases the contractions of smooth GI muscles and leads to vasodilation. It is theorized that the NK1 receptor antagonists exert their main antiemetic action by depressing the neural activity of the nucleus tractus solitarius (NTS) lying ventrally to the area postrema. Netupitant was shown to cross the blood brain barrier with a NK1 receptor occupancy of 92.5%, 86.5%, 85%, 78%, and 76% in striatum at 6, 24, 48, 72, and 96 hours, respectively, after administration of 300 mg netupitant. Peripheral blockade by NK1 receptor antagonists at receptors located on the vagal terminals in the gut is an additional hypothesized mechanism of action. Peripheral blockade may decrease the intensity of the emetic afferent message to the central emetic circuitry. As with 5HT3 antagonists, a combination of peripheral and central mechanisms is plausible.
Palonosetron: Palonosetron selectively blocks serotonin 5-HT3 receptors to prevent emesis and appears to have little to no affinity for other serotonin receptors. 5-HT3 receptors are found centrally in the chemoreceptor trigger zone (CTZ) of the area postrema, and peripherally at vagal nerve terminals in the intestines. Emesis during chemotherapy appears to be associated with the release of serotonin from enterochromaffin cells in the small intestine. The released serotonin then activates the 5-HT3 receptors located on vagal afferent nerves to initiate the vomiting reflex. Palonosetron, by blocking the vagal nerve endings in the intestines, prevents signal transmission to the CTZ, and reduces the incidence of chemotherapy-induced nausea and vomiting (CINV).

Netupitant; palonosetron is administered orally; fosnetupitant; palonosetron is administered intravenously.
Netupitant: In adult cancer patients netupitant disposition was characterized by a large apparent volume of distribution that exceed total body volume. Human plasma protein binding of netupitant is greater than 99.5% at drug concentrations ranging from 10 to 1300 ng/mL, and greater than 97% protein binding of the major metabolites at drug concentrations ranging from 100 to 2000 ng/mL. Once absorbed, netupitant is extensively metabolized primarily by CYP3A4 and to a lesser extent by CYP2C9 and CYP2D6. Metabolites M1, M2 and M3 bind to the substance P/neurokinin 1 (NK1) receptor. Netupitant is eliminated from the body in a multi-exponential fashion, with an apparent elimination half-life (T1/2) in cancer patients of 80 +/- 29 hours (mean +/- SD) and with an estimated systemic clearance of 20.3 +/- 9.2 L/hour (mean +/- SD) after a single oral dose of netupitant; palonosetron. After a single oral dose of netupitant, approximately 50% of the dose was recovered from urine and feces within 120 hours of dosing. The total of 3.95% and 70.7% of the radioactive dose was recovered in the urine and feces collected over 336 hours, respectively. Renal clearance is not a significant elimination route for netupitant or its metabolites. About 86.5% and 4.7% of administered radioactivity was estimated to be excreted via the feces and urine, respectively, in 30 days post-dose.
Fosnetupitant: The mean +/- SD volume of distribution (Vz) of fosnetupitant in healthy subjects and in patients was 124 +/- 76 L and 296 +/- 535 L, respectively. The human plasma protein binding of fosnetupitant was 92% at 1 micromolar and 95% at 10 micromolar. Fosnetupitant is converted in vivo to netupitant by metabolic hydrolysis. In patients receiving fosnetupitant; palonosetron intravenously, netupitant exposure was 17-fold fosnetupitant exposure, as determined by their AUC. After intravenous administration of fosnetupitant; palonosetron for injection, fosnetupitant plasma concentrations declined in a biexponential manner. Thirty minutes after the end of the infusion, the mean plasma concentration of fosnetupitant was less than 1% of Cmax. After a single intravenous dose of fosnetupitant; palonosetron, the mean +/- SD of terminal elimination half-life and systemic plasma clearance of fosnetupitant were 0.75 +/- 0.40 hours and 249 +/- 270 L/hour, respectively in cancer patients. They were 0.96 +/- 0.55 hours (mean +/- SD) and 90 +/- 13 L/hour in healthy subjects after a single intravenous dose of fosnetupitant.
Palonosetron: Palonosetron has a volume of distribution of approximately 8.3 +/- 2.5 L/kg. Approximately 62% of palonosetron is bound to plasma proteins. It has a long half-life (roughly 40 hours). Palonosetron and metabolites are primarily eliminated renally via metabolic pathways. The parent drug represented 40% of the dose, while inactive metabolites accounted for roughly 50% of the dose. In healthy subjects, total body clearance was roughly 160 mL/hour/kg and renal clearance was 67 mL/hour/kg.
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, P-glycoprotein (P-gp), CYP2C9, CYP2D6 for netupitant
Netupitant, fosnetupitant:
Netupitant is extensively metabolized primarily by CYP3A4, and to a lesser extent by CYP2C9 and CYP2D6. In vitro studies have shown that netupitant and its metabolite M1 are CYP3A4 inhibitors. An in vivo study has confirmed that netupitant is a moderate inhibitor of CYP3A4. Based on the in vitro studies, netupitant and its metabolites are unlikely to exhibit in vivo drug-drug interactions via inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 at the single clinical dose of 300 mg PO. Netupitant and its metabolites, M1, M2 and M3, are not inducers of CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4.
Netupitant also affects some drug transporters. Based on in vitro studies, netupitant is an inhibitor of P-gp and BCRP transporters. In addition, metabolite M2 is a substrate for P-gp; however, netupitant is not a substrate for P-gp. In vitro studies indicate that netupitant and its three major metabolites are unlikely to have in vivo drug-drug interactions with human efflux transporters BSEP, MRP2, and human uptake transporters OATP1B1, OATP1B3, OAT1, OAT3, OCT1, and OCT2 at the clinical dose of 300 mg.
In vitro studies indicated that fosnetupitant is an inhibitor of OATP1B1 and OATP1B3 transporters. However, an in vivo interaction between fosnetupitant and OATP1B1, OATP1B3, and P-gp substrates is considered unlikely. In vitro studies indicated that fosnetupitant is not an inhibitor of MATE2-K transporter. Based on in vitro studies, fosnetupitant is not a substrate of BCRP, BSEP, MDR1 and MATE1, MATE2-K, OAT1, OAT3, OATP2B1, OCT1 and OCT2.
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP2D6, CYP3A4, CYP1A2 for palonosetron
Palonosetron: In vitro studies have suggested that CYP2D6, and to a lesser extent CYP3A4 and CYP1A2, are involved in the metabolism of palonosetron. Palonosetron pharmacokinetic parameters do not differ between poor and extensive metabolizers of CYP2D6, suggesting that inhibition or induction of the CYP2D6 enzyme by other drugs would not affect its disposition. Palonosetron does not inhibit CYP1A2, CYP2C9, CYP2D6, CYP2E1, CYP34/5 or induce CYP1A2, CYP2D6, CYP3A4/5, which constitute many of the clinically important enzymes from a drug interaction perspective. Palonosetron also does not inhibit CYP2A6 or CYP2B6 enzymes. CYP2C19 has not been investigated; other 5HT-3 antagonists have not been shown to have interactions via the CYP2C19 enzyme. In vitro, palonosetron was an inhibitor of MATE1, MATE2-k, OCT1, and OCT2, and OCT3 transporters. An in vivo interaction between palonosetron and transporter substrates is considered unlikely.

Oral Route

Netupitant: After oral administration of a single dose of netupitant, the drug was measurable in plasma between 15 minutes and 3 hours after dosing. Maximum plasma concentrations (Cmax) are attained in approximately 5 hours. Cmax and AUC of netupitant in adult cancer patients were similar to those in healthy adult subjects. Systemic exposure to netupitant is similar under fed and fasting conditions.
Palonosetron: After oral administration of palonosetron, the bioavailability is 97%. Plasma concentrations rise initially, then are followed by a slow elimination. Cmax and AUC are dose-proportional over the range of 0.3 to 90 mcg/kg in healthy adult subjects and cancer patients. Systemic exposure to palonosetron is similar under fed and fasting conditions.

Intravenous Route

Following single intravenous doses of fosnetupitant; palonosetron for injection in patients or fosnetupitant in healthy subjects, Cmax of netupitant and palonosetron were achieved at the end of the 30-minute infusion.

Pregnancy

Limited available data with netupitant, fosnetupitant; palonosetron use in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. Based on animal data for netupitant studies, advise pregnant women of the potential risk to a fetus. Other alternatives are available for treating and preventing nausea/vomiting due to cancer chemotherapy, which is the indication for use for this combination product. The American College of Obstetricians and Gynecologists (ACOG) includes ondansetron as a 3rd line pharmacologic treatment option for nausea and vomiting of pregnancy in patients who have failed other therapies. Daily administration of netupitant (3.7 times the human AUC at the recommended single human dose to be given with each cycle of chemotherapy) in rats during organogenesis through lactation produced no adverse effects in the offspring. However, in animal reproduction studies with fosnetupitant, delayed ossification of pubis occurred after intravenous administration in rats during the period of organogenesis at a dose 3 times the human AUC for netupitant at the recommended single dose to be given with each cycle of chemotherapy. A dose-dependent increase in adverse effects on embryo-fetal development was observed following daily administration of netupitant in pregnant rabbits during the period of organogenesis with doses 10 mg/kg/day and higher (at least 0.2 times the human AUC at the recommended single human dose to be given with each cycle of chemotherapy). Adverse effects included an increased incidence of external and skeletal abnormalities (positional abnormalities in the limbs and paws, and fused sternebrae) in rabbit fetuses. Reduction in fetal rabbit weight occurred at 30 mg/kg/day. Maternal toxicity in rabbits (i.e., loss of bodyweight during the treatment period) was also observed at 30 mg/kg/day. In pregnant rabbits, an increase in resorptions was observed with daily IV administration of fosnetupitant during the period of organogenesis at doses up to 9 times the human AUC for fosnetupitant and 0.4 times the human AUC for netupitant at the recommended single dose to be given with each cycle of chemotherapy. Daily IV administration of fosnetupitant (3 times the human AUC for netupitant at the recommended single dose to be given with each cycle of chemotherapy) in rats during organogenesis through lactation produced lower bodyweight in offspring at birth through maturation, and delayed physical development. Animal-based teratology studies with palonosetron during the period of organogenesis at doses up to 921 and 1841 times the recommended human oral dose in rats and rabbits, respectively, have not revealed evidence of impaired fertility or harm to the fetus.

There are no data on the presence of netupitant, fosnetupitant; palonosetron in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for the drug and any potential adverse effect on the breastfed child from the drug or from the underlying maternal condition. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.