Netupitant and palonosetron hydrochloride (netupitant/palonosetron) is a fixed combination of 2 antiemetic agents; netupitant is a selective antagonist at substance P/neurokinin-1 (NK1) receptors and palonosetron is a selective, second-generation inhibitor of type 3 serotonergic (5-HT3) receptors.1
Fosnetupitant and palonosetron hydrochloride (fosnetupitant/palonosetron) is a fixed combination of fosnetupitant, the prodrug of netupitant, and palonosetron.1
Chemotherapy-induced Nausea and Vomiting
Netupitant and palonosetron hydrochloride are used orally in fixed combination for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy.1, 2, 3, 26, 37 Fosnetupitant and palonosetron hydrochloride are used parenterally in fixed combination for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy.1, 38 Palonosetron prevents nausea and vomiting during the acute phase and netupitant or fosnetupitant prevents nausea and vomiting during both the acute and delayed phase after cancer chemotherapy.1 Fixed-combination netupitant and palonosetron or fosnetupitant and palonosetron is used in an antiemetic regimen that also includes dexamethasone.1 Injectable formulations of fosnetupitant and palonosetron in fixed combination have not been studied for the prevention of nausea and vomiting associated with chemotherapy regimens containing an anthracycline plus cyclophosphamide.1
Efficacy and safety of fixed-combination oral netupitant and palonosetron in combination with dexamethasone in the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of chemotherapy have been established in 2 randomized, double-blind, multicenter, controlled clinical studies.1, 2, 3 One of the trials was conducted in patients receiving highly emetogenic chemotherapy and the other trial was conducted in patients receiving moderately emetogenic chemotherapy.1, 2, 3 In both trials, complete response rates (i.e., no emetic episodes and no use of rescue therapy) were substantially higher with fixed-combination netupitant and palonosetron than with palonosetron alone.1, 2, 3
In study 1, which was dose-finding in design, efficacy and safety of a single oral dose of netupitant (300 mg) in combination with oral palonosetron (0.5 mg), administered with oral dexamethasone (12 mg on day 1 and 8 mg once daily on days 2-4), were compared with a single oral dose of palonosetron (0.5 mg), administered with oral dexamethasone (20 mg on day 1 and 8 mg twice daily on days 2-4), in 694 chemotherapy-naïve, adult cancer patients receiving a highly emetogenic, cisplatin-based chemotherapy regimen (median cisplatin dose was 75 mg/m2).1, 2 In this study, 86% of the patients who received netupitant in combination with palonosetron concomitantly received an antineoplastic agent in addition to protocol-mandated cisplatin.1 The most common antineoplastic agents and the percentage of patients exposed were cyclophosphamide (34%), fluorouracil (24%), etoposide (21%), and doxorubicin (16%).1 Primary efficacy endpoints were complete responses (i.e., no emetic episodes and no use of rescue therapy) in the delayed phase (25-120 hours), complete responses in the acute phase (0-24 hours), and complete responses in the overall phase (0-120 hours) after the initiation of treatment with cisplatin.1, 2 A substantially greater proportion of patients in the netupitant and palonosetron treatment arm attained complete responses (90.4% [delayed phase], 98.5% [acute phase], and 89.6% [overall phase]) compared with those who received palonosetron alone (80.1% [delayed phase], 89.7% [acute phase], and 76.5% [overall phase]).1, 2
In study 2, efficacy and safety of a single oral dose of netupitant (300 mg) in combination with oral palonosetron (0.5 mg) were compared with a single dose of oral palonosetron (0.5 mg) in 1455 chemotherapy-naïve, adult cancer patients scheduled to receive their first cycle of a moderately emetogenic chemotherapy regimen containing an anthracycline and cyclophosphamide for treatment of a solid malignant tumor.1, 3 All patients also received a single oral dose of dexamethasone (12 or 20 mg on day 1 in patients who received netupitant in combination with palonosetron or palonosetron alone, respectively).1, 3 After completion of cycle 1, patients had the option to enter a multiple-cycle extension phase and receive the same treatment assigned in cycle 1.1, 3 Of the 1450 patients who received either netupitant in combination with palonosetron or palonosetron alone, 1438 patients (99%) completed cycle 1; 1286 patients (88%) continued treatment in the multiple-cycle extension phase, and 907 patients (62%) completed the multiple-cycle extension phase up to a maximum of 8 treatment cycles.1 The majority of patients who received netupitant in combination with palonosetron were treated with cyclophosphamide, and all patients also received either doxorubicin (68%) or epirubicin (32%).1, 3 During the first cycle, 32% of patients treated with fixed-combination netupitant and palonosetron received a concomitant chemotherapeutic agent in addition to protocol-mandated regimens; the most common chemotherapeutic agents administered were fluorouracil (28%) and docetaxel (3%).1
The primary efficacy endpoint in study 2 was the complete response rate in the delayed phase (25-120 hours) following initiation of the chemotherapy regimen; secondary endpoints included complete response in the acute phase (0-24 hours) and overall phase (0-120 hours).1, 3 Patients continued into the multiple-cycle extension phase for up to 7 additional cycles of chemotherapy; however, only a limited number of patients received treatment beyond cycle 6.1 In cycle 1, a greater proportion of patients in the fixed-combination netupitant and palonosetron treatment arm attained a complete response (77% [delayed phase], 88% [acute phase], and 74% [overall phase]) compared with those who received palonosetron alone (70% [delayed phase], 85% [acute phase], and 67% [overall phase]).1, 3 During all subsequent cycles, the complete response rate in the delayed phase was higher in patients who received netupitant in combination with palonosetron compared with those who received palonosetron alone.1 In addition, the antiemetic activity of netupitant in combination with palonosetron was maintained throughout repeat cycles in those patients who continued to receive the fixed combination in each of the multiple cycles.1
Two additional clinical trials were conducted to support the efficacy of oral netupitant and palonosetron in fixed combination.1, 26 In study 3, which was multinational, randomized, and double-blind in design, efficacy of a single oral dose of netupitant (300 mg) in fixed combination with palonosetron (0.5 mg) given on day 1 with oral dexamethasone was maintained throughout all cycles in 309 chemotherapy-naïve, adult cancer patients undergoing initial and repeat cycles of moderately or highly emetogenic chemotherapy (including carboplatin, cisplatin, oxaliplatin, and doxorubicin-containing regimens).1, 26 The fixed-dose combination of netupitant and palonosetron also was found to be well tolerated when given over multiple chemotherapy cycles in this study.26
In a multinational, randomized, active-controlled, double-blind, clinical noninferiority study (study 4), efficacy and safety of a single oral dose of palonosetron (0.5 mg) were compared with IV palonosetron (0.25 mg) in 739 cancer patients scheduled to receive highly emetogenic cisplatin-based chemotherapy (70 mg/m2 or more).1, 37 The intent of this study was to demonstrate that oral palonosetron (0.5 mg) contributes to the efficacy of fixed-combination netupitant and palonosetron during the acute phase (i.e., the first 24 hours after cancer chemotherapy) in the setting of cisplatin-based chemotherapy.1, 37 The primary efficacy endpoint was complete response (defined as no emetic episode and no use of rescue medication) within 24 hours (acute phase) following initiation of cisplatin-based chemotherapy.1, 37 In patients who received oral palonosetron, 89.4% attained a complete response in the acute phase compared with 86.2% of those who received IV palonosetron; noninferiority of oral versus IV palonosetron was demonstrated in a statistical analysis of the complete response results.1, 37
A separate multinational, randomized, active-controlled, double-blind, clinical noninferiority study (study 5) compared efficacy and safety of a single dose of IV palonosetron 0.25 mg given as an infusion over 30 minutes to a bolus dose of IV palonosetron 0.25 mg given over 30 seconds in 425 cancer patients scheduled to receive highly emetogenic chemotherapy with a regimen that included cisplatin 70 mg/m2, cyclophosphamide 1500 mg/m2, carmustine >250 mg/m2, dacarbazine, or mechlorethamine.1, 38 The intent of this study was to demonstrate that IV palonosetron (0.25 mg) given over 30 minutes is non-inferior to administration of IV palonosetron over 30 seconds during the acute phase (i.e., the first 24 hours after cancer chemotherapy) in the setting of highly emetogenic chemotherapy.1, 38 The primary efficacy endpoint was complete response (defined as no emetic episode and no use of rescue medication) within 24 hours (acute phase) following initiation of highly emetogenic chemotherapy.1, 38 In patients who received palonosetron as an IV infusion, 82.7% attained a complete response in the acute phase compared with 86.3% of those who received palonosetron as an IV bolus; noninferiority of IV infusion versus IV bolus palonosetron was demonstrated in a statistical analysis of the complete response results.1
The American Society of Clinical Oncology (ASCO) guidelines on the use of antiemetics for prevention of chemotherapy-induced nausea and vomiting in adults recommend a 4-drug antiemetic regimen consisting of a neurokinin 1 (NK1) receptor antagonist, a type 3 serotonin (5-HT3) receptor antagonist, dexamethasone, and olanzapine for patients receiving high-emetic-risk agents (i.e., incidence of emesis exceeds 90% if no antiemetics are administered).400 A 3-drug combination (a NK1 receptor antagonist, a 5-HT3 receptor antagonist, and dexamethasone) is recommended in adults receiving carboplatin (target AUC ≥4 mg/mL per minute) and a 2-drug regimen (a 5-HT3 receptor antagonist and dexamethasone) is recommended in adults receiving other chemotherapy of moderate emetic risk (i.e., incidence of emesis without antiemetics exceeds 30% but does not exceed 90%).400 For moderate-risk agents (e.g., cyclophosphamide, doxorubicin, oxaliplatin) with known delayed nausea and vomiting, dexamethasone may be used.400 A single dose of a 5-HT3 receptor antagonist or dexamethasone may be offered to adults receiving chemotherapy regimens with low-emetic risk (i.e., incidence of emesis without antiemetics exceeds 10% but does not exceed 30%).400 Routine antiemetic prophylaxis is not necessary in adults receiving chemotherapy with minimal antiemetic risk (i.e., incidence of emesis is less than 10% without antiemetics).400 For patients experiencing nausea and vomiting despite optimal antiemetic therapy, an antiemetic from a different therapeutic class may be used in addition to continuing the standard antiemetic regimen.400
The fixed combination of netupitant and palonosetron hydrochloride (netupitant/palonosetron) is supplied as capsules for oral administration.1
The fixed combination of fosnetupitant chloride hydrochloride and palonosetron hydrochloride (fosnetupitant/palonosetron) is administered by IV infusion; it is supplied as a lyophilized powder for injection in single-dose vials that must be reconstituted and further diluted, as an injection solution in a Ready-to-Use formulation that does not require further dilution, or in a To-Be-Diluted formulation that must be diluted prior to administration.1
Netupitant/palonosetron capsules are administered orally approximately 1 hour before the start of chemotherapy without regard to meals.1
For highly emetogenic chemotherapy (including cisplatin-based chemotherapy), the antiemetic regimen also includes oral dexamethasone 12 mg administered 30 minutes prior to chemotherapy on day 1, followed by oral dexamethasone 8 mg on days 2—4.1 For anthracycline- and cyclophosphamide-based chemotherapy and chemotherapy not considered highly emetogenic, the antiemetic regimen also includes oral dexamethasone 12 mg administered 30 minutes prior to chemotherapy on day 1.1
Store the capsules at 20—25°C (excursions permitted between 15—30°C).1
Vials of fosnetupitant/palonosetron do not contain any antimicrobial preservatives and are intended for single use only.1
Fosnetupitant/palonosetron is incompatible with any solution containing divalent cations (e.g., calcium, magnesium), including Lactated Ringer's injection and Hartmann's Solution.1
With the exception of IV dexamethasone sodium phosphate, there are limited available data on the compatibility of fixed-combination fosnetupitant/palonosetron with other IV substances, additives, or other drugs.1 Other IV substances, additives, or other drugs should therefore not be added to the fosnetupitant/palonosetron solution or infused simultaneously.1 If the same IV 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.1
Lyophilized Powder for Injection
Fixed-combination fosnetupitant/palonosetron lyophilized powder for injection requires reconstitution and dilution prior to administration.1 The lyophilized powder for injection is compatible with IV dexamethasone sodium phosphate, which can be added to the infusion bag containing fosnetupitant/palonosetron solution or infused simultaneously.1
Store unopened vials of fosnetupitant/palonosetron lyophilized powder for injection in the original carton, at 2—8°C, protected from light.1
To reconstitute the lyophilized powder for injection, inject 20 mL of 0.9% sodium chloride or 5% dextrose injection into the fosnetupitant/palonosetron vial using aseptic technique.1 Ensure the solvent is added to the vial along the vial wall and not jetted in order to prevent foaming; swirl the vial gently.1 Prepare an infusion vial or bag filled with 30 mL of 0.9% sodium chloride or 5% dextrose injection.1 Withdraw the entire volume of solution from the fosnetupitant/palonosetron vial and transfer it into the infusion vial or bag containing 30 mL of 0.9% sodium chloride or 5% dextrose injection, to yield a total volume of 50 mL.1 Gently invert the vial or bag to ensure complete dissolution.1 Before administration, visually inspect the final diluted solution, and discard the vial or bag if particulates and/or discoloration are observed.1 Administer as an IV infusion.1 To ensure complete drug administration, after the infusion is complete, flush the infusion line with the same carrier solution (i.e., 0.9% sodium chloride or 5% dextrose injection).1
The total time from reconstitution to the start of the infusion, with or without IV dexamethasone sodium phosphate, should not exceed 24 hours.1 Store the reconstituted solution and the final diluted solution at room temperature at 20—25°C.1
Fixed-combination fosnetupitant/palonosetron injection (Ready-to-Use) does not require dilution prior to administration.1 The Ready-to-Use injection is compatible with IV dexamethasone sodium phosphate, which can be infused simultaneously; do not add dexamethasone sodium phosphate to the Ready-to-Use vial.1
Store the vial of fosnetupitant/palonosetron Ready-to-Use injection in the original carton, at 20—25°C, protected from light.1
Before administration, inspect the solution for particulates and/or discoloration; discard the vial if particulates and/or discoloration are observed.1 Using aseptic technique, insert a vented IV set through the septum of the vial.1 Once the stopper is punctured, use the drug immediately.1 To administer, invert and hang the vial utilizing the strap affixed to the bottom of the vial.1 Administer as an IV infusion.1 To ensure complete drug administration, after the infusion is complete, flush the infusion line with 0.9% sodium chloride or 5% dextrose injection.1
To-Be-Diluted vials of fixed-combination fosnetupitant/palonosetron injection require dilution prior to administration.1 The To-be-Diluted injection is compatible with IV dexamethasone sodium phosphate, which can be added to the infusion bag containing fosnetupitant/palonosetron solution or infused simultaneously.1
Store unopened vials of fosnetupitant/palonosetron To-Be-Diluted injection in the original carton, at 20—25°C, protected from light.1
Before dilution, inspect the solution for particulates and/or discoloration; discard the vial if particulates and/or discoloration are observed.1 Using aseptic technique, prepare an infusion vial or bag filled with 30 mL of 0.9% sodium chloride or 5% dextrose injection.1 Withdraw the entire volume of solution from the fosnetupitant/palonosetron vial (20 mL) and transfer it into the infusion vial or bag containing 30 mL of 0.9% sodium chloride or 5% dextrose injection, to yield a total volume of 50 mL.1 Gently invert the vial or bag to ensure complete dissolution.1 Before administration, visually inspect the final diluted solution, and discard the vial or bag if particulates and/or discoloration are observed.1 Administer as an IV infusion.1 To ensure complete drug administration, after the infusion is complete, flush the infusion line with the same carrier solution (i.e., 0.9% sodium chloride or 5% dextrose injection).1
The total time from dilution to the start of the infusion, with or without IV dexamethasone sodium phosphate, should not exceed 24 hours.1 Store the final diluted solution at room temperature at 20—25°C.1
Administer the IV infusion over 30 minutes.1
Netupitant and palonosetron hydrochloride is a fixed combination capsule preparation containing 300 mg of netupitant and 0.5 mg of palonosetron per capsule.1 Fosnetupitant chloride hydrochloride and palonosetron hydrochloride is a fixed combination preparation for IV administration; each vial contains 235 mg of fosnetupitant and 0.25 mg of palonosetron.1
Dosages of palonosetron hydrochloride and fosnetupitant chloride hydrochloride are expressed in terms of palonosetron and fosnetupitant, respectively.1
Chemotherapy-induced Nausea and Vomiting
For the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including cisplatin-based chemotherapy in adults, the recommended oral dosage of fixed-combination netupitant and palonosetron is 1 capsule (300 mg of netupitant and 0.5 mg of palonosetron) administered approximately 1 hour prior to the start of chemotherapy; dexamethasone 12 mg should be administered orally 30 minutes prior to chemotherapy on day 1, followed by 8 mg orally once daily on days 2-4 of the treatment regimen.1
For the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of anthracycline- and cyclophosphamide-based chemotherapy and chemotherapy not considered highly emetogenic in adults, the recommended oral dosage of fixed-combination netupitant and palonosetron is 1 capsule (300 mg of netupitant and 0.5 mg of palonosetron) administered approximately 1 hour prior to the start of chemotherapy; dexamethasone 12 mg should be administered orally 30 minutes prior to chemotherapy on day 1 of the treatment regimen.1 The manufacturer states that administration of dexamethasone on days 2-4 is not necessary.1
For the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including cisplatin-based chemotherapy in adults, the recommended IV dosage of fixed-combination fosnetupitant and palonosetron is 1 vial (235 mg of fosnetupitant and 0.25 mg of palonosetron) infused over 30 minutes starting 30 minutes prior to chemotherapy; dexamethasone 12 mg should be administered orally 30 minutes prior to chemotherapy on day 1, followed by 8 mg orally once daily on days 2-4 of the treatment regimen.1
Dosage adjustments are not necessary when fixed-combination netupitant (or fosnetupitant) and palonosetron is used in patients with mild or moderate hepatic impairment (Child-Pugh score of 5-8).1 However, fixed-combination netupitant (or fosnetupitant) and palonosetron should not be used in patients with severe hepatic impairment (Child-Pugh score greater than 9) because the fixed combination has not been adequately studied in such patients.1
Dosage adjustments are not necessary when fixed-combination netupitant (or fosnetupitant) and palonosetron is used in patients with mild to moderate renal impairment (creatinine clearance 30—60 mL/minute).1 However, fixed-combination netupitant (or fosnetupitant) and palonosetron should not be used in patients with severe renal impairment (creatinine clearance <30 mL/minute) or end-stage renal disease.1
In general, use caution when dosing fixed-combination netupitant (or fosnetupitant) and palonosetron in geriatric patients because of the greater frequency of decreased hepatic, renal, and/or cardiac function and concomitant diseases and other drug therapy in such patients.1
Hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving palonosetron, one of the ingredients in the fixed combination of netupitant (or fosnetupitant) and palonosetron; the reactions have occurred in patients with or without known hypersensitivity to other type 3 serotonergic (5-HT3) receptor antagonists.1
Development of serotonin syndrome has been reported in patients receiving 5-HT3 receptor antagonists.1 Most of the cases have been associated with concomitant use of other serotonergic drugs (e.g., selective serotonin-reuptake inhibitors [SSRIs], serotonin- and norepinephrine-reuptake inhibitors [SNRIs], monoamine oxidase [MAO] inhibitors, mirtazapine, fentanyl, lithium, tramadol, IV methylene blue).1 Some of the reported cases of serotonin syndrome were fatal.1 Serotonin syndrome occurring with overdosage of another 5-HT3 receptor antagonist alone has also been reported.1 The majority of reports of serotonin syndrome related to 5-HT3 receptor antagonist use have occurred in a post-anesthesia care unit or an infusion center.1
Manifestations associated with serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), and seizures with or without GI symptoms (e.g., nausea, vomiting, diarrhea).1
Patients receiving 5-HT3 receptor antagonists, including fixed-combination netupitant (or fosnetupitant) and palonosetron, should be informed about the increased risk of serotonin syndrome and monitored for the emergence of serotonin syndrome, particularly with concomitant use of other serotonergic drugs.1 If symptoms of serotonin syndrome occur, fixed-combination netupitant (or fosnetupitant) and palonosetron should be discontinued, and supportive treatment should be initiated.1
There are limited available data with the use of fixed-combination netupitant (or fosnetupitant) and palonosetron in pregnant women to inform a drug-associated risk of adverse developmental outcomes.1
In animal reproduction studies with oral netupitant, there were no adverse effects on embryo-fetal development following daily administration of the drug in pregnant rats during organogenesis at doses up to 3.7 times the human AUC at the recommended single dose to be given with each chemotherapy cycle.1 However, there was a dose-dependent increase in adverse effects on embryo-fetal development following daily administration in pregnant rabbits during organogenesis with doses ≥0.2 times the human AUC at the recommended single dose to be given with each chemotherapy cycle.1 Following daily oral administration in rats during organogenesis through lactation at doses up to 3.7 times the human AUC at the recommended dose, no adverse effects were observed in offspring.1
In animal reproduction studies with fosnetupitant, delayed ossification of the pubis was observed following IV administration of the drug in rats during organogenesis at a dose 3 times the human AUC for netupitant at the recommended single dose to be given with each chemotherapy cycle.1 An increase in resorptions was observed in pregnant rabbits with daily IV administration of fosnetupitant during 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 chemotherapy cycle.1 Following daily IV administration of fosnetupitant (3 times the human AUC for netupitant at the recommended single dose to be given with each chemotherapy cycle) in rats during organogenesis through lactation, lower bodyweight in offspring at birth through maturation, and delayed physical development, were observed.1 Maternal toxicity (reduced weight gain and food consumption) also occurred.1
In animal reproduction studies with palonosetron, there were no adverse effects on embryo-fetal development following oral administration of the drug during organogenesis at doses up to 921 and 1841 times the recommended oral dosage in rats and rabbits, respectively.1
Based on data from netupitant studies in animals, apprise pregnant women of the potential hazard to a fetus.1
It is not known whether netupitant, fosnetupitant, or palonosetron is distributed into human milk, or affects the breast-fed infant or milk production.1
Consider the benefits of breast-feeding and the clinical importance of netupitant (or fosnetupitant) and palonosetron to the mother along with potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.1
The safety and efficacy of netupitant (or fosnetupitant) and palonosetron have not been established in pediatric patients younger than 18 years of age.1
In the main clinical studies with the fixed combination of netupitant and palonosetron, 18% of adult cancer patients were 65 years of age or older and 2% were 75 years of age or older.1 No overall differences in safety were observed in these geriatric patients compared with younger adults in these studies.1 Exploratory analyses of the effect of age on efficacy were performed in 2 clinical studies comparing the fixed combination of netupitant and palonosetron with palonosetron.1 In study 1, patients received cisplatin chemotherapy and the difference in complete response rates between fixed-combination netupitant and palonosetron and palonosetron alone was similar between patients 65 years of age or older and those younger than 65 years of age in both the acute and delayed phases.1 In study 2, patients received anthracycline plus cyclophosphamide chemotherapy and the difference in complete response rates between fixed-combination netupitant and palonosetron and palonosetron alone was also similar between patients 65 years of age or older and those younger than 65 years of age in the acute phase.1 In the delayed phase, the difference in complete response rates between fixed-combination netupitant and palonosetron and palonosetron alone was higher in patients younger than 65 years of a this difference may be explained, at least in part, by a higher complete response rate in the delayed phase with palonosetron alone in geriatric patients (81%) compared with younger patients treated with palonosetron alone (67%).1
Of the 239 adult cancer patients in the clinical studies of the fixed combination of fosnetupitant and palonosetron, 36% of patients were 65 years of age or older, while 4% were 75 years of age or older.1 The nature and frequency of adverse reactions were similar in geriatric and younger patients.1
In a population pharmacokinetic analysis, age (within the range of 29-75 years of age) did not affect the pharmacokinetics of netupitant or palonosetron in cancer patients receiving the fixed combination.1 In healthy individuals older than 65 years of age, mean systemic exposure and peak plasma concentrations were 25% and 36% higher for netupitant, respectively, and 37% and 10% higher for palonosetron, respectively, compared with those in healthy younger adults (22-45 years of age).1 The increase in the systemic exposure to netupitant in geriatric subjects is not considered to be clinically important.1
Caution is advised when dosing fixed-combination netupitant (or fosnetupitant) and palonosetron in geriatric patients because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant diseases and other drug therapy in such patients.1
The effects of hepatic impairment on the pharmacokinetics of netupitant and palonosetron were studied following administration of a single oral dose of the fixed combination to patients with mild (Child-Pugh score of 5-6), moderate (Child-Pugh score of 7-9), or severe (Child-Pugh score exceeding 9) hepatic impairment.1 In patients with mild or moderate hepatic impairment, mean exposure of netupitant was 67% and 86% higher, respectively, than in healthy individuals and mean peak plasma concentration for netupitant was approximately 40% and 41% higher, respectively, than in healthy individuals.1 In patients with mild or moderate hepatic impairment, mean exposure of palonosetron was 33% and 62% higher, respectively, than in healthy individuals and mean peak plasma concentration for palonosetron was approximately 14% higher and unchanged, respectively, compared with healthy individuals.1 The manufacturer states that no dosage adjustment is necessary in patients with mild to moderate hepatic impairment.1
The pharmacokinetics of netupitant and palonosetron were available from only 2 patients with severe hepatic impairment, and the manufacturer states that the data are too limited to draw a conclusion.1 Use of fixed-combination netupitant (or fosnetupitant) and palonosetron should therefore be avoided in patients with severe hepatic impairment.1
In a population pharmacokinetic analysis, mild and moderate renal impairment (creatinine clearance 30—60 mL/minute) did not substantially affect the pharmacokinetics of netupitant or palonosetron.1 The manufacturer states that no dosage adjustment of fixed-combination netupitant (or fosnetupitant) and palonosetron is necessary in patients with mild to moderate renal impairment.1 The pharmacokinetics and safety of netupitant have not been studied in patients with severe renal impairment; however, severe renal impairment (creatinine clearance <30 mL/minute) did not substantially affect the pharmacokinetics of palonosetron.1 In a study with IV palonosetron, total systemic exposure to palonosetron increased by approximately 28% in patients with severe renal impairment, compared with healthy individuals.1 The pharmacokinetics of netupitant and palonosetron have not been studied in patients with end-stage renal disease requiring hemodialysis.1 Use of fixed-combination netupitant (or fosnetupitant) and palonosetron should be avoided in patients with severe renal impairment or end-stage renal disease.1
Adverse effects reported in ≥3% patients receiving the oral fixed combination of netupitant and palonosetron include headache, asthenia, dyspepsia, fatigue, constipation, and erythema.1
The safety profile of fixed-combination fosnetupitant/palonosetron is generally comparable to that observed with the oral netupitant/palonosetron capsules.1
Metabolism of netupitant is primarily mediated by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, by CYP2C9 and CYP2D6.1 Netupitant is a CYP3A4 substrate.1
Based on in vitro studies and confirmed in an in vivo study, netupitant is a moderate inhibitor of CYP3A4; its M1 metabolite also is an inhibitor of CYP3A4 based on in vitro studies.1
Based on in vitro studies, netupitant and its metabolites are unlikely to have clinically important pharmacokinetic drug interactions via inhibition of CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, and 2D6 at the usual clinical oral dosage.1
Netupitant and its metabolites (M1, M2, and M3) do not induce CYP isoenzymes 1A2, 2B6, 2C9, 2C19, and 3A4.1
Based on in vitro studies, netupitant inhibits P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters.1 Netupitant is not a substrate for P-gp, but its M2 metabolite is a P-gp substrate.1
In vitro studies indicate that netupitant and its 3 major metabolites are unlikely to have clinically important drug interactions with human efflux transporters bile salt export pump (BSEP), multidrug resistance protein (MRP) 2, and human uptake transporters organic anion transport protein (OATP) 1B1 or 1B3, organic anion transporter (OAT) 1 or 3, and organic cation transporter (OCT) 1 or 2 at the usual clinical dose of 300 mg.1
In vitro studies indicate that fosnetupitant is an inhibitor of OATP1B1, OATP1B3, and P-gp transporters.1 However, an in vivo interaction between fixed-combination fosnetupitant/palonosetron and OATP1B1, OATP1B3, and P-gp substrates is considered unlikely.1
In vitro studies indicate that fosnetupitant is not an inhibitor of multidrug and toxin extrusion (MATE) 2-K transporter, and not a substrate of BCRP, BSEP, multidrug resistance (MDR) 1 and MATE1, MATE2-K, OAT1, OAT3, OATP2B1, OCT1, and OCT2.1
In vitro studies suggest that CYP2D6 and, to a lesser extent, CYP3A4 and CYP1A2 are involved in the metabolism of palonosetron.1 Palonosetron does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C9, 2D6, 2E1, and 3A4/5 or induce CYP isoenzymes 1A2, 2D6, or 3A4/5 based on in vitro studies; CYP2C19 was not studied.1 Palonosetron is a CYP3A4 substrate.1
In vitro studies indicate that palonosetron is an inhibitor of MATE1, MATE2-K, OCT1, OCT2, and OAT3 transporters.1 An in vivo interaction between fixed-combination netupitant/palonosetron or fosnetupitant/palonosetron and transporter substrates is considered unlikely.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
CYP3A4 Substrates: Fixed-combination netupitant and palonosetron should be used with caution in patients concomitantly receiving drugs that are principally metabolized by CYP3A4.1 A single oral dose of netupitant 300 mg significantly inhibits CYP3A4 for 6 days.1 Avoid concomitant use with CYP3A4 substrates for one week, if feasible.1 If concomitant use is not avoidable, consider dosage reduction of the CYP3A4 substrate.1
Strong CYP3A4 Inhibitors: Concomitant use of fixed-combination netupitant and palonosetron with strong CYP3A4 inhibitors (e.g., ketoconazole) can substantially increase systemic exposure to the netupitant component of the fixed combination.1 However, the manufacturer states that dosage adjustment is not necessary for single-dose administration of fixed-combination netupitant and palonosetron during concomitant use of strong CYP3A4 inhibitors.1
Strong CYP3A4 Inducers: Strong CYP3A inducers can decrease the efficacy of fixed-combination netupitant and palonosetron by substantially reducing plasma concentrations of the netupitant component.1 The manufacturer therefore states that concomitant use of fixed-combination netupitant and palonosetron should be avoided in patients who are receiving long-term therapy with a strong CYP3A4 inducer (e.g., rifampin).1
Systemic exposure to antineoplastic agents that are metabolized by CYP3A4 (e.g., docetaxel, paclitaxel, etoposide, irinotecan, cyclophosphamide, ifosfamide, imatinib, vinorelbine, vinblastine, vincristine) can increase when administered concomitantly with the fixed combination of netupitant and palonosetron.1
Systemic exposure to IV docetaxel, etoposide, and cyclophosphamide was increased when administered with fixed-combination netupitant/palonosetron in patients with cancer compared with palonosetron administration alone.1 Concurrent administration of fixed-combination netupitant/palonosetron increased the mean peak plasma concentration and AUC of docetaxel by 49% and 35%, respectively; increased the mean peak plasma concentration and AUC of etoposide by 10% and 28%, respectively; and increased the mean peak plasma concentration and AUC of cyclophosphamide by 27% and 20%, respectively, compared with concomitant administration of palonosetron alone.1
The mean AUC of palonosetron was approximately 65% higher when fixed-combination netupitant/ palonosetron was concomitantly administered with docetaxel than with etoposide or cyclophosphamide; the mean AUC of netupitant was similar among groups that received docetaxel, etoposide, or cyclophosphamide.1
Caution and monitoring for chemotherapy-related adverse effects are advised in patients concomitantly receiving antineoplastic agents that are principally metabolized by CYP3A4.1
Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been reported following the concomitant use of type 3 serotonin (5-HT3) receptor antagonists and other serotonergic drugs, including selective serotonin-reuptake inhibitors (SSRIs), serotonin- and norepinephrine-reuptake inhibitors (SNRIs), monoamine oxidase (MAO) inhibitors, mirtazapine, fentanyl, lithium, tramadol, and IV methylene blue.1 Patients should be monitored for the emergence of serotonin syndrome, particularly during concomitant use of fixed-combination netupitant (or fosnetupitant) and palonosetron and other serotonergic drugs.1
If symptoms of serotonin syndrome occur, fixed-combination netupitant (or fosnetupitant) and palonosetron should be discontinued, and supportive treatment should be initiated.1
The pharmacokinetics of netupitant and palonosetron were not substantially affected when oral netupitant (450 mg) and oral palonosetron (0.75 mg) were concurrently administered alone or in combination (1.5 times the recommended dosage of fixed-combination netupitant/palonosetron capsules).1
Concomitant administration of a single dose of netupitant (300 mg) or a single fosnetupitant infusion (235 mg) increased the systemic exposure of dexamethasone by more than 2-fold on days 2 and 4.1 Therefore, the manufacturer states that a reduced dose of dexamethasone should be administered when used with fixed-combination netupitant (or fosnetupitant) and palonosetron.1
In healthy subjects, oral administration of fixed-combination netupitant and palonosetron (single capsule) with dexamethasone (12 mg on day 1 followed by once-a-day administrations of 8 mg on days 2, 3, 4, 6, 8, and 10) increased the plasma concentrations of dexamethasone for 6 days.1
In healthy subjects, co-administration of fosnetupitant (single IV dose of 235 mg) with oral dexamethasone (20 mg on day 1 followed by twice-a-day administrations of 8 mg on days 2, 3, and 4) increased dexamethasone exposure 2.4-fold on day 4.1 Considering the limited fosnetupitant exposure in human plasma and its conversion to netupitant within 30 minutes following completion of infusion, the observed effects are ascribed to netupitant.1
Concurrent administration of netupitant (450 mg) did not substantially affect systemic exposure and urinary excretion of digoxin, a P-gp substrate, at steady state.1 Therefore, concurrent administration of fixed-combination netupitant (or fosnetupitant) and palonosetron and digoxin is not expected to affect systemic exposure of digoxin.1
Systemic exposure of erythromycin was highly variable and the mean peak concentration and AUC of erythromycin were increased by 92 and 56%, respectively, when erythromycin (500 mg) was concurrently administered with netupitant (300 mg).1 The change in exposure is not clinically important.1
A single dose of fixed-combination netupitant and palonosetron was administered following once-daily administration of ketoconazole 400 mg for 12 days.1 Concurrent administration of ketoconazole increased the mean peak plasma concentrations and AUC of netupitant by 25 and 140%, respectively, and increased mean AUC and peak plasma concentrations of palonosetron by 10 and 15%, respectively, compared with administration of fixed-combination netupitant and palonosetron alone.1
Although ketoconazole can substantially increase systemic exposure to the netupitant component of the fixed combination, the manufacturer states that dosage adjustment is not necessary for single-dose administration of fixed-combination netupitant (or fosnetupitant) and palonosetron.1
Systemic exposure of midazolam was substantially higher when administered with netupitant.1 Following concomitant administration of netupitant (300 mg) and a single oral dose of midazolam (7.5 mg), the mean peak plasma concentration and AUC of midazolam were 36 and 126% higher, respectively.1
The manufacturer states that the potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized by CYP3A4 (e.g., alprazolam, triazolam) should be considered when administering these drugs with fixed-combination netupitant (or fosnetupitant) and palonosetron.1
There is no clinically important effect of fixed-combination netupitant (or fosnetupitant) and palonosetron on the efficacy of oral contraceptives containing levonorgestrel and ethinyl estradiol.1
Single-dose netupitant in fixed combination with palonosetron, when given with a single oral dose of ethinyl estradiol 60 mcg and levonorgestrel 300 mcg, increased the AUC of levonorgestrel by 46% but did not affect peak plasma concentrations.1 Fixed-combination netupitant and palonosetron increased the peak plasma concentration and AUC of ethinyl estradiol by 5% and 16%, respectively, but this change is not clinically important.1
A single-dose of fixed-combination netupitant and palonosetron was administered following once-daily administration of rifampin 600 mg for 17 days.1 Concurrent administration of rifampin decreased the AUC and mean peak plasma concentration of netupitant by 62% and 82%, respectively, compared with those following administration of fixed-combination netupitant and palonosetron alone.1 Concurrent administration of rifampin decreased the AUC and mean peak plasma concentration of palonosetron by 19% and 15%, respectively.1
Because strong CYP3A4 inducers can decrease the efficacy of fixed-combination netupitant (or fosnetupitant) and palonosetron by substantially reducing plasma concentrations of the netupitant component, use of fixed-combination netupitant (or fosnetupitant) and palonosetron should be avoided in patients who are chronically receiving a strong CYP3A4 inducer such as rifampin.1
It is predicted that concomitant use of IV fixed-combination fosnetupitant and palonosetron with warfarin would not substantially increase the systemic exposure to S-warfarin (CYP2C9 substrate), the active enantiomer; however, the effects of fixed-combination netupitant and palonosetron on international normalized ratio (INR) and prothrombin time have not been studied.1 Monitor INR and adjust the dosage of warfarin as needed with concomitant use.1
Netupitant and palonosetron hydrochloride is a fixed oral combination of 2 antiemetic agents: netupitant, a selective antagonist at substance P/neurokinin-1 (NK1) receptors, and palonosetron, a selective inhibitor of type 3 serotonergic (5-HT3) receptors.1 Palonosetron has strong binding affinity for the 5-HT3 receptor and exhibits little or no affinity for other receptors.1 Palonosetron is also available in fixed combination with fosnetupitant, the prodrug of netupitant; this fixed combination is available for parenteral administration.1
Palonosetron prevents nausea and vomiting during the acute phase after chemotherapy, and netupitant or fosnetupitant prevents nausea and vomiting during both the acute and delayed phase after chemotherapy.1 Current evidence suggests that chemotherapeutic agents produce nausea and vomiting by increasing endogenous serotonin release from the enterochromaffin cells of the small intestine.1 Serotonin then stimulates 5-HT3 receptors on vagal afferents to initiate the vomiting reflex.1 Thus, the development of acute emesis is dependent on serotonin, and its 5-HT3 receptors selectively stimulate the emetic response.1 The antiemetic activity of palonosetron for acute nausea and vomiting appears to be mediated via inhibition of serotonin activity both centrally and peripherally.1 Delayed emesis has been mainly associated with the activation of tachykinin family NK1 receptors, which are widely distributed in the central and peripheral nervous systems, by substance P.1 Netupitant has been shown to inhibit substance P-mediated responses in in vitro and in vivo studies.1 Netupitant crosses the blood-brain barrier and occupies NK1 receptors in the brain.1
Following single-dose, oral administration of fixed-combination netupitant and palonosetron in healthy individuals, levels of netupitant and palonosetron were measurable within 1 hour and peak plasma concentrations were achieved within approximately 4-5 hours.1 The absolute bioavailability of palonosetron was approximately 97% following oral administration.1 When fixed-combination netupitant and palonosetron hydrochloride capsules were administered under fed conditions, the systemic exposure to netupitant and palonosetron was similar to that observed under fasting conditions.1
A greater than dose-proportional increase in the systemic exposure of oral netupitant was observed when the dose of netupitant was increased from 10 mg to 300 mg, and a dose-proportional increase in the systemic exposure was observed when the netupitant dose was increased from 300 mg to 450 mg.1 After administration of single oral doses of palonosetron ranging from 0.25-6.8 mg using a buffered solution, the peak plasma concentration and AUC of the drug were dose proportional in healthy subjects.1
Following single IV doses of fixed-combination fosnetupitant and palonosetron in patients, or fosnetupitant in healthy subjects, the peak plasma concentrations of netupitant and palonosetron were achieved at the end of the 30-minute infusion.1 In healthy subjects, a dose-proportional increase in the systemic exposure was observed when the dose of fosnetupitant was increased from 17.6 mg to 353 mg.1
After administration of fixed-combination netupitant and palonosetron capsules (single dose), netupitant and palonosetron were widely distributed throughout the body.1 Plasma protein binding of netupitant is greater than 99.5% at drug concentrations ranging from 10-1300 ng/mL and protein binding of its principal metabolites is greater than 97% at drug concentrations ranging from 100-2000 ng/mL.1 Approximately 62% of palonosetron is bound to plasma proteins.1 The human plasma protein binding of fosnetupitant was 92% and 95% at 1 micromolar and 10 micromolar, respectively.1
Netupitant is extensively metabolized to form 3 principal metabolites: a desmethyl derivative (M1), an N-oxide derivative (M2), and a OH-methyl derivative (M3).1 Metabolism of netupitant is primarily mediated by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, by CYP2C9 and CYP2D6.1 The metabolites M1, M2, and M3 bind to the substance P/NK1 receptor.1 The time to peak plasma concentrations was 5 hours for the M2 metabolite and approximately 17 to 32 hours for metabolites M1 and M3, respectively.1 Fosnetupitant is converted to netupitant in vivo by metabolic hydrolysis.1 In patients receiving fixed-combination fosnetupitant and palonosetron, netupitant exposure was 17-fold fosnetupitant exposure.1 Netupitant metabolites M1, M2, and M3 were generated from the released netupitant, and their exposures were 32, 21, and 28% of netupitant exposure, respectively.1 The median time to peak plasma concentrations for the M1, M2, and M3 metabolites was 12, 2, and 12 hours, respectively, following administration of fixed-combination fosnetupitant and palonosetron.1 Palonosetron is eliminated by several routes with approximately 50% metabolized to form 2 primary metabolites: N-oxide-palonosetron and 6-hydroxypalonosetron; these metabolites each have <1% of the 5-HT receptor antagonist activity of palonosetron.1 Metabolism of palonosetron is primarily mediated by CYP2D6 and, to a lesser extent, by CYP3A4 and CYP1A2.1
Approximately 50% of a single, oral radiolabeled dose of netupitant was recovered in urine and feces within 120 hours following oral administration.1 A total of approximately 4% and 71% of a radiolabeled dose of netupitant was recovered in urine and feces collected over 336 hours, respectively; less than 1% of the dose was recovered in urine as unchanged drug.1 Following IV administration of fixed-combination fosnetupitant and palonosetron, fosnetupitant plasma concentrations decreased in a biexponential manner.1 Thirty minutes following the end of the infusion, the mean plasma concentration of fosnetupitant was <1% of the peak plasma concentration.1 Following oral administration of a single dose of radiolabeled palonosetron in healthy individuals, 85-93% of the dose was excreted in urine and 5-8% was excreted in feces; approximately 40% of the dose was recovered in urine as unchanged drug.1
After a single dose of fixed-combination netupitant and palonosetron capsules, the mean apparent elimination half-life of netupitant was 96 hours in healthy subjects and 80 hours in patients with cancer.1 Following IV infusion of fixed-combination fosnetupitant and palonosetron, the terminal half-life of netupitant was 144 hours.1 Following a single IV dose of fixed-combination fosnetupitant and palonosetron, the mean terminal half-life of fosnetupitant was 0.75 hours in patients with cancer.1 The half-life of fosnetupitant was 0.96 hours in healthy subjects after a single IV dose of fosnetupitant.1 Following administration of fixed-combination netupitant and palonosetron capsules, the mean half-life of palonosetron was 44 hours in healthy subjects and 50 hours in patients with cancer.1 Following IV infusion of fixed-combination fosnetupitant and palonosetron, the terminal half-life of palonosetron was 58 hours.1
In a pooled analysis of data following administration of fixed-combination netupitant and palonosetron, peak plasma concentration of netupitant was 35% higher in females than in males, while AUC was similar between males and females.1 In females, mean AUC and peak plasma concentration of palonosetron were 35 and 26% higher, respectively, compared with males.1 The pharmacokinetics of fosnetupitant, netupitant, netupitant metabolites and palonosetron were not affected by sex after a single IV dose of fixed-combination fosnetupitant and palonosetron.1 There was no effect of sex on the pharmacokinetics of fosnetupitant, netupitant, and its metabolites after a single IV dose of fosnetupitant alone in healthy subjects.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | Netupitant 300 mg and palonosetron 0.5 mg | Akynzeo® | Helsinn |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Concentrate, for injection, for IV infusion | Fosnetupitant 235 mg and palonosetron 0.25 mg per 20 mL (11.75 mg/0.0125 mg per mL) | Akynzeo® | |
Injection, for IV infusion (Ready-to-Use Formulation) | Fosnetupitant 235 mg and palonosetron 0.25 mg per 20 mL (11.75 mg/0.0125 mg per mL) | Akynzeo® | ||
For injection, for IV infusion | Fosnetupitant 235 mg and palonosetron 0.25 mg | Akynzeo® |
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions November 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Helsinn Therapeutics, Inc. Akynzeo® (netupitant and palonosetron hydrochloride) capsules and (fosnetupitant and palonosetron) injection prescribing information. Lugano, Switzerland; 2023 Feb.
2. Hesketh PJ, Rossi G, Rizzi G et al. Efficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy: a randomized dose-ranging pivotal study. Ann Oncol . 2014; 25:1340-6. [PubMed 24608196]
3. Aapro M, Rugo H, Rossi G et al. A randomized phase III study evaluating the efficacy and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy. Ann Oncol . 2014; 25:1328-33. [PubMed 24603643]
26. Gralla RJ, Bosnjak SM, Hontsa A et al. A phase III study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting over repeated cycles of chemotherapy. Ann Oncol . 2014; 25:1333-9. [PubMed 24631949]
37. Karthaus M, Tibor C, Lorusso V, et al. Efficacy and safety of oral palonosetron compared with IV palonosetron administered with dexamethasone for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients with solid tumors receiving cisplatin-based highly emetogenic chemotherapy (HEC). Support Care Cancer. 2015;23(10):2917-23.
38. Karthaus M, Voisin D, Rizzi G, Ciuleanu T. Phase 3 study of palonosetron IV infusion vs. IV bolus for chemotherapy-induced nausea and vomiting prophylaxis after highly emetogenic chemotherapy. J Pain Symptom Manage. 2020;60(3):568-576.
400. Hesketh P, Kris M, Basch E, et al. Antiemetics: ASCO guideline update. J Clin Oncol. 2020;38:2782-2797.