VA Class:GA605
ATC Class:A04AA55
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, 2, 3, 27, 28, 35, 36
Cancer Chemotherapy-induced Nausea and Vomiting
Netupitant and palonosetron hydrochloride are used orally in fixed combination (Akynzeo®) 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 Palonosetron prevents nausea and vomiting during the acute phase and netupitant prevents nausea and vomiting during both the acute and delayed phase after cancer chemotherapy.1 Fixed-combination netupitant and palonosetron is used in an antiemetic regimen that also includes dexamethasone.1
To prevent chemotherapy-induced nausea and vomiting associated with highly emetogenic chemotherapy regimens (including an anthracycline plus cyclophosphamide), the American Society of Clinical Oncology (ASCO) currently recommends a 3-drug antiemetic regimen consisting of a neurokinin-1 (NK1) receptor antagonist (e.g., either oral aprepitant or IV fosaprepitant dimeglumine), a type 3 serotonin (5-HT3) receptor antagonist (e.g., dolasetron, granisetron, ondansetron, palonosetron, ramosetron [not commercially available in the US], tropisetron [not commercially available in the US]), and dexamethasone.28, 33 ASCO states that oral, fixed-combination netupitant and palonosetron plus dexamethasone is an additional antiemetic treatment option in this setting.33
For patients receiving moderately emetogenic chemotherapy regimens, ASCO recommends a 2-drug antiemetic regimen preferably consisting of palonosetron and dexamethasone.28, 33 If palonosetron is not available, a first-generation 5-HT3 receptor antagonist (preferably granisetron or ondansetron) may be substituted.28 Limited evidence suggests that aprepitant may be added to this regimen; in such cases, ASCO states that any of the 5-HT3 receptor antagonists is appropriate.28
For patients receiving chemotherapy regimens with a low emetogenic risk , ASCO recommends administration of a single dose of dexamethasone prior to chemotherapy.28
In patients receiving chemotherapy regimens with a minimal emetogenic risk, antiemetics should not be routinely administered prior to or following chemotherapy.28
Efficacy and safety of fixed-combination 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-naive, 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-naive, 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 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-naive, 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 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 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 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
For IV use of palonosetron hydrochloride as an antiemetic, see Palonosetron Hydrochloride 56:22.20.
The fixed-combination capsules containing netupitant and palonosetron hydrochloride (netupitant/palonosetron; Akynzeo®) are administered orally approximately one hour before the start of chemotherapy without regard to meals.1
The manufacturer states that the antiemetic regimen also should include oral dexamethasone administered 30 minutes prior to chemotherapy on days 1-4 for highly emetogenic chemotherapy (including cisplatin-based chemotherapy), or on day 1 only for anthracycline- and cyclophosphamide-based chemotherapy and chemotherapy not considered highly emetogenic.1
Netupitant and palonosetron hydrochloride is a fixed combination preparation containing 300 mg of netupitant and 0.5 mg of palonosetron.1
The netupitant component is provided as netupitant;1 the palonosetron component is provided as palonosetron hydrochloride (dosage of this component is expressed in terms of palonosetron).1
Cancer 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 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 (See Drug Interactions: Dexamethasone.)
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 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 (See Drug Interactions: Dexamethasone.)
Dosage adjustments are not necessary when fixed-combination netupitant and palonosetron is used in patients with mild or moderate hepatic impairment (Child-Pugh score of 5-8).1 However, fixed-combination netupitant and palonosetron should not be used in patients with severe hepatic impairment (Child-Pugh score exceeding 9) because the fixed combination has not been adequately studied in such patients.1
Dosage adjustments are not necessary when fixed-combination netupitant and palonosetron is used in patients with mild to moderate renal impairment.1 However, fixed-combination netupitant and palonosetron should not be used in patients with severe renal impairment or end-stage renal disease.1
Caution generally should be used when dosing fixed-combination netupitant 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
The manufacturer states there are no known contraindications to the use of the fixed combination of netupitant and palonosetron hydrochloride.1
Hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving palonosetron; the reactions have occurred in patients with or without known hypersensitivity to other type 3 serotonergic (5-HT3) receptor antagonists.1, 29, 30 (See Advice to Patients.)
Other Warnings and Precautions
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 (ondansetron) also has been reported.1, 31 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 and palonosetron, should be 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 and palonosetron should be discontinued, and supportive treatment should be initiated.1 (See Drug Interactions: Serotonergic Agents and also see Advice to Patients.)
Category C.1 (See Users Guide.)
It is not known whether netupitant or palonosetron is distributed into human milk.1 Because many drugs are excreted in milk and because of the potential tumorigenicity palonosetron demonstrated in an animal carcinogenicity study, a decision should be made whether to discontinue nursing or the fixed combination of netupitant and palonosetron, taking into account the importance of the drugs to the woman.1
The manufacturer states that the safety and efficacy of netupitant and palonosetron hydrochloride 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 in patients receiving cisplatin chemotherapy, 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 in patients receiving anthracycline plus cyclophosphamide chemotherapy, the difference in complete response rates between fixed-combination netupitant and palonosetron and palonosetron alone also was 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
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 of the 2 drugs.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
Caution is advised when dosing fixed-combination netupitant 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 and palonosetron should therefore be avoided in patients with severe hepatic impairment.1
In a population pharmacokinetic analysis, mild and moderate renal impairment did not substantially affect the pharmacokinetics of netupitant in cancer patients.1 The manufacturer states that no dosage adjustment of fixed-combination netupitant 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 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 The manufacturer states that use of fixed-combination netupitant and palonosetron should be avoided in patients with severe renal impairment or end-stage renal disease.1
Adverse effects reported in 3% or more of patients receiving the oral fixed combination of netupitant and palonosetron concomitantly with highly emetogenic, cisplatin-based chemotherapy and that occurred more frequently than in those receiving palonosetron alone include dyspepsia,1, 2 fatigue,1 constipation,1, 26 and erythema.1
Adverse effects reported in 3% or more of patients receiving fixed-combination netupitant with palonosetron concomitantly with anthracycline- and cyclophosphamide-based chemotherapy (cycle 1) and that occurred at a rate that exceeded palonosetron alone include headache,1 asthenia,1 and fatigue.1, 3, 26
Metabolism of netupitant is primarily mediated by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, by CYP2C9 and CYP2D6.1
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 dose of 300 mg.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 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
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Concomitant use of fixed-combination netupitant and palonosetron with potent CYP3A4 inhibitors (e.g., ketoconazole) can substantially increase systemic exposure to the netupitant component of the fixed combination.1 (See Drug Interactions: Ketoconazole.) However, the manufacturer states that dosage adjustment is not necessary for single-dose administration of fixed-combination netupitant and palonosetron during concomitant use of potent CYP3A4 inhibitors.1
Plasma concentrations of CYP3A4 substrates may increase when used concomitantly with fixed-combination netupitant and palonosetron.1 The inhibitory effect of netupitant on CYP3A4 can last for multiple days.1 Therefore, fixed-combination netupitant and palonosetron should be used with caution in patients concomitantly receiving drugs that are principally metabolized by CYP3A4.1
Potent 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 potent CYP3A4 inducer (e.g., rifampin).1 (See Drug Interactions: Rifampin.)
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. Systemic exposure to IV docetaxel, etoposide, and cyclophosphamide was increased when administered with fixed-combination netupitant with palonosetron. Systemic exposure to IV docetaxel, etoposide, and cyclophosphamide was increased when administered with fixed-combination netupitant with palonosetron compared with palonosetron administration alone in patients with cancer.1
Concurrent administration of fixed-combination netupitant and palonosetron increased the mean peak plasma concentration and area under the concentration-time curve (AUC) of docetaxel by 49 and 35%, respectively, and increased the mean peak plasma concentration and AUC of etoposide by 10 and 28%, respectively, compared with palonosetron administration alone.1
Following concomitant administration of fixed-combination netupitant and palonosetron, mean peak plasma concentration and AUC of cyclophosphamide were 27 and 20% higher, respectively, compared with concomitant administration of palonosetron alone.1
The mean AUC of palonosetron was approximately 65% higher when fixed-combination netupitant and 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 and palonosetron and other serotonergic drugs.1 If symptoms of serotonin syndrome occur, fixed-combination netupitant and palonosetron should be discontinued, and supportive treatment should be initiated.1 (See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions and also see Advice to Patients.)
The pharmacokinetics of netupitant and palonosetron were not substantially affected when oral netupitant (450 mg) and oral palonosetron (0.75 mg) were concurrently administered.1, 32
Concomitant administration of a single dose of netupitant (300 mg on day 1) and a dexamethasone regimen (20 mg on day 1, followed by 8 mg twice daily on days 2-4) increased systemic exposure to dexamethasone approximately twofold.1 The mean AUC of dexamethasone increased by 1.7-fold on day 1 and up to 2.4-fold on days 2 and 4; the duration of this effect was not studied beyond 4 days.1 Therefore, the manufacturer states that a reduced dose of dexamethasone (i.e., 8 or 12 mg orally) should be administered when used with fixed-combination netupitant and palonosetron.1 (See Dosage and Administration: Dosage.)
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 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 pharmacokinetics of netupitant were not affected by concurrent administration of erythromycin.34
A single dose of fixed-combination netupitant and palonosetron was administered with ketoconazole (a potent CYP3A4 inhibitor) 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 and palonosetron.1
Systemic exposure of midazolam was substantially higher when administered with netupitant.1, 34 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 pharmacokinetics of netupitant were unaffected by concomitant administration of midazolam.34 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 and palonosetron.1, 34
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%.1 However, fixed-combination netupitant and palonosetron did not substantially affect the AUC of ethinyl estradiol.1, 32 A clinically important effect of fixed-combination netupitant and palonosetron on the efficacy of oral contraceptives containing levonorgestrel and ethinyl estradiol is therefore considered unlikely,1, 32 and dosage adjustments are not necessary during concomitant use of these drugs.32
Single-dose, fixed-combination netupitant and palonosetron was administered with rifampin, a potent CYP3A4 inducer, following once-daily administration of rifampin (600 mg for 17 days).1 Concurrent administration of rifampin decreased the mean peak plasma concentration and exposure 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 mean peak plasma concentration and AUC of palonosetron by 15 and 19%, respectively.1
Because potent CYP3A4 inducers can decrease the efficacy of fixed-combination netupitant and palonosetron by substantially reducing plasma concentrations of the netupitant component, use of fixed-combination netupitant and palonosetron should be avoided in patients receiving long-term therapy with potent CYP3A4 inducers such as rifampin.1
Netupitant and palonosetron hydrochloride is a fixed oral combination of 2 antiemetic agents: netupitant, a highly selective antagonist at substance P/neurokinin-1 (NK1) receptors, and palonosetron, a selective, second-generation inhibitor of type 3 serotonergic (5-HT3) receptors.1, 2, 3, 27, 28, 35, 36
Palonosetron is pharmacologically related to first-generation 5-HT3 receptor antagonists (e.g., dolasetron, granisetron, ondansetron). However, palonosetron has a higher potency, higher binding affinity for 5-HT3 receptors, a longer elimination half-life, and a different molecular interaction with 5-HT3 receptors than other commercially available 5-HT3 receptor antagonists and exhibits little or no affinity for other receptors.1, 2, 3, 5, 11, 27, 28, 35, 36
Current evidence suggests that chemotherapeutic agents produce acute nausea and vomiting by inducing degenerative changes in the GI tract (e.g., small intestine), thereby increasing endogenous serotonin release from the enterochromaffin cells of the small intestine. Serotonin then stimulates 5-HT3 receptors on vagal and splanchnic nerves that project to the medullary vomiting (emetic) center of the brain and also appears to stimulate 5-HT3 receptors in the area postrema.1, 5, 6, 7, 8, 9, 10, 12, 13, 15, 16, 17 Thus, 5-HT3 receptor antagonists appear to prevent or ameliorate acute chemotherapy-induced emesis by inhibiting visceral (from the GI tract) afferent stimulation of the emetic center probably indirectly at the level of the area postrema and by directly inhibiting serotonin activity within the area postrema and chemoreceptor trigger zone (CTZ).1, 5, 6, 7, 8, 9, 10, 12, 13, 15, 16, 17
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 In addition, the combination of palonosetron and netupitant may inhibit the action of substance P synergistically.2, 3, 27, 35, 36
Following single-dose, oral administration of fixed-combination netupitant and palonosetron hydrochloride in healthy individuals, peak plasma concentrations of netupitant and palonosetron are achieved within approximately 5 hours.1
In a pooled analysis, 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
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 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 Following a single oral dose of netupitant, the apparent elimination half-life in cancer patients is 80 hours.1 The elimination half-life of palonosetron in cancer patients is 48 hours.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 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
Importance of reading patient information provided by the manufacturer before beginning therapy and rereading it each time the fixed-combination netupitant and palonosetron hydrochloride is taken.1
Importance of informing patients to take fixed-combination netupitant and palonosetron hydrochloride with or without food approximately 1 hour before initiation of antineoplastic chemotherapy.1
Importance of informing patients that hypersensitivity reactions, including anaphylaxis, have been reported in patients receiving palonosetron.1 Clinicians should advise patients to seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction occur while receiving netupitant and palonosetron in fixed combination.1
Importance of informing patients of the possibility of serotonin syndrome, particularly with concomitant use of fixed-combination netupitant and palonosetron and another serotonergic agent such as antidepressants and antimigraine agents.1 Clinicians should advise patients to seek immediate medical attention should they experience any of the following serotonin syndrome symptoms: changes in mental status, autonomic instability, or neuromuscular symptoms, either with or without GI symptoms.1
Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1
Importance of informing patients of other precautionary information.1 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
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.
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions March 4, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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