"The U.S. Food and Drug Administration approved Varubi (rolapitant) to prevent delayed phase chemotherapy-induced nausea and vomiting (emesis). Varubi is approved in adults in combination with other drugs (antiemetic agents) that prevent nausea an"...
Mechanism Of Action
Fosaprepitant is a prodrug of aprepitant and accordingly, its antiemetic effects are attributable to aprepitant.
Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT 3), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CINV). Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human Positron Emission Tomography (PET) studies with aprepitant have shown that it crosses the blood brain barrier and occupies brain NK 1 receptors. Animal and human studies show that aprepitant augments the antiemetic activity of the 5-HT 3-receptor antagonist ondansetron and the corticosteroid dexamethasone and inhibits both the acute and delayed phases of cisplatin-induced emesis.
In a randomized, double-blind, positive-controlled, thorough QTc study, a single 200-mg dose of fosaprepitant (approximately 1.3 times the recommended dose) had no effect on the QTc interval.
Aprepitant after Fosaprepitant Administration
Following administration of a single intravenous 150-mg dose of fosaprepitant, a prodrug of aprepitant administered as a 20-minute infusion to healthy subjects, the mean AUC 0-∞ of aprepitant was 37.4 (± 14.8) mcg•hr/mL and the mean maximal aprepitant concentration (C max ) was 4.2 (± 1.2) mcg/mL. Plasma concentrations of fosaprepitant are below the limits of quantification (10 ng/mL) within 30 minutes of the completion of infusion.
Aprepitant is greater than 95% bound to plasma proteins. The mean apparent volume of distribution at steady state (Vd ss) was approximately 70 L in humans.
Aprepitant crosses the blood brain barrier in humans [see Mechanism of Action].
Fosaprepitant is converted to aprepitant in in vitro incubations with human liver preparations and in S9 preparations from multiple other human tissues including kidney, lung and ileum. Thus, it appears that the conversion of fosaprepitant to aprepitant can occur in multiple extrahepatic tissues in addition to the liver.
Aprepitant undergoes extensive metabolism. In vitro studies using human liver microsomes indicate that aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. Metabolism is largely via oxidation at the morpholine ring and its side chains. No metabolism by CYP2D6, CYP2C9, or CYP2E1 was detected.
In healthy young adults, aprepitant accounts for approximately 24% of the radioactivity in plasma over 72 hours following a single oral 300-mg dose of [14C]-aprepitant, indicating a substantial presence of metabolites in the plasma. Seven metabolites of aprepitant, which are only weakly active, have been identified in human plasma.
Following administration of a single intravenous 100-mg dose of [14C]-fosaprepitant to healthy subjects, 57% of the radioactivity was recovered in urine and 45% in feces.
Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted. The apparent terminal half-life ranged from approximately 9 to 13 hours.
Age: Geriatric Population
Following oral administration of a single 125-mg dose of aprepitant on Day 1 and 80 mg once daily on Days 2 through 5, the AUC 0-24hr of aprepitant was 21% higher on Day 1 and 36% higher on Day 5 in elderly (65 years and older) relative to younger adults. The C max was 10% higher on Day 1 and 24% higher on Day 5 in elderly relative to younger adults. These differences are not considered clinically meaningful [see Use in Specific Populations].
Following oral administration of a single dose of aprepitant, ranging from 40 mg to 375 mg, the AUC 0-24hr and Cmax are 14% and 22% higher in females as compared with males. The half-life of aprepitant is 25% lower in females as compared with males and T max occurs at approximately the same time. These differences are not considered clinically meaningful.
Following oral administration of a single dose of aprepitant, ranging from 40 mg to 375 mg, the AUC 0-24hr and C max are approximately 42% and 29% higher in Hispanics as compared with Caucasians. The AUC 0-24hr and C max were 62% and 41% higher in Asians as compared to Caucasians. There was no difference in AUC 0-24hr or C max between Caucasians and Blacks. These differences are not considered clinically meaningful.
A single 240-mg oral dose of aprepitant was administered to patients with severe renal impairment (creatinine clearance less than 30 mL/min/1.73 m² as measured by 24-hour urinary creatinine clearance) and to patients with end stage renal disease (ESRD) requiring hemodialysis.
In patients with severe renal impairment, the AUC 0-∞ of total aprepitant (unbound and protein bound) decreased by 21% and C max decreased by 32%, relative to healthy subjects (creatinine clearance greater than 80 mL/min estimated by Cockcroft-Gault method). In patients with ESRD undergoing hemodialysis, the AUC 0-∞ of total aprepitant decreased by 42% and C max decreased by 32%. Due to modest decreases in protein binding of aprepitant in patients with renal disease, the AUC of pharmacologically active unbound drug was not significantly affected in patients with renal impairment compared with healthy subjects. Hemodialysis conducted 4 or 48 hours after dosing had no significant effect on the pharmacokinetics of aprepitant; less than 0.2% of the dose was recovered in the dialysate.
Fosaprepitant is metabolized in various extrahepatic tissues; therefore hepatic impairment is not expected to alter the conversion of fosaprepitant to aprepitant.
Following administration of a single 125-mg oral dose of aprepitant on Day 1 and 80 mg once daily on Days 2 and 3 to patients with mild hepatic impairment (Child-Pugh score 5 to 6), the AUC 0-24hr of aprepitant was 11% lower on Day 1 and 36% lower on Day 3, as compared with healthy subjects given the same regimen. In patients with moderate hepatic impairment (Child-Pugh score 7 to 9), the AUC 0-24hr of aprepitant was 10% higher on Day 1 and 18% higher on Day 3, as compared with healthy subjects given the same regimen. These differences in AUC 0-24hr are not considered clinically meaningful. There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score greater than 9) [see Use In Specific Populations].
Body Mass Index (BMI)
For every 5 kg/m² increase in BMI, AUC 0-24hr and C max of aprepitant decrease by 11%. BMI of subjects in the analysis ranged from 18 kg/m² to 36 kg/m² . This change is not considered clinically meaningful.
Drug Interactions Studies
Fosaprepitant, given as a single 150-mg dose, is a weak inhibitor of CYP3A4, with no evidence of inhibition or induction of CYP3A4 observed on Day 4. The weak inhibition of CYP3A4 continues for 2 days after single dose administration of fosaprepitant. Aprepitant is a substrate, an inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9.
Fosaprepitant or aprepitant is unlikely to interact with drugs that are substrates for the Pglycoprotein transporter.
Effects of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Drugs
Midazolam: Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the AUC 0-∞ of midazolam by approximately 1.8-fold on Day 1 and had no effect on Day 4 when midazolam was coadministered as a single oral dose of 2 mg on Days 1 and 4.
Dexamethasone: Fosaprepitant administered as a single 150 mg intravenous dose on Day 1 increased the AUC 0-24hr of dexamethasone, administered as a single 8-mg oral dose on Days 1, 2, and 3, by approximately 2-fold on Days 1 and 2 [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS].
Methylprednisolone: W hen oral aprepitant as a 3-day regimen (125-mg/80-mg/80-mg) was administered with intravenous methylprednisolone 125 mg on Day 1 and oral methylprednisolone 40 mg on Days 2 and 3, the AUC of methylprednisolone was increased by 1.34-fold on Day 1 and by 2.5-fold on Day 3 [see DRUG INTERACTIONS].
Docetaxel: In a pharmacokinetic study, oral aprepitant administered as a 3-day regimen (125mg/80-mg/80-mg) did not influence the pharmacokinetics of docetaxel.
Vinorelbine: In a pharmacokinetic study, oral aprepitant administered as a 3-day regimen (125mg/80-mg/80-mg) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree.
Oral contraceptives: W hen oral aprepitant was administered as a 3-day regimen (125-mg/80-mg/80mg) with ondansetron and dexamethasone, and coadministered with an oral contraceptive containing ethinyl estradiol and norethindrone, the trough concentrations of both ethinyl estradiol and norethindrone were reduced by as much as 64% for 3 weeks post-treatment [see DRUG INTERACTIONS].
CYP2C9 Substrates (Warfarin, Tolbutamide)
Warfarin: A single 125-mg dose of oral aprepitant was administered on Day 1 and 80 mg/day on Days 2 and 3 to subjects who were stabilized on chronic warfarin therapy. Although there was no effect of oral aprepitant on the plasma AUC of R(+) or S(-) warfarin determined on Day 3, there was a 34% decrease in S(-) warfarin trough concentration accompanied by a 14% decrease in the prothrombin time (reported as International Normalized Ratio or INR) 5 days after completion of dosing with oral aprepitant [see DRUG INTERACTIONS].
Tolbutamide: Oral aprepitant, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered prior to the administration of the 3-day regimen of oral aprepitant and on Days 4, 8, and 15. This effect was not considered clinically important.
P-glycoprotein substrates: Aprepitant is unlikely to interact with drugs that are substrates for the Pglycoprotein transporter, as demonstrated by the lack of interaction of oral aprepitant with digoxin in a clinical drug interaction study.
5-HT3 antagonists: In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron).
Effect of Other Drugs on the Pharmacokinetics of Fosaprepitant/Aprepitant
Rifampin: W hen a single 375-mg dose of oral aprepitant was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold [see DRUG INTERACTIONS].
Ketoconazole: W hen a single 125-mg dose of oral aprepitant was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold [see DRUG INTERACTIONS].
Diltiazem: In a study in 10 patients with mild to moderate hypertension, administration of 100 mg of fosaprepitant as an intravenous infusion with 120 mg of diltiazem, a moderate CYP3A4 inhibitor administered three times daily, resulted in a 1.5-fold increase in the aprepitant AUC and a 1.4-fold increase in the diltiazem AUC.
When fosaprepitant was administered with diltiazem, the mean maximum decrease in diastolic blood pressure was significantly greater than that observed with diltiazem alone [24.3 ± 10.2 mm Hg with fosaprepitant versus 15.6 ± 4.1 mm Hg without fosaprepitant]. The mean maximum decrease in systolic blood pressure was also greater after co-administration of diltiazem with fosaprepitant than administration of diltiazem alone [29.5 ± 7.9 mm Hg with fosaprepitant versus 23.8 ± 4.8 mm Hg without fosaprepitant]. Co-administration of fosaprepitant and diltiazem; however, did not result in any additional clinically significant changes in heart rate or PR interval, beyond those changes observed with diltiazem alone [see DRUG INTERACTIONS].
Paroxetine: Coadministration of once daily doses of oral aprepitant 170 mg, with paroxetine 20 mg once daily, resulted in a decrease in AUC by approximately 25% and C max by approximately 20% of both aprepitant and paroxetine. This effect was not considered clinically important.
Prevention Of Nausea And Vomiting Associated With HEC
In a randomized, parallel, double-blind, active-controlled study, EMEND for injection 150 mg as a single intravenous infusion (N=1147) was compared to a 3-day oral EMEND regimen (N=1175) in patients receiving a HEC regimen that included cisplatin ( ≥ 70 mg/m²). All patients in both groups received dexamethasone and ondansetron (see Table 7). Patient demographics were similar between the two treatment groups. Of the total 2322 patients, 63% were men, 56% W hite, 26% Asian, 3% American Indian/Alaska Native, 2% Black, 13% Multi-Racial, and 33% Hispanic/Latino ethnicity. Patient ages ranged from 19 to 86 years of age, with a mean age of 56 years. Other concomitant chemotherapy agents commonly administered were fluorouracil (17%), gemcitabine (16%), paclitaxel (15%), and etoposide (12%).
Table 7 : Treatment Regimens
in HEC Trial*
|Day 1||Day 2||Day 3||Day 4|
|EMEND for injection||150 mg intravenously over 20 to 30 minutes approximately 30 minutes prior to chemotherapy||none||none||none|
|Oral dexamethasone†||12 mg||8 mg||8 mg twice daily||8 mg twice daily|
|Oral EMEND Regimen|
|EMEND capsules||125 mg||80 mg||80 mg||none|
|Oral dexamethasone§||12 mg||8 mg||8 mg||8 mg|
|*EMEND for injection placebo,
EMEND capsules placebo and dexamethasone placebo (in the evenings on Days 3 and
4) were used to maintain blinding.
†Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 through 4. Dexamethasone was also administered in the evenings on Days 3 and 4. The 12 mg dose of dexamethasone on Day 1 and the 8 mg once daily dose on Day 2 reflects a dosage adjustment to account for a drug interaction with the EMEND for injection regimen [see Pharmacokinetics].
‡Ondansetron 32 mg intravenous was used in the clinical trials of EMEND. Although this dose was used in clinical trials, this is no longer the currently recommended dose. Refer to the ondansetron prescribing information for the current recommended dose.
§Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 through 4. The 12 mg dose of dexamethasone on Day 1 and the 8 mg once daily dose on Days 2 through 4 reflects a dosage adjustment to account for a drug interaction with the oral EMEND regimen [see Pharmacokinetics].
The efficacy of EMEND for injection was evaluated based on the primary and secondary endpoints listed in Table 8 and was shown to be non-inferior to that of the 3-day oral aprepitant regimen with regard to complete response in each of the evaluated phases. The pre-specified non-inferiority margin for complete response in the overall phase was 7%. The pre-specified non-inferiority margin for complete response in the delayed phase was 7.3%. The pre-specified non-inferiority margin for no vomiting in the overall phase was 8.2%.
Table 8 : Percent of
Patients Receiving Highly Emetogenic Chemotherapy Responding by Treatment Group
and Phase — Cycle 1
|ENDPOINTS||EMEND for Injection Regimen
(N = 1106)* %
|Oral EMEND Regimen
(N = 1134)* %
|Difference† (95% CI)|
|*N: Number of patients included
in the primary analysis of complete response.
†Difference and Confidence interval (CI) were calculated using the method proposed by Miettinen and Nurminen and adjusted for Gender.
‡Complete Response = no vomiting and no use of rescue therapy.
§Overall = 0 to 120 hours post-initiation of cisplatin chemotherapy.
¶ Delayed phase = 25 to 120 hours post-initiation of cisplatin chemotherapy.
Prevention Of Nausea And Vomiting Associated With MEC
In a randomized, parallel, double-blind, active comparator-controlled study, EMEND for injection 150 mg as a single intravenous infusion (N=502) in combination with ondansetron and dexamethasone (EMEND regimen) was compared with ondansetron and dexamethasone alone (standard therapy) (N=498) (see Table 9) in patients receiving a MEC regimen. Patient demographics were similar between the two treatment groups. Of the total 1,000 patients included in the efficacy analysis, 41% were men, 84% W hite, 4% Asian, 1% American Indian/Alaska Native, 2% Black, 10% Multi-Racial, and 19% Hispanic/Latino ethnicity. Patient ages ranged from 23 to 88 years of age, with a mean age of 60 years. The most commonly administered MEC chemotherapeutic agents were carboplatin (51%), oxaliplatin (24%), and cyclophosphamide (12%).
Table 9 : Treatment Regimens
in MEC Trial*
|Day 1||Day 2||Day 3|
|EMEND for Injection||150 mg intravenously over 20 to 30 minutes approximately 30 minutes prior to chemotherapy||none||none|
|Oral Dexamethasone†||12 mg||none||none|
|Oral Ondansetron‡||8 mg for 2 doses||none||none|
|Oral Dexamethasone||20 mg||none||none|
|Oral Ondansetron‡||8 mg for 2 doses||8 mg twice daily||8 mg twice daily|
|*EMEND for injection placebo
and dexamethasone placebo (on Day 1) were used to maintain blinding.
†Dexamethasone was administered 30 minutes prior to chemotherapy treatment on Day 1. The 12 mg dose reflects a dosage adjustment to account for a drug interaction with the EMEND for injection regimen [see Pharmacokinetics].
‡The first ondansetron dose was administered 30 to 60 minutes prior to chemotherapy treatment on Day 1 and the second dose was administered 8 hours after first ondansetron dose.
The primary endpoint was complete response (defined as no vomiting and no rescue therapy) in the delayed phase (25 to 120 hours) of chemotherapy-induced nausea and vomiting. The results by treatment group are shown in Table 10.
Table 10 : Percent of
Patients Receiving Moderately Emetogenic Chemotherapy Responding by Treatment
|ENDPOINTS||EMEND for Injection Regimen
(N = 502)* %
|Standard Therapy Regimen
(N = 498)* %
|P-Value||T reatment Difference (95% CI)|
|Delayed phase‡||78.9||68.5||< 0.001||10.4
|*N: Number of patients included
in the intention to treat population.
†Complete Response = no vomiting and no use of rescue therapy.
‡Delayed phase = 25 to 120 hours post-initiation of chemotherapy.
Last reviewed on RxList: 2/16/2016
This monograph has been modified to include the generic and brand name in many instances.
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