aprepitant and fosaprepitant

Ifosfamide is one of the chemotherapy regimens which potentially causes neurotoxicity in patients up to 30%. Aprepitant is administered as an anti-emetic agent in chemotherapy and regarding the inhibitory effect on CYP3A4, aprepitant can increase the risk of ifosfamide adverse effects. This study aims to systematically investigate the relation of ifosfamide-induced neurotoxicity and aprepitant or fosaprepitant in chemotherapy cancer patients. Four databases including PubMed, Scopus, Web of Science, and Embase were systematically reviewed without language restriction and hand searching was performed until December 2021. Total 1639 publications were retrieved and nine studies fulfilled the eligibility criteria. For quality assessment, we used Newcastle-Ottawa quality assessment scales (NOS) for retrospective cohort studies and Cochrane Collaboration tool to assess the risk of bias for a randomized controlled trial. Overall, the results of our systematic review indicated a positive enhanced trend between neurotoxicity and concomitant use of ifosfamide and aprepitant or fosaprepitant, but the association was not statistically significant. As indicated by our findings, several studies identified low albumin as a risk factor for ifosfamide-induced encephalopathy. However, further clinical studies with a larger population of patients are required to evaluate the clinical significance of ifosfamide-related neurotoxicity and aprepitant or fosaprepitant.

Topics: Aprepitant; Humans; Ifosfamide; Morpholines; Neurotoxicity Syndromes; Randomized Controlled Trials as Topic; Retrospective Studies

Aprepitant and fosaprepitant, commonly used for the prevention of chemotherapy-induced nausea and vomiting, alter cytochrome P450 activity. This systematic review evaluates clinically significant pharmacokinetic drug interactions with aprepitant and fosaprepitant and describes adverse events ascribed to drug interactions with aprepitant or fosaprepitant.. We systematically reviewed the literature to September 11, 2016, to identify articles evaluating drug interactions involving aprepitant/fosaprepitant. The clinical significance of each reported pharmacokinetic drug interaction was evaluated based on the United States Food and Drug Administration guidance document on conducting drug interaction studies. The probability of an adverse event reported in case reports being due to a drug interaction with aprepitant/fosaprepitant was determined using the Drug Interaction Probability Scale.. A total of 4377 publications were identified. Of these, 64 met inclusion eligibility criteria: 34 described pharmacokinetic drug interactions and 30 described adverse events ascribed to a drug interaction. Clinically significant pharmacokinetic interactions between aprepitant/fosaprepitant and bosutinib PO, cabazitaxel IV, cyclophosphamide IV, dexamethasone PO, methylprednisolone IV, midazolam PO/IV, oxycodone PO and tolbutamide PO were identified, as were adverse events resulting from an interaction between aprepitant/fosaprepitant and alcohol, anthracyclines, ifosfamide, oxycodone, quetiapine, selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors and warfarin.. The potential for a drug interaction with aprepitant and fosaprepitant should be considered when selecting antiemetic therapy.

Topics: Antiemetics; Antineoplastic Agents; Aprepitant; Cytochrome P-450 CYP2C9 Inducers; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Ethanol; Humans; Injection Site Reaction; Morpholines; Nausea; Oxycodone; Quetiapine Fumarate; Selective Serotonin Reuptake Inhibitors; Serotonin and Noradrenaline Reuptake Inhibitors; Vomiting

Purpose Aprepitant and its parenteral formulation fosaprepitant are widely used for the prevention of chemotherapy-induced nausea and vomiting. Aprepitant exerts modest inhibitory effect on CYP3A4 and modest inductive effect on CYP2C9 substrates such as some antineoplastics and multiple other medications. This article is aimed to provide pharmacists and other healthcare professionals with an updated summary of drug-drug interactions of aprepitant/fosaprepitant and implications for clinical practice. Method We reviewed publications reporting drug-drug interactions between aprepitant/fosaprepitant and other medications. Results Coadministration of aprepitant with antineoplastics or opiods may result in significant elevations in the serum levels of the agents metabolized via CYP3A4, with the best documentation for cyclophosphamide, ifosfamide, erlotinib and oxycodone. These alterations did not translate into adverse outcomes and/or necessitate dosing adjustments. The levels of warfarin were significantly decreased by aprepitant requiring prolonged monitoring after discontinuation of aprepitant. Among direct oral anticoagulants, a theoretical interaction between aprepitant and rivaroxaban or apixaban exists. Interactions between aprepitant and quetiapine or diltiazem or sirolimus required dose reductions to avoid adverse outcomes. The intravenous route had a weaker inhibitory effect on CYP3A4 than the oral pathway. Conclusion The evidence on drug interactions of aprepitant with other medications is limited, and the impact on therapeutic outcomes remains to be determined. The intravenous regimen may be a preferred option. As utilization of aprepitant is expanding, practitioners and patients need to be educated about the potential for drug interactions and a need for careful monitoring of patients concurrently receiving aprepitant and CYP2C9 or CYP3A4 substrates, especially those with a narrow therapeutic window.

Topics: Analgesics, Opioid; Anticoagulants; Antiemetics; Antineoplastic Agents; Aprepitant; Cytochrome P-450 CYP3A; Drug Interactions; Humans; Morpholines

Chemotherapy-induced nausea and vomiting (CINV) is a common adverse event associated with anticancer treatment that can have a significant adverse impact on patient health-related quality of life and that can potentially undermine the effectiveness of chemotherapy. Traditional regimens to prevent CINV generally involved a combination of a corticosteroid plus a 5-hydroxytryptamine (5HT3) receptor antagonist (RA). In the past 10 years, antiemetic treatment has greatly advanced with the availability of the neurokinin-1 receptor antagonist (NK1 RA) aprepitant and its prodrug fosaprepitant. NK1 RAs have a different mechanism of action in CINV than corticosteroids and 5HT3 RAs, thus their use can complement traditional antiemetic drugs and can enhance control of CINV. This review examined accumulated data regarding the safety and efficacy of aprepitant and fosaprepitant over the decade since the first regulatory approval. Data from key studies of aprepitant and fosaprepitant in the prevention of CINV in patients receiving moderately and highly emetogenic chemotherapy were explored, as were recommendations in currently available guidelines for their use. In addition, their use as antiemetic therapy in special patient populations was highlighted. Future perspectives on potential uses of aprepitant and fosaprepitant for indications other than CINV are presented.

Topics: Administration, Intravenous; Administration, Oral; Antiemetics; Antineoplastic Agents; Aprepitant; Drug Interactions; Guidelines as Topic; Humans; Morpholines; Nausea; Stem Cell Transplantation; Vomiting

The substance P (SP)/neurokinin (NK)-1 receptor system is involved in many pathological processes. NK-1 receptor antagonists have many promising therapeutic indications. However, the only NK-1 receptor antagonist used in clinical practice is the drug aprepitant and its intravenously administered prodrug, fosaprepitant. In general, NK-1 receptor antagonists are safe and well tolerated.. A search was carried out in Medline using the following terms: adverse events, aprepitant, casopitant, clinical trials, CP-122,721, ezlopitant, fosaprepitant, NK-1 receptor antagonists, randomized, safety, side effects, tolerability and vofopitant.. Most clinical trials have focused on the antiemetic action of aprepitant in cancer patients treated with chemotherapy. However, the efficacy and safety of aprepitant have not been fully tested in other diseases in which the SP/NK-1 receptor system is involved (e.g., cancer, HIV, alcoholism); thus, clinical trials are required. The use of NK-1 receptor antagonists in oncology therapy is quite promising, but to date pharmacological therapy has not exploited the many possible therapies offered by such antagonists.

Topics: Aprepitant; Humans; Morpholines; Neurokinin-1 Receptor Antagonists

For patients receiving cancer chemotherapy, the ongoing development of antiemetic treatment is of significant importance. Patients consider nausea and vomiting among the most distressing symptoms of chemotherapy, and as new antiemetics have been very successful in prevention of vomiting, agents effective against nausea have become one of the major unmet needs. The neurokinin (NK)(1) receptor antagonist aprepitant potentiates the antiemetic efficacy of the combination of a serotonin receptor antagonist and a corticosteroid. Fosaprepitant (intravenous prodrug of aprepitant) given as a single intravenous dose of 150 mg can replace the aprepitant 3-day oral regimen. This article focuses on the development and clinical application of fosaprepitant.

Topics: Animals; Antiemetics; Antineoplastic Agents; Aprepitant; Clinical Trials as Topic; Humans; Morpholines; Nausea; Neurokinin-1 Receptor Antagonists; Receptors, Neurokinin-1; Treatment Outcome; Vomiting

To update the American Society of Clinical Oncology (ASCO) guideline for antiemetics in oncology.. A systematic review of the medical literature was completed to inform this update. MEDLINE, the Cochrane Collaboration Library, and meeting materials from ASCO and the Multinational Association for Supportive Care in Cancer were all searched. Primary outcomes of interest were complete response and rates of any vomiting or nausea.. Thirty-seven trials met prespecified inclusion and exclusion criteria for this systematic review. Two systematic reviews from the Cochrane Collaboration were identified; one surveyed the pediatric literature. The other compared the relative efficacy of the 5-hydroxytryptamine-3 (5-HT(3)) receptor antagonists.. Combined anthracycline and cyclophosphamide regimens were reclassified as highly emetic. Patients who receive this combination or any highly emetic agents should receive a 5-HT(3) receptor antagonist, dexamethasone, and a neurokinin 1 (NK(1)) receptor antagonist. A large trial validated the equivalency of fosaprepitant, a single-day intravenous formulation, with aprepitant; either therapy is appropriate. Preferential use of palonosetron is recommended for moderate emetic risk regimens, combined with dexamethasone. For low-risk agents, patients can be offered dexamethasone before the first dose of chemotherapy. Patients undergoing high emetic risk radiation therapy should receive a 5-HT(3) receptor antagonist before each fraction and for 24 hours after treatment and may receive a 5-day course of dexamethasone during fractions 1 to 5. The Update Committee noted the importance of continued symptom monitoring throughout therapy. Clinicians underestimate the incidence of nausea, which is not as well controlled as emesis.

Topics: Antiemetics; Antineoplastic Agents; Aprepitant; Dexamethasone; Drug Administration Schedule; Humans; Infusions, Intravenous; Isoquinolines; Morpholines; Nausea; Neurokinin-1 Receptor Antagonists; Palonosetron; Quinuclidines; Radiotherapy; Serotonin Antagonists; Surveys and Questionnaires; Vomiting

Chemotherapy induced nausea and vomiting (CINV) is a common complication in the treatment of patients with cancer. The introduction of the first in class neurokinin-1 receptor antagonist aprepitant provided additive control on CINV in combination to existing antiemetics. Due to formulation issues, aprepitant is only available for oral administration. Fosaprepitant, a prodrug of aprepitant, was introduced to the market in 2008 as an intravenous bioequivalent to aprepitant.. This review examines the chemical development of fosaprepitant, its pharmacokinetic properties, approved uses and potential applications.. The reader will get up-to-date information on the pharmacology and clinical uses of fosaprepitant. Clinical studies have demonstrated pharmacokinetic bioequivalence of aprepitant 125 mg to fosaprepitant 115 mg, as well as comparable efficacy in prevention of acute and delayed emesis following the first day of chemotherapy regimens.. Fosaprepitant is an intravenous prodrug of aprepitant that offers a new alternative to patients with CINV. Currently, fosaprepitant can substitute oral aprepitant in day 1 of a 3-day regimen. Current studies show that a single-day fosaprepitant regimen is also bioequivalent to the 3-day aprepitant regimen; this could significantly simplify the care for CINV patients in the future.

Topics: Animals; Antiemetics; Antineoplastic Agents; Aprepitant; Humans; Morpholines; Nausea; Neoplasms; Neurokinin-1 Receptor Antagonists; Prodrugs; Therapeutic Equivalency; Vomiting

Chemotherapy-induced nausea and vomiting (CINV) is a distressing and common adverse event associated with cancer treatment. Updated antiemetic guidelines were published in 2008 by the National Comprehensive Cancer Network and, in 2006, by the American Society of Clinical Oncology, which have included the use of the new and more effective antiemetic agents 5-hydroxytryptamine-3 (5-HT(3)) receptor antagonist and neurokinin (NK)-1 receptor antagonist. Aprepitant is a selective NK-1 receptor antagonist approved as part of combination therapy with a corticosteroid and a 5-HT(3) receptor antagonist for the prevention of acute and delayed CINV in patients receiving moderately and highly emetogenic chemotherapy. Fosaprepitant (also known as MK-0517 and L-758,298) is a water-soluble phosphoryl prodrug for aprepitant, which, when administered intravenously, is converted to aprepitant within 30 min of intravenous administration via the action of ubiquitous phosphatases. Owing to the rapid conversion of fosaprepitant to the active form (aprepitant), fosaprepitant 115 mg provided the same aprepitant exposure in terms of AUC as aprepitant 12 mg orally, and fosaprepitant is expected to provide a correspondingly similar antiemetic effect as aprepitant. Clinical studies have suggested that fosaprepitant could be appropriate as an intravenous alternative to the aprepitant oral capsule. In a study in healthy subjects, fosaprepitant 115 mg was generally well tolerated at a final drug concentration of 1 mg/ml, and fosaprepitant 115 mg was AUC bioequivalent to aprepitant 125 mg. Fosaprepitant in the dose of 115 mg has been approved by the US FDA, the EU and the Australian authorities on day 1 of a 3-day oral aprepitant regimen, with oral aprepitant administered on days 2 and 3. Fosaprepitant may be a useful parenteral alternative to oral aprepitant. Further study is needed to clarify the utility of fosaprepitant in the prevention of CINV and to clarify optimal dosing regimens that may be appropriate substitutes for oral aprepitant.

Topics: Animals; Antineoplastic Agents; Aprepitant; Clinical Trials as Topic; Humans; Morpholines; Nausea; Neurokinin-1 Receptor Antagonists; Receptors, Neurokinin-1; Vomiting

This paper reviews the existing literature on fosaprepitant, an intravenous neurokinin-1 anatgonist for the prevention of chemotherapy induced nausea and vomiting.. To describe the development of fosaprepitant and to situate the intravenous form of aprepitant in the current market of available antiemetics.. Literature was screened and selected in order to compare the intravenous form of the already commonly used NK-1 receptor antagonist aprepitant.. Aprepitant is the first and still the only marketed neurokinin-1 (NK-1) antagonist. Interestingly, the first studies were performed with fosaprepitant dimeglumine (MK-0517 or L-785,298), the water-soluble prodrug of aprepitant. Fosaprepitant is converted into aprepitant within 30 min after intravenous administration. Based on equivalence studies, 115 mg fosaprepitant seems to be the substitute for 125 mg orally administrated aprepitant. Tolerability of the prodrug is no different from the active drug. The number of efficacy studies with fosaprepitant is very limited and most data are derived from existing aprepitant results. Fosaprepitant has recently been approved by FDA and EMEA as an intravenous substitute for oral aprepitant on day 1 of the standard 3-day CINV prevention regimen, which also includes dexamethasone and a 5-HT3 antagonist.

Topics: Antiemetics; Aprepitant; Humans; Injections, Intravenous; Molecular Structure; Morpholines; Nausea; Neurokinin-1 Receptor Antagonists; Prodrugs; Treatment Outcome; Vomiting

Chemotherapy-induced nausea and vomiting (CINV) is a distressing and common adverse event associated with cancer treatment. Updated anti-emetic guidelines were published in 2007 by the National Comprehensive Cancer Network and in 2006 by the American Society of Clinical Oncology, which have included the use of the new and more effective anti-emetic agents (5-hydroxytryptamine-3 [5-HT(3)] receptor antagonists and neurokinin-1 [NK-1] receptor antagonists). Aprepitant is a selective NK-1 receptor antagonist approved as part of combination therapy with a corticosteroid and a 5-HT(3) receptor antagonist for the prevention of acute and delayed CINV. Fosaprepitant (also known as MK-0517 and L-758,298) is a water-soluble phosphoryl prodrug for aprepitant, which, when administered intravenously, is converted to aprepitant within 30 min after intravenous administration via the action of ubiquitous phosphatases. Because fosaprepitant is rapidly converted to the active form (aprepitant), it is expected to provide the same aprepitant exposure in terms of AUC, and a correspondingly similar anti-emetic effect. Clinical studies have suggested that fosaprepitant could be appropriate as an intravenous alternative to the aprepitant oral capsule. In a study in healthy subjects, fosaprepitant was well tolerated up to 150 mg (1 mg/ml), and fosaprepitant 115 mg was bioequivalent in its AUC to aprepitant 125 mg. Fosaprepitant 115 mg has been submitted for FDA approval as an alternative on day 1 of a 3-day oral aprepitant regimen, with oral aprepitant administered on days 2 and 3. Fosaprepitant may be a useful parenteral alternative to oral aprepitant. Further study is needed to clarify the use of fosaprepitant for the prevention of CINV, and to clarify optimal dosing regimens that may be appropriate substitutes for oral aprepitant.

Topics: Animals; Antineoplastic Agents; Aprepitant; Humans; Morpholines; Nausea; Neurokinin-1 Receptor Antagonists; Receptors, Neurokinin-1; Vomiting

Highly emetogenic chemotherapy induces emesis in cancer patients without prophylaxis. The purpose of this study was to evaluate the efficacy and safety of a fosaprepitant-based triple antiemetic regimen for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients with solid malignant tumors, determine risk factors and externally validate different personalized risk models for CINV.. This phase III trial was designed to test the non-inferiority of fosaprepitant toward aprepitant in cancer patients who were to receive the first cycle of single-day cisplatin chemotherapy. The primary endpoint was complete response (CR) during the overall phase (OP) with a non-inferiority margin of 10.0%. Logistic regression models were used to assess the risk factors of CR and no nausea. To validate the personalized risk models, the accuracy of the risk scoring systems was determined by measuring the specificity, sensitivity and area under the receiver operating characteristic (ROC) curve (AUC), while the predictive accuracy of the nomogram was measured using concordance index (C-index).. A total of 720 patients were randomly assigned. CR during the OP in the fosaprepitant group was not inferior to that in the aprepitant group (78.1% vs. 77.7%, P = 0.765) with a between-group difference of 0.4% (95% CI, -5.7% to 6.6%). Female sex, higher cisplatin dose (≥ 70 mg/m. Fosaprepitant-based triple prophylaxis demonstrated non-inferior control for preventing CINV in patients treated with cisplatin-base chemotherapy. Female cancer patients without a history of alcohol consumption, with larger BSA and received high-dose cisplatin might be more vulnerable to CINV. Three personalized prediction models were well-validated and could be used to optimize antiemetic therapy for individual patients.

Topics: Antiemetics; Antineoplastic Agents; Aprepitant; Cisplatin; Female; Humans; Nausea; Neoplasms; Vomiting

A protocol was developed to evaluate the value of an NK-1 receptor antagonist for preventing nausea and vomiting resulting from highly emetogenic chemotherapy when an olanzapine-based antiemetogenic regimen was used.. A221602, a prospective double-blind, placebo-controlled clinical trial, was developed to compare 2 -olanzapine-containing antiemetic regimens, one with an NK-1 receptor antagonist (aprepitant or fosaprepitant) and one without. Trial patients had a malignant disease for which they received intravenous highly emetogenic chemotherapy (single day cisplatin ≥ 70 mg/m2 or doxorubicin plus cyclophosphamide on 1 day). Patients on both arms received commonly administered doses of a 5-HT3 receptor antagonist, dexamethasone, and olanzapine. Additionally, patients were randomized to receive an NK-1 receptor antagonist (fosaprepitant 150 mg IV or aprepitant 130 mg IV) or a corresponding placebo. The primary objective was to compare the proportion of patients with no nausea for 5 days following chemotherapy between the 2 study arms. This trial was designed to test for the noninferiority of deleting the NK-1 receptor antagonist, with noninferiority defined as a decrease in freedom from nausea by less than 10%.. A total of 690 patients were entered on this trial, 50% on each arm. The proportion of patients without nausea for the complete 5-day study period was 7.4% lower (upper limit of the one-sided 95% confidence interval was 13.5%) in the arm without an NK-1 receptor antagonist compared with the arm with an NK-1 receptor antagonist.. This trial did not provide sufficient evidence to support that deletion of the NK-1 receptor antagonist was as good as keeping it, as a part of a 4-drug antiemetic regimen for highly emetogenic chemotherapy (ClinicalTrials.gov Identifier: NCT03578081).

Topics: Antiemetics; Antineoplastic Agents; Aprepitant; Dexamethasone; Double-Blind Method; Humans; Nausea; Olanzapine; Prospective Studies; Receptors, Neurokinin-1; Vomiting

This trial is an open-label, single-arm, multicentre phase II trial. Patients who receive CBDCA (AUC ≥4)-based therapy and have never been administered moderate to high emetogenic chemotherapy will be enrolled. All patients will receive OLZ (5 mg oral administration on days 1-4, after supper) in combination with 5-HT. The study protocol was approved by the institutional review board at each of the participating centres. Data will be presented at international conferences and published in peer-reviewed journals.. UMIN000031646.

Topics: Antiemetics; Antineoplastic Agents; Aprepitant; Carboplatin; Dexamethasone; Drug Therapy, Combination; Female; Genital Neoplasms, Female; Granisetron; Humans; Morpholines; Nausea; Neurokinin-1 Receptor Antagonists; Olanzapine; Serotonin 5-HT3 Receptor Antagonists; Treatment Outcome; Vomiting

Fosaprepitant, an intravenous (IV) aprepitant prodrug for chemotherapy-induced nausea and vomiting prophylaxis, is associated with systemic and infusion-site reactions attributed in part to its surfactant, polysorbate 80. HTX-019 is an IV aprepitant formulation free of polysorbate 80 and other synthetic surfactants.. This open-label, single-dose, randomized, two-way crossover bioequivalence study compared pharmacokinetics and safety of HTX-019 and fosaprepitant. Healthy subjects received single-dose HTX-019 (130 mg) or fosaprepitant (150 mg) IV over 30 min, with ≥7-day washout between doses. Blood samples were evaluated for pharmacokinetics and bioequivalence; safety evaluation included treatment-emergent adverse events (TEAEs) and serious adverse events. Ninety-seven of one hundred enrolled subjects completed the study.. HTX-019 was bioequivalent to fosaprepitant and may provide a safer alternative to fosaprepitant for chemotherapy-induced nausea and vomiting prophylaxis.

Topics: Administration, Intravenous; Adult; Antiemetics; Aprepitant; Area Under Curve; Cross-Over Studies; Female; Humans; Male; Middle Aged; Morpholines; Neurokinin-1 Receptor Antagonists; Prodrugs; Therapeutic Equivalency; Young Adult

Evaluate safety of HTX-019, a novel polysorbate 80- and synthetic surfactant-free intravenous formulation of neurokinin 1 receptor antagonist aprepitant for chemotherapy-induced nausea and vomiting.. Two open-label, randomized, two-way crossover studies evaluated treatment-emergent adverse events (TEAEs) in 200 healthy subjects. Subjects received HTX-019 130 mg (30-min infusion) and fosaprepitant 150 mg (20- or 30-min infusion), with ≥7-day washout between doses.. Less than or equal to 30 min after start of infusion, TEAEs occurred in 5 (3%) HTX-019 and 30 (15%) fosaprepitant recipients. No HTX-019 recipients had infusion-site adverse events, versus 15 (8%) fosaprepitant recipients. Treatment-related dyspnea occurred in one HTX-019 and six fosaprepitant recipients. No severe/serious TEAEs occurred; all TEAEs resolved.. HTX-019 may provide a safer aprepitant formulation than fosaprepitant for chemotherapy-induced nausea and vomiting prevention.

Topics: Adult; Antiemetics; Antineoplastic Agents; Aprepitant; Cross-Over Studies; Dyspnea; Female; Healthy Volunteers; Humans; Infusions, Intravenous; Male; Middle Aged; Morpholines; Nausea; Neoplasms; Neurokinin-1 Receptor Antagonists; Treatment Outcome; Vomiting; Young Adult

The prevention of chemotherapy-induced nausea and vomiting was one of the most challenging supportive care issues in oncology, especially to highly emetogenic chemotherapy (HEC). A total of 645 patients were randomized into fosaprepitant group (fosaprepitant/placebo 150 mg d1 in combination with granisetron and dexamethasone) or aprepitant group (aprepitant/placebo 125 mg d1; 80 mg d2-d3 plus granisetron and dexamethasone).The primary endpoint was the percentage of patients who had a complete response (CR) over the entire treatment course (0-120 hr, overall phase [OP]). It was assessed by using a non-inferiority model, with a non-inferiority margin of 10%. The difference of the CR rate was compared between two groups with chi-square analysis. Six hundred and twenty-six patients were included in the per protocol analysis. The percentage of patients with a CR in the fosaprepitant group was not inferior to that in the aprepitant group (90.85% versus 94.17%, p = .1302) during OP. Whether the cisplatin-based chemotherapy or not, the CR rate of the fosaprepitant group was not inferior to that of the aprepitant group. Both regimens were well tolerated. The most common adverse event was constipation. Fosaprepitant provided effective and well-tolerated control of nausea and vomiting associated with HEC in Chinese patients.

Topics: Adult; Aged; Antiemetics; Antineoplastic Agents; Aprepitant; Asian People; China; Cisplatin; Dexamethasone; Double-Blind Method; Drug Therapy, Combination; Female; Granisetron; Humans; Male; Middle Aged; Morpholines; Nausea; Treatment Outcome; Vomiting; Young Adult

We previously reported in the SENRI trial on the usefulness of aprepitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) in colorectal cancer patients receiving an oxaliplatin-based regimen which is classified as moderately emetogenic cancer chemotherapy. In the present subgroup analysis of the SENRI trial, we assessed the risk factors for CINV in colorectal cancer patients who received oxaliplatin-based chemotherapy.. Multivariate logistic regression models were used to assess the impact of aprepitant use and patient characteristics on vomiting and nausea. We also assessed the proportion of CINV in patients by gender.. Female gender and aprepitant use were associated with the incidence of vomiting and no significant nausea. Significantly more men achieved no vomiting than women (92.9 vs 84.5 % in men and women, respectively; P = 0.0001). The rate of no nausea, complete response, complete protection, and total control was also higher in men. The rate rescue therapy use was significantly higher in women than men. We compared the rate of CINV between aprepitant and control groups and found a significant difference in male patients who achieved no vomiting and complete protection in the overall phase. In women, the rate of no nausea, no vomiting, and total control was higher in the aprepitant group than in the control group.. Gender and aprepitant use were risk factors for CINV in colorectal patients who received oxaliplatin-based chemotherapy. Aprepitant therapy was more effective for women than for men in the prevention of CINV in colorectal cancer patients receiving an oxaliplatin-based regimen.

Topics: Adult; Aged; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Aprepitant; Colorectal Neoplasms; Female; Humans; Logistic Models; Male; Middle Aged; Morpholines; Nausea; Organoplatinum Compounds; Oxaliplatin; Risk Factors; Vomiting

We aimed to compare the preventive effect of 5-day administration of aprepitant with single administration of fosaprepitant meglumine against nausea and vomiting symptoms due to highly emetogenic chemotherapy regimens comprising cisplatin (CDDP).. Subjects were inpatients who underwent chemotherapy for gastric cancer, esophageal cancer, lung cancer, or head and neck cancer with a regimen comprising 60 mg/m(2) or higher dose of CDDP. In this randomised, open-label, controlled study, the subjects were assigned to a group given aprepitant for 5 days or a group given a single administration of fosaprepitant meglumine. The nausea and vomiting symptoms that emerged within 7 days after the first CDDP administration were investigated with a questionnaire form; the results were compared between the two groups. Risk factors affecting nausea and vomiting symptoms were also investigated.. Of the 101 patients enrolled, 93 patients were included (48 in the 5-day aprepitant group and 45 in the single fosaprepitant meglumine group). No significant intergroup differences in the complete response rate or the complete control rate were found over the entire period. The nausea score tended to increase from day 3 in both groups, but no significant intergroup difference was observed. Furthermore, the investigation of risk factors affecting moderate or severe nausea symptoms indicated that the fosaprepitant meglumine administration was not a risk factor.. Single administration of fosaprepitant meglumine was not inferior to 5-day administration of aprepitant for preventing acute and delayed nausea and vomiting symptoms occurring after administration of CDDP (60 mg/m(2) or higher).

Topics: Aged; Antiemetics; Aprepitant; Cisplatin; Esophageal Neoplasms; Female; Head and Neck Neoplasms; Humans; Lung Neoplasms; Male; Meglumine; Middle Aged; Morpholines; Nausea; Risk Factors; Stomach Neoplasms; Surveys and Questionnaires; Treatment Outcome; Vomiting

The purpose of this pilot study was to compare the response rates and daily living activities of patients with newly diagnosed gynecologic cancer treated with fosaprepitant or aprepitant in the management of chemotherapy-induced nausea and vomiting.. Eligible participants were randomized to either intravenous fosaprepitant (150 mg, day 1) or oral aprepitant (125 mg on day 1 and 80 mg on days 2-3) before undergoing weekly paclitaxel (80 mg/2)(2) and monthly carboplatin (AUC 6)-based chemotherapy. In addition, standard premedications (eg, ranitidine, dexamethasone, and diphenhydramine) were administered intravenously on day 1. Response evaluation and impact on daily life were measured throughout the acute phase (0-24 hours), delayed period (days 2-4), and overall phase (0-120 hours) of the patients' initial chemotherapy cycle via the Functional Living Index-Emesis.. In the current investigation, 20 gynecologic cancer subjects were treated with either fosaprepitant (n = 10) or aprepitant (n = 10) before their first chemotherapy cycle. We observed 7 overall complete responses (70%, no emetic episodes or rescue medications) in the aprepitant group and 6 (60%) in the fosaprepitant cohort (P = 0.660). In addition, both treatment groups reported similarly, favorable rates of daily living activities throughout the acute (P = 0.626) and delayed (P = 0.648) phases of cycle 1 chemotherapy.. The findings from the current analysis suggest that intravenous fosaprepitant and oral aprepitant confer beneficial antiemetic prevention. Moreover, the 2 medications theoretically afford a favorable impact on daily living, thereby potentially facilitating the completion of a patient's clinically prescribed chemotherapy regimen.

Topics: Adult; Aged; Antiemetics; Antineoplastic Agents; Aprepitant; Female; Genital Neoplasms, Female; Humans; Middle Aged; Morpholines; Nausea; Pilot Projects; Vomiting

We examined the efficacy of olanzapine for the prevention of nausea and vomiting in patients receiving highly emetogenic chemotherapy.. In a randomized, double-blind, phase 3 trial, we compared olanzapine with placebo, in combination with dexamethasone, aprepitant or fosaprepitant, and a 5-hydroxytryptamine type 3-receptor antagonist, in patients with no previous chemotherapy who were receiving cisplatin (≥70 mg per square meter of body-surface area) or cyclophosphamide-doxorubicin. The doses of the three concomitant drugs administered before and after chemotherapy were similar in the two groups. The two groups received either 10 mg of olanzapine orally or matching placebo daily on days 1 through 4. Nausea prevention was the primary end point; a complete response (no emesis and no use of rescue medication) was a secondary end point.. In the analysis, we included 380 patients who could be evaluated (192 assigned to olanzapine, and 188 to placebo). The proportion of patients with no chemotherapy-induced nausea was significantly greater with olanzapine than with placebo in the first 24 hours after chemotherapy (74% vs. 45%, P=0.002), the period from 25 to 120 hours after chemotherapy (42% vs. 25%, P=0.002), and the overall 120-hour period (37% vs. 22%, P=0.002). The complete-response rate was also significantly increased with olanzapine during the three periods: 86% versus 65% (P<0.001), 67% versus 52% (P=0.007), and 64% versus 41% (P<0.001), respectively. Although there were no grade 5 toxic effects, some patients receiving olanzapine had increased sedation (severe in 5%) on day 2.. Olanzapine, as compared with placebo, significantly improved nausea prevention, as well as the complete-response rate, among previously untreated patients who were receiving highly emetogenic chemotherapy. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT02116530.).

Topics: Adult; Aged; Aged, 80 and over; Antiemetics; Antineoplastic Agents; Aprepitant; Benzodiazepines; Dexamethasone; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Intention to Treat Analysis; Male; Middle Aged; Morpholines; Nausea; Olanzapine; Vomiting

The oral neurokinin-1 antagonist aprepitant is recommended in several guidelines for preventing chemotherapy-induced nausea & vomiting (CINV) due to highly emetogenic cancer chemotherapy. Little is known about the feasibility and safety of aprepitant in patients treated with oxaliplatin.. In this multicentre, open label, randomised, phase 3 trial, we recruited patients with colorectal cancer who underwent an oxaliplatin-based chemotherapy. Patients were centrally randomised in a 1:1 ratio to the control group (5-HT3-receptor antagonist+dexamethasone) or aprepitant group (5-HT3-receptor antagonist+dexamethasone+aprepitant or fosaprepitant) in the first course. All patients were treated with aprepitant/fosaprepitant therapy in the second course. The primary end-point was the proportion of patients with no emesis.. A total of 413 patients entered this clinical trial from 25 centres in Japan. Significantly more patients in the aprepitant group achieved no vomiting overall and delayed phase than those in the control group (95.7% versus 83.6%, and 95.7% versus 84.7%, respectively). The aprepitant group also had statistically significantly higher percentages of no significant nausea, complete response and complete protection than the control group overall. In the control group, the percentages of no vomiting were higher in the second cycle than in the first cycle. The incidence of vomiting occurred day 7 or later was significantly higher in the control group compared with the aprepitant group. Other adverse events were not significant between the groups.. The aprepitant therapy was more effective than the control therapy for prevention of CINV in colorectal cancer patients receiving an oxaliplatin-based regimen.

Topics: Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Aprepitant; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Drug Therapy, Combination; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Morpholines; Nausea; Organoplatinum Compounds; Oxaliplatin; Oxaloacetates; Vomiting

We evaluated the efficacy and safety of single-dose fosaprepitant in combination with intravenous granisetron and dexamethasone.. Patients receiving chemotherapy including cisplatin (≥70 mg/m(2)) were eligible. A total of 347 patients (21% had received cisplatin with vomiting) were enrolled in this trial to receive the fosaprepitant regimen (fosaprepitant 150 mg, intravenous, on day 1 in combination with granisetron, 40 μg/kg, intravenous, on day 1 and dexamethasone, intravenous, on days 1-3) or the control regimen (placebo plus intravenous granisetron and dexamethasone). The primary end point was the percentage of patients who had a complete response (no emesis and no rescue therapy) over the entire treatment course (0-120 h).. The percentage of patients with a complete response was significantly higher in the fosaprepitant group than in the control group (64% versus 47%, P = 0.0015). The fosaprepitant regimen was more effective than the control regimen in both the acute (0-24 h postchemotherapy) phase (94% versus 81%, P = 0.0006) and the delayed (24-120 h postchemotherapy) phase (65% versus 49%, P = 0.0025).. Single-dose fosaprepitant used in combination with granisetron and dexamethasone was well-tolerated and effective in preventing chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic cancer chemotherapy, including high-dose cisplatin.

Topics: Adult; Aged; Aprepitant; Cisplatin; Dexamethasone; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Granisetron; Humans; Male; Middle Aged; Morpholines; Nausea; Neoplasms; Vomiting

Aprepitant or its prodrug fosaprepitant, in combination with a corticosteroid and a 5-HT(3) receptor antagonist, are used to prevent chemotherapy-induced nausea and vomiting. This study evaluated the effect of fosaprepitant 150 mg on CYP3A4 metabolism. Fosaprepitant 150 mg has been submitted to regulatory agencies for consideration of approval as a single-day alternative to the 3-day oral aprepitant antiemetic regimen currently marketed. Part 1 of the study evaluated the drug interaction between fosaprepitant 150 mg and oral dexamethasone (8 mg daily for 3 days). Part 2 of the study evaluated the drug interaction between fosaprepitant 150 mg and oral midazolam (2 mg on days 1 and 4). Thirteen subjects were enrolled in part 1 and 10 in part 2. For dexamethasone, fosaprepitant increased the area under the plasma concentration-time curve from 0 to 24 hours by approximately 2.0-fold on days 1 and 2 and to a lesser extent (~1.2-fold) on day 3. Similarly, for midazolam, fosaprepitant increased the area under the plasma concentration-time curve from 0 hours to infinity by approximately 1.8-fold on day 1 but had no effect on midazolam pharmacokinetics on day 4. Fosaprepitant 150 mg is a weak inhibitor of CYP3A4. Oral dexamethasone doses on days 1 and 2 should be reduced by approximately 50% when coadministered with intravenous fosaprepitant 150 mg on day 1.

Topics: Administration, Oral; Adolescent; Adult; Antiemetics; Aprepitant; Cross-Over Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Dexamethasone; Female; Humans; Injections, Intravenous; Male; Midazolam; Morpholines; Neurokinin-1 Receptor Antagonists; Young Adult

Addition of aprepitant, a neurokinin-1 receptor antagonist (NK1RA), to an ondansetron and dexamethasone regimen improves prevention of chemotherapy-induced nausea/vomiting (CINV), particularly during the delayed phase (DP; 25 to 120 hours). Therefore, recommended antiemetic regimens include multiple-day NK1RA administration. Preliminary data suggested that single-dose aprepitant before chemotherapy could provide CINV protection throughout the overall risk phase (OP; 0 to 120 hours). This study compared a 3-day oral aprepitant schedule to a regimen containing a single dose of the intravenous NK1RA fosaprepitant.. A randomized, double-blind, active-control design was used to test whether fosaprepitant is noninferior to aprepitant. Patients receiving cisplatin ≥ 70 mg/m(2) for the first time received ondansetron and dexamethasone with a standard aprepitant regimen (125 mg on day 1, 80 mg on day 2, 80 mg on day 3) or a single-dose fosaprepitant regimen (150 mg on day 1). The primary end point was complete response (CR; no vomiting, no rescue medication) during OP. Secondary end points were CR during DP and no vomiting during OP. Accrual of 1,113 evaluable patients per treatment arm was planned to confirm noninferiority with expected CR of 67.7% and noninferiority margin of minus 7 percentage points.. A total of 2,322 patients were randomly assigned, and 2,247 were evaluable for efficacy. Antiemetic protection with aprepitant and fosaprepitant was equivalent within predefined bounds for noninferiority. Both regimens were well tolerated, although more frequent infusion site pain/erythema/thrombophlebitis was seen with fosaprepitant relative to aprepitant (2.7% v 0.3%, respectively).. Given with ondansetron and dexamethasone, single-dose intravenous fosaprepitant (150 mg) was noninferior to standard 3-day oral aprepitant in preventing CINV during OP and DP.

Topics: Adult; Aged; Aged, 80 and over; Antiemetics; Antineoplastic Agents; Aprepitant; Cisplatin; Dexamethasone; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Morpholines; Nausea; Ondansetron; Treatment Outcome; Vomiting

A single 115-mg dose of fosaprepitant, the IV prodrug of the NK(1) receptor antagonist aprepitant, is bioequivalent to a 125-mg dose of oral aprepitant. Thus far, fosaprepitant/aprepitant has not shown a meaningful effect on QTc intervals; in this study, we sought to confirm these findings.. This double-blind, active-controlled, randomized, three-treatment, three-period, crossover study in healthy young subjects evaluated the effect of a 200-mg dose of fosaprepitant on QTc prolongation. In each period, subjects received 400 mg moxifloxacin per os, 200 mg fosaprepitant IV, or placebo in randomized sequence. The effect of fosaprepitant on QTc interval was assessed by 12-lead electrocardiograms (ECGs). The baseline value for QTc interval for each subject during each period was defined as the average of five replicate baseline QTc intervals extracted from predose ECGs. ECGs were performed at predose, 2, 5, 10, 15, 20, 30, 45 min; and 1, 1.5, 2, 3, 4, 6, and 8 h postinfusion. Values for individual QTc change from baseline were evaluated in a repeated-measures mixed model appropriate for a crossover design. A two-sided 90% confidence interval (CI) for the true difference in QTc interval change from baseline at each timepoint was calculated for fosaprepitant versus placebo and for moxifloxacin versus placebo.. After fosaprepitant 200-mg administration, the mean (95% CI) QTc interval change from baseline at T(max) was -1.45 (-4.67 to 1.77) ms, and the placebo-corrected mean (90% CI) QTc interval change from baseline was -1.37 (-4.78 to 2.05) ms. Neither was statistically significant at alpha = 0.05. After 400 mg moxifloxacin administration, the mean (95% CI) QTc interval change from baseline at 2 h was 9.71 (6.49-12.93) ms, and the placebo-corrected mean (90% CI) QTc interval change from baseline at moxifloxacin T(max) was 10.50 (7.09-13.92) ms. Both were statistically significant at alpha = 0.05. The maximum aprepitant concentration after fosaprepitant 200 mg administration was 6300 ng/mL (approximately twofold, fourfold, and ninefold higher than that observed historically with fosaprepitant 115 mg [3095 ng/mL], aprepitant 125 mg [1600 ng/mL], and aprepitant 40 mg [675 ng/mL]).. In subjects receiving fosaprepitant 200 mg, no clinically meaningful increases in QTc were seen at any timepoint, whereas after moxifloxacin 400 mg, increases were observed at the approximate T(max) of moxifloxacin and additional timepoints. The lack of QTc increase at this high dose of fosaprepitant and resulting aprepitant plasma exposures support the expectation that clinical doses of fosaprepitant or aprepitant will not be associated with significant QTc prolongation.

Topics: Adolescent; Adult; Anti-Infective Agents; Antidepressive Agents; Aprepitant; Aza Compounds; Cross-Over Studies; Double-Blind Method; Electrocardiography; Electrocardiography, Ambulatory; Female; Fluoroquinolones; Heart Rate; Humans; Linear Models; Male; Middle Aged; Morpholines; Moxifloxacin; Prodrugs; Quinolines; Young Adult

Fosaprepitant is an intravenous formulation of aprepitant, an oral NK1 antagonist used to prevent chemotherapy-induced nausea and vomiting. This randomized study was designed to evaluate fosaprepitant in polysorbate 80 vehicle for tolerability and bioequivalency to aprepitant. Tolerability was assessed by physical and laboratory examinations and adverse events. Plasma collected for 72 hours was assayed for aprepitant and fosaprepitant. Analysis of variance models were applied to natural log-transformed aprepitant area under the curve (AUC) data. Fosaprepitant up to 150 mg (1 mg/mL) was generally well tolerated. Fosaprepitant 115 mg was AUC bioequivalent to aprepitant 125 mg; the 90% confidence interval for the geometric mean ratio of aprepitant AUC for fosaprepitant 115 mg/aprepitant 125 mg fell within prespecified equivalence bounds of 0.80 to 1.25.

Topics: Administration, Oral; Adult; Analysis of Variance; Antiemetics; Aprepitant; Area Under Curve; Cross-Over Studies; Female; Humans; Injections, Intravenous; Male; Middle Aged; Morpholines; Neurokinin-1 Receptor Antagonists; Prodrugs; Therapeutic Equivalency

Fosaprepitant dimeglumine, an injectable phosphorylated prodrug of aprepitant, has been approved for preventing chemotherapy-induced nausea and vomiting. A novel stability-indicating HPLC method was designed and validated to determine process- and degradation-related impurities of fosaprepitant dimeglumine in an injection formulation. Chromatographic separation was done on a NanoChrom C18 (250 mm×4.6 mm, 5µm) column at a column oven temperature of 35

Topics: Acetonitriles; Aprepitant; Chromatography, High Pressure Liquid; Morpholines

To evaluate the impact on cost, time, resource use, and clinic workflow of converting the route of drug administration from a neurokinin-1 receptor antagonist (NK-1 RA) 30-min intravenous (IV) infusion to aprepitant IV, and more specifically to IV push, within a multicenter community oncology practice.. This was a retrospective, multicenter time, motion, and resource/cost evaluation study. Conversion to aprepitant IV was determined by calculating number of doses of aprepitant IV versus fosaprepitant administered in patients receiving moderately or highly emetogenic chemotherapy regimens. Operational advantages (i.e., supply costs, time saved) of switching from fosaprepitant IV infusion to aprepitant administered as a 2-min IV push were assessed.. A total of 12,908 doses of aprepitant IV 130 mg were administered at 13 Rocky Mountain Cancer Centers clinics over an 18-month period. Conversion from fosaprepitant to aprepitant IV reached 90% after 9 months of aprepitant IV initiation. Supply costs per administration were reduced ($2.51 to $0.52) when aprepitant was prepared as an IV push versus an NK-1 RA infusion. The overall time savings per administration of aprepitant was reduced by 90% (from 36.5 to 3.5 min, 33 min saved) as an IV push rather than an infusion. Most of the time saved per administration (30 min) pertained to the infusion nurse, and 3 min was saved by the pharmacy technician.. Successful conversion to aprepitant, and specifically to a 2-min IV push, provides time, cost, and resource savings, improves operational efficiency, and avoids the negative impact of potential future IV fluid shortages.. Chemotherapy-induced nausea and vomiting (CINV) can have a major impact on quality of life for patients receiving chemotherapy. Intravenous (IV) aprepitant is an approved neurokinin-1 receptor antagonist (NK-1 RA) that has been effective and safe when administered as part of a guideline-recommended regimen in patients receiving chemotherapy. In addition to being approved as a 30-min infusion, aprepitant IV is the only NK-1 RA approved for administration as a 2-min injection. These factors contributed to Rocky Mountain Cancer Centers (RMCC), which is a physician-owned community oncology practice, evaluating the impact on cost, time, and resource use of converting from a 30-min infusion of fosaprepitant to aprepitant IV, and more specifically a 2-min injection. Within 9 months of implementing aprepitant IV at RMCC, the percent utilization compared to fosaprepitant reached over 90%, signifying a successful conversion within the practice. Furthermore, a 2-min injection of aprepitant IV resulted in several operational advantages compared to a 30-min infusion. When accounting for all 13 clinics within RMCC, total monthly time savings to the practice would be over 28,000 min, or approximately 60 workdays per month of saved time. This new workflow is more efficient and allows for pharmacy technicians to complete other necessary tasks in the pharmacy such as cleaning, organizing, managing inventory, drug ordering, and charge/documentation corrections. Time saved by the nurses could be used for enhanced patient care, thoroughly reviewing chemotherapy or other orders, and assisting other nurses.

Topics: Administration, Intravenous; Adult; Aged; Aged, 80 and over; Antiemetics; Antineoplastic Agents; Aprepitant; Female; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Middle Aged; Morpholines; Nausea; Neoplasms; Retrospective Studies; Vomiting

Cisplatin is classified as a drug with high emetic risk; thus, the use of aprepitant or fosaprepitant in addition to a 5-hydroxytryptamine-3 (5-HT

Topics: Aged; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Aprepitant; Cisplatin; Dexamethasone; Drug Therapy, Combination; Esophageal Neoplasms; Female; Humans; Infusions, Intravenous; Magnesium Sulfate; Male; Middle Aged; Morpholines; Nausea; Premedication; Quality of Life; Retrospective Studies; Serotonin 5-HT3 Receptor Antagonists; Solutions; Treatment Outcome; Vomiting

Fosaprepitant, an intravenous neurokinin-1 receptor antagonist for chemotherapy-induced nausea and vomiting, contains polysorbate 80, which is associated with infusion-site adverse events (ISAEs) and hypersensitivity systemic reactions (HSRs). This study investigated ISAEs/HSRs following fosaprepitant with anthracycline-containing chemotherapy.. This retrospective chart review noted ISAEs/HSRs following the anthracycline doxorubicin+cyclophosphamide and a three-drug fosaprepitant regimen, via peripheral line.. 35/127 patients (28%) developed ISAEs/HSRs with chemotherapy and antiemetic therapy: 32 developed 137 individual ISAEs, primarily erythema, pain and catheter-site swelling; 16 developed 50 individual HSRs, primarily edema/swelling, erythema or dermatitis (no anaphylaxis).. Fosaprepitant is associated with a significant ISAE/HSR rate following anthracycline-containing chemotherapy via peripheral line. Polysorbate 80-free intravenous neurokinin-1 receptor antagonist may provide a safer chemotherapy-induced nausea and vomiting prophylaxis option.

Topics: Administration, Intravenous; Adult; Aged; Anthracyclines; Antiemetics; Aprepitant; Cyclophosphamide; Doxorubicin; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Morpholines; Nausea; Neurokinin-1 Receptor Antagonists; Polysorbates; Vomiting

Chemotherapy-induced nausea and vomiting (CINV) may occur during the acute (0-24 h) or delayed (25-120 h) phase following chemotherapy administration. The addition of a neurokinin 1 receptor antagonist to antiemetic regimens containing a 5-hydroxytryptamine type 3 receptor antagonist and dexamethasone has resulted in improved CINV prophylaxis. Due to numerous adverse events and hypersensitivity reactions associated with fosaprepitant, a commonly used neurokinin 1 receptor antagonist, there remains an unmet need for better-tolerated formulations. HTX-019, the US FDA-approved polysorbate 80- and synthetic surfactant-free aprepitant injectable emulsion, is bioequivalent to and better tolerated (fewer treatment-emergent adverse events) than fosaprepitant. HTX-019 represents a valuable alternative to fosaprepitant for CINV prophylaxis.

Topics: Aprepitant; Clinical Trials as Topic; Drug-Related Side Effects and Adverse Reactions; Humans; Induction Chemotherapy; Morpholines; Nausea; Neurokinin-1 Receptor Antagonists; Polysorbates; Receptors, Neurokinin-1; Vomiting

Single-dose i.v. fosaprepitant has been approved as an alternative to 3 day oral aprepitant, a neurokinin-1 receptor antagonist, and improves prevention of chemotherapy-induced nausea and vomiting (CINV). Because fosaprepitant has shown similar efficacy to aprepitant in adult patients only, this study compared the efficacy and safety of aprepitant and fosaprepitant in pediatric patients.. Children younger than 18 years who received aprepitant or fosaprepitant to manage CINV between January 2015 and March 2018 at the National Cancer Center Hospital (Tokyo) were recruited to this study. The primary endpoint was complete response (CR; no vomiting/rescue medication) between 0 and 120 h after the start of chemotherapy. Secondary endpoints were safety based on the frequency of severe adverse events, and evaluation of patient characteristics as risk factors (effect of age and sex).. A total of 125 chemotherapy cycles were evaluated. In the aprepitant group, CR was observed in 36 of 80 treatment cycles (45.0%), whereas in the fosaprepitant group, it was observed in 19 of 45 cycles (42.2%; P = 0.852). No treatment-related severe adverse events were observed in either group. The number of non-CR was greater than that of CR in patients aged 6-14 years. The difference in CR rate between male and female patients was not statistically significant (47.1% vs 40.0%, respectively; P = 0.471).. Aprepitant and fosaprepitant were safely used and may be equally useful for pediatric patients receiving highly emetogenic chemotherapy. CR rate may be associated with patient age.

Topics: Adolescent; Antiemetics; Antineoplastic Agents; Aprepitant; Child; Child, Preschool; Female; Humans; Infant; Male; Morpholines; Retrospective Studies; Risk Factors; Tokyo; Treatment Outcome; Vomiting

HTX-019 [CINVANTI. This retrospective review involved six sites in Alabama, USA. Analyzed patients were 18-94 years old with an Eastern Cooperative Oncology Group performance status ranging from 0 to 4. Seventy-six chemotherapy regimens were utilized (emetogenicity high, n = 35; moderate, n = 35; low, n = 6) and patients received HTX-019 130 mg only or switched from fosaprepitant 150 mg to HTX-019 130 mg within a three-drug antiemetic regimen with a 5-hydroxytryptamine type 3 RA and dexamethasone. HTX-019 was administered via IV push. Electronic medical records of patients receiving HTX-019 were queried for nursing and medical documentation associated with infusion-site adverse events (ISAEs). The detailed notes were also reviewed for any discontinuation of HTX-019 or substitution of HTX-019 with another NK-1 RA.. The HTX-019 safety profile was analyzed on the basis of 2066 IV push administrations in 591 cancer patients (most common diagnoses: lung, n = 107; breast, n = 100; colon, n = 92). No clinically significant ISAEs or adverse events associated with HTX-019 were reported. Also, no patients discontinued HTX-019 treatment, and none switched from HTX-019 to another NK-1 RA.. This is the first study to demonstrate that HTX-019 can be safely administered via IV push in patients with cancer receiving emetogenic chemotherapy while negating the need for fluid bags, which are scarce.. Heron Therapeutics, Inc., San Diego, CA, USA. Plain language summary available for this article.

Topics: Administration, Intravenous; Adolescent; Adult; Aged; Aged, 80 and over; Antiemetics; Antineoplastic Agents; Aprepitant; Female; Humans; Male; Middle Aged; Morpholines; Nausea; Neoplasms; Neurokinin-1 Receptor Antagonists; Retrospective Studies; Vomiting; Young Adult

Clinical trials have shown that the addition of aprepitant (APR) or a phosphorylated prodrug of aprepitant, fosaprepitant (FosAPR) as prophylactic antiemetic therapy consisting of a 5-hydrotryptamine-3 receptor antagonist and dexamethasone is effective in patients receiving highly emetogenic chemotherapy. These combination therapies have been commonly used in Japan. In the present study, we performed a cost-utility analysis of APR and FosAPR in the context of the Japanese medical insurance system, and economic efficiency was compared.. Data from randomized controlled trials that examined the efficacy of APR and FosAPR in the Japanese population were used. A decision tree was constructed to estimate the effectiveness of chemotherapy for 5 days from the day of the treatment and the cost associated with outpatient chemotherapy from the perspective of a payer. Health outcome was expressed in quality-adjusted life-years (QALYs), and costs were estimated based on medical fees and drug prices from 2018. An incremental cost-effectiveness ratio (ICER) was calculated for each regimen containing either APR or FosAPR. The robustness of the model was assessed using 1-way and probabilistic sensitivity analysis.. The base-case analysis estimated that the addition of APR or FosAPR would have incremental effects of 0.00166 and 0.00143 QALY and incremental costs of 8305 and 11,348 JPY (74 and 101 USD [1 USD = 112.17 JPY]), resulting in ICERs of 4,992,172 and 7,955,560 JPY/QALY (44,505 and 70,924 USD/QALY), respectively. Sensitivity analysis revealed that the probability of a complete response for delayed chemotherapy-induced nausea and vomiting had the most influence on the ICERs. Reductions in the drug costs of APR and FosAPR also had an effect on the ICERs. According to the probabilistic sensitivity analysis, APR and FosAPR were dominant in terms of cost-effectiveness in 48.7% and 8.55% of cases, respectively.. The ICER of outpatient prophylactic antiemetic therapy in patients receiving highly emetogenic chemotherapy was calculated in the context of the Japanese medical insurance system. Assuming the willingness-to-pay of 5,000,000 JPY/QALY based on the calculated ICER, our findings suggest that although the addition of APR is cost-effective, FosAPR is not cost-effective.

Topics: Antiemetics; Antineoplastic Agents; Aprepitant; Cost-Benefit Analysis; Dexamethasone; Drug Costs; Female; Humans; Japan; Male; Morpholines; Nausea; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Vomiting

Chemotherapy-induced nausea and vomiting (CINV) remains a challenge in cancer care. Improved understanding of CINV pathophysiology has triggered the development of new antiemetic therapeutic options, such as selective neurokinin-1 (NK

Topics: Antiemetics; Aprepitant; Dexamethasone; Humans; Morpholines; Nausea; Neoplasms; Neurokinin-1 Receptor Antagonists; Receptors, Neurokinin-1; Risk Factors; Serotonin 5-HT3 Receptor Antagonists; Sex Characteristics; Treatment Outcome; Vomiting

Topics: Aprepitant; Contraceptive Agents; Humans; Morpholines; Nausea

Topics: Aprepitant; Contraceptive Agents; Humans; Morpholines; Nausea

The objective of this study was to determine the effect of aprepitant(from days 1 to 3, po)and fosaprepitant(day 1, iv) for nausea in patients with oral cancer receiving combination chemotherapy with docetaxel, nedaplatin, or cisplatin(divided doses for 5 days), and 5-fluorouracil(TPF).The incidence rate of nausea in the aprepitant group was 60%(6/10), and that in the fosaprepitant group was 90%(9/10).The incidence rate of continuous nausea for more than 2 days was significantly lower in the aprepitant group than in the fosaprepitant group(40%[4/10]vs 90%[9/10], p=0.02; c 2 test).In addition, the mean area under the curve of the chronological changes in the grade of nausea tended to be lower in the aprepitant group than in the fosaprepitant group.In both groups, 3 cases(30%)of vomiting were observed.However, the incidence of continued daily vomiting tended to be lower in the aprepitant group than in the fosaprepitant group.These results suggest that aprepitant is more effective than fosaprepitant for nausea induced by TPF.

Topics: Aged; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Aprepitant; Cisplatin; Docetaxel; Female; Fluorouracil; Humans; Male; Morpholines; Nausea; Organoplatinum Compounds; Taxoids

Neuroblastoma is the most common extracranial tumor in children. Despite aggressive multimodal treatment, high-risk neuroblastoma remains a clinical challenge with survival rates below 50%. Adding targeted drugs to first-line therapy regimens is a promising approach to improve survival in these patients. TACR1 activation by substance P has been reported to be mitogenic in cancer cell lines. Tachykinin receptor (TACR1) antagonists are approved for clinical use as an antiemetic remedy since 2003. Tachykinin receptor inhibition has recently been shown to effectively reduce growth of several tumor types. Here, we report that neuroblastoma cell lines express TACR1, and that targeting TACR1 activity significantly reduced cell viability and induced apoptosis in neuroblastoma cell lines. Gene expression profiling revealed that TACR1 inhibition repressed E2F2 and induced TP53 signaling. Treating mice harboring established neuroblastoma xenograft tumors with Aprepitant also significantly reduced tumor burden. Thus, we provide evidence that the targeted inhibition of tachykinin receptor signaling shows therapeutic efficacy in preclinical models for high-risk neuroblastoma.

Topics: Animals; Antineoplastic Agents; Apoptosis; Aprepitant; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Evaluation, Preclinical; E2F2 Transcription Factor; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Gene Expression Profiling; Humans; Mice; Mice, Nude; Molecular Targeted Therapy; Morpholines; Neuroblastoma; Neurokinin-1 Receptor Antagonists; Prodrugs; Receptors, Neurokinin-1; Signal Transduction; Treatment Outcome; Tumor Burden; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Fosaprepitant is an antiemetic used for chemotherapy-induced nausea and vomiting. We recently reported increased infusion site adverse events (ISAE) in a cohort of breast cancer patients receiving chemotherapy with doxorubicin and cyclophosphamide (AC). In this current study, we evaluated the venous toxicity of fosaprepitant use with non-anthracycline platinum-based antineoplastic regimens.. A retrospective review was conducted of the first 81 patients initiated on fosaprepitant among patients receiving highly emetogenic chemotherapy, on or after January 1, 2011 at Mayo Clinic Rochester. None of these regimens included an anthracycline. Data collected included baseline demographics, chemotherapy regimen, type of intravenous access and type, and severity of ISAE. Data from these patients were compared to previously collected data from patients who had received AC. Statistical analysis using χ 2 and univariate logistic regression was used to evaluate the association between treatment regimen, fosaprepitant, and risk of ISAE.. Among these 81 patients, the incidence of ISAE was 7.4% in the non-anthracycline platinum group. The most commonly reported ISAE were swelling (3%), extravasation (3%), and phlebitis (3%). When stratified by regimen, fosaprepitant was associated with a statistically significant increased risk of ISAE in the anthracycline group (OR 8.1; 95% CI 2.0-31.9) compared to the platinum group.. Fosaprepitant antiemetic therapy causes significant ISAE that are appreciably higher than previous reports. Patients receiving platinum-based chemotherapy appear to have less significant ISAE than do patients who receive anthracycline-based regimens.

Topics: Adult; Aged; Anthracyclines; Antiemetics; Antineoplastic Agents; Aprepitant; Cyclophosphamide; Doxorubicin; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Morpholines; Nausea; Neoplasms; Phlebitis; Retrospective Studies; Vomiting; Young Adult

The purpose of this study was to investigate the incidence of fosaprepitant-associated infusion site adverse events (ISAEs) among a cohort of breast cancer patients receiving doxorubicin/cyclophosphamide (AC) chemotherapy.. A retrospective review of electronic medical record (EMR) data was performed for all patients who were initiated on AC from January 2011 to April 2012. Data collected included baseline demographics, antiemetic regimen, documentation of ISAEs, and type of intravenous (IV) access. Descriptive statistics (mean and standard deviation or percentages) were summarized overall, by type of IV access and initial antiemetic given.. Among the 148 patients included in this analysis, 98 initially received fosaprepitant and 44 received aprepitant. The incidence of ISAEs associated with fosaprepitant administration was 34.7 % (n=34), while the incidence of aprepitant-associated ISAEs was 2.3 % (n=1). All ISAEs were associated with peripheral IV access. The most commonly reported ISAEs were infusion site pain (n=26), erythema (n=22), swelling (n=12), superficial thrombosis (n=8), infusion site hives (n=5), and phlebitis/thrombophlebitis (n=5). Twenty-six patients experienced more than one type of ISAE.. The incidence and severity of ISAEs associated with fosaprepitant administration among a group of patients receiving AC chemotherapy are significant and appreciably higher than what has been previously reported.

Topics: Adult; Aged; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Aprepitant; Breast Neoplasms; Cyclophosphamide; Doxorubicin; Female; Humans; Infusions, Intravenous; Middle Aged; Morpholines; Nausea; Phlebitis; Retrospective Studies; Vomiting

Antiemetic triplet therapy including dexamethasone (DEX) is widely used for patients receiving highly emetogenic chemotherapy (HEC). In Japan, the appropriate dose of DEX has not been established for this combination.. To assess the efficacy and safety of increased-dose DEX, we retrospectively examined patients receiving HEC with antiemetic triplet therapy.. Twenty-four patients (fosaprepitant group) were given an increased-dose of DEX (average total dose: 45.8mg), fosaprepitant, and 5-HT3 antagonist. A lower-dose of DEX (33.6mg), oral aprepitant, and 5-HT3 antagonist were administered to the other 48 patients (aprepitant group). The vomiting control rates in the fosaprepitant and aprepitant groups were 100% and 85.4% in the acute phase, and were 75.0% and 64.6% in the delayed phase. The incidences of toxicity were similar comparing the two groups.. Triplet therapy using an increased-dose of DEX is suggested to be safe and effective for patients receiving HEC.

Topics: Adult; Aged; Antiemetics; Antineoplastic Agents; Aprepitant; Benzimidazoles; Dexamethasone; Drug Therapy, Combination; Female; Granisetron; Humans; Isoquinolines; Japan; Male; Middle Aged; Morpholines; Neoplasms; Palonosetron; Quinuclidines; Retrospective Studies; Serotonin Antagonists; Vomiting

Fosaprepitant dimeglumine for injection is the water-soluble phosphorylated prodrug of the neurokinin-1 receptor antagonist aprepitant. Both agents are approved (in combination with a 5-HT3 antagonist and a corticosteroid) for prevention of chemotherapy-induced nausea and vomiting. Because fosaprepitant is likely to be combined and stored in the same intravenous (IV) bag with 5-HT3 antagonists and corticosteroids, the in vitro compatibility of fosaprepitant with these agents and other IV diluents was assessed.. Fosaprepitant (1 mg/mL in 0.9 % sodium chloride injection solution) was combined in binary or tertiary fashion with therapeutic-dose preparations of a 5-HT3 antagonist (ondansetron, granisetron, palonosetron, or tropisetron) and/or a corticosteroid (dexamethasone sodium phosphate or methylprednisolone sodium succinate). For diluent compatibility assessment, fosaprepitant was also prepared 1 mg/mL in 0.9 % sodium chloride injection solution, water for injection, or 5 % dextrose injection solution. After 24-h storage under ambient conditions, samples were assayed for degradation.. Fosaprepitant demonstrated compatibility when combined in the same IV infusion bag with common 5-HT3 antagonists and corticosteroids for storage and IV coadministration, with the exception of palonosetron (incompatible under all experimental conditions) and tropisetron (incompatible unless combined with a corticosteroid). No incompatibility was observed between fosaprepitant and any of the 3 diluents tested.. Use of fosaprepitant in combination with other antiemetics may provide a flexible option for administration of antiemetics to patients receiving moderately or highly emetogenic chemotherapy.

Topics: Antiemetics; Aprepitant; Dexamethasone; Drug Combinations; Drug Incompatibility; Drug Stability; Drug Storage; Glucocorticoids; Glucose; Infusions, Intravenous; Methylprednisolone Hemisuccinate; Morpholines; Serotonin 5-HT3 Receptor Antagonists; Sodium Chloride

The type 1 neurokinin receptor (NK1R) antagonist aprepitant and its i.v. prodrug fosaprepitant have been approved for prevention of acute and delayed nausea and vomiting associated with chemotherapy. This study evaluated the magnitude and duration of brain NK1R occupancy over a period of 5 days after single-dose i.v. infusion of 150-mg fosaprepitant and single-dose oral administration of 165-mg aprepitant, using serial [(18)F]MK-0999 positron emission tomography (PET) in 16 healthy subjects. Each subject underwent three scans. Brain NK1R occupancy rates after i.v. fosaprepitant at time to peak concentration (T(max); ~30 min), 24, 48, and 120 h after the dose were 100, 100, ≥97, and 41-75%, respectively. After aprepitant, NK1R occupancy rates at these time points (T(max) ~4 h) were ≥99, ≥99, ≥97, and 37-76%, respectively. Aprepitant plasma concentration profiles were comparable for the two dosage forms. The study illustrates the utility of PET imaging in determining central bioequivalence in a limited number of subjects.

Topics: Adult; Antiemetics; Antineoplastic Agents; Aprepitant; Brain; Dose-Response Relationship, Drug; Female; Humans; Male; Morpholines; Nausea; Neurokinin-1 Receptor Antagonists; Positron-Emission Tomography; Prodrugs; Receptors, Neurokinin-1; Therapeutic Equivalency; Vomiting; Young Adult

It is recommended that patients initiate triple antiemetic therapy with one of the 5-hydroxytryptamine receptor antagonists (5-HT(3) RAs), aprepitant (or its intravenous prodrug fosaprepitant) and dexamethasone prior to the start of highly emetogenic chemotherapy (HEC). However, the impact of 5-HT(3) RA selection within triple antiemetic regimens on the risk of uncontrolled chemotherapy-induced nausea and vomiting (CINV) with HEC has not been well studied.. To assess the likelihood of an uncontrolled CINV event following antiemetic prophylaxis with the 5-HT(3) RA palonosetron + aprepitant/fosaprepitant + dexamethasone (palonosetron cohort) versus any of the other 5-HT(3) RAs + aprepitant/fosaprepitant + dexamethasone (other 5-HT(3) RA cohort) among single-day HEC cycles.. Single-day HEC cycles (a gap of at least 5 days between two administrations) among patients with a cancer diagnosis and receiving antiemetic prophylaxis with the aforementioned regimens between 1/1/2006 and 6/30/2010 were identified from the IMS LifeLink claims database. Uncontrolled CINV events were identified through ICD-9-CM codes (nausea and vomiting), Current Procedural Terminology codes (hydration), rescue medications and/or use of antiemetic therapy from days 2-5 following HEC administration. Risks for an uncontrolled CINV event among all patients, and within breast cancer and multiple cancer subpopulations, were analyzed at cycle level using logistic multivariate regression models.. A total of 8018 cycles for the palonosetron cohort and 1926 cycles for the other 5-HT(3) RA cohort (3574 and 978 patients, respectively) were analyzed. Single-day HEC cycles received by the palonosetron cohort had a significantly lower unadjusted risk of an uncontrolled CINV event (17.5 vs 20.7% for the other 5-HT(3) RA cohort; p = 0.0010), with a 17% lower adjusted risk for palonosetron-administered cycles (odds ratio: 0.83; 95% CI: 0.73-0.94; p = 0.0042). Results in the breast cancer and multiple cancer subgroups were consistent with those for the overall population.. In this retrospective claims data analysis, single-day HEC cycles administered with palonosetron + aprepitant/fosaprepitant + dexamethasone had a lower risk for an uncontrolled CINV event versus other 5-HT(3) RAs + aprepitant/fosaprepitant + dexamethasone.

Topics: Adult; Antiemetics; Antineoplastic Agents; Aprepitant; Databases, Factual; Dexamethasone; Drug Therapy, Combination; Female; Humans; Isoquinolines; Logistic Models; Male; Middle Aged; Morpholines; Multivariate Analysis; Nausea; Palonosetron; Quinuclidines; Retrospective Studies; Serotonin 5-HT3 Receptor Antagonists; Vomiting