fosaprepitant and Vomiting

In recent years, chemotherapy-induced nausea and vomiting (CINV) has become the most common adverse effect of chemotherapy in oncology patients. The CINV may reduce the quality of life in mild cases, or even make the patients resist or delay further treatment. Fosaprepitant is a newly marketed neurokinin-1 receptor antagonist (NK-1RA), which can be combined with 5-hydroxytryptamine 3 receptor antagonists (5-HT3RAs) and dexamethasone to prevent chemotherapy-induced vomiting. The dimeglumine salt form of fosaprepitant can be utilized as an intravenous injectable drug, which surpasses aprepitant's oral admistration limits. Fosaprepitant is effective and safe in the control of CINV in cancer patients receiving highly emetogenic chemotherapy (HEC), and may be an alternative option for antiemetic therapy. In general, fosaprepitant is worthy of clinical promotion and has a large market potential. This article reviews the clinical studies on fosaprepitant conducted in recent years, with the aim of providing a basis for the rational clinical selection of antiemetic drugs.

Topics: Antiemetics; Antineoplastic Agents; Humans; Nausea; Neoplasms; Quality of Life; Vomiting

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

Antiemetic prophylaxis for the prevention of chemotherapy-induced nausea and vomiting, and the development of new antiemetic drugs are expanding areas of research. However, studies of antiemetic prophylaxis in chemoradiotherapy have not been prioritised, and little is known about the proper timing, duration, and combination of antiemetic drugs for the prevention of chemoradiotherapy-induced nausea and vomiting (C-RINV).. The article summarises the available antiemetic studies, the evidence for antiemetic prophylaxis of C-RINV, and the future perspectives for antiemetic research in chemoradiotherapy.. Antiemetic prophylaxis for patients receiving concomitant chemoradiotherapy has, for many years, been an orphan research area. The distinction between acute and delayed nausea and vomiting does not apply to fractionated radiotherapy, and prophylaxis should be considered to cover the entire course of treatment and not only the acute and delayed chemotherapy-induced nausea and vomiting. The best prophylaxis in women receiving fractionated radiotherapy and concomitant weekly cisplatin is a combination of the neurokinin receptor antagonist fosaprepitant with palonosetron and dexamethasone. Even with this three-drug combination nausea is a significant problem and the effect of multi-receptor targeting antiemetics such as olanzapine and amisulpride should be explored in this setting.

Topics: Antiemetics; Antineoplastic Agents; Cisplatin; Drug Therapy, Combination; Humans; Isoquinolines; Morpholines; Nausea; Neoplasms; Palonosetron; Quinuclidines; Receptors, Serotonin, 5-HT3; Vomiting

Intravenous fosaprepitant dimeglumine (Emend(®) for injection, IVEmend(®); henceforth referred to as fosaprepitant) is a prodrug of and is rapidly converted to the antiemetic aprepitant, and is approved in several countries worldwide (as part of an antiemetic regimen) for the prevention of nausea and vomiting associated with highly and moderately emetogenic chemotherapy (HEC and MEC). This narrative review discusses the pharmacological properties of intravenous fosaprepitant and its clinical efficacy and tolerability in the prevention of nausea and vomiting associated with HEC and MEC. In large, randomized phase III clinical trials, a single intravenous dose of fosaprepitant 150 mg was an effective and generally well tolerated addition to an antiemetic regimen that included dexamethasone and a serotonin 5-HT3 receptor antagonist in adult cancer patients undergoing treatment with HEC or MEC. It was also noninferior to an oral aprepitant-based regimen in adult cancer patients undergoing HEC treatment. The tolerability profile of a fosaprepitant-based regimen was typical of that in patients receiving emetogenic chemotherapy, and adverse events were generally consistent with those observed with an aprepitant-based regimen. Fosaprepitant provides a useful addition to antiemetic therapy regimens.

Topics: Animals; Antiemetics; Antineoplastic Agents; Clinical Trials, Phase III as Topic; Humans; Morpholines; Nausea; Neoplasms; Vomiting

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

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

Advances in antiemetic therapy for chemotherapy-induced emesis have resulted in improved protection against symptoms occurring within 24 h of chemotherapy. However, the vomiting which tends to occur beyond 24 h after chemotherapy (delayed-phase vomiting) is still relatively poorly controlled by the currently available drugs, suggesting that more than one mechanism may mediate these symptoms. The standard antiemetic regimen currently recommended for prevention of chemotherapy-induced emesis includes a serotonin (5-HT(3)) antagonist and a corticosteroid. The neurokinin-1 (NK(1)) antagonist aprepitant represents a new class of antiemetic currently in clinical development. Using data obtained in 2 Phase II clinical trials of aprepitant in patients receiving chemotherapy based on the highly emetogenic chemotherapeutic agent cisplatin, we compared the time course of antiemetic effect of aprepitant, a 5-HT(3) antagonist, or a combination of both. Over the entire observation period (up to 7 days post-cisplatin), patients who received the NK(1) antagonist had a superior prevention of emesis. However, in the first 24 h after cisplatin, emesis occurred in fewer patients who received the 5-HT(3) antagonist than in patients who did not receive this class of drug. Furthermore, the majority of treatment failures in patients who received the NK(1) antagonist occurred within the first 8-12 h of chemotherapy, whereas the treatment failures in patients who received a 5-HT(3) antagonist were more evenly distributed over time. Patients who received both drugs had superior control of symptoms compared with patients who received one or the other. The difference in the time course of emesis blockade observed with two different classes of receptor antagonists provides substantial evidence for involvement of separate pathophysiological mechanisms in chemotherapy-induced vomiting. Serotonin mediates the early vomiting process that occurs within 8-12 h following cisplatin-based chemotherapy, after which time substance P acting at NK(1) receptors becomes the dominant mediator of vomiting

Topics: Antiemetics; Antineoplastic Agents; Aprepitant; Cisplatin; Clinical Trials, Phase II as Topic; Drug Therapy, Combination; Granisetron; Humans; Morpholines; Neoplasms; Neurokinin-1 Receptor Antagonists; Neurotransmitter Agents; Ondansetron; Prodrugs; Serotonin; Serotonin Antagonists; Substance P; 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

Even though chemotherapy-induced nausea and vomiting (CINV) can be well controlled in the acute phase, the incidence of delayed CINV remains high. In this study, we intend to investigate whether prolonged use of NK-1 receptor antagonist (RA) in addition to 5-HT3 RA and dexamethasone (DEX) was more effective in preventing delayed CINV.. This randomised, open-label, controlled study was designed to compare the efficacy and safety of fosaprepitant 150 mg given on days 1,3 (prolonged group) versus on day 1 (regular group) in patients receiving highly emetogenic chemotherapy (HEC). All patients also treated with palonosetron on day 1 and DEX on days 1-3. The primary endpoint was the incidence of delayed nausea and vomiting. The second endpoint was AEs. All the above endpoints were defined according to CTCAE 5.0.. Seventy-seven patients were randomly assigned to prolonged group and seventy-nine to regular group. Prolonged group demonstrated superiority in controlling delayed CINV to regular group, with statistically significant lower incidence of nausea (6.17% vs 12.66%, P = 0.0056), and slightly lower incidence of grade 1 vomiting (1.62% vs 3.80%, P = 0.0953) in the delayed phase. In addition, prolonged use of fosaprepitant was safe. No significant difference was found between the two groups regarding constipation, diarrhea, hiccough, fatigue, palpitation and headache in delayed phase.. Prolonged use of fosaprepitant can effectively and safely prevent delayed CINV in patients receiving HEC.

Topics: Antineoplastic Agents; Humans; Morpholines; Nausea; Vomiting

Unlike substantial evidence in the prevention of chemotherapy-induced nausea and vomiting (CINV), research in the prevention of nausea and vomiting caused by concurrent chemoradiotherapy (CCRT) is currently lacking.. To compare the efficacy and safety of fosaprepitant weekly vs every 3 weeks for the prevention of nausea and emesis caused by CCRT among patients with nasopharyngeal carcinoma.. This pilot randomized clinical trial was conducted at a single cancer center from November 24, 2020, to July 26, 2021, among patients with nasopharyngeal carcinoma who had achieved CINV control after 2 to 3 cycles of induction chemotherapy. Efficacy analyses were performed in the intention-to-treat population. Data were analyzed on November 4, 2022.. Eligible patients were randomly assigned (1:1) to receive fosaprepitant either weekly or every 3 weeks.. The primary end point was the proportion of patients with sustained complete response (defined as no emesis and no rescue therapy) during CCRT. Secondary end points were sustained no emesis, no nausea, no significant nausea, mean time to first emetic episode, quality of life, and 1-year progression-free survival (PFS).. A total of 100 patients (mean [SD] age, 46.6 [10.9] years; 83 [83.0%] male) who had achieved CINV control after induction chemotherapy were randomly assigned to receive fosaprepitant weekly (50 patients) or every 3 weeks (50 patients). There was no significantly significant difference in cumulative risk of emesis or rescue therapy in the group that received weekly fosaprepitant compared with those who received fosaprepitant every 3 weeks (subhazard ratio, 0.66 [95% CI, 0.43-1.02]; P = .06). The proportion of patients with sustained no emesis (38% vs 14%; P = .003) or no significant nausea (92% vs 72%; P = .002) was significantly higher in the group that received fosaprepitant weekly vs those who received fosaprepitant every 3 weeks. Treatments were well tolerated. Patients in the weekly group had improved scores for multiple quality-of-life measures. There was no significant difference in survival outcomes between groups (91.8% vs 93.7%; P = .99). In the mean brainstem dose subgroups, a possible treatment interaction effect was observed in sustained complete response (mean brainstem dose ≥36 Gy: hazard ratio [HR], 0.32 [95% CI, 0.15-0.69]; mean brainstem dose <36 Gy: HR, 0.95 [95% CI, 0.55-1.63]) and sustained no emesis (mean brainstem dose ≥36 Gy: HR, 0.21 [95% CI, 0.08-0.53]; mean brainstem dose <36 Gy: HR, 0.73 [95% CI, 0.41-1.28]).. In this pilot randomized clinical trial, there was no statistically significant difference in the complete response primary end point, but patients receiving weekly fosaprepitant were less likely to experience emesis compared with those who received fosaprepitant every 3 weeks, especially in the subgroup with a mean brainstem dose of 36 Gy or more. Weekly fosaprepitant was well tolerated and improved quality of life of patients without compromising survival.. ClinicalTrials.gov Identifier: NCT04636632.

Topics: Chemoradiotherapy; Female; Humans; Male; Middle Aged; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Nausea; Pilot Projects; Quality of Life; Vomiting

There are no well-recognized guidelines for antiemesis during concurrent chemoradiotherapy (CCRT) for cervical cancer (CC) and nasopharyngeal cancer (NPC) until now. The study was designed to assess the efficacy and safety of fosaprepitant combined with tropisetron and dexamethasone in preventing nausea and vomiting during 5 weeks of fractionated radiotherapy and concomitant weekly low-dose cisplatin chemotherapy in patients with CC or NPC.. Patients with CC or NPC were scheduled to receive fractionated radiotherapy and weekly cisplatin (25-40 mg/m. Between July 2020 and July 2022, 116 patients consented to the study of whom 103 were included in this interim analysis (fosaprepitant group [N = 52] vs control group [N = 51]). The cumulative incidence of emesis at 5 weeks (competing risk analysis) was 25% (95% CI 14.2-37.4) for the fosaprepitant group compared with 59% (95% CI 43.9-71.0) for the control group. There was a significantly lower cumulative risk of emesis in the fosaprepitant group (HR 0.35 [95% CI 0.19-0.64]; p < 0.001). Fosaprepitant was well tolerated as the incidences of adverse events in the two groups were comparable.. The addition of fosaprepitant to tropisetron plus dexamethasone significantly reduced the risk of nausea and vomiting during 5 weeks of CCRT in patients with CC or NPC, and fosaprepitant was well tolerated.. The trial was registered with ClinicalTrials.gov on October 3, 2022, number NCT05564286.

Topics: Antiemetics; Antineoplastic Agents; Cisplatin; Dexamethasone; Dose Fractionation, Radiation; Drug Therapy, Combination; Female; Humans; Nasopharyngeal Neoplasms; Nausea; Prospective Studies; Tropisetron; Uterine Cervical Neoplasms; Vomiting

We evaluated the efficacy and safety of fosnetupitant (FosNTP) versus fosaprepitant (FosAPR) for preventing highly emetogenic chemotherapy-induced nausea and vomiting. This phase III study was the first head-to-head comparison between two different neurokinin-1 receptor antagonists in combination with palonosetron and dexamethasone.. Patients scheduled to receive cisplatin-based chemotherapy were randomly assigned 1:1 to FosNTP 235 mg or FosAPR 150 mg in combination with palonosetron 0.75 mg and dexamethasone. The primary end point was overall (0-120 hours) complete response (CR; no emetic event and no rescue medication) rate, stratified by sex and age category, to show the noninferiority of FosNTP to FosAPR (noninferiority margin, -10% for the difference in the overall CR rate).. Overall, 795 patients were randomly assigned, of whom 785 received the study drug (FosNTP [N = 392]. FosNTP demonstrated noninferiority to FosAPR, with a favorable safety profile and lower risk for injection site reactions. Thus, FosNTP is valuable in the prophylaxis of acute, delayed, and beyond delayed chemotherapy-induced nausea and vomiting.

Topics: Adult; Aged; Aged, 80 and over; Antiemetics; Antineoplastic Agents; Cisplatin; Dexamethasone; Double-Blind Method; Drug Combinations; Female; Humans; Isoquinolines; Japan; Male; Middle Aged; Morpholines; Nausea; Neurokinin-1 Receptor Antagonists; Pyridines; Quinuclidines; Time Factors; Treatment Outcome; Vomiting

The purpose of this study was to evaluate the cost-effectiveness and budget impact of fosaprepitant (FosAPR)-containing regimen for the prevention of chemotherapy-induced nausea and vomiting (CINV) among patients receiving high emetogenic chemotherapy (HEC) from the Chinese payer's perspective.. A decision tree model was established to measure the 5-day costs and health outcomes between the APR-containing regimen (aprepitant, granisetron, and dexamethasone) and FosAPR-containing regimen (fosaprepitant, granisetron, and dexamethasone). Clinical data were derived from a randomized, double-blind controlled trial on Chinese inpatients who received HEC. Quality-adjusted life-years (QALYs) were used to estimate the utility outcomes and the incremental cost-effectiveness ratio (ICER) was calculated to assess the economics of FosAPR. A static budget impact model was developed to assess the impact of FosAPR as a new addition to the National Reimbursement Drug List (NRDL) on the medical insurance fund within 3 years in Nanjing, China.. Compared with APR, FosAPR had a mean health-care savings of ¥121.56 but got a reduction of 0.0001815 QALY, resulting in an ICER of ¥669926.19 per QALY. Deterministic sensitivity analysis revealed that the cost of APR was the most influential factor to the ICER. The cost of FosAPR and the complete control rate of the delayed period also had a high impact on the results. According to the probabilistic analysis, the acceptability of FosAPR was more than 80% when the Chinese willingness-to-pay (WTP) was ¥215,999. FosAPR would lead to a 3-year medical insurance payment increase of ¥1.84 million compared with ¥1.49 million before FosAPR entered NRDL in Nanjing. The total budget increased with a cumulative cost of ¥694,829 and covered an additional 341 patients who benefited from FosAPR in Nanjing. Deterministic sensitivity analysis showed that the model of budget impact analysis was stable.. FosAPR had a similar treatment effect to APR but was cost-effective in China at the current WTP threshold. The total budget of medical insurance payments of Nanjing slightly increased year by year after the inclusion of FosAPR. Its inclusion in the NRDL would be acceptable and also expand the coverage of patients who benefited from FosAPR.

Topics: Antiemetics; Antineoplastic Agents; Cost-Benefit Analysis; Dexamethasone; Granisetron; Humans; Morpholines; Nausea; Vomiting

To investigate whether palonosetron is better than granisetron in preventing chemotherapy-induced nausea and vomiting (CINV) in a three-drug combination with dexamethasone and fosaprepitant (Fos) in patients with breast cancer who are placed on anthracycline and cyclophosphamide (AC-based regimen).. Chemo-naive women with primary breast cancer were randomly administered either palonosetron 0.75 mg (day 1) or granisetron 1 mg (day 1) combined with dexamethasone (12 mg at day 1, 8 mg at day 2 and day 3) and Fos 150 mg (day 1) before receiving AC-based regimen in a double-blind study. The primary endpoint was the complete response (CR) rate of emesis in cycle 1 in the delayed phase. This was defined as neither vomiting nor rescue drug usage for emesis at >24-120 hours after chemotherapy. Secondary endpoints were the CR in the acute/overall phase (0-24/0-120 hours, respectively, after chemotherapy), no nausea and vomiting, Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and safety.. From December 2012 to October 2014, 326 patients were treated and evaluated (164/162 evaluable patients in granisetron/palonosetron arm, respectively). The CR during the delayed phase was 60.4% in the granisetron regimen and 62.3% in the palonosetron regimen. The CR during acute phase (73.2% vs 75.9%, respectively) and the CR during overall phase (54.9% in both regimens) were very identical. A significantly higher number of patients in the palonosetron arm were free from nausea during the delayed phase (28% vs 40.1%; P = .029). Adverse events were also identical, although infusion site reactions (ISR) were higher (20.3%-23.3%) than preceding studies in both regimens.. In combination with dexamethasone and Fos, this study suggests that palonosetron is not better than granisetron in chemo-naive patients with primary breast cancer receiving AC-based regimen. Administration of Fos in peripheral veins after AC-based regimen increased ISR.

Topics: Adult; Aged; Aged, 80 and over; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Dexamethasone; Double-Blind Method; Doxorubicin; Drug Therapy, Combination; Epirubicin; Female; Fluorouracil; Granisetron; Humans; Middle Aged; Morpholines; Nausea; Palonosetron; Patient Reported Outcome Measures; Vomiting

Results from a phase III, randomized, double-blind, active comparator-controlled, parallel-group trial evaluating fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) found that a single-day, triple-antiemetic fosaprepitant regimen resulted in a significantly higher proportion of patients achieving a complete response (CR; no vomiting or rescue medication use) in the delayed phase (25-120 h after chemotherapy initiation), compared with a 3-day control regimen ( ClinicalTrials.gov , NCT01594749). As the risk for CINV is dependent on chemotherapy regimen and generally guided by tumor type, this post hoc analysis evaluated the efficacy and safety of this regimen by cancer subpopulations (gastrointestinal [GI] or colorectal, lung, breast, and gynecologic cancers).. Subjects with confirmed cancer who were naive to highly and moderately emetogenic chemotherapy (HEC and MEC) and were scheduled to receive intravenous (IV) anthracycline-cyclophosphamide (AC)-based MEC on the first day of chemotherapy were randomly assigned to receive oral ondansetron and oral dexamethasone plus either a single IV dose of fosaprepitant 150 mg (fosaprepitant regimen) or placebo (control regimen). The primary efficacy end point was the proportion of subjects achieving CR in the delayed phase. CR rates in the overall and acute phases (0-120 h and 0-24 h after MEC initiation, respectively) were assessed as secondary end points. Safety and tolerability were also assessed.. CR rates in the delayed phase favored the fosaprepitant regimen over the control regimen across the GI/colorectal, lung, breast, and gynecologic cancer subgroups (range, 6.2-22%); similar findings were observed for CR in the overall phase. CR in the acute phase was high for all groups (≥87%). The fosaprepitant regimen was well tolerated in all cancer subgroups.. This post hoc analysis indicated that a single-day fosaprepitant regimen was effective in preventing CINV in patients receiving MEC, regardless of cancer type.. ClinicalTrials.gov NCT01594749 , registered May 9, 2012.

Topics: Adult; Aged; Aged, 80 and over; Antiemetics; Double-Blind Method; Female; Humans; Male; Middle Aged; Morpholines; Nausea; Neoplasms; Vomiting; Young Adult

Fosaprepitant is a neurokinin-1 receptor antagonist, approved for the prevention of chemotherapy-induced nausea and vomiting. The data on the use of fosaprepitant in children are limited and therefore we conducted a phase III randomized controlled trial.. Children aged 1-12 years scheduled to receive moderately or highly emetogenic chemotherapy were randomly assigned to arm-A (fosaprepitant) or arm-B (placebo). Children recruited to arm-A received intravenous ondansetron plus dexamethasone followed by fosaprepitant infusion. Children recruited to arm-B received the same drugs as those given to children in arm-A, except that fosaprepitant was substituted with a placebo. Ondansetron and dexamethasone were continued for 48 hours after completion of chemotherapy. The primary end point of the study was to determine the proportion of patients who achieved a complete response (CR), defined as no vomiting, no retching, and no use of rescue medication, during the 24-120 hours (delayed phase) after administration of the last dose of chemotherapy. Secondary end points were the proportion of patients who achieved a CR during the acute phase (0-24 hours) and overall after administration of the last dose of chemotherapy.. One-hundred-sixty-three patients were analyzed (81 in the fosaprepitant arm and 82 in the placebo arm). CR rates were significantly higher in the fosaprepitant arm compared to those in the placebo arm during the acute phase (86% vs 60%, P < 0.001), delayed phase (79% vs 51%, P < 0.001), and overall phase (70% vs 41%, P < 0.001). Three (4%) patients in the fosaprepitant arm and sixteen (20%) in the placebo arm required rescue anti-emetics (P = 0.0017).. Addition of fosaprepitant to ondansetron and dexamethasone improved chemotherapy-induced vomiting control in children treated with moderately or highly emetogenic chemotherapy.

Topics: Administration, Intravenous; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Case-Control Studies; Child; Child, Preschool; Double-Blind Method; Female; Follow-Up Studies; Humans; Infant; Male; Morpholines; Nausea; Neoplasms; Prognosis; 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

Current antiemetic regimens are less effective in children than in adults. Fosaprepitant was recently approved for prevention of chemotherapy-induced nausea and vomiting (CINV) in children aged six months and older.. The pharmacokinetic (PK)/pharmacodynamic (PD) profile, safety, and tolerability of a single intravenous dose of fosaprepitant administered concomitantly with ondansetron with/without dexamethasone were evaluated in pediatric patients with cancer receiving emetogenic chemotherapy. PK/PD from three doses of fosaprepitant (3.0, 1.2, and 0.4 mg/kg, up to 150, 60, and 20 mg, respectively) were compared with placebo in 2- to 17-year-old subjects; an open-label amendment evaluated a fourth dose (5.0 mg/kg, up to 150 mg) in those under 12 years old. Historical adult PK data were used for comparison. Efficacy was measured as an exploratory endpoint.. PK data were evaluable for 167/234 subjects who completed cycle one. Aprepitant exposures were dose proportional; adolescents (12 to 17 years) receiving fosaprepitant 150 mg had exposures similar to adults at the same dose. Higher weight-normalized doses (5 mg/kg) were necessary for children aged < 12 years to achieve comparable adult exposures. The adverse event profile was typical of cancer patients receiving emetogenic chemotherapy. Drug-related adverse events were reported in 16 (6.8%) subjects, with hiccups being most common (n = 5; 2.1%).. Intravenous fosaprepitant was well tolerated by pediatric subjects with cancer, and dose-proportional exposures were observed. Subjects < 12 years old required higher doses to achieve comparable adult exposures.

Topics: Adolescent; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Male; Morpholines; Nausea; Neoplasms; Prognosis; Tissue Distribution; Vomiting

Fosaprepitant improved prevention of chemotherapy-induced nausea and vomiting (CINV) in a randomized, double-blind phase III trial (PN031). This post hoc analysis explored factors that may have influenced response.. Adult subjects (N = 1000) scheduled to receive non-anthracycline and cyclophosphamide (AC) moderately emetogenic chemotherapy (MEC) on day 1 were randomly assigned 1:1 to a single-dose, 150-mg intravenous fosaprepitant regimen or a control regimen. Both regimens included dexamethasone and ondansetron on day 1, with ondansetron continuing through day 3 in the control arm only. Complete response (CR; no vomiting and no rescue medication) rates in the acute, delayed, and overall phases (0-25, 25-120, and 0-120 h, respectively) were analyzed by chemotherapy type (carboplatin-based vs non-carboplatin-based), chemotherapy duration (single-day vs multiple-day), and baseline characteristics.. Most subjects received single-day chemotherapeutic regimens (70.6%), which were mainly carboplatin-based (67.6%). CR with fosaprepitant was consistent (76-80%) during the delayed and overall phases in carboplatin-based and non-carboplatin-based subgroups and in subgroups receiving single-day or multiple-day MEC regimens. Treatment effects favored fosaprepitant for the carboplatin-based versus the non-carboplatin-based group during the delayed phase (14.1 vs 6.5%; p = 0.06), and for the single-day versus the multiple-day subgroup during the delayed (13.2 vs 3.2%; p = 0.02) and overall phases (12.8 vs 4.0%; p = 0.06).. This exploratory analysis confirms that single-dose fosaprepitant is effective for the prevention of CINV in subjects receiving carboplatin or non-carboplatin in both single- and multiple-day non-AC MEC chemotherapy regimens. This trial is registered at ClinicalTrials.gov , number NCT01594749.

Topics: Adult; Aged; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cyclophosphamide; Dexamethasone; Double-Blind Method; Female; Humans; Induction Chemotherapy; Male; Middle Aged; Morpholines; Nausea; Neoplasms; Ondansetron; Vomiting

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

Evidence supports olanzapine for prophylaxis of chemotherapy-induced nausea/vomiting (CINV) for highly emetogenic chemotherapy; however, most studies focus on solid malignancies and single-day regimens. A randomized, double-blinded, placebo-controlled trial was conducted to compare the addition of olanzapine to triplet therapy (fosaprepitant, ondansetron, dexamethasone [FOND-O]) versus triplet therapy alone (FOND) in preventing CINV in hematology patients receiving single-day and multiple-day highly emetogenic chemotherapy and hematopoietic cell transplant (HCT) regimens (NCT02635984). The primary objective of this study was to compare complete response (CR; no emesis and minimal nausea, <25 mm on a 100-mm visual analog scale) during the overall assessment period (chemotherapy days plus 5 days after). Secondary objectives were the number of emesis, number of rescue medications, percent achieving minimal nausea, and percent achieving complete protection (CP; no emesis, rescue antiemetic, or significant nausea), all of which are reported as acute (chemotherapy days), delayed (5 days after chemotherapy), and overall phases. Olanzapine 10 mg or matching placebo were given on each chemotherapy day and 3 days after. Adults with hematologic malignancy receiving HCT regimens of melphalan, BEAM (carmustine, etoposide, cytarabine, melphalan), busulfan (Bu)/cyclophosphamide (Cy), Bu/fludarabine (Flu), Bu/melphalan, FluCy, FluCy-total body irradiation (TBI), etoposide-TBI, and ICE (ifosfamide, carboplatin, etoposide) or 7+3 chemotherapy regimens were included. An estimated 98 patients were required using alpha = .05 and 80% power. No significant differences existed in baseline characteristics between FOND-O (n = 51) and FOND (n = 50) arms. Mean duration of olanzapine was 7.7 days (range, 4 to 11). Discontinuation for possible adverse events occurred in 3 placebo and 0 olanzapine patients. CR was significantly higher for FOND-O in overall (55% versus 26%, P = .003) and delayed (60.8% versus 30%, P = .001) but not acute (P = .13) phases. Significantly more patients receiving FOND-O achieved no more than minimal nausea in overall (P = .001) and delayed phases (P = .0002), as well as fewer overall mean emesis counts (P = .005). CP rates were not different in any assessment phase (P ≥ .05 each). Within the HCT subgroup (n = 64), the CR, CP, and no significant nausea rates were significantly better for FONDO-O in overall and delayed phases (all P < .05). Analysis within th

Topics: Adult; Aged; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Induction Chemotherapy; Male; Melphalan; Middle Aged; Morpholines; Nausea; Olanzapine; Ondansetron; Podophyllotoxin; Vomiting

Combination therapy of fosaprepitant, dexamethasone (DEX) and a serotonin (5-HT3) receptor antagonist is a standard antiemetic prophylaxis for patients receiving highly emetogenic chemotherapy (HEC). However, the appropriate dose of DEX has not been established in Japan. This study determined the efficacy and safety of triplet antiemetic prophylaxis in Japanese patients receiving HEC when administered the same doses of DEX as those given in a previous international phase 3 study on this drug.. To assess the efficacy and safety of a sufficient dose of DEX (12 mg on day 1, 8 mg on day 2, 16 mg on days 3 and 4) in combination with intravenous fosaprepitant and granisetron, we prospectively examined patients receiving HEC including cisplatin (≥50 mg/m). The primary endpoint was to determine the percentage of patients who had achieved a complete response (CR), which was defined as no vomiting and no rescue therapy during the entire treatment course.. Between February 2013 and January 2015, 44 patients were enrolled with a median age of 65 years (range, 30-75). There were 34 males (77.3%) in the study. Most of the patients had upper gastrointestinal cancers. The CR rate during the treatment course was 70% (95% confidence interval [CI]: 55%-83%) in the overall phase and 91% (95% CI: 78%-97%) in the acute phase and 70% (95% CI: 55%-83%) in the delayed phase. Appreciable severe toxicities related to the antiemetic therapy were not observed.. These results suggest that a sufficient dose of DEX in combination with fosaprepitant and granisetron is optimal as an antiemetic prophylaxis for Japanese patients receiving HEC.

Topics: Adult; Aged; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Drug Therapy, Combination; Female; Gastrointestinal Neoplasms; Granisetron; Humans; Male; Middle Aged; Morpholines; Nausea; Prospective Studies; Serotonin Antagonists; Vomiting

To determine if a lower dose of dexamethasone can be used in combination with fosaprepitant and palonosetron for cisplatin-induced nausea and vomiting in head and neck cancer patients, we conducted a single-center, two-arm, cross-over comparison study.. Patients were randomly assigned to either standard dose dexamethasone group: intravenous 9.9 mg on day 1 and 6.6 mg on days 2-4 or low-dose dexamethasone group: intravenous 3.3 mg on days 1-4 for the first course and crossed over to the other treatment for the second course. The primary endpoint was complete response (CR) in the overall period.. Twenty-five patients were screened for the study and 22 were evaluable. Eleven patients were randomly assigned to the standard dose dexamethasone group and 12 patients to the low-dose dexamethasone group. The CR rate in the overall period was 86% in the standard dose group and 73% in the low-dose group, showing no significant difference (p = .61).. The efficacy of low-dose dexamethasone with fosaprepitant and palonosetron was not inferior to that of the standard dose dexamethasone in the highly emetogenic cisplatin-based treatment for head and neck cancer patients.

Topics: Aged; Antiemetics; Antineoplastic Agents; Cisplatin; Dexamethasone; Drug Therapy, Combination; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Morpholines; Nausea; Palonosetron; Vomiting

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

To establish the role of antiemetic therapy with neurokinin-1 (NK1) receptor antagonists (RAs) in nonanthracycline and cyclophosphamide (AC)-based moderately emetogenic chemotherapy (MEC) regimens, this study evaluated single-dose intravenous (i.v.) fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) associated with non-AC MEC.. In this international, phase III, double-blind trial, adult cancer subjects scheduled to receive ≥1 non-AC MEC on day 1 were randomized to a regimen comprising single-dose i.v. fosaprepitant 150 mg or placebo along with ondansetron and dexamethasone on day 1; control regimen recipients received ondansetron on days 2 and 3. Primary end points were the proportion of subjects achieving a complete response (CR; no vomiting and no use of rescue medication) in the delayed phase (25-120 h after MEC initiation) and safety. Secondary end points included CR in the overall and acute phases (0-120 and 0-24 h after MEC initiation, respectively) and no vomiting in the overall phase. Nausea and the Functional Living Index-Emesis were assessed as exploratory end points.. The fosaprepitant regimen improved CR significantly in the delayed (78.9% versus 68.5%; P < 0.001) and overall (77.1% versus 66.9%; P < 0.001) phases, but not in the acute phase (93.2% versus 91.0%; P = 0.184), versus control. In the overall phase, the proportion of subjects with no vomiting (82.7% versus 72.9%; P < 0.001) and no significant nausea (83.2% versus 77.9%; P = 0.030) was also significantly improved with the fosaprepitant regimen. The fosaprepitant regimen was generally well tolerated.. Single-dose fosaprepitant added to a 5-HT3 RA and dexamethasone was well tolerated and demonstrated superior control of CINV (primary end point achieved) associated with non-AC MEC. This is the first study to evaluate NK1 RA therapy as an i.v. formulation in a well-defined non-AC MEC population.. NCT01594749 (https://clinicaltrials.gov/ct2/show/NCT01594749).

Topics: Antiemetics; Antineoplastic Agents; Double-Blind Method; Female; Humans; Lung Neoplasms; Male; Middle Aged; Morpholines; Nausea; 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

The role of the neurokinin-1 (NK-1) receptor antagonists in the prevention of radiation-induced nausea and vomiting has not been established. The purpose of the GAND-emesis study was to investigate the efficacy and safety of fosaprepitant in combination with palonosetron and dexamethasone in the prevention of nausea and vomiting during 5 weeks of fractionated radiotherapy and concomitant weekly cisplatin in patients with cervical cancer.. This investigator initiated, multinational, randomised, double-blind, placebo-controlled phase 3 trial, included women with cervical cancer scheduled to receive fractionated radiotherapy and weekly cisplatin 40 mg/m(2) for 5 weeks. Patients had to be naive to chemotherapy and radiotherapy. Patients were randomly assigned to receive either single doses of fosaprepitant 150 mg intravenously or placebo (saline) in combination with palonosetron 0·25 mg intravenously and dexamethasone 16 mg orally before cisplatin administration. Randomisation was done by the unmasked pharmacist, who used a list of six numbers (a block) provided in a sealed envelope. A web-based randomisation number generator was used to generate the full list of randomisation numbers that was split up in blocks of six numbers. All patients received oral dexamethasone 8 mg twice a day on day 2, 4 mg twice a day on day 3, and 4 mg once on day 4. The treatment was repeated for 5 weeks. The primary endpoint was the proportion of patients with sustained no emesis after 5 weeks of treatment. The modified intention-to-treat population (all patients who received study medication) was used for the statistical analyses. The study was registered with ClinicalTrials.gov, number NCT01074697.. Between June 15, 2010, and March 8, 2015, 246 patients from four countries consented to the study and were randomly assigned. Of these, 234 patients were eligible, having received study medication (118 received fosaprepitant, 116 received placebo). The proportion of patients with sustained no emesis at 5 weeks (competing risk analysis) was 48·7% (95% CI 25·2-72·2) for the placebo group compared with 65·7% (42·2-89·2) of patients for the fosaprepitant group. There was a significantly lower cumulative risk of emesis in the fosaprepitant group compared with the placebo group (subhazard ratio 0·58 [95% CI 0·39-0·87]; p=0·008). Treatments were generally well tolerated with few grade 3 adverse events none of which were related to the study treatment; the most common grade 3 adverse event during the 5 weeks of treatment was diarrhoea (11 [9%] of 118 patients in the fosaprepitant group vs six [5%] of 116 patients in the placebo group). There was only one report of a grade 4 adverse event (neutropenia), in the fosaprepitant group. No deaths were recorded in either group.. To our knowledge, this is the first study to investigate safety and efficacy of a NK-1 receptor antagonist during 5 weeks of radiotherapy and concomitant weekly cisplatin. Patients receiving fosaprepitant in addition to palonosetron and dexamethasone were less likely to experience emesis and nausea compared with those receiving palonosetron and dexamethasone alone. Both treatments were safe and well tolerated. Further investigations in other radiotherapy settings are warranted.. Private and hospital or university funding, unrestricted grants from Biovitrum and Helsinn Healthcare SA.

Topics: Adult; Aged; Antineoplastic Agents; Chemoradiotherapy; Cisplatin; Dexamethasone; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Isoquinolines; Middle Aged; Morpholines; Nausea; Palonosetron; Quinuclidines; Uterine Cervical Neoplasms; Vomiting

APF530, extended-release granisetron, provides sustained release for ≥5 days for acute- and delayed-phase chemotherapy-induced nausea and vomiting (CINV). We compared efficacy and safety of APF530 versus ondansetron for delayed CINV after highly emetogenic chemotherapy (HEC), following a guideline-recommended three-drug regimen.. HEC patients received APF530 500 mg subcutaneously or ondansetron 0.15 mg/kg intravenously, with dexamethasone and fosaprepitant. Primary end point was delayed-phase complete response (no emesis or rescue medication).. A higher percentage of APF530 versus ondansetron patients had delayed-phase complete response (p = 0.014). APF530 was generally well tolerated; treatment-emergent adverse event incidence was similar across arms, mostly mild-to-moderate injection-site reactions.. APF530 versus the standard three-drug regimen provided superior control of delayed-phase CINV following HEC. ClinicalTrials.gov : NCT02106494.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Delayed-Action Preparations; Dexamethasone; Double-Blind Method; Drug Therapy, Combination; Female; Granisetron; Humans; Injections, Subcutaneous; Male; Middle Aged; Morpholines; Nausea; Ondansetron; Treatment Outcome; Vomiting; Young Adult

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

Although palonosetron (PALO) and NK1 receptor antagonist both reduce chemotherapy-induced nausea and vomiting, no comparison trial in moderately emetogenic chemotherapy (MEC) had been reported. The purpose of this study was to find out which drug combinations are preferable for patients receiving MEC.. Chemotherapy-naive patients receiving MEC were randomized to two groups; group A first received PALO therapy [PALO plus 1-day dexamethasone (DEX)], and group B first received fosaprepitant (FAPR) therapy [FAPR, granisetron (GRAN), and DEX]. Patients were re-allocated to the other therapy, respectively, for the second cycle of chemotherapy. We administered intravenous PALO (0.75 mg) and DEX (9.9 mg) to the PALO therapy group, and FAPR (150 mg), DEX (4.95 mg), and GRAN (3 mg) to the FAPR therapy group, on Day 1. Complete response (CR) was the primary endpoint; complete control (CC), total control (CT), and the therapy chosen by the patients for their third and following cycles of antiemetic therapy were the secondary endpoints. We evaluated CR, CC, and TC in the acute phase, in the delayed phase, and over the whole period.. A total of 35 patients and 70 cycles of therapy was evaluable for analysis. No significant difference was found at all evaluation points. Overall CR rates for PALO and FAPR therapy were 74 vs 69 % (P = 0.567), CC rates 66 vs 69 % (P = 0.521), and TC rates 46 vs 60 % (P = 0.235), respectively. Patients also showed no clear preference for their third and following cycles of chemotherapy, choosing both regimens almost equally often (PALO 10 vs FAPR 13).. PALO and 1-day DEX is almost equivalent to FAPR, GRAN, and DEX for MEC.

Topics: Aged; Antiemetics; Antineoplastic Agents; Cross-Over Studies; Dexamethasone; Drug Therapy, Combination; Female; Granisetron; Humans; Isoquinolines; Male; Middle Aged; Morpholines; Nausea; Palonosetron; Patient Preference; Prospective Studies; Quinuclidines; Single-Blind Method; Treatment Outcome; 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

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

Recent studies have suggested that antiemetic therapy with a triple combination of the neurokinin-1 receptor antagonist MK-869, a serotonin (5-HT(3)) antagonist, and dexamethasone provides enhanced control of cisplatin-induced emesis compared with standard therapy regimens. The authors compared the antiemetic activity of a dual combination of MK-869 and dexamethasone with that of a standard dual combination of ondansetron and dexamethasone to characterize further the efficacy and tolerability profile of MK-869.. This was a multicenter, double-blind, randomized, active agent-controlled study of 177 cisplatin-naïve patients with malignant disease. On Day 1, MK-869 was given intravenously as its water-soluble prodrug, L-758,298. Patients were randomized to one of three groups as follows. Group I received L-758,298 100 mg intravenously (i.v.), then dexamethasone 20 mg i.v., and cisplatin >or= 70 mg/m(2) on Day 1 followed by 300 mg MK-869 (tablet) orally on Days 2-5; Group II received L-758,298 100 mg i.v., then dexamethasone 20 mg i.v., and cisplatin >or= 70 mg/m(2) on Day 1 followed by placebo on Days 2-5; and Group III received ondansetron 32 mg i.v., then dexamethasone 20 mg i.v., and cisplatin >or= 70 mg/m(2) on Day 1 followed by placebo on Days 2-5. Emesis was recorded over Days 1-5 in a diary. Nausea was assessed every 24 hours by visual analog scale. Additional medication was available for emesis or nausea at any time. The primary efficacy parameters of interest were the proportion of patients without emesis and the proportion without emesis or rescue therapy on Day 1 (acute phase) and on Days 2-5 (delayed phase).. No serious adverse events were attributed to L-758,298 or MK-869. On Day 1, the proportions of patients with no emesis and no use of rescue medication were 44% of patients in Group I, 36% of patients in Group II, 40% of patients in Groups I and II combined, and 83% of patients in Group III (P < 0.001 for Group III vs. the combined Groups I and II). The proportions of patients with no emesis and no use of rescue medication on Days 2-5 were 59% of patients in Group I, 46% of patients in Group II, and 38% of patients in Group III (P < 0.05 for Group I vs. Group III). The proportions of patients who were without emesis on Day 1 were 49% of patients in Group I, 47% of patients in Group II, and 84% of patients in Group III (P < 0.01 for Group I or II vs. Group III). On Days 2-5, however, the proportions of patients who were without emesis on Days 2-5 were 65% of patients in Group I, 61% of patients in Group II, and 41% of patients in Group III (P < 0.05 for Group I or II vs. Group III). Nausea scores in the acute phase were lower for Group III than for Group I, Group II, or Groups I and II combined (P < 0.05), although there was no significant difference among groups either for the delayed phase or overall for Days 1-5.. Although the L-758,298 and dexamethasone combination reduced acute (Day 1) emesis compared with historic rates, dual therapy with ondansetron and dexamethasone was superior in controlling acute emesis. Continued dosing with MK-869 may enhance control of other measures of delayed emesis, such as the use of rescue medication, although confirmation is required before a definitive conclusion may be drawn. MK-869 given as dual therapy with dexamethasone was superior to ondansetron with dexamethasone for the control of delayed emesis (Days 2-5) and control of the need for rescue medication on Days 2-5.

Topics: Adolescent; Adult; Aged; Antiemetics; Antineoplastic Agents; Aprepitant; Cisplatin; Dexamethasone; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Morpholines; Neoplasms; Neurokinin-1 Receptor Antagonists; Ondansetron; Vomiting

Substance P is localised in brainstem regions associated with emesis. Based on studies in the ferret, it was postulated that a neurokinin-1 (NK1) receptor antagonist would have antiemetic activity as monotherapy in humans receiving chemotherapy. L-758,298 is a water-soluble, intravenous (i.v.) prodrug for L-754,030, a potent and selective NK1 receptor antagonist. This double-blind, randomised, active-agent (ondansetron)-controlled study enrolled 53 cisplatin-naïve patients and evaluated the prevention of both acute (0-24 h) and delayed (days 2-7) emesis after cisplatin treatment (50-100 mg/m(2)). All patients received i.v. L-758,298 (60 or 100 mg) (n=30) or ondansetron (32 mg) (n=23) before cisplatin and efficacy was evaluated up to day 7 post-cisplatin. Nausea was assessed by means of a four-point ordinal scale at intervals over the 7 day period. In the acute period, the proportion of patients without emesis in the L-758,298 and ondansetron groups was 37 and 52%, respectively (no significant difference between the groups). Comparing the distribution of average nausea scores over the entire first 24 h revealed no significant difference between the groups. In the delayed period, the proportion of patients without emesis in the L-758,298 and ondansetron treatment groups was 72 and 30%, respectively (P=0.005). The distribution of average nausea scores in the delayed period was lower in the L-758,298 group compared with the ondansetron group (P=0.15 for the entire delayed period and P=0.043 for day 2 only). No serious adverse events were attributed to L-758,298. A single dose of L-758,298 substantially suppressed the delayed nausea and vomiting characteristic of high dose cisplatin and also appeared to reduce acute emesis post-cisplatin. The data also support the proposition that the underlying mechanism(s) of acute and delayed emesis are different.

Topics: Acetals; Adult; Aged; Antiemetics; Antineoplastic Agents; Aprepitant; Cisplatin; Double-Blind Method; Female; Humans; Male; Middle Aged; Morpholines; Nausea; Ondansetron; Patient Satisfaction; Prodrugs; Vomiting

Chemotherapy-induced nausea and vomiting (CINV) is common in patients with lymphoma and multiple myeloma (MM) receiving high-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT). Despite a standard triple antiemetic regimen of a neurokinin-1 (NK1) receptor antagonist (RA), a 5-hydroxytryptamine-3 (5-HT3) RA, and dexamethasone is recommended, how to control the protracted CINV in ASCT setting remains an intractable problem. Here, we retrospectively analyze CINV data of 100 patients who received either SEAM (semustine, etoposide, cytarabine, melphalan) or MEL140-200 (high-dose melphalan) before ASCT, evaluate the efficacy and safety of multiple-day administration of fosaprepitant combined with tropisetron and olanzapine (FTO), and compare the results to those of patients who received a standard regimen of aprepitant, tropisetron, and dexamethasone (ATD). The overall rate of complete response (CR), defined as no emesis and no rescue therapy, is 70% in the FTO group compared to 36% in the ATD group. Although CR rates are comparable in the acute phase between the two groups, significantly more patients treated by FTO achieve CR in the delayed phase than those treated by ATD (74% vs. 38%, p < 0.001). Moreover, FTO treatment significantly reduced the percentage of patients who are unable to eat, as well as the requirement for rescue medications. Both regimens are well tolerated and most adverse events (AEs) were generally mild and transient. In conclusion, the antiemetic strategy containing multiple-day administration of fosaprepitant is safe and effective for preventing CINV in lymphoma and MM patients, particularly in the delayed phase.

Topics: Antiemetics; Antineoplastic Agents; Dexamethasone; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Melphalan; Morpholines; Multiple Myeloma; Nausea; Olanzapine; Retrospective Studies; Transplantation Conditioning; Transplantation, Autologous; Tropisetron; Vomiting

Fosaprepitant, an NK1 receptor antagonist, inhibits and induces cytochrome P450 3A4 (CYP3A4) as its substrate. Contrarily dexamethasone is metabolized by CYP3A4. Therefore, in combination therapy wherein both agents interact with each other, it is recommended that the dexamethasone dose be reduced in the first two days. Thus far, there are only a few studies on the optimum dose of dexamethasone after day 3. Thus, we aimed to determine the pharmacokinetics of dexamethasone on day3 when administered together with fosaprepitant and investigate the dose-dependent differences in its antiemetic effect in patients with cancer.. Twelve patients with esophageal, stomach, or lung cancer received primary highly emetogenic chemotherapy (HEC). We intravenously administered 9.9 mg and 6.6 mg of dexamethasone on days 1 and 2, respectively, and 6.6 mg or 13.2 mg on day 3 together with the administration of 150 mg fosaprepitant and 0.75 mg palonosetron. We assessed the pharmacokinetics of dexamethasone on day 3 by dose and examined the dose-dependent antiemetic effect.. No differences were observed in the time-to-maximum concentration and blood half-life of dexamethasone between patient groups that received dexamethasone at doses of 6.6 mg and 13.2 mg. In contrast, the area under the blood concentration-time curve and the maximum concentration of dexamethasone correlated with its dose. Moreover, the blood dexamethasone concentration on day 3 increased by twofold after the administration of a higher dose than after a lower dose. The severity of nausea in the delayed phase significantly decreased in a dose-dependent manner.. Administration of a higher dexamethasone dose on day 3 improved the antiemetic effect of the combined regimen in patients with cancer who underwent HEC.
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Topics: Aged; Antiemetics; Antineoplastic Agents; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP3A Inhibitors; Dexamethasone; Dose-Response Relationship, Drug; Drug Interactions; Esophageal Neoplasms; Female; Humans; Lung Neoplasms; Male; Middle Aged; Morpholines; Nausea; Stomach Neoplasms; Vomiting

At our institution, an increased incidence of hypersensitivity reactions was reported following standardization of fosaprepitant as the preferred agent for the prophylaxis of chemotherapy induced nausea and vomiting (CINV) caused by highly emetogenic therapies. The purpose of this evaluation was to assess the incidence of systemic hypersensitivity reactions (HSRs) to fosaprepitant infusions compared to available literature.. This evaluation is a retrospective review of electronic health records of adult patients who received their first dose of fosaprepitant for CINV prophylaxis beginning January 1, 2017 through June 30, 2017 at the University of Colorado Cancer Center outpatient infusion center. Subjects were identified using medication administration reports. Individual chart reviews were performed for all patients who received fosaprepitant during the specified timeframe and had a reaction reported on the same date.. A total of 868 patients received fosaprepitant in the outpatient infusion center during the study time period. Four patients (0.461%) had a systemic HSR attributed to fosaprepitant. Two of the reactions were reported as HSRs in the adverse reaction reporting system and two were found in provider notes during chart review. Due to the small sample size, risk factors for HSRs to fosaprepitant were not able to be determined.. The incidence of HSRs to fosaprepitant at our institution was found to be consistent with the <1% incidence currently noted in literature. Based on these findings, opportunities have been identified for education on fosaprepitant-associated HSRs, proper documentation and patient-specific precautions.

Topics: Academic Medical Centers; Adolescent; Adult; Aged; Aged, 80 and over; Antiemetics; Cancer Care Facilities; Cohort Studies; Drug Evaluation; Drug Hypersensitivity; Female; Humans; Male; Middle Aged; Morpholines; Nausea; Neoplasms; Retrospective Studies; Risk Factors; Vomiting; Young Adult

Chemotherapy-induced nausea and vomiting (CINV) is a severe and distressing complication during allogeneic hematopoietic stem cell transplantation (alloHSCT). The antiemetic fosaprepitant has shown favorable results in pediatric and adult patients receiving chemotherapy. Data on fosaprepitant in children and adolescents undergoing alloHSCT are missing.. During MEC, significantly more patients in the CG experienced vomiting during the first 0-24 h (58.6 vs. 25.0%; p = 0.0156) and during > 24-120 h (93.1% vs. 57.1%; p = 0.0020), compared with the FG. Likewise, significantly more vomiting events (269 vs. 136; p < 0.0001) were registered in the CG. During HEC, significantly more patients in the CG experienced vomiting during the first 0-24 h (32.3 vs. 9.4%; p = 0.0319) compared with the FG. Significantly more vomiting events (241 vs. 99; p < 0.0001) were registered in the CG. Laboratory and clinical adverse events were not significantly different between the two groups (p > 0.05).. Antiemetic prophylaxis with fosaprepitant and granisetron was well tolerated, safe, and effective in pediatric patients undergoing alloHSCT. However, larger prospective trials are necessary to evaluate these findings.

Topics: Adolescent; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Granisetron; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Morpholines; Nausea; Transplantation Conditioning; Vomiting

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

Studies report a wide range of incidence and severity of infusion site adverse events (ISAEs) following fosaprepitant administration.. The purposes of this study were (a) to determine the incidence of suspected extravasation in patients with cancer receiving fosaprepitant infusions with chemotherapy and (b) to determine whether the documented signs, symptoms, and management strategies aligned with the diagnostic criteria for extravasation versus non-extravasation ISAEs.. Electronic health records were used to identify patients who received fosaprepitant infusion with chemotherapy and had documentation for suspected extravasation. Chart reviews were conducted for a sample of patients to determine whether documentation was consistent with extravasation.. About 3% (n = 460 of 15,667) of patients who received fosaprepitant had documentation for suspected extravasation. Among a random sample of patients (N = 110) with suspected extravasation, 6% (n = 6) had documentation consistent with extravasation.

Topics: Antiemetics; Humans; Morpholines; Nausea; Vomiting

Chemotherapy-induced nausea and vomiting (CINV) are a major burden for patients undergoing emetogenic chemotherapy. International guidelines recommend an antiemetic prophylaxis with corticosteroids, 5-HT. This non-interventional observation study analyzed 303 chemotherapy courses administered to 83 pediatric patients with a median age of 9 years (2-17 years), who received antiemetic prophylaxis either with fosaprepitant and granisetron with or without dexamethasone (fosaprepitant group/FG; n=41), or granisetron with or without dexamethasone (control group/CG; n=42), during moderately (CINV risk 30-90%) or highly (CINV risk>90%) emetogenic chemotherapy. The two groups' results were compared with respect to the safety and efficacy of the antiemetic prophylaxis during the acute (0-24hrs after chemotherapy), delayed (>24-120hrs after chemotherapy) and both CINV phases. Laboratory and clinical adverse events were compared between the two cohorts.. Adverse events were not significantly different in the two groups (p>0.05). Significantly fewer vomiting events occurred during antiemetic prophylaxis with fosaprepitant in the acute (23 vs 142 events; p<0.0001) and the delayed (71 vs 255 events; p<0.0001) CINV phase. In the control group, the percentage of chemotherapy courses with vomiting was significantly higher during the acute (24%/FG vs 45%/CG; p<0.0001) and delayed CINV phase (28%/FG vs 47%/CG; p=0.0004). Dimenhydrinate (rescue medication) was administered significantly more often in the CG, compared to the FG (114/FG vs 320/CG doses; p<0.0001). Likewise, in the control group, dimenhydrinate was administered in significantly more (p<0.0001) chemotherapy courses during the acute and delayed CINV phases (79 of 150; 52.7%), compared to the fosaprepitant group (45 of 153; 29.4%).. Antiemetic prophylaxis with fosaprepitant and granisetron with or without dexamethasone was well tolerated, safe and effective in pediatric patients. However, larger prospective trials are needed to evaluate these findings.

Topics: Adolescent; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cohort Studies; Dexamethasone; Drug Therapy, Combination; Female; Granisetron; Humans; Male; Morpholines; Nausea; Vomiting

Chemotherapy-induced nausea and vomiting (CINV) belong among the most burdensome side effects in hemato-oncology. Mostly, a combination of ondansetron and dexamethasone is used as antiemetic prophylaxis in pediatric patients undergoing emetogenic chemotherapy. However, dexamethasone is prohibited in different pediatric chemotherapy protocols. Currently, data on the use of ondansetron with the new antiemetic agent fosaprepitant without dexamethasone is not available for pediatric patients.. In this non-interventional observation study, 79 pediatric patients with a median age of 8.0 years (range 0.5-17.9 years) who received a CINV prophylaxis regimen with either fosaprepitant (4 mg/kg; maximum 150 mg) and ondansetron (as 24-h continuous infusion) (n = 40; fosaprepitant group/FG) or ondansetron only (n = 39; control group/CG) during moderately or highly emetogenic chemotherapy were analyzed. The groups were analyzed and compared for frequency of vomiting, administered doses of on-demand antiemetic dimenhydrinate and adverse events during the acute (0-24 h after chemotherapy administration) and delayed (> 24 h-120 h) CINV phases.. A total of 112 and 116 chemotherapy blocks were analyzed in the fosaprepitant and the control group, respectively. The emetogenic potential of the administered chemotherapy did not significantly differ (p = 0.8812) between the two cohorts. In the acute CINV phase, the percentage of patients experiencing vomiting (n = 26 patients) and the vomiting events were significantly higher (p = 0.0005 and p < 0.0001, respectively) in the CG (n = 26 patients (66.7%); 88 events) compared with the FG (n = 10 patients (25.0%); 37 events). In the delayed CINV phase, the percentage of patients experiencing vomiting and the vomiting events were also significantly higher (p = 0.0017 and p < 0.0001, respectively) in the CG (n = 31 patients (79.5%); 164 events) compared with the FG (n = 17 patients (42.5%); 103 events). Additionally, significantly more dimenhydrinate doses were administered in the CG compared with the FG patients (n = 322/n = 198; p < 0.0001). The occurrence of adverse events did not significantly differ between the two groups (p > 0.05).. Fosaprepitant (4.0 mg/kg) in addition to ondansetron, without application of dexamethasone, was well tolerated, safe, effective and superior to ondansetron only as CINV prophylaxis in pediatric patients during moderately and highly emetogenic chemotherapy.

Topics: Adolescent; Antiemetics; Antineoplastic Agents; Case-Control Studies; Child; Child, Preschool; Feasibility Studies; Female; Humans; Infant; Male; Morpholines; Nausea; Neoplasms; Ondansetron; Patient Safety; Treatment Outcome; Vomiting

Fosaprepitant (Emend®) is an antiemetic frequently used for the prevention of chemotherapy-induced nausea and vomiting. We previously documented an overall 28.7% incidence of infusion-site reactions in patients receiving fosaprepitant via peripheral venous access. These data resulted in a practice change within our institution; fosaprepitant is administered in more dilute concentrations over 30 min to prevent these adverse events. This retrospective study explored the impact of this practice change on the incidence of infusion-site reactions.. Medical records of patients with cancer receiving intravenous fosaprepitant through a peripheral intravenous line were reviewed. The primary objective of this study was to compare the incidence of infusion-site reactions before the practice change to the incidence after the practice change. Data collection included demographics, fosaprepitant infusion information, and grading of reactions.. Between September 2013 and December of 2013, charts of 122 patients receiving intravenous fosaprepitant through a peripheral line at the The Arthur G. James Cancer Hospital at The Ohio State University were reviewed. We found a 5.74% incidence of infusion-site reactions which is significantly lower than the prechange incidence of 28.7% (p < 0.001).. Infusion-site reactions were significantly reduced when fosaprepitant was diluted to 150 mg/250 ml and infused over 30 min. We recommend oncology pharmacists consider using the more dilute fosaprepitant preparation and 30 min infusion duration when administering via a peripheral intravenous line to improve patient tolerance.

Topics: Antiemetics; Cancer Care Facilities; Data Collection; Female; Humans; Incidence; Infusions, Intravenous; Male; Middle Aged; Morpholines; Nausea; Neoplasms; Pharmacists; Retrospective Studies; 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

Chemotherapy-induced nausea and vomiting diminishes quality of life and increases healthcare resource use. This retrospective medical records analysis evaluated hydration requirements with emetogenic chemotherapy.. Cancer patients received moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC), and antiemetics palonosetron or granisetron extended-release subcutaneous (GERSC), neurokinin 1 receptor antagonist and dexamethasone. Unscheduled hydration event rates were determined.. For 186 patients (92 palonosetron, 94 GERSC) overall, mean hydration rate was significantly higher with palonosetron (0.6 vs 0.2; p = 0.0005). Proportion of patients with ≥1 hydration event was significantly higher with palonosetron overall (54 vs 33%; p = 0.0033) and in cycles 2-4 and the HEC subgroup.. GERSC within a three-drug antiemetic regimen may reduce unscheduled hydration requirements with MEC or HEC.

Topics: Adult; Aged; Aged, 80 and over; Antiemetics; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Delayed-Action Preparations; Dexamethasone; Female; Fluid Therapy; Granisetron; Humans; Male; Middle Aged; Morpholines; Nausea; Neoplasms; Neurokinin-1 Receptor Antagonists; Palonosetron; Retrospective Studies; Serotonin 5-HT3 Receptor Antagonists; Vomiting; Young Adult

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

Chemotherapy-induced nausea and vomiting are concerning adverse events resulting from cancer treatment, and current guidelines recommend the use of neurokinin-1-selective antagonists, such as fosaprepitant, in highly emetogenic schemes. However, the implementation of this strategy may be limited by the cost of treatment. GSTP1 c.313A>G genotype was recently described as a predictor of vomiting related to high-dose cisplatin. We hypothesized that the inclusion of routine GSTP1 c.313A>G screening may be promising in financial terms, in contrast to the wide-spread use of fosaprepitant.. A cost-minimization analysis was planned to compare GSTP1 c.313A>G genotyping versus overall fosaprepitant implementation for patients with head and neck cancer under chemoradiation therapy with high-dose cisplatin. A decision analytic tree was designed, and conditional probabilities were calculated under Markov chain Monte Carlo simulations using the Metropolis-Hastings algorithm. The observed data included patients under treatment without fosaprepitant, while priors were derived from published studies.. To introduce screening with real-time polymerase chain reaction, an initial investment of U$ 39,379.97 would be required, with an amortization cost of U$ 7,272.97 per year. The mean cost of standard therapy with fosaprepitant is U$ 243.24 per patient, and although the initial cost of routine genotyping is higher, there is a tendency of progressive minimization at a threshold of 155 patients (Credible interval-CI: 119 to 216), provided more than one sample is incorporated for simultaneous analysis. A resulting reduction of 35.83% (CI: 30.31 to 41.74%) in fosaprepitant expenditures is then expected with the implementation of GSTP1 c.313A>G genotyping.. GSTP1 c.313A>G genotyping may reduce the use of preventive support for chemotherapy induced nausea and lower the overall cost of treatment. Despite the results of this simulation, randomized, interventional studies are required to control for known and unknown confounders as well as unexpected expenses.

Topics: Algorithms; Antiemetics; Antineoplastic Agents; Bayes Theorem; Chemoradiotherapy; Cisplatin; Computer Simulation; Costs and Cost Analysis; Decision Trees; Drug Costs; Glutathione S-Transferase pi; Head and Neck Neoplasms; Humans; Markov Chains; Monte Carlo Method; Morpholines; Nausea; Neurokinin-1 Receptor Antagonists; Pharmacogenomic Testing; Real-Time Polymerase Chain Reaction; Vomiting

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

A neurokinin-1 (NK1) receptor antagonist is recommended with a 5-HT3 receptor antagonist and dexamethasone for prevention of chemotherapy-induced nausea and vomiting (CINV) in adult patients receiving highly emetogenic chemotherapy. Data for fosaprepitant use in pediatric patients is lacking. A retrospective chart review was conducted using an electronic medical record to characterize the use of fosaprepitant in patients aged 10 months to 18 years at a single institution from August 2015 to January 2017. Thirty-nine patients received fosaprepitant 4 mg/kg (maximum, 150 mg) for prevention of CINV, and 35 were included in the analysis. Ten patients 5 years of age or older who received fosaprepitant after October 2016 were eligible for a follow-up phone call to assess control of delayed CINV. Complete control of emesis was observed in 89% of patients during the acute phase, 63% during the delayed phase, and 60% overall. Overall incidence of nausea as documented in the medical record was 43%. Among the 10 patients who completed follow-up phone calls, 30% experienced emesis and 50% experienced nausea after discharge. Fosaprepitant may be safe and effective in the prevention of CINV in pediatric patients as young as 10 months of age.

Topics: Adolescent; Child; Child, Preschool; Female; Humans; Infant; Interviews as Topic; Male; Medical Records; Morpholines; Nausea; Retrospective Studies; Vomiting

To assess the impact of single-dose fosaprepitant on nausea and emesis after BEAM and high-dose melphalan conditioning regimens for autologous hematopoietic stem cell transplantation.. In a single-center cohort study patients receiving melphalan containing hematopoietic stem cell transplantation regimens who received a one-time dose of 150 mg IV fosaprepitant (n = 56) were compared to a historical control (n = 70).. The primary endpoint of no emesis from melphalan administration through five days afterward was 80% for the fosaprepitant group versus 66% in the control group (p = 0.068). Addition of fosaprepitant demonstrated significant improvement in emetic episodes per patient during the entire assessment period (p = 0.011) and days 1-5 after melphalan (p = 0.045). Fosaprepitant resulted in no substantial nausea during the entire assessment period in 37% of high-dose melphalan patients and 57% of BEAM patients.. Further studies are suggested to investigate the optimal number and timing of doses of fosaprepitant in this setting.

Topics: Aged; Antiemetics; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cohort Studies; Cytarabine; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Morpholines; Nausea; Podophyllotoxin; Prospective Studies; Retrospective Studies; Transplantation Conditioning; Vomiting

Chemotherapy-induced nausea and vomiting (CINV) is a major concern for cancer patients and, if uncontrolled, can seriously compromise quality of life (QOL) and other treatment outcomes. Because of the expense of antiemetic medications used to prevent CINV (particularly oral medications filled through Medicare Part D), disparities in their use may exist. We used 2006-2012 SEER-Medicare data to evaluate the use of neurokinin-1 receptor antagonists (NK1s), a potent class of antiemetics, among black and white women initiating highly emetogenic chemotherapy for the treatment of early-stage breast cancer. We used modified Poisson regression to assess the relationship between race and (1) any NK1 use, (2) oral NK1 (aprepitant) use, and (3) intravenous NK1 (fosaprepitant) use. We report adjusted risk ratios (aRR) and 95 % confidence intervals (CI). The study included 1130 women. We observed racial disparities in use of any NK1 (aRR: 0.68, 95 % CI 0.51-0.91) and in use of oral aprepitant specifically (aRR: 0.54, 95 % CI 0.35-0.83). We did not observe disparities in intravenous fosaprepitant use. After controlling for variables related to socioeconomic status, disparities in NK1 and aprepitant use were reduced but not eliminated. We found racial disparities in women's use of oral NK1s for the prevention of CINV. These disparities may be partly explained by racial differences in socioeconomic status, which may translate into differential ability to afford the medication.

Topics: Administration, Intravenous; Administration, Oral; Antineoplastic Agents; Black People; Breast Neoplasms; Female; Humans; Morpholines; Nausea; Neurokinin-1 Receptor Antagonists; Quality of Life; Regression Analysis; SEER Program; Socioeconomic Factors; Treatment Outcome; Vomiting; White People

Fosaprepitant dimeglumine (Emend IV®) is an IV antiemetic that may be beneficial to patients receiving highly emetogenic regimens. Aprepitant (Emend®) is an oral medication that is administered for three consecutive days, whereas fosaprepitant is a single-dose IV medication that is administered on the day of chemotherapy for 20-30 minutes (depending on the IV access type). Fosaprepitant may be useful, yet it can also present a risk for hypersensitivity reactions and phlebitis. Oncology nurses must be aware of the signs and symptoms of these potential adverse events to properly care for their patients.

Topics: Adult; Aged; Aged, 80 and over; Antiemetics; Antineoplastic Agents; Female; Humans; Male; Middle Aged; Morpholines; Nausea; Neoplasms; Risk Assessment; Vomiting

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

After fosaprepitant (FOS)was added to the National Health Insurance drug reimbursement price list, we switched the route of administration of antiemetics from oral to intravenous in chemotherapy regimens for colon cancer to improve patient medication adherence. However, because the number of patients reporting application-site disorders after administration of FOS increased, we monitored the incidence of these disorders in patients with colon cancer to identify ways to avoid them. In our prospective study, patients receiving conventional FOS dosing regimens (control group)were compared with those receiving diluted FOS solutions (study group). There were no significant differences between the two groups with respect to the incidence of application-site disorders, and contrary to expectations, the incidence was higher in the study group than in the control group. On the basis of the principle of non-maleficence and the availability of alternative therapies using oral aprepitant (APR), we terminated this study early and adopted the basic strategy that all patients with application-site disorders, except for those with central venous access devices, should be treated with oral APR after confirming their preferences.

Topics: Aged; Aged, 80 and over; Antiemetics; Antineoplastic Agents; Colonic Neoplasms; Female; Humans; Male; Middle Aged; Morpholines; Nausea; Vomiting

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

Epirubicin hydrochloride injection is indicated as a therapy for patients with primary breast cancer. This drug has been reclassified as a drug with high emetic potential according to the American Society of Clinical Oncology Guidelines for Antiemetics in Oncology. Therefore, patients who receive this agent should also receive fosaprepitant dimeglumine, an anti-emetic agent. However, it has been reported that fosaprepitant induces vascular pain when used in anthracycline-based regimens administered via the peripheral veins. In order to relieve the fosaprepitant and epirubicin-induced vascular pain associated with vasculitis, dexamethasone was administered at the onset of vascular pain. There is a possibility that the fosaprepitant and epirubicin-induced pain may improve owing to the administration of dexamethasone; however, further trials are required to confirm the effect of this method.

Topics: Adult; Aged; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Dexamethasone; Epirubicin; Humans; Middle Aged; Morpholines; Pain; Vomiting; Young Adult

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

The regioselective dibenzylphosphorylation of 2 followed by catalytic reduction in the presence of N-methyl-D-glucamine afforded 2-(S)-(1-(R)-(3, 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(5-(2- phosphoryl-3-oxo-4H,-1,2,4-triazolo)methylmorpholine, bis(N-methyl-D-glucamine) salt, 11. Incubation of 11 in rat, dog, and human plasma and in human hepatic subcellular fractions in vitro indicated that conversion to 2 would be expected to occur in vivo most readily in humans during hepatic circulation. Conversion of 11 to 2 occurred rapidly in vivo in the rat and dog with the levels of 11 being undetectable within 5 min after 1 and 8 mg/kg doses iv in the rat and within 15 min after 0.5, 2, and 32 mg/kg doses iv in the dog. Compound 11 has a 10-fold lower affinity for the human NK-1 receptor as compared to 2, but it is functionally equivalent to 2 in preclinical models of NK-1-mediated inflammation in the guinea pig and cisplatin-induced emesis in the ferret, indicating that 11 acts as a prodrug of 2. Based in part on these data, 11 was identified as a novel, water-soluble prodrug of the clinical candidate 2 suitable for intravenous administration in humans.

Topics: Acetals; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antiemetics; Antineoplastic Agents; Aprepitant; Cisplatin; Dogs; Drug Evaluation, Preclinical; Ferrets; Guinea Pigs; Humans; Morpholines; Neurokinin-1 Receptor Antagonists; Prodrugs; Rats; Solubility; Stereoisomerism; Structure-Activity Relationship; Vomiting; Water

The anti-emetic profile of the novel brain penetrant tachykinin NK1 receptor antagonist MK-0869 (L-754,030) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluor o)phenyl-4-(3-oxo-1,2,4-triazol-5-yl)methylmorpholine and its water soluble prodrug, L-758,298, has been examined against emesis induced by cisplatin in ferrets. In a 4 h observation period, MK-0869 and L-758,298 (3 mg/kg i.v. or p.o.) inhibited the emetic response to cisplatin (10 mg/kg i.v.). The anti-emetic protection afforded by MK-0869 (0.1 mg/kg i.v.) was enhanced by combined treatment with either dexamethasone (20 mg/kg i.v.) or the 5-HT3 receptor antagonist ondansetron (0.1 mg/kg i.v.). In a model of acute and delayed emesis, ferrets were dosed with cisplatin (5 mg/kg i.p.) and the retching and vomiting response recorded for 72 h. Pretreatment with MK-0869 (4-16 mg/kg p.o.) dose-dependently inhibited the emetic response to cisplatin. Once daily treatment with MK-0869 (2 and 4 mg/kg p.o.) completely prevented retching and vomiting in all ferrets tested. Further when daily dosing began at 24 h after cisplatin injection, when the acute phase of emesis had already become established, MK-0869 (4 mg/kg p.o. at 24 and 48 h after cisplatin) prevented retching and vomiting in three out of four ferrets. These data show that MK-0869 and its prodrug, L-758,298, have good activity against cisplatin-induced emesis in ferrets and provided a basis for the clinical testing of these agents for the treatment of emesis associated with cancer chemotherapy.

Topics: Acetals; Acute Disease; Animals; Antiemetics; Antineoplastic Agents; Aprepitant; CHO Cells; Cisplatin; COS Cells; Cricetinae; Dose-Response Relationship, Drug; Ferrets; Humans; Male; Morpholines; Neurokinin-1 Receptor Antagonists; Prodrugs; Rats; Receptors, Neurokinin-1; Solubility; Vomiting