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1.  Impact of 5-HT3 receptor antagonists on chemotherapy-induced nausea and vomiting: a retrospective cohort study 
1st generation 5-hydroxytryptamine receptor antagonists (5-HT3 RAs), and palonosetron, a 2nd generation 5-HT3 RA, are indicated for the prevention of chemotherapy (CT)-induced nausea and vomiting (CINV) associated with moderately (MEC) and highly emetogenic CT agents (HEC). This study explores the impact of step therapy policies requiring use of an older 5-HT3 RA before palonosetron on risk of CINV associated with hospital or emergency department (ED) admissions.
Patients who received cyclophosphamide post breast cancer (BC) surgery or who were diagnosed with lung cancer on carboplatin (LC-carboplatin) or cisplatin (LC-cisplatin) were selected from PharMetrics’ (IMS LifeLink) claims dataset (2005-2008). Patients were followed for 6 months from initial CT administration for CINV events identified through ICD-9-CM codes. Patients were grouped into those initiated with older, generic 5-HT3 RAs (ondansetron, granisetron, and dolasetron) and those initiated and maintained on palonosetron throughout study follow-up. CINV events and CINV days were analyzed using multivariate regressions controlling for demographic and clinical variables.
Eligible patients numbered 3,606 in BC, 4,497 in LC-carboplatin and 1,154 in LC-cisplatin cohorts, with 52%, 40%, and 34% in the palonosetron group, respectively. There was no significant difference between the two 5-HT3 RA groups in age or Charlson Comorbidity Index among the two MEC cohorts (BC and LC-carboplatin). Among the LC-cisplatin cohort, palonosetron users were older with more males than the older 5-HT3 RA group (age: 60.1 vs. 61.3; males, 66.9% vs. 56.9%). Compared to the older 5-HT3 RAs, the palonosetron groups incurred 22%-51% fewer 5-HT3 RA pharmacy claims, had fewer patients with CINV events (3.5% vs. 5.5% in BC, 9.5% vs. 12.8% in LC-carboplatin, 16.4% vs. 21.7% in LC-cisplatin), and had lower risk for CINV events (odds ratios 0.62, 0.71, or 0.71, respectively; p < 0.05). The BC and LC-carboplatin palonosetron groups experienced 50% and 30% fewer CINV days than the generic 5-HT3 RA group (p < 0.05).
Patients with breast or lung cancer initiated and maintained on palonosetron were at significantly lower risk for potentially costly CINV versus those on older 5-HT3 RAs. Further studies on impact of step therapy policy are warranted in order to minimize the clinical and economic burden of CINV.
PMCID: PMC3437203  PMID: 22823909
2.  Prevention of acute chemotherapy-induced nausea and vomiting: the role of palonosetron 
Prevention of nausea and vomiting is the main goal of antiemetic treatment in cancer patients scheduled to receive chemotherapy. To prevent acute emesis, antiemetics should be administered just before chemotherapy and patients should be protected for up to 24 hours after chemotherapy initiation. The emetogenic potential of chemotherapeutic agents guides clinicians towards the most appropriate antiemetic prophylaxis. Current guidelines recommend the use of 5-HT3 receptor antagonist (RA) either alone or in combination with dexamethasone and/or a neurokinin-1 RA both in the acute and delayed phases. The second-generation 5-HT3RA palonosetron exhibits a longer half-life and a higher binding affinity than older antagonists. Palonosetron has been approved by the FDA for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients scheduled to receive either moderately (MEC) or highly emetogenic chemotherapy (HEC) and for the prevention of delayed CINV in patients receiving MEC. The present review will discuss the role of palonosetron in the prevention of acute CINV.
PMCID: PMC3004669  PMID: 21188127
antiemetics; chemotherapy; nausea; vomiting; serotonin-receptor antagonists; palonosetron
3.  Palonosetron (Aloxi): a second-generation 5-HT3 receptor antagonist for chemotherapy-induced nausea and vomiting 
In July 2003, the Food and Drug Administration approved palonosetron hydrochloride injection for the treatment of chemotherapy-induced nausea and vomiting (CINV). The newest agent in the class of 5-HT3 receptor antagonists (5-HT3RAs), palonosetron differs from other agents in its class by its higher receptor-binding affinity and longer half-life. These pharmacological properties have resulted in improved antiemetic activity in clinical trials, particularly in the treatment of delayed CINV following moderate emetogenic chemotherapy. Based on the results of these clinical studies, palonosetron is the only 5-HT3RA approved for delayed CINV. Palonosetron is given as a single 0.25-mg intravenous dose 30 minutes before the initial dose of chemotherapy. Headache and constipation were the most common adverse events reported with palonosetron therapy.
PMCID: PMC1618755  PMID: 17106506
4.  Outcomes Associated with 5-HT3-RA Therapy Selection in Patients with Chemotherapy-Induced Nausea and Vomiting: A Retrospective Claims Analysis 
Chemotherapy-induced nausea and vomiting (CINV) is a common side effect of chemotherapy, and may present during the administration of chemotherapy (ie, acute CINV) or within 25 to 120 hours of chemotherapy (ie, delayed CINV). Preventing CINV with the initiation of chemotherapy is important, because the risk for CINV in future chemotherapy cycles increases if CINV occurs in the first or previous treatment cycle. Inadequately controlled CINV is associated with increased resource utilization and costs, particularly for patients receiving highly or moderately emetogenic chemotherapy.
To evaluate the clinical and economic impacts of delayed CINV events in patients who receive initial and maintenance therapy with the newer-generation 5-hydroxytryptamine3 receptor antagonist (5-HT3-RA) palonosetron compared with patients who receive initial and maintenance therapy with an older 5-HT3-RA agent.
A retrospective database analysis was conducted using the OptumInsight database covering the years 2005–2011 (96% commercially insured members, 4% Medicaid members). Patients with cancer who received initial therapy with an emetogenic single-day chemotherapy regimen and a 5-HT3-RA agent (ie, dolasetron, granisetron, ondansetron, or palonosetron) were included in the analysis. The outcomes measured included the overall rates of delayed CINV for cycles 1 to 6, by 5-HT3-RA cohort. For cycles 2 to 6, calculations were based on patients who experienced CINV in the previous cycle, maintained the same 5-HT3-RA for all cycles, and had chemotherapy with a similar level of emetic potential. The economic outcomes (ie, cost and utilization) were also collected and calculated.
A total of 26,974 patients were included in the analysis. The overall rate for delayed CINV at cycle 1 was 15.6%, and the lowest rate was for palonosetron at 15%. The patients who initiated palonosetron had lower CINV rates throughout all cycles. The regression analysis compared individual agents to palonosetron and demonstrated higher odds of CINV in the second cycle for the older agents (ondansetron: odds ratio [OR], 1.41; 95% confidence interval [CI], 1.14–1.74; P <.002; granisetron: OR, 1.70; 95% CI, 1.39–2.08; P <.001; dolasetron: OR, 1.65; 95% CI, 1.27–2.15; P = .002). This trend continued through cycle 6, and not all ORs were significant. Over 6 cycles, ondansetron cost an additional $126,775 compared with palonosetron; granisetron an additional $169,838 versus palonosetron; and dolasetron an additional $148,960.
Current guidelines support the use of 5-HT3-RA agents for the prevention of CINV. As shown in this analysis, the selection of a specific 5-HT3-RA agent has a clinical and subsequent economic impact on patients with cancer experiencing delayed CINV. Specifically, patients receiving therapy with palonosetron had a lower incidence of delayed CINV and incurred lower overall costs.
PMCID: PMC4031742  PMID: 24991390
5.  Antiemetic therapy options for chemotherapy-induced nausea and vomiting in breast cancer patients 
Chemotherapy-induced nausea and vomiting (CINV) continues to be one of the most distressing side effects of chemotherapy in breast cancer patients, which can result in poor compliance to therapy that may, in turn, affect overall survival. The extent of CINV is dependent on the emetogenic potential of the individual cytotoxic agents or regimens employed as well as certain patient factors. Advances in our understanding in the pathophysiology of CINV and the identification of risk factors have enabled the utilization of appropriate antiemetic regimens to improve the control of CINV. Most of the chemotherapy regimens used in this patient population are considered to be moderately emetogenic; 60%–90% of chemotherapeutic regimens used in breast cancer patients cause nausea and vomiting, amongst which regimens doxorubicin-cyclophosphamide (AC) combination is commonly regarded as of relatively higher emetogenicity. Currently, corticosteroids, 5-hydroxytryptamine 3 (5-HT3) receptor antagonists, and neurokinin 1 (NK-1) receptor antagonists are the three classes of antiemetic agents with the highest therapeutic index, which have been supported by data from large-scale randomized clinical trials. Treatment guidelines enable physicians to integrate the latest research data into their clinical practices. This review focuses on the three classes of antiemetic therapy options for CINV in breast cancer patients, as well as their safety and tolerability profiles. Recommendations from major guidelines/consensus including from the Multinational Association for Supportive Care in Cancer/European Society of Medical Oncology (MASCC/ESMO), the American Society of Clinical Oncology (ASCO), and the US National Comprehensive Cancer Network (NCCN), are also discussed. With the correct use of antiemetic regimens, chemotherapy-induced vomiting could be prevented in the majority of patients. However, chemotherapy-induced nausea remains an important symptom and a challenge for physicians to manage.
PMCID: PMC3846417  PMID: 24367184
cytotoxics; 5-HT3 antogonist; NK-1 antagonist
6.  Combination of aprepitant, palonosetron and dexamethasone as antiemetic prophylaxis in lung cancer patients receiving multiple cycles of cisplatin-based chemotherapy 
With repeated courses of chemotherapy, chemotherapy-induced nausea and vomiting (CINV) becomes progressively more difficult to control. The aim of this study was to evaluate whether the antiemetic efficacy of the triple combination aprepitant, palonosetron and dexamethasone could be sustained for up to six cycles of highly emetogenic chemotherapy (HEC) (cisplatin ≥ 50 mg/m2).
Chemotherapy-naive patients receiving cisplatin-based HEC, were treated with palonosetron 0.25 mg/i.v., dexamethasone 20 mg/i.v. and aprepitant 125 mg/p.o. 1 h before chemotherapy. Aprepitant 80 mg/p.o. and dexamethasone 4 mg/p.o. were administered on days 2–3. The primary endpoint was complete response (CR, no vomiting and no use of rescue medication), over 5 days following HEC in up to six cycles. Secondary endpoints were emesis-free and nausea-free rates. Safety was also evaluated.
One hundred and fifty six lung cancer patients were included in the study; the median age was 64 years and 76.9% were men. The minimum cisplatin dosage was 75 mg/m2, and in most patients was combined with another drug (87.4%). CR ranged from 74.4% (first cycle) to 82% (sixth cycle). More than 90% and 60% of patients were emesis-free and nausea-free during all chemotherapy cycles. The most commonly reported side effects were constipation and headache.
The triple combination of aprepitant, palonosetron and dexamethasone enhanced not only the antiemetic protection during the first cycle, but its efficacy was also sustained for up to six cycles of cisplatin-based HEC in lung cancer patients.
PMCID: PMC3437500  PMID: 22805267
7.  Palonosetron exhibits higher total control rate compared to first-generation serotonin antagonists and improves appetite in delayed-phase chemotherapy-induced nausea and vomiting 
Molecular and Clinical Oncology  2014;2(3):375-379.
In order to ensure the continuity of chemotherapy, it is crucial to provide appropriate supportive care to prevent chemotherapy-induced nausea and vomiting (CINV). The frequency of CINV is greatly affected by the type and combination of chemotherapy employed, which requires further investigation. With the use of patient diaries, a prospective study on the efficacy of antiemetic regimens for nausea and vomiting was conducted in 103 patients receiving highly or moderately emetogenic chemotherapy in the Ambulatory Therapy Center of our institution between August, 2010 and March, 2011. In this study, the efficacy of palonosetron in the delayed phase was affirmed. On days 4 and 5, in particular, palonosetron exhibited a significantly higher efficacy compared to that of other conventional serotonin (5-HT3) receptor antagonists (5-HT3RAs). When the effects of chemotherapy on food intake were assessed by switching granisetron to palonosetron, an improvement in appetite was observed in one-quarter of the cases in the delayed phase. In addition, palonosetron has not been associated with any severe adverse drug reactions. It was therefore suggested that the use of palonosetron be recommended as a 5-HT3RA. In conclusion, our data suggested that palonosetron is effective and may be used as a 5-HT3RA, since it is crucial that we take adequate measures against CINV in order to maintain the patients’ quality of life and to develop antiemetic regimens that ensure the continuity of chemotherapy without dose reduction.
PMCID: PMC3999141  PMID: 24772303
chemotherapy-induced nausea and vomiting; appetite; palonosetron; total control; serotonin receptor antagonists; selective neurokinin-1 receptor antagonist
8.  Palonosetron for the prevention of chemotherapy-induced nausea and vomiting: approval and efficacy 
Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient characteristics (female gender, younger age, low alcohol consumption, history of motion sickness) are the major risk factors for CINV. This review provides a detailed description of palonosetron, a second-generation 5-hydroxytryptamine 3 (5-HT3) receptor antagonist. The chemistry and pharmacology of palonosetron are described, as well as the initial and recent clinical trials. Palonosetron has a longer half-life and a higher binding affinity than the first-generation 5-HT3 receptor antagonists. Palonosetron has been approved for the prevention of acute CINV in patients receiving either moderately or highly emetogenic chemotherapy and for the prevention of delayed CINV in patients receiving moderately emetogenic chemotherapy. In recent studies, compared to the first-generation 5-HT3 receptor antagonists, palonosetron in combination with dexamethasone demonstrated better control of delayed CINV in patients receiving highly emetogenic chemotherapy. There were no clinically relevant adverse reactions reported in the palonosetron clinical trials which were different from the common reactions reported for the 5-HT3 receptor antagonist class. Due to its efficacy in controlling both acute and delayed CINV, palonosetron may be very effective in the clinical setting of multiple-day chemotherapy and bone marrow transplantation.
PMCID: PMC3004672  PMID: 21188135
anti-emetics; chemotherapy-induced nausea and vomiting; serotonin receptor antagonists; palonosetron
9.  Safety, efficacy, and patient acceptability of single-dose fosaprepitant regimen for the prevention of chemotherapy-induced nausea and vomiting 
Control of chemotherapy-induced nausea and vomiting (CINV) is a crucial factor in ensuring that patients undergoing cancer chemotherapy can get the full benefit of therapy. Current antiemetic guidelines recommend that the neurokinin-1 receptor (NK-1R) antagonist aprepitant should be used as part of a combination regimen with dexamethasone and a serotonin receptor antagonist for the prevention of CINV in patients receiving highly emetogenic chemotherapy (HEC). Fosaprepitant is a water-soluble N-phosphoryl derivative of aprepitant that, when infused, is rapidly metabolized back to an active aprepitant. The existing literature in PubMed about fosaprepitant was screened and selected in order to address the emerging data from two randomized clinical trials evaluating the efficacy and safety of a single-dose fosaprepitant regimen. These phase III trials demonstrated that fosaprepitant given as a single intravenous dose of 150 mg was either noninferior to the conventional 3-day aprepitant or significantly superior to placebo for the prevention of acute and delayed CINV in patients receiving high-dose cisplatin. In both trials, fosaprepitant was well tolerated although more frequent infusion-site adverse events were observed with fosaprepitant. The new dosage regimen of fosaprepitant, therefore, would be an option for CINV control in patients receiving cisplatin-based chemotherapy. The clinical efficacy is consistent with the findings from a time-on-target, positron-emission tomography study evaluating the NK-1R occupancy in the central nervous system (CNS) over 5 days after a single-dose infusion of 150 mg fosaprepitant in healthy participants. The single-dose regimen is capable of blocking more than 90% of the NK-1Rs in the CNS for at least 48 hours after infusion, which is sufficient to control delayed CINV for 2 to 5 days after HEC. The new dosage regimen of fosaprepitant can provide a simplified treatment option that maintains high protection while ensuring adherence to scheduled antiemetic medication throughout most of the 5-day period encompassing the major risk for CINV.
PMCID: PMC3653760  PMID: 23687442
fosaprepitant; neurokinin-1 receptor antagonist; chemotherapy-induced nausea and vomiting
10.  Antiemetics for Chemotherapy-Induced Nausea and Vomiting Occurring Despite Prophylactic Antiemetic Therapy 
Journal of Palliative Medicine  2011;14(7):810-814.
Chemotherapy-induced nausea and vomiting (CINV) is a debilitating side effect. Previous studies have primarily focused on prophylactic therapy, but no published reports have evaluated the treatment of breakthrough CINV.
A prospective, pilot study was performed to provide preliminary prospective evidence of the efficacy of individual agents prescribed for the treatment of breakthrough CINV. Enrolled patients were receiving moderately or highly emetogenic chemotherapy and prophylactic treatment of CINV based on antiemetic guidelines. Patients were prescribed an antiemetic for breakthrough CINV at the discretion of their treating oncologist. If patients had breakthrough CINV that required a breakthrough antiemetic medication, they were instructed to complete a questionnaire every 30 minutes for 4 hours after taking the antiemetic. Levels of nausea (0–10), vomiting, and side effects were recorded.
Of the 96 patients enrolled, 27 (28%) reported breakthrough nausea and/or vomiting requiring medication and completed the questionniare. Eighty-eight percent (n = 24) reported the use of prochlorperazine; they experienced a 75% median nausea reduction after 4 hours, with minimal side effects. Three patients (12%) reported the use of a 5-hydroxytryptophan (5-HT) receptor antagonist for treatment of breakthrough nausea. These patients reported a median nausea reduction of 75% after 4 hours and no perceived toxicities.
Prochlorperazine and 5-HT receptor antagonists appear to be effective breakthrough antiemetic therapies. The described study methodology can be used to conduct randomized clinical trials to find more effective drugs for treating established nausea.
PMCID: PMC3118930  PMID: 21554125
11.  Exploring Chemotherapy-Induced Toxicities through Multivariate Projection of Risk Factors: Prediction of Nausea and Vomiting 
Toxicological Research  2012;28(2):81-91.
Many risk factors exist for chemotherapy-induced nausea and vomiting (CINV). This study utilized a multivariate projection technique to identify which risk factors were predictive of CINV in clinical practice. A single-centre, prospective, observational study was conducted from January 2007~July 2010 in Singapore. Patients were on highly (HECs) and moderately emetogenic chemotherapies with/without radiotherapy. Patient demographics and CINV risk factors were documented. Daily recording of CINV events was done using a standardized diary. Principal component (PC) analysis was performed to identify which risk factors could differentiate patients with and without CINV. A total of 710 patients were recruited. Majority were females (67%) and Chinese (84%). Five risk factors were potential CINV predictors: histories of alcohol drinking, chemotherapy-induced nausea, chemotherapy-induced vomiting, fatigue and gender. Period (ex-/current drinkers) and frequency of drinking (social/chronic drinkers) differentiated the CINV endpoints in patients on HECs and anthracycline-based, and XELOX regimens, respectively. Fatigue interference and severity were predictive of CINV in anthracycline-based populations, while the former was predictive in HEC and XELOX populations. PC analysis is a potential technique in analyzing clinical population data, and can provide clinicians with an insight as to what predictors to look out for in the clinical assessment of CINV. We hope that our results will increase the awareness among clinician-scientists regarding the usefulness of this technique in the analysis of clinical data, so that appropriate preventive measures can be taken to improve patients' quality of life.
PMCID: PMC3834412  PMID: 24278593
Chemotherapy-induced nausea and vomiting; Multivariate projection; Principal component analysis; Principal variables; Risk factors
12.  Efficacy of oral palonosetron compared to intravenous palonosetron for the prevention of chemotherapy-induced nausea and vomiting associated with moderately emetogenic chemotherapy: a phase 3 trial 
Supportive Care in Cancer  2013;21(5):1453-1460.
Palonosetron (Aloxi®, Onicit®) is a pharmacologically unique 5-HT3 receptor antagonist (RA) approved as a single IV injection for the prevention of nausea and vomiting induced by chemotherapy (CINV) of either moderate or highly emetogenic potential (MEC and HEC, respectively). An oral palonosetron formulation has been developed and compared to the IV formulation.
In this multinational, multicenter, double-blind, double-dummy, dose-ranging trial, 651 patients were randomly assigned to receive one of the following as a single dose prior to moderately emetogenic chemotherapy: oral palonosetron 0.25, 0.50, and 0.75 mg or IV palonosetron 0.25 mg. Patients were also randomized (1:1) to receive dexamethasone 8 mg IV or matched placebo on day 1. The primary endpoint was complete response (CR; no emesis, no rescue therapy) during the acute phase (0–24 h).
Acute CR rates were 73.5, 76.3, 74.1, and 70.4 % for all patients receiving the palonosetron 0.25, 0.50, and 0.75 mg oral doses, and for IV palonosetron 0.25 mg, respectively; delayed CR (24–120 h) rates were 59.4, 62.5, 60.1, and 65.4 %, and overall CR (0–120 h) rates were 53.5, 58.8, 53.2, and 59.3 %, respectively. The addition of dexamethasone improved emetic control (acute CR rate) by at least 15 % for all groups except oral palonosetron 0.25 mg, where the acute CR improvement was approximately 7 %. Adverse events were similar in nature, incidence, and intensity for all oral and IV palonosetron groups, and were the expected adverse events for 5-HT3 RAs (primarily headache and constipation).
Oral palonosetron has a similar efficacy and safety profile as IV palonosetron 0.25 mg and may be the preferred formulation in certain clinical situations. Among the tested oral treatments, a palonosetron 0.50-mg oral dose has been favored for the prevention of CINV in patients receiving moderately emetogenic chemotherapy due to a numerical gain in efficacy without a side effect disadvantage.
PMCID: PMC3612585  PMID: 23354552
Palonosetron; Chemotherapy-induced nausea and vomiting; Moderately emetogenic chemotherapy; 5-Ht3 receptor antagonist
13.  A phase III study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting over repeated cycles of chemotherapy 
Annals of Oncology  2014;25(7):1333-1339.
In this multinational, phase III study, the safety and efficacy of NEPA, a convenient, fixed-dose antiemetic combination of netupitant, a highly selective NK1 receptor antagonist (RA), and palonosetron, a distinct 5-HT3 RA, were evaluated over multiple cycles of highly and moderately emetogenic chemotherapy. NEPA was shown to be safe, well tolerated and highly effective over 1961 chemotherapy cycles.
Safe, effective and convenient antiemetic regimens that preserve benefit over repeated cycles are needed for optimal supportive care during cancer treatment. NEPA, an oral fixed-dose combination of netupitant, a highly selective NK1 receptor antagonist (RA), and palonosetron (PALO), a distinct 5-HT3 RA, was shown to be superior to PALO in preventing chemotherapy-induced nausea and vomiting after a single cycle of highly (HEC) or moderately (MEC) emetogenic chemotherapy in recent trials. This study was designed primarily to assess the safety but also to evaluate the efficacy of NEPA over multiple cycles of HEC and MEC.
Patients and methods
This multinational, double-blind, randomized phase III study (NCT01376297) in 413 chemotherapy-naïve patients evaluated a single oral dose of NEPA (NETU 300 mg + PALO 0.50 mg) given on day 1 with oral dexamethasone (DEX). An oral 3-day aprepitant (APR) regimen + PALO + DEX was included as a control (3:1 NEPA:APR randomization). In HEC, DEX was administered on days 1–4 and in MEC on day 1. Safety was assessed primarily by adverse events (AEs), including cardiac AEs; efficacy by complete response (CR: no emesis, no rescue).
Patients completed 1961 total chemotherapy cycles (76% MEC, 24% HEC) with 75% completing ≥4 cycles. The incidence/type of AEs was comparable for both groups. Most frequent NEPA-related AEs included constipation (3.6%) and headache (1.0%); there was no indication of increasing AEs over multiple cycles. The majority of AEs were mild/moderate and there were no cardiac safety concerns based on AEs and electrocardiograms. The overall (0–120 h) CR rates in cycle 1 were 81% and 76% for NEPA and APR + PALO, respectively, and antiemetic efficacy was maintained over repeated cycles.
NEPA, a convenient single oral dose antiemetic targeting dual pathways, was safe, well tolerated and highly effective over multiple cycles of HEC/MEC.
PMCID: PMC4071753  PMID: 24631949
neurokinin-1 receptor antagonist; NEPA; netupitant; palonosetron; CINV; multiple chemotherapy cycles
14.  Palonosetron as an anti-emetic and anti-nausea agent in oncology 
Palonosetron (Aloxi®, Onicit®, Paloxi®) is a second-generation 5-HT3 receptor antagonist (RA) with an extended half-life of ~40 hours and high binding affinity for the 5-HT3 receptor that is markedly different from other 5-HT3 RAs. Phase III trials demonstrate that a single dose of palonosetron compared with traditional 5-HT3 RAs is more effective in preventing chemotherapy-induced nausea and vomiting (CINV) during the first 24 hours following chemotherapy (acute CINV), and also exhibits prolonged efficacy to provide significantly better protection from CINV in the delayed and overall phases. This superior and extended protection from CINV conferred by palonosetron following a single intravenous dose before chemotherapy simplifies dosing schedules. Recent research has focused on optimization of palonosetron-based antiemetic regimens, particularly in combination with steroids and neurokinin-1 RAs. The available clinical data indicate high control rates for palonosetron, suggesting a synergistic potential for protection in patients scheduled to receive emetogenic drug regimens.
PMCID: PMC2387285  PMID: 18516316
palonosetron; CINV; 5-HT3 receptor antagonists; moderately emetogenic chemotherapy (MEC); highly emetogenic chemotherapy (HEC)
15.  Palonosetron in combination with 1-day versus 3-day dexamethasone for prevention of nausea and vomiting following moderately emetogenic chemotherapy: a randomized, multicenter, phase III trial 
Supportive Care in Cancer  2010;19(8):1217-1225.
A phase III trial assessed the efficacy of palonosetron plus dexamethasone given once in preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV) following a broad range of moderately emetogenic chemotherapy (MEC) regimens.
This multicentre, randomized, open-label, non-inferiority trial evaluated two different treatment groups. One group received palonosetron (0.25 mg intravenously) and dexamethasone (8 mg intravenously) before chemotherapy, while the other was administered the same regimen on day 1 followed by dexamethasone 8 mg orally on days 2 and 3. The primary endpoint was complete response (CR; defined as no emetic episodes and no rescue medication) during the overall phase (days 1–5 after chemotherapy initiation). The non-inferiority margin was predefined as a 15% difference between groups in the primary endpoint.
Of 332 chemotherapy-naïve patients included in the intention-to-treat analysis, 65.1% were female, and 35.2% received anthracycline plus cyclophosphamide (AC)-based regimens. Overall CR rates were 67.5% for those administered dexamethasone only on day 1 (n = 166), and 71.1% for those also administered dexamethasone on days 2 and 3 (n = 166; difference −3.6% (95% confidence interval, −13.5 to 6.3)). CR rates were not significantly different between groups during the acute (0–24 h post-chemotherapy; 88.6% versus 84.3%; P = 0.262) and delayed phases (days 2–5; 68.7% versus 77.7%; P = 0.116).
Palonosetron plus single-dose dexamethasone administered before common MEC regimens provide protection against acute and delayed CINV which is non-inferior to that of palonosetron plus dexamethasone for 3 days. However, the major benefit of the single-day regimen occurs in patients receiving non-AC MEC regimens.
PMCID: PMC3128271  PMID: 20574663
Palonosetron; Serotonin antagonists; Dexamethasone; Moderately emetogenic chemotherapy; Nausea; Vomiting
16.  Pooled analysis of phase III clinical studies of palonosetron versus ondansetron, dolasetron, and granisetron in the prevention of chemotherapy-induced nausea and vomiting (CINV) 
Supportive Care in Cancer  2013;22:469-477.
Preventing chemotherapy-induced nausea and vomiting (CINV) is integral to treatment success in patients with cancer. This analysis was undertaken to assess the relative efficacy and safety of palonosetron versus older 5HT3 RAs in preventing CINV associated with moderately or highly emetogenic chemotherapy.
Patient-level data from four randomized, double-blind, phase III trials comparing palonosetron 0.25 or 0.75 mg with ondansetron 32 mg, dolasetron 100 mg, or granisetron 40 μg/kg were analyzed. Endpoints included complete response (CR: no emesis and no rescue antiemetics) in the acute (0–24 h), delayed (>24–120 h), and overall (0–120 h) postchemotherapy periods (primary), complete control (CC: no emesis, no rescue antiemetics, and no more than mild nausea), number of emetic episodes, and nausea severity.
CR rates were significantly higher for palonosetron (n = 1,787) versus older 5HT3 RAs (n = 1,175) in the delayed (57 vs 45 %, P < 0.0001) and overall periods (51 vs 40 %, P < 0.0001); odds ratios (95 % CI) in the acute, delayed, and overall periods were 1.15 (0.98–1.34), 1.62 (1.40–1.88), and 1.56 (1.34–1.81), respectively. Significant differences in CC rates and nausea severity were observed for the delayed and overall periods and in emetic episodes for all three periods. The incidence of treatment-related adverse events was similar with palonosetron (0.25 mg, 20.0 %; 0.75 mg, 26.5 %) and older 5HT3 RAs (27.5 %).
Palonosetron is more effective than older 5HT3 RAs for controlling CINV in the delayed and overall postchemotherapy periods.
PMCID: PMC3889920  PMID: 24141698
Palonosetron; Serotonin antagonists; CINV; Nausea; Vomiting; Cancer chemotherapy
17.  Aprepitant: the evidence for its place in the prevention of chemotherapy-induced nausea and vomiting 
Core Evidence  2007;2(1):15-30.
Chemotherapy-induced nausea and vomiting (CINV) represents a significant burden on patients and healthcare systems. Despite the introduction of serotonin antagonists, many patients still experience CINV, particularly delayed symptoms occurring more than 24 hours after chemotherapy. Aprepitant is a selective neurokinin-1 (NK1) receptor antagonist approved for use with other antiemetics to prevent CINV caused by moderately to highly emetogenic chemotherapy.
To review the evidence underlying the use of aprepitant to prevent CINV.
Evidence review:
In patients receiving moderately and highly emetogenic chemotherapy, adding aprepitant to standard antiemetic therapy with dexamethasone and a serotonin antagonist significantly improved control of CINV. The degree of control of delayed CINV was particularly pronounced, and effectiveness was more likely to be maintained in multiple cycles compared with standard therapy. Nausea was generally less frequent among patients taking aprepitant. More patients receiving aprepitant were satisfied with their treatment and reported minimal/no impact of CINV on daily activities. Aprepitant appears to be well tolerated, with fatigue being the most commonly reported adverse event. The drug is an inhibitor and inducer of cytochrome P450 (CYP) 3A4, resulting in contraindications and caution with some concomitant medication. Limited economic evidence suggests that a proportion of the acquisition cost of aprepitant may be offset by savings in overall direct costs of managing CINV.
Place in therapy:
The evidence supports the recommended use of aprepitant in clinical guidelines for the prevention of CINV due to highly emetogenic chemotherapy, and its recently approved role in regimens with moderate risk. It is particularly useful for delayed symptoms.
PMCID: PMC3012554  PMID: 21221195
aprepitant; chemotherapy; evidence; nausea; vomiting
18.  Fosaprepitant and aprepitant: an update of the evidence for their place in the prevention of chemotherapy-induced nausea and vomiting 
Core Evidence  2010;5:77-90.
The selective neurokinin-1 receptor antagonist aprepitant is effective in the treatment of acute and delayed chemotherapy-induced nausea and vomiting (CINV) associated with both moderately and highly emetogenic chemotherapy. Fosaprepitant has been developed as an intravenous prodrug of aprepitant.
To update the evidence underlying the use of fosaprepitant to prevent CINV.
Evidence review:
Aprepitant in combination with a serotonin antagonist and a corticosteroid controls acute and delayed symptoms of CINV in patients receiving moderately to highly emetogenic chemotherapy. Bioequivalence of fosaprepitant with aprepitant has recently been demonstrated, which has led to its inclusion in clinical guidelines for treatment of acute CINV with highly, and some regimens of moderately, emetogenic chemotherapy. Early studies of the clinical efficacy of fosaprepitant have shown improvement over treatment with ondansetron. Both aprepitant and fosaprepitant are well tolerated with most adverse events observed of mild or moderate intensity. Conflicting economic evidence has shown that whilst aprepitant provides an increased quality of life in patients treated for CINV, there are differing views over its absolute cost in relation to standard therapy. The incremental cost-effectiveness ratio of aprepitant, however, appears to lie within acceptable bounds.
Place in therapy:
Fosaprepitant and aprepitant are recommended in guidelines for preventing CINV due to moderately and highly emetogenic chemotherapy. Fosaprepitant is bioequivalent to aprepitant, and could offer potential benefits for patients who may be unable to tolerate oral administration of antiemetics during an episode of nausea or vomiting.
PMCID: PMC2963924  PMID: 21042544
fosaprepitant; aprepitant; chemotherapy; nausea; vomiting
19.  Antiemetic efficacy of single-dose palonosetron and dexamethasone in patients receiving multiple cycles of multiple day-based chemotherapy 
Supportive Care in Cancer  2012;20(12):3241-3246.
The goal of pharmacological prophylaxis of chemotherapy-induced nausea and vomiting (CINV) should be the elimination of both nausea and vomiting symptoms during all planned chemotherapy cycles. The aim of this study was to assess the efficacy of a single dose of palonosetron and dexamethasone to prevent CINV and to guarantee an adequate food intake (FI) in patients receiving several cycles of multiple day-based chemotherapy (MD-CT).
Patients with advanced cancer but without a compromised nutritional status (bone mass index ≥ 18.5) were treated with 0.25 mg palonosetron plus 20 mg dexamethasone before MD-CT. The MD-CT regimen was either epirubicin plus ifosfamide or paclitaxel plus cisplatin and ifosfamide. Nausea, vomiting, and FI were monitored in a 7-day diary. Complete response (CR: no vomiting and no rescue therapy) was the primary endpoint, while complete control (CC: CR and no more than mild nausea) and the evaluation of FI were secondary endpoints. The endpoints were evaluated during the overall timescale (0–168 h) of the chemotherapy regimen.
Fifty patients were enrolled, 80% of whom achieved CR and 78% achieved CC. During the six chemotherapy cycles, CR and CC ranged from 76% to 88% and from 62% to 88%, respectively. Moreover, patients with CR had a significantly (p < 0.0001) higher weekly food intake compared with patients not achieving CR.
This trial was the first to assess the efficacy of palonosetron and dexamethasone for the prevention of both nausea and vomiting in patients receiving multiple cycles of MD-CT. In this trial, the ability of patients to intake an adequate amount of food each week was correlated with nausea, thus providing clinicians with an objective parameter for the measurement of the effects of nausea. A single dose of palonosetron and dexamethasone was able to prevent CINV in most patients receiving 3 days of chemotherapy during all planned chemotherapy cycles.
PMCID: PMC3480578  PMID: 22534864
Chemotherapy-induced nausea and vomiting (CINV); Food intake; Multiple day chemotherapy; Multiple cycles; Palonosetron
20.  Chemotherapy-Induced Nausea and Vomiting: Optimizing Prevention and Management 
American Health & Drug Benefits  2012;5(4):232-240.
Nausea and vomiting are serious side effects of cancer chemotherapy that can cause significant negative impacts on patients’ quality of life and on their ability to tolerate and comply with therapy. Despite advances in the prevention and management of chemotherapy-induced nausea and vomiting (CINV), these side effects remain among the most distressing for patients.
To discuss CINV and the current pharmacologic approaches to its management.
This article outlines the mechanism of CINV followed by a review of current approaches to pharmacologic therapy and current practice guidelines from national cancer organizations. This information will help providers and payers understand the optimal management of patients with CINV including practical considerations and value-based decision-making that considers cost issues.
Numerous preventive and treatment options are available to manage CINV Addressing antiemetic regimens requires ongoing patient evaluation to determine the best approach for each individual patient.
PMCID: PMC4046471
21.  Chemotherapy-induced nausea and vomiting in daily clinical practice: a community hospital-based study 
Supportive Care in Cancer  2011;20(1):107-117.
Chemotherapy-induced nausea and vomiting (CINV) are major adverse effects of cancer chemotherapy. This study investigated: (1) the impact of CINV on patients' health-related quality of life (HRQL) in daily clinical practice; (2) the association between patient characteristics and type of antiemetics and CINV; and (3) the role of CINV in physicians' decisions to modify antiemetic treatment.
Patients and methods
This prospective, multicenter study was conducted in nine general hospitals in the Netherlands. During three consecutive chemotherapy cycles, patients used a diary to record episodes of nausea, vomiting and antiemetic use. For each cycle, these ratings were made 1 day prior to and 7 days after having received chemotherapy. The influence of CINV on patients' HRQL was evaluated with the Functional Living Index-Emesis (FLIE) questionnaire at day 6 of each treatment cycle. (Changes in) antiemetic use were recorded by the treating nurse. Patient inclusion took place between May 2005 and May 2007.
Two hundred seventy-seven patients were enrolled in the study. Acute and delayed nausea during the first treatment cycle was reported by 39% and 68% of the patients, respectively. The comparable figures for acute and delayed vomiting were 12% and 23%. During the first and subsequent treatment cycle, approximately one-third of the patients indicated that CINV had a substantial impact on their daily lives. Female patients and younger patients reported significantly more CINV than male and older patients. At all treatment cycles, patients receiving treatment with moderately emetogenic chemotherapy, containing anthracycline, reported more acute nausea than patients receiving highly emetogenic chemotherapy. Acute vomiting was associated significantly with change in (i.e., additional) antiemetic treatment. Delayed CINV did not influence antiemetic treatment.
CINV continues to be a problem that adversely affects the daily lives of patients. CINV is worse in women and in younger patients. In daily clinical practice, acute CINV, but not delayed CINV, results in changes in antiemetic treatment. In view of the effects of not only acute, but also delayed CINV on daily life, more attention should be paid to adjustment of antiemetic treatment to cover CINV complaints, later during the chemotherapy cycle.
PMCID: PMC3223596  PMID: 21258948
Chemotherapy-induced nausea and vomiting; Antiemetics; Symptom management
22.  Comparison of granisetron plus dexamethasone versus an antiemetic cocktail containing midazolam and diphenhydramine for chemotherapy induced nausea and vomiting in children 
Chemotherapy induced nausea and vomiting (CINV) is one of the most disturbing side-effects in children receiving highly emetogenic chemotherapy. We aimed to assess whether the addition of an antiemetic cocktail containing midazolam and diphenhydramine to granisetron plus dexamethasone combination could ameliorate CINV in this study.
Patients and Methods:
A total of 23 children aged between 1 and 16 years to receive cisplatin containing chemotherapy in our clinic were included in this study from April 2007 to April 2008. 76 cycles in 23 patients were randomly assigned to receive either antiemetic regimen 1 or antiemetic regimen 2. Antiemetic regimen 1 containing granisetron 0, 04 mg/kg plus dexamethasone 0, 2 mg/kg were given in 45 chemotherapy cycles. In 31 cycles, an antiemetic cocktail containing midazolam 0, 04 mg/kg, diphenhyramine 2, 5 mg/-kg in addition to granisetron plus dexamethasone was given. Number of vomiting, severity of nausea, the use of rescue therapy and adverse events were assessed between day 1 and day 5.
Complete response for the acute phase was observed 38/45 (84, 4%) cycles in regimen 1 as compared with 28/31 (90, 3%) in regimen 2, antiemetic cocktail regimen (P > 0.05). Complete response for delayed emesis after 24 h of the beginning of chemotherapy was observed in 29/45 (64, 4 %) in regimen 1 and 16/31 (51, 6%) in regimen 2. Antiemetic cocktail was not superior to the granisetron plus dexamethasone combination in controlling emesis in acute and delayed phase. Furthermore, patients receiving antiemetic regimen 2 were noted significantly more side effects.
Our data showed that antiemetic cocktail containing midazolam and diphenhydramine was not better in controlling acute and delayed emesis. A slightly more toxicity with additional drugs was also observed.
PMCID: PMC3932594  PMID: 24604956
Antiemetics; cancer; chemotherapy; children; nausea; vomiting
23.  Pilot study on the efficacy of an ondansetron-versus palonosetron-containing antiemetic regimen prior to highly emetogenic chemotherapy 
Nausea and vomiting are among the most feared complications of chemotherapy reported by patients. The objective of this study was to establish the overall complete response (CR; no emesis or use of rescue medication 0–120 h after chemotherapy) with either ondansetron- or palonosetron-containing antiemetic regimens in patients receiving highly emetogenic chemotherapy (HEC).
This was a prospective, open-label, randomized, single-center, pilot study that enrolled patients receiving their first cycle of HEC. Patients were randomized to receive either palonosetron 0.25 mg IV (PAD) or ondansetron 24 mg orally (OAD) on day 1 prior to HEC. All patients received oral aprepitant 125 mg on day 1, then 80 mg on days 2 and 3, and oral dexamethasone 12 mg on day 1, then 8 mg on days 2, 3, and 4. Descriptive statistics were used to summarize the data.
A total of 40 patients were enrolled, 20 in each arm. All patients were female, and 39 received doxorubicin/cyclophosphamide chemotherapy for breast cancer. For the primary endpoint, 65 % (95 % CI, 40.8–84.6 %) of patients in the PAD arm and 40 % (95 % CI, 19.1–63.9 %) of patients in the OAD arm achieved an overall CR.
While CR rates for aprepitant and dexamethasone plus palonosetron or ondansetron-containing regimens have been published previously, this is the first documentation of CR rates with these regimens in the same patient population. These results may be used to design a larger, adequately powered, prospective study comparing these regimens.
PMCID: PMC3769492  PMID: 23748485
Ondansetron; Palonosetron; Aprepitant; Dexamethasone; Highly emetogenic chemotherapy
24.  Recent advances in pharmacotherapy of chemotherapy-induced nausea and vomiting 
Nausea and vomiting remain among the most feared side effects of chemotherapy for cancer patients. Significant progress has been made in the last 15 years in developing more effective and better-tolerated measures to minimize chemotherapy-induced nausea and vomiting (CINV). During the 1990s, the selective 5-hydroxytryptamine receptor antagonists were first introduced for the treatment of CINV, and resulted in more effective and better tolerated treatment of CINV. Despite recent progress, however, a significant number of patients still develop CINV, particularly during the 2-5-day period (delayed emesis) following chemotherapy. There is evidence that this may be an underappreciated problem on the part of some caregivers. Recently, two new antiemetics, aprepitant, the first member of the neurokinin-1 antagonists, and palonosetron, a second-generation 5-hydroxytryptamine receptor antagonist, received regulatory approval in the U.S. Both represent useful additions to the therapeutic armamentarium for the management of CINV.
PMCID: PMC3560125  PMID: 23378940
Antiemetics; cancer; chemotherapy; nausea; vomiting
25.  Cost-effectiveness of an aprepitant regimen for prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer in the UK 
Prevention of chemotherapy-induced nausea and vomiting (CINV) remains an important goal for patients receiving chemotherapy. The objective of this study was to define, from the UK payer perspective, the cost-effectiveness of an antiemetic regimen using aprepitant, a selective neurokinin-1 receptor antagonist, for patients receiving chemotherapy for breast cancer.
A decision-analytic model was developed to compare an aprepitant regimen (aprepitant, ondansetron, and dexamethasone) with a standard UK antiemetic regimen (ondansetron, dexamethasone, and metoclopramide) for expected costs and health outcomes after single-day adjuvant chemotherapy for breast cancer. The model was populated with results from patients with breast cancer participating in a randomized trial of CINV preventative therapy for cycle 1 of single-day chemotherapy.
During 5 days after chemotherapy, 64% of patients receiving the aprepitant regimen and 47% of those receiving the UK comparator regimen had a complete response to antiemetic therapy (no emesis and no rescue antiemetic therapy). A mean of £37.11 (78%) of the cost of aprepitant was offset by reduced health care resource utilization costs. The predicted gain in quality-adjusted lifeyears (QALYs) with the aprepitant regimen was 0.0048. The incremental cost effectiveness ratio (ICER) with aprepitant, relative to the UK comparator, was £10,847/QALY, which is well below the threshold commonly accepted in the UK of £20,000–£30,000/QALY.
The results of this study suggest that aprepitant is cost-effective for preventing CINV associated with chemotherapy for patients with breast cancer in the UK health care setting.
PMCID: PMC3742066  PMID: 23950658
antiemetic therapy; emesis; CINV

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