Netupitant And Palonosetron Research Articles

Efficacy and safety of netupitant/palonosetron in preventing nausea and vomiting in diffuse large B cell lymphoma patients undergoing R–CHOP chemotherapy

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin’s lymphoma, for which cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab(R–CHOP) is one of the standard regimens. Given that R–CHOP is highly emetogenic, chemotherapy-induced nausea and vomiting (CINV) prevention is clinically important. However, there is a paucity of studies focusing on these patients. This study aimed to ascertain the effectiveness of an oral fixed-dose combination of netupitant and palonosetron (NEPA) in preventing CINV in patients with DLBCL undergoing first-line R-CHOP chemotherapy. Seventy patients were enrolled in this single-center prospective non-comparative study conducted between November 2020 and May 2023 in South Korea. NEPA was administered 1 h prior to chemotherapy initiation on day 1. The primary endpoint of the study was the complete response rate (no emesis, and no rescue medication) during the acute, delayed, and overall phases, which were assessed over a period of 120 h post-chemotherapy. The complete response rates for NEPA were 90.0% [95% CI 80.5, 95.9] for the acute phase, 85.7% [95% CI 75.3, 92.9] for the delayed phase, and 84.3% [95% CI 73.6, 91.9] for the overall phase, with no-emesis rates (acute: 97.1% [95% CI 97.1, 99.7], delayed: 95.7% [95% CI 88.0, 99.1], overall: 92.9% [95% CI 84.1, 97.6]). NEPA was well tolerated with no severe treatment-emergent adverse events. NEPA exhibited substantial efficacy in mitigating CINV in DLBCL patients undergoing R–CHOP chemotherapy, demonstrating high CR and no-emesis rates, and favorable safety profiles.

The Effectiveness of an Oral Fixed-Dose Combination of Netupitant and Palonosetron (NEPA) in Patients With Multiple Risk Factors for Chemotherapy-Induced Nausea and Vomiting: A Multicenter, Observational Indian Study.

BackgroundFemale gender, young age, first chemotherapy cycle, and low alcohol intake have all been linked to an increased risk of nausea and vomiting from chemotherapy. We intended to see if netupitant and palonosetron (NEPA) could prevent chemotherapy-induced nausea and vomiting (CINV) in patients with risk factors such as age, gender, chemotherapy cycle number, and alcohol consumption history.MethodsIn this retrospective study, chemotherapy-naïve patients who were prescribed netupitant (300 mg) and palonosetron (0.50 mg) (NEPA) before the first cycle of chemotherapy were analyzed for overall, acute, and delayed phases of complete response (CR), complete protection (CP), and control.ResultsIn the acute phase (AP), delayed phase (DP), and overall phase (OP), complete response was 88.23%, 86.27%, and 86.27%, respectively; complete protection was 80.39%, 78.43%, and 76.47%, respectively; and complete control was 76.47%, 72.54%, and 70.58%, respectively, in the whole population (i.e., 51 patients). Complete response, protection, and control in the overall phase were achieved by 86.27%, 72.72%, and 68.18% of patients who received the highly emetogenic chemotherapy (HEC) regimen (i.e., 44 patients), respectively.ConclusionNEPA provided a consistent magnitude of benefit for patients who are at high risk, receiving HEC and moderately emetogenic chemotherapy (MEC), and having good control in the acute, delayed, and overall phases of CINV.

Real-world multicenter study of the safety and efficacy of netupitant plus palonosetron fixed-dose combination to prevent chemotherapy-induced nausea and vomiting among Malaysian patients receiving moderately or highly emetogenic chemotherapy.

A large proportion of cancer patients are at high risk for chemotherapy-induced nausea and vomiting (CINV), but the choice of anti-emetics for CINV in Malaysia is limited. This was a real-world study of a fixed-dose combination of netupitant and palonosetron (NEPA) to inhibit CINV in adult patients receiving moderately (MEC) or highly emetogenic chemotherapy (HEC) for solid/hematological malignancies at eight Malaysian centers. Each HEC/MEC cycle received one dose of NEPA + dexamethasone for CINV prevention. Complete response (no emesis, no rescue medication) (CR), no more than mild nausea (severity score≤2.5), and complete control (CR) (no more than mild nausea) during the acute (0-24h), delayed (25-120h), and overall (0-120h) phases post-chemotherapy were measured. Treatment-related adverse events (AEs) were recorded. During March 2016-April 2018 (NMRR-17-3286-38282), NEPA + dexamethasone was administered to 54 patients (77.8% solid, 22.2% hematological malignancies). Note that 59.3% received HEC, while 40.7% received MEC regimen. During the overall phase of the first cycle, the majority had CR (77.8%), no more than mild nausea (74.1%), and complete control (61.1%). Seventeen patients received two consecutive cycles at any point of chemotherapy cycles. During the overall phases across two consecutive cycles, all patients achieved CR, and the majority reported no more than mild nausea and complete control. No grades 3-4 AEs were reported. NEPA had sustained efficacy and tolerability at first administration and across two cycles of MEC/HEC for CINV prevention.

Palonosetron for Patients Undergoing High or Moderate Emetogenic Chemotherapy


 This report identified high to moderate quality evidence from clinical studies and economic evaluations, as well as high-quality guidelines regarding the use of palonosetron in the prevention of chemotherapy-induced nausea and vomiting in adult and pediatric patients receiving different emetogenic chemotherapies. Interpretations of the findings should be taken with caution because of the presence of some identified limitations in both clinical and economic evidence.
 In adult patients receiving high emetogenic chemotherapy, a fixed antiemetic combination of netupitant and palonosetron (NEPA) plus dexamethasone demonstrated noninferiority relative to a triple regimen of granisetron-aprepitant-dexamethasone. Similarly, palonosetron had similar efficacy compared to granisetron with the co-administration of neurokinin 1 receptor antagonist (e.g., aprepitant or fosaprepitant) and dexamethasone. However, in the absence of aprepitant, a 2-drug combination of palonosetron-dexamethasone appeared to be significantly more effective than granisetron-dexamethasone for the prevention of both acute and delayed emesis.
 In adult patients receiving moderate emetogenic chemotherapy, palonosetron plus dexamethasone was found to be noninferior compared with ondansetron plus dexamethasone. Similar efficacy was also observed between palonosetron plus dexamethasone and transdermal granisetron plus dexamethasone.
 In a mixed population of adult patients receiving high or moderate emetogenic chemotherapy, a palonosetron regimen appeared to have greater efficacy than ondansetron for delayed emesis. The efficacy of triple regimen of palonosetron-aprepitant-dexamethasone and granisetron-aprepitant-dexamethasone was comparable at all phases.
 In pediatric patients receiving high emetogenic chemotherapy, palonosetron plus dexamethasone had similar efficacy compared with ondansetron plus dexamethasone in the acute phase, but was more effective in delayed and overall phases of chemotherapy-induced nausea and vomiting.
 In a mixed population of pediatric patients receiving high or moderate emetogenic chemotherapy, palonosetron plus dexamethasone was noninferior to ondansetron plus dexamethasone.
 There were no significant differences between palonosetron and ondansetron or between palonosetron and granisetron treatment regimens in adverse events or quality of life.
 A cost-utility analysis revealed that NEPA plus dexamethasone was dominant (i.e., cost less, more effective) relative to granisetron-aprepitant-dexamethasone and ondansetron-aprepitant or fosaprepitant-dexamethasone in adult patients receiving high emetogenic chemotherapy. In contrast, double or triple regimens of palonosetron was not cost-effective compared to granisetron regimens, mainly due to large difference in price and small quality-adjusted life-years gained. These economic evaluations may not be applicable to the Canadian context.
 The identified high-quality guidelines have recommendations on the use of specific antiemetic regimens for adult and pediatric patients receiving high emetogenic chemotherapy or moderate emetogenic chemotherapy and suggest that palonosetron may be offered as an alternative to other 5-hydroxytryptamine-3 receptor antagonists and that 1 5-hydroxytryptamine-3 receptor antagonist is not preferred over another based on the available evidence.

Dexamethasone-Sparing Regimens with Oral Netupitant and Palonosetron for the Prevention of Emesis Caused by High-Dose Cisplatin: A Randomized Noninferiority Study.

BackgroundTo reduce the overall exposure to dexamethasone (DEX) in patients receiving cisplatin‐based chemotherapy, we evaluated the noninferiority of DEX on day 1, with or without low‐dose DEX on days 2 and 3, combined with an oral fixed‐dose combination of netupitant and palonosetron (NEPA), compared with the guideline‐consistent use of 4‐day DEX.Patients and MethodsIn this open‐label, multicenter study, chemotherapy‐naïve patients undergoing high‐dose cisplatin (≥70 mg/m2), were given NEPA and DEX (12 mg) on day 1 and randomized (1:1:1 ratio) to receive either (a) no further DEX (DEX1), (b) oral DEX (4 mg daily) on days 2–3 (DEX3), or (c) DEX (4 mg twice daily) on days 2–4 (DEX4). The primary efficacy endpoint was complete response (CR: no emesis and no rescue medication) during the 5‐day overall phase. The noninferiority margin was set at −15% difference (DEX1 or DEX3 minus DEX4). Secondary efficacy endpoints included complete protection (CP: CR and none or mild nausea).ResultsTwo‐hundred twenty‐eight patients, 76 in each arm, were assessable. Noninferiority was met for both DEX‐sparing regimens and the reference arm, with overall phase CR rates of 76.3% in each of the DEX1 and DEX3 arms and 75.0% in the DEX4 arm (95% confidence interval, −12.3% to 15% for each comparison). During the overall phase, CP rates were similar between groups.ConclusionA simplified regimen of NEPA plus single‐dose DEX offers comparable chemotherapy‐induced nausea and vomiting prevention throughout 5 days post‐chemotherapy with the advantage of sparing patients additional doses of DEX in the high–emetic‐risk setting of cisplatin‐based chemotherapy.Implications for PracticeDexamethasone (DEX) has traditionally played an integral role in the management of chemotherapy‐induced emesis. Although generally considered safe, even short‐term DEX use is associated with various side effects, and some evidence suggests that concurrent steroids may reduce the efficacy of immunotherapies. This study demonstrates comparable antiemetic control during the 5 days post‐chemotherapy with a simplified regimen of netupitant/palonosetron plus single‐dose DEX versus the standard 4‐day DEX reference treatment in high‐dose cisplatin. This represents a clinically relevant achievement as it not only simplifies antiemetic prophylaxis but also offers an opportunity to appropriately use in patients where caution with corticosteroid use is advised.

PCN18 A Budget IMPACT Analysis of Fixed Dose Combination of Netupitant and Palonosetron (NEPA) for the Prevention of Chemotherapy-Induced Nausea and Vomiting (CINV) in Malaysia

PCN18 A Budget IMPACT Analysis of Fixed Dose Combination of Netupitant and Palonosetron (NEPA) for the Prevention of Chemotherapy-Induced Nausea and Vomiting (CINV) in Malaysia

Effectiveness of a novel, fixed dose combination of netupitant and palonosetron in prevention of chemotherapy induced nausea and vomiting: A real-life study from India.

BACKGROUNDA new, oral fixed dose combination of highly selective neurokinin-1 receptor antagonist, netupitant with 5HT3 receptor antagonist, netupitant and palonosetron (NEPA) was approved in India for prevention of chemotherapy induced nausea and vomiting (CINV).AIMTo assess effectiveness of NEPA in real-world scenario.METHODSWe retrospectively assessed the medical records and patient dairies of adult patients who received highly emetogenic or moderately emetogenic chemotherapy (HEC/MEC) and treated with NEPA (Netupitant 300 mg + Palanosetron 0.50 mg) for prevention of CINV. Complete response (CR) was defined as no emesis or no requirement of rescue medication in overall phase (0 to 5 d), acute phase (0-24 h) and delayed phase (2 to 5 d).RESULTSIn 403 patients included in the analysis, mean age was 56.24 ± 11.11 years and 55.09% were females. Breast cancer (25.06%) was most common malignancy encountered. HEC and MEC were administered in 54.6% and 45.4% patients respectively. CR in overall phase was 93.79% whereas it was 98.01% in acute CINV and 93.79% in delayed CINV. Overall CR in HEC and MEC groups was 93.63% and 93.98% respectively. CR was more than 90% in different chemotherapy cycles except in group of patients of cycle 4 where CR was 88.88%.CONCLUSIONNEPA is a novel combination that is effective in preventing CINV in up to 93% cases treated with highly emetogenic or moderately emetogenic chemotherapy. This study brings the first real-life evidence of its effectiveness in India population.

Cost-effectiveness of newer regimens for the prophylaxis of chemotherapy-induced nausea and vomiting: review of the literature and real-world data.

To investigate the cost of netupitant and palonosetron (NEPA) in the prophylaxis of chemotherapy-induced nausea and vomiting (CINV) in adults receiving highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC) for cancer treatment in real life. A retrospective analysis of all consecutives patients with advanced lung cancer treated in platinum-based (carboplatin or cisplatin) chemotherapy and with breast cancer treated with anthracycline and cyclophosphamide -based chemotherapy at our Medical Oncology Unit during 4 years was performed. The costs of drugs are at the Pharmacy of our Hospital (&OV0556;). We evaluated 110 patients with lung cancer and 55 patients with breast cancer. Concerning lung cancer, we have obtained an advantage of 133 &OV0556; in monthly medical costs of NEPA and dexamethasone (DEX) vs. the combination of palonosetron (PALO) and DEX for each patient. Concerning breast cancer, we have obtained an advantage of 78 &OV0556; in monthly medical costs of NEPA and DEX vs. the combination of PALO and DEX for each patient. Combining the medical costs of antiemetic therapy with the measure of efficacy represented by the complete response, the combination of NEPA and DEX is cost-effective for preventing CINV in HEC and MEC cancer treatment.

Cost-effectiveness of a fixed combination of netupitant and palonosetron (NEPA) relative to aprepitant plus granisetron (APR + GRAN) for prophylaxis of chemotherapy-induced nausea and vomiting (CINV): a trial-based analysis

PurposeTo assess, from a United States (US) perspective, the cost-effectiveness of chemotherapy-induced nausea and vomiting (CINV) prophylaxis using a single dose of netupitant and palonosetron in a fixed combination (NEPA) versus aprepitant plus granisetron (APR + GRAN), each in combination with dexamethasone, in chemotherapy-naïve patients receiving highly emetogenic chemotherapy (HEC).MethodsWe analyzed patient-level outcomes over a 5-day post-HEC period from a randomized, double-blind, phase 3 clinical trial of NEPA (n = 412) versus APR + GRAN (n = 416). Costs and CINV-related utilities were assigned to each subject using published sources. Parameter uncertainty was addressed via multivariate probabilistic sensitivity analyses (PSA).ResultsCompared to APR + GRAN, NEPA resulted in a gain of 0.09 quality-adjusted life-days (QALDs) (4.04 vs 3.95; 95% CI −0.06 to 0.25) and a significant total per-patient cost reduction of $309 ($943 vs $1252; 95% CI $4–$626), due principally to $258 in lower medical costs of CINV-related events ($409 vs $668; 95% CI −$46 to $572) and $45 in lower study drug costs ($531 vs $577). In the PSA, NEPA resulted in lower costs and higher QALD in 86.5% of cases and cost ≤ $25,000 per quality-adjusted life-year gained in 97.8% of cases.ConclusionsThis first-ever economic analysis using patient-level data from a phase 3 trial comparing neurokinin-1 receptor antagonist (NK1 RA) antiemetic regimens suggests that NEPA is highly cost-effective (and in fact cost-saving) versus an aprepitant-based regimen in post-HEC CINV prevention. Actual savings may be higher, as we focused only on the first chemotherapy cycle and omitted the impact of CINV-related chemotherapy discontinuation.

Effectiveness of Antiemetic Regimens for Highly Emetogenic Chemotherapy-Induced Nausea and Vomiting: A Systematic Review and Network Meta-Analysis.

It is important to control chemotherapy-induced nausea and vomiting (CINV) to maintain dose intensity and patients' quality of life. The National Comprehensive Cancer Network guidelines suggest combination therapy of antiemetic agents. The growing number of antiemetic regimens, and in particular the growing use of regimens containing antagonists to the Nk-1 receptor (NK1RAs) and the antipsychotic drug olanzapine (OLZ), call for the re-evaluation of the optimal regimen for CINV. This study assessed the efficacy and safety of antiemetic regimens for highly emetogenic chemotherapy, using Bayesian network meta-analysis. Randomized trials that compared different antiemetic regimens were included. We strictly followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The main outcomes were the odds ratio (OR) for overall complete response (absence of vomiting). We conducted network meta-analysis within a Bayesian model to combine the direct and indirect evidence. Safety was assessed from the trial description. All statistical tests were two-sided. We systematically reviewed 27 randomized control trials (13,356 participants), which compared 12 different antiemetic regimens: serotonin-3 receptor antagonist (5HT3), 5HT3 + dexamethasone (Dex), palonosetron (PAL), PAL + Dex, PAL at 0.75 mg (PAL0.75), PAL0.75 + Dex, NK1RA + 5HT3 + Dex, NK1RA + PAL + Dex, an oral combination of netupitant and palonosetron (NEPA) + Dex, OLZ + 5HT3 + Dex, OLZ + PAL + Dex, and OLZ + NK1RA + 5HT3 + Dex. An NK1RA + 5HT3 + Dex regimen and an NK1RA + palonosetron + Dex regimen gave a higher complete response (CR) rate than the reference regimen, 5HT3 + Dex (OR, 1.75; 95% credibility interval [95% CrI], 1.56-1.97, and OR, 2.25; 95% CrI, 1.66-3.03, respectively). A regimen containing NEPA was more effective in producing CR than conventional regimens without NEPA or olanzapine. Further analysis, based on the surface under the cumulative ranking probability curve, indicated that olanzapine-containing regimens were the most effective in producing CR. Our meta-analysis supports the conclusion that olanzapine-containing regimens are the most effective for CINV of highly emetogenic chemotherapy. We confirmed that NK1RA + PAL + Dex is the most effective of conventional regimens. Substituting olanzapine for an Nk-1 receptor antagonist may offer a less costly and more effective alternative for patients. Nausea and vomiting during chemotherapy often pose difficulties for patients and doctors, making it hard to continue the proper therapy and to maintain the quality of life. This article gives insights into the optimal choice of medicine to treat nausea during chemotherapy. The findings reported here provide readers with a robust efficacy ranking of antinausea medicine, which can be used as a reference for the best possible treatment. Furthermore, the 70% less costly drug, olanzapine, is suggested to be equally effective to aprepitant in reducing nausea and vomiting. The possibility of offering a cost-effective treatment to a wider range of the population is discussed.

Abstract P3-14-11: Comparative effectiveness of antiemetic regimens for highly emetogenic chemotherapy-induced nausea and vomiting: A systematic review and network meta-analysis

Abstract Background The optimal choice of antiemetic therapy for chemotherapy-induced nausea and vomiting (CINV) needs to be clarified. This study assessed the efficacy and safety of antiemetic regimens for highly emetogenic chemotherapy (HEC). Methods Randomized trials that compared different antiemetic regimens were included from MEDLINE. Quality was assessed using the Cochrane risk-of-bias tool. We followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Data were pooled using random-effects models. We conducted indirect comparisons using network meta-analysis of a Bayesian model. The main outcomes were the odds ratio (OR) for overall complete response (CR [i.e., no emesis and no rescue]). Safety was assessed from the trial description. All statistical tests were two-sided. Findings We systematically reviewed 24 randomized control trials (12,104 participants), which compared 12 different antiemetic regimens. Palonosetron (PAL) 0·75 mg (PAL0·75) + dexamethasone (Dex); aprepitant (APR) + a serotonin-3 receptor antagonist (5HT3) + Dex; and APR + PAL (0·25 mg or 0·50 mg) + Dex were more favorable than the reference regimen (OR, 1·51; 95% credibility interval [95%CrI], 1·18-1·91; OR, 1·78; 95%CrI, 1·58-2·05; and OR, 2·28; 95%CrI, 1·66-3·18, respectively). The oral combination of netupitant and palonosetron (NEPA) was more effective than conventional regimens (OR, 2·39; CrI, 1·73-3·30). Olanzapine (OLZ)-containing regimens were apparently the most effective: the ORs of OLZ + 5HT3 + Dex, OLZ + PAL + Dex, and OLZ + APR + 5HT3 + Dex were 2·78, 2·58, and 4·98, respectively. Interpretation The regimens of PAL0·75 + Dex, APR + 5HT3 + Dex, and APR + PAL + Dex were more favorable in conventional regimens (i.e., regimens without NEPA or OLZ), which support the NCCN guideline strategy. NEPA could be a better choice than conventional regimens. OLZ-containing regimens could be an optimal choice; thus, more trials need to be accumulated. Citation Format: Yokoe T, Hayashida T, Nagayama A, Seki T, Takahashi M, Takano T, Abe T, Kitagawa Y. Comparative effectiveness of antiemetic regimens for highly emetogenic chemotherapy-induced nausea and vomiting: A systematic review and network meta-analysis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-14-11.

The safety and efficacy of NEPA (netupitant and palonosetron) in the treatment of chemotherapy-induced nausea and vomiting

Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The combination of a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist, dexamethasone, and a neurokinin-1 (NK-1) receptor antagonist has significantly improved the control of CINV. Palonosetronis a second generation 5-HT3 receptor antagonist. Netupitant is a new NK-1 receptor antagonist with a high binding affinity and a long half-life of 90 hours. NEPA is an oral fixed-dose combination of netupitant and palonosetron (300 mg of netupitant plus 0.50 mg of palonosetron). Phase II and phase III clinical trials have demonstrated that NEPA significantly improved the prevention of CINV compared to the use of palonosetron alone in patients receiving either highly or moderately emetogenic chemotherapy. Adverse events were similar for the NEPA and the palonosetron groups. NEPA (Akynzeo) has recently been approved by the Food and Drug Administration (FDA) to treat nausea and vomiting in patients undergoing cancer chemotherapy.

Safety of an Oral Fixed Combination of Netupitant and Palonosetron (NEPA): Pooled Data From the Phase II/III Clinical Program

Standard prophylaxis for chemotherapy-induced nausea and vomiting (CINV) with highly emetogenic and anthracycline-cyclophosphamide-based chemotherapy includes a 5-hydroxytryptamine-3 receptor antagonist, a neurokinin-1 receptor antagonist (NK1RA), and corticosteroid therapy. NEPA is a fixed combination of netupitant and palonosetron. The primary objective of this analysis was to document the safety profile, including cardiac safety, of NEPA + dexamethasone in comparison with current therapies across all phase II/III trials. This pooled analysis was based on data from 3,280 patients in 4 randomized, double-blind clinical trials. Patients were categorized into 1 of 3 pooled groups on the basis of actual treatment received: NEPA + dexamethasone, palonosetron + dexamethasone, and aprepitant + ondansetron/palonosetron + dexamethasone. Safety was assessed by number and frequency of adverse events (AEs) and changes from baseline electrocardiogram measures. Most patients were female and younger than 65 years of age. Demographic characteristics varied among studies and pooled groups. Frequencies of treatment-emergent AEs (TEAEs) and treatment-related AEs (TRAEs) were similar across groups. TEAEs were mostly mild and consistent with expected chemotherapy and disease-related AEs (hematologic events, hair loss, general weakness). TRAEs in ≥2% of patients were headache and constipation. Frequencies of cardiac TEAEs were similar across groups, with QT prolongation (1.6%), tachycardia (1.1%), and dyspnea (0.9%) the most common. Serious cardiac TEAEs were rare. NEPA was well-tolerated, with an AE profile as expected for the regimen. Sample size, demographic characteristics, study design, chemotherapy, and antiemetic regimen differences across the four studies may have contributed to differences in frequencies of neutropenia and alopecia. Adding an NK1RA to a CINV prophylaxis regimen can improve outcomes without additional toxicity. Supportive care for cancer should ideally be efficacious, convenient, and well-tolerated. There have been concerns about cardiac safety with current antiemetic prophylactic agents, namely dolasetron and ondansetron. This pooled safety analysis demonstrates that the new oral fixed combination therapy NEPA can be safely added to an antiemetic regimen without increased toxicity.

Update on the management of chemotherapy-induced nausea and vomiting - focus on palonosetron.

PurposeNausea and vomiting are major adverse effects of chemotherapy and can greatly impact patients’ quality of life. Although chemotherapy-induced nausea and vomiting (CINV) prevalence is high, treatment remains difficult. Palonosetron is a 5-hydroxytryptamine receptor antagonist (5-HT3RA) approved for treatment of CINV. The purpose of this review is to discuss existing and emerging therapeutic options, and examine studies focusing on palonosetron with regards to efficacy, pharmacology, tolerability, safety, and patient-derived outcomes.MethodsA literature search was conducted using Ovid MEDLINE and EMBASE to identify relevant studies using palonosetron alone or in combination with other antiemetics. Studies were extracted if they included complete response (CR), complete control (CC), no nausea, no vomiting, and no rescue medications as an endpoint. Studies were also included if safety endpoints were examined.ResultsPalonosetron alone has been shown to improve CR and CC rates for patients receiving low, moderate, or high emetogenic chemotherapy. Rates were further improved with the addition of dexamethasone, a corticosteroid. Furthermore, the addition of neurokinin-1 receptor antagonists, such as netupitant markedly improved efficacy profiles compared to palonosetron alone. Aprepitant is an antiemetic that has exhibited positive results in combination with palonosetron. Recently, a new drug consisting of netupitant and palonosetron (NEPA) has demonstrated significantly more efficacious prevention of CINV. Regardless of the combination, palonosetron has been well tolerated. The most common adverse events were constipation, headache, fatigue, and dizziness, with the majority of patients describing them as only mild or moderate.ConclusionPalonosetron, alone or with other antiemetics, has improved CINV treatment due to its ability to significantly reduce delayed phases of CINV, compared to similar 5-HT3RAs. Palonosetron is both more effective than first generation 5-HT3RAs and safer, as it results in a smaller prolongation of the QTc interval, compared to other 5-HT3RAs.

Review of oral fixed-dose combination netupitant and palonosetron (NEPA) for the treatment of chemotherapy-induced nausea and vomiting.

Current guidelines recommend the combination of a neurokinin-1 (NK1) receptor antagonist (RA) and a 5-hydroxytryptamine-3 (5-HT3) RA, together with corticosteroids, in order to prevent chemotherapy-induced nausea and vomiting with anthracycline-cyclophosphamide and highly emetogenic chemotherapy, and it is to be considered with moderately emetogenic chemotherapy. Netupitant and palonosetron (NEPA) is a fixed-dose combination of netupitant, a novel, highly selective NK1 RA, and palonosetron, a new-generation 5-HT3 RA, targeting two major emetic pathways in a single oral capsule. In clinical trials, NEPA administered on day 1 together with dexamethasone was highly effective and well tolerated in the prevention of chemotherapy-induced nausea and vomiting in patients with solid tumors undergoing moderately emetogenic chemotherapy or highly emetogenic chemotherapy. NEPA offers maximal convenience, and as a simple guideline-based regimen, has the potential to improve adherence to guidelines.

75 Improving the functional status of patients with cancer by more effectively preventing chemotherapy-induced nausea and vomiting (CINV): results of a phase 3 study of NEPA (fixed-dose combination of netupitant and palonosetron)

75 Improving the functional status of patients with cancer by more effectively preventing chemotherapy-induced nausea and vomiting (CINV): results of a phase 3 study of NEPA (fixed-dose combination of netupitant and palonosetron)

Effects of combined netupitant and palonosetron (NEPA), a cancer supportive care antiemetic, on the ECG of healthy subjects: an ICH E14 thorough QT trial.

Chemotherapy-induced nausea and vomiting is ranked among the worst side effects of chemotherapy. NEPA is an oral fixed-dose combination antiemetic under development, consisting of netupitant 300 mg, a highly selective NK1 receptor antagonist (RA), and palonosetron 0.5 mg, a pharmacologically and clinically distinct 5-HT3 RA. Although palonosetron is not associated with relevant ECG effects, this study evaluated cardiovascular safety of netupitant in combination with palonosetron, as well as its tolerability.This randomised, placebo- and positively controlled study in 197 subjects included 4 treatment groups: placebo, 200 mg netupitant + 0.5 mg palonosetron (NEPA200/0.5), 600 mg netupitant + 1.5 mg palonosetron (NEPA600/1.5, a supratherapeutic dose), and 400 mg moxifloxacin. Assessments included a 24-h baseline ECG recording, followed by a single dose of treatment and ECG measurements for 2 days.Mean placebo-corrected time-averaged changes from baseline were similar in NEPA200/0.5 and NEPA600/1.5 groups primarily for individually heart rate-corrected QT interval (QTcI: +4.7 and +3.6 ms, respectively) and for heart rate (HR: –3.3 bpm and –3.0 bpm), PR interval (–0.4 ms and 0.2 ms), and QRS interval (1 ms and 0.5 ms). The time-matched analysis showed no upper confidence interval >10 ms, with no suggestion of a QTc effect by pharmacokinetic-pharmacodynamic modeling for parent/metabolites. Moxifloxacin showed the expected placebo-corrected change from baseline (+8.4 ms time average) and the expected profile to establish assay sensitivity. No new morphologic changes of clinical relevance were observed. Treatment-related adverse events were comparable among groups.This study showed that NEPA treatments produced no significant effects on QTcI, HR, PR interval, QRS interval, and cardiac morphology relative to placebo, even at supratherapeutic doses.

Effect of netupitant, a highly selective NK1 receptor antagonist, on the pharmacokinetics of palonosetron and impact of the fixed dose combination of netupitant and palonosetron when coadministered with ketoconazole, rifampicin, and oral contraceptives

Neurokinin-1 receptor antagonists (NK1 RAs) are commonly coadministered with a 5-HT3 RA such as palonosetron to prevent nausea and vomiting induced by chemotherapy. Netupitant, a new highly selective NK1 RA, is both a substrate for and a moderate inhibitor of CYP3A4. Three studies were designed to evaluate the potential drug-drug interaction of netupitant with palonosetron and of the fixed dose combination of netupitant and palonosetron, NEPA, with an inhibitor (ketoconazole), an inducer (rifampicin) and a substrate (oral contraceptives) of CYP3A4. Study 1 was a three-way crossover in 18 healthy subjects receiving netupitant alone, palonosetron alone, and the combination of both antiemetics. Studies 2 and 3 were two-way crossover trials where healthy subjects received NEPA (the fixed dose combination of netupitant and palonosetron). In study 2, 36 subjects received NEPA alone (day 1) and in combination with ketoconazole or rifampicin. In study 3, 24 healthy women received ethinylestradiol/levonorgestrel alone or in combination with NEPA (day 1). There were no significant pharmacokinetic interactions between netupitant and palonosetron. Ketoconazole increased netupitant area under curve (AUC) by 140 % and C max by 25 %. Rifampicin decreased netupitant AUC by 83 % and C max by 62 %. NEPA did not significantly affect exposure to ethinylestradiol, while systemic exposure to levonorgestrel increased by 40 %, but this was not considered clinically relevant. There were no clinically relevant interactions between netupitant and palonosetron, or between NEPA and oral contraceptives. The coadministration of NEPA with inhibitors or inducers of CYP3A4 may require dose adjustments. Treatments were well tolerated.

Effects of NEPA (novel combination of netupitant and palonosetron) on ECG of healthy volunteers: A randomized, controlled, thorough ECG trial.

e20538 Background: Despite advances in supportive cancer care, chemotherapy-induced nausea and vomiting (CINV) is ranked by patients among the worst side effects of chemotherapy. NEPA is a new antiemetic under development composed of a unique fixed-dose combination of netupitant (NETU, 300 mg), a new, highly selective NK1 receptor antagonist (RA), and palonosetron (PALO, 0.5 mg), a pharmacologically and clinically distinct 5-HT3RA. NEPA targets the 2 most important emetic pathways with a single oral dose. Although PALO is not associated with cardiovascular issues, this study aimed to evaluate the tolerability and cardiovascular safety of different doses of NETU + PALO. Methods: This randomized, double-blind, parallel-group, placebo- and open-label positive-controlled study in 197 volunteers (106 men) included 4 treatment groups: placebo, 200 mg NETU + 0.5 mg PALO (NEPA 200/0.5), 600 mg NETU + 1.5 mg PALO (NEPA 600/1.5), and 400 mg moxifloxacin. Assessments, based on ICH E14 Guidelines, included a 24-h baseline ECG after which volunteers received a single dose of treatment, followed by ECG measurements for 2 days. The primary objective was to determine the individual heart rate-corrected QT interval (QTcI) (n=196). Safety and tolerability of NEPA groups were also assessed (n=197). Results: Mean placebo-corrected QTcI change from baseline was +5 and +4 ms for NEPA200/0.5 and NEPA600/1.5, respectively. Mean placebo-corrected change from baseline for heart rate (HR) was -3 bpm for the 2 NEPA groups. Placebo-corrected changes in pulse rate (PR) and QRS durations were similar in both NEPA groups (0 to 1 ms) and not clinically different from placebo. These data show no signs of an effect of NEPA groups on QTcI. In comparison, the moxifloxacin showed the expected increase in QTcI vs placebo (+8/9 ms). The frequency of all treatment-related AEs (TRAEs) for NEPA200/0.5 was lower than placebo but slightly higher in volunteers treated with NEPA600/1.5. The most commonly reported TRAEs in the NEPA groups were constipation, upper abdominal pain, and headache. Conclusions: NEPA treatments produced no significant effects on QTcI, HR, PR, QRS interval, or cardiac morphology relative to placebo.