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Cleveland Clinic Journal of Medicine Aug 2002Our understanding of the pathophysiology of emesis has improved over the past 2 decades, and we now have drugs that can prevent acute emesis in most patients. Prevention... (Review)
Review
Our understanding of the pathophysiology of emesis has improved over the past 2 decades, and we now have drugs that can prevent acute emesis in most patients. Prevention and treatment of the delayed and anticipatory forms of chemotherapy-induced emesis remain a challenge.
Topics: Antiemetics; Antineoplastic Agents; Dexamethasone; Granisetron; Humans; Indoles; Nausea; Neurotransmitter Agents; Ondansetron; Quinolizines; Vomiting
PubMed: 12184469
DOI: 10.3949/ccjm.69.8.609 -
The Oncologist Apr 2016Standard prophylaxis for chemotherapy-induced nausea and vomiting (CINV) with highly emetogenic and anthracycline-cyclophosphamide-based chemotherapy includes a...
BACKGROUND
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.
MATERIALS AND METHODS
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.
RESULTS
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.
CONCLUSION
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.
IMPLICATIONS FOR PRACTICE
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.
Topics: Adult; Aged; Antiemetics; Biomarkers, Pharmacological; Dexamethasone; Drug Combinations; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Isoquinolines; Male; Middle Aged; Nausea; Neoplasms; Neurokinin-1 Receptor Antagonists; Pyridines; Quinuclidines; Randomized Controlled Trials as Topic; Serotonin 5-HT3 Receptor Antagonists; Vomiting
PubMed: 27000465
DOI: 10.1634/theoncologist.2015-0301 -
BMC Health Services Research Jul 20121st generation 5-hydroxytryptamine receptor antagonists (5-HT3 RAs), and palonosetron, a 2nd generation 5-HT3 RA, are indicated for the prevention of chemotherapy... (Comparative Study)
Comparative Study
BACKGROUND
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.
METHODS
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.
RESULTS
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).
CONCLUSIONS
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.
Topics: Adult; Antineoplastic Agents; Breast Neoplasms; Carboplatin; Cisplatin; Female; Health Care Surveys; Hospitalization; Humans; Isoquinolines; Logistic Models; Lung Neoplasms; Male; Middle Aged; Nausea; Palonosetron; Quinuclidines; Retrospective Studies; Serotonin 5-HT3 Receptor Antagonists; Vomiting
PubMed: 22823909
DOI: 10.1186/1472-6963-12-215 -
Current Cardiology Reviews Aug 2009Severe and occasionally fatal arrhythmias, commonly presenting as Torsade de Pointes [TdP] have been reported with Class III-antiarrhythmics, but also with...
Severe and occasionally fatal arrhythmias, commonly presenting as Torsade de Pointes [TdP] have been reported with Class III-antiarrhythmics, but also with non-antiarrhythmic drugs. Most cases result from an action on K(+) channels encoded by the HERG gene responsible for the IKr repolarizing current, leading to a long QT and repolarization abnormalities. The hydrophobic central cavity of the HERG-K+ channels, allows a large number of structurally unrelated drugs to bind and cause direct channel inhibition. Some examples are dofetilide, quinidine, sotalol, erythromycin, grepafloxacin, cisapride, dolasetron, thioridazine, haloperidol, droperidol and pimozide. Other drugs achieve channel inhibition indirectly by impairing channel traffic from the endoplasmic reticulum to the cell membrane, decreasing channel membrane density (pentamidine, geldalamicin, arsenic trioxide, digoxin, and probucol). Whereas, ketoconazole, fluoxetine and norfluoxetine induce both direct channel inhibition and impaired channel trafficking. Congenital long QT syndrome, subclinical ion-channel mutations, subjects and relatives of subjects with previous history of drug-induced long QT or TdP, dual drug effects on cardiac repolarization [long QT plus increased QT dispersion], increased transmural dispersion of repolarization and T wave abnormalities, use of high doses, metabolism inhibitors and/or combinations of QT prolonging drugs, hypokalemia, structural cardiac disease, sympathomimetics, bradycardia, women and older age, have been shown to increase the risk for developing drug-induced TdP. Because most of these reactions are preventable, careful evaluation of risk factors and increased knowledge of drugs use associated with repolarization abnormalities is strongly recommended. Future genetic testing and development of practical and simple provocation tests are in route to prevent iatrogenic TdP.
PubMed: 20676275
DOI: 10.2174/157340309788970397 -
British Journal of Anaesthesia Feb 2003Remifentanil is used as an analgesic for different procedures performed during monitored anaesthesia care. Opioid-induced nausea and vomiting can be troublesome. (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Dolasetron prophylaxis reduces nausea and postanaesthesia recovery time after remifentanil infusion during monitored anaesthesia care for extracorporeal shock wave lithotripsy.
BACKGROUND
Remifentanil is used as an analgesic for different procedures performed during monitored anaesthesia care. Opioid-induced nausea and vomiting can be troublesome.
METHODS
This prospective, randomized, double-blind study was performed to evaluate the efficacy of prophylaxis with dolasetron in reducing the frequency of postoperative nausea and duration of discharge time. Forty urological patients, undergoing elective ambulatory extracorporeal shock wave lithotripsy (ESWL) received randomly either dolasetron 12.5 mg i.v. (Group 1) or placebo (Group 2) 10 min before a patient-adapted continuous infusion of remifentanil 0.15-0.4 micro g kg(-1) min(-1) was administered. Frequency and intensity (VAS 0-100 mm) of nausea, retching, and vomiting were assessed by patients and blinded investigators during and after the procedure.
RESULTS
Patient characteristics, baseline values, duration of ESWL, and total dose of remifentanil did not differ between groups. The frequency (Group 1/Group 2; 20/55%; P<0.05) and mean (SD) maximal intensity [15 (9)/45 (14) mm; P<0.05] of nausea during 24 h was significantly reduced after dolasetron and discharge times in Group 1 were less than Group 2 [22 (14)/45 (28) min; P<0.05].
Topics: Adult; Aged; Ambulatory Surgical Procedures; Analgesics, Opioid; Anesthesia Recovery Period; Anesthesia, Intravenous; Antiemetics; Double-Blind Method; Female; Humans; Indoles; Infusions, Parenteral; Lithotripsy; Male; Middle Aged; Monitoring, Intraoperative; Patient Satisfaction; Piperidines; Postoperative Nausea and Vomiting; Prospective Studies; Quinolizines; Remifentanil
PubMed: 12538377
DOI: 10.1093/bja/aeg047 -
European Journal of Hospital Pharmacy :... May 2017Patients can benefit from the coadministration of several medications because of the shorter infusion time and more rapid administration. The use of extemporaneously...
OBJECTIVES
Patients can benefit from the coadministration of several medications because of the shorter infusion time and more rapid administration. The use of extemporaneously prepared admixtures of dexamethasone sodium phosphate (DSP) and 5-HT receptor antagonists (5-HT3RAs) must be supported by sufficient documentation of their compatibility. The objective of this study was to comprehensively investigate the compatibility of DSP with 5-HT3RAs in infusion solutions.
METHODS
Admixtures of DSP with six different 5-HT3RAs (ondansetron hydrochloride, tropisetron hydrochloride, dolasetron mesylate, azasetron hydrochloride, palonosetron hydrochloride and ramosetron hydrochloride) were prepared in non-polyvinyl chloride (non-PVC) infusion bags filled with 5% glucose or 0.9% NaCl. Bags were stored at ambient temperature (25±2°C) without protection from light. Samples were taken immediately after preparation (0 hour) and at predetermined intervals (12, 24 and 48 hours after preparation). Particulate matter of admixtures was inspected visually and particles were counted with a particle counter. The pH of each sample was also determined. Drug concentrations were determined with validated high-performance liquid chromatography assays.
RESULTS
No visible haze or particulate formation, colour change or gas evolution and no notable changes in pH were observed, and particulate matter was acceptable up to 48 hours. All preparations maintained more than 90.0% of the initial concentration over the study period.
CONCLUSIONS
All the admixtures of DSP and the 5-HT3RAs studied were compatible and stable for at least 48 hours in a 5% glucose injection or a 0.9% NaCl injection stored in non-PVC infusion bags under ambient conditions.
PubMed: 31156929
DOI: 10.1136/ejhpharm-2016-000980 -
Anaesthesia Aug 2007It is not known whether dexamethasone increases the effectiveness of anti-emetics when given to treat postoperative nausea and vomiting (PONV). In a randomised study,... (Comparative Study)
Comparative Study Randomized Controlled Trial
It is not known whether dexamethasone increases the effectiveness of anti-emetics when given to treat postoperative nausea and vomiting (PONV). In a randomised study, 242 patients who were experiencing PONV received dolasetron and placebo, haloperidol and placebo, dolasetron and dexamethasone, or haloperidol and dexamethasone. The results from 228 patients were suitable for analysis. PONV recurred significantly less frequently in patients treated with additional dexamethasone (33%) than in patients treated without additional dexamethasone (51%). The combination of dexamethasone with dolasetron or dexamethasone with haloperidol is superior to dolasetron or haloperidol alone for the treatment of PONV.
Topics: Adolescent; Adult; Aged; Antiemetics; Dexamethasone; Drug Therapy, Combination; Female; Haloperidol; Humans; Indoles; Male; Middle Aged; Postoperative Nausea and Vomiting; Quinolizines; Risk Factors; Serotonin Antagonists; Treatment Outcome
PubMed: 17635430
DOI: 10.1111/j.1365-2044.2007.05136.x -
American Health & Drug Benefits Jan 2014Chemotherapy-induced nausea and vomiting (CINV) is a common side effect of chemotherapy, and may present during the administration of chemotherapy (ie, acute CINV) or...
BACKGROUND
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.
OBJECTIVE
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
PubMed: 24991390
DOI: No ID Found -
Journal of Pharmaceutical Analysis Dec 2016A simple and straightforward method for the determination of dolasetron mesylate (DM) in aqueous solution was developed based on the fluorescence quenching of...
A simple and straightforward method for the determination of dolasetron mesylate (DM) in aqueous solution was developed based on the fluorescence quenching of 3-Mercaptopropionic acid (MPA) capped CdS quantum dots (QDs). The structure, morphology, and optical properties of synthesized QDs were characterized by using UV-Vis absorption spectroscopy, fluorescence spectroscopy, transmission electron microscopy (TEM) and dynamic light scattering (DLS) measurements. Under the optimum conditions, the MPA-CdS QDs fluorescence probe offered good sensitivity and selectivity for detecting DM. The probe provided a highly specific selectivity and a linear detection of DM in the range of 2-40 µg/mL with detection limit (LOD) 1.512 µg/mL. The common excipients did not interfere in the proposed method. The fluorescence quenching mechanism of CdS QDs is also discussed. The developed sensor was applied to the quantification of DM in urine and human serum sample with satisfactory results.
PubMed: 29404011
DOI: 10.1016/j.jpha.2016.07.002 -
AAPS PharmSciTech Jun 2014It has been advocated that biopharmaceutic risk assessment should be conducted early in pediatric product development and synchronized with the adult product development...
It has been advocated that biopharmaceutic risk assessment should be conducted early in pediatric product development and synchronized with the adult product development program. However, we are unaware of efforts to classify drugs into a Biopharmaceutics Classification System (BCS) framework for pediatric patients. The objective was to classify five drugs into a potential BCS. These five drugs were selected since both oral and intravenous pharmacokinetic data were available for each drug, and covered the four BCS classes in adults. Literature searches for each drug were conducted using Medline and applied to classify drugs with respect to solubility and permeability in pediatric subpopulations. Four pediatric subpopulations were considered: neonates, infants, children, and adolescents. Regarding solubility, dose numbers were calculated using a volume for each subpopulation based on body surface area (BSA) relative to 250 ml for a 1.73 m(2) adult. Dose numbers spanned a range of values, depending upon the pediatric dose formula and subpopulation. Regarding permeability, pharmacokinetic literature data required assumptions and decisions about data collection. Using a devised pediatric BCS framework, there was agreement in adult and pediatric BCS class for two drugs, azithromycin (class 3) and ciprofloxacin (class 4). There was discordance for the three drugs that have high adult permeability since all pediatric permeabilities were low: dolasetron (class 3 in pediatric), ketoprofen (class 4 in pediatric), and voriconazole (class 4 in pediatric). A main contribution of this work is the identification of critical factors required for a pediatric BCS.
Topics: Administration, Intravenous; Administration, Oral; Adolescent; Adult; Age Factors; Azithromycin; Biological Availability; Biopharmaceutics; Body Surface Area; Child; Child, Preschool; Ciprofloxacin; Drug Dosage Calculations; Humans; Indoles; Infant; Infant, Newborn; Ketoprofen; Models, Biological; Pediatrics; Permeability; Quinolizines; Risk Assessment; Solubility; Terminology as Topic; Voriconazole
PubMed: 24557773
DOI: 10.1208/s12249-014-0084-0