-
Supportive Care in Cancer : Official... Jan 1997The potent serotonin receptor (5-HT3) antagonists are new highly selective agents for the prevention and control of chemotherapy-induced nausea and vomiting that have... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
A double-blind, multicentre comparison of intravenous dolasetron mesilate and metoclopramide in the prevention of nausea and vomiting in cancer patients receiving high-dose cisplatin chemotherapy.
The potent serotonin receptor (5-HT3) antagonists are new highly selective agents for the prevention and control of chemotherapy-induced nausea and vomiting that have been shown to be comparable to or more effective than traditional metoclopramide regimens. This study was designed to compare the antiemetic efficacy of dolasetron and metoclopramide in chemotherapy-naive and non-naive cancer patients receiving high-dose cisplatin-containing chemotherapy. This multicentre, double-blind, randomized trial compared the efficacy and safety of single i.v. doses of dolasetron mesilate salt (1.2 or 1.8 mg/kg) and metoclopramide (7 mg/kg) in 226 patients for the prevention of acute emesis and nausea associated with the administration of high-dose (> or = 80 mg/m2) cisplatin. Efficacy and safety were evaluated for 24 h. Complete responses were achieved by 57%, 48%, and 35% of patients given dolasetron mesilate 1.8 mg/kg (P = 0.0009 vs metoclopramide), dolasetron mesilate 1.2 mg/kg (P = 0.0058 vs metoclopramide), and metoclopramide, respectively. Overall, dolasetron was significantly more effective than metoclopramide for time to first emetic episode, nausea, patient satisfaction, and investigator global assessment of efficacy. Males, chemotherapy-naive patients, and alcoholics had higher response rates. Dolasetron was well tolerated, with mild-to-moderate headache most commonly reported. Twelve percent of patients receiving metoclopramide reported extrapyramidal symptoms compared with 0% of patients receiving dolasetron. In conclusion, dolasetron mesilate was effective for the prevention of CINV with high-dose cisplatin. Single i.v. doses of dolasetron mesilate were more effective than 7 mg/kg metoclopramide in preventing nausea and vomiting induced by highly emetogenic cisplatin-containing chemotherapy. In addition, 1.8 mg/kg dolasetron mesilate consistently produced the highest response rates and appears to be the most effective dose for further clinical development.
Topics: Acute Disease; Alcoholism; Antiemetics; Antineoplastic Agents; Basal Ganglia Diseases; Cisplatin; Double-Blind Method; Female; Headache; Humans; Indoles; Injections, Intravenous; Male; Metoclopramide; Middle Aged; Nausea; Neoplasms; Patient Satisfaction; Quinolizines; Remission Induction; Safety; Serotonin Antagonists; Sex Factors; Vomiting
PubMed: 9010986
DOI: 10.1007/BF01681958 -
Current Therapeutic Research, Clinical... Sep 2005Of the US Food and Drug Administration (FDA)-approved5-hydroxytryptamine type 3 (5-HT3)-receptor antagonists, dolasetron, ondan-setron, granisetron, and palonosetron,...
An evaluation of potential signals for ventricular arrhythmia and cardiac arrest with dolasetron, ondansetron, and granisetron in the fda combined spontaneous reporting system/adverse event reporting system.
BACKGROUND
Of the US Food and Drug Administration (FDA)-approved5-hydroxytryptamine type 3 (5-HT3)-receptor antagonists, dolasetron, ondan-setron, granisetron, and palonosetron, only dolasetron and palonosetron have a precaution in their FDA labeling concerning corrected QT interval (QTc) prolongation. At FDA approved doses, QTc prolongation has been observed in clinical trials with some 5-HT3 receptor antagonists (however, palonosetron has been only recently approved, with few published clinical data available). However, due to patient exclusion criteria, such trials with 5-HT3 receptor antagonists may have failed to examine the risk of these agents in "real world" patients with cancer.
OBJECTIVE
The aim of this analysis was to assess the potential risk for selected cardiac adverse events associated with dolasetron, ondansetron, and granisetron use.
METHODS
The FDA combined Spontaneous Reporting System/Adverse Event Reporting System database was analyzed. The process of analyzing such a database for early warnings of potential hazards is known as signal generation. The statistical technique proportional reporting ratio (PRR) was used to aid detection of a potential signal within the database. PRR is the observed proportion of a given adverse event for the drug of interest (the number of events of interest for the drug divided by the total number of reports for the drug) divided by the expected proportion. Through the third quarter of 2002, the database was searched using the preferred term electrocardiogram qt corrected interval prolonged.
RESULTS
One, 3, and 0 cases were reported for dolasetron, ondansetron, andgranisetron, respectively. The number of cases did not satisfy 1 of the 3 criteria we utilized to define a potential signal, the 3 criteria being: 3 or more reported cases of the adverse event, a PRR value of at least 2, and a χ(2) value of >4. As this term may be unlikely to be reported, the database was also searched using the term ventricular arrhythmias and cardiac arrest. The PRR, used as a parameter to detect a potential signal within the database, was 3.23, 1.31, and 1.13 for dolasetron, ondansetron, and granisetron, respectively. The number of observed ventricular arrhythmias and cardiac arrests was ∼3-fold higher with dolasetron compared with the expected value (calculated by dividing the individual agent's total number of events reported by the proportion of adverse events for all agents combined). The results for dolasetron fulfilled the criteria we used to define a potential signal.
CONCLUSIONS
This analysis detected a potential signal for ventricular arrhythmiasand cardiac arrest with dolasetron, but not with ondansetron or granisetron. However, there are limitations of a PRR analysis, which include only measuring cases that have been reported, providing relative frequencies instead of actual rates, and not providing information on the severity of adverse events or causal relationships. In addition, our analysis does not include consideration of concomitant medications, and only 2 search terms were used. Errors in identifying potential signals may also include confounding factors, such as the underlying disease, potential confusion with reporting under trade and generic names, and potential multiple reporting of the same case.
PubMed: 24790242
DOI: 10.1016/j.curtheres.2005.10.003 -
Supportive Care in Cancer : Official... Sep 2009The objective of this study was to characterize the impact of casopitant, a novel neurokinin-1 receptor antagonist under investigation for the prevention of...
OBJECTIVE
The objective of this study was to characterize the impact of casopitant, a novel neurokinin-1 receptor antagonist under investigation for the prevention of postoperative and chemotherapy-induced nausea and vomiting, on the pharmacokinetics of the commonly prescribed 5-hydroxytryptamine receptor 3 receptor antagonists, dolasetron or granisetron.
MATERIALS AND METHODS
In a phase I, open-label, two-part, two-period, single-sequence study, two cohorts of healthy subjects received either oral dolasetron (100 mg once daily for 3 days) or oral granisetron (2 mg once daily for 3 days) alone (period 1) and combined with oral casopitant, 150 mg day 1, 50 mg days 2 and 3 (period 2). Pharmacokinetics of hydrodolasetron and granisetron were assessed on days 1 and 3 of each period. Log-transformed area under the curve (AUC) and Cmax were statistically analyzed by performing an analysis of variance. Eighteen subjects were enrolled in the dolasetron cohort; nine subjects were CYP2D6 extensive metabolizers (EMs) and nine subjects were CYP2D6 poor metabolizers. Nineteen subjects were enrolled in the granisetron cohort.
RESULTS
The largest changes in hydrodolasetron exposure after coadministration with casopitant were seen in CYP2D6 EMs, with a 24% increase in hydrodolasetron AUC on day 1 and 30% increase in Cmax on days 1 and 3. All other changes in hydrodolasetron exposure were <20%, and granisetron exposure was not altered to any relevant extent (<11%).
CONCLUSION
None of the changes observed are considered clinically meaningful, and coadministration of casopitant with dolasetron or granisetron was well tolerated.
Topics: Adolescent; Adult; Antiemetics; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Granisetron; Humans; Indoles; Male; Middle Aged; Nausea; Piperazines; Piperidines; Quinolizines; Vomiting; Young Adult
PubMed: 19205754
DOI: 10.1007/s00520-008-0572-4 -
American Health & Drug Benefits May 2014Individual studies have assessed the impact of standard prophylactic therapy with 5-hydroxytryptamine receptor antagonists (5-HT3RAs) for chemotherapy-induced nausea and... (Review)
Review
BACKGROUND
Individual studies have assessed the impact of standard prophylactic therapy with 5-hydroxytryptamine receptor antagonists (5-HT3RAs) for chemotherapy-induced nausea and vomiting (CINV) on cost and utilization, but no synthesis of the findings exists.
OBJECTIVE
To systematically review published literature on costs and utilization associated with CINV prophylaxis with palonosetron and other 5-HT3RAs.
METHODS
PubMed and the National Institute for Health Research Centre for Reviews and Dissemination databases, conferences of 4 organizations (ie, Academy of Managed Care Pharmacy, American Society of Clinical Oncology, International Society for Pharmacoeconomics and Outcomes Research, and Multinational Association of Supportive Care in Cancer), and the bibliographies of relevant articles were queried for the medical subject headings and key terms of "ondansetron," "granisetron," "palonosetron," "dolasetron mesylate," "costs," "cost analysis," and "economics." We included records published (full-length articles after 1997 and conference presentations after 2010) in English and with human patients, reporting data on cost and utilization (rescue medication, outpatient and inpatient services) associated with the use of 5-HT3RAs for the treatment or prevention of CINV.
RESULTS
Of the 434 identified studies, 32 are included in the current analysis: 7 studies report costs, 18 report utilization, and 7 studies report both. The costs are reported in US dollars (7 studies), in Euros (5 studies), and in Canadian dollars (2 studies). The studies vary in designs, patients, 5-HT3RA regimens, and the definition of outcomes. The US studies report higher drug costs for CINV prophylaxis with palonosetron compared with ondansetron, lower medical outpatient and inpatient costs for palonosetron versus other 5-HT3RAs, and higher acquisition costs for palonosetron versus ondansetron or other 5-HT3RAs. Fewer patients receiving palonosetron versus with ondansetron or other 5-HT3RAs required rescue medication or used outpatient or inpatient care. In Europe and in Canada, the total pharmacy costs and use of rescue medications reported are lower for patients receiving prophylaxis with palonosetron.
CONCLUSIONS
This analysis shows that prophylaxis with palonosetron for the treatment of CINV is associated with higher acquisition treatment costs, but also with lower use of rescue medications and outpatient and inpatient services compared with ondansetron or other 5-HT3RAs in the United States. Therefore, the use of palonosetron as a standard treatment may lead to reduced service utilization for CINV.
PubMed: 24991400
DOI: No ID Found -
Supportive Care in Cancer : Official... Feb 2014Preventing chemotherapy-induced nausea and vomiting (CINV) is integral to treatment success in patients with cancer. This analysis was undertaken to assess the relative... (Randomized Controlled Trial)
Randomized Controlled Trial
Pooled analysis of phase III clinical studies of palonosetron versus ondansetron, dolasetron, and granisetron in the prevention of chemotherapy-induced nausea and vomiting (CINV).
PURPOSE
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.
METHODS
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.
RESULTS
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 %).
CONCLUSIONS
Palonosetron is more effective than older 5HT3 RAs for controlling CINV in the delayed and overall postchemotherapy periods.
Topics: Antiemetics; Antineoplastic Agents; Double-Blind Method; Female; Granisetron; Humans; Indoles; Isoquinolines; Male; Middle Aged; Nausea; Neoplasms; Ondansetron; Palonosetron; Quinolizines; Quinuclidines; Serotonin Antagonists; Treatment Outcome; Vomiting
PubMed: 24141698
DOI: 10.1007/s00520-013-1999-9 -
The Oncologist 2002Nausea and vomiting can cause considerable distress and discomfort to patients undergoing chemotherapy, radiotherapy, or surgery. Several classes of antiemetic agents... (Review)
Review
Nausea and vomiting can cause considerable distress and discomfort to patients undergoing chemotherapy, radiotherapy, or surgery. Several classes of antiemetic agents exist to combat these side effects, though the 5-HT(3)-receptor antagonists have become the first-line treatment choice for many cancer patients and are considered the "gold standard" in antiemetic therapy. Compared with the older generation antiemetic drugs, 5-HT(3)-receptor antagonists are effective, well tolerated, and associated with few side effects. However, emerging differences among these agents suggest that the incidence and/or intensity of adverse events should not be regarded as a class effect. The side-effect profile of any supportive care therapy is particularly important in certain subgroups of patients, including pediatric patients and the elderly, as well as those suffering comorbid conditions, such as cardiovascular disease and renal or hepatic impairment. Indeed, dolasetron is associated with cardiovascular effects, and thus, should be used with extreme caution in patients who suffer from or may develop prolongation of cardiac conduction intervals. Ondansetron, on the other hand, is associated with a greater incidence of central nervous system side effects than either dolasetron or ondansetron, and pharmacokinetic parameters are affected in patients with hepatic impairment, thereby requiring dose adjustments. Clinicians are encouraged to evaluate patients on an individual basis when choosing which 5-HT(3)-receptor antagonist to prescribe.
Topics: Antiemetics; Antineoplastic Agents; Humans; Nausea; Neoplasms; Radiotherapy; Serotonin Antagonists; Surgical Procedures, Operative; Vomiting
PubMed: 12401905
DOI: 10.1634/theoncologist.7-5-424 -
Experimental Hematology Apr 2007Management of radiation-induced nausea and vomiting (RINV) includes both prevention and therapy. Primary prevention involves implementation of measures to modify risk... (Review)
Review
Management of radiation-induced nausea and vomiting (RINV) includes both prevention and therapy. Primary prevention involves implementation of measures to modify risk factors. Secondary prevention involves prophylaxis and treatment with 5HT(3) receptor antagonists (5HT(3)RAs) with or without corticosteroids, dopamine antagonists, antihistamines, or anticholinergics. 5HT(3)RAs are also useful in treatment of RINV with significantly better outcomes, compared to other antiemetics or placebo. Agents include ondansetron, granisetron, dolasetron, palonosetron, and tropisitron. These agents may be useful in both the radiotherapy patient and the individual who has been accidentally exposed to ionizing radiation.
Topics: Antiemetics; Humans; Nausea; Radiation Injuries; Radioactive Hazard Release; Radiotherapy; Serotonin 5-HT3 Receptor Antagonists; Vomiting
PubMed: 17379085
DOI: 10.1016/j.exphem.2007.01.010 -
Journal of Nuclear Medicine : Official... Apr 2008The goal of this study was to reduce the salivary symptoms of pain and xerostomia caused by 131I therapy for papillary and follicular thyroid carcinoma. (Randomized Controlled Trial)
Randomized Controlled Trial
UNLABELLED
The goal of this study was to reduce the salivary symptoms of pain and xerostomia caused by 131I therapy for papillary and follicular thyroid carcinoma.
METHODS
In a single-blind controlled prospective study of 60 patients, we investigated whether pilocarpine, 5 mg orally every 8 h for 1 wk after 131I therapy, would reduce salivary symptoms. All patients received 8 mg of dexamethasone and 100 mg of dolasetron mesylate orally 2 h before therapy and every 12 h for another 5 doses after 131I ingestion. In addition, for a week after therapy all drank 2,400 mL of nondairy liquid per day and had sugar-free gum or candy in their mouths at all times when awake for a week and, for the first 3 nights, every 3 h after retiring. All brushed their mouths out every 3 h while awake and also for the first 3 nights after 131I therapy. Symptoms and signs were followed by frequent telephone calls over the first week and every 8-12 wk thereafter, a physical examination within the first 10 d after therapy, and a clinic visit 6-8 mo after therapy. Statistical comparisons were by chi2 analysis.
RESULTS
The 2 patient groups were not statistically different in age, sex, type of thyroid cancer, or 131I activity administered (P > 0.05). There were no statistical differences between the groups in the prevalence of sialadenitis, stomatitis, xerostomia, or dysgeusia over the next 6 mo (P > 0.05).
CONCLUSION
Under the conditions of the study, pilocarpine did not reduce the occurrence of radiation sialadenitis or stomatitis. The occurrence, however, was lower than had previously been reported in the literature, possibly because of the concurrent stringent application of physiologic sialogogues (candy, gum, fluids), dexamethasone, and dolasetron mesylate, a serotonin receptor antagonist.
Topics: Adult; Dexamethasone; Female; Humans; Indoles; Iodine Radioisotopes; Male; Middle Aged; Pilocarpine; Prospective Studies; Quinolizines; Sialadenitis; Single-Blind Method; Thyroid Neoplasms
PubMed: 18344428
DOI: 10.2967/jnumed.107.049411 -
BMC Medicine Jun 2015Serotonin (5-HT3) receptor antagonists are commonly used to decrease nausea and vomiting for surgery patients, but these agents may be harmful. We conducted a systematic... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Serotonin (5-HT3) receptor antagonists are commonly used to decrease nausea and vomiting for surgery patients, but these agents may be harmful. We conducted a systematic review on the comparative safety of 5-HT3 receptor antagonists.
METHODS
Searches were done in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials to identify studies comparing 5-HT3 receptor antagonists with each other, placebo, and/or other antiemetic agents for patients undergoing surgical procedures. Screening search results, data abstraction, and risk of bias assessment were conducted by two reviewers independently. Random-effects pairwise meta-analysis and network meta-analysis (NMA) were conducted. PROSPERO registry number: CRD42013003564.
RESULTS
Overall, 120 studies and 27,787 patients were included after screening of 7,608 citations and 1,014 full-text articles. Significantly more patients receiving granisetron plus dexamethasone experienced an arrhythmia relative to placebo (odds ratio (OR) 2.96, 95 % confidence interval (CI) 1.11-7.94), ondansetron (OR 3.23, 95 % CI 1.17-8.95), dolasetron (OR 4.37, 95 % CI 1.51-12.62), tropisetron (OR 3.27, 95 % CI 1.02-10.43), and ondansetron plus dexamethasone (OR 5.75, 95 % CI 1.71-19.34) in a NMA including 31 randomized clinical trials (RCTs) and 6,623 patients of all ages. No statistically significant differences in delirium frequency were observed across all treatment comparisons in a NMA including 18 RCTs and 3,652 patients.
CONCLUSION
Granisetron plus dexamethasone increases the risk of arrhythmia.
Topics: Antiemetics; Humans; Postoperative Nausea and Vomiting; Registries; Serotonin 5-HT3 Receptor Antagonists; Vomiting
PubMed: 26084332
DOI: 10.1186/s12916-015-0379-3 -
Structure (London, England : 1993) Oct 2020Inaccurately perceived as niche drugs, antiemetics are key elements of cancer treatment alleviating the most dreaded side effect of chemotherapy. Serotonin 5-HT3...
Inaccurately perceived as niche drugs, antiemetics are key elements of cancer treatment alleviating the most dreaded side effect of chemotherapy. Serotonin 5-HT3 receptor antagonists are the most commonly prescribed class of drugs to control chemotherapy-induced nausea and vomiting. These antagonists have been clinically successful drugs since the 1980s, yet our understanding of how they operate at the molecular level has been hampered by the difficulty of obtaining structures of drug-receptor complexes. Here, we report the cryoelectron microscopy structure of the palonosetron-bound 5-HT3 receptor. We investigate the binding of palonosetron, granisetron, dolasetron, ondansetron, and cilansetron using molecular dynamics, covering the whole set of antagonists used in clinical practice. The structural and computational results yield detailed atomic insight into the binding modes of the drugs. In light of our data, we establish a comprehensive framework underlying the inhibition mechanism by the -setron drug family.
Topics: Animals; Antiemetics; Binding Sites; Cryoelectron Microscopy; Hydrogen Bonding; Mice; Molecular Dynamics Simulation; Palonosetron; Protein Conformation; Receptors, Serotonin, 5-HT3; Serotonin; Serotonin 5-HT3 Receptor Antagonists
PubMed: 32726573
DOI: 10.1016/j.str.2020.07.004