Cardiac safety concerns for ondansetron, an antiemetic commonly used for nausea linked to cancer treatment and following anaesthesia

Introduction: Ondansetron is a 5-HT3 receptor antagonist commonly used as an anti-emetic to prevent the nausea and vomiting associated with anti-cancer drugs, cancer radiotherapy, or postoperatively. Recently, the US Food and Drug Administration (FDA) issued a warning for ondansetron due to a potential for prolongation of the QT interval of the electrocardiogram (ECG), a phenomenon that is associated with an increased risk of the potentially fatal arrhythmia torsade de pointes. Areas covered: We undertook a review of the cardiac safety of ondansetron. Our primary sources of information were PubMed (with downloading of full articles), and the internet. Expert opinion: The dose of ondansetron that the FDA has concerns about is 32 mg iv (or several doses that are equivalent to this), which is only used in preventing nausea and vomiting associated with cancer chemotherapy. This suggests that ondansetron may be safe in the lower doses used to prevent the nausea and vomiting in radiation treatment or postoperatively. However, as there is a report that a lower dose of ondansetron prolonged the QT interval in healthy volunteers, this needs to be clarified by the FDA. More research needs to be undertaken of the relationship between QT prolongation and torsades in order that the FDA can produce clear-cut evidence of pro-arrhythmic risk when introducing warnings for this.

Profilaxia do prurido causado pela administração subaracnóidea de sufentanil: efeitos do droperidol, da nalbufina, do ondansetron e da combinação deles

JUSTIFICATIVA E OBJETIVOS: O uso espinhal de opióides pode causar alguns efeitos indesejáveis, dentre os quais, o mais freqüente é o prurido que, apesar de sua baixa morbidade, pode proporcionar desconforto intenso ao paciente e prolongar o período de internação. O objetivo deste estudo foi avaliar diversas opções terapêuticas no tratamento profilático do prurido após administração de sufentanil por via subaracnóidea. MÉTODO: Foram distribuídos de maneira aleatória, por sorteio, 100 pacientes a serem submetidos à intervenção cirúrgica não-obstétricas em cinco grupos, de acordo com o tratamento utilizado: controle (ausência de tratamento - C); droperidol 2,5 mg (D); nalbufina 10 mg (N); associação dos medicamentos anteriores (DN) e ondansetron 8 mg (O). O prurido foi avaliado quantitativamente 30 minutos, 1, 2, e 3 horas após a administração subaracnóidea de sufentanil. RESULTADOS: Os grupos C e O apresentaram incidência significativamente maior de prurido em relação aos grupos D, N e DN. Entretanto, não houve diferença significativa na necessidade de tratamento específico com naloxona entre os grupos tratados. CONCLUSÕES: O tratamento profilático do prurido neste estudo, independentemente do fármaco utilizado, diminuiu sua intensidade e limitou a necessidade de tratamento específico com naloxona.

Eficácia do ondansetron e da alizaprida na prevenção de náusea e vômito em laparoscopia ginecológica

JUSTIFICATIVA E OBJETIVOS: A laparoscopia ginecológica é procedimento que determina alta incidência de náusea e vômito no pós-operatório. Este estudo teve por finalidade comparar a eficácia do ondansetron e da alizaprida na prevenção de náusea e vômito em pacientes submetidas à laparoscopia ginecológica. MÉTODO: Participaram do estudo 52 pacientes, estado físico ASA I ou II, com idades entre 21 e 50 anos, sem queixas gástricas prévias, submetidas à laparoscopia para diagnóstico ou cirurgia. As pacientes foram divididas em 2 grupos: o grupo 1 recebeu ondansetron (4 mg) e o grupo 2, alizaprida (50 mg), por via venosa, antes da indução da anestesia. Todas as pacientes receberam midazolam (7,5 mg) por via oral como medicação pré-anestésica, sufentanil (0,5 µg.kg-1) e propofol (2 mg.kg-1) para indução, propofol (115 µg.kg-1) e N2O/O2 em fração inspirada de O2 a 40% para manutenção e atracúrio (0,5 mg.kg-1) como bloqueador neuromuscular. A analgesia pós-operatória foi realizada com cetoprofeno (100 mg) e buscopam composto®. RESULTADOS: Ambos os grupos foram idênticos quanto aos dados antropométricos e à duração da cirurgia e da anestesia. No grupo 1 (n=27) uma paciente apresentou náusea, No grupo 2, uma paciente apresentou náusea e três vomitaram, resultados estatisticamente não significativos. CONCLUSÕES: O ondansetron e a alizaprida foram similares na prevenção de náusea e vômito em pacientes submetidas à laparoscopia ginecológica.

Associação do methimazole e do ondansetron à quimioterapia com cisplatina em cães submetidos a quatro diferentes protocolos de fluidoterapia

Utilizaram-se 12 cães, machos, distribuídos em quatro grupos (G) experimentais, selecionados de acordo com o tempo de fluidoterapia com solução fisiológica 0,9%: G1 (sem fluidoterapia), G2 (uma hora de fluidoterapia antes da cisplatina), G3 (uma hora de fluidoterapia antes da cisplatina e uma hora após) e G4 (duas horas de fluidoterapia antes da cisplatina e uma após). Todos os animais receberam a cisplatina (70mg/m²), pela via intravenosa, sendo os ciclos de quimioterapia realizados em intervalos de três semanas, num total de três ciclos. O ondansetron (0,4mg/kg) foi administrado pela via intravenosa, a cada oito horas, no dia da quimioterapia e, a seguir, a cada 12 horas, por dois dias. O methimazole (40mg/kg) foi pela via oral, 30 minutos antes da cisplatina e quatro horas após. Avaliaram-se os parâmetros hematológicos, bioquímicos, urinários e dosagem de tiroxina e triiodotironina a cada sete dias até o término do experimento. Esse protocolo foi eficaz e seguro em cães que permaneceram sob fluidoterapia durante duas a três horas. Os animais que não receberam fluidoterapia e os que ficaram somente uma hora sob infusão intravenosa de solução fisiológica apresentaram alterações que resultaram em não-recomendação do protocolo.

Associação do methimazole e do ondansetron à quimioterapia com cisplatina em cães submetidos à quatro diferentes protocolos de fluidoterapia

Pós-graduação em Cirurgia Veterinária - FCAV

Comparação entre o ponto P6 (NEIGUAM), ondansetron e da associação de ambos na prevenção de náuseas e vômitos em cirurgia ortopédica de membros inferiores sob bloqueio subaracnoideo

Pós-graduação em Anestesiologia - FMB

Comparison of droperidol and ondansetron prophylactic effect on subarachnoid morphine-induced pruritus

The prophylactic effect of ondansetron on subarachnoid morphine-induced pruritus is controversial, while evidence suggests that droperidol prevents pruritus. The aim of this study is to compare the effects of droperidol and ondansetron on subarachnoid morphine-induced pruritus. 180 ASA I or II patients scheduled to undergo cesarean sections under subarachnoid anesthesia combined with morphine 0.2mg were randomized to receive, after the child's birth, metoclopramide 10mg (Group I - control), droperidol 2.5mg (Group II) or ondansetron 8mg (Group III). Postoperatively, the patients were assessed for pruritus (absent, mild, moderate or severe) or other side effects by blinded investigators. Patients were also blinded to their group allocation. The tendency to present more severe forms of pruritus was compared between groups. NNT was also determined. Patients assigned to receive droperidol [Proportional odds ratio: 0.45 (95% confidence interval 0.23-0.88)] reported less pruritus than those who received metoclopramide. Ondansetron effect was similar to metoclopramide [Proportional odds ratio: 0.95 (95% confidence interval 0.49-1.83)]. The NNT for droperidol and ondansetron was 4.0 and 14.7, respectively. Ondansetron does not inhibit subarachnoid morphine-induced pruritus.

Enantioselective determination of ondansetron and 8-hydroxyondansetron in human plasma from recovered surgery patients by liquid chromatography-tandem mass spectrometry

A liquid chromatographic-mass spectrometric assay with atmospheric pressure chemical ionization for quantification of ondansetron and its main metabolite 8-hydroxyondansetron in human plasma was presented. The enantiomeric separation was achieved on a Chiralcel OD-R column containing cellulose tris-(3,5-dimethylphenylcarbamate). The validation data were within the required limits. The assay was successfully applied to authentic plasma samples. Quantitative results from postoperative patients receiving ondansetron demonstrated a great interindividual variability in postoperative plasma drug concentrations, the metabolites were not detected in their unconjugated form. A wide variation in the S-(+)-/R-(-)-ondansetron concentration ratio between 0.14 and 7.18 is indicative for a stereoselective disposition or metabolism. In further studies CYP2D6 and CYP3A4 genotype dependent metabolism of ondansetron enantiomers as well as of co-administered drugs and clinical efficacy of the medication should be tested.

Antagonistic effects of ondansetron and tramadol? A randomized placebo and active drug controlled study

Opposing effects of ondansetron and tramadol on the serotonin pathway have been suggested which possibly increase tramadol consumption and emesis when co-administered. In a randomized, double-blinded study, 179 patients received intravenous ondansetron, metoclopramide, or placebo for emesis prophylaxis. Analgesic regimen consisted of tramadol intraoperative loading and subsequent patient-controlled analgesia. Tramadol consumption and response to antiemetic treatment were compared. Additionally, plasma concentrations of ondansetron and (+)O-demethyltramadol and CYP2D6 genetic variants were analyzed as possible confounders influencing analgesic and antiemetic efficacy. Tramadol consumption did not differ between the groups. Response rate to antiemetic prophylaxis was superior in patients receiving ondansetron (85.0%) compared with placebo (66.7%, P = .046), with no difference to metoclopramide (69.5%). Less vomiting was reported in the immediate postoperative hours in the verum groups (ondansetron 5.0%, metoclopramide 5.1%) compared with placebo (18.6%; P = .01). Whereas plasma concentrations of (+)O-demethyltramadol were significantly correlated to CYP2D6 genotype, no influence was detected for ondansetron. Co-administration of ondansetron neither increased tramadol consumption nor frequency of PONV in this postoperative setting. PERSPECTIVE: Controversial findings were reported for efficacy of tramadol and ondansetron when co-administered due to their opposing serotonergic effects. Co-medication of these drugs neither increased postoperative analgesic consumption nor frequency of emesis in this study enrolling patients recovering from major surgery.

CYP2D6- and CYP3A-dependent enantioselective plasma concentrations of ondansetron in postanesthesia care

An influence of polymorphic cytochromes P450 (CYP) 2D6 genetic variants on antiemetic efficacy of ondansetron has been suggested. However, the role of CYP3A in ondansetron metabolism and efficacy has been unclear. In this study, we evaluated the hypothesis that genotype-dependent CYP2D6 and CYP3A activity selectively influences plasma concentrations of ondansetron enantiomers. Additionally, the effects of doubling the ondansetron dose on genotype-dependent plasma concentrations were investigated.

Ondansetron does not reduce the shivering threshold in healthy volunteers

BACKGROUND: Ondansetron, a serotonin-3 receptor antagonist, reduces postoperative shivering. Drugs that reduce shivering usually impair central thermoregulatory control, and may thus be useful for preventing shivering during induction of therapeutic hypothermia. We determined, therefore, whether ondansetron reduces the major autonomic thermoregulatory response thresholds (triggering core temperatures) in humans. METHODS: Control (placebo) and ondansetron infusions at the target plasma concentration of 250 ng ml(-1) were studied in healthy volunteers on two different days. Each day, skin and core temperatures were increased to provoke sweating; then reduced to elicit peripheral vasoconstriction and shivering. We determined the core-temperature sweating, vasoconstriction and shivering thresholds after compensating for changes in mean-skin temperature. Data were analysed using t-tests and presented as means (sds); P<0.05 was taken as significant. RESULTS: Ondensetron plasma concentrations were 278 (57), 234 (55) and 243 (58) ng ml(-1) at the sweating, vasoconstriction and shivering thresholds, respectively; these corresponded to approximately 50 mg of ondansetron which is approximately 10 times the dose used for postoperative nausea and vomiting. Ondansetron did not change the sweating (control 37.4 (0.4) degrees C, ondansetron 37.6 (0.3) degrees C, P=0.16), vasoconstriction (37.0 (0.5) degrees C vs 37.1 (0.3) degrees C; P=0.70), or shivering threshold (36.3 (0.5) degrees C vs 36.3 (0.6) degrees C; P=0.76). No sedation was observed on either study day. CONCLUSIONS: /b>. Ondansetron appears to have little potential for facilitating induction of therapeutic hypothermia.

Safety of ondansetron loading doses in children with cancer

INTRODUCTION: In highly emetogenic chemotherapy, the recommended dose of the serotonin-receptor antagonist ondansetron (5 mg/m(2) q8h) may be insufficient to prevent chemotherapy-induced nausea and vomiting. In adults, ondansetron-loading doses (OLD) of 32 mg are safe. We aimed to evaluate in children the safety of an OLD of 16 mg/m(2) (top, 24 mg) i.v., followed by two doses of 5 mg/m(2) q8h. MATERIALS AND METHODS: This retrospective single-center study included all pediatric oncology patients having received >/=1 OLD between 2002 and 2005. Adverse events (AE) definitely, probably, or possibly related to OLD were studied, excluding AE not or unlikely related to the OLD. Associations between potential predictors and at least moderate AE were analyzed by mixed logistic regression. RESULTS: Of 167 patients treated with chemotherapy, 37 (22%) received 543 OLD. The most common AE were hypotension, fatigue, injection site reaction, headache, hot flashes/flushes, and dizziness. At least mild AE were described in 139 OLD (26%), at least moderate AE in 23 (4.2%), and severe AE in 5 (0.9%; exact 95% confidence interval [CI], 0.4-2.1). Life-threatening or lethal AE were not observed (0.0%; 0.0-0.6). At least moderate AE were significantly more frequent in female patients (odds ratio [OR] 3.5; 95% CI 1.4-8.8; p = 0.010), after erroneously given second OLD (17.0; 1.9-154; p = 0.012) and higher 24 h cumulative surface corrected dose (1.26 per mg/m(2); 1.06-1.51; p = 0.009). OLD given to infants below 2 years were not associated with more frequent AE. CONCLUSIONS: Ondansetron-loading doses of 16 mg/m(2) (top, 24 mg) i.v. seem to be safe in infants, children, and adolescents.

Comparison of the eficacy and safety of 4 mg of ondansetron vs. 4 mg of nalbuphine for the treatment of neuraxial morphineinduced pruritus

Objective: To compare the eficacy and safety of 4 mg of ondansetron vs. 4 mg of nalbuphine for the treatment of neuraxial morphine-induced pruritus, in patients at the “Dr. José Eleuterio González” University Hospital from September 2012 to August 2013. Material and methods: A controlled, prospective, randomized study of 28 patients (14 per group) receiving neuraxial morphine analgesia was conducted, which was registered and approved by the ethics Committee of the Institution and patients agreed to participate in the study under informed consent. The results were segmented and contrasted (according to drug) by hypothesis testing; the association was determined by X2 with a 95% conidence interval (CI). Results: Pruritus was effectively resolved in both groups and no signiicant difference was found in the rest of the variables. An increase in the visual analogue scale (eVA) was observed at 6 and 12 hours for the ondansetron group, which was statistically signiicant (p≤0.05), however both groups had an eVA of less than 3. Conclusions: When comparing the eficacy and safety of ondansetron 4 mg vs. nalbuphine 4 mg for the treatment of neuraxial morphine induced pruritus, the only signiicant difference found was the mean eVA at 6 and 12 hours, favoring the ondansetron group. However, both groups scored less than 3 on the eVA. Therefore, we consider that both treatments are effective and safe in the treatment of pruritus caused by neuraxial morphine.