Administration Of Palonosetron Research Articles

The intravenously administered palonosetron does not affect the spinal anesthesia

The 5-hydroxytryptamine Type 3 (5-HT3) antagonists are a class of drugs frequently used to prevent and treat nausea and vomiting. It has been shown that a 5-HT3 receptor exists in the spinal nerves and affects pain control in animals [1]. In one study, ondansetron administered to prevent nausea and vomiting interrupted sensory deprivation in spinal anesthesia performed with lidocain [2]. Another study showed that other 5-HT3 antagonists such as granisetron enhanced recovery of the sensory nerves during spinal anesthesia [3]. Palonosetron, a second-generation 5-HT3 receptor antagonist approved in 2003, is known to have the strongest affinity to the 5-HT3 receptor, with a receptor binding affinity about 30 times stronger than that of ondansetron and granisetron. In addition, its elimination half-life is about 40 hours, far longer than that of other 5-HT3 antagonists. Therefore, a small dose, generally 0.075 mg, is rec ommended to prevent nausea and vomiting after general opera tions [4]. However, as the effect of palonosetron on spinal anes thesia has not been studied, it is unclear whether preoperative administration of palonosetron interrupts the anesthetic effect. In this study, we investigated the effect of palonosetron on spinal anesthesia by examining the level of sensory block, the timing of sensory recovery, and the timing of motor recovery in spinal anesthesia performed with bupivacaine 8 mg when palonosetron 0.075 mg or normal saline solution 1.5 ml was intravenously injected preoperatively. This study was conducted with the approval of the Institutional Review Board at our hospital. The subjects were 80 American Society of Anesthesiologists (ASA) class I-II patients who were scheduled to undergo transurethral surgery under spinal anesthesia. The objective and methods of the study were explained to them before the operation, and informed consent was obtained from each patient. The subjects were randomly assigned either to a group in which normal saline solution 1.5 ml was injected 15 minutes before the operation (Group C) or to a group in which palonosetron 0.075 mg (1.5 ml) was intravenously injected 15 minutes before the operation (Group P). Patients who had undergone lumbar surgery or those who had been administered drugs that could affect spinal anesthesia, such as an analgesic, a calcium channel blocking agent, or an alpha 2 agonist, were excluded from the study. An anesthetist performed anesthesia without knowledge of the intravenously injected drug, and the same anesthetist observed the patients in the operating room and the recovery room. Vital signs such as electrocardiography, blood pressure, and oxygen saturation were monitored in the operating room. Before the induction of anesthesia, normal saline solution 300 ml was intravenously injected in all patients. Anesthesia was performed by having the patient lie in the lateral recumbent position and inserting a 25 G Whitacre needle (Becton-Dickinson, Franklin Lakes, NJ, USA) through the midline of the L4-5 intervertebral space. After checking the outflow of the cerebrospinal fluid, 0.5% hyperbaric bupivacaine 8 mg was injected for 10 seconds. After the injection, the patient adopted the supine posi tion. After the sensory block was checked, the patient adopted the lithotomy position. With respect to the sensory block, the level at which the pinprick sensation disappeared was recorded every 10 minutes, and the highest sensory block level was also recorded. The time to

P1-096 - Clinical Significance of Preventing Chemotherapy-Induced Nausea and Vomiting (CINV) in Outpatient'S Chemotherapy Center

ABSTRACT Background To prevent chemotherapy-induced nausea and vomiting (CINV), it is important to use effective antiemetic drugs according to the risk of emetogenicity. 5-HT3 inhibitors and antagonist of NK1 receptor, including palonosetron and aprepitant, which are new approved drugs with long acting function, are available in cancer chemotherapy. Aim and methods To evaluate the usage of antiemetic drugs in outpatient's chemotherapy center of Kumamoto University Hospital, frequency and severity of CINV were analyzed according to the risk of emetic regimen (high, moderate and low) in two periods of 6 months around approval of palonosetron and aprepitant [from April to September 2009 (before approval of drugs) (n = 1439) and from April to September 2011 (after approval of drugs)(n = 1852)]. Results In high emetic risk regimens, half of all patients (38/76 cases) were used aprepitant and the percentage of the administration of palonosetron was 30% (23/76 cases). In the moderate emetic risk group, the usage of aprepitant and palonosetron was 24% (114/484 cases) and 5% (26/484 cases), respectively. The incidence of CINV was higher in the moderate-risk group than the high-risk group. The episode of CINV was significantly reduced in all of the risk group of patients in 2011 compared with them in 2009. Conclusion This study indicated that the incidence of CINV in high emetic risk regimens was reduced by the administration of aprepitant and palonosetron. The aggressive use of antiemetic drugs would be better to improve the quality of life in outpatient's chemotherapy, even if moderate risk of emetic regimens.

Comparative efficacy and safety of palonosetron with the first 5-HT3 receptor antagonists for the chemotherapy-induced nausea and vomiting: a meta-analysis

A number of studies have reported the difference between the 5-HT3 receptor antagonists and palonosetron in preventing the chemotherapy-induced nausea and vomiting (CINV). Through analysing the efficacy and safety in palonosetron-treated patients, it can provide evidence for palonosetron administration. We identified randomised controlled clinical trials comparing palonosetron with the first-generation 5-HT3 receptor antagonists in the prevention of CINV in cancer patients. Nine studies investigated the outcomes in a total of 3463 cases. Compared with the first-generation 5-HT3 receptor antagonists, the cumulative incidences of emesis were significantly reduced in the patients treated with palonosetron (0.25 mg i.v.) on the first day [relative risk (RR) = 1.11, 95% confidence interval (CI): 1.05-1.17], from 2 to 5 days (RR = 1.26, 95% CI: 1.16-1.36) and the overall five days (RR = 1.23, 95% CI: 1.13-1.34). Regarding the drug safety, there was no significant difference between palonosetron-treated group and the first-generation 5-HT3 receptor antagonists-treated group. Results from the analysis suggest that palonosetron is highly effective in preventing nausea and vomiting in the days after administration of moderately or highly emetogenic chemotherapy agents.

Acute effect of palonosetron on electrocardiographic parameters in cancer patients: a prospective study

Palonosetron is a novel 5-hydroxytryptamine(3) (5 HT(3)) receptor antagonist, which has been shown to be superior to first generation 5 HT(3) receptor antagonists regarding the prevention of acute, delayed and overall chemotherapy-induced nausea and vomiting. First generation 5 HT(3) receptor antagonists may induce electrocardiographic changes of heart rate and repolarization. The acute cardiac effect of palonosteron is unknown. The purpose of this study is to determine acute effects of palonosetron on electrocardiographic (ECG) parameters in cancer patients. The study had a prospective design. Seventy-six cancer patients with normal cardiac function who received palonosetron for prevention of chemotherapy-induced nausea and vomiting were enrolled. Standard 12-lead ECG recordings were performed at baseline and 30 min after palonosetron administration. P wave durations and corrected QT intervals were measured; P wave dispersion (Pd) and QTc dispersion were calculated. Median heart rate did not differ among 76 patients enrolled before and after palonosetron administration (p: 0.6). Systolic and diastolic blood pressures were not significantly different before and after palonosteron (p values 0.9 and 0.3, respectively). Although median QT min value was higher after palonosetron administration than before palonosetron administration, the difference was not statistically significant (p: 0.6). Palonosetron seems to have no acute arrhythmogenic potential.

The acute effects of palonosetron on ECG parameters in patients with cancer.

e19693 Background: Serotonin receptor (5HT3) antagonists like dolasetron, ondansetron, granisetron and tropisetron have shown to cause QT prolongation. However, there is few data about palonosetron-related cardiac side effects. In this study, we aimed to determine the acute effects of palonosetron on QT interval, heart rate and arterial blood pressure. Methods: 101 cancer patients (51 female, 50 male) were enrolled to the study. Pts with acute ischemic heart disease and arrhythmia were excluded. Pts received 0.25 mg of palonosetron for prevention of chemotherapy-induced emesis. Standard 12-lead ECG recordings, heart rate (HR) and blood pressure (BP) measurements were performed at baseline, 30 minutes and 60 minutes after the palonosetron administration. By using Bazzet Formula, corrected QT interval (QTc) and QT dispersion (QTd) were calculated. Results: The mean age of pts was 54 ±13 years. In whole patient group, there were no differences in QTc, QTd measurements at 30 and 60 minutes after palonosetron injection when compared to baseline measurements. However, HR significantly decreased at 30 and 60 minutes after palonosetron injection. Compared with the baseline, systolic BP decreased nonsignificantly at 30 minute and then returned to baseline levels at 60 minute after palonosetron administration. When body surface area was taken into consideration, patients who received palonosetron over a dose of 0.13 mg/m2 had a decrease of QTc, HR and systolic BP at 30 minute and increase of these parameters at 60 minute. Conclusions: Palonosetron does not cause QT prolongation in standard doses, but causes a decrease in heart rate. Although there is no significant risk of QT prolongation with palonosetron, caution should be taken when QT prolonging drugs are used concomitantly and in patients with long QT syndrome. The routine administration of the drug at a fixed dose without any adjustment for body weight and body surface area can increase the risk of cardiac side effects in lean patients.

The acute effect of palonosetron on ECG parameters in patients with cancer.

e19686 Background: The 5-hydroxytryptamine 3 receptor antagonists are used for the prevention and treatment of chemotherpy and radiotherapy-induced emesis. Despite their effectiveness and safety profile, it was reported in many studies that they may cause electrocardiographic changes related to heart rate and repolarization. The purpose of this study is to determine acute influence of paronosetron on ECG parameters in cancer patients. Methods: Forty-seven cancer patients with normal cardiac function who received paronosetron for the prevention of chemotherapy/radiotherapy induced emesis were enrolled into this prospective study. Standard 12-lead ECG recordings were performed at baseline and 30 min after palonosetron administration. P wave durations and corrected QT intervals were measured; P wave dispersion (Pd) and QTc dispersion were calculated. Statistical comparison of quantitative data was performed by paired sample t test. A P value of <0.05 was considered to be statistically significant. Results: In comparison with baseline, no statistically significant change in any ECG parameters, including QT and RR intervals, P wave durations, Pd and QTd, was observed after infusion of Palonosetron. Conclusions: In this study palonosetron did not show any ventricular and atrial arrhythmogenic effect because of repolarization abnormalities.

Single-dose palonosetron and dexamethasone in preventing nausea and vomiting induced by moderately emetogenic chemotherapy in breast and colorectal cancer patients

Palonosetron, a unique second-generation 5-HT3 receptor antagonist, has been demonstrated to control emesis related to chemotherapy-induced nausea and vomiting (CINV). The aim of this study was to evaluate the efficacy and tolerability of palonosetron followed by a single dose of dexamethasone in patients with breast cancer (BC) or colorectal cancer (CRC) receiving moderate emetogenic chemotherapy (MEC). Chemotherapy-naive BC and CRC patients were given MEC as adjuvant or first-line treatment. Palonosetron (0.25 mg IV) and dexamethasone (8 mg IV) were administered before chemotherapy on day 1. The primary endpoint was complete response (CR; no vomiting and no use of rescue medication) during the overall study period (days 1-5). The antiemetic response was evaluated during the acute (day 1) and delayed (days 2-5) phases. Sixty-eight patients were enrolled (median age 61 years, 56 females; BC = 40, CRC = 28). CR was observed in 46 of 68 patients (67.6%), while CR during the acute and delayed phases was 75.0% in each cancer group. The antiemetic regimen was well tolerated. A single administration of palonosetron and dexamethasone on day 1 in BC and CRC patients adequately controls CINV during the entire period of emetic risk.

Palonosetron-induced migraine-type headache

To the Editor, I read with great interest the case written by Singh et al. regarding ondansetron-induced migraine-type headache. I recently encountered a case of severe migraine-type headache triggered in a young female following the administration of palonosetron for postoperative nausea and vomiting (PONV) prophylaxis prior to two different anesthetic exposures. The patient provided her consent to publish details about this case. A 25-yr-old female with primary infertility was scheduled to undergo diagnostic laparoscopy. Her medical history included occasional migraines and anxiety for which she was taking oral propanolol 80 mg once a day. Physical examination and investigations were unremarkable. The patient fasted overnight, and she was premedicated with diazepam 5 mg po and ranitidine 150 mg po the night before and the morning of surgery. She was also given propanolol 80 mg po the morning of surgery. After applying routine anesthesia monitors in the operating room, an 18G venous access was secured in the patient’s right upper limb. Subsequently, palonosetron 0.075 mg iv was administered over ten seconds for the prophylaxis of PONV. After approximately ten minutes and before induction of anesthesia, the patient complained of a severe throbbing headache that was reported as predominantly unilateral and frontal in location. The patient described the headache as similar to her previous migraine attacks. The symptoms lasted for 25 min and responded to treatment with a bolus of propofol 20 mg iv followed by a propofol infusion at the rate of 150 mg hr. Additionally, paracetamol 1 g iv was given over 20 min. After discussion with the patient and the surgeon, anesthesia was induced intravenously with fentanyl 100 lg and propofol 80 mg. The airway was secured with a 7.5-mm internal diameter endotracheal tube after adequate neuromuscular blockade with intravenous vecuronium. The procedure lasted about 45 min, and the patient’s trachea was extubated after she awoke following reversal of neuromuscular blockade with neostigmine and glycopyrolate. There was no headache on recovery, and the patient was transferred to the postanesthesia care unit. The patient was rescheduled for tubal reconstruction one week later. After an 18G epidural catheter was secured at the L1-L2 interspace for intraoperative and postoperative pain management, a pre-emptive dose of palonosetron was administered as PONV prophylaxis. Once again, the patient developed a similar migraine-like headache after five minutes, which was treated effectively with propofol sedation. With the patient’s agreement, anesthesia was induced with propofol and fentanyl. Anesthetic maintenance and recovery were uneventful. On the first postoperative day, intravenous paracetamol 1 g was given every six hours to prevent repeated attacks of migraine, and epidural analgesia with a continuous infusion of a dilute solution of local anesthetic was provided for 48 hr. The patient remained asymptomatic except for dull migraine following discharge to the ward. Palonosetron is the latest 5-hydroxytryptamine-3 (5-HT3) antagonist, which is being described as the first of a ‘‘second generation’’ of 5-HT3 antagonists. Following successful Phase III clinical trials, the Food and Drug Administration approved its use for prevention of PONV in A. Jain, MD (&) Alchemist Hospitals Ltd., Panchkula, India e-mail: amitvasujain@gmail.com

Palonosetron induced anaphylaxis in an adult female

We report a case of anaphylactic shock following intravenous (i.v.) administration of palonosetron. A 40 year old woman with relapsed breast cancer was scheduled for first cycle of chemotherapy with cyclophosphamide, epirubicin, 5-flurouracil and docetaxel. Prior to the start of chemotherapy, i.v. palonosetron 0.25 mg (5 ml) was administered to prevent nausea and vomiting. Within a few seconds the patient experienced difficulty in breathing, generalized itching and dizziness. Bronchial wheeze was present, blood pressure was unrecordable and oxygen saturation by pulse oximetry was 75%. She was immediately moved to the intensive care unit and was resuscitated with oxygen, i.v. crystalloid and i.v. adrenaline (1 : 10 000), hydrocortisone and pheniramine. Within 1 h the patient was haemodynamically stabilized. Laboratory tests revealed no abnormality in liver or renal function. Palonosetron was discontinued and the next day she was premedicated with i.v. metoclopramide, dexamethasone, pheniramine and ranitidine and chemotherapy was initiated. Thereafter, the patient did not develop any other problem and was asymptomatic after 72 h of follow-up. The patient had no history of concomitant medications (including herbal medicines), allergy to food or other drugs (including other 5-HT3-receptor antagonists) or addiction to tobacco or alcohol. Medical history of any chronic systemic disease was also absent. However, she revealed a history of allergic dermatitis to household detergents and caustic soda. Re-challenge with palonosetron was not carried out due to the life threatening nature of the adverse drug reaction (ADR). Causality assessment was carried out using the World Health Organization-Uppsala Monitoring Centre criteria and the adverse reaction had ‘certain’ relationship with palonosetron administration. The strong temporal relationship between administration of palonosetron and onset of symptoms of anaphylaxis and their amelioration with discontinuation of the drug suggested this relationship. The casual association was also evaluated using the Naranjo algorithm and a score of 7 indicated a ‘probable’ relationship [1]. The ADR was reported to the national pharmacovigilance centre under the National Pharmacovigliance Programme, India. Palonosetron is a relatively new 5-HT3 receptor antagonist that was approved in 2003 by the US FDA for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderate to highly emetogenic cancer chemotherapy. It has at least 30-fold higher affinity for the 5-HT3 receptor compared with the first-generation 5-HT3 receptor antagonists like ondansetron, granisetron and dolasetron. In addition, palonosetron also has higher potency and is three-fold more potent than granisetron and up to 55-times more potent than ondansetron [2]. It is generally well tolerated, and in clinical trials, headache (9%) and constipation (5%) were the most commonly reported adverse drug reactions. Less frequently reported adverse reactions include diarrhoea, dizziness, fatigue, abdominal pain and insomnia. The severity and frequency of the adverse reactions are similar to those observed with ondansetron and dolasetron [3]. A recent case report described the occurrence of generalized tonic clonic seizures after i.v. palonosetron in a patient with breast carcinoma scheduled for chemotherapy [4]. To the best of our knowledge, this is probably the first case of i.v. palonosetron-induced anaphylaxis to be reported. However, anaphylactoid reaction has been reported with the use of i.v. ondansetron. The very rare (less than 1/10 000) incidence of hypersensitivity encountered during post marketing surveillance of palonosetron has been mentioned in its package insert and the use of palonosetron has been contraindicated in patients who are hypersensitive to it or other 5-HT3 receptor antagonists [5]. Although this patient did not have a history of drug allergy, it is possible that she may have been pre-sensitized to 5-HT3 receptor antagonists during her earlier hospital visits for surgery of the tumour. The widespread and easy availability of 5HT3-receptor antagonists in the Indian market has promoted the off label use of these drugs, such as in the treatment of antimalarial-induced vomiting, gastritis, migraine and other emetogenic conditions [6]. In view of the life threatening yet avoidable nature of the anaphylactic reaction developing after i.v. palonosetron, those prescribing it or other 5-HT3 receptor antagonists should exercise extreme caution, especially in patients with history of any sort of hypersensitivity. Whenever possible, alternatives like metoclopramide or domperidone should be prescribed for such patients.

Pharmacokinetics of palonosetron in combination with aprepitant in healthy volunteers

ABSTRACTBackground: Palonosetron is a second-generation 5-HT3 receptor antagonist with a prolonged duration of action and higher receptor binding affinity than first-generation agents (ondansetron, granisetron, and dolasetron). Aprepitant is a selective antagonist of substance P/neurokinin 1 that augments the benefit of 5-HT3 receptor antagonists in the prevention of chemotherapy-induced nausea and vomiting.Methods: This randomized, open-label, two-way, crossover trial was designed to evaluate the effect of oral aprepitant on the pharmacokinetics and safety of a single intravenous (IV) dose of palonosetron in 12 healthy subjects. Treatment A consisted of a single IV bolus dose of palonosetron 0.25 mg on day 1. Treatment B added oral aprepitant 125 mg on day 1 (30 minutes prior to palonosetron) and 80 mg on days 2 and 3. Blood for pharmacokinetic evaluations was collected through 168 hours after palonosetron administration on days 1 and 15; safety was monitored through day 22.Results: Mean plasma concentration-time plots for palonosetron were virtually identical for palonosetron administered alone or with concomitant aprepitant. The ratio of geometric least-square mean values (with:without aprepitant) for Cmax was 98.6% (90% confidence interval [CI]: 61.8–157%), and for AUC0–∞ the ratio was 101% (90% CI: 85.6–119%). With and without aprepitant coadministration, respectively, mean plasma elimination half-life was 40 hours and 43 hours (difference: –3.0 hours; p = 0.348), mean total body clearance was 130 mL/min and 136 mL/min (difference: –5.6 mL/min; p = 0.735), and mean volume of distribution at steady-state was 410.9 L and 442.3 L (difference: –31.4 L; p = 0.463). Palonosetron alone and the palonosetron/aprepitant regimen were well tolerated.Conclusion: These results indicate no significant differences in pharmacokinetic parameters for palonosetron between the two treatments, and suggest that palonosetron can be safely coadministered with aprepitant with no alterations in the expected safety profile and no dosage adjustment necessary.