Aloxi

Aloxi

palonosetron

Manufacturer:

Mundipharma

Distributor:

DKSH
Full Prescribing Info
Contents
Palonosetron.
Description
Each 5 mL and 1.5 mL vial contains palonosetron base 250 mcg and 75 mcg equivalent to palonosetron hydrochloride 250 mcg and 84 mcg. Aloxi also contains the following excipients: Mannitol 207.5 mg and 83 mg, disodium edetate and citrate buffer in water for IV administration.
Aloxi is an antiemetic and antinauseant agent. It is a serotonin subtype 3 (5-HT3) receptor antagonist with a strong binding affinity for this receptor. Chemically, palonosetron hydrochloride is: (3aS)-2-[(S)-1-Azabicyclo [2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo1Hbenz[de]isoquinoline hydrochloride. The empirical formula is C19H24N2O·HCl, with a molecular weight of 332.87. Palonosetron hydrochloride exists as a single isomer.
Palonosetron hydrochloride is a white to off-white crystalline powder. It is freely soluble in water, soluble in propylene glycol, and slightly soluble in ethanol and 2-propanol.
The pH of the solution in the 5 mL and 1.5 mL vial is 4.5-5.5.
Action
Pharmacology: Pharmacodynamics: The effect of palonosetron on blood pressure, heart rate and electrocardiogram (ECG) parameters including QTc were comparable to ondansetron and dolasetron in chemotherapy-induced nausea and vomiting (CINV) clinical trials. In postoperative nausea and vomiting (PONV) clinical trials, the effect of palonosetron on the QTc interval was no different from placebo. In non-clinical studies, palonosetron possesses the ability to block ion channels involved in ventricular de- and repolarization and to prolong action potential duration.
The effect of palonosetron on QTc interval was evaluated in a double-blind, randomized, parallel, placebo and positive (moxifloxacin) controlled trial in adult men and women. The objective was to evaluate the ECG effects of IV administered palonosetron at single doses ofd 250 mcg, 75 mcg or 2.25 mg in 221 healthy subjects. The study demonstrated no significant effect on any ECG interval including QTc duration (cardiac repolarization) at doses up to 2.25 mg.
Mechanism of Action:
Palonosetron is a serotonin receptor antagonist (5-HT3) with a strong binding affinity for this receptor and little or no affinity with other receptors.
Cancer chemotherapy may be associated with a high incidence of nausea and vomiting, particularly when certain agents eg, cisplatin, are used. Serotonin receptor antagonist (5-HT3) receptors are located on the nerve terminals of the vagus in the periphery and centrally in the chemoreceptor trigger zone of the area postrema. It is thought that chemotherapeutic agents produce nausea and vomiting by releasing serotonin from the enterochromaffin cells of the small intestine and that the released serotonin then activates 5-HT3 receptors located on vagal afferents to initiate the vomiting reflex.
Postoperative nausea and vomiting is influenced by multiple patient, surgical and anesthesia related factors and is triggered by release of 5-HT in a cascade of neuronal events involving both the central nervous system and the gastrointestinal tract. The 5-HT3 receptor has been demonstrated to selectively participate in the emetic response.
Clinical Studies: Chemotherapy-Induced Nausea and Vomiting: Efficacy of single-dose palonosetron injection in preventing acute and delayed nausea and vomiting induced by both moderately and highly emetogenic chemotherapy was studied in 3 phase 3 trials and 1 phase 2 trial. In these double-blind studies, complete response rates (no emetic episodes and no rescue medication) and other efficacy parameters were assessed through at least 120 hrs after administration of chemotherapy. The safety and efficacy of palonosetron in repeated courses of chemotherapy was also assessed.
Moderately Emetogenic Chemotherapy:
Two (2) phase 3, double-blind trials involving 1,132 patients compared single-dose IV Aloxi with either single-dose IV ondansetron (study 1) or dolasetron (study 2) given 30 min prior to moderately emetogenic chemotherapy including carboplatin, cisplatin ≤50 mg/m², cyclophosphamide <1,500 mg/m², doxorubicin >25 mg/m², epirubicin, irinotecan and methotrexate >250 mg/m². Concomitant corticosteroids were not administered prophylactically in study 1 and were only used by 4-6% of patients in study 2. The majority of patients in these studies were women (77%), White (65%) and naive to previous chemotherapy (54%). The mean age was 55 years.
Highly Emetogenic Chemotherapy: A phase 2, double-blind, dose-ranging study evaluated the efficacy of single-dose IV palonosetron from 0.3-90 mcg/kg (equivalent to <0.1 mg to 6 mg fixed dose) in 161 chemotherapy-naive adult cancer patients receiving highly emetogenic chemotherapy (either cisplatin ≥70 mg/m² or cyclophosphamide >1,100 mg/m²). Concomitant corticosteroids were not administered prophylactically. Analysis of data from this trial indicates that 25 mcg is the lowest effective dose in preventing acute nausea and vomiting induced by highly emetogenic chemotherapy.
A phase 3, double-blind trial involving 667 patients compared single-dose IV Aloxi with single-dose IV ondansetron (study 3) given 30 min prior to highly emetogenic chemotherapy including cisplatin ≥60 mg/m², cyclophosphamide >1,500 mg/m² and dacarbazine. Corticosteroids were co-administered prophylactically before chemotherapy in 67% of patients. Of the 667 patients, 51% were women, White 60% and naive to previous chemotherapy 59%. The mean age was 52 years.
Efficacy Results: The antiemetic activity of Aloxi was evaluated during the acute phase (0-24 hrs) (Figure 1), delayed phase (24-120 hrs) (Figure 2) and overall phase (0-120 hrs) (Figure 3) postchemotherapy in phase 3 trials. (See Figure 1.)

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These studies show that Aloxi was effective in the prevention of acute nausea and vomiting associated with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy. In study 3, efficacy was greater when prophylactic corticosteroids were administered concomitantly. Clinical superiority over other 5-HT3 receptor antagonists has not been adequately demonstrated in the acute phase. (See Figure 2.)

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These studies show that Aloxi was effective in the prevention of delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy. (See Figure 3.)

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These studies show that Aloxi was effective in the prevention of nausea and vomiting throughout the 120 hrs (5 days) following initial and repeat courses of moderately emetogenic cancer chemotherapy.
Chemotherapy-Induced Nausea and Vomiting in Children: One double-blind, active-controlled clinical trial was conducted in pediatric cancer patients. The total population (N=327) had a mean age of 8.3 years (range 2 months to 16.9 years) and were male 53% and White 96%. Patients were randomized and received a 20 mcg/kg (maximum 1.5 mg) IV infusion of Aloxi 30 min prior to the start of emetogenic chemotherapy (followed by placebo infusions 4 and 8 hrs after the dose of palonosetron) or 0.15 mg/kg of IV ondansetron 30 min prior to the start of emetogenic chemotherapy (followed by ondansetron 0.15 mg/kg infusions 4 and 8 hrs after the 1st dose of ondansetron, with a maximum total dose of 32 mg). Emetogenic chemotherapies administered included doxorubicin, cyclophosphamide (<1500 mg/m2), ifosfamide, cisplatin, dactinomycin, carboplatin and daunorubicin. Adjuvant corticosteroids, including dexamethasone, were administered with chemotherapy in 55% of patients.
Complete response in the acute phase of the 1st cycle of chemotherapy was defined as no vomiting, no retching and no rescue medication in the first 24 hrs after starting chemotherapy. Efficacy was based on demonstrating non-inferiority of palonosetron IV compared to ondansetron IV. Non-inferiority criteria were met if the lower bound of the 97.5% confidence interval for the difference in complete response rates of palonosetron IV minus ondansetron IV was larger than -15%. The non-inferiority margin was 15%.
Efficacy Results: As shown in Table 1, Aloxi IV 20 mcg/kg (maximum 1.5 mg) demonstrated non-inferiority to the active comparator during the 0-24 hr time interval. (See Table 1.)

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In patients that received Aloxi at a lower dose than the recommended dose of 20 mcg/kg, non-inferiority criteria were not met.
Post-Operative Nausea and Vomiting (PONV): In 1 multicenter, randomized, stratified, double-blind, parallel-group, phase 3 clinical study (study 1), palonosetron was compared with placebo for the prevention of PONV in 546 patients undergoing abdominal and gynecological surgery. All patients received general anesthesia. Study 1 was a pivotal study conducted predominantly in the US in the outpatient setting for patients undergoing elective gynecologic or abdominal laparoscopic surgery and stratified at randomization for the following risk factors: Gender, non-smoking status, history of PONV and/or motion sickness.
In study 1 patients were randomized to receive palonosetron 0.025 mg, 0.05 mg or 0.075 mg or placebo, each given IV immediately prior to induction of anesthesia. The antiemetic activity of palonosetron was evaluated during the 0-72 hr time period after surgery.
Of the 138 patients treated with palonosetron 0.075 mg in study 1 and evaluated for efficacy, 96% were women; 66% had a history of PONV or motion sickness; 85% were non-smokers. As for race, 63% were White, 20% were Black, 15% were Hispanic and 1% were Asian. The age of patients ranged from 21-74 years, with a mean age of 37.9 years. Three (3) patients were >65 years.
Co-primary efficacy measures were complete response (CR) defined as no emetic episode and no use of rescue medication in the 0-24 hrs and 24-72 hrs post-operatively.
Secondary Efficacy Endpoints Included: Complete response (CR) 0-48 hrs and 0-72 hrs; complete control (CC) defined as CR and no more than mild nausea; severity of nausea (none, mild, moderate, severe).
The primary hypothesis in study 1 was that at least 1 of the 3 palonosetron doses were superior to placebo.
Results for CR in study 1 for palonosetron 0.075 mg versus placebo are described in Table 2. (See Table 2.)

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Palonosetron 0.075 mg reduced the severity of nausea compared to placebo. Analyses of other secondary endpoints indicate that palonosetron 0.075 mg was numerically better than placebo, however, statistical significance was not formally demonstrated.
A phase 2 randomized, double-blind, multicenter, placebo-controlled, dose ranging study was performed to evaluate palonosetron IV for the prevention of PONV following abdominal or vaginal hysterectomy. Five (5) palonosetron IV doses (0.1, 0.3, 1, 3 and 30 mcg/kg) were evaluated in a total of 381 intent-to-treat patients. The primary efficacy measure was the proportion of patients with CR in the first 24 hrs after recovery from surgery. The lowest effective dose was palonosetron 1 mcg/kg (approximately 0.075 mg) which had a CR rate of 44% versus 19% for placebo, p=0.004. Palonosetron 1 mcg/kg also significantly reduced the severity of nausea versus placebo, p=0.009.
Pharmacokinetics: After IV dosing of palonosetron in healthy subjects and cancer patients, an initial decline in plasma concentrations is followed by a slow elimination from the body. Mean maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC0-∞) are generally dose-proportional over the dose range of 0.3–90 mcg/kg in healthy subjects and in cancer patients. Following single IV dose of palonosetron at 3 mcg/kg (or 0.21 mg/70 kg) to 6 cancer patients, mean (±SD) Cmax was estimated to be 5.6±5.5 ng/mL and mean AUC was 35.8±20.9 ng•hr/mL.
Following IV administration of palonosetron 0.25 mg once every other day for 3 doses in 11 cancer patients, the mean increase in plasma palonosetron concentration from day 1 to day 5 was 42±34%. Following IV administration of palonosetron 0.25 mg once daily for 3 days in 12 healthy subjects, the mean (±SD) increase in plasma palonosetron concentration from day 1 to day 3 was 110±45%.
After IV dosing of palonosetron in patients undergoing surgery (abdominal surgery or vaginal hysterectomy), the pharmacokinetic characteristics of palonosetron were similar to those observed in cancer patients.
Distribution: Palonosetron has a volume of distribution of approximately 8.3±2.5 L/kg. Approximately 62% of palonosetron is bound to plasma proteins.
Metabolism: Palonosetron is eliminated by multiple routes with approximately 50% metabolized to form 2 primary metabolites: N-oxide-palonosetron and 6-S-hydroxy-palonosetron. These metabolites each have <1% of the 5-HT3 receptor antagonist activity of palonosetron. In vitro metabolism studies have suggested that CYP2D6 and to a lesser extent, CYP3A4 and CYP1A2 are involved in the metabolism of palonosetron. However, clinical pharmacokinetic parameters are not significantly different between poor and extensive metabolizers of CYP2D6 substrates.
Elimination: After a single IV dose of 10 mcg/kg [14C]-palonosetron, approximately 80% of the dose was recovered within 144 hrs in the urine with palonosetron representing approximately 40% of the administered dose. In healthy subjects, the total body clearance of palonosetron was 160±35 mL/hr/kg and renal clearance was 66.5±18.2 mL/hr/kg. Mean terminal elimination half-life (t½) is approximately 40 hrs.
Special Populations: Children: Single-dose Aloxi IV pharmacokinetic data was obtained from a subset of pediatric cancer patients that received 10 mcg/kg or 20 mcg/kg. When the dose was increased from 10 mcg/kg to 20 mcg/kg a dose-proportional increase in mean AUC was observed. Following single dose IV infusion of Aloxi 20 mcg/kg, peak plasma concentrations (CT) reported at the end of the 15 min infusion were highly variable in all age groups and tended to be lower in patients <6 years than in older patients. Median t½ was 29.5 hrs in overall age groups and ranged from about 20-30 hrs across age groups after administration of 20 mcg/kg.
The total body clearance (L/hr/kg) in patients 12-17 years was similar to that in healthy adults. There are no apparent differences in volume of distribution when expressed as L/kg. (See Table 3.)

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Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: In a 104-week carcinogenicity study in CD-1 mice, animals were treated with oral doses of palonosetron at 10, 30 and 60 mg/kg/day. Treatment with palonosetron was not tumorigenic. The highest tested dose produced a systemic exposure to palonosetron (plasma AUC) of about 150-289 times the human exposure (AUC=29.8 ng•hr/mL) at the recommended IV dose of 0.25 mg. In a 104-week carcinogenicity study in Sprague-Dawley rats, male and female rats were treated with oral doses of 15, 30 and 60 mg/kg/day and 15, 45 and 90 mg/kg/day, respectively. The highest doses produced a systemic exposure to palonosetron (plasma AUC) of 137 and 308 times the human exposure at the recommended dose. Treatment with palonosetron produced increased incidences of adrenal benign pheochromocytoma and combined benign and malignant pheochromocytoma, increased incidences of pancreatic islet cell adenoma and combined adenoma and carcinoma and pituitary adenoma in male rats. In female rats, it produced hepatocellular adenoma and carcinoma and increased the incidences of thyroid C-cell adenoma and combined adenoma and carcinoma.
Palonosetron was not genotoxic in the Ames test, the Chinese hamster ovarian cell (CHO/HGPRT) forward mutation test, the ex vivo hepatocyte unscheduled deoxyribonucleic acid synthesis (UDS) test or the mouse micronucleus test. It was, however, positive for clastogenic effects in the Chinese hamster ovarian (CHO) cell chromosomal aberration test.
Palonosetron at oral doses up to 60 mg/kg/day (about 1,894 times the recommended human IV dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.
Indications/Uses
Chemotherapy-Induced Nausea and Vomiting: Moderately emetogenic cancer chemotherapy for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses. Highly emetogenic cancer chemotherapy for the prevention of acute nausea and vomiting associated with initial and repeat courses.
Chemotherapy-Induced Nausea and Vomiting in Children <17 years to 1 month: Prevention of acute nausea and vomiting associated with initial and repeat courses of moderately or highly emetogenic cancer chemotherapy.
Post-Operative Nausea and Vomiting (PONV): Prevention of PONV for up to 24 hrs following surgery. Efficacy beyond 24 hrs has not been demonstrated.
As with other antiemetics, routine prophylaxis is not recommended in patients in whom there is little expectation that nausea and/or vomiting will occur post-operatively. In patients where nausea and vomiting must be avoided during the post-operative period, Aloxi is recommended even where the incidence of PONV is low.
Dosage/Direction for Use
Chemotherapy-Induced Nausea and Vomiting: Recommended Dose: See Table 4.

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Postoperative Nausea and Vomiting:
Adult: 0.075 mg IV single dose administered over 10 sec immediately before the induction of anesthesia.
Administration:
Instructions for IV Administration: Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit.
Aloxi is supplied ready for IV administration at a concentration of 0.05 mg/mL (50 mcg/mL). Aloxi should not be mixed with other drugs. Flush infusion live with normal saline after administration.
Overdosage
There is no known antidote to Aloxi. Overdose should be managed with supportive care.
Fifty (50) adult cancer patients were administered palonosetron at a dose of 90 mcg/kg (equivalent to 6 mg fixed dose) as part of a dose ranging study. This is approximately 25 times the recommended dose of 0.25 mg. This dose group had a similar incidence of adverse events compared to the other dose groups and no dose response effects were observed.
Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron overdosage. A single IV dose of palonosetron at 30 mg/kg (947 and 474 times the human dose for rats and mice, respectively, based on body surface area) was lethal to rats and mice. The major signs of toxicity were convulsions, gasping, pallor, cyanosis and collapse.
Contraindications
Hypersensitivity to palonosetron or to any of the excipients of Aloxi.
Special Precautions
Hypersensitivity: Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other 5-HT3 receptor antagonists.
Serotonin Syndrome: The development of serotonin syndrome has been reported with 5-HT3 receptor antagonists. Most reports have been associated with concomitant use of serotonergic drugs [eg, selective serotonin-reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and intravenous methylene blue]. Some of the reported cases were fatal. Serotonin syndrome occurring with overdose of another 5-HT3 receptor antagonist alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT3 receptor antagonist use occurred in a post- anesthesia care unit or an infusion center.
Symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (eg, agitation, hallucinations, delirium, and coma), autonomic instability (eg, tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures with or without gastrointestinal symptoms (eg, nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of Aloxi and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue Aloxi and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if Aloxi is used concomitantly with other serotonergic drugs (see Interactions).
Race: Palonosetron IV pharmacokinetics was characterized in 24 healthy Japanese subjects over the dose range of 3-90 mcg/kg. Total body clearance was 25% higher in Japanese subjects compared to Whites, however, no dose adjustment is required. The pharmacokinetics of palonosetron in Blacks has not been adequately characterized.
Renal Impairment: Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. Total systemic exposure increased by approximately 28% in severe renal impairment relative to healthy subjects. Dosage adjustment is not necessary in patients with any degree of renal impairment.
Hepatic Impairment: Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the healthy subjects. Dosage adjustment is not necessary in patients with any degree of hepatic impairment.
Use in pregnancy: Teratogenic Effects: Category B. Teratology studies have been performed in rats at oral doses up to 60 mg/kg/day [1,894 times the recommended human IV dose based on body surface area (BSA)] and rabbits at oral doses up to 60 mg/kg/day (3,789 times the recommended human IV dose based on BSA) and have revealed no evidence of impaired fertility or harm to the fetus due to palonosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, palonosetron should be used during pregnancy only if clearly needed.
Labor and Delivery:
Since the effect of palonosetron is unknown on mother or child, it should not be administered to patients during labour and delivery.
Use in lactation: It is not known whether palonosetron is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and the potential for tumorigenicity shown for palonosetron in the rat carcinogenicity study, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Use in children: The safety and efficacy of Aloxi in children aged <1 month have not been established. No data are available. There is limited data on the use of Aloxi in the prevention of nausea and vomiting in children <2 years.
Chemotherapy-Induced Nausea and Vomiting:
Safety and effectiveness of Aloxi have been established in pediatric patients aged <17 years to 1 month for the prevention of acute nausea and vomiting associated with initial and repeat courses of moderately or highly emetogenic cancer chemotherapy. Use is supported by a clinical trial where 165 pediatric patients 2 months to <17 years were randomized to receive a single dose of palonosetron 20 mcg/kg (maximum 1.5 mg) administered as an IV infusion 30 min prior to the start of emetogenic chemotherapy (see Pharmacology: Clinical Studies under Action). While this study demonstrated that pediatric patients require a higher palonosetron dose than adults to prevent chemotherapy-induced nausea and vomiting, the safety profile is consistent with the established profile in adults (see Adverse Reactions).
Safety and effectiveness of Aloxi in neonates (<1 month) have not been established.
Post-Operative Nausea and Vomiting (PONV) Studies: Safety and efficacy have not been established in pediatric patients for prevention of PONV. Two (2) pediatric trials were performed.
Pediatric study 1, a dose finding study was conducted to compare two doses of palonosetron, 1 mcg/kg (max 0.075 mg) versus 3 mcg/kg (max 0.25 mg). A total of 150 pediatric surgical patients participated, age range 1 month to <17 years. No dose response was observed.
Pediatric study 2, a multicenter, double-blind, double-dummy, randomized, parallel group, active control, single-dose non-inferiority study, compared IV palonosetron (1 mcg/kg, max 0.075 mg) versus IV ondansetron. A total of 670 pediatric surgical patients participated, age 30 days to <17 years. The primary efficacy endpoint, complete response (CR: No vomiting, no retching, and no antiemetic rescue medication) during the first 24 hrs post-operatively was achieved in 78.2% of patients in the palonosetron group and 82.7% in the ondansetron group. Given the pre- specified non-inferiority margin of -10%, the stratum adjusted Mantel-Haenszel statistical non-inferiority confidence interval for the difference in the primary endpoint, complete response (CR), was [-10.5, 1.7%], therefore non-inferiority was not demonstrated. Adverse reactions to palonosetron were similar to those reported in adults (see Table 6 under Adverse Reactions).
Use in the elderly: Population pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients ≥65 years of age and younger patients (18-64 years). Of the 1,374 adult cancer patients in clinical studies of palonosetron, 316 (23%) were ≥65 years, while 71 (5%) were ≥75 years. No overall differences in safety or effectiveness were observed between these subjects and the younger subjects, but greater sensitivity in some older individuals cannot be ruled out. No dose adjustment or special monitoring are required for geriatric patients.
Of the 1,520 adult patients in Aloxi PONV clinical studies, 73 (5%) were ≥65 years. No overall differences in safety were observed between older and younger subjects in these studies, though the possibility of heightened sensitivity in some older individuals cannot be excluded. No differences in efficacy were observed in geriatric patients for the CINV indication and none are expected for geriatric PONV patients. However, Aloxi efficacy in geriatric patients has not been adequately evaluated.
Adverse Reactions
Since clinical trials are conducted under varying conditions, the adverse reactions observed in trials may not reflect the rates observed in clinical practice.
Chemotherapy-Induced Nausea and Vomiting: Adults: In clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic chemotherapy, 1,374 adult patients received palonosetron. Adverse reactions were similar in frequency and severity with Aloxi and ondansetron or dolasetron following is a listing of all adverse reactions reported by ≥2% of patients in these trials. (See Table 5.)

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In other studies, 2 subjects experienced severe constipation following a single palonosetron dose of approximately 0.75 mg, 3 times the recommended dose. One (1) patient received a 10 mcg/kg oral dose in a postoperative nausea and vomiting study and 1 healthy subject received a 0.75 mg IV dose in a pharmacokinetic study.
In clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of Aloxi to adult patients receiving concomitant cancer chemotherapy: Cardiovascular: 1%: Non-sustained tachycardia, bradycardia, hypotension. <1%: Hypertension, myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles and QT prolongation. In many cases, the relationship to Aloxi was unclear.
Dermatological: <1%: Allergic dermatitis, rash.
Hearing and Vision:
<1%: Motion sickness, tinnitus, eye irritation and amblyopia.
Gastrointestinal System: 1%: Diarrhea. <1%: Dyspepsia, abdominal pain, dry mouth, hiccups and flatulence.
General:
1%: Weakness. <1%: Fatigue, fever, hot flash, flu-like syndrome.
Liver: <1%: Transient, asymptomatic increases in aspartate transaminase (AST) and/or alanine aminotransferase (ALT) and bilirubin. These changes occurred predominantly in patients receiving highly emetogenic chemotherapy.
Metabolic:
1%: Hyperkalemia. <1%: Electrolyte fluctuations, hyperglycemia, metabolic acidosis, glycosuria, decreased appetite, anorexia.
Musculoskeletal:
<1%: Arthralgia.
Nervous System: 1%: Dizziness. <1%: Somnolence, insomnia, hypersomnia, paresthesia.
Psychiatric: 1%: Anxiety. <1%: Euphoric mood.
Urinary System:
<1%: Urinary retention.
Vascular: <1%: Vein discoloration and distention.
Children: In a pediatric clinical trial for the prevention of chemotherapy-induced nausea and vomiting 163 cancer patients received a single 20 mcg/kg (maximum 1.5mg) IV infusion of palonosetron 30 min before beginning the 1st cycle of emetogenic chemotherapy. Patients had a mean age of 8.4 years (range 2 months to 16.9 years) and were male 46% and White 93%.
The following adverse reactions were reported for palonosetron: Nervous System: <1%: headache, dizziness, dyskinesia.
General: <1%: infusion site pain.
Dermatological: <1%: allergic dermatitis, skin disorder.
In the trial, adverse reactions were evaluated in pediatric patients receiving palonosetron for up to 4 chemotherapy cycles.
Post-Operative Nausea and Vomiting: The adverse reactions cited in Table 3 were reported in ≥2% of adults receiving IV Aloxi 0.075 mg immediately before induction of anesthesia in 1 phase 2 and 2 phase 3 randomized placebo-controlled trials. Rates of events between palonosetron and placebo groups were indistinguishable. Some events are known to be associated with, or may be exacerbated by concomitant perioperative and intraoperative medications administered in this surgical population. (See Table 6.)

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In these clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of Aloxi to adult patients receiving concomitant peri- and intraoperative medications including those associated with anesthesia: Cardiovascular: 1%: Electrocardiogram (ECG) QTc prolongation, sinus bradycardia, tachycardia. <1%: Decreased blood pressure, hypotension, hypertension, arrhythmia, ventricular extrasystoles, generalized edema; decreased ECG T-wave amplitude, decreased platelet count. The frequency of these adverse effects did not appear to be different from placebo.
Dermatological:
1%: Pruritus.
Gastrointestinal System: 1%: Flatulence. <1%: Dry mouth, upper abdominal pain, salivary hypersecretion, dyspepsia, diarrhea, intestinal hypomotility, anorexia.
General:
<1%: Chills.
Liver:
1%: Increases in AST and/or ALT. <1%: Increased hepatic enzyme.
Metabolic:
<1%: Hypokalemia, anorexia.
Nervous System: <1%: Dizziness.
Respiratory: <1%: Hypoventilation, laryngospasm.
Urinary System: 1%: Urinary retention.
Post-Marketing Experience: The following adverse reactions have been identified during post-approval use of Aloxi. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Very rare cases (<1/10,000) of hypersensitivity reactions and injection site reactions (burning, induration, discomfort and pain) were reported from post-marketing experience of Aloxi 0.25 mg in the prevention of chemotherapy-induced nausea and vomiting.
Drug Interactions
Palonosetron is eliminated from the body through both renal excretion and metabolic pathways with the latter mediated via multiple CYP enzymes. Further in vitro studies indicated that palonosetron is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4/5 (CYP2C19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6 or CYP3A4/5. Therefore, the potential for clinically significant drug interactions with palonosetron appears to be low.
Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT3 receptor antagonists and other serotonergic drugs, including SSRIs and SNRIs (see Precautions).
Co-administration of palonosetron 0.25 mg IV and dexamethasone IV 20 mg in healthy subjects revealed no pharmacokinetic drug-interactions between palonosetron and dexamethasone.
In an interaction study in healthy subjects where palonosetron 0.25 mg (IV bolus) was administered on day 1 and oral aprepitant for 3 days (125 mg/80 mg/80 mg), the pharmacokinetics of palonosetron were not significantly altered (AUC: No change, Cmax: 15% increase).
A study in healthy volunteers involving single-dose IV palonosetron (0.75 mg) and steady-state oral metoclopramide (10 mg 4 times daily) demonstrated no significant pharmacokinetic interaction.
In controlled clinical trials, Aloxi injection has been safely administered with corticosteroids, analgesics, antiemetics/antinauseants, antispasmodics and anticholinergic agents.
Palonosetron did not inhibit the antitumor activity of the 5 chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C) in murine tumor models.
Caution For Usage
Instructions for Disposal: Single use only, any unused solution should be discarded.
Any unused product or waste material should be disposed of in accordance with the local requirements.
Storage
Store below 30°C. Protect from light.
Shelf-Life:
3 years.
Upon opening of the vial, use immediately and discard any unused solution.
ATC Classification
A04AA05 - palonosetron ; Belongs to the class of serotonin (5HT3) antagonists. Used for the prevention of nausea and vomiting.
Presentation/Packing
Soln for inj (vial, sterile, clear, colorless, nonpyrogenic, isotonic, buffered soln) 250 mcg/5 mL x 1's. 75 mcg/1.5 mL x 1's.
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