Aloxi

Palonosetron HCl.

Capsule: Each soft gel capsule contains Palonosetron HCl 500 mcg.
IV Inj: 250 mcg/5 mL: Each 5 mL vial contains 250 mcg palonosetron base as 280 mcg palonosetron HCl.
IV Inj: 75 mcg/1.5 mL: Each 1.5 mL vial contains 75 mcg palonosetron base as 84 mcg palonosetron HCl.
PALONOSETRON HCl (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 HCl is: (3aS)-2-[(S)-1-Azabicyclo[2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo-1Hbenz[de]isoquinoline hydrochloride. The empirical formula is C₁₉H₂₄N₂O•HCl, with a molecular weight of 332.87. Palonosetron HCl exists as a single isomer.
Palonosetron HCl 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.
PALONOSETRON HCl (ALOXI) injection is a sterile, clear, colorless, non-pyrogenic, isotonic, buffered solution for intravenous administration.
The pH of the solution in the 1.5 mL or 5 mL vial is 4.5 to 5.5.
Excipients/Inactive Ingredients: Capsule: Capsule content: Mono/diglycerides of caprylic/capric acid; Polyglycerol oleate; Glycerol; Purified water; Butylhydroxyanisole (BHA).
Capsule shell: Gelatin; Sorbitol (E420); Glycerol; Titanium dioxide (E171).
Printing Ink: Iron oxide black (E172); Polyvinyl acetate phthalate; Macrogol 400.
250 mcg/5 mL: 207.5 mg mannitol, disodium edetate and citrate buffer in water for intravenous administration.
75 mcg/1.5 mL: 83 mg mannitol, disodium edetate and citrate buffer in water for intravenous administration.

Pharmacotherapeutic Group: Antiemetics and antinauseants, Serotonin (5HT₃) antagonists. ATC Code: A04AA05.
Pharmacology: Pharmacodynamics: Capsule: Palonosetron is a selective high-affinity receptor antagonist of the 5HT₃ receptor.
In a multicenter, randomized, double-blind active control clinical trial of 635 patients set to receive moderately emetogenic cancer chemotherapy. A single-dose of 250 mcg, 500 mcg, or 750 mcg oral palonosetron capsules given one hour prior to moderately emetogenic chemotherapy was compared to a single-dose of 250 mcg intravenous PALONOSETRON HCl (ALOXI) given 30 minutes prior to chemotherapy. Patients were randomised to either dexamethasone or placebo in addition to their assigned treatment. The majority of patients in the study were women (73%), white (69%), and naïve to previous chemotherapy (59%). The antiemetic activity was observed during 0-24 hours, 24-120 hours and 0-120 hours.
Efficacy was based on demonstrating non-inferiority of oral palonosetron doses compared to the approved intravenous formulation. Non-inferiority criteria were met if the lower bound of the two-sided 98.3 % confidence interval for the difference in complete response rates of oral palonosetron dose minus approved intravenous formulation was larger than -15%. The non-inferiority margin was 15%.
As shown in Table 1, oral PALONOSETRON HCl (ALOXI) capsules 500 micrograms demonstrated non-inferiority to the active comparator during the 0 to 24 hour and 0 to 120 hour time intervals; however, for the 24 to 120 hour time period, non-inferiority was not shown.
Although comparative efficacy of palonosetron in multiple cycles has not been demonstrated in controlled clinical trials, 217 patients were enrolled in a multicentre, open label safety study and were treated with palonosetron capsules 750 micrograms for up to 4 cycles of chemotherapy in a total of 654 chemotherapy cycles. Approximately 74% of patients also received single dose oral or intravenous dexamethasone 30 minutes before chemotherapy. Complete Response was not formally evaluated for the repeat cycle application. However, in general the antiemetic effect for the 0-24 hour interval was similar throughout the consecutively repeated cycles and the overall safety was maintained during all cycles. (See Table 1.)

Click on icon to see table/diagram/image

In non-clinical studies palonosetron possesses the ability to block ion channels involved in ventricular de- and re-polarization 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 of 0.25, 0.75 or 2.25 mg in 221 healthy subjects. The study demonstrated no effect on QT/QTc interval duration as well as any other ECG interval at doses up to 2.25 mg. No clinically significant changes were shown on heart rate, atrioventricular (AV) conduction and cardiac repolarization.
Pediatric population: Prevention of Chemotherapy Induced Nausea and Vomiting (CINV): The safety and efficacy of Palonosetron i.v at single doses of 3 μg/kg and 10 μg/kg was investigated in the first clinical study in 72 patients in the following age groups, >28 days to 23 months (12 patients), 2 to 11 years (31 patients), and 12 to 17 years of age (29 patients), receiving highly or moderately emetogenic chemotherapy. No safety concerns were raised at either dose level. The primary efficacy variable was the proportion of patients with a complete response (CR, defined as no emetic episode and no rescue medication) during the first 24 hours after the start of chemotherapy administration. Efficacy after palonosetron 10 μg/kg compared to palonosetron 3 μg/kg was 54.1% and 37.1% respectively.
The efficacy of PALONOSETRON HCl (ALOXI) for the prevention of chemotherapy-induced nausea and vomiting in pediatric cancer patients was demonstrated in a second non-inferiority pivotal trial comparing a single intravenous infusion of PALONOSETRON HCl (ALOXI) versus an i.v. ondansetron regimen. A total of 493 pediatric patients, aged 64 days to 16.9 years, receiving moderately (69.2%) or highly emetogenic chemotherapy (30.8%) were treated with palonosetron 10 μg/kg (maximum 0.75 mg), palonosetron 20 μg/kg (maximum 1.5 mg) or ondansetron (3 x 0.15 mg/kg, maximum total dose 32 mg) 30 minutes prior to the start of emetogenic chemotherapy during Cycle 1. Most patients were non-naïve to chemotherapy (78.5%) across all treatment groups. 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. The primary efficacy endpoint was Complete Response in the acute phase of the first cycle of chemotherapy, defined as no vomiting, no retching, and no rescue medication in the first 24 hours after starting chemotherapy. Efficacy was based on demonstrating non-inferiority of intravenous palonosetron compared to intravenous ondansetron. Non-inferiority criteria were met if the lower bound of the 97.5% confidence interval for the difference in Complete Response rates of intravenous palonosetron minus intravenous ondansetron was larger than -15%. In the palonsetron 10 μg/kg, 20 μg/kg and ondansetron groups, the proportion of patients with CR0-24h was 54.2%, 59.4% and 58.6%. Since the 97.5% confidence interval (stratum adjusted Mantel-Haenszel test) of the difference in CR0-24h between palonosetron 20 μg/kg and ondansetron was [-11.7%, 12.4%], the 20 μg/kg palonosetron dose demonstrated non-inferiority to ondansetron.
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). Pharmacokinetic information is provided as follows.
Prevention of Post-Operative Nausea and Vomiting (PONV): Two pediatric trials were performed. The safety and efficacy of palonosetron i.v at single doses of 1 μg/kg and 3 μg/kg was compared in the first clinical study in 150 patients in the following age groups, >28 days to 23 months (7 patients), 2 to 11 years (96 patients), and 12 to 16 years of age (47 patients) undergoing elective surgery. No safety concerns were raised in either treatment group. The proportion of patients without emesis during 0-72 hours post-operatively was similar after palonosetron 1 μg/kg or 3 μg/kg (88% vs 84%).
The second pediatric trial was a multicenter, double-blind, double-dummy, randomised, parallel group, active control, single-dose non-inferiority study, comparing i.v. palonosetron (1 μg/kg, max 0.075 mg) versus i.v. ondansetron. A total of 670 pediatric surgical patients participated, age 30 days to 16.9 years. The primary efficacy endpoint, Complete Response (CR: no vomiting, no retching, and no antiemetic rescue medication) during the first 24 hours postoperatively 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 No new safety concerns were raised in either treatment group. (See Dosage & Administration for information on pediatric use.)
Solution for Injection: The effect of palonosetron on blood pressure, heart rate, and ECG parameters including QTc were comparable to ondansetron and dolasetron in CINV clinical trials. In 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 re polarization 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 I.V. administered palonosetron at single doses of 250 mcg, 750 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 5-HT₃ receptor antagonist with a strong binding affinity for this receptor and little or no affinity for other receptors.
Cancer chemotherapy may be associated with a high incidence of nausea and vomiting, particularly when certain agents, such as cisplatin, are used. 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.
75 mcg/1.5 mL: 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: 250 mcg/5 mL: Chemotherapy-Induced Nausea and Vomiting in Adults: 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 Phase 2 trials and Phase 3 trials. In these double-blind studies, complete response rates (no emetic episodes and no rescue medication) and complete control rates (no emetic episodes, no use of rescue medication, and no more than mild nausea), as well as other efficacy parameters were assessed through at least 120 hours after administration of chemotherapy. The safety and efficacy of palonosetron in repeated courses of chemotherapy was also assessed.
Moderately Emetogenic Chemotherapy: Two Phase 3, double-blind trials involving 1132 patients compared single-dose I.V. PALONOSETRON HCl (ALOXI) with either single-dose I.V. ondansetron (study 1) or dolasetron (study 2) given 30 minutes prior to moderately emetogenic chemotherapy including carboplatin, cisplatin ≤50 mg/m², cyclophosphamide <1500 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 naïve 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 I.V. palonosetron from 0.3 to 90 mcg/kg (equivalent to <100 mcg to 6 mg fixed dose) in 161 chemotherapy-naïve adult cancer patients receiving highly-emetogenic chemotherapy (either cisplatin ≥70 mg/m² or cyclophosphamide >1100 mg/m²). Concomitant corticosteroids were not administered prophylactically. Analysis of data from this trial indicates that 250 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 I.V. PALONOSETRON HCl (ALOXI) with single-dose I.V. ondansetron (study 3) given 30 minutes prior to highly emetogenic chemotherapy including cisplatin ≥60 mg/m², cyclophosphamide >1500 mg/m², and dacarbazine. Corticosteroids were co-administered prophylactically before chemotherapy in 67% of patients. Of the 667 patients, 51% were women, 60% White, and 59% naïve to previous chemotherapy. The mean age was 52 years.
A phase 3 double blind trial involving 1114 patients who were receiving highly emetogenic chemotherapy (i.e. cisplatin, or an anthracyclin cyclophosphamide combination [AC/EC]) were randomly assigned to either single-dose of palonosetron (750 mcg) or granisetron (40 µg/kg) 30 minutes before chemotherapy on day 1. Both groups were given dexamethasone (16 mg IV) on day 1 and additional doses (8 mg IV for patients receiving cisplatin or 4 mg orally for patients receiving AC/EC) on days 2 and 3. Of the 1114 patients, 58.3% were women and 92.9% had never received any previous chemotherapy. The mean age for both groups was 58 years old.
Efficacy Results: The antiemetic activity of PALONOSETRON HCl (ALOXI) was evaluated during the acute phase (0-24 hours) [Figure 1], delayed phase (24-120 hours) [Figure 2], and overall phase (0-120 hours) [Figure 3] post-chemotherapy in Phase 3 trials. (See Figure 1.)

Click on icon to see table/diagram/image

These studies show that PALONOSETRON HCl (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.)

Click on icon to see table/diagram/image

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

Click on icon to see table/diagram/image

These studies show that PALONOSETRON HCl (ALOXI) was effective in the prevention of nausea and vomiting throughout the 120 hours (5 days) following initial and repeat courses of moderately emetogenic cancer chemotherapy.
The succeeding tables show the complete response (Table 2) and complete control rates (Table 3) of PALONOSETRON (ALOXI) in assessing its antiemetic property against nausea and vomiting after highly emetogenic chemotherapy during the acute phase (0-24 hours) and delayed phase (24-120 hours). (See Table 2.)

Click on icon to see table/diagram/image

This study shows that the proportion of patients with complete response in the delayed phase (24-120 hours) was significantly higher in the palonosetron group than in the granisetron group (56.8% vs 44.5%; p<0.0001). (See Table 3.)

Click on icon to see table/diagram/image

This study shows that more patients achieved complete control in the palonosetron group than the granisetron group during the delayed period (53% vs 42.4%; 0.0003) and overall period (47.9% vs 38.1%; 0.0007).
Chemotherapy-Induced Nausea and Vomiting in Pediatrics: 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 53% male; and 96% white. Patients were randomized and received a 20 mcg/kg (maximum 1.5 mg) intravenous infusion of PALONOSETRON HCl (ALOXI) 30 minutes prior to the start of emetogenic chemotherapy (followed by placebo infusions 4 and 8 hours after the dose of palonosetron) or 150 mcg/kg of intravenous ondansetron 30 minutes prior to the start of emetogenic chemotherapy (followed by ondansetron 150 mcg/kg infusions 4 and 8 hours after the first 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 first cycle of chemotherapy was defined as no vomiting, no retching, and no rescue medication in the first 24 hours after starting chemotherapy. Efficacy was based on demonstrating non-inferiority of intravenous palonosetron compared to intravenous ondansetron. Non-inferiority criteria were met if the lower bound of the 97.5% confidence interval for the difference in Complete Response rates of intravenous palonosetron minus intravenous ondansetron was larger than -15%. The non-inferiority margin was 15%.
Efficacy Results: As shown in Table 4, intravenous PALONOSETRON HCl (ALOXI) 20 mcg/kg (maximum 1.5 mg) demonstrated non-inferiority to the active comparator during the 0 to 24 hour time interval. (See Table 4.)

Click on icon to see table/diagram/image

In patients that received PALONOSETRON HCl (ALOXI) at a lower dose than the recommended dose of 20 mcg/kg, non-inferiority criteria were not met.
75 mcg/1.5 mL: A phase 2 randomized, double-blind, multicenter, placebo-controlled, dose ranging study (Study 1) was performed to evaluate I.V. palonosetron for the prevention of post-operative nausea and vomiting following abdominal or vaginal hysterectomy. Five I.V. palonosetron doses (0.1, 0.3, 1.0, 3.0 and 30 μg/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 hours after recovery from surgery. The lowest effective dose was palonosetron 1 μg/kg (approximately 75 mcg) which had a CR rate of 44% versus 19% for placebo, p=0.004. Palonosetron 1 μg/kg also significantly reduced the severity of nausea versus placebo, p=0.009.
In one multicenter, randomized, stratified, double-blind, parallel-group, phase 3 clinical study (Study 2), palonosetron was compared with placebo for the prevention of PONV in 546 patients undergoing abdominal and gynecological surgery. All patients received general anesthesia. In this pivotal study, patients were stratified at randomization for the following risk factors: gender, non-smoking status, history of post-operative nausea and vomiting and/or motion sickness. Patients were also randomized to receive palonosetron 25 mcg, 50 mcg or 75 mcg or placebo, each given intravenously immediately prior to induction of anesthesia. The antiemetic activity of palonosetron was evaluated during the 0 to 72 hour time period after surgery.
This study showed that a larger number of patients who received palonosetron 75 mcg did not develop nausea and also a significantly less intense distribution of nausea compared with patients who received placebo during the 0-6 h, 6-72 h, and overall time course 0-72 h. Palonosetron 75 mcg reduced the severity of nausea compared to placebo. Analyses of other secondary endpoints indicate that palonosetron 75 mcg was numerically better than placebo.
In another multicenter randomized, double-blind, phase 3 clinical study (Study 3) palonosetron was compared with placebo to determine it safety and efficacy in the prevention of PONV in inpatients after 72 hours after surgery. Five hundred and forty four (544) female patients undergoing either elective gynecologic or breast surgery were stratified according to PONV risk factors: nonsmoking status and history of PONV and/or motion sickness. These patients were randomized to receive one of the three doses of IV palonosetron (25 mcg, 50 mcg, 75 mcg) or placebo immediately before induction of anesthesia. The primary efficacy endpoint was complete response (CR: no emesis and no use of rescue medications) evaluated at the 0-24 and 24-72 hours time intervals after surgery.
This study showed that during the 0-6 h, 6-72 h, and overall 0-72 h time intervals, patients who received palonosetron 75 mcg had significantly higher CR rates compared to placebo. In terms of use of rescue therapy, more patients who received placebo required rescue therapy compared with palonosetron 75 mcg (46% vs 27%, P<0.001).
With regards to emetic episodes and nausea, this study showed that with palonosetron 75 mcg a significantly longer median time to first emesis (>72 hours) (P=0.002) was achieved. Furthermore, there was also a less intense distribution of nausea compared with placebo over the 0-24 h interval (P<0.001) and also during the 6-72 h (P=0.011) and 0-72 h (P<0.001) intervals.
One comparative study (Study 4) compared palonosetron with granisetron for the prevention of post-operative nausea and vomiting after a laparoscopic procedure. Sixty female patients were randomized to two groups to receive either granisetron 2.5 mg intravenously or palonosetron 75 mcg intravenously as bolus before induction. In this study all episodes of PONV were recorded for 0-3 hours in the post anesthesia care unit and from 3-48 hours in the postoperative ward.
This study showed that a complete response during 24-48 hours in the postoperative period was significantly higher in patients who had received palonosetron than in those who had received granisetron (66% vs 90%, p<0.05). This study suggests that palonosetron has an antiemetic effect that lasts longer than granisetron and that prophylactic therapy with palonosetron is more effective than granisetron for the long term prevention of PONV after a laparoscopic procedure. Adverse effects of palonosetron in the study were not clinically serious.
Pharmacokinetics: Solution for Injection: After intravenous 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 (C_max) and area under the concentration-time curve (AUC_0-∞) are generally dose-proportional over the dose range of 0.3-90 mcg/kg in healthy subjects and in cancer patients. Following single I.V. dose of palonosetron at 3 mcg/kg (or 210 mcg/70 kg) to six cancer patients, mean (±SD) maximum plasma concentration was estimated to be 5630±5480 ng/L and mean AUC was 35.8±20.9 h·mcg/L.
Following I.V. administration of palonosetron 250 mcg 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 I.V. administration of palonosetron 250 mcg 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 intravenous 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.
Absorption: Capsule: Following oral administration, palonosetron is well absorbed with its absolute bioavailability reaching 97%. After single oral doses using buffered solution mean maximum palonosetron concentrations (C_max) and area under the concentration-time curve (AUC0-∞) were dose proportional over the dose range of 3.0 to 80 μg/kg in healthy subjects.
In 36 healthy male and female subjects given a single oral dose of palonosetron capsules 500 micrograms, maximum plasma palonosetron concentration (C_max) was 0.81±0.17 ng/mL (mean±SD) and time to maximum concentration (T_max) was 5.1±1.7 hours. In female subjects (n=18), the mean AUC was 35% higher and the mean C_max was 26 % higher than in male subjects (n=18).
In 12 cancer patients given a single oral dose of palonosetron capsules 500 micrograms one hour prior to chemotherapy, C_max was 0.93±0.34 ng/mL and T_max was 5.1±5.9 hours. The AUC was 30% higher in cancer patients than in healthy subjects.
A high fat meal did not affect the C_max and AUC of oral palonosetron. Therefore, PALONOSETRON HCl (ALOXI) capsules may be taken without regard to meals.
Distribution: Capsule: Palonosetron at the recommended dose is widely distributed in the body with a volume of distribution of approximately 6.9 to 7.9 L/kg. Approximately 62% of palonosetron is bound to plasma proteins.
Solution for Injection: Palonosetron has a volume of distribution of approximately 8.3±2.5 L/kg. Approximately 62% of palonosetron is bound to plasma proteins.
Biotransformation: Capsule: Palonosetron is eliminated by dual route, about 40% eliminated through the kidney and with approximately 50% metabolised to form two primary metabolites, which have less than 1% of the 5HT₃ receptor antagonist activity of palonosetron. In vitro metabolism studies have shown that CYP2D6 and to a lesser extent, CYP3A4 and CYP1A2 isoenzymes are involved in the metabolism of palonosetron. However, clinical pharmacokinetic parameters are not significantly different between poor and extensive metabolisers of CYP2D6 substrates. Palonosetron does not inhibit or induce cytochrome P450 isoenzymes at clinically relevant concentrations.
Metabolism: Solution for Injection: Palonosetron is eliminated by multiple routes with approximately 50% metabolized to form two primary metabolites: N-oxide-palonosetron and 6-S-hydroxy-palonosetron. These metabolites each have less than 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: Following administration of a single oral 750 micrograms dose of [¹⁴C]-palonosetron to six healthy subjects, 85% to 93% of the total radioactivity was excreted in urine, and 5% to 8% was eliminated in feces. The amount of unchanged palonosetron excreted in the urine represented approximately 40% of the administered dose. In healthy subjects given palonosetron capsules 500 micrograms, the terminal elimination half-life (t½) of palonosetron was 37±12 hours (mean±SD), and in cancer patients, t½ was 48±19 hours. After a single-dose of approximately 0.75 mg intravenous palonosetron, 8 the total body clearance of palonosetron in healthy subjects was 160±35 mL/h/kg (mean±SD) and renal clearance was 66.5±18.2 mL/h/kg.
Solution for Injection: After a single intravenous dose of 10 mcg/kg [¹⁴C]-palonosetron, approximately 80% of the dose was recovered within 144 hours in the urine with palonosetron representing approximately 40% of the administered dose. In healthy subjects, the total body clearance of palonosetron was 0.160±0.035 L/h/kg and renal clearance was 0.067±0.018 L/h/kg. Mean terminal elimination half-life is approximately 40 hours.
Capsule: Pharmacokinetics in special populations: Elderly people: Age does not affect the pharmacokinetics of palonosetron. No dose adjustment is necessary in elderly patients.
Gender: Gender does not affect the pharmacokinetics of palonosetron. No dose adjustment is necessary based on gender.
Pediatric patients: Single-dose i.v. PALONOSETRON HCl (ALOXI) pharmacokinetic data was obtained from a subset of paediatric cancer patients (n=280) that received 10 μg/kg or 20 μg/kg. When the dose was increased from 10 μg/kg to 20 μg/kg a dose-proportional increase in mean AUC was observed. Following single dose intravenous infusion of PALONOSETRON HCl (ALOXI) 20 μg/kg, peak plasma concentrations (C_Τ) reported at the end of the 15 minute infusion were highly variable in all age groups and tended to be lower in patients <6 years than in older paediatric patients. Median half-life was 29.5 hours in overall age groups and ranged from about 20 to 30 hours across age groups after administration of 20 μg/kg.
The total body clearance (L/h/kg) in patients 12 to 17 years old was similar to that in healthy adults. There are no apparent differences in volume of distribution when expressed as L/kg. (See Table 5.)

Click on icon to see table/diagram/image

250 mcg/5 mL: Pediatric Patients: Single-dose I.V. PALONOSETRON HCl (ALOXI) 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 intravenous infusion of PALONOSETRON HCl (ALOXI) 20 mcg/kg, peak plasma concentrations (CT) reported at the end of the 15 minute infusion were highly variable in all age groups and tended to be lower in patients <6 years than in older patients. Median half-life was 29.5 hours in overall age groups and ranged from about 20 to 30 hours across age groups after administration of 20 mcg/kg.
The total body clearance (L/h/kg) in patients 12 to 17 years old was similar to that in healthy adults. There are no apparent differences in volume of distribution when expressed as L/kg. (See Table 6.)

Click on icon to see table/diagram/image

Capsule: Renal impairment: Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. Severe renal impairment reduces renal clearance, however total body clearance in these patients is similar to healthy subjects. No dose adjustment is necessary in patients with renal insufficiency. No pharmacokinetic data in hemodialysis patients are available.
Hepatic impairment: Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the healthy subjects. While the terminal elimination half-life and mean systemic exposure of palonosetron is increased in the subjects with severe hepatic impairment, this does not warrant dose reduction.
75 mcg/1.5 mL: See Precautions and Use in Pregnancy & Lactation.
Toxicology: Preclinical Safety Data: Capsule: Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
Non-clinical studies indicate that palonosetron, only at very high concentrations, may block ion channels involved in ventricular de- and re-polarization and prolong action potential duration.
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development. Only limited data from animal studies are available regarding the placental transfer (see Use in Pregnancy & Lactation).
Palonosetron is not mutagenic. High doses of palonosetron (each dose causing at least 15 times the human therapeutic exposure) applied daily for two years caused an increased rate of liver tumours, endocrine neoplasms (in thyroid, pituitary, pancreas, adrenal medulla) and skin tumors in rats but not in mice.
The underlying mechanisms are not fully understood, but because of the high doses employed and since PALONOSETRON HCl (ALOXI) is intended for single application in humans, these findings are not considered relevant for clinical use.
Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Solution for Injection: 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 to 289 times the human exposure (AUC=29.8 h·mcg/mL) at the recommended intravenous dose of 250 mcg. 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 DNA 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 1894 times the recommended human intravenous dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.

Capsule: PALONOSETRON HCl (ALOXI) is indicated in adults for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy.
Solution for Injection: 250 mcg/5 mL: Chemotherapy-Induced Nausea and Vomiting in Adults: PALONOSETRON HCl (ALOXI) 50 mcg/mL (250 mcg/5 mL) is indicated for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy.
Chemotherapy-Induced Nausea and Vomiting in Pediatric Patients Aged 1 month to Less than 17 Years: PALONOSETRON HCl (ALOXI) 50 mcg/mL (250 mcg/5 mL) is indicated for prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy.
75 mcg/1.5 mL: PALONOSETRON HCl (ALOXI) 50 mcg/mL (75 mcg/1.5 mL) is indicated for prevention of postoperative nausea and vomiting (PONV) for up to 72 hours following surgery.
As with other antiemetics, routine prophylaxis is not recommended in patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. In patients where nausea and vomiting must be avoided during the postoperative period, PALONOSETRON HCl (ALOXI) is recommended even where the incidence of postoperative nausea and/or vomiting is low.

Capsule: Adults: 500 micrograms administered orally approximately one hour before the start of chemotherapy.
250 mcg/5 mL: Recommended Dosing: See Table 7.

Click on icon to see table/diagram/image

75 mcg/1.5 mL: Recommended Dosing: Adults Single 75 mcg I.V. dose administered over 10 seconds immediately before the induction of anesthesia.
Elderly population: No dose adjustment is necessary for the elderly.
Pediatric population: The safety and efficacy of PALONOSETRON HCl (ALOXI) in children have not been established. Currently available data are described in Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions, but no recommendation on posology can be made. Hepatic impairment No dose adjustment is necessary for patients with impaired hepatic function.
Renal impairment: No dose adjustment is necessary for patients with impaired renal function.
No data are available for patients with end stage renal disease undergoing hemodialysis.
Hepatic impairment: No dose adjustment is necessary for patients with impaired hepatic function.
Administration: Capsule: For oral use. PALONOSETRON HCl (ALOXI) can be taken with or without food.
Instructions for I.V. Administration: PALONOSETRON HCl (ALOXI) is supplied ready for intravenous administration at a concentration of 0.05 mg/mL (50 mcg/mL). PALONOSETRON HCl (ALOXI) should not be mixed with other drugs. The infusion line should be flushed with normal saline before and after administration of PALONOSETRON HCl (ALOXI). Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit.

Capsule: No case of overdose has been reported.
Doses of up to 6 mg have been used in clinical trials. The highest dose group showed a similar incidence of adverse reactions compared to the other dose groups and no dose response effects were observed. In the unlikely event of overdose with PALONOSETRON HCl (ALOXI), this should be managed with supportive care. Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for PALONOSETRON HCl (ALOXI) overdose.
Solution for Injection: There is no known antidote to PALONOSETRON HCl (ALOXI). Overdose should be managed with supportive care.
Fifty 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 250 mcg. 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 overdose. A single intravenous 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.

PALONOSETRON HCl (ALOXI) is contraindicated in patients known to have hypersensitivity to the drug or any of its components (see Adverse Reactions).

Capsule: As palonosetron may increase large bowel transit time, patients with a history of constipation or signs of subacute intestinal obstruction should be monitored following administration. Two cases of constipation with fecal impaction requiring hospitalization have been reported in association with palonosetron 750 micrograms.
At all dose levels tested, palonosetron did not induce clinically relevant prolongation of the QT corrected (QTc) interval. A specific thorough QT/QTc study was conducted in healthy volunteers for definitive data demonstrating the effect of palonosetron on QT/QTc (see Pharmacology: Pharmacodynamics under Actions).
However, as for other 5-HT antagonists, caution should be exercised in the use of palonosetron in patients who have or are likely to develop prolongation of the QT interval. These conditions include patients with a personal or family history of QT prolongation, electrolyte abnormalities, congestive heart failure, bradyarrhythmias, conduction disturbances and in patients taking anti-arrhythmic agents or other medicinal products that lead to QT prolongation or electrolyte abnormalities. Hypokalemia and hypomagnesemia should be corrected prior to 5-HT₃-antagonist administration.
There have been reports of serotonin syndrome with the use of 5-HT₃ antagonists either alone or in combination with other serotonergic drugs (including selective serotonin reuptake inhibitors (SSRI) and serotonin noradrenaline reuptake inhibitors (SNRIs). Appropriate observation of patients for serotonin syndrome-like symptoms is advised.
PALONOSETRON HCl (ALOXI) should not be used to prevent or treat nausea and vomiting in the days following chemotherapy if not associated with another chemotherapy administration.
PALONOSETRON HCl (ALOXI) contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicinal product. PALONOSETRON HCl (ALOXI) capsules may also contain a trace of lecithin derived from soya. Therefore, patients with known hypersensitivity to peanut or soya, should be monitored closely for signs of an allergic reaction.
Hypersensitivity: Hypersensitivity reactions, including anaphylaxis, have been reported with or without known 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 (e.g., 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 (e.g. agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of PALONOSETRON HCl (ALOXI) and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue PALONOSETRON HCl (ALOXI) and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if PALONOSETRON HCl (ALOXI) is used concomitantly with other serotonergic drugs (see Interactions).
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.
Race: Intravenous palonosetron pharmacokinetics was characterized in twenty-four 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.
Effects on ability to drive and use machines: Capsule: No studies on the effects on the ability to drive and use machines have been performed. Since palonosetron may induce dizziness, somnolence or fatigue, patients should be cautioned when driving or operating machines.
Pediatric Use: 250 mcg/5 mL: Chemotherapy-Induced Nausea and Vomiting: Safety and effectiveness of PALONOSETRON HCl (ALOXI) have been established in pediatric patients aged 1 month to less than 17 years for the prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy. Use is supported by a clinical trial where 165 pediatric patients aged 2 months to <17 years were randomized to receive a single dose of palonosetron 20 mcg/kg (maximum 1.5 mg) administered as an intravenous infusion 30 minutes prior to the start of emetogenic chemotherapy (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions). 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 PALONOSETRON HCl (ALOXI) in neonates (less than 1 month of age) have not been established.
75 mcg/1.5 mL: Postoperative Nausea and Vomiting Studies: Safety and efficacy have not been established in pediatric patients for prevention of postoperative nausea and vomiting. Two pediatric trials were performed.
Pediatric Study 1, a dose finding study was conducted to compare two doses of palonosetron, 1 mcg/kg (max 75 mcg) versus 3 mcg/kg (max 250 mcg). 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 I.V. palonosetron (1 mcg/kg, max 75 mcg) versus I.V. 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 hours postoperatively was achieved in 78.2% of patients in the palonosetron group and 82.7% in the ondansetron group. Given the prespecified 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 8 under Adverse Reactions.)
Geriatric Use: Solution for Injection: Population pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients ≥65 years of age and younger patients (18 to 64 years). Of the 1374 adult cancer patients in clinical studies of palonosetron, 316 (23%) were ≥65 years old, while 71 (5%) were ≥75 years old. 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 is required for geriatric patients.
Of the 1520 adult patients in PALONOSETRON HCl (ALOXI) PONV clinical studies, 73 (5%) were ≥65 years old. 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, PALONOSETRON HCl (ALOXI) efficacy in geriatric patients has not been adequately evaluated.

Pregnancy: Capsule: For Palonosetron, no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development. Only limited data from animal studies are available regarding the placental transfer (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). There is no experience of palonosetron in human pregnancy so palonosetron should not be used in pregnant women unless it is considered essential by the physician.
Solution for Injection: Pregnancy Category B.
Risk Summary: Adequate and well controlled studies with PALONOSETRON HCl (ALOXI) have not been conducted in pregnant women. In animal reproduction studies, no effects on embryo-fetal development were observed with the administration of oral palonosetron during the period of organogenesis at doses up to 1894 and 3789 times the recommended human intravenous dose in rats and rabbits, respectively. Because animal reproduction studies are not always predictive of human response, PALONOSETRON HCl (ALOXI) should be used during pregnancy only if clearly needed.
Animal Data: In animal studies, no effects on embryo-fetal development were observed in pregnant rats given oral palonosetron at doses up to 60 mg/kg/day (1894 times the recommended human intravenous dose based on body surface area) or pregnant rabbits given oral doses up to 60 mg/kg/day (3789 times the recommended human intravenous dose based on body surface area) during the period of organogenesis.
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.
Breast-feeding: Capsule: As there are no data concerning palonosetron excretion in breast milk, breast-feeding should be discontinued during therapy.
Nursing Mothers: Solution for Injection: It is not known whether PALONOSETRON HCl (ALOXI) is present 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 (see Pharmacology: Toxicology: Non-clinical Toxicology under Actions), 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.
Fertility: Capsule: There are no data concerning the effect of palonosetron on fertility.

Capsule: In clinical studies at a dose of 500 micrograms (total 161 patients) the most frequently observed adverse reaction, at least possibly related to PALONOSETRON HCl (ALOXI), was headache (3.7 %).
In the clinical studies the following adverse reactions (ARs) were observed as possibly or probably related to PALONOSETRON HCl (ALOXI). These were classified as common (≥1/100 to <1/10) or uncommon (≥1/1,000 to <1/100). (See Table 8.)

Click on icon to see table/diagram/image

In post marketing very rare cases (<1/10,000) of hypersensitivity reactions occurred with palonosetron solution for injection for intravenous use.
Solution for Injection: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
250 mcg/5 mL: Chemotherapy-Induced Nausea and Vomiting: Adults: In clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic chemotherapy, 1374 adult patients received palonosetron. Adverse reactions were similar in frequency and severity with PALONOSETRON HCl (ALOXI) and ondansetron or dolasetron. Following is a listing of all adverse reactions reported by ≥2% of patients in these trials (see Table 9).

Click on icon to see table/diagram/image

In other studies, 2 subjects experienced severe constipation following a single palonosetron dose of approximately 750 mcg, three times the recommended dose. One patient received a 10 mcg/kg oral dose in a post-operative nausea and vomiting study and one healthy subject received a 750 mcg I.V. 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 PALONOSETRON HCl (ALOXI) to adult patients receiving concomitant cancer chemotherapy: Cardiovascular: 1%: Non-sustained tachycardia, bradycardia, hypotension. <1%: hypertension, myocardial ischemia, extra systoles, sinus tachycardia, sinus arrhythmia, supraventricular extra systoles and QT prolongation. In many cases, the relationship to PALONOSETRON HCl (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 AST and/or ALT and bilirubin. These changes occurred predominantly in patients receiving highly emetogenic chemotherapy.
Metabolic: 1%: Hyperkalemia. <1%: Electrolyte fluctuations, hyperglycemia, metabolic acidosis, glycosuria, appetite decrease, 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, vein distention.
Pediatrics: In a pediatric clinical trial for the prevention of chemotherapy-induced nausea and vomiting 163 cancer patients received a single 20 mcg/kg (maximum 1.5 mg) intravenous infusion of palonosetron 30 minutes before beginning the first cycle of emetogenic chemotherapy. Patients had a mean age of 8.4 years (range 2 months to 16.9 years) and were 46% male; and 93% white.
The following adverse reactions were reported for PALONOSETRON HCl (ALOXI): 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.
75 mcg/1.5 mL: Postoperative Nausea and Vomiting: The adverse reactions cited in Table 10 were reported in ≥2% of adults receiving I.V. PALONOSETRON HCl (ALOXI) 75 mcg immediately before induction of anesthesia in one phase 2 and two phase 3 randomized placebo-controlled trials. Rates of events between palonosetron and placebo groups were similar. Some events are known to be associated with, or may be exacerbated by concomitant perioperative and intraoperative medications administered in this surgical population. Please refer to Pharmacology: Pharmacodynamics under Actions, thorough QT/QTc study results, for definitive data demonstrating the lack of palonosetron effect on QT/QTc. (See Table 10.)

Click on icon to see table/diagram/image

In these clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of PALONOSETRON HCl (ALOXI) to adult patients receiving concomitant perioperative and intraoperative medications including those associated with anesthesia: Cardiovascular: 1%: Electrocardiogram QTc prolongation, sinus bradycardia, tachycardia. <1%: Blood pressure decreased, hypotension, hypertension, arrhythmia, ventricular extrasystoles, generalized edema; ECG T wave amplitude decreased, platelet count decreased. 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%: Hepatic enzyme increased.
Metabolic: <1%: Hypokalemia, anorexia.
Nervous System: <1%: Dizziness.
Respiratory: <1%: Hypoventilation, laryngospasm.
Urinary System: 1%: Urinary retention.
Postmarketing Experience: Solution for Injection: The following adverse reactions have been identified during post approval use of PALONOSETRON HCl (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 including anaphylaxis and anaphylactic shock and injection site reactions (burning, induration, discomfort and pain) were reported from post marketing experience of PALONOSETRON HCl (ALOXI) 250 mcg in the prevention of chemotherapy-induced nausea and vomiting.

Capsule: Palonosetron is mainly metabolised by CYP2D6, with minor contribution by CYP3A4 and CYP1A2 isoenzymes. Based on in vitro studies, palonosetron does not inhibit or induce cytochrome P450 isoenzyme at clinically relevant concentrations.
Chemotherapeutic medicinal products: In preclinical studies, palonosetron did not inhibit the antitumour activity of the five chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C).
Metoclopramide: In a clinical study, no significant pharmacokinetic interaction was shown between a single intravenous dose of palonosetron and steady state concentration of oral metoclopramide, which is a CYP2D6 inhibitor.
CYP2D6 inducers and inhibitors: In a population pharmacokinetic analysis, it has been shown that there was no significant effect on palonosetron clearance when co-administered with CYP2D6 inducers (dexamethasone and rifampicin) and inhibitors (including amiodarone, celecoxib, chlorpromazine, cimetidine, doxorubicin, fluoxetine, haloperidol, paroxetine, quinidine, ranitidine, ritonavir, sertraline or terbinafine).
Corticosteroids: Palonosetron has been administered safely with corticosteroids.
Serotonergic Drugs (e.g. SSRIs and SNRIs): There have been reports of serotonin syndrome following concomitant use of 5-HT₃ antagonists and other serotonergic drugs (including SSRIs and SNRIs).
Other medicinal products: Palonosetron has been administered safely with analgesics, antiemetic/antinauseants, antispasmodics and anticholinergic medicinal products.
Solution for Injection: 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 selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) (see Precautions).
Coadministration of 250 mcg I.V. palonosetron and 20 mg I.V. dexamethasone in healthy subjects revealed no pharmacokinetic drug-interactions between palonosetron and dexamethasone. In an interaction study in healthy subjects where palonosetron 250 mcg (I.V. 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 I.V. palonosetron (750 mcg) and steady state oral metoclopramide (10 mg four times daily) demonstrated no significant pharmacokinetic interaction.
In controlled clinical trials, PALONOSETRON HCl (ALOXI) injection has been safely administered with corticosteroids, analgesics, antiemetics/antinauseants, antispasmodics and anticholinergic agents.
Palonosetron did not inhibit the antitumor activity of the five chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C) in murine tumor models.

Special precautions for disposal: Solution for Injection: Single use only, any unused solution should be discarded.
Any unused product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: Capsule: Not applicable.

Store at temperatures not exceeding 30°C.
Shelf-Life: Capsule: 4 years.
Solution for Injection: 60 months.
Upon opening of the vial, use immediately and discard any unused solution.

Solution for Injection: Patients should be advised to report to the physician all of the medical conditions, any pain, redness, or swelling in and around the infusion site (see Adverse Reactions).
Advise patients of the possibility of serotonin syndrome, especially with concomitant use of PALONOSETRON HCl (ALOXI) and another serotonergic agent such as medications to treat depression and migraines. Advise patients to seek immediate medical attention if the following symptoms occur: Changes in mental status, autonomic instability, neuromuscular symptoms with or without gastrointestinal symptoms (see Precautions).

Antiemetics

A04AA05 - palonosetron ; Belongs to the class of serotonin (5HT3) antagonists. Used for the prevention of nausea and vomiting.

Rx

Softgel cap 500 mcg (light beige, opaque, oval, imprinted with black logo "AIO", filled with a clear yellowish soln) x 1's, 5's. Soln for inj (vial, white to off-white crystalline powd, sterile, clear, colorless, non-pyrogenic, isotonic, buffered soln) 50 mcg/mL x 5 mL x 1's. 75 mcg/1.5 mL x 5's.