April 28, 2016
Recommended Topic Related To:

Aloxi

"Oct. 24, 2012 -- It is not a desired discussion for the doctor, and certainly not for the patient. But an overwhelming majority of people with advanced cancer are under the impression that the chemotherapy they are receiving will cure their disea"...

A A A

Aloxi




CLINICAL PHARMACOLOGY

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.

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.

Pharmacodynamics

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 0.25, 0.75, 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.

Pharmacokinetics

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 (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 I.V. dose of palonosetron at 3 mcg/kg (or 0.21 mg/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 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 I.V. 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 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.

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 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

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.

Specific Populations

Pediatric Patients

Single-dose I.V. 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 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.

Table 3: Pharmacokinetics Parameters in Pediatric Cancer Patients Following Intravenous Infusion of ALOXI at 20 mcg/kg over 15 min

PK Parameter a Pediatric Age Group
< 2 y
N=12
2 to < 6 y
N=42
6 to < 12 y
N=38
12 to < 17 y
N=44
CT b, ng/L 9025 (197) 9414 (252) 16275 (203) 11831 (176)
    N=5 N=7 N=10
AUC0-∞, h•mcg/L   103.5 (40.4) 98.7 (47.7) 124.5 (19.1)
  N=6 N=14 N=13 N=19
Clearance c, L/h/kg 0.31 (34.7) 0.23 (51.3) 0.19 (46.8) 0.16 (27.8)
Vss c, L/kg 6.08 (36.5) 5.29 (57.8) 6.26 (40.0) 6.20 (29.0)
a Geometric Mean (CV) except for t½ which is median values.
b CT is the plasma palonosetron concentration at the end of the 15 minute infusion.
c Clearance and Vss calculated from 10 and 20 mcg/kg and are weight adjusted.

Clinical Studies

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 three Phase 3 trials and one 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 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. 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/m, cyclophosphamide < 1500 mg/m, doxorubicin > 25 mg/m, epirubicin, irinotecan, and methotrexate > 250 mg/m. 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 nave 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 < 0.1 mg to 6 mg fixed dose) in 161 chemotherapy-nave adult cancer patients receiving highly-emetogenic chemotherapy (either cisplatin ≥ 70 mg/m or cyclophosphamide > 1100 mg/m). Concomitant corticosteroids were not administered prophylactically. Analysis of data from this trial indicates that 0.25 mg 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. ALOXI with single-dose I.V. ondansetron (study 3) given 30 minutes prior to highly emetogenic chemotherapy including cisplatin ≥ 60 mg/m, cyclophosphamide > 1500 mg/m, and dacarbazine. Corticosteroids were co-administered prophylactically before chemotherapy in 67% of patients. Of the 667 patients, 51% were women, 60% White, and 59% nave to previous chemotherapy. The mean age was 52 years.

Efficacy Results

The antiemetic activity of ALOXI was evaluated during the acute phase (0-24 hours) [Table 4], delayed phase (24-120 hours) [Table 5], and overall phase (0-120 hours) [Table 6] post-chemotherapy in Phase 3 trials.

Table 4: Prevention of Acute Nausea and Vomiting (0-24 hours): Complete Response Rates

Chemotherapy Study Treatment Group Na % with Complete Response p-value b 97.5% Confidence Interval
ALOXI minus Comparator c
Moderately Emetogenic 1 ALOXI 0.25 mg 189 81 0.009 ALOXI® (palonosetron HCl) Structural Formula Illustration
Ondansetron 32 mg I.V. 185 69
  2 ALOXI 0.25 mg 189 63 NS
Dolasetron 100 mg I.V. 191 53
Highly Emetogenic 3 ALOXI 0.25 mg 223 59 NS
Ondansetron 32 mg I.V. 221 57
a Intent-to-treat cohort
b 2-sided Fisher's exact test. Significance level at &apha;=0.025.
c These studies were designed to show non-inferiority. A lower bound greater than –15% demonstrates non-inferiority between ALOXI and comparator.

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.

Table 5: Prevention of Delayed Nausea and Vomiting (24-120 hours): Complete Response Rates

Chemotherapy Study Treatment Group Na % with Complete Response p-value b 97.5% Confidence Interval ALOXI minus Comparator c
Moderately Emetogenic 1 ALOXI 0.25 mg 189 74 < 0.001 ALOXI® (palonosetron HCl) Structural Formula Illustration
Ondansetron 32 mg I.V. 185 55
2 ALOXI 0.25 mg 189 54 0.004
Dolasetron 100 mg I.V. 191 39
a Intent-to-treat cohort
b 2-sided Fisher's exact test. Significance level at &apha;=0.025.
c These studies were designed to show non-inferiority. A lower bound greater than –15% demonstrates non-inferiority between ALOXI and comparator.

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.

Table 6: Prevention of Overall Nausea and Vomiting (0-120 hours): Complete Response Rates

Chemotherapy Study Treatment
Group
N a % with Complete Response p-value b 97.5% Confidence Interval ALOXI minus Comparator c
Moderately Emetogenic 1 ALOXI 0.25 mg 189 6950 < 0.001  
Ondansetron 32 mg I.V. 185 ALOXI® (palonosetron HCl) Structural Formula Illustration
2 ALOXI 0.25 mg 189 46 0.021
Dolasetron 100 mg I.V. 191 34
a Intent-to-treat cohort
b 2-sided Fisher's exact test. Significance level at &apha;=0.025.
c These studies were designed to show non-inferiority. A lower bound greater than –15% demonstrates non-inferiority between ALOXI and comparator.

These studies show that 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.

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 ALOXI 30 minutes prior to the start of emetogenic chemotherapy (followed by placebo infusions 4 and 8 hours after the dose of palonosetron) or 0.15 mg/kg of intravenous ondansetron 30 minutes prior to the start of emetogenic chemotherapy (followed by ondansetron 0.15 mg/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 7, intravenous ALOXI 20 mcg/kg (maximum 1.5 mg) demonstrated non-inferiority to the active comparator during the 0 to 24 hour time interval.

Table 7: Prevention of Acute Nausea and Vomiting (0-24 hours): Complete Response Rates

I.V. ALOXI 20 mcg/kg
(N=165)
I.V. Ondansetron 0.15 mg/kg x 3
(N=162)
Difference [97.5% Confidence Interval]*: I.V. ALOXI minus I.V. Ondansetron Comparator
59.4% 58.6% 0.36% [-11.7%, 12.4%]
* To adjust for multiplicity of treatment groups, a lower-bound of a 97.5% confidence interval was used to compare to -15%, the negative value of the non-inferiority margin.

In patients that received ALOXI at a lower dose than the recommended dose of 20 mcg/kg, non-inferiority criteria were not met.

Postoperative Nausea And Vomiting

In one 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 out-patient 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 post operative nausea and vomiting and/or motion sickness.

In Study 1 patients were randomized to receive palonosetron 0.025 mg, 0.050 mg or 0.075 mg 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.

Of the 138 patients treated with 0.075 mg palonosetron 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 to 74 years, with a mean age of 37.9 years. Three patients were greater than 65 years of age.

Co-primary efficacy measures were Complete Response (CR) defined as no emetic episode and no use of rescue medication in the 0-24 and in the 24-72 hours postoperatively.

Secondary efficacy endpoints included:

  • Complete Response (CR) 0-48 and 0-72 hours
  • 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 one of the three palonosetron doses were superior to placebo.

Results for Complete Response in Study 1 for 0.075 mg palonosetron versus placebo are described in the following table.

Table 8: Prevention of Postoperative Nausea and Vomiting: Complete Response (CR), Study 1, Palonosetron 0.075 mg Vs Placebo

Treatment n/N (%) Palonosetron Vs Placebo
Δ p-value*
Co-primary Endpoints
CR 0-24 hours
Palonosetron 59/138 (42.8%) 16.8% 0.004
Placebo 35/135 (25.9%)    
CR 24-72 hours
Palonosetron 67/138 (48.6%) 7.8% 0.188
Placebo 55/135 (40.7%)  
* To reach statistical significance for each co-primary endpoint, the required significance limit for the lowest p-value was p < 0.017.
Δ Difference (%): palonosetron 0.075 mg minus placebo

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 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 0.075 mg) 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.

Last reviewed on RxList: 3/14/2016
This monograph has been modified to include the generic and brand name in many instances.

Aloxi - User Reviews

Aloxi User Reviews

Now you can gain knowledge and insight about a drug treatment with Patient Discussions.

Here is a collection of user reviews for the medication Aloxi sorted by most helpful. Patient Discussions FAQs

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


Cancer

Get the latest treatment options.