Clinical UM Guideline

 

Subject: Palonosetron
Guideline #:  CG-DRUG-33 Publish Date:    12/27/2017
Status: Reviewed Last Review Date:    11/02/2017

Description

This document addresses palonosetron, an intravenous (IV) antiemetic that is a selective type 3 serotonin receptor antagonist. The drug blocks two pathways of serotonin release to help prevent nausea and vomiting in certain individuals. Not addressed in this document is the oral combination of netupitant-palonosetron (Akynzeo®).

Clinical Indications

Medically Necessary:

Palonosetron is considered medically necessary for adults as prevention of any of the following:

  1. Acute or delayed nausea and vomiting associated with initial and repeat courses of moderately or highly emetogenic cancer chemotherapy; or
  2. Postoperative nausea and vomiting (PONV) for up to 24 hours following surgery.          

Palonosetron is considered medically necessary for an infant, child, or adolescent (age 1 month to less than 17 years) as prevention of acute nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including highly emetogenic cancer chemotherapy.

Not Medically Necessary:

Palonosetron is considered not medically necessary for all other uses.

Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

HCPCS

 

J2469

Injection, palonosetron HCl, 25 mcg

 

 

ICD-10 Diagnosis

 

C00.0-C96.9

Malignant neoplasms

D00.00-D09.9

In situ neoplasms

K91.0

Vomiting following gastrointestinal surgery

R11.0-R11.2

Nausea and vomiting

T81.89XA-T81.89XS

Other complications of procedures, not elsewhere classified

Z51.11-Z51.12

Encounter for antineoplastic chemotherapy and immunotherapy

Z85.00-Z85.9

Personal history of malignant neoplasm

Discussion/General Information

Palonosetron is an intravenous serotonin 3 (5-HT3) receptor antagonist with a strong binding affinity for this receptor and little or no affinity for other receptors. The drug responds to high levels of serotonin released after chemotherapy and also binds to the serotonin receptors in the gastrointestinal tract, to keep the vomiting center in the brain from being stimulated. Palonosetron is available as a generic and also under the trade name of Aloxi.

Palonosetron was initially approved by the FDA in 2003 for adult use and subsequently in May 2014, pediatric indications were added for the branded Aloxi.

FDA approved indications for palonesetron (Aloxi) in adults are:

FDA approved indications for palonesetron (Aloxi) in infants and children age 1 month to less than 17 years are:

Currently available published literature demonstrates the safety and efficacy of palonosetron for adults and the pediatric population age 1 month to 17 years of age for the specific FDA approved indications. The safety and efficacy of palonosetron have not been established in the infants and children for prevention of postoperative nausea and vomiting.

Adults

Moderately Emetogenic Cancer Chemotherapy

In 2 randomized clinical trials (n=1132) (Eisenberg, 2003; Gralla, 2003), complete response (CR) rates defined as no emetic episodes and no rescue medication over 0 to 24 hours (acute phase) were 81% and 63% for palonosetron 0.25 mg IV compared with 69% for ondansetron 32 mg IV and 53% for dolasetron 100 mg IV. For prevention of delayed emesis (24 to 120 hours), complete response (CR) rates were 74% and 54% compared with 55% and 39%, respectively. Overall CR rates were 69% and 46% compared with 50% and 34%, respectively. About half of participants were chemotherapy-naive and only a few received concomitant prophylactic corticosteroids.

Highly Emetogenic Cancer Chemotherapy

In a phase III clinical trial, Aapro and colleagues (2006) evaluated the safety and efficacy of palonosetron in preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV) following highly emetogenic chemotherapy (HEC). Subjects were randomized to a single intravenous dose of palonosetron 0.25 mg or 0.75 mg, or ondansetron 32 mg prior to HEC. Dexamethasone pre-treatment (with stratification) was used at investigator discretion. The primary efficacy endpoint was the proportion of subjects with CR during the first 24 hours post-chemotherapy (acute phase). In the intent-to-treat analysis (n=667), palonosetron 0.25 mg and 0.75 mg were at least as effective as ondansetron in preventing acute CINV (59.2%, 65.5%, and 57.0% CR rates, respectively); CR rates were slightly higher with palonosetron than ondansetron during the delayed (24-120 h) and overall (0–120 h) phases. Two thirds of subjects (n=447) received concomitant dexamethasone. Subjects pre-treated with palonosetron 0.25 mg and dexamethasone had significantly higher CR rates than those treated with ondansetron plus dexamethasone during the delayed (42.0% versus 28.6%) and overall (40.7% versus 25.2%) phases. The authors concluded that single-dose palonosetron was as effective as ondansetron in preventing acute CINV following HEC. In addition, when dexamethasone was given as a pre-treatment, the effectiveness of palonosetron was significantly increased over ondansetron throughout the 5-day period after chemotherapy.

Prevention of Post-operative Nausea and Vomiting

Kovac and colleagues (2008) performed a multicenter, randomized, double-blind study to assess the efficacy and safety of different doses of palonosetron versus placebo on the incidence and severity of PONV for up to 72 hours postoperatively. A total of 544 female subjects undergoing either elective gynecological or breast surgery were stratified according to risk factors of non-smoking status and history of motion sickness or PONV. Subjects were randomized to receive palonosetron 0.025 mg (n=136), palonosetron 0.050 mg (n=137), palonosetron 0.075 mg (n=135) or placebo (n=136) immediately prior to the start of anesthesia. The primary efficacy end-point was CR (CR: no emesis and no use of rescue medications) evaluated at the 0–24 and 24–72 hour time intervals after surgery. CR rates for placebo and palonosetron 0.075 mg were 36% and 56% for 0–24 hours and 36% and 52% for the 0–72 hour postoperative period. Palonosetron 0.075 mg was associated with less intense nausea versus placebo during the 0–24 hour time interval and significantly delayed median time to emesis and treatment failure. In the safety population, most adverse events were either mild or moderate in intensity and no subject was withdrawn from the study due to adverse events. The proportion of subjects with treatment-related adverse events was similar among all treatments groups, including placebo.

Infants and Children

The FDA pediatric approval of palonosetron was based on a phase III, multi-center, international, randomized, double-blind, non-inferiority trial of children aged 0 to younger than 17 years scheduled to undergo moderately or highly emetogenic chemotherapy for the treatment of malignant disease (Kovacs, 2016). Between September 2011 and October 2012, a total of 502 subjects were randomly assigned to receive up to 4 cycles of 10 µg/kg palonosetron (n=169), or 20 µg/kg of palonosetron on day one (n=169), or three 150 µg/kg doses of ondansetron on day 1, scheduled 4 hours apart (n=164). Of these, 166, 165 and 162 subjects, respectively were included in the final efficacy analysis. Non-inferiority versus ondansetron was demonstrated for 20 µg/kg of palonosetron in the acute phase; however, non-inferiority versus ondansetron was not demonstrated for 10 µg/kg palonosetron in the acute phase. Complete response rates (no vomiting, retching, or rescue medication) were 59.4% for palonosetron and 58.6% for ondansetron. Approximately 55% of study participants received adjuvant corticosteroids; emetogenic chemotherapies included doxorubicin, cyclophosphamide, ifosfamide, cisplatin, dactinomycin, carboplatin, and daunorubicin. In the first treatment cycle, treatment-emergent adverse events occurred in 134 (80%) of 167 children who received 10 μg/kg palonosetron, 113 (69%) of 163 who received 20 μg/kg palonosetron, and 134 (82%) of 164 who received ondansetron. The most common drug-related treatment-emergent adverse events were nervous system disorders, mainly headaches.

Additional Considerations

The American Society of Clinical Oncology (ASCO) (2017) includes the following drugs as high and moderate emetic risk intravenous antineoplastic agents*:

*List may not be all inclusive.

The NCCN Practice Guidelines in Oncology for Antiemesis (V2.2017) recommends intravenous palonosetron as a preferred 5-HT3 antagonist for moderately emetogenic chemotherapy when the regimen includes dexamethasone but does not include a neurokinin-1 receptor antagonist (NK1 RA). When an NK1 RA is used in the regimen, a single dose of palonosetron has not shown better results than a single dose of a first-generation 5-HT3 antagonist.

The NCCN drug compendium (2017) issued 1 and 2A recommendations for the use of palonosetron in combination with dexamethasone prior to intravenous antineoplastic therapy that is moderate or highly emetogenic. For highly emetogenic chemotherapy, the NCCN recommends a 3-drug regimen that includes an NK1 RA.
NCCN includes the following combinations:

Contraindications, Warnings and Precautions, Drug Interactions, and Use in Specific Populations

The FDA prescribing information (2015) for palonosetron (Aloxi) includes the following contraindications, warnings and precautions, drug interactions, and use in specific populations:

Contraindications

Aloxi is contraindicated in individuals known to have hypersensitivity to the drug or any of its components.

Warnings and Precautions

Drug Interactions

The potential for clinically significant drug interactions with palonosetron appears to be low.

Use in Specific Populations

The NCCN states that “depending on the route of administration and dose, 5-HT3 RAs may increase the risk of developing prolongation of the QT interval of the ECG.” The warning is not included on the palonosetron drug inserts. Caution and monitoring should be used for individuals with QT prolongation risk factors.

Definitions

Emetogenic: Having the capacity to induce vomiting.

References

Peer Reviewed Publications:

  1. Aapro MS, Grunberg SM, Manikhas GM, et al. A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol. 2006; 17(9):1441-1449.
  2. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al.; 99-04 Palonosetron Study Group. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003; 98(11):2473-2482.
  3. Gralla R, Lichinitser M, Van Der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003; 14 (10):1570-1577.
  4. Kovac AL, Eberhart L, Kotarski J, et al; Palonosetron 04-07 Study Group. A randomized, double-blind study to evaluate the efficacy and safety of three different doses of palonosetron versus placebo in preventing postoperative nausea and vomiting over a 72-hour period. Anesth Analg. 2008; 107(2):439-444.
  5. Kovács G, Wachtel AE, Basharova EV, et al. Palonosetron versus ondansetron for prevention of chemotherapy-induced nausea and vomiting in paediatric patients with cancer receiving moderately or highly emetogenic chemotherapy: a randomised, phase 3, double-blind, double-dummy, non-inferiority study. Lancet Oncol. 2016; 17(3):332-344.
  6. Sepúlveda-Vildósola AC, Betanzos-Cabrera Y, Lastiri GG, et al. Palonosetron hydrochloride is an effective and safe option to prevent chemotherapy-induced nausea and vomiting in children. Arch Med Res. 2008; 39(6):601-606.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Aloxi® [Product Information]. Albuquerque, NM. OSO Biopharmaceuticals; December 2015. Available at: http://www.aloxi.com/docs/pdf/PI.pdf. Accessed on August 9, 2017.
  2. Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetic Use in Oncology: Updated Guideline Recommendations from ASCO. Am Soc Clin Oncol Educ Book. 2012:532-540.
  3. Hesketh PJ, Kris MG, Basch, E, et al. Antiemetics: American Society of Clinical Oncology Clinical Practice Update. J Clin Oncol. 2017 July 31 [Epub ahead of print]. Available at: http://ascopubs.org/doi/abs/10.1200/JCO.2017.74.4789. Accessed on August 9, 2017.
  4. National Comprehensive Cancer Network®. NCCN Antiemesis Guidelines. V2.2017. For additional information visit the NCCN website: http://www.nccn.org. Accessed on August 9, 2017.
  5. National Comprehensive Cancer Network®. NCCN Drugs & Biologic Compendium (electronic version). For additional information visit the NCCN website: http://www.nccn.org. Accessed on August 9, 2017.
  6. Palonosetron HCl. In: DrugPoints System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated June 22, 2017. Available at: http://www.micromedexsolutions.com. Accessed on August 9, 2017.
  7. Palonosetron HCL Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised March 8, 2017. Accessed on August 9, 2017.
  8. Palonosetron Hydrochloride Injection [Product Information]. Lenoir, NC. Exela Pharma Sciences LLC; August 2016. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207963s000lbl.pdf. Accessed on August 9, 2017.
History

Status

Date

Action

Reviewed

11/02/2017

Medical Policy & Technology Assessment Committee (MPTAC) review.

Reviewed

11/01/2017

Hematology/Oncology Subcommittee review. Discussion and Reference sections updated. The document header wording updated from “Current Effective Date” to “Publish Date.”

Revised

11/03/2016

MPTAC review.

Revised

11/02/2016

Hematology/Oncology Subcommittee review. Brand name removed from title of document and position statement. Discussion and Reference sections updated.

Revised

11/05/2015

MPTAC review.

Revised

11/04/2015

Hematology/Oncology Subcommittee review. Medically necessary and not medically necessary statements clarified with addition of brand name. Description, Discussion and Reference sections updated. Removed ICD-9 codes from Coding section.

New

11/13/2014

MPTAC review.

New

11/12/2014

Hematology/Oncology Subcommittee review. Initial document development.