Palonosetron: A novel 5-HT3 receptor antagonist for chemotherapy-associated nausea and vomiting

Chemotherapy-induced nausea and vomiting (CINV) is among the most feared adverse effects associated with cancer treatment.¹ The likelihood of patients experiencing this entity depends on both patient-related and treatment-related factors. Not all chemotherapeutic products induce equivalent amounts of CINV resulting in the formation of groups contingent on the frequency of CINV in patients receiving a product without antiemetic prophylaxis (Table 1).²

In the early 1990s the management of CINV was drastically changed with the development of 5-hydroxytryptamine (5-HT₃) receptor antagonists, which are
 now considered the most effective class of antiemetic agents.³ Combinations of 5-HT₃ antagonists and other antiemetics are standard recommendations for the prevention of CINV in patients receiving moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC).^2,4,5 This mixture of medications is hypothesized to combat multiple pathways and various mechanisms associated with development of CINV.

Four 5-HT₃ antagonists are now available in the United States: dolasetron, granisetron, ondansetron, and palonosetron. Palonosetron was granted approval from FDA in 2003 with an indication for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of MEC and HEC.⁶

Palonosetron has recently been recommended as the preferred agent among the 5-HT₃ antagonists for CINV prevention after single-day MEC by several guidelines.^2,4,5 Additionally, one guideline recommends palonosetron as the preferred 5-HT₃ antagonist for patients receiving single-day HEC.² This novel agent is believed to bind to an allosteric site in addition to the 5-HT₃ receptor causing a conformational change of the receptor resulting in possible receptor internalization.⁷ Palonosetron’s extended half-life of approximately 40 hours and higher binding affinity for the 5-HT₃ receptor in comparison to the remaining medications in its class also provides the medication with an added benefit of a one-time administration per cycle.⁶ This convenience of administration comes at a price, however; palonosetron can cost up to 50 times that of its counterparts (Table 2).⁸

Contrary to the aforementioned CINV guideline recommendations, investigators have reported that there appear to be insufficient data to support palonosetron’s preferred status. Following a review of current literature to support palonosetron over generic serotonin type 3 receptor antagonists for CINV, the authors identified several potential flaws in the studies utilized to garner the preferred status of palonosetron. The article stated that the antiemetic regimens examined did not reflect current US standard of care nor were they consistent with current guidelines recommendations.⁹ Studies comparing single-dose palonosetron versus a single dose of other 5-HT₃ antagonists for the treatment of delayed CINV were also identified as potentially flawed due to the variations in the previously mentioned half-lives of the drug class.⁹

Based on those investigations, further research is warranted to more effectively determine the validity of a superiority claim for palonosetron versus other 5-HT₃ antagonists. Although current guidelines may recommend palonosetron as a preferred agent, the shortcomings in current clinical evidence to support those claims should be carefully evaluated when making formulary decisions.

Dr. Moore is assistant professor, clinical and administrative sciences, Howard University College of Pharmacy, Washington, D.C.

Disclosure information: The author reports no financial disclosures as related to products discussed in this article.

Note: This table is an example of intravenous antineoplastic agents associated with emetic risk listed in NCCN Clinical Practice Guidelines in Oncology; it is not a complete list of all the agents associated with emetic risk in the NCCN Guidelines.

Source: Ref 2

Adapted, with permission, from NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Antiemesis V.2.2014. 

Note: Drug prices estimated from a third-party perspective, based on reimbursement rates from Centers for Medicare and Medicaid Services (CMS), 4th quarter 2013, computed at manufacturer’s average sales price (ASP) + 6%.

*Treatment cycle assumed for single-day agents.

**Transdermal cost not listed in CMS ASP drug pricing files.

Source: Ref 8

References

1. de Boer-Dennert M, de Wit R, Schmitz PI, et al. Patient perceptions of the side-effects of chemotherapy: the influence of 5HT₃ antagonists. Br J Cancer. 1997;76(8):1055–1061.

2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Antiemesis V.2.2014. National Comprehensive Cancer Network, Inc., 2014. Accessed May 12, 2014.

3. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med. 2008;358(23):2482–2494.

4. Basch E, Prestud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2011:29(31):4189–4198.

5. Roila F, Herrstedt J, Aapro M, et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol. 2010;21 (Suppl 5):v232–v243.

6. Aloxi (palonosetron) HCl injection [package insert]. Bloomington, MN: MGI Pharma, Inc.; 2004. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021372s005lbl.pdf. Accessed June 2, 2014.

7. Rojas C, Stathis M, Thomas AG, et al. Palonosetron exhibits unique molecular interactions with the 5-HT3 receptor. Anesth Analg. 2008;107(2):469–478.

8. Centers for Medicare and Medicaid Services. ASP drug pricing files. April 2014 update. www.cms.gov/Medicare/Medicare-Fee-for-Service-Part-B-Drugs/McrPartBDrugAvgSalesPrice/2014ASPFiles.html. Accessed May 30, 2014.

9. Yeh YC, Blouin GC, Reddy P. Evidence to support use of palonosetron over generic serotonin type 3-receptor antagonists for chemotherapy-induced nausea and vomiting. Am J Health-Syst Pharm. 2014;71(6):500–506.

Note: Drug prices estimated from a third-party perspective, based on reimbursement rates from Centers for Medicare and Medicaid Services (CMS), 4th quarter 2013, computed at manufacturer’s average sales price (ASP) + 6%.

*Treatment cycle assumed for single-day agents.

**Transdermal cost not listed in CMS ASP drug pricing files.

Source: Ref 8