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Palonosetron Hydrochloride

Class: 5-HT3 Receptor Antagonists
VA Class: GA700
Chemical Name: (3aS)-2,3,3a,4,5,6-Hexahydro-2-[(3S)-3-quinuclidinyl]-1H-benz[de]isoquinolin-1-one monohydrochloride
Molecular Formula: C19H24N2O•HCl
CAS Number: 135729-62-3
Brands: Aloxi

Introduction

Antiemetic; selective inhibitor of type 3 serotonergic (5-HT3) receptors.1 17

Uses for Palonosetron Hydrochloride

Cancer Chemotherapy-induced Nausea and Vomiting

Prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy.1

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Prevention of acute nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy.1

Palonosetron Hydrochloride Dosage and Administration

Administration

IV Administration

Administer by direct IV injection.1

Do not mix with other drugs; flush tubing with 0.9% sodium chloride injection before and after administration.1

Rate of Administration

Inject over a period of 30 seconds.1

Dosage

Available as palonosetron hydrochloride; dosage expressed in terms of palonosetron.1

Adults

Cancer Chemotherapy-induced Nausea and Vomiting
IV

0.25 mg as a single dose administered approximately 30 minutes before administration of emetogenic chemotherapy.1

An additional dose within a 7-day period is not recommended; safety and efficacy of repeat doses (e.g., on consecutive or alternate days) not established.1

Prescribing Limits

Adults

Cancer Chemotherapy-induced Nausea and Vomiting
IV

Maximum of one 0.25-mg dose within 7 days.1

Special Populations

Hepatic Impairment

No dosage adjustments required.1

Renal Impairment

No dosage adjustments required.1

Geriatric Patients

No dosage adjustments required.1

Cautions for Palonosetron Hydrochloride

Contraindications

  • Known hypersensitivity to palonosetron or any ingredient in the formulation.1

Warnings/Precautions

Sensitivity Reactions

Sensitivity reactions may occur in patients with history of hypersensitivity to other 5-HT3 receptor antagonists.1

General Precautions

Cardiovascular Effects

Prolongation of QT interval reported.1

Use with caution in patients who have or may develop prolongation of cardiac conduction intervals (particularly QTc), including those with congenital QT syndrome, those with uncorrected hypokalemia or hypomagnesemia, patients receiving diuretics that may induce electrolyte abnormalities, patients receiving antiarrhythmic agents or other drugs that alter cardiac conduction (e.g., prolong QT interval), and those receiving cumulative high-dose anthracycline therapy.1

Specific Populations

Pregnancy

Category B.1

Lactation

Not known whether palonosetron is distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1

Common Adverse Effects

Headache, constipation.1

Interactions for Palonosetron Hydrochloride

Approximately 50% metabolized, principally by CYP2D6 and to a lesser extent by CYP3A and CYP1A2;1 however, pharmacokinetics are not substantially different between poor and extensive CYP2D6 substrate metabolizers.1

Does not inhibit activity of isoenzymes 1A2, 2A6, 2B6, 2C9, 2D6, 2E1, or 3A4/5; effect on isoenzyme 2C19 activity undetermined.1 Does not induce activity of isoenzymes 1A2, 2D6, or 3A4/5.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Clinically important pharmacokinetic interactions are unlikely.1

Drugs that Prolong QT Interval

Possible additive effect of QT-interval prolongation.1 Use concomitantly with caution.1

Specific Drugs

Palonosetron has been administered safely with analgesics, anticholinergic agents, antiemetics, antispasmodics, and corticosteroids in clinical studies.1

Drug

Interaction

Comments

Anthracyclines (e.g., doxorubicin)

Potential QTc interval prolongation with cumulative high-dose anthracycline therapy1

Antineoplastic activity of doxorubicin not inhibited in animal tumor models1

Use with caution1

Antiarrhythmics

Possible additive effect of QT-interval prolongation1

Use with caution1

Cisplatin

Antineoplastic activity not inhibited in animal tumor models1

Cyclophosphamide

Antineoplastic activity not inhibited in animal tumor models1

Cytarabine

Antineoplastic activity not inhibited in animal tumor models1

Diuretics

May induce electrolyte abnormalities and increase risk of QTc interval prolongation1

Use with caution1

Metoclopramide

Pharmacokinetic interaction unlikely1

Mitomycin

Antineoplastic activity not inhibited in animal tumor models1

Palonosetron Hydrochloride Pharmacokinetics

Distribution

Plasma Protein Binding

Approximately 62%.1

Elimination

Metabolism

Approximately 50% metabolized (principally by CYP2D6 and to a lesser extent by CYP3A and CYP1A2) to 2 metabolites with <1% of the 5-HT3 receptor inhibitor activity of palonosetron.1 However, pharmacokinetics are not substantially different between poor and extensive CYP2D6 substrate metabolizers.1

Elimination Route

Eliminated principally in urine (80% in 144 hours, 40% as palonosetron).1

Half-life

Approximately 40 hours.1

Stability

Storage

Parenteral

Injection

20–25°C (may be exposed to 15–30°C).1 Protect from light; do not freeze.1

Actions

  • Antiemetic activity for acute nausea and vomiting appears to be mediated via inhibition of serotonin activity both centrally (in area postrema and chemoreceptor trigger zone) and peripherally (in GI tract).2 3 4 5 6 8 11 18 19 20

  • Alternative mechanisms to peripheral and CNS stimulation by serotonin appear to be responsible for delayed nausea and vomiting.2 3 5 6 7 8 9 10 11 12 13 14 15 16 Risk of delayed nausea and vomiting may be decreased by effective prevention of acute nausea and vomiting in the same chemotherapy cycle.13 20 Palonosetron’s potency and long plasma half-life may contribute to its efficacy in delayed nausea and vomiting.7 11 17 21

Advice to Patients

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 26

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, especially other drugs that may affect the QT interval (e.g., antiarrhythmic agents, diuretics, anthracyclines).1 26

  • Importance of informing clinician of any concomitant illnesses (e.g., cardiac conditions, electrolyte disturbances).26

  • Importance of informing patients of other important precautionary information.1 26 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Palonosetron Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for IV use

0.05 mg (of palonosetron) per mL

Aloxi

MGI Pharma

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Aloxi 0.25MG/5ML Solution (EISAI): 5/$407.00 or 15/$1,116.03

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions May 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. MGI Pharma. Aloxi (palonosetron hydrochloride) injection prescribing information. Bloomington, MN; 2006 Jan.

2. McKeage MJ. Comparative adverse effect profile of platinum drugs. Drug Saf. 1995; 13:228-44. [PubMed 8573296]

3. Cubeddu LX, Hoffmann IS. Participation of serotonin on early and delayed emesis induced by initial and subsequent cycles of cisplatinum-based chemotherapy: effects of antiemetics. J Clin Pharmacol. 1993; 33:691-7. [IDIS 319277] [PubMed 7691898]

4. Hesketh PJ, Gandara DR. Serotonin antagonists: a new class of antiemetic agents. J Natl Cancer Inst. 1991; 83:613-20. [PubMed 1850806]

5. Gralla RJ. Adverse effects of treatment: antiemetic therapy. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 4th ed. Philadelphia: J.B. Lippincott Company; 1993:2338-48.

6. Plosker GL, Goa KL. Granisetron: a review of its pharmacological properties and therapeutic use as an antiemetic. Drugs. 1991; 42:805-24. [PubMed 1723376]

7. Di Vall MV, Cersosimo RJ. Palonosetron. A novel 5-HT3 receptor antagonist for chemotherapy-associated nausea and vomiting. Formulary. 2003; 38:414-30.

8. Barger AM, Clark-Snow RA. Adverse effects of treatment. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: principles & practice of oncology. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001: 2869-80

9. De Mulder PHM, Seynaeve C, Vermorken JB et al. Ondansetron compared with high-dose metoclopramide in prophylaxis of acute and delayed cisplatin-induced nausea and vomiting: a multicenter, randomized, double-blind, crossover study. Ann Intern Med. 1990; 113:834-40. [IDIS 274419] [PubMed 2146911]

10. Gebbia V, Cannata G, Testa A et al. Ondansetron versus granisetron in the prevention of chemotherapy- induced nausea and vomiting. Results of a prospective randomized trial. Cancer. 1994; 74:1945-52. [IDIS 336138] [PubMed 8082100]

11. , Donnerer J, Beubler E. 5-HT3 receptor antgaonists in antiemetic therapy. In: Donnerer J (ed.): Antiemetic therapy. Basel:Karger; 2003: 22-32.

12. Kris MG, Pisters KM, Hinkley L. Delayed emesis following anticancer chemotherapy. Support Care Cancer. 1994; 2:297- 300. [PubMed 8000726]

13. Gregory RE, Ettinger DS. 5-HT3 receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting. Drugs. 1998; 55: 173-89. [PubMed 9506240]

14. Merck. Emend (aprepitant) capsules prescribing information. Whitehouse Station, NJ; 2003 Mar.

15. Sorbera LA, Castaner J, Bayes M at al. Aprepitant and L758298. Drugs Fut. 2002; 27:211-22.

16. Merck. Emend (aprepitant) product information form for the American Hospital Formulary Service. 2003.

17. Eglen RM, Lee CH, Smith WL at al. Pharmacological characterization of RS 25259-17, a novel and selective 5-HT3 receptor antagonist, in vivo. Br J Pharmacol. 1995; 114:860-6 [PubMed 7773547]

18. Perez EA. Review of the preclinical pharmacology and comparative efficacy of 5-Hydroxytryptamine-3 receptor antagonists for chemotherapy-induced emesis. J Clin Oncol. 1995; 13:1036-43. [IDIS 344879] [PubMed 7707101]

19. Lindley C, Blower P. Oral serotonin type 3-recpetor antagonists for prevention of chemotherapy-induced emesis. Am J Health-Syst Pharm. 2000; 57:1685-97. [IDIS 452881] [PubMed 11006796]

20. Schnell FM. Chemotherapy-induced nausea and vomiting: the importance of acute antiemetic control. The Oncologist. 2003; 8:187-98. [PubMed 12697943]

21. MGI Pharma. Aloxi (palonosetron hydrochloride) injection. Overview. Bloomington, MN; [2003 Aug 28]. From MGI Pharma web site (http://www.mgipharma.com).

22. Wong EH, Clark R, Leung E et al. The interaction of RS-25259-197, a potent and selective antagonist, with 5-HT3 receptos. Br J Pharmacol. 1995; 114:851-9. [PubMed 7773546]

23. Clark RD, Miller AB, Berger J et al. 2 (Quinuclidin-3-yl) pyrido [4,3-b]indol-1-ones and isoquinolin-1-ones. Potent conformationally restricted 5-HT3 receptor antagonists. J Med Chem. 1993; 36:2645-57. [PubMed 8410977]

24. Gralla R, Lichinitster 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 andansetron. Ann Oncol. 2003; 14:570-7. [PubMed 12649103]

25. MGI Pharma, Bloomington, MN: Personal communication.

26. MGI Pharma. Aloxi (palonosetron hydrochloride) patient information. Bloomington, MN. Undated. Available at: . Accessed 2006 Dec 6.

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