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Leucovorin Calcium Injection

[01 December 2014]

Products Affected - Description

Leucovorin Calcium Lyophilized Powder for Injection, Fresenius Kabi
500 mg vial, 1 count (NDC 63323-0711-00)

Leucovorin Calcium Lyophilized Powder for Injection, West-Ward (formerly Bedford product)
50 mg vial, 10 count (NDC 55390-0051-10)
100 mg vial, 10 count (NDC 55390-0052-10)
200 mg vial, 1 count (NDC 55390-0053-01)
350 mg vial, 1 count (NDC 55390-0054-01)

Leucovorin Calcium Solution for Injection, West-Ward (formerly Bedford product)
10 mg/mL, 50 mL vial (NDC 55390-0009-01)
 
Leucovorin Calcium Lyophilized Powder for Injection, Teva
100 mg vial, 1 count (NDC 00703-5140-01)

Reason for the Shortage

  • West-Ward Pharmaceuticals’ parent company, Hikma Pharmaceuticals, acquired leucovorin calcium injection from Bedford in July 2014. West-Ward is not actively marketing leucovorin calcium injection at this time.1
  • Teva has leucovorin on shortage due to manufacturing delays. Teva imported leucovorin calcium (calcium folinate solution) 30 mL vials available; however, all product expired in July 2014. Teva will not be importing any additional calcium folinate solution.2
  • Fresenius Kabi (formerly APP) has leucovorin on shortage due to increase demand.3
  • Fusilev (levoleucovorin) and leucovorin oral tablets are not affected by the shortage.4-7

Available Products

Leucovorin Calcium Lyophilized Powder for Injection, Fresenius Kabi
200 mg vial, 1 count (NDC 63323-0710-50)

Leucovorin Calcium Lyophilized Powder for Injection, Sagent
50 mg vial, 10 count (NDC 25021-0813-10)
100 mg vial, 10 count (NDC 25021-0814-30)
200 mg vial, 1 count (NDC 25021-0815-30)
350 mg vial, 1 count (NDC 25021-0816-30)
 
Leucovorin Calcium Lyophilized Powder for Injection, Teva
350 mg vial, 1 count (NDC 00703-5145-01)

Estimated Resupply Dates

  • Fresenius Kabi has leucovorin 500 mg vials on back order and the company estimates a release date of early- to mid-December 2014.3
  • Teva has leucovorin 100 mg vials on back order and the company estimates a release date of mid-December 2014.2

Implications for Patient Care

  • Two folinic acid products are currently marketed in the US – leucovorin and Fusilev.9-12 Leucovorin is the racemic mixture9,10 while Fusilev (levoleucovorin) is the active isomer of folinic acid.10-12 Folinic acid is a cofactor in purine and pyrimidine synthesis, nucleotide synthesis, and erythropoiesis. The inactive precursor, folic acid, must be metabolized to folinic acid in order to have pharmacologic activity.10,13,14
  • Terminology for these products may be confusing, because both folinic acid products have several synonyms. Racemic leucovorin may be referred to as leucovorin, leucovorin calcium, calcium folinic acid, calcium folinate, d,l-leucovorin, folinate calcium, or citrovorum factor; these are identical drugs.9-11,13,14 Fusilev may be referred to as levoleucovorin, levoleucovorin calcium, calcium levoleucovorin, levo-folinic acid, S-leucovorin, or l-leucovorin, all of which are identical drugs.10,11,13-15
  • Leucovorin injection is labeled in adults for colorectal cancer (combined with fluorouracil); and for megaloblastic anemias due to folic acid deficiency, as an alternative to oral therapy.9 Both leucovorin injection and leucovorin tablets are labeled in adults and children for methotrexate rescue in osteogenic sarcoma; to reduce toxicity in patients with impaired methotrexate elimination; and to reduce toxicity after inadvertent folic acid antagonist overdose.9,10 Leucovorin tablets or injection may be used off-label for methotrexate rescue in non-Hodgkin lymphoma.10-12
  • Fusilev is labeled in adults for methotrexate rescue in osteogenic sarcoma; to reduce toxicity in patients with impaired methotrexate elimination; and to reduce toxicity after inadvertent folic acid antagonist overdose. It is also labeled for palliative treatment of colorectal cancer in combination with fluorouracil. In pediatric patients, it is labeled for methotrexate rescue in osteogenic sarcoma.15

Safety

  • There is potential for dosing errors when interchanging leucovorin and levoleucovorin (Fusilev). The dose of levoleucovorin (Fusilev) is one-half the dose of racemic leucovorin injection (e.g., levoleucovorin [Fusilev] 7.5 mg = racemic leucovorin 15 mg).10-14
  • Folic acid may not be used interchangeably with folinic acid products (racemic leucovorin, levoleucovorin [Fusilev]) for oncology indications or for inadvertent overdose with folic acid antagonists.10,13,14

Alternative Agents & Management

  • Reserve folinic acid products (racemic leucovorin, levoleucovorin [Fusilev]) for oncology patients receiving chemotherapy and patients with inadvertent folic acid antagonist overdose.10-12
  • Folic acid is not an alternative for oncology uses or for folic acid antagonist overdose. Use folic acid for patients with megaloblastic anemias due to folic acid deficiency.13
  • Reserve injectable folinic acid products for use in patients with colorectal cancer receiving combination therapy with fluorouracil.10-12 Oral therapy has been evaluated in this setting,17 but may be less practical because of the large number of tablets required.  Consider use of lower-dose injectable folinic acid regimens in patients with colorectal cancer when possible.18,19 If folinic acid injectable products are not available, treatment with fluorouracil alone may be considered and may allow for use of slightly higher fluorouracil doses (~10%) in patients with colorectal cancer as tolerated.18,19
  • Use oral leucovorin whenever possible for methotrexate rescue in osteogenic sarcoma, to reduce toxicity in patients with impaired methotrexate elimination, and to reduce toxicity after inadvertent folic acid antagonist overdose. However, injectable folinic acid products may be necessary when oral therapy is not an option in these patients (e.g., swallowing difficulty, gastrointestinal absorption problems).10-12
  • The Table lists potential alternatives for folinic acid products.

Related Shortages

References

  1. West-Ward (personal communications). August 6 and 21, and September 22, 2014.
  2. Teva (personal communications). November 7 and 19, December 8 and 15, 2008; January 8, February 4 and 23, March 3 and 23, April 13 and 27, May 11 and 18, June 1 and 22, July 13, August 11, September 21, October 14, November 6, 2009; June 7, 22, and 30, July 6 and 20, August 17, September 2 and 14, October 14, and December 7, 2010; January 18 and 31, February 25, and March 22, May 31, July 13, August 1 and 31, September 27, November 10, 2011; January 4 and 20, February 7 and 22, March 28, May 8, June 1, July 2, August 6, September 28, November 7, and December 12, 2012; February 6, March 18, April 17, June 18, July 31, August 28, November 4, 2013; January 13, February 3, March 3, April 7 and 21, May 7 and 21, June 23, July 21, August 7 and 26, September 22, October 31, and November 26, 2014.
  3. Fresenius Kabi (personal communications). January 4 and 20, February 1 and 8, March 14 and 30, April, 12, June 1 and 22, July 13, August 3 and 23, November 8, December 1, 2011; January 4 and 18, February 1 and 22, March 28, May 10, June 1, July 3, September 26, November 5, December 12, 2012; January 3 and 22, February 4 and 18, March 18, April 17, May 20, June 17, July 30, August 8 and 26, September 9, November 8, 18, and 22, 2013; January 13, February 6 and 28, March 24 and 31, April 4 and 21, May 6 and 16, June 26, July 21, August 6 and 22, September 22, October 13 and 29, and November 12 and 26, 2014.
  4. Spectrum Pharmaceuticals (personal communications). November 7, 19, and 20, December 8, 2008; and January 12, 2009; January 20, February 1 and 11, March 1, 14, 23, and 30, April 11 and 19, May 20, and June 15, August 3, and November 10, 2011; January 4, 20, 23, and 27, March 28, June 1, July 2, August 6, October 1, and December 12, 2012; March 21, April 17, July 31, November 8, 2013; and January 13, March 3, and April 7, 2014.
  5. Barr (personal communications). November 7 and 19, 2008.
  6. Boehringer Ingelheim (personal communications). November 7 and 19, 2008.
  7. Mylan (personal communications). November 7 and 19, 2008.
  8. Sagent Pharmaceuticals (personal communications). January 3 and 22, February 5 and 11, March 18, April 17, May 20, June 17, July 23, August 8 and 19, September 12, November 8 and 26, 2013; January 6, February 3 and 27, March 14 and 24, April 21, May 8 and 15, June 23, July 21, August 1 and 15, September 22, October 10 and 29, and November 13, 2014.
  9. Leucovorin Calcium Injection Package Insert. Bedford Laboratories: Bedford, OH. September 2000.
  10. Wickersham RM, Novak KK, managing eds. Drug Facts and Comparisons. St. Louis, MO: Wolters Kluwer Health, Inc.; 2012.
  11. Beckwith MC, Tyler LS, eds. Cancer Chemotherapy Manual. St. Louis, MO: Wolters Kluwer Health; 2012.
  12. Dorr VJ, Morris D, Lorber M. Chemotherapy programs. In: Perry MC, ed. The Chemotherapy Source Book. 2nd ed. Baltimore: Williams and Wilkins,1996:845-887.
  13. McEvoy GK, ed. AHFS 2012 Drug Information. Bethesda, MD: American Society of Health-Systems Pharmacists; 2012.
  14. Lacy CF, Armstrong LL, Goldman MP, Lance LL. Drug Information Handbook. Hudson, OH: Lexi-Comp; 2012.
  15. Fusilev (Levoleucovorin) Injection Package Insert. Spectrum Pharmaceuticals: Irvine, CA. 2011.
  16. Teva Pharmaceuticals. Dear Healthcare Professional Letter (customer letter). Accessed 6/29/11.
  17. Goldberg RM, Hatfield AK, Kahn M, et al. Prospectively randomized North Central Cancer Treatment Group trial of intensive-course fluorouracil combined with the l-isomer of intravenous leucovorin, oral leucovorin, or intravenous leucovorin for the treatment of advanced colorectal cancer. J Clin Oncol. 1997;15(11):3320-3329.
  18. National Comprehensive Cancer Network. The NCCN Clinical Practice Guidelines in Oncology, Rectal Cancer.  Version 3.2012. Accessed 1/30/12. Fort Washington, PA: National Comprehensive Cancer Network; 2012.
  19. National Comprehensive Cancer Network. The NCCN Clinical Practice Guidelines in Oncology, Colon Cancer. Version 3.2012. Accessed 1/30/12. Fort Washington, PA: National Comprehensive Cancer Network; 2012.
  20. Buroker TR, O'Connell MJ, Wieand HS, et al. Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer. J Clin Oncol. 1994;12:14-20.
  21. Poon MA, O'Connell MJ, Moertel CG, et al. Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol. 1989;7:1407-1417.
  22. Poon MA, O'Connell MJ, Wieand HS, et al. Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer. J Clin Oncol. 1991;9:1967-1972.
  23. Jager, E, Heike M, Bernhard H, et al. Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter trial. Study Group for Palliative Treatment of Metastatic Colorectal Cancer Study Protocol 1. J Clin Oncol. 1996;14:2274-2279.
  24. Cheeseman SL, Joel SP, Chester JD, et al. A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer. 2002;87(4):393-399.
  25. Hochster HS, Hart LL, Ramanathan RK, et al. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol. 2008;26(21):3523-3529.
  26. King Guide to Parenteral Admixtures Online (2012). Via Lexi-Drugs Online [database online]. Hudson, OH, Lexi-Comp, Inc.
  27. Anon, Ed. (2012). Trissel’s 2 IV CompatibilityOnline. via Drugdex System [internet database]. Greenwood Village, CO, Thomson Healthcare.
  28. Lexi-Drugs Online (2012). Hudson, OH, Lexi-Comp, Inc.
  29. Chen E, Jonker D, Gauthier I, et al. Phase I study of cediranib in combination with oxaliplatin and infusional 5-Fluorouracil in patients with advanced colorectal cancer. Clin Cancer Res. 2009;15(4):1481-1486.
  30. James E, Podoltsev N, Salehi E, Curtis BR, Saif MW. Oxaliplatin-induced immune thrombocytopenia: another cumulative dose-dependent side effect? Clin Colorectal Cancer. 2009;8(4):220-224.
  31. Maindrault-Goebel F, de Gramont A, Louvet C, et al. High-dose intensity oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX 7). Eur J Cancer. 2001;37(8):1000-1005.
  32. Tournigand C, Cervantes A, Figer A, et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-Go fashion in advanced colorectal cancer--a GERCOR study. J Clin Oncol. 2006;24(3):394-400.
  33. Masi G, Allegrini G, Cupini S, et al. First-line treatment of metastatic colorectal cancer with irinotecan, oxaliplatin and 5-fluorouracil/leucovorin (FOLFOXIRI): results of a phase II study with a simplified biweekly schedule. Ann Oncol. 2004;15(12):1766-1772.

Updated

Updated December 1, 2014, by Leslie Jensen, PharmD, Drug Information Specialist. Created November 7, 2008, by Jane Chandramouli, PharmD, and M. Christina Beckwith, PharmD, Drug Information Specialists. Copyright 2014, Drug Information Service, University of Utah, Salt Lake City, UT.

Disclaimer

This information is provided through the support of Novation to ASHP solely as a service to its members, which shall not use this information for their further commercial use. The content was prepared by the Drug Information Center of University of Utah. Novation, ASHP, and the University of Utah make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, which respect to such information, and specifically disclaim all such warranties. Users of this information are advised that decisions regarding the use of drugs and drug therapies are complex medical decisions and that in using this information, each user must exercise his or her own independent professional judgment. Neither Novation, ASHP nor the University of Utah assumes any liability for persons administering or receiving drugs or other medical care in reliance upon this information, or otherwise in connection with this bulletin. Neither Novation, ASHP nor University of Utah endorses or recommends the use of any drug.

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