Leucovorin Injection

18 August 2010

Products Affected - Description

Reason for the Shortage

• Bedford cannot provide a reason for the shortage.¹
• Teva has leucovorin on shortage due to manufacturing delays.²

Estimated Resupply Dates

• Bedford has all leucovorin presentations on back order and the company estimates that some products will be available starting in late-August, 2010.¹  
• Teva has leucovorin calcium lyophilized powder 100 mg vials on allocation. The 350 mg vials are on back order and the company estimates a release date in the 4th quarter of 2010.²
• Spectrum Pharmaceuticals has available Fusilev (levoleucovorin) 50 mg single use vials (NDC 68152-0101-00).³ For assistance ordering Fusilev, healthcare providers may contact their region’s account representative.
• Leucovorin oral tablets are available from Barr, Boehringer Ingelheim, and Mylan in a variety of strengths, including 5, 10, 15, and 25 mg.^4-6

Implications for Patient Care

• Two folinic acid products are currently marketed in the US – leucovorin and levoleucovorin (Fusilev).^7-10 Leucovorin is the racemic mixture^7,8, whereas levoleucovorin (Fusilev) is the active isomer of folinic acid.^8-10 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.^8,11,12
• 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.⁷ 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.^7,8 Leucovorin tablets or injection may be used off-label for methotrexate rescue in non-Hodgkin's lymphoma.^8-10
• Levoleucovorin (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. In pediatric patients, it is labeled for methotrexate rescue in osteogenic sarcoma.¹³ It is used off-label for colorectal cancer (combined with fluorouracil).^8-10

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).^8-12
• 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.^8,11,12

Alternative Agents & Management

• Reserve folinic acid products (racemic leucovorin, levoleucovorin [Fusilev]) for oncology patients receiving chemotherapy and patients with inadvertent folic acid antagonist overdose.^8-10
• 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.¹¹
• Reserve injectable folinic acid products for use in patients with colorectal cancer receiving combination therapy with fluorouracil.^8-10 Oral therapy has been evaluated in this setting,¹⁴ but may be less practical because of the large number of tablets required.
• 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).^8-10
• The Table lists potential alternatives for folinic acid products.

Related Shortages

• Alendronate Sodium Tablets— Resolved
• Colchicine Injection— No Longer Available
• Colchicine Tablets— Resolved
• Cyclosporine Injection— Resolved
• Daclizumab Injection— No Longer Available
• Dexrazoxane Injection
• Isosulfan Blue Injection— Resolved
• Methylene Blue Injection— Resolved
• Metyrosine Capsules— Resolved
• Muromonab-CD3 Solution for Injection— Resolved
• Pralidoxime Chloride Injection— Resolved
• Pralidoxime Injection— Resolved
• Sodium Fluoride Chewable Tablets— Resolved

References

1. Bedford (personal communications). November 7, 19, 20, and 26, and December 8 and 15, 2008; January 8, February 4 and 23, March 3, 10, and 23, April 13 and 27, May 11 and 18, June 1 and 22, July 13, August 11, September 21, October 14, and November 6, 2009; June 7, 15, 22 and 29, July 6 and 20, and August 17, 2010.
2. Teva (personal communications). November 7 and 19, and 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, and November 6, 2009; June 7, 22, and 30, July 6 and 20, and August 17, 2010.
3. Spectrum Pharmaceuticals (personal communications). November 7, 19, and 20, and December 8, 2008; and January 12, 2009.
4. Barr (personal communications). November 7 and 19, 2008.
5. Boehringer Ingelheim (personal communications). November 7 and 19, 2008.
6. Mylan (personal communications). November 7 and 19, 2008.
7. Leucovorin Calcium Injection Package Insert. Bedford Laboratories: Bedford, OH. September 2000.
8. Wickersham RM, Novak KK, managing eds. Drug Facts and Comparisons. St. Louis, MO: Wolters Kluwer Health, Inc.; 2008.
9. Beckwith MC, Tyler LS, eds. Cancer Chemotherapy Manual. St. Louis, MO: Wolters Kluwer Health; 2008.
10. 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.
11. McEvoy GK, ed. AHFS 2008 Drug Information. Bethesda, MD: American Society of Health-Systems Pharmacists; 2008.
12. Lacy CF, Armstrong LL, Goldman MP, Lance LL. Drug Information Handbook. Hudson, OH: Lexi-Comp; 2007.
13. Fusilev (Levoleucovorin) Injection Package Insert. Spectrum Pharmaceuticals: Irvine, CA. 2008.
14. 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.
15. 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.
16. 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.
17. 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.

Updated

Updated August 18, 2010, by Dave Peterson, Pharm.D., Drug Information Specialist. Created November 7, 2008, by Jane Chandramouli, Pharm.D., and M. Christina Beckwith, Pharm.D., Drug Information Specialists. Copyright 2010, Drug Information Service, University of Utah, Salt Lake City, UT.

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