Products Affected - Description

Reason for the Shortage

• Ben Venue voluntarily entered into a consent decree with FDA in late-January, 2013. The terms allow Ben Venue to continue to manufacture over 100 medications as long as they are compliant with the decree. FDA will continue to work with Ben Venue to ensure the products are being made with federal current good manufacturing practice requirements. Ben Venue supplies many multiple products for Bedford Laboratories, a division of Ben Venue.
• Teva has leucovorin on shortage due to manufacturing delays.²
• Spectrum has Fusilev (levoleucovorin) readily available.³
• APP and Sagent have leucovorin on shortage due to increase demand.^4,5
• Leucovorin oral tablets are not affected by the shortage.^6-8

Available Products

Estimated Resupply Dates

• Bedford has leucovorin calcium 50 mg, 100 mg, 200 mg, and 350 mg vials available in limited supply for drop shipment or direct order upon allocation approval. The 10 mg/mL 50 mL vials are on long-term back order and the company cannot estimate a release date. Production will not resume until capacity permits.¹
• Teva has leucovorin calcium lyophilized powder 100 mg and 350 mg vials on back order and the company cannot estimate a release date. Teva has the imported leucovorin calcium (calcium folinate solution) 10 mL vials on back order and the company cannot estimate a release date.²
• APP has leucovorin lyophilized powder 200 mg and 500 mg vials on intermittent back order and the company is allocating product as it becomes available.⁴

Implications for Patient Care

• Two folinic acid products are currently marketed in the US – leucovorin and Fusilev.^9-12 Leucovorin is the racemic mixture^9,10 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
• FDA is allowing temporary importation of racemic leucovorin calcium (calcium folinate) solution from Teva UK.¹⁶ The main difference between the two products is that the imported product is available as a solution while the US product is a lyophilized powder requiring reconstitution. The strength of both preparations is the same, 10 mg/mL. Additionally, the imported product requires refrigeration (store at 2-8°C), while the Teva US product is stored at room temperature (15-30°C). The bar coding for the Teva UK product will not provide correct information to bar code readers since the manufacturing code is not an NDC number. More information regarding the imported product and ordering procedures can be found online.

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

• Alcohol Dehydrated Injection (Ethanol)
• Allopurinol Injection
• Amifostine Injection
• Azathioprine Injection
• Colchicine Tablets— Resolved
• Dexrazoxane Injection
• Drotrecogin Alfa (Activated) Injection— No Longer Available
• Foscarnet Injection— Resolved
• Levocarnitine Injection
• Mechlorethamine Hydrochloride Injection— Resolved
• Metyrosine Capsules
• Octreotide Injection
• Sodium Fluoride Oral Drops— Resolved
• Surgical Lubricant— Resolved
• Trace Elements Injection
• Zinc Injection

1. Bedford (personal communications). November 7, 19, 20, and 26, 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, November 6, 2009; June 7, 15, 22, and 29, July 6 and 20, August 17, September 1, 14, and 17, October 14, November 2 and 8, December 10, 2010; January 5 and 19, February 1 and 8, March 1, 22, and 30, April 11 and 18, May 20, June 1, 15, 23, and 29, July 12 and 20, August 3, 10, 24, and 30, September 27, November 9, December 1, 2011; January 9, February 16, March 29, April 5, May 3 and 29, July 3 and 11, August 6 and 30, September 24, November 7, December 12 and 17, 2012; January 2, February 6 and 20, March 18, and April 17, 2013.
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, and April 17, 2013.
3. 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, Apri 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, and April 17, 2013.
4. APP (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, and April 17, 2013.
5. Sagent Pharmaceuticals (personal communications). January 3 and 22, February 5 and 11, March 18, and April 17, 2013.
6. Barr (personal communications). November 7 and 19, 2008.
7. Boehringer Ingelheim (personal communications). November 7 and 19, 2008.
8. Mylan (personal communications). November 7 and 19, 2008.
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 April 19, 2013 by Leslie Jensen, PharmD, Drug Information Specialist. Created November 7, 2008, by Jane Chandramouli, PharmD, and M. Christina Beckwith, PharmD, Drug Information Specialists. Copyright 2013, Drug Information Service, University of Utah, Salt Lake City, UT.