Parenteral Nutrition Multivitamin Product Shortage Considerations

The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) is a professional society of physicians, nurses, dietitians, pharmacists, other allied health professionals, and researchers. A.S.P.E.N. envisions an environment in which every patient receives safe, efficacious, and high-quality patient care. A.S.P.E.N.’s mission is to improve patient care by advancing the science and practice of clinical nutrition and metabolism. A.S.P.E.N. has developed parenteral nutrition (PN) shortage considerations in order to assist its members and other clinicians in coping with PN shortages for their patients.

For the most up-to-date product shortage information, see these websites:
American Society of Health-System Pharmacists (ASHP), Drug Shortages Resource Center
U.S. FDA Drug Shortages
A.S.P.E.N. Product Shortage Latest News

During the shortage period, consider one or more of the following measures:
  1. Assess and routinely reassess each patient as to the indication for PN and provide nutrition via the oral or enteral route when possible. 
  2. Reserve intravenous multivitamins for those patients receiving solely PN or those with a therapeutic medical need for intravenous multivitamins.
  3. Purchase only as much supply as needed. In the interest of patient safety and fair allocation to all patients nationally, please do not stockpile.
  4. During prolonged shortages of intravenous multivitamin products, the FDA may approve the temporary importation of alternative products. These products may have different vitamin profiles, ratios (doses), packaging and labeling than United States products. The Dear Healthcare Professional Letter accompanying imported products should be read carefully.
  5. Compound PN in a single, central location (either in a centralized pharmacy or as outsourced preparation) in order to decrease inventory waste. Consider a supply outreach to other facilities in your geographic location.
  6. Facilities and practitioners need to continue to observe and be compliant with the product labeling (e.g., package insert), USP General Chapter <797> Pharmaceutical Compounding-Sterile Preparations, and state Boards of Pharmacy and federal rules and regulations.
  7. Include PN component shortages and outages in the health care organization’s strategies and procedures for managing medication shortages and outages. These procedures should include:
    1. a  process to identify and monitor patients who receive no intravenous multivitamins or individual vitamin entities, especially thiamine, 
    2. a process to notify providers when this situation occurs, and
    3. a process to notify patients receiving long-term PN therapy when their PN formulation has been adjusted for shortages and outages of PN components.
  8. Observe for an increase in deficiencies with the ongoing shortages. Increase your awareness and assessment for signs and symptoms of vitamin deficiencies. Monitor serum vitamin concentrations or other appropriate serum biochemical markers to evaluate vitamin status.
  9. Report severe drug product shortage information to the FDA Drug Shortage Program (DSP). 
  10. R eport any patient adverse events or medication hazard related to shortages to ISMP Medication Errors Reporting Program (MERP). 
Considerations for a shortage of intravenous ADULT multivitamin products:
  1. The use of pediatric intravenous multivitamins for adults is not recommended. Using pediatric intravenous multivitamins for adults may contribute to a shortage of pediatric products. A shortage of pediatric intravenous multivitamins could create a potential risk of vitamin deficiencies in neonatal and pediatric patients that may have an even greater need for vitamins. Furthermore, pediatric intravenous multivitamins contain vitamins in doses or ratios that may be unsuitable for adults.
  2. Consider switching to oral or enterally administered multivitamins when oral/enteral intake is initiated (excluding patients with malabsorption syndromes). Oral liquid, chewable or gummy multivitamin products may not provide a complete vitamin profile. The vitamin profile should be reviewed and missing components supplemented, if available. Consult a pharmacist for assistance with selecting an appropriate oral multivitamin product. Note many oral liquid medications contain sorbitol that may cause diarrhea or gastrointestinal intolerance.
  3. If unable to obtain a 13-vitamin product, a 12-vitamin product (without vitamin K) may be used with vitamin K supplementation. The dose of vitamin K in the 13-vitamin products is 150 mcg. Alternative intravenous vitamin K dosing is 0.5-1 mg/day or 5-10 mg per week. See Table 1 below for ingredients in each product.
  4. If unable to obtain a 12-vitamin product (without vitamin K), a 13-vitamin product (with vitamin K) may be used. Coagulation activity of the patient receiving warfarin therapy must be closely monitored and adjusted accordingly. The amount of vitamin K in the 13-vitamin product (150 mcg) may or may not affect the warfarin coagulation activity. See Table 1 below for ingredients in each product.
  5. When all options to obtain intravenous multivitamins have been exhausted, ration intravenous multivitamins in PN, such as reducing the daily dose by 50% or giving one multivitamin infusion dose three times a week. 
  6. If intravenous multivitamins are no longer available, administer individual parenteral vitamin entities.
    1. T hiamine, ascorbic acid, pyridoxine, and folic acid should be given daily. 
    2. Thiamine is critical as several deaths have resulted from thiamine deficiency when long-term PN patients did not receive vitamins for three to four weeks. Patients receiving a carbohydrate load are particularly susceptible to thiamine deficiency. 
    3. It should also be noted that megaloblastic anemia secondary to folate deficiency has been reported in PN patients who did not receive folate for 4-5 weeks. 
    4. Unless deficiency is suspected or otherwise clinically indicated suggested doses of intravenous or other non-oral routes of administration for vitamins are:

Vitamin

Dose for Adults

Thiamine

6 mg daily

Folate

0.6 mg daily

Ascorbic acid

200 mg daily

Pyridoxine

6 mg daily

Vitamin K

150 mcg daily or 5-10 mg weekly

Cyanocobalamin (B12)

100-1000 mcg intramuscular or deep subcutaneous at least once monthly or
500 mcg intranasal once weekly or
1000 mcg sublingual once daily

NOTE: Individual intravenous vitamin entities are highly concentrated and very small volumes are required to provide the suggested dose. Dilution of the vitamin product may be necessary to accurately measure the dose. The small volume required for a single dose and the vial size of the vitamin product presentation may result in significant wastage. In such situations, clinicians may consider administering larger doses less frequently than daily and cohort patients on the same day.
 
Considerations for a shortage of intravenous PEDIATRIC multivitamin products:
  1. Consider switching to oral or enterally administered multivitamins when oral/enteral intake is greater than 50% of needs (excluding patients with malabsorption syndromes). Oral liquid or gummy multivitamins may not provide a complete vitamin profile. The vitamin profile should be reviewed and missing components supplemented, if available. Consult a pharmacist for assistance with selecting an appropriate oral multivitamin product. Note many oral liquid products contain sorbitol that may cause diarrhea or gastrointestinal intolerance. 
  2. Reserve pediatric intravenous multivitamins for children less than 2.5 kg or less than 36 weeks gestational age.
  3. Consider use of adult intravenous multivitamins for children during the shortage; use 5 mL of adult multivitamins in all children more than 2.5 kg or 36 weeks gestation while saving the pediatric product for smaller neonates in order to conserve the supply. Supplement intravenous vitamin K daily (total daily dose = 200 mcg). The vitamin K content of the adult multivitamin product should be noted when supplementing with additional vitamin K. See Table 1 below for ingredients in intravenous multivitamin products.
  4. In the event that no pediatric intravenous multivitamins are available, infants less than 2.5 kg or less than 36 weeks gestation should receive an adult intravenous multivitamin at a daily dose of 1 mL/kg up to a maximum of 2.5 mL/day. 
  5. When using adult intravenous multivitamin products in neonates be aware that these products contain propylene glycol, polysorbate, and aluminum, which may be toxic to neonates. Adult intravenous multivitamins may contain more aluminum than pediatric products. Clinical judgment must prevail by weighing potential vitamin deficiencies against potential propylene glycol, polysorbate and aluminum toxicity. 
  6. Use the full adult dose (10 mL) of adult intravenous multivitamins for children greater than 11 years of age. [Please refer to the adult multivitamin recommendations in the event of a concurrent shortage.] 
  7. If neither pediatric nor adult intravenous multivitamins are available, administer individual parenteral vitamin entities in doses that are appropriate for the patient’s age and weight. 
    1. Thiamine, ascorbic acid, pyridoxine, folic acid, cyanocobalamin and vitamin K should be given daily. 
    2. Thiamine is critical as several deaths have resulted from thiamine deficiency when long-term PN patients did not receive vitamins for three to four weeks. Patients receiving a carbohydrate load are particularly susceptible to thiamine deficiency. 
    3. Unless deficiency is suspected or otherwise clinically indicated suggested intravenous daily doses of vitamins are:

Vitamin

  Infants

 Children

Thiamine

0.35-0.5 mg/kg

1.2 mg

Folic acid

56 mcg

140 mcg

Ascorbic acid

15-25 mg/kg

80 mg

Pyridoxine

0.15-0.2 mg/kg

1 mg

Cyanocobalamin

0.3 mcg/kg

1 mcg

Vitamin K

10 mcg/kg

200 mcg

Greene HL, Hambidge M, Schanler R, Tsang R. Guidelines for the use of vitamins, trace elements, calcium, magnesium, and phosphorus in infant and children receiving total parenteral nutrition: report of the Subcommittee on Pediatric Parenteral Nutrient Requirements  from the Committee on Clinical Practice Issues of the American Society for Clinical Nutrition. Am J Clin Nutr. 1988;48:1324-1342.

NOTE: Individual intravenous vitamin entities are highly concentrated and very small volumes are required to provide the suggested dose. Dilution of the vitamin product may be necessary to accurately measure the dose. The small volume required for a single dose and the vial size of the vitamin product presentation may result in significant wastage. In such situations, clinicians may consider administering larger doses less frequently than daily and cohort patients on the same day. 
Table 1 U.S. Commercially Available Intravenous Multivitamin Products

VITAMIN

M.V.I. ADULT™
(HOSPIRA)

(PER 10 ML)

M.V.I.-12®
(HOSPIRA)

(PER 10 ML)

INFUVITE® ADULT
(BAXTER)

(PER 10 ML)

M.V.I.® PEDIATRIC
(HOSPIRA)

(PER 5 ML)

INFUVITE® PEDIATRIC
(BAXTER)

(PER 5 ML)

A *

1 mg *

(retinol)

1 mg *

(retinol)

3300 units

(palmitate)

0.7 mg **

 (retinol)

2300 units**

(palmitate)

D*

5 mcg*

(ergocalciferol)

5 mcg*

(ergocalciferol)

200 units

 (cholecalciferol)

10 mcg**

(ergocalciferol)

400 units**

(cholecalciferol)

E* (dl-alpha tocopheryl acetate)

10 mg*

10 mg*

10 units

7 mg**

7 units**

K (phytonadione)

150 mcg

None

150 mcg

200 mcg

200 mcg

C (ascorbic acid)

200 mg

200 mg

200 mg

80 mg

80 mg

B-1 (thiamine)

6 mg

6 mg

6 mg

1.2 mg

1.2 mg

B-2 (riboflavin)

3.6 mg

3.6 mg

3.6 mg

1.4 mg

1.4 mg

Niacinamide

40 mg

40 mg

40 mg

17 mg

17 mg

Dexpanthenol

15 mg

15 mg

15 mg

5 mg

5 mg

B-6 (pyridoxine)

6 mg

6 mg

6 mg

1 mg

1 mg

B-12 (cyanocobalamin)

5 mcg

5 mcg

5 mcg

1 mcg

1 mcg

Biotin

60 mcg

60 mcg

60 mcg

20 mcg

20 mcg

Folic Acid

600 mcg

600 mcg

600 mcg

140 mcg

140 mcg

 

 

 

 

 

 

Other:

 

 

 

 

 

Aluminum

43-183 mcg/L ***

43-78 mcg/L ***

70 mcg/L*** 

42 mcg /L ***

30 mcg/L*** 

Polysorbate 80

160 mg

160 mg

140 mg

50 mg

50 mg

Polysorbate 20

2.8 mg

2.8 mg

None

0.8 mg

None

Propylene Glycol

3 g

3 g

3 g

None

None

* 1 mg Vitamin A = 3,300 USP units
5 mcg Vitamin D = 200 USP units
10 mg Vitamin E = 10 USP units
** 0.7 mg Vitamin A = 2,300 USP units
10 mcg Vitamin D = 400 USP units
7 mg Vitamin E = 7 USP units
*** Maximum, labeled concentration at product expiration date; Hospira products vary depending if it is unit vial, single-dose or multi-dose packaging.
Consult manufacturer’s product literature for a complete list of inactive ingredients.

Suggested Readings:
  • Ayers P, Adams S, Boullata JI, et al. A.S.P.E.N. Parenteral nutrition safety consensus recommendations. JPEN J Parenter Enteral Nutr. 2014;38;296-333.
  • Task Force for the Revision of Safe Practices for Parenteral Nutrition: Mirtallo J, Canada T, Johnson D, Kumpf V, Petersen C, Sacks G, Seres D, Guenter P. Safe practices for parenteral nutrition. JPEN J Parenter Enteral Nutr. 2004;28:S39- S70. Errata: JPEN J Parenter Enteral Nutr. 2006;30: 177.
  • Boullata JI, Gilbert K, Sacks G, et al. A.S.P.E.N. Clinical guidelines: Parenteral nutrition ordering, order review, compounding, labelling, and dispensing. JPEN J Parenter Enteral Nutr. 2014;38:334-371.
  • Storey MA, WeberN RJ, Besco K, Beatty S, Aizawa K, Mirtallo J. An evaluation of parenteral nutrition errors in an era of drug shortages. Nutr Clin Pract. 2016, DOI: 10.1177/0884533615608820.
  • The Joint Commission. Medication Management Standard MM. 02.01.01: The hospital selects and procures medications. Elements of performance 1-16, 2016.
  • Vanek VW, Borum P, Buchman A, et al. A.S.P.E.N. position paper recommendations for changes in commercially available parenteral multivitamin and multi-trace element products. Nutr Clin Pract. 2012;27:440-491.
  • Centers for Disease Control and Prevention. Deaths associated with thiamine-deficient total parenteral nutrition. MMWR Morb Mortal Wkly Rep. 1989;38:43.
  • Centers for Disease Control and Prevention. Lactic acidosis traced to thiamine deficiency related to nationwide shortage of multivitamins for total parenteral nutrition -- United States, 1997. MMWR Morb Mortal Wkly Rep. 1997 Jun 13;46:523-528.
  • Romanski SA, McMahon MM. Metabolic acidosis and thiamine deficiency. Mayo Clin Proc. 1999;74:259-263.
  • Sriram K, Manzanares W, Jospeh K. Thiamine in nutrition therapy. Nutr Clin Pract. 2012;27:41-50.
  • Infante MT, Fancellu R, Murialdo A, Barletta L, Castellan L, Serrati C. Wernicke encephalopathy: Challenges in diagnosis and treatment: Report of 2 cases. Nutr Clin Pract. first published on February 11, 2016 as doi:10.1177/0884533615621753. 
  • Giacalone M, Martinelli R, Abramo A, et al. Rapid reversal of severe lactic acidosis after thiamin administration in critically ill adults: a report of 3 cases. Nutr Clin Pract. 2015; 30:104-110. 
  •  Ferrie S. Case report of acute thiamine deficiency occurring as a complication of vitamin-free parenteral nutrition. Nutr Clin Pract. 2012;27:65-68. 
  • Alloju M, Ehrinpreis NM. Shortage of intravenous multivitamin solution in the United States. N Engl J Med. 1997;337:54.
  • Kudsk KA, Holcombe BJ, Bernstein E. Response to shortage of intravenous multivitamin solution in the United States. N Engl J Med. 1997;337:54.
  • Rulewski N. Response to shortage of intravenous multivitamin solution in the United States. N Engl J Med. 1997;337:54.
  • Temeck J, Sobel S. Response to shortage of intravenous multivitamin solution in the United States. N Engl J Med. 1997;337:55.
  • Francini-Pesenti F, Brocadello F, Famengo S, et al. Wernicke’s encephalopathy during parenteral nutrition. J Parenter Enteral Nutr. 2007;31:69-71.
  • Velez RJ, Myers B, Guber MS. Severe acute metabolic acidosis (acute beriberi): an avoidable complication of total parenteral nutrition, JPEN J Parenter Enteral Nutr. 1985:9:216-9.
  • Hahn JS, Berquist W, Alcorn DM, Chamberlain L, Bass D. Wernicke encephalopathy and beriberi during total parenteral nutrition attributable to multivitamin infusion shortage. Pediatrics. 1998;10: E1.
  • Corkins MR, Griggs KC, Groh-Wargo S, Han-Markey TL, Helms RA, Muir LV, Szeszyski EE, Task Force on Standards for Specialized Nutrition Support for Hospitalized Pediatric Patients and the American Society for Parenteral and Enteral Nutrition Board of Directors. Standards for Specialized Nutrition Support: Hospitalized Pediatric Patients. Nutr Clin Pract. 2013;28:263-276.
  • Koo W, Christie J, Saba M, Lulic-Botica M, Warren L. Water-soluble essential micronutrients. In: Corkins MR, ed. A.S.P.E.N. Pediatric Nutrition Support Core Curriculum, 2nd ed. Silver Spring: A.S.P.E.N., 2015:69-90.
  • Koo W, Saba M, Lulic-Botica M, Christie J. Fat-soluble vitamins. In: Corkins MR, ed. A.S.P.E.N. Pediatric Nutrition Support Core Curriculum, 2nd ed. Silver Spring: A.S.P.E.N., 2015:91-106.
  • The American Society for Parenteral and Enteral Nutrition Aluminum Task Force: Pamela J. Charney, MS, RD, LD, CNSD, Chair. A.S.P.E.N. Statement on Aluminum in Parenteral Nutrition Solutions Nutr Clin Pract. Aug 2004; 19: 416 - 417.
  • Poole RL, Schiff L, Hintz SR., et al. Aluminum content of parenteral nutrition in neonates: measured versus calculated levels. J Pediatr Gastroenterol Nutr. 2010: 50(2):208-211.
  • American Academy of Pediatrics Committee on Drugs. “Inactive” ingredients in pharmaceutical products: Update (subject review). Pediatrics. 1997; 99:268-278.
  • Greene HL, Hambidge KM, Schanler R, et al. Guidelines for the use of vitamins, trace elements, calcium, magnesium, and phosphorus in infants and children receiving total parenteral nutrition: Report of the Subcommittee on Pediatric Parenteral Nutrient Requirements from the Committee on Clinical Practice Issues of the American Society for Clinical Nutrition. Am J Clin Nutr. 1988;48:1324-1342.
  • Hanson C, Thoene M, Wagner J, Collier D, Lecci K, Anderson-Berry A. Parenteral nutrition additive shortages: the short-term, long-term and potential epigenetic implications in premature and hospitalized infants. Nutrients. 2012;4:1977-1988. 
  • Oriot D, Wood C, Gottesman R, Huault G. Severe lactic acidosis related to acute thiamine deficiency. JPEN J Parenter Enteral Nutr. 1991;15:105-109. 
  • Klein CJ. Nutrient requirements for preterm infant formulas. J Nutr. 2002;132:1395S-1577S.

Important Note: These recommendations do not constitute medical or professional advice, and should not be taken as such. To the extent the information published herein may be used to assist in the care of patients, this is the result of the sole professional judgment of the attending health professional whose judgment is the primary component of quality medical care. The information presented herein is not a substitute for the exercise of such judgment by the health professional.

Revised by the A.S.P.E.N. Clinical Practice Committee’s Nutrition Product Shortage Subcommittee: Steve Plogsted, PharmD, BCNSP, CNSC (Chair); Stephen C. Adams, MS, RPh, BCNSP; Karen Allen, MD; M. Petrea Cober, PharmD, BCNSP; June Greaves, RD, CNSC, CD-N, LD, LDN; Kris M. Mogensen, MS, RD, LDN, CNSC; Amy Ralph, MS, RD, CNSC, CSO, CDN; Ceressa Ward, PharmD, BCPS, BCNSP; and Joe Ybarra, PharmD, BCNSP.

Approved by the A.S.P.E.N. Clinical Practice Committee and the Board of Directors on March 16, 2016.

Questions regarding these recommendations should be directed to Beverly Holcombe,
PharmD, BCNSP, FASHP, FASPEN; Clinical Practice Specialist, A.S.P.E.N. at [email protected]