A.S.P.E.N. Releases New Parenteral Nutrition L-Cysteine 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 supply information, please 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

Cysteine is an amino acid which is important in the synthesis of proteins and has a role in growth and the production of antioxidants. It is considered a conditionally essential amino acid in preterm infants due to the biochemical immaturity of the enzyme cystathionase, which converts methionine to cysteine and ultimately to taurine. An additional consideration for the addition of L-cysteine as the hydrochloride (HCl) salt to PN admixtures is for further acidification of the admixture thus improving calcium and phosphorus, as phosphate, solubility. Every 160 mg of L-cysteine delivers 1 mmole HCl. While there is no replacement for L-cysteine, dose conservation measures can be taken.

During the L-cysteine shortage period, consider one or more of the following measures:

  1. Assess each patient as to the indication for PN and provide nutrition via the oral or enteral route when possible.
  2. Discontinue L-cysteine supplementation in PN for neonates receiving a minimum dose of 3 g/kg per day of commonly-prescribed amino acids solutions. This dose of amino acids will provide sufficient amount of sulfur amino acid substrate (methionine) for the  transsulfuration pathway to produce adequate cysteine and thus no need to supplement parenteral nutrition (PN) with L-cysteine. However, L-cysteine supplementation may be necessary to decrease the pH of the PN admixture in order to enhance calcium and phosphate solubility.
  3. Reduce L-cysteine supplementation in PN formulations to 20 mg per gram of amino acids provided. Common dosing of L-cysteine in PN formulations is 30-40 mg per gram of amino acids provided. However, studies have documented that as little as 20 mg per gram of amino acids is adequate.
  4. Assess the PN formulation to determine if the daily calcium and phosphorus requirements are considered compatible and within solubility limits and can be attained without the addition of L-cysteine.
  5. When removing or reducing the dose of L-cysteine in the PN formulation re-evaluate the calcium-phosphorus solubility charts or software to insure that a precipitate will not develop due to the increase in the pH of the PN admixture. Consider using calcium-phosphorus solubility data that do not include the presence of L-cysteine in the PN formulation.
  6. Consider using organic phosphate injections, if available. Organic phosphates, as compared to inorganic phosphorus products, have favorable compatibility with calcium and may be considered as a measure to provide adequate calcium and phosphate to patients with decreased risk of precipitate formation.
  7. Discourage using L-cysteine as an agent to re-establish vascular access device catheter patency.
  8. Purchase only as much L-cysteine injections supply as needed. In the interest of fair allocation to all patients nationally, please do not stockpile.
  9. 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.
  10. If using an automated compounding device (ACD) to prepare PN formulations add the L-cysteine to the PN as a separate additive rather than adding it to the amino acid solution (so that it is pumped as a single component). This will conserve supplies and reserve its use for the intended population. Consult the ACD manufacturer for proper placement of L-cysteine on the ACD configuration. For manual compounding, add the L-cysteine to the PN immediately before or after adding the amino acids solution and prior to adding the calcium.
  11. Facilities and practitioners must 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.
  12. Report severe drug product shortage information to the FDA Drug Shortage Program (DSP) .
  13. Report any patient problems related to shortages to ISMP Medication Errors Reporting Program (MERP) .

Suggested Readings:

  1. Riedijk MA, van Beek RHT, Voortman G, de Bie HMA, Dassel ACM, van Goudoever JB. Cysteine: a conditionally essential amino acid in low-birth-weight preterm infants? Am J Clin Nutr. 2007; 86:1120-1125.
  2. Riedijk MA, Voortman G, van Beek RHT, Baartsman MGA, Wafelman LS, van Goudoever JB. Cyst(e)ine requirements in enterally fed very low birth weight infants. Pediatrics . 2008;121(3):e561-567.
  3. Courtney-Martin G, Moore AM, Ball RO, Pencharz PB. The addition of cysteine to the total sulphur amino acid requirement as methionine does not increase erythrocytes glutathione synthesis in the parenterally fed human neonate. Pediatr Res. 2010;67:320-324.
  4. Calkins KL, Sanchez LA, Tseng CH, et al. Effect of high-dose cysteine supplementation on erythrocyte glutathione: a double-blinded, randomized placebo-controlled pilot study in critically ill neonates. JPEN J Parenter Enteral Nutr. 2014 Aug 19. 0148607114546375 [Epub ahead of print]
  5. Shew SB, Keshen TH, Jahoo F, Jaksic T. Assessment of cysteine synthesis in very low–birth weight neonates using a [13C6]glucose tracer. J Pediatr Surg. 2005; 40:52-56.
  6. Trissel LA. Trissel’s Calcium and Phosphate Compatibility in Parenteral Nutrition, 2001. TriPharma Communications, Houston, TX.
  7. MacKay M, Anderson C. Physical compatibility of sodium glycerophosphate and calcium gluconate in pediatric parenteral nutrition solutions. JPEN J Parenter Enteral Nutr. 0148607114528982, first published on April 2, 2014.
  8. Jackson AA. Amino acids: essential and non-essential? Lancet . 1983;1:1034–1037.
  9. Snyderman SE. The protein and amino acid requirements of the premature infant. In: Ionxix JHP, Visser HKA, Troelstra JD, eds. Metabolic Processes in the Fetus and Newborn Infant. Leiden, The Netherlands: HE Stenfert Kroesse NV; 1971:128–141.
  10. Pohlandt F. Cystine: a semi-essential amino acid in the newborn infant. Acta Pediatr Scand. 1974;63:801–804.
  11. Gaull G, Sturman JA, Raiha NCR. Development of mammalian sulfur metabolism: absence of cystathionase in human fetal tissues. Pediatr Res. 1972;6:538–547.
  12. Sturman JA, Gaull G, Raiha NCR. Absence of cystathionase in human fetal liver: Is cystine essential? Science . 1970;169:74–76.
  13. Zlotkin SH, Anderson GH. Sulfur balances in intravenously fed infants: effects of cysteine supplementation. Am J Clin Nutr . 1982;36:862–867.
  14. Lyons J, Rauh-Pfeiffer A, Ming-Yu Y, et al. Cysteine metabolism and whole blood glutathione synthesis in septic pediatric patients. Crit Care Med. 2001;29(4):870–877.

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.

Developed by an ad hoc L-cysteine shortage workgroup: Steve Plogsted, PharmD, BCNSP, CNSC (leader); M. Petrea Cober, PharmD, BCNSP; Kathleen M. Gura, PharmD, BCNSP, FASHP, FPPAG, FASPEN; Richard A. Helms, PharmD; and Daniel Robinson, MD; the A.S.P.E.N. CPC Shortage Subcommittee: Steve Plogsted, PharmD, BCNSP, CNSC (Chair); Steve Adams, MS, RPh, BCNSP; Karen Allen, MD; M. Petrea Cober, PharmD, BCNSP; June Greaves , RD, CNSC, CD-N, LD, LDN; and Joe Ybarra, PharmD, BCNSP. Approved by the Clinical Practice Committee, and the A.S.P.E.N. Board of Directors.

Questions regarding these recommendations should be directed to Beverly Holcombe, PharmD, BCNSP, FASHP, Clinical Practice Specialist, A.S.P.E.N.