September 2013 Issue

Parenteral Nutrition Drug Shortages — An Ongoing but Solvable Problem
By Mandy L. Corrigan, MPH, RD, LD, CNSC
Today’s Dietitian
Vol. 15 No. 9 P. 46

Dietitians can implement strategies to help patients continue getting the nutrients they need for optimal health.

Since 2010, the United States has experienced a parenteral nutrition (PN) drug shortage affecting almost all patients requiring PN in the hospital or at home. Every component of PN, with the exception of 70% dextrose, has been on the product shortage list at one time or another. Currently, many of these drugs remain in short supply, requiring RDs who care for PN patients to constantly be aware of the many challenges this presents.

This article will discuss the reasons for the drug shortages, the PN drugs that often are in short supply, the dietitian’s role in this crisis, and the substitutions that can and should be used to ensure patients receive optimal nutrition.

Why the Shortages?
There are several causes of PN drug shortages in the United States. Product quality issues, problems obtaining raw materials to make injectable drugs, loss of manufacturing sites due to natural disasters, product discontinuations, delays in drug production, and increased demand all play a role.

Making PN drugs also isn’t particularly profitable, as only a small, specialized population requires them. This may cause some manufacturers that previously made these products to instead make more profitable alternatives. Also, since many industries have moved to just-in-time manufacturing models, there’s no longer an inventory that can be used if manufacturing temporarily shuts down. Moreover, there’s a limited number of manufacturers of PN drug products, and often there’s only one company that produces them in the United States.

The impact of PN drug shortages has been brought into the spotlight by organizations such as the American Society for Parenteral and Enteral Nutrition (ASPEN) and has gained the attention of legislators and the national news. How have the shortages impacted patients needing PN care? RDs have had to grapple with patient safety issues and the inability to give patients the macronutrients, micronutrients, and electrolytes they need, leading to deficiencies, plus they’ve witnessed the crisis claim the lives of infants in the neonatal ICU.

Legislation
In July 2012, President Obama signed into law the FDA Safety and Innovation Act (FDASIA), creating new requirements for drug manufacturers to notify the FDA of any issues that can lead to a potential drug shortage or that can disrupt the supply chain. Previously, the FDA was notified only about discontinued drugs. FDASIA requires maintaining a publicly available, ongoing list of drug shortages that includes information on the cause and the anticipated duration of the shortage.

Another key component of the law is that the FDA has the right to inspect and expedite reviews of manufacturer and raw material producer facilities to prevent unnecessary delays in bringing products back to market.

The RDs’ Role
Some of the chief responsibilities of dietitians include assessing the appropriateness of PN care, evaluating a patient’s ability to transition to enteral nutrition (EN), and recommending EN alternatives (see sidebar below). Based on these responsibilities, RDs play an important role as members of an interdisciplinary team caring for PN patients.

First, dietitians should evaluate all patients currently receiving PN (or who soon will be) to determine the appropriateness of the therapy. Any patient who shouldn’t be receiving PN should be transitioned to EN. This is paramount so clinicians can prioritize who receives the limited supply of PN drugs.

Of all the care team members, RDs have the most training in recognizing physical signs of nutrient deficiencies such as koilonychias (spooning of the nails seen in iron deficiency), scurvy (characterized by anemia, edema, and exhaustion from vitamin C deficiency), and Bitot’s spots (a buildup of keratin debris on the conjunctiva seen in vitamin A deficiency). A nutrition-focused physical examination is key for uncovering clues that point to signs of deficiency and then confirming clinical findings with laboratory studies.

Many clinicians have never seen the clinical manifestations of nutrient deficiencies because these conditions often aren’t found in the United States. Increasing knowledge in this area requires review of the literature. In fact, many clinical nutrition references include pictures of deficiencies that may be helpful.

Dietitians who must prioritize a limited supply of PN drug components require knowledge of a patient’s medical and surgical history as well as clinical guidelines to help navigate drug shortages. Dietitians and pharmacists should become familiar with guidelines and resources from professional societies and discuss options with the physician who ultimately makes decisions regarding a patient’s clinical and PN care. These tools can guide clinical decision making and product rationing by decreasing doses.

It’s prudent for RDs to recommend increased monitoring for all patients receiving less-than-optimal dosing of PN components. Understanding a patient’s surgical history will help prioritize who should receive PN and determine whether enteral substitutions are appropriate. For example, patients receiving long-term PN who have had multiple surgical resections leading to short-bowel syndrome should be given priority over patients needing PN for a short time for a postoperative ileus or obstruction and who will soon transition to EN. RDs should work with the pharmacy department to determine whether the pharmacy should provide a premixed PN solution as an alternative. Premixed PN products may be an option for institutions or facilities with low PN usage.

Often those working in procurement or supply chain management aren’t clinicians. However, this presents an important opportunity for RDs to discuss product substitutions from a clinical perspective with supply management teams. For example, the supply chain team may not be able to obtain zinc sulfate, but nonclinicians may not be aware that zinc chloride is an alternative that’s compatible with PN solutions if, historically, only zinc sulfate has been used in the hospital. Another alternative is for RDs to suggest an amino acid solution that contains inherent phosphates if the facility can’t obtain sources of parenteral phosphorus (either sodium or potassium).

Patients and their family members should know about drug shortages that are impacting PN care. This is an important opportunity for clinicians to explain that the shortages are a national problem, and that there’s much being done at the individual patient level (eg, product substitutions, enteral alternatives, increased monitoring) to avoid any significant health consequences as a result of the shortages. Patients receiving PN should be educated about potential symptoms of electrolyte abnormalities they could experience if any PN components are reduced or omitted because of product shortages.

Monitoring and Patient Safety
Drug shortages or substitutions pose safety risks to the entire PN process, from physician ordering and procurement to compounding and patient outcomes. When less desirable or less familiar products are used, the potential for medical errors increases. Medication errors should be reported to the FDA or other professional organizations to keep abreast of the drug shortage issue (see the Professional Resources sidebar below for more information).

Drugs Affected
As mentioned, all PN products have been in short supply with the exception of 70% dextrose. What follows is a discussion about the alternative products available that RDs can recommend and suggestions for decreasing dosages to maximize PN delivery to as many patients as possible. In all cases, dietitians should prioritize the delivery of PN drugs to the pediatric population.

Macronutrients
If PN macronutrients such as amino acids, IV fat emulsions, and IV multiple vitamins are in short supply, dietitians can explore other avenues to ensure patients receive optimal nutrition care.

Amino Acids
When there are amino acid shortages, RDs can try ordering an alternative amino acid product from another manufacturer. Amino acid solutions are available in several different concentrations, such as 8.5%, 10%, 15%, and 20%. Higher concentration amino acid solutions (eg, 15% and 20%) should be prioritized to volume-restricted patients receiving PN (those who can’t tolerate large amounts of fluid).

If all avenues have been explored to obtain different amino acids or concentrations from various manufacturers, RDs should evaluate the usefulness of administering a premixed PN solution until they can begin using a customized PN solution when amino acids become available again. Specialty amino acid products, such as specialized hepatic solutions and pediatric amino acids, shouldn’t be substituted for standard amino acid products in adults.

IV Fat Emulsions
If IV fat emulsions are in short supply, different concentrations can be substituted. RDs should keep in mind that essential fatty acid deficiency can occur after two weeks of lipid-free intake when substituting with lipid-free PN.

Two US manufacturers produce three lipid concentrations (10%, 20%, and 30%) of IV fat emulsions. The 30% concentration can be used only in total nutrient admixtures. ICU patients receiving propofol can forgo IV fat emulsions, since propofol is in a lipid-based emulsion that provides 1.1 kcal/mL, just like the 10% IV fat emulsion.

Since essential fatty acid deficiency doesn’t develop until after two weeks of lipid-free PN, IV fat emulsions can be safely withheld for the first two weeks if lipids are in short supply.1 After two weeks of lipid-free PN, the minimum dose of IV fat emulsions, which is 100 g/week, can be provided to prevent essential fatty acid deficiency.

IV fat emulsions should be discontinued in patients tolerating EN and who don’t have malabsorption concerns.

IV Multiple Vitamins
When there’s a shortage of IV multiple vitamins, dietitians should evaluate all patients for their ability to absorb enteral multiple vitamin supplements in capsule, tablet, liquid, or chewable forms. For patients who can’t absorb enteral vitamin supplements, the IV multiple vitamin dose should be decreased from 10 mL to 5 mL/day to conserve supplies. If IV multiple vitamins remain in short supply despite conservation efforts, the standard dose of 10 mL should be given three times per week.2

If supplies have been exhausted, PN must be supplemented intravenously with individual parenteral vitamins according to the following ASPEN recommendations: thiamin: 6 mg; folate: 0.6 mg; ascorbic acid: 200 mg; pyridoxine: 6 mg; and vitamin K: 0.5 to 1 mg/day or 5 to 10 mg/week.2 In addition, cyanocobalamin (vitamin B12) must be given intramuscularly at least once per month.2

Trace Elements
Combination trace elements and individual trace element products offer alternatives to PN products in short supply.

Combination Multiple Trace Element Products
Dietitians have a choice of two different multiple trace element combination products: MTE4 and MTE5. MTE4 products contain zinc, copper, chromium, and manganese and come in a standard 3 mL dose or a 1 mL concentrated dose. MTE5 products contain the same four trace elements with the addition of selenium in either the standard 3 mL dose or the 1 mL concentrated dose.

If there’s a shortage of the concentrated products, RDs can use the standard 3 mL dose of MTE4 and MTE5. When MTE4 products aren’t available, RDs can substitute the MTE5 products. If MTE5 products aren’t available, RDs should substitute MTE4 products and add 60 mcg of selenium individually to achieve the equivalent composition of MTE5.

When there are limited supplies of all MTE4 or MTE5 products, RDs should discontinue all MTE products for any patients tolerating EN care without malabsorption concerns. For patients who can’t absorb trace elements through the enteral route, RDs should decrease the doses of MTE products by 50% on a daily basis or deliver the full dose of the product three times per week.3 If no MTE products are available, individual trace elements should be added to PN solutions.

Individual Trace Elements
Individual trace elements are used when combination trace element products are unavailable or when additional supplementation of one component is needed because of deficiencies. RDs should assess patients to determine whether they can absorb enteral trace element supplements. In instances when enteral supplements can’t be used or absorbed, RDs should prioritize the use of individual trace elements to these patients.

There’s no need to supplement manganese when there are shortages of multiple trace element products. Whole blood manganese levels frequently are elevated in long-term PN patients, and manganese contamination often occurs in other PN products. No alternative IV forms of chromium are available but, like manganese, there may be some chromium despite the fact it isn’t intentionally added because of its contamination potential in other PN products. RDs can evaluate a patient’s ability to absorb chromium as part of multivitamin and mineral supplementation through the enteral route and monitor for signs of deficiencies.

Other than the selenium content of MTE5 products, selenium is available as a single IV trace element product. When MTE5 products and individual IV selenium products aren’t available, RDs can consider using oral selenium supplementation.

Copper is available as a single PN trace element in two forms: IV copper chloride or IV cupric sulfate. If all supplies of IV copper have been exhausted, a patient should be evaluated for oral copper supplements.

Zinc is available in either IV zinc sulfate or IV zinc chloride. It’s important to note that if zinc is given enterally in high doses, RDs should monitor for a copper deficiency, as zinc and copper both compete for absorption with the same carrier protein when EN is used.

Electrolytes
The electrolytes calcium, magnesium, phosphorus, potassium, and sodium are critical components in PN care. When shortages occur, it’s imperative for dietitians to know what to substitute, how to monitor patients for deficiencies, and what to do if deficiencies occur.

Calcium
Dietitians should prioritize all calcium for pediatric patients, but they can safely exclude it in adult patients on short-term PN. Clinicians should evaluate ionized calcium levels rather than serum calcium, since serum calcium is protein bound. If ionized calcium levels are low, IV calcium chloride or IV calcium gluconate can be delivered apart from the PN bag.

It’s important to note that IV calcium gluconate and IV calcium chloride doses aren’t equivalent. There’s three times more calcium per gram in calcium chloride than in calcium gluconate, which is important to factor into calculations when using calcium chloride, especially if it’s used as a product substitution. This is an example of a possible medical error that can occur when using unfamiliar products that pose safety concerns.

If calcium gluconate is available, dietitians should give long-term PN-dependent patients at least 5 to 10 mEq when possible. Long-term PN patients have the potential for developing metabolic bone disease. Avoiding a negative calcium balance is critical since the lack of calcium plays a critical role in metabolic bone disease.

There’s limited stability data on the use of calcium chloride in PN solutions, so this should be reviewed with a pharmacist before recommending its use if calcium gluconate isn’t available for compounding the PN solution in long-term PN patients. Calcium can be omitted for short-term PN patients as long as the RD closely monitors ionized calcium levels.

Magnesium
There are two forms of magnesium that dietitians can use interchangeably in PN solutions: magnesium sulfate and magnesium chloride. Both forms of the IV magnesium salts have the same amount of magnesium per gram. If magnesium salts are in short supply, RDs can decrease the dose in PN solutions to maintain serum magnesium levels at the low end of normal.

If no magnesium is available, dietitians can suggest oral magnesium supplements. Oral magnesium lactate or oral magnesium gluconate are superior choices to oral magnesium oxide because they don’t have the laxative effect of magnesium oxide.

Phosphorus
Sodium phosphate and potassium phosphate are the two phosphate salts available for compounding PN solutions. Clinicians can switch between the two salts but, as an important safety measure, they should adjust the overall potassium composition of the PN solution. For example, if a patient previously received sodium phosphorus and began receiving potassium phosphate, the RD would calculate how much potassium would be provided after switching to potassium phosphate and adjust the other potassium salts in the PN solution to ensure the patient didn’t receive excess potassium.

If there are no IV potassium phosphates available, one option is to provide an amino acid solution that has inherent phosphate salts (10 mmol of inherent phosphates per 100 g of the amino acid solution). An alternative option, although not as useful in patients requiring PN, is to consider the oral route for phosphorus supplementation in patients without malabsorption or diarrhea. RDs should familiarize themselves with potential side effects of oral phosphate supplements, specifically exacerbations of gastrointestinal stool losses.

If IV phosphates are unavailable and oral phosphate products aren’t a good choice for a patient, dietitians should screen the patient for phosphorus deficiency symptoms and monitor the serum phosphorus laboratory studies more frequently. Dietitians should consider temporarily decreasing the IV dextrose load provided by PN or slowly increasing dextrose in patients starting on PN to circumvent the intracellular shifts in phosphorus.

The use of supplemental IV phosphorus products given outside of PN should be rationed and prioritized to remedy deficiencies in serum phosphorus levels. For example, a clinician would provide an IV bolus of sodium or potassium phosphorus when serum phosphorus levels reached a predetermined critical level established by the health care institution or when patients exhibited severe physical manifestations of a deficiency. Creating these protocols for restricted use helps reserve supplies for patients with the greatest need.

Potassium
Either potassium chloride or potassium acetate can be used for potassium delivery in PN solutions. If there’s a shortage of potassium acetate, RDs should switch from potassium acetate to potassium chloride and adjust the acid-base balance of the PN solution with sodium acetate. If potassium chloride is in short supply, they should switch to 100% potassium acetate and adjust the acid-base balance using sodium chloride.

Moreover, potassium phosphorus is an option if no potassium chloride or acetate salts are available. For safety reasons, it’s important to calculate the amount of phosphorus that will be provided and adjust the other phosphate-containing portions of the PN solution so excess phosphorus isn’t administered. Oral potassium preparations are viable options when no potassium is available to add to the PN solution, but increased monitoring is imperative.

Sodium
The main options for sodium delivery in PN solutions are sodium chloride and sodium acetate salts. Sodium phosphorus provides a small amount of sodium, but this isn’t the main source. When a shortage of sodium chloride occurs, RDs can suggest switching to sodium acetate and using potassium chloride to balance the acid base while keeping total potassium measures the same.

If sodium acetate is in short supply or unavailable, the acetate should be maximized by using potassium acetate while keeping the total potassium content the same. Sodium bicarbonate isn’t compatible with PN solutions and shouldn’t be used. The sodium deficit shouldn’t be replaced with sodium chloride, as this may worsen acidosis.

Dietitians can consider oral sodium bicarbonate supplements. They can be crushed in applesauce for patients with malabsorption and diarrhea.

Institutions should allow for mild hyponatremia and mild acidosis but have predetermined cut-off values for delivering IV sodium bicarbonate apart from the PN solution.

European Importation
On May 29, the FDA approved importing pediatric and adult trace elements (Pediatrace and Addamel N) as well as an organic phosphate product (Glycophos) from Europe. However, these products have different labeling and composition compared with the trace and phosphate products available in the United States.

RDs should work with pharmacists and physicians to understand the indications, dosing, administration, contraindications, and prescribing information for using these PN drugs.

Collaborative Solutions
No simple solution exists for dealing with PN drug shortages. The solution requires collaboration with the interdisciplinary team. While substitutions are available, monitoring and safety checks should be increased to minimize the potential for medical errors. It’s important for clinicians to report outcomes, educate PN patients, and provide data to regulatory departments in government.

Dietitians and other clinicians shouldn’t avoid using European products because of unfamiliarity, but they should seize the opportunity to provide these products to patients and learn about their composition and use. All recommendations for substitutions or changes to PN solutions should be discussed with the managing physician, who is the ultimate decision maker for the patient’s PN and medical care.

— Mandy L. Corrigan, MPH, RD, LD, CNSC, is a nutrition support dietitian with Coram Specialty Infusion Pharmacy.

 

RD Responsibilities During PN Drug Shortages
• Assess the appropriateness of parenteral nutrition (PN).

• Assess the ability to transition to enteral nutrition.

• Recommend supplementation, enteral alternatives, and adjustments to PN additives.

• Become familiar with potential side effects of substitute drug products (ie, oral/enteral drug substitutes).

• Become familiar with physical and biochemical signs and symptoms of deficiencies.

• Prioritize limited supplies according to patients with the greatest needs.

• Become familiar with resources and guidelines from professional societies.

• Communicate information about shortages to patients and their family members.

• Work with the hospital and home care supply chain to recommend alternative products for PN solutions.

— MLC

 

Professional Resources
• American Society of Health-System Pharmacists Drug Shortages Resource Center: www.ashp.org/menu/DrugShortages

• American Society for Parenteral and Enteral Nutrition Drug Shortages Update: www.nutritioncare.org/Professional_Resources/Drug_Shortages_Update

• FDA Current Drug Shortages Index: www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm050792.htm

• FDA Fact Sheet: Drug Products in Shortage in the United States: www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/
SignificantAmendmentstotheFDCAct/FDASIA/ucm313121.htm

• FDA Frequently Asked Questions About Drug Shortages: www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm050796.htm

• Fresenius Kabi Adult Multitrace Element Availability (product information): www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM355392.pdf

• Fresenius Kabi Pediatric Multitrace Element Availability (product information): www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM354265.pdf

• Fresenius Kabi Phosphate Injection Availability (product information): www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM354277.pdf

• National Medication Errors Reporting Program (patients and clinicians): www.ismp.org/orderforms/reporterrortoISMP.asp

 

For More Information
The following references can serve as viable resources for dietitians to learn more about parenteral nutrition drug shortages and their impact on patient safety and patient care:

• Buchman AL, Howard LJ, Guenter P, Nishikawa RA, Compher CW, Tappenden KA. Micronutrients in parenteral nutrition: too little or too much? The past, present, and recommendations for the future. Gastroenterology. 2009;137(5 Suppl):S1-S6.

• Corrigan ML, Kirby DF. Impact of a national shortage of sterile ethanol on a home parenteral nutrition practice: a case series. JPEN J Parenter Enteral Nutr. 2012;36(4):476-480.

• Holcombe B. Parenteral nutrition product shortages: impact on safety. JPEN J Parenter Enteral Nutr. 2012;36(2 Suppl):44S-47S.

• Holcombe B, Andris DA, Brooks G, Houston DR, Plogsted SW. Parenteral nutrition electrolyte/mineral product shortage considerations. JPEN J Parenter Enteral Nutr. 2011;35(4):434-436.

• Mirtallo JM, Holcombe B, Kochevar M, Guenter P. Parenteral nutrition product shortages: the A.S.P.E.N. strategy. Nutr Clin Pract. 2012;27(3):385-391.

 

References
1. Parenteral nutrition product shortage considerations. American Society for Parenteral and Enteral Nutrition website. http://www.nutritioncare.org/Professional_Resources/Drug_Shortages/IV_Fat_
Emulsions_Product. May 2013. Accessed May 3, 2013.

2. Information to use in the event of an intravenous multivitamin shortage — May 2012. American Society for Parenteral and Enteral Nutrition website. http://www.nutritioncare.org/lcontent.aspx?id=5346. May 2012. Accessed May 1, 2013.

3. Parenteral nutrition trace element product shortage considerations. American Society for Parenteral and Enteral Nutrition website. http://www.nutritioncare.org/News/Parenteral_Nutrition_Trace_Element_Product_
Shortage_Considerations. May 2011. Accessed May 1, 2013.