We have been faced with many drug shortages over the past several years. When reviewing the literature for publications about drug shortages, the populations most effected appear to be intensive care and oncology patients.
Of course, there are some articles, although few, related to the effect of drug shortages in the neonatal population. This occurs for several reasons. While there are several drugs used routinely in the NICU population, there are far more used in the adult population. Also, the neonatal population is far smaller, by comparison than even the adult intensive care population or oncology population. However, given that many of the drugs used routinely in the NICU are not FDA approved for use for this population (simply owing to the absence of adequate studies) the absence of these drugs being available for NICU use may not be considered by the FDA . With the shortage of a drug with which providers are familiar, other drugs may be brought in for use with similar action but unknown side effects or even efficacy in the neonate.
But first, let’s consider why the shortages. Rider et al reported the number of drug shortages by year from 2001 through 2011.1 There were fewer than 100 drug shortages reported in the early 2000’s with the numbers steadily climbing since 2007 and approaching 300 in 2011. Most of these drugs are sterile injectable drugs. Apparently, and not surprisingly, this process is more costly for production. Reasons for reported shortages include:
· Shortage or lack of available components
· Sterility concerns in the final product (leading to a stop in production)
· Updating of manufacturing facilities
· Few manufacturers for the same or similar products
· Inability of manufacturers to “ramp up” production on short notice
· Increased/unexpected use of a specific product
· Lack of financial incentive (orphan drugs or low use drugs)
On July 9, 2012, a law was enacted requiring that manufacturers notify the FDA of an anticipated shortage (www.gpo.gov/fdsys/pkg/PLAW-112publ144/pdf/PLAW-112publ144.pdf). This makes it possible for pharmacists and physicians to be alerted to a possible shortage and begin making plans for alternatives. However, when no alternative exists, it doesn’t solve the problem. In addition, some hospitals, physicians or pharmacies may stock pile the drug, creating even more critical shortages that cannot be anticipated. It has been reported that, in some cases, so-called “gray-market” drugs may be used.2 These are the same or similar drugs manufactured in less than sterile conditions. One published report attributes the use of a “gray-market” drug to the outbreak of fungal meningitis.3
Specific to the NICU, certain preservatives are known to be harmful to the developing human body and therefore avoided. A necessary drug alternative may be available but if it contains mercury or benzyl alcohol, for instance, it is necessary to avoid use in the neonatal population. Therefore, the preservative-free version needed for the NICU may only be used in this population, making it very, very expensive to produce and ultimately to use. The price tag may be too great if the charge reflected the cost to the producer. Because it is used in a relatively small population, the manufacturer eventually may stop production for financial reasons. This has been raised as a potential issue in the adult population as calls are raised to decrease costs of health care by limiting coverage of drugs. These more costly drugs become unavailable, then when an alternative is needed, there is none.
While all of this is frustrating to every healthcare provider, what is the effect on the patient? Are we able to find an alternative most of the time? Where do we look for possible alternatives?
Some reports exist of detrimental effects on the patient. Ruktanonchi et al report on some cases of erosive dermatitis or blistering of the skin related to the recent (and ongoing) shortage in zinc injectables appropriate for use in the neonate.4 There was a request for these to be reported through the American Academy of Pediatrics and state departments of health which ultimately was reported to the Centers for Disease Control. Likely, not every case was reported and some may not have even been diagnosed as the effects disappeared once the infant was on adequate oral feedings and there are many underlying factors to dermatitis in the NICU. Many of you will remember the unavailability of hyaluronidase (sold as Wydase™). There were many years when we did not have this available for treatment of intravenous infiltrations. How many of those developed in to delays in discharge, pain, scarring, limitations in mobility, even infections due to the lack of this product?
As for alternatives, we can usually find something but it may take time during which we have nothing or the alternative may not yield the same benefit. Propofol is now in short supply. This is a common anesthetic agent and used for sedation during intubation. Studies show this leads to shorter duration of mechanical ventilation, shorter hospital stays and other beneficial outcomes in the adult population. With the passage of the Food and Drug Administration Safety and Innovation Act (FDASI), the reporting of potential shortages is required 6 months in advance. This allows the FDA what they perceive to be sufficient time to find alternatives. In some cases, the drug is brought in from manufacturers outside the U.S. (after the FDA has guaranteed adequate manufacturing processes) or other sources within the U.S. may be contacted to increase production. In the instance of the zinc shortage, no suitable alternatives were available for use in the neonate and could not be secured quickly enough.
These are examples of known detriment from specific medication shortages.
In summary, drug shortages appear to be a part of healthcare today and for at least the foreseeable future. Our challenge is to deal with them in the most effective way. The FDA’s website at https://www.fda.gov/drugs/drugsafety/drugshortages/ provides updates on drugs that are or are expected to be in short supply or not available. At present, there is no coordinated way of recommending alternatives. This process has to be developed by each individual institution or healthcare system. It is important, however to officially report any patient effects from lack of a medication or replacement products.
1. Rider AE, Templet DJ, Daley MJ, Shuman C, Smith LV. Clinical dilemmas and a review of strategies to manage drug shortages. Journal of Pharmacy Practice. 2013;26(3):183-191.
2. Gupta DK, Huang SM. Drug shortages in the United States: A critical evaluation of root causes and the need for action. Clinical Pharmacology and Therapeutics. 2013;93(2):133-135.
3. Outterson K. Regulating compounding pharmacies after NECC. N Engl J Med. 2012;367:1969-1972.
4. Ruktanonchai D, Lowe M, Norton S, et al. Zinc deficiency-associated dermatitis in infants during a nationwide shortage of injectable zinc – Washington, DC, and Houston, Texas, 2012-2013. Morbidity and Mortality Weekly Report. 2014;63(2):35-37.
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