Disruptions in the Supply of Medications Used in Transplantation: Implications and Management Strategies for the Transplant Clinician

Abstract

Drug shortages are a threat to patient care and public health, and the number of drugs on shortage is growing at an exponential rate. The major therapy areas affected by these shortages are oncology, anti-infective, cardiovascular and central nervous system. However, drugs utilized in the transplant patient population have not been exempt, and can have significant influence on posttransplant outcomes. The purpose of this review is to discuss the current and historical solid organ transplant-related disruptions in the supply of medications and implications on patient care and safety. Transplant centers should be armed with an implementation plan when imperative transplant-related drugs such as tacrolimus, mycophenolate, or antithymocyte globulin go on shortage. This plan should provide steps to manage the shortage, and provide effective therapeutic alternatives.

Abbreviations

ASHP,

American Society of Health-Systems Pharmacy

ATG,

antithymocyte globulin

AWP,

average wholesale price

CMV,

cytomegalovirus

FDA,

Food and Drug Administration

HSV,

herpes simplex virus

IL-2RA,

interleukin-2 receptor antagonist

ISMP,

Institute for Safe Medication Practices

IVIg,

intravenous immune globulin

PJP,

pneumocystis jiroveci pneumonia

rATG,

rabbit antithymocyte globulin

SMX/TMP,

sulfamethoxazole/trimethoprim

VZV,

varicella zoster virus.

From newspaper articles, to segments on the news, statements from professional medical associations, and a Presidential Executive Order, the impact of drug shortages is a highly visible threat to patient care and public health. According to the US Food and Drug Administration (FDA), there are 120 drugs currently on shortage, the American Society of Health-Systems Pharmacy (ASHP) cites 277 drug shortages currently [1, 2]. From 2006 to 2011 we have seen a 200% increase in the number of drug shortages (Figure 1) [3]. More than 80% of the total national shortages affect generic sterile injectable medications. Causes identified for shortages include unknown reasons (54%), manufacturing problems (25%), supply/demand (12%), discontinuations (6%) and lack of raw materials (3%) (Personal Communication, Erin Fox, PharmD, Manager of Drug Information Services at University of Utah, May 2012).

Figure 1. National drug shortages January 2001 to March 31, 2012. Note: Each column represents the # of new shortages identified during that year. Source: University of Utah Drug Information Services 2012.

Currently, drug shortages span across all major therapy areas with oncology (16%), anti-infective (15%), cardiovascular (12%) and central nervous system (11%) drug classes accounting for the largest percentage [4]. Medications utilized in solid organ transplantation have not been exempt from the effects of drug shortages (Table 1). In September 2012, transplant clinicians will be impacted by changes to the distribution of alemtuzumab as a result of the US Campath® Distribution Program [5]. Additionally, one generic manufacturer of tacrolimus removed product from the market, which may result in temporary disruptions in the supply of this crucial immunosuppressant.

Table 1. Current and historical drug shortages

Medication	Shortage specifics	Therapeutic use in transplant	Management and recommendations
Current shortages
Alemtuzumab	• Change in distribution September 4, 2012[5]• Only available via the US Campath Distribution Program[5]	• Induction agent[10]	First line[10]• High immunologic risk: Antithymocyte globulin• Low immunologic risk: Basiliximab
Sulfamethoxazole/ Trimethoprim	• Shortage since March 2010[1]• IV product only[1]• Due to single manufacturer, product recall and manufacturing difficulties[1]	• Treatment and prophylaxis of Pneumocystis jiroveci pneumonia[11, 12]• Treatment of Nocardia species, Stenotrophomonas maltophilia[13]	Prophylaxis of Pneumocystis[11]First line• Oral SMX/TMP 1 SS or DS tablet dailySecond line• Inhaled pentamidine 300 mg every 4 weeks• Oral dapsone 100 mg daily or 50 mg twice daily• Oral atovaquone 1500 mg daily
			Treatment of Pneumocystis[12]First line
			• Oral SMX/TMP 15–20 mg/kg/day of TMP component given in divided doses every 6–h
			Second line• Pentamidine isethionate IV 4 mg/kg/day over 1–2 h, then reduce to 2–3 mg/kg/day if needed• Oral dapsone 100 mg daily with oral trimethoprim 15 mg/kg/day divided three times daily• Oral atovaquone 750 mg twice daily• Oral clindamycin 600–900 mg every 6–8 h with oral primaquine 15–30 mg daily
			Nocardia treatment[13]
			First line• Oral SMX/TMP 15 mg/kg/day of TMP component in 2–4 divided doses for 3–4 weeks, then 10 mg/kg/day of TMP component in 2–4 divided doses
			Second line (should rely on susceptibilities)[13]• Third-generation cephalosporins• Minocycline• Carbapenems• Amikacin
Cyclosporine	• IV product shortage since February 2010[1]• IV product shortage following one manufacturer's discontinuation of production[1]• Oral product shortage since March 2012[1]	• Maintenance immunosuppression[14]	First line[14, 15, 19]• Oral tacrolimus 0.1–0.2 mg/kg/day divided twice daily, adjusted based on trough concentrations• IV tacrolimus 0.03–0.05 mg/kg continuous infusion, adjusted based on levels• Alternative cyclosporine product, with dose adjustments based on trough concentrations
	• Oral (modified, microemulsion) product ongoing shortages due to manufacturing delays and other reasons not provided[1]		Second line[15]• Oral sirolimus 2 mg daily, adjusted based on levels• Oral everolimus 0.75 mg twice daily, adjusted based on levels
Azathioprine	• Shortage since May 2011[1]• IV product only[1]• Ongoing shortage due to single manufacturer suspended production[1]	• Maintenance immunosuppression[14, 19]	First line[14, 19]• Mycophenolate mofetil 1 g IV/PO twice daily• Oral azathioprine 3–5 mg/kg (induction) and then 1–3 mg/kg (maintenance)
Ganciclovir	• Shortage since May 2009[1]	• CMV prophylaxis[35]	First line[15, 35]
	• Oral capsule product on shortage due to lack of raw material[1]		• Oral valganciclovir 900 mg daily• Preemptive CMV monitoring with serial CMV PCRs for those that cannot afford valganciclovir copays
			Second line[15, 35]• IV ganciclovir 5 mg/kg every 12 h or q24 h for prophylaxis
Acyclovir	• IV product shortage since April 2012[1]• IV (lyophilized product) on shortage due to decreased production and shift in demand[1]• Intermittent PO product shortage since December 2009[1]• PO (capsules, tablets) on shortage due to multiple reasons, including unavailable raw material[1]• Intermittent PO product shortage since December 2009[1]	• Prophylaxis and treatment of herpes simplex virus (HSV)[13, 15, 35]• Treatment of varicella zoster virus (VZV)[13, 15]	HSV prophylaxis[13, 15, 35]First line• Oral acyclovir product should be used as available• Oral valacyclovir 500 mg to 1 g dailySecond line• Oral famciclovir 250–500 mg twice daily, caution with use in immunocompromised patientsHSV and VZV Treatment[13, 15]First line• Oral or IV acyclovir products should be used as available• Oral valacyclovir 1 g twice daily (HSV) or 1 g three times daily (uncomplicated VZV)Second line• Oral famciclovir 500 mg twice daily (HSV) or 500 mg three times daily (uncomplicated VZV), caution with use in immunocompromised patients
			Third line• IV foscarnet 40 mg/kg every 8–12 h (HSV) or 90 mg/kg every 12 h (VZV)
Alprostadil	• Shortage since November 2008[1]• Due to cessation in production[1]	• Enhance perfusion in liver transplant recipients at risk for primary graft nonfunction, improve renal function after liver transplant[20]	No appropriate therapeutic alternatives have been studied
Phytonadione	• Shortage since April 2012[1]• Ongoing shortage due to manufacturing delays[1]	• Liver transplantation to reverse coagulopathies[36]• Reverse warfarin therapy for procedures or due to bleeding[22]	First line[21, 22]• Oral vitamin K 1–10 mg based on INR and risk or severity of bleedingSecond line—for severe or life-threatening bleeding[15]• FFP or factor VIIa 20–90 mcg/kg IV push• PCC 50 IU/kg IV push with or without factor VIIa
Historical shortages or product discontinuations
Orthoclone®, OKT3 (muromonab-CD3)	• Withdrawn from the market in 2010 due to decreased market demand and significant decline in use[30]	• Induction therapy[27, 29]• Treatment of rejection[27, 29]	Induction Therapy [14, 15, 27]First line• Antithymocyte globulin 1.5 mg/kg IV daily for 3–5 doses• Anti-CD52 antibody (alemtuzumab) 30 mg IV once
			Second line• Interleurkin-2 receptor antagonist (basiliximab) 20 mg IV on days 0 and 4 (usually recommended for lower immunologic risk patients)
			Treatment of rejection [14, 15, 27]
			First line• Antithymocyte globulin 1.5 mg/kg IV daily for 7–14 days• Anti-CD52 antibody (alemtuzumab) 30 mg IV once (limited data for use to reverse acute rejection)
			Second line• Horse antithymocyte globulin 10–15 mg/kg/day daily for 14 days, then every other day for 14 days
			Third line• IVIg with or without plasmapheresis
Daclizumab	• Withdrawn from the market due to decreased market demand and available alternatives[1]• Last produced lot expired in 2011[1]	• Induction therapy[14]	First line[15]• Basiliximab 20 mg IV on days 0 and 4Second line (usually reserved for high immunologic risk patients)[15]• Antithymocyte globulin 1.5 mg/kg IV daily for 3–5 doses• Anti-CD52 antibody (alemtuzumab) 30 mg IV once
Methylprednisolone	• Shortage was due to decreased production from several companies and inability for other companies to meet demand[1]• Shortage on and off for 10 years[1]• Resolved in 2011[1]	• Treatment of rejection[15]• Induction to prevent rejection[15]• Premedication prior to blood products, anti-thymocyte globulin and IVIg[15]	Equivalent doses to 100 mg IV methylprednisoloneFirst line[15]• 18.75 mg IV dexamethasone• 500 mg IV hydrocortisoneSecond line[15]• 100 mg oral methylprednisolone (divided doses to minimize GI issues)• 125 mg oral prednisone methylprednisolone (divided doses to minimize GI issues)
Aminocaproic acid	• Shortage was due to decreased production from several companies and inability for other companies to meet demand[1]	• Prevent fibrinolysis during or immediately following orthotopic liver transplantation[23]	First line[23]• Tranexamic acid 10 mg/h IV infusion
	• Shortage lasted ∼10 months[1]
	• Resolved in 2012[1]
Cytomegalovirus hyperimmune globulin (Cytogam®)	• Shortage was due to lack of supply[37]• Resolved in 2006[37]	• Prophylaxis of CMV in D+/R−[15]• Treatment of severe CMV disease (limited data for this indication)	CMV Prophylaxis[15]First line• Valganciclovir 900 mg PO dailyCMV treatment[15]First line• IVIG 1–2 gm/kg in divided doses (limited data)• Ganciclovir 5 mg /kg IV q12 h
			Second line• IV Foscarnet 90–120 mg/kg once daily
Intravenous immune globulin	• Shortage was due to multiple reasons including product recall, scrutiny of manufacturing practices, increased use of product[26]	• Desensitization protocols[25]• Treatment of antibody mediated rejection[25]	No appropriate therapeutic alternatives have been studied
	• Shortage was on and off for several years[26]
	• Resolved[26]

Drug shortages can pose minor to major disruptions to hospitals and clinics depending on the availability of therapeutic alternatives. In a majority of cases the alternative is not as effective or is unfamiliar to clinicians. According to the Institute for Safe Medication Practices (ISMP), 15 patient deaths nationally were attributed to mistakes related to drug shortages. In a 2010 ISMP survey, clinicians reported they experienced a near miss (35%), actual error (25%), or reported adverse patient outcomes (20%) related to a drug shortage [6]. Managing the constant movement of supply, in-house inventory levels and communication to physicians, pharmacists, nurses, patients and outside third party health care vendors provides a significant challenge to organizations. An estimated $216 million is spent annually to oversee and manage drug shortages [7].

The White House released a Presidential Executive Order in October 2011 for drug shortages that allows the FDA to broaden reporting of potential shortages, expedite regulatory review, and increase staffing resources for the FDA's drug shortage program [8]. Voluntary early notification by manufacturers has allowed the FDA to prevent 137 drug shortages since the beginning of 2010 through inviting other manufacturers to increase production, lessening manufacturer quality issues and accelerating regulatory review submissions. In July 2012, President Obama signed ‘The Food and Drug Administration Safety and Innovation Act’. This bipartisan legislation requires manufacturers to notify the FDA of production interruptions and discontinuation at least 6 months in advance, and gives the FDA authority to speed approval of products and new drug applications and creates a generic user fee program intended to stimulate FDA approval of generics [9].

In the wake of nationwide medication supply disruptions, transplant clinicians should be prepared to address potential shortages of imperative drugs to this population. The purpose of this review is to discuss the current and historical solid organ transplant-related drug shortages and implications on patient care and medication safety. Additionally, the management and strategies to optimize care surrounding shortages is discussed.

Current Shortages/Changes in Product Availability

Alemtuzumab (intravenous)

Although not FDA approved, alemtuzumab is used for induction in transplantation [10]. However, it was recently announced that as of September 4, 2012, alemtuzumab will only be available in the United States via the Campath® Distribution Program [5]. This decision is being made following the manufacturer's desire to focus use in multiple sclerosis. The impact of this change will vary across transplant centers depending on current induction protocols. This will lead to increased regulation and processes to gain access to this commonly used induction therapy. Transplant centers must stay vigilant to maintain adequate supply, and continually resubmit documentation for additional product.

Sulfamethoxazole/trimethoprim (intravenous)

Pneumocystis jiroveci pneumonia (PJP) is a well-recognized opportunistic infection in immunosuppressed patients, and nearly all patients posttransplant are initiated on chemoprophylaxis [11]. The therapy of choice for an active severe PJP infection is IV SMX/TMP [12]. Unfortunately, there is a long-standing national shortage of this product due to manufacturing problems, product recall and a single manufacturer [1, 2].

The issues surrounding the use of therapy alternatives include lower efficacy and higher rates of toxicity. IV SMX/TMP is also the therapy of choice for severe Nocardia species infections [13].

Unfortunately, without access to IV SMX/TMP these serious infections may be treated inadequately. Clinical unfamiliarity with alternative therapies increases the risk for medication errors and adverse drug events through improper dosing or inadequate monitoring.

Cyclosporine (intravenous and oral, modified)

Cyclosporine established calcineurin inhibitors as essential to maintenance immunosuppression regimens [14]. Most transplant centers have transitioned to tacrolimus as the calcineurin inhibitor of choice, but cyclosporine continues to be an important therapeutic alternative. IV cyclosporine was available as a generic injection as well as brand name, Sandimmune®[15]; however, after one generic manufacturer discontinued the product, and another voluntarily suspended its manufacturing and distribution, the only IV product currently on the market is Sandimmune®[1].

Further complicating this picture is the ongoing shortage of oral cyclosporine modified products. Oral cyclosporine is available as a modified (microemulsion) or oil-based cyclosporine product. Clinically, the products are not considered bioequivalent and cannot be interchanged without dose modification and therapeutic drug monitoring [16]. Oral oil-based cyclosporine is available as generic or brand name Sandimmune®[15]. The modified cyclosporine is available as generic, branded generic (Gengraf®), or brand name Neoral®. Clinically, the modified formulation has more predictable bioavailability, and is the preferred product [17]. The shortage of the generic modified cyclosporine has led to medication errors and confusion by both patients and outside pharmacies. Patients are being converted between nonbioequivalent formulations, which cause fluctuations or dramatic changes in blood trough concentrations [18]. Even when conversions are appropriately conducted between bioequivalent formulations, trough concentration fluctuations are a concern, and patient unintentional nonadherence may occur due to confusions with product color and shape changes.

Azathioprine (intravenous)

Azathioprine, an antiproliferative agent, is only available from a single manufacturer, which has voluntarily suspended production [1, 14, 19]. This occurred in November 2011 for maintenance and requalification of equipment, and is still ongoing. The oral preparation has not been effected by this shortage [1].

Clinically, mycophenolate products have replaced most of the use of azathioprine due to improved efficacy [14]. However, there are situations when intolerability to mycophenolate can occur, and the loss of azathioprine as an option leaves a gap in the armamentarium for immunosuppressant regimens.

Ganciclovir (oral)

Ganciclovir is approved for the prevention and treatment of CMV disease [15]. Although valganciclovir is the agent of choice for CMV prophylaxis, ganciclovir is still utilized (particularly in Europe and Asia), and may be required by some prescription drug benefits organizations (PBMs). Currently, this agent is on a significant long-term shortage due to a lack of raw drug material, and it is unclear whether the agent will return to the US market [1].

This shortage is most prudent for those patients whose prescription insurance plans will only cover oral ganciclovir. Despite this shortage being in place for over a year, there are still situations where insurance companies have denied coverage for valganciclovir with the rationale to utilize oral ganciclovir. Even if covered by the prescription drug plan, the high cost of valganciclovir can result in high out-of-pocket copays for patients, which may preclude its use for patients of limited means. Without the option of generic oral ganciclovir, some must forgo CMV prophylaxis and be closely monitored with preemptive monitoring. Although this may not result in significant differences in clinical outcomes, transplant center resources or costs may be higher with this option [20, 21]. It is not known when this shortage will resolve, or even if any manufacturers have the impetus to reintroduce generic oral ganciclovir back to the market.

Acyclovir (intravenous and oral)

Acyclovir is an antiviral agent used to prevent or treat herpes simplex (HSV) and varicella zoster viral (VZV) infections. The IV acyclovir product is available as a lyophilized powder or as a solution for injection; currently the lyophilized product is on shortage. While one company temporarily suspended the manufacturing, another company could not keep up with shift in demand [1]. Additionally, there is an ongoing shortage of oral acyclovir products [1]. Fortunately, with multiple manufacturers, complete supply disruptions are rare.

Alprostadil products

Alprostadil, prostaglandin E₁, causes vasodilation and platelet inhibition. Although not FDA approved, alprostadil has been used in liver transplantation to enhance graft perfusion, and avoid primary graft nonfunction [22]. Evidence supporting its use has been controversial [22]. Since there are little to no data examining the use of other PGE analogs, the shortage of alprostadil does not leave a therapeutic alternative.

Phytonadione, vitamin K (intravenous)

Currently, the shortage of IV vitamin K product is due to production delays from one manufacturer, and inability of a second manufacturer to keep up with increased demand. For patients able to take PO medications, oral vitamin K is a reasonable alternative. Oral and IV administration are both effective at INR reversal [23]. Oral vitamin K doses of 2.5–5 mg were found to have similar efficacy to 0.5–1 mg IV vitamin K in one study, although other studies have used doses of 10 mg oral or IV [23, 24].

This discussion of current drug shortages is not a complete review, but details the most important disruptions relevant to transplant clinicians. Additional medications that may be important in transplantation on national shortage include IV fluconazole, leflunomide tablets and IV phosphorus replacement products [1, 2].

Historical Shortages/Discontinuations

Methylprednisolone (intravenous and oral)

Corticosteroids are essential components to induction immunosuppression and for the treatment of cellular rejection, with upwards of 70% of transplant patients receiving these agents for chronic maintenance therapy [14, 19, 25].

The shortage of IV methylprednisolone several years ago, which lasted for longer than 6 months, required alternative corticosteroids to be utilized for both prevention and treatment of rejection [1]. In terms of comparative potency, hydrocortisone has higher mineralocorticoid activity, and dexamethasone has no mineralocorticoid activity but does have a longer half-life than methylprednisolone [15]. Many centers during the shortage relied on dexamethasone, although no consensus on the clinical equivalence of these agents has been determined. Fortunately, companies were able to increase production and market supply returned to normal in 2011[1]. Given the ubiquitous use of this agent, it has a high likelihood of future supply disruptions, and transplant centers should have comparative dosing charts for back-up IV corticosteroid use.

Aminocaproic acid (intravenous)

Currently, there are two FDA approved antifibrinolytic agents: tranexamic acid and aminocaproic acid [26]. Aminocaproic acid is widely used and less expensive compared to the alternatives [26]. In early 2011, one of the manufacturers of aminocaproic acid had production temporarily suspended leading to significant disruption in supply.

In the face of the aminocaproic acid shortage, tranexamic acid was the available alternative as aprotinin was removed from the US market [15, 27]. Tranexamic acid has been studied in very few prospective, double-blind, controlled trials compared to the other antifibrinolytics, and the ideal dose for use in liver transplantation has not been identified [26].

Intravenous immune globulin (intravenous)

Intravenous immune globulin (IVIg) is derived from pooled plasma, and has been utilized in dozens of autoimmune and inflammatory disorders [28]. Within solid organ transplant IVIg is considered essential for the treatment of antibody-mediated rejection, and is incorporated into many desensitization protocols [28]. Beginning in the late 1990s and extending into the 2000s there was intermittent shortages in the supply of IVIg [29]. Reasons included product recall, increased scrutiny of manufacturing practices, shortage of plasma for production and exponential increase in use of approved and unapproved indications [29]. During these periods of shortage, utilization stewardship was imperative as there is no acceptable alternative to IVIg.

Muromonab-CD3, OKT3 (intravenous) and daclizumab (intravenous)

Although these agents were not on shortage, it is important to recognize how their removal from the market affected transplant patient care. Muromonab-CD3, OKT3, is a monoclonal antibody that was commonly used in previous years to prevent and treat acute rejection following transplantation [14, 15, 30]. After several studies comparing OKT3 to antithymocyte globulin (ATG) illustrated that ATG had improved efficacy with less cytokine release syndrome, the OKT3 market demand dramatically declined [31]. A Cochrane Review comparing polyclonal and monoclonal antibodies in episodes of rejection found no benefit of OKT3, and the manufacturer made the decision to no longer produce the agent [32, 33]. This left a potential hole in the armamentarium of agents to treat severe acute rejection refractory to rabbit ATG, as the use of horse ATG has many disadvantages [34, 35]. With the changes to alemtuzumab supply processes, it is unclear what clinicians will turn to when treating these severe rejections if rabbit ATG is not an option.

Similarly, daclizumab, an interleukin-2 receptor antagonist (IL-2RA), was withdrawn secondary to decreased demand and available alternative, basiliximab, for treatment options.

Potential future drug Shortages: understanding and preparing for the “Worst Case Scenarios”

The drug shortages discussed within this article have all impacted patient care. Fortunately, available alternatives have circumvented most negative effects on patient outcomes, but there is a strong possibility that the crucial medications used in transplantation may have supply disruptions sometime in the not too distant future. These would include medications such as rATG, basiliximab, tacrolimus, mycophenolate or valganciclovir. rATG is the induction agent of choice in more than 40% of kidney transplantations [25]. Since this agent is manufactured at one location for worldwide distribution, it is not unreasonable to consider a scenario in the current regulatory environment where rATG is in low supply [36]. The results of such a scenario could profoundly impact patient care. Additionally, the change in alemtuzumab distribution could have secondary impact on rATG supply, as more centers turn to rATG for prevention and treatment of rejection.

The majority of US transplant centers utilize tacrolimus and mycophenolate as the cornerstone of immunosuppression regimens; up to 80% of patients of patients are discharged on the combination [25]. Due to multiple manufacturers of the oral generic products, it is unlikely that a drug shortage will occur in the near future. As the average wholesale prices (AWP) continue to decline for both products, a number of generic manufacturers are likely to discontinue production due to a loss of profit margins. Consider the example of generic cyclosporine. The generic bioequivalent products to Neoral® (modified cyclosporine) entered the market in May 2000; within a year, there were at least four generic equivalents being manufactured [37]. Yet, currently, there is a shortage of this product. This process occurred within 10 years of the release of generic modified cyclosporine. Generic mycophenolate became available in July 2008 and tacrolimus in April 2010; therefore, it is possible that one of these agents may go on shortage within the next 6 years. Without appropriate alternatives, the shortage of mycophenolate or tacrolimus would have devastating effects on transplant patients.

Even if a shortage does not affect all generic manufacturers equally (the complete supply chain of a particular product), the supply disruption for one particular generically manufactured product can substantially affect patient care. This is the current situation with generic tacrolimus. At least one manufacturer currently has recalled its product, causing a temporary minor disruption in the supply chain for several national pharmacies, and requiring patients to change to a different manufacturer. If a patient has to frequently change between various generic formulations, this will inevitably lead to more variations in trough concentrations, more frequent dose adjustments and monitoring, and patient unintentional medication nonadherence. Confusion to changes in shape and color of various product formulations in conjunction with more frequent dosing modifications will lead to more patient nonadherence, and has the potential to substantially impact clinical outcomes, including late acute rejections and graft loss. These manufacturer-specific drug shortages are very common, and are a substantial, yet underappreciated, cause of medication errors and adverse drug events.

Strategic planning for future drug shortages

Although it is nearly impossible to predict if a drug will go on shortage, it is important to have a formal structure in place that can be efficiently enacted upon the discovery of a drug shortage. The next section will discuss how to develop and implement such a plan within a transplant center [38].

The first part of this strategic plan (Figure 2) is to develop a process to quickly and proactively identify any potential drug shortage. This can be achieved by having a working relationship with the drug manufacturers and product distributors, and an electronic inventory monitoring system with accurate par levels based on utilization reviews. If this process is functioning correctly, institutions should have at least 2 weeks, notice before stock depletion. Once a product is identified as being in short supply, early communication and activation of a strategic process to handle this shortage is crucial.

Figure 2. Strategic management algorithm for solid-organ transplant drug shortages. Adapted from: ASHP Expert Panel on Drun Product Shortages, Am J Health-Syst Pharm 2009.

The next steps in this process are to conduct operational and therapeutic assessments [38]. The operational assessment will determine how severe the shortage is and determine the potential length of time the shortage will occur. The therapeutic assessment will identify which patient populations are going to be affected by the shortage and identify potential alternatives. A multidisciplinary team that includes physicians, pharmacists, nurses and other health care disciplines as necessary should conduct this assessment and plan. The plan should include the identification of therapeutic alternatives, restriction designations of remaining product, new distribution processes, new administration processes, an institutional cost analysis and determination of possible secondary shortages.

The final part of the plan is communication, education and implementation. All disciplines should be educated before the plan is implemented. Medications errors occur from drug shortages. Transplant centers have experienced drug errors secondary to prescribers switching between cyclosporine formulations, resulting in subtherapeutic cyclosporine levels. Education is crucial to prevent errors and should include multiple platforms, including emails, staff meetings, bulletin boards, websites, dashboards and inservices.

Conclusion

Drug shortages continue to have a major impact on patient care, including the care of transplant patients. Clinicians should be aware of current and previous shortages, and prepare for potential shortages of vital transplant drugs. Transplant centers should be armed with the knowledge to implement a protocol for management and therapeutic alternatives.

Disclosure

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.