On June 1, 2008, the United States Pharmacopeia (USP) General Chapter 797 Pharmaceutical Compounding – Sterile Compounding (USP <797>) was made official. This version of the standards and guidance chapter, known as <797> (2008), is still the official version of sterile compounding standards, although a 2021 revised version is under review. The 2008 revisions to sterile compounding standards set off a series of events that changed the course of some therapies, and not for the better. Only now are we seeing the rise of alternative treatment solutions that resolve a key challenge for physicians, hospital pharmacies, and patients created by USP <797> (2008).
The preparation of medications and drug combinations to create a customized product for the specific needs of individual patients is referred to as compounding. Preparing compounded sterile preparations can present a far greater risk to patients than preparing compounded nonsterile preparations. USP standards provide guidance for preparing compounded sterile preparations and are deferred to as authoritative by many states’ professional authorities and accreditation bodies. When adopted directly or indirectly by state professional boards, these standards can become legally enforceable, and when adopted by accreditation bodies (eg, The Joint Commission), they can threaten hospital accreditation, which terminates the organization’s ability to bill the Centers for Medicare & Medicaid Services.
New Risk Categories Led to Hospital Pharmacy Challenges
New standards in USP <797> (2008) defined risk levels for compounding that were based on the possible likelihood of patient harm from microbial contamination of a compounded sterile preparation. Few sterile ingredients and minimal manipulation via sterile channels were considered to represent “low-risk” conditions. When ≥3 ingredients and multiple injections are required for one container, USP deemed this to be “medium-risk.” Compounding sterile dosage forms that included nonsterile ingredients, or that were exposed to nonsterile pathways, were categorized as “high-risk.” Higher risk levels that indicate a greater risk for contamination or lack of sterility naturally lead to an expected increased risk for patient harm. Most hospital pharmacies engage in low- and medium-risk compounding, because the oversight, facilities, management, and complexity required for high-risk compounding are burdensome and expensive. Under pressure for compliance and review from entities such as The Joint Commission, most hospital pharmacies chose to stop compounding treatments that would raise them into the high-risk compounding levels following the publication of <797> (2008).
Negative Effects of Reducing High-Risk Compounding at Hospitals
Patients and physicians were adversely affected by the reduction in high-risk compounding at hospitals, and a change in the treatment of diffuse bleeding in the bladder (eg, hemorrhagic cystitis [HC]) is a prime example of one of these negative effects.
Patients with HC face challenges related to treatment and have limited options. Two agents indicated in the guidelines to treat HC are aluminum and formaldehyde (formalin), which have historically been available only as bulk, nonsterile active pharmaceutical ingredients. Because the bladder is a sterile internal body cavity, compounds used for administration (an internal “wash”) could be expected to meet the USP standards for sterile products. The treatments are prepared by combining the nonsterile active pharmaceutical ingredient with sterile products and were the most effective standard of care, according to medical literature published prior to 2008.
Kong Ho and Zainuddin wrote the following1:
The advantage of alum irrigation compared to other treatment methods for haemorrhagic cystitis is that it is generally safe, effective, well-tolerated, and cost-effective. There is no need for regional or general anaesthesia unlike when using formalin, phenol, silver nitrate or hydrostatic bladder distension. It is a simple procedure that does not require open surgery or elaborate radiological procedures. In addition, local tissue histology is not distorted.
In 2008, USP <797> defined “high-risk” compounding as sterilizing drugs compounded from nonsterile ingredients. The Joint Commission adopted USP’s definition, which caused hospital pharmacies to abandon producing such compounds. Notably, there was a marked lack of references or documented evidence supporting the reasons for the high-risk designation; the opinions of a volunteer “expert committee” were stated as a new standard. One newly designated “high-risk” compound was alum irrigation for HC and its absence left physicians and patients with limited options to effectively manage this condition.
Impact on Oncology and Urology Patients
HC can range from mild and microscopic to life-threatening gross hematuria with clots. It is most often caused by chemotherapy (ie, cyclophosphamide and ifosfamide [Ifex]) and pelvic radiation therapy, but it can also develop post-transplantation or be mediated by infection. Initial treatment is conservative, but intravesical alum irrigation is a well-tolerated and effective first-line treatment option for persistent HC. Intravesical formalin is used to treat moderate-to-severe intractable HC, typically reserved as a last-line option before cystectomy.2
Chronic HC that does not respond to available treatments may require surgery, including open cystotomy, permanent urinary diversion, vesical artery embolization, or cystectomy, which exposes patients to postsurgical complications and permanent anatomical changes.
Alum irrigation was considered advantageous over other treatment methods in that it was generally safe, effective, well-tolerated, and cost-effective. It is a simple, noninvasive option that requires no regional or general anesthesia, open surgery, or other elaborate procedures.1 Since first described in 1982, several studies (albeit smaller caseloads) have reported response rates ranging from 50% to 100% with HC. Intravesical therapy with formalin is more controversial, with significant possible complications.3 Given its favorable safety and efficacy profile, intravesical alum should be considered a first-line treatment option for patients with HC.4
No Evidence to Support How Pharmacy Standards Restricted Treatment
If hospital pharmacies decided, after USP <797> (2008) was published, to cease performing the preparation of alum for irrigation under the high-risk compounding designation, many physicians and patients were unable to access this standard-of-care, first-line treatment option. The Mayo Clinic did continue to treat patients with intravesical alum and in 2016, published evidence of their successes from 1997 to 2014. Interestingly, there was no finding of adverse events for treatment performed prior to the 2008 standards insisting on more costly “high-risk” compounding procedures4:
We found here that intravesical alum instillation for patients with refractory HC was associated with a response rate of approximately 60% and resulted in a decrease in patient’s subsequent transfusion requirement. Approximately one-third of patients experienced a durable response to therapy, without the need for additional interventions or hospital readmission for HC. Moreover, treatment was well-tolerated, with bladder spasms representing the most frequent side effect, and no clinical evidence of aluminum toxicity noted. To our knowledge, this represents the largest reported series to date on the use of intravesical alum for refractory hemorrhagic cystitis.
Were patients better served by a new costly and burdensome compounding standard that restricted access to appropriate care? Was the risk of contamination associated with mixing nonsterile ingredients with sterile ingredients quantified and justified against the risk of loss of a historically safe and effective noninvasive treatment option? These and other questions are being raised more frequently now that the USP is attempting to expand its reach into medical prescribing decisions.
In fact, when one reads USP <797> (2008), its predecessors, and the still controversial USP General Chapter 800 Hazardous Drugs – Handling in Healthcare Settings, there are few identifiable references (evidence and justification) for the statements, measures, quantities, and expectations set forth in these standards. References in these general chapters primarily refer to each other, and other USP documents.
Sterile Alum Is Back and Available Despite the USP
Fortunately for physicians and their patients with HC, alum is now being produced in sterile form in qualified environments. These product alternatives qualify as low- or medium-risk, relieving the facility of the sterilization step in the hospital pharmacy. One of these products comes as a solution from at least 1 registered outsourcing facility, whereas the other is a sterile powder that can be reconstituted with a sterile diluent and is available to hospitals through the usual drug supply chain.
Will This Standard of Care Be Resumed?
Although there are still limited options for treating patients with HC, will most hospital pharmacies add alum to their formularies again? Will physicians who started practicing after 2010 become familiar with it as a first-line treatment? Are physicians so used to being told by their hospital pharmacies that it is not available, that they will never ask?
Avoiding Nonevidence-Based Issuances Dictating Available Treatments
When do we ask for proof of evidence for changes to operations, standards, or formularies to justify the loss of access to standard-of-care treatments? How do we tap into our collective medical memory for information about effective treatments that may have been pushed aside due to opinion-based decisions rather than evidence or innovation? Fourteen years have passed since intravesical alum became essentially unavailable based more on “best practice” opinions than evidence. It is fortunate that a revised option has now become available, but what was the negative impact on patients in the meantime?
Alum irrigation is available again as a first-line treatment for patients with HC. Hospital pharmacies are now able to dilute a sterile ingredient without being forced into costly high-risk compounding compliance scenarios. Oncologists and urologists can consider intravesical alum as a treatment option and reasonably expect that the hospital pharmacy will provide the mixture.
More than a decade has passed since this treatment option was relegated and the history of its value and experience of its use has faded. Commercial alum options are now available, but we will never know how many patients were adversely affected by the loss of a safe and effective first-line treatment that, by all accounts, was associated with infrequent and manageable side effects. Hopefully in the future, we can pivot to a more value-based process that balances disrupters in care delivery with the direct impact on patient access to standard treatments.
- Kong Ho CC, Zainuddin ZM. Alum irrigation for the treatment of intractable haematuria. Malays J Med Sci. 2009;16:66-68.
- Wright EB, Hansen KN, Thompson AC. Solving compounding challenges in hemorrhagic cystitis management. October 2021. www.pppmag.com/article/2823. Accessed March 28, 2022.
- Petca R-C, Popescu R-I, Toma C, et al. Chemical hemorrhagic cystitis: diagnostic and therapeutic pitfalls (review). Exp Ther Med. 2021;21:624.
- Westerman ME, Boorjian SA, Linder BJ. Safety and efficacy of intravesical alum for intractable hemorrhagic cystitis: a contemporary evaluation. Int Braz J Urol. 2016;42:1144-1149.