Solving Compounding Challenges in Hemorrhagic Cystitis Management

October 2021 - Vol.18 No. 10 - Page #8
Category: USP Training Programs

In the acute care setting, treating persistent hemorrhagic cystitis—a syndrome of diffuse bleeding of the endothelial lining of the bladder—can be challenging given the current lack of effective FDA approved medication therapies. As such, it is prudent to evaluate published scientific literature to guide therapy using off-label medication indications. For instillation therapy, medications cited in the guidelines include aluminum (alum) and formaldehyde (formalin).1 These two agents represent a challenge to the compounder given that, historically, alum and formalin were only available as bulk, non-sterile active pharmaceutical ingredients (APIs). As the bladder is a sterile internal body cavity, compounds for this route of administration are required to be sterilized prior to administration and must meet other quality standards to ensure patient safety.2 This requires the compounder to engage in high-risk compounding as defined by USP <797>.

Many of the studies and case reports on the use of alum and formalin to treat hemorrhagic cystitis were published prior to 2008; thus, preceding the introduction of USP <797>.3-5 Due to the heightened requirements and risks for the pharmacy department to engage in high-risk compounding following these standards, many have discontinued providing these agents altogether, leaving urologists with limited options to effectively manage this disease state. As these agents can be quite effective for certain patient cases, we explore current options and approaches to safely and efficiently provide intravesical alum and formalin as an option to treat persistent hemorrhagic cystitis.

Hemorrhagic Cystitis

Hemorrhagic cystitis is defined by hematuria, which can range from mild and microscopic to life-threatening gross hematuria with clots.1,6,7 This is often accompanied by bladder pain and lower urinary tract symptoms such as dysuria, urinary frequency, and urgency. Hemorrhagic cystitis is most often caused by chemotherapy (namely cyclophosphamide and ifosfamide) and pelvic radiation therapy but can also develop post-transplant or be mediated by infection.6 There is a lack of quality evidence or consensus in the treatment of hemorrhagic cystitis, as much of the evidence comes from observational or case studies. Generally, initial treatment is conservative, including cystoscopy and fulguration (electrocautery) of bleeding vessels, clot evacuation, and continuous bladder irrigation with normal saline (NS).1,6,8 For persistent bleeding, there are numerous options, including ablation with laser or argon beam; hyperbaric oxygen therapy; intravesical agents including alum, hyaluronic acid, aminocaproic acid, and prostaglandins; and systemic agents including sodium pentosan polysulfate, tranexamic acid, and aminocaproic acid.1,6,8 For refractory or life-threatening bleeding, treatment moves to more invasive options, including intravesical formalin, selective arterial embolization, and urinary diversion with or without cystectomy.1,6,8

Intravesical Alum

Intravesical alum is a well-tolerated and effective treatment option for persistent hemorrhagic cystitis and is considered one of the first-line options.6,8,9 Potassium aluminum, as a 1% solution in sterile water for irrigation or sterile NS for irrigation, is administered as a continuous bladder irrigation at a rate of 250-300 mL/hour, typically for about 1 to 5 days.6 Aluminum works as an astringent, causing protein precipitation, decreased capillary permeability, and vasoconstriction, leading to decreased bleeding.6,9 Though well-tolerated, intravesical alum can cause bladder spasms and suprapubic pain, and there is a potential risk for aluminum toxicity in patients with impaired renal function.1,6,9

Challenges

Historically, compounding alum for intravesical irrigation presented many challenges, encompassing issues with patient and staff safety, as well as the training and equipment necessary for the procedure. One such issue was the sterility of alum—this agent was only available as a nonsterile bulk powder, though the intravesical route of administration requires the preparation to be sterile, per USP <797>.2 Thus, preparing alum intravesical irrigation required that alum go through either a filtration or terminal sterilization process to create a sterile preparation. This high-risk compounding process introduced increased requirements for staff training and evaluation, including more frequent media-fill and glove fingertip testing.2

Solubility issues also presented a challenge, as compounding the alum irrigation solution required heating the solution to boiling to allow the powder to fully dissolve.10 Once dissolved, staff needed to work quickly while the solution was still hot to filter it through a 0.22-micron filter for sterilization and add it to a larger volume of sterile water before crystallization could occur.10 This procedure introduced risk to the compounder due to the heated solution and required the use of heating elements that might not otherwise be on hand. Additionally, sterile alum for bladder irrigation is typically requested on an emergency basis, and large volumes are required for treatment. These methods can take a significant amount of time to prepare and may delay care.

Compounding Solutions

Two options are now available for compounding 1% alum solution for intravesical administration, both of which eliminate the need for high-risk compounding, as the starting ingredients are all sterile.

Sterile API Powder: Alum is available as a terminally sterilized, pre-measured API powder. The available product comes as a package of 3 vials, each containing 10 g of alum powder. All three vials are necessary for compounding a 1% solution of 30 g alum per 3,000 mL.

With the sterile alum powder, the solubility issue is overcome by splitting the alum between 3 vials with 100 mL capacity, allowing for enough diluent to fully dissolve the powder without having to heat the solution. To do so, 100 mL of diluent (sterile NS or sterile water for irrigation) must be transferred to each of the 3 vials, and then the reconstituted solution must be transferred back to the bag using either the syringe-transfer method or the gravity method.

One challenge with this method is efficiency. Initially, the largest sterile syringes stocked by the pharmacy department were 50 mL, which would require 4 entries into each vial and 12 total syringe-transfers (with 12 entries into the bag’s medication port) to move volume back and forth between the bag and the vials. This presents some issues, such as increased risk of contamination due to multiple entries into each vial and into the bag’s medication port, as well the amount of time required to make multiple transfers. Upon further investigation, our department sourced sterile syringes with 120 mL capacity, which decrease both the potential for contamination—due to fewer volume transfers—and the time needed to compound. Of note, sterile 120 mL syringes were only available from one company at the time of writing, which illustrates the need for wider availability of products such as these that can solve compounding challenges.

For the gravity method, a fluid transfer set (with a vented spike on one end and a needle on the other) can be used. Using the needle end to enter the medication port on the 3 L bag of diluent, each vial is spiked and allowed to have approximately 100 mL of diluent drain into it. Once all vials are swirled for several minutes to allow the powder to fully dissolve, each vial may be spiked once more, and the fluid drained back into the 3 L bag of diluent. This method decreases the risk of contamination, as there is only one entry into the bag’s medication port and two entries into each vial and eliminates the difficulty of manipulating large syringes.

Both volume-transfer methods require a similar amount of time to perform, and the limiting step is the dissolution of the powder. Once the diluent is transferred to each vial, it takes about 6 minutes of swirling each vial to fully dissolve the powder. To save time, the compounder could swirl multiple vials at once, take turns swirling each vial, or use a laboratory shaker/rotator if available.

Sterile Concentrated Solution: A sterile concentrated alum solution is also available, via 503B outsourcing facilities. This product is supplied as a filled bag of 30 g per 300 mL sterile aluminum potassium sulfate solution, which then requires dilution to 3,000 mL.

A key advantage of this option is that the powder is already dissolved, which decreases the time needed to compound. Nevertheless, 300 mL of diluent must be removed from a 3 L bag of sterile NS or sterile water for irrigation and the 300 mL concentrated solution added to the irrigation bag. The methods described above for volume transfer could be employed with this product as well. With the concentrated solution, there is a patient safety concern as it could be accidentally infused because it looks like a ready-to-use filled bag. There is a prominent label stating, “Dilute before use, pharmacy compounding only,” but labels can be overlooked.

A major difference between the two products is the shelf-life. The sterile concentrated solution has a 90-day beyond-use date (BUD), whereas the sterile powder has a multiple year shelf-life. To keep the concentrated solution stocked in the pharmacy department, it would need to be replaced regularly to stay within the 90-day BUD. It can also be obtained as needed from the outsourcing facility; however, the risk of a delay in treatment would need to be considered. For a preparation that is not often requested but is required urgently, there would need to be communication between compounding leaders and medical staff to determine what option is best suited for their institution.

Intravesical Formalin

Another treatment option for moderate to severe or intractable hemorrhagic cystitis is intravesical formalin. Formalin is the nomenclature used in urology literature to identify an aqueous solution of diluted 37% formaldehyde administered via bladder instillation.11 Formalin acts by hydrolyzing proteins and coagulating the tissue on a superficial level, controlling hemorrhage in the mucosa and submucosa.5 This agent is typically reserved as a last line option before cystectomy because it induces permanent changes to the bladder endothelium, leading to bladder dysfunction.

There have been several studies evaluating the use of formalin for hemorrhagic cystitis, and there is no standard concentration that is universally accepted.5,11 Formalin concentrations of up to 10% have been reported in the literature, but lower concentrations (1% to 4%) are more commonly used in an effort to achieve similar efficacy with fewer adverse effects.3,12-14 Some providers may favor a low initial formalin concentration of 1% to 2% with the option to escalate the concentration in cases of treatment failure.11, 13 Dwell times for formalin irrigation also vary significantly, but times up to 30 minutes have been reported.5 This procedure must be performed with the patient under anesthesia given the pain involved with formalin due to its caustic nature.

Challenges

The preparation of formalin for bladder irrigation is fraught with hazards for pharmacy compounding staff. Formaldehyde in an aqueous solution is a colorless, highly toxic liquid with a pungent and irritating odor. Its vapors are flammable at room temperature and can lead to explosion if improperly stored. In addition to its volatile nature, formaldehyde is a known carcinogen and exposure causes irritation to the respiratory system, skin, and mucous membranes.15 Compounding this hazardous drug requires proper training, storage, externally ventilated biological safety cabinets, and personal protective equipment (PPE) to ensure both a safe final product for the patient and a safe working environment for the compounder.16

In addition to compounding equipment and PPE, staff training and competencies are vitally important to the safe the preparation of this and any compounded product. This is particularly crucial for facilities that use formalin sporadically. Formalin at 100% concentration is, by definition, 37% formaldehyde, and thus the terms “formalin” and “formaldehyde” cannot be used interchangeably when describing the concentration. Errors may occur during formalin compounding if confusion exists between formalin and formaldehyde concentration in the solution. For staff without recent experience in compounding this product, it may be easy for calculation errors to occur.

These potential issues are compounded by the route of administration. Because formalin is used as a bladder instillation, the final product must be sterile. However, formaldehyde is not currently available as a sterile API, making high-risk compounding the only option, yet traditional forms of sterilization may not be feasible with formalin solutions. For example, specialized filters are required as formaldehyde can damage certain filter material types, which could then lead to a failed sterilization.

State boards of pharmacy may also require a separate pharmacy registration for high-risk compounding, which may not be in place at pharmacies that do not typically compound these materials. This registration could trigger an increase in inspection frequency or a more exacting focus on compounding practices within the pharmacy. Thus, a careful balance is required to ensure patient needs can be met in a timely manner, while also preserving patient safety, employee safety, and regulatory compliance.

Compounding Options

There are two options available for this preparation that meet patient needs while also addressing staff safety.

Intravesical Formalin Solution: Intravesical formalin solution may be prepared in-house by hospital pharmacy cleanroom staff trained in hazardous, high-risk pharmaceutical compounding. As there are no commercially available sterile API formulations of formalin, this CSP requires sterilization, usually performed by filtration.

However, in the absence of final sterility testing, beyond-use dating is limited for high-risk compounds such as formalin. Furthermore, patient cases where formalin is requested from pharmacy may be rare. For many institutions, this limited beyond-use dating and high potential for product waste negates the feasibility of keeping a stock of ready-to-administer solution on hand as patient needs arise.

Outsourced Compounding: Hospital pharmacy leaders may partner with a local 503A pharmacy that routinely performs hazardous, high-risk compounding. These facilities remove some of the burden for hospitals to maintain related staff competencies and training, specialized compounding equipment, and formaldehyde-specific storage policies for a product that they may rarely dispense. Outsourcing also decreases the risk of exposure to compounding staff. It may also help to cultivate an ongoing relationship with pharmacy colleagues in another practice setting who may be able to provide useful information or alternative compounded products in the future.

One consideration with this approach is the turnaround time for orders. 503A compounding pharmacies may have limited hours of operation and specific requirements around advance notice for compounded preparations. Hospital pharmacy compounding leaders must be able to communicate with ordering providers and come to a prearranged agreement on an acceptable turnaround time to ensure that expectations for product delivery are aligned. Because of formalin’s place in therapy, it may be appropriate to have a provider place an order for formalin and continue to explore alternative therapy options with the patient while the formalin order is being compounded and delivered.

Conclusion

Both alum and formalin are cited as treatment options with clinical success for hemorrhagic cystitis. For alum, there are new options on the market that allow compounders to prepare a sterile solution using all sterile starting ingredients, thus avoiding the need to perform high-risk compounding. The availability of a novel sterile API presents an exciting opportunity for other drugs where there are no conventionally manufactured or sterile formulations of a specific drug on the market. Further, the use of sterile 100 mL and larger syringes could be highly effective and efficient tools to use for CSPs requiring high-volume fluid or medication transfer in the cleanroom.

Formalin continues to be a challenge for compounders given the lack of availability of a sterile formulation (commercially or through a 503B outsourcing compounder) and the special handling precautions that must be taken to prevent employee exposure and harm. Partnering with a local 503A pharmacy that routinely performs high-risk compounding may be a viable alternative for certain organizations with low or sporadic usage, rather than attempting to prepare formalin within the hospital pharmacy cleanroom and maintaining competencies for high-risk compounding. As always, it is important for pharmacy leaders to consider each option carefully and choose the approach that supports the pharmacy’s workflow while also prioritizing patient and provider safety.


Ellen B. Wright, PharmD, is a nuclear pharmacist with PETNET Solutions, a Siemens Healthineers company. She graduated from the University of North Carolina Eshelman School of Pharmacy with a doctor of pharmacy degree.

Kevin N. Hansen, PharmD, MS, BCPS, BCSCP, is the assistant director of pharmacy at Moses H. Cone Memorial Hospital in Greensboro, North Carolina. He graduated from the Lake Erie College of Osteopathic Medicine with a doctor of pharmacy degree and received an MS in pharmaceutical sciences from the University of North Carolina Eshelman School of Pharmacy.

Amy C. Thompson, PharmD, MBA, MS, BCPS is a clinical pharmacy coordinator at Alamance Regional Medical Center in Burlington, North Carolina. She received her doctor of pharmacy degree and MBA from Wingate University and holds an MS in pharmaceutical sciences from the University of North Carolina.

PATIENT CASE: ALUM
A 43-year-old female patient with stage III estrogen receptor-positive breast cancer being treated with paclitaxel presented with shortness of breath and right leg pain. An ultrasound showed extensive right lower extremity deep vein thrombosis along with right-sided pulmonary emboli on CT angiography. The patient was started on intravenous anticoagulation to treat thromboses but later developed gross hematuria and a drop in hemoglobin requiring transfusion. The patient was diagnosed with hemorrhagic cystitis, undergoing cystoscopy with clot evacuation and fulguration and continuous bladder irrigation. However, she continued to have worsening hematuria and was subsequently treated with intravesical 1% alum bladder irrigation at a rate of 200 mL/hour for 24 hours. Alum irrigation completely cleared the patient’s hematuria, and she was discharged in good condition.

PATIENT CASE: FORMALIN
An 88-year-old male patient with radiation cystitis following treatment for prostate cancer presented with urinary retention and hematuria. Urology was consulted and attempted multiple interventions including cystoscopy with clot evacuation and fulguration, alum instillation, and carboprost instillation, but none were successful. Given his refractory hemorrhagic cystitis, the decision was made to proceed with formalin bladder irrigation. Before this procedure, formalin bladder irrigation had not been used in this health system for several years. The patient was taken to the operating room and treated with intravesical instillation of formalin 5% (formaldehyde 1.85%) with a 25-minute dwell time followed by bladder irrigation. Postoperatively, the patient experienced no complications from the procedure and was eventually discharged with no further episodes of hematuria.


References

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