Developing nurse guidance for IV busulfan chemotherapy

Abstract
Kennedy, D. (2008) Developing nurse guidance for IV busulfan chemotherapy. This is an extended version of the article published in Nursing Times; 104: 33, 26-27.

Busulfan is a major agent used in the conditioning regimens of haematopoietic progenitor cell transplantations. Initially it was only available as an oral preparation but over the last 5-6 years, it has been increasingly used as an IV infusion. Due to increasing use of the drug in the transplant setting and the change in preparation, it was important to develop clear and concise guidelines for chemotherapy nurses administering it by the IV route. This article outlines how the guidance was developed and summarises key points from it.

Author
Danielle Kennedy, BSc, RGN, is bone marrow transplant ward manager, King's College Hospital, London.

Blood and marrow transplantation

According to data from the Center for International Blood and Marrow Transplant Research (2008), 50,000–60,000 blood and marrow transplants (BMTs) are performed throughout the world each year.

These offer patients diagnosed with haematological malignancies (such as leukaemia, myelodysplastic syndrome, multiple myeloma and lymphoma) or acquired conditions (such as aplastic anaemia) high-dose treatment of their disease. In some cases, it may result in a potential cure. It allows the delivery of intensive treatment which totally ablates the bone marrow. In the absence of cells to transplant, the bone marrow which is irreparably damaged may never recover. The result of this would certainly be death, due to bleeding or infection (Leukaemia Research, 2006).

There are two types of transplant: autologous, where the cells for the transplant are sourced from the patient; or allogeneic, where the cells come from a donor. The cells themselves can be infused as peripheral blood stem cells, bone marrow or cord blood. Before the cells are infused, patients receive a conditioning regimen. This regimen consists of a combination of chemotherapy, with or without radiotherapy (Leukaemia Research, 2006).

Hundreds of conditioning regimens exist and new ones are constantly evolving. They consist of different combinations and the choice depends on multiple factors, such as patients' disease and disease status at the time of decision to transplant, age and cell source. Conditioning regimens are administered before transplantation of the cells. They aim to eradicate residual malignant cells, make space in the bone marrow for the introduction of the transplanted cells/marrow, and, in the case of allogeneic transplants, reduce patients' immune response to prevent graft rejection,.

How the conditioning regimen is delivered is a key element in the success of the transplant. Depending on the regimen used, they usually last 1-10 days.

Busulfan

Busulfan is a potent cytotoxic agent initially indicated as a myeloablative and antileukaemic treatment of chronic myelogenous leukaemia, where it was used as an oral preparation in the stages before a BMT. In recent times, it has been commonly used in conditioning regimens of allogeneic transplants.

The oral form continued to be used in the transplant setting for many years but clinicians alluded to the need for an IV form to allow precise dosing, and to eliminate some of the problems associated with oral administration, such as veno-occlusive disease (VOD). When the IV formulation was developed, it aimed to address the practical and clinical issues associated with emesis, dose assurance, adequate myeloablation, and reduction of any adverse events (Kashyap et al, 2002).

The problems identified in early studies associated with the oral preparation are ones which could lead to graft rejection, relapse or, as with VOD, fatality. The higher doses of oral busulfan required for use in BMT conditioning regimens showed inconsistent blood plasma concentrations, which may be reduced through gastrointestinal absorption rates. In addition, in tablet form, they come in 2mg tablets only. In a standard busulfan and cyclophosphamide (BUCY) conditioning regimen, an adult patient weighing 60kg would be required to take 120 tablets each day. The higher doses of oral busulfan also increased the risk of VOD, a life-threatening post-transplant complication that occurred in around 20-40% of patients. However, the incidence of VOD with IV busulfan has reduced dramatically (Lee et al, 2005; Kashyap et al, 2002).

The use of IV busulfan has a prime place in the BMT setting, especially in allogeneic transplantation, and it is currently used in the major conditioning regimens.

Identifying the need for guidelines

When the change occurred from the oral to IV preparation, it was difficult to ensure that nurses administering the chemotherapy had all the necessary information. According to the NMC's (2007) Standards for Medicines Management, 'you must know the therapeutic uses of the medicine to be administered, its normal dosage, side-effects, precautions and contraindications'.

In a literature search, the only guidance identified was a user's guide, developed by the manufacturer of the IV busulfan preparation (Pierre Fabre Ltd, 2006), which covers both adults and children and offers only general information. There are also a couple of paragraphs in the British National Formulary and snippets of information in current chemotherapy administration books. All of this information is generally inaccessible and does not fully prepare nurses for the administration of IV busulfan, especially clinical aspects.

A project to develop busulfan guidelines specifically for nurses began, in association with the manufacturer. Information was gathered from a variety of sources. The user's guide was reviewed and relevant information used, advice was gathered from pharmacy technicians, haematology consultants, chemotherapy nurses and from first-hand experience, through clinical work.

Developing the guidance

After the need for these guidelines was identified, I began the process of gathering and collating information. The manufacturer was pivotal in the development of the guidance, as they assisted in gathering all the available product information and literature and were on hand to answer any queries or unanswered questions that arose.

Initially, the current and available user's guide was reviewed and any information relevant to clinical practice was set aside. It became apparent that this information was in many ways very detached from the clinical setting. Many discrepancies and questions were also raised and the company was able to liaise with its colleagues to answer most of these.

Clinical administration was observed, practised and appraised. I sought advice and opinions from other practitioners to gather their practical experiences and also to understand what information should be included and was necessary for nurses to have before administering busulfan. The information gathered from the clinical experts was amalgamated with the product information in a succinct manner and the guidelines were developed. The full guidelines are available in PDF format (see below).

Guideline basics

Drug action
Busulfan is a major agent in conditioning regimens in haematopoietic progenitor cell transplantations (stem cell, bone marrow and cord). It is a potent cytotoxic alkylating agent, which acts primarily on the granocyte precursors in the bone marrow. It is cell cycle non-specific, working on all phases of the cell cycle and is metabolised primarily in the liver, with a moderate amount excreted in the urine over 48 hours. It also crosses the blood-brain barrier.

Treatment regimens using busulfan
The current allogeneic (sibling and matched unrelated) transplant protocols in clinical use include:

• BUCY - busulfan and cyclophosphamide;

• FBC - fludarabine, busulfan and campath (alemtuzumab);

• FB ATG - fludarabine, busulfan and rabbit anti-thymocyte globulin;

• TBI + BUCY - total body irradiation + busulfan and cyclophosphamide).

The current allogeneic (cord) transplant protocol in clinical use is: thiotepa, IV busulfan, fludarabine, and rabbit anti-thymocyte globulin (ATG).

IV busulfan dosage
Dosage should be based on actual body weight. In obese patients dosing should be adjusted to ideal body weight. In renally impaired patients, dose modification is not recommended, as it is only moderately excreted in urine. Busulfan should be used with caution in hepatically impaired patients. In both instances, patients should be carefully monitored for any signs of toxicity.

The ideal drug times to give busulfan are related to the specific regimen the patient is having and a guide is as follows:

• 0.4mg/kg qds for TBI BUCY 5am, 11am, 5pm and 11pm;

• 0.8mg/kg qds – for BUCY, FBC, FB ATG 5am, 11am, 5pm and 11pm;

• 3.2mg/kg once/day (over three hours) - cord protocol.

Please note: if a dose is inadvertently missed, that is, during four-times-daily regimens, an additional dose can be administered at the end of the regimen after seeking further medical advice.

Preparation and stability
IV busulfan is prepared by the aseptics department within pharmacy and in standard regimens; it will be diluted with 50 or 100ml normal saline (depending on the dose) or 5% glucose. In the cord blood regimen, it will be diluted with 250ml N/saline or 5% glucose. In order to ensure product stability, the volume of the diluent should be 10 times the volume of IV busulfan, ideally making the final concentration 0.5mg/m2.

Stability after dilution in either glucose 5% or sodium chloride (0.9%) solution for injection has been demonstrated for:

• Eight hours (including infusion time) when stored at 20°C ± 5°C;

• Twelve hours when stored at 2°C-8°C followed by three hours stored at 20°C ± 5°C (including infusion time).

The product should be used immediately after dilution to reduce the risk of microbiological contamination. If it is not used immediately, it should be stored in the fridge at 2°-8°C.

Administration
Busulfan must only be infused centrally (vesicant properties are unknown) and should not be given by bolus or rapid infusion. Practitioners should also not infuse concurrently with any other IV solution.

Steps of administration

1. Remove the busulfan bag from the fridge 30 minutes before being administered.

2. Aseptically withdraw 3-5ml from the central line to check line positioning.

3. Flush the line with 10ml N/saline to ensure patency.

4. Attach the primed giving set, with N/saline or 5% glucose, depending on diluent.

5. Infuse the entire solution at rate of 50ml/hour (over two hours) or over three hours if following the cord regimen.

6. At completion, flush with 100ml of the same diluent that busulfan has been prepared in.

7. If flushing with 5% glucose, flush the central line with a further 10ml N/saline
   

Side-effects
Busulfan-associated side-effects are listed in Table 1 below, according to various body systems.

Table 1. Side-effects of busulfan

Potential drug interactions
A few drug interactions have been identified in clinical trials or pharmaceutical studies and are as follows:

Itraconazole: may reduce the metabolism of busulfan;

Metronidazole: may increase plasma concentrations of busulfan when infused simultaneously;

Paracetamol: may decrease the metabolism of busulfan when administering it within 72 hours before starting busulfan and also when using simultaneously;

Phenytoin: increases metabolism of the busulfan in the liver.

Laboratory tests required
While a patient is receiving busulfan, certain laboratory tests should be monitored:

• Full blood count – daily to check bone marrow function;

• Serum transaminases, alkaline phosphatase and bilirubin – daily until 28 days post-infusion to detect hepatotoxicity, which may herald the onset of hepatic VOD.
  

Nursing considerations
Nursing assessments and interventions are also important for patients on conditioning regimens that include busulfan. Below are some of the important considerations:

• Ensure the patient has antiemetics before first dose and is also prescribed them regularly (for example, domperidone 20mg tds and ondansetron 8mg tds);

• Anti-convulsant prophylactic therapy should be initiated before busulfan treatment. The patient will be given a loading dose of oral phenytoin the evening before commencing busulfan. The phenytoin loading dose the night before is 900mg, then 300mg orally daily for seven days;

• Red blood cell and platelet support;

• Granulocyte colony-stimulating factor (GCSF) should be used post-BMT (usually starting seven days after the infusion of the transplant or as prescribed);

• Prophylactic anti-infectives need to be given throughout and following treatment to prevent cytomegalovirus (CMV) reactivation or fungal infections (for example, oral aciclovir 200mg tds or 500mg/m2 IV, and oral itraconazole 200mg bd);

• Weigh all patients twice daily and ensure strict fluid balance charts;

• Assess oral cavity during each shift and promote mouth care in all patients (chlorhexidine mouthwash four times daily and nystatin suspension four times daily).

Safety
If the solution comes into contact with skin, wash thoroughly with warm water immediately for a minimum of 10 minutes and then seek medical assistance for possible treatment. An adverse incident form should be completed.

Implications for practice

• Technical information on the use of products and medications is often written in an inaccessible style and may not contain the specific clinical information nurses need. Manufacturers can often help in developing protocols and guidelines to enable nurses to use their products safely and effectively.

• Such guidelines are important when nurses are using unfamiliar products or medications, or familiar medications using a new route of administration.

• The guidelines should include the necessary practical clinical information, as well as other relevant material to ensure patient safety.

• Practitioners and clinical experts should be involved in deciding what information is needed in protocols and guidelines, and in reviewing the information gathered for accuracy and accessibility.

Conclusion

A leaflet for chemotherapy nurses was developed to provide guidance and support on the administration of IV busulfan. This was prompted by the changes in the preparation of busulfan to an IV solution and also the increased use of this agent in conditioning regimens of haematopoietic progenitor cell transplantations. The leaflet provides chemotherapy nurses with concise, accessible information, in a clear and simple format. The guidelines, as shown in this article, include an overview on the pharmakinetics, dosage, preparation, administration, side-effects and nursing considerations when administering busulfan.

Click here for the guidelines in PDF format

Declaration of interest: The manufacturer of bulsulfan had no influence over the content of this article with the exception of providing advice on correct usage of the drug.

References

Center for International Blood and Marrow Transplant Research (2008) www.cibmtr.org

Kashyap, A. et al (2002) Intravenous versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation: Decreased incidence of hepatic venoocclusive disease (HVOD), HVOD-related mortality, and overall 100-day mortality. Biology of Blood and Marrow Transplantation; 8: 9, 493–500.

Lee, J. et al (2005) Decreased incidence of hepatic veno-occlusive disease and fewer hemostatic derangements associated with intravenous busulfan vs oral busulfan in adults conditioned with busulfan + cyclophosphamide for allogeneic bone marrow transplantation. Annals of Haematology; 84: 5, 321-30.

Leukaemia Research (2006) Bone Marrow and Stem Cell Transplantation. www.lrf.org.uk

NMC (2007) Standards for Medicines Management. www.nmc-uk.org

Pierre Fabre Ltd (2006) User's Guide. Busilvex: busulfan IV for Adults and Children. Winchester: Pierre Fabre Ltd.

The following sources were also used in developing the guidance:

Barton-Burke, M. et al (2002) Cancer Chemotherapy Care PlansHandbook (3rd ed). London: Jones and Bartlett Publishers (UK).

Chu, E., DeVita, V. (2006) Physicians' Cancer Chemotherapy: Drug Manual: 2006. Ontario: Jones and Bartlett Publishers (Canada).

Pierre Fabre Ltd (2006) Summary of Product Characteristics. Winchester: Pierre Fabre Ltd.