Volume 29, Issue 4 • Fall 2019
eISSN: 2368-8076
FEA TURES /Ch R o niq UES
Practical considerations for the integration of
subcutaneous targeted therapies into the oncology clinic
by Angela Boudreau
ABstrAct
The oncology clinic is changing, with an increasing number of cancer therapies becoming available as formulations for subcutaneous (SC) injection. Using tar- geted therapies, such as alemtuzumab, bortezomib, rituximab or trastuzumab, via SC injection can be advantageous for patients, healthcare professionals, and healthcare systems. However, their use can also present challenges, and nurses have a unique opportunity to positively influence the integration of SC agents in the clinic.
This article summarizes practical sugges- tions for optimal administration of SC tar- geted therapies, and provides pragmatic considerations for managing the change process related to their adoption.
iNtrOductiON
O
ncologic treatment has advanced exponentially over the past two decades. While the majority of therapies are delivered by intravenous (IV), the development of subcutaneous (SC) for- mulations has been steadily increasing.Since 2012, the IV targeted therapies alemtuzumab, bortezomib, rituximab and trastuzumab have been developed as SC formulations (Stilgenbauer et al., 2009; Janssen Inc., 2018; Hoffmann-La Roche Ltd., 2018a; b).
The benefits of SC for the patient, healthcare professional, and healthcare system include preference, costs-sav- ings, time-savings, and capacity
improvements compared to the origi- nal IV formulations (Jackisch, Müller, Maintz, Hell, & Ataseven, 2014; Martin, Beegle, Zhu, & Hanisch, 2015; Davies et al., 2017; Dent et al., 2019). One of the challenges of administering SC targeted therapies is the potential for pain or other administration-related reactions (ARRs).
Successful integration of SC ther- apies into the clinic requires both practical knowledge of their optimal administration, as well as thought- ful consideration and planning from a change management perspective.
PrActicAl GuidANce
The decision to use a SC targeted therapy affects many aspects of the clinic. For scheduling, flexibility in IV chair time may be required in case a switch from SC back to IV is necessary.
A private setting or full resuscitation facilities may be advised. Additionally, staffing schedules could rotate nurses administering SC injections to reduce potential physical strain from repeated injections.
Formulation of SC treatments has been challenging due to the resistance of the SC extracellular matrix; injecting volumes greater than 2 mL can lead to tissue distortion and pain (Haller, 2007).
This has been overcome by dividing injections into smaller volumes (e.g., azacitidine), developing more concen- trated solutions (e.g., bortezomib), or co-formulating with the enzyme hyalu- ronidase (e.g., rituximab, trastuzumab) (Table 1) (Leveque, 2014). Hyaluronidase temporarily degrades hyaluranon, allowing for larger volumes of fluid to be administered (Haller, 2007).
Pre-administration
Nurses support the assessment of patients considering SC oncology
treatment by reviewing medical his- tory, prior adverse reactions, and family and lifestyle priorities. Pre- administration counselling should include reinforcement of treatment decisions, tailored patient education, and setting realistic expectations to alleviate anxiety (Table 2).
The safety profiles of IV and SC formulations of the same drug are generally similar and in some cases improved. Patients should continue to be counselled on possible medica- tion adverse events (AEs) regardless of the route of administration. One main difference relates to reactions that are administration related. Hypersensitivity and infusion-related reactions are com- mon AEs associated with IV adminis- tration. With SC administration, local cutaneous ARRs (SC-ARRs) are more common. SC-ARRs are generally mild to moderate in severity, resolve with- out treatment, and tend to diminish in likelihood with subsequent administra- tion (Hoffmann-La Roche Ltd., 2018a; b;
Janssen Inc., 2018; Lundin et al., 2002).
Administration
Because good administration tech- nique can reduce the incidence of SC-ARRs, nurses play a critical role in the success of SC therapy (Martin et al., 2015). Injection sites vary by prod- uct (Table 1) but should, if possible, be rotated. Subsequent injections should be given at least 2.5 cm from the previ- ous site. Avoid injecting into skin that is red, bruised, tender, hard, or where there are moles, scars or birthmarks.
Any other SC medications should be injected at a different site (Hoffmann-La Roche Ltd., 2018a; b; Janssen Inc., 2018).
Bringing syringes to room tem- perature can reduce viscosity and facilitate injection (MacDonald et al., 2017). Attaching a fresh needle prior
ABOut tHe AutHOr
Angela Boudreau, RN, MN, CON(C), Advanced Practice Nurse, Department of Nursing, Sunnybrook Odette Cancer Centre, 2075 Bayview Ave., Toronto, ON M4N 3M5
FEA TURES /Ch R o niq UES
to injection avoids leaving an irritating injection track of drug (Martin et al., 2015). When using longer needles (>
1/4 inch), injecting at a 45o angle into the skin fold can prevent intramuscu- lar injection (Kurtin et al., 2012; Martin et al., 2015). Select a needle gauge of 25 or 27 to align with that used in clin- ical trials; do not use a larger gauge for larger volumes (Carlson et al., 2015;
MacDonald et al., 2017). Slower rates of SC injection reduce ARRs experienced by patients (Martin et al., 2015).
Another technique to reduce SC-ARRs is the use of an air-sandwich within the syringe (Figure 1) (Kurtin et al., 2012). Pulling air into the needle, fol- lowed by drug, followed by air into the bottom of the syringe barrel effectively seals in the medication and prevents leakage (Kurtin et al., 2012; Martin et al., 2015). Consider implementing the air sandwich for all SC injections to stan- dardize the approach.
Table 1. Key features of and considerations for oncologic SC targeted therapies Alemtuzumab*
(Lundin et al., 2002;
Stilgenbauer et al., 2009)
Bortezomib
(Janssen Inc., 2018) Rituximab
(Hoffmann-La Roche Ltd., 2018b)
Trastuzumab
(Hoffmann-La Roche Ltd., 2018a)
Indication Off-label: CLL MM and MCL NHL and CLL HER2+ BC
SC formulation Off-label: 30 mg vial for
IV injection Single-use vial, for
reconstitution: 3.5 mg Single-dose vials, ready to use: 1400 mg and 1600 mg‡
Single-dose vial, ready to use: 600 mg‡
SC dose Fixed, following initial
escalation Variable, based on body
surface area† Fixed, following successful
IV administration Fixed, no loading dose required
Stability in syringe Not reported 8 hrs at 25°C in normal
indoor lighting 48 hrs at 2-8°C, then 8 hrs at 30°C in diffused daylight
48 hrs at 2-8°C, then 6 hrs at ambient temperature in diffused daylight
Duration of SC injection Not reported Not specified; Survey:
majority 3-10 sec/mL (Martin et al., 2015)
5 to 7 min 2 to 5 min
Volume of SC injection ≤ 1 mL Average <1 mL (Martin,
2013) 11.7-13.4 mL 5 mL
Site of SC injection Thigh
Abdomen (BC Cancer Agency, 2015)
Thigh
Abdomen Abdomen Thigh (Möbus et al., 2018)
BC, breast cancer; CLL, chronic lymphocytic leukemia; IV, intravenous; MCL, mantle cell lymphoma; MM, multiple myeloma; NHL, Non- Hodgkin’s lymphoma; rHuPH20, recombinant human hyaluronidase PH20; SC, subcutaneous
*SC use is not approved (Sanofi Genzyme, 2018); refer to local guidelines for common use
†different concentration than IV
‡contains rHuPH20
Table 2. Patient counselling points for SC targeted therapy. (BC Cancer Agency, 2015;
Carlson et al, 2015; Kurtin et al, 2012; MacDonald et al, 2017) Pre-Administration
• Reinforce treatment decisions
• Review differences versus IV
• Review any pre-medications
• Prepare for injection: avoid lotions and wear non-restrictive clothing that allows access to the injection site.
Administration
• Remind patient about injection duration
• Make conversation to reduce anxiety Post-Administration
• Avoid friction to the site and monitor daily
• Show visuals of potential skin reactions
• Most resolve in 1-2 days; report to oncology healthcare team if not resolving
• Topical steroid and/or cool compress may be used after 4 hours
• Acetaminophen or anti-histamine for mild reactions
• Inform patient when to contact physician or visit emergency
• Review any unreported reactions before next injection
FEA TURES /Ch R o niq UES
In the event of pain during admin- istration, the injection can be paused;
keep the needle in place, check place- ment, and consult colleagues before removing, repositioning, or resuming (MacDonald et al., 2017). If interrupted, administration should be restarted at another location (Carlson et al., 2015).
Medications containing hyaluro- nidase can be more difficult to push and, given the duration of injection, the patient and nurse should be posi- tioned properly. With consideration to privacy, the patient should be comfort- able and the injection site accessible, while the nurse sits with a straight pos- ture and feet flat on the floor. The nurse should apply even pressure and push the syringe using the palm of his/her hand. While using a butterfly needle can increase space between the patient and nurse, and improve ergonomics, this has not been investigated in clinical trials and care is advised to ensure the full dose is administered (Carlson et al., 2015; MacDonald et al., 2017). For tras- tuzumab, an injection device has been
trialled but not marketed, and the use of others may be cost restrictive (De Cock et al., 2016; Pivot et al., 2017).
Post-administration
Once complete, the site can be cov- ered and the patient observed (Carlson et al., 2015). A small case series reported the efficacy of topical evening primrose oil in alleviating SC-ARRs (Platzbecker et al., 2010). Serious ARRs can be treated with an analgesic/antipyretic or antihistamine (Hoffmann-La Roche Ltd., 2018a). Patients should be coun- selled on how to manage reactions including what, when, and to whom to report (Table 2).
cHANGe MANAGeMeNt
For successful integration of SC ther- apies into the clinic, it is important to recognize common reasons for failure in change implementation and pro- actively consider remedies (Barrow &
Toney-Butler, 2019; Davidson, 2015).
1. Planning: Create a working group to review all functions, systems and
processes that may be impacted by the change, including: order entry (paper or computerized), medication storage, medication preparation/dos- ing, scheduling, clinical protocols, and supportive educational materials (Dent et al., 2019; Martin et al., 2015).
2. Motivation: Ensure all staff are aware of the personal, patient, and system benefits of switching SC: chemother- apy and clinic nurses, administrative staff, pharmacists, pharmacy tech- nicians, and all physicians (includ- ing inpatient). Proactively address concerns regarding capacity shifts and occupational health. Consider sharing motivators of change such as practice or clinical guidelines, best practices from other centres, or patient experiences (Martin et al., 2015).
3. Communication: Develop a cross-functional team to guide the vision, solicit feedback, and keep all stakeholders informed. Educate and train each stakeholder, including patients, with practical information relevant to their role.
4. Change frequency: Consider what amount of change is tolerable. Ease transitions by identifying barriers and implementing solutions.
cONclusiON
Understanding the key consider- ations for administration and using effective change management tech- niques can help the healthcare team maximize the benefits and minimize the challenges associated with integrat- ing SC targeted therapies into clinical practice.
AcKNOWledGeMeNt
Medical writing assistance for this piece was provided by Stevie Kenyon, independent medical writer, and paid for by Hoffmann-La Roche Ltd. (Mississauga, ON, Canada).
Figure 1. Air sandwich
FEA TURES /Ch R o niq UES reFereNces
Barrow, J. M., & Toney-Butler, T. J. (2019).
Change Management. In StatPearls.
Retrieved from http://www.ncbi.nlm.nih.
gov/books/NBK459380/
BC Cancer Agency. (2015). BC Cancer Agency Drug Manual: alemtuzumab.
Retrieved from http://www.bccancer.
bc.ca/drug-database-site/Drug%20Index/
Alemtuzumab_Monograph_1May2015.pdf Carlson, J., Cox, K., Bedwell, K., & Ku, M.
(2015). Rituximab for subcutaneous delivery: Clinical management principles from a nursing perspective. International Journal of Nursing Practice, 21(S3), 1–13.
https://doi.org/10.1111/ijn.12413
Davidson, J. (2015). What’s all the buzz about change management? Healthcare Management Forum, 28(3), 118–120.
https://doi.org/10.1177/0840470415570174 Davies, A., Berge, C., Boehnke, A.,
Dadabhoy, A., Lugtenburg, P., Rule, S., … Badoux, X. (2017). Subcutaneous Rituximab for the treatment of B-Cell Hematologic Malignancies: A Review of the Scientific Rationale and Clinical Development. Advances in Therapy, 34(10), 2210–2231. https://doi.org/10.1007/
s12325-017-0610-z
De Cock, E., Pivot, X., Hauser, N., Verma, S., Kritikou, P., Millar, D., & Knoop, A. (2016). A time and motion study of subcutaneous versus intravenous trastuzumab in patients with HER2‐
positive early breast cancer. Cancer Medicine, 5(3), 389–397. https://doi.
org/10.1002/cam4.573
Dent, S., Ammendolea, C., Christofides, A., Edwards, S., Incekol, D., Pourmirza, B.,
… Poirier, B. (2019). A multidisciplinary perspective on the subcutaneous administration of trastuzumab in HER2- positive breast cancer. Current Oncology, 26(1), e70–e80. https://doi.org/10.3747/
co.26.4220
Haller, M. F. (2007). Converting intravenous dosing to subcutaneous dosing with recombinant human hyaluronidase.
Pharmaceutical Technology, 31(10).
Retrieved from http://www.pharmtech.
com/converting-intravenous-dosing- subcutaneous- dosing-recombinant- human-hyaluronidase
Hoffmann-La Roche Ltd. (2018a).
HERCEPTIN SC (trastuzumab) Product Monograph. Retrieved from https://
health-products.canada.ca/dpd-bdpp/
info.do?lang=en&code=97124
Hoffmann-La Roche Ltd. (2018b).
RITUXAN SC (rituximab) Product Monograph. Retrieved from https://
health-products.canada.ca/dpd-bdpp/
info.do?lang=en&code=94441
Jackisch, C., Müller, V., Maintz, C., Hell, S., & Ataseven, B. (2014). Subcutaneous administration of monoclonal antibodies in oncology. Geburtshilfe Und Frauenheilkunde, 74(4), 343–349. https://
doi.org/10.1055/s-0034-1368173
Janssen Inc. (2018). VELCADE (bortezomib) Product Monograph.
Retrieved from https://health- products.canada.ca/dpd-bdpp/info.
do?lang=en&code=74782
Kurtin, S., Knop, C. S., & Milliron, T.
(2012). Subcutaneous administration of Bortezomib: Strategies to reduce injection site reactions. Journal of the Advanced Practitioner in Oncology, 3(6), 406–410.
Leveque, D. (2014). Subcutaneous administration of anticancer agents.
Anticancer Research, 34(4), 1579–1586.
Lundin, J., Kimby, E., Björkholm, M., Broliden, P.-A., Celsing, F., Hjalmar, V., … Österborg, A. (2002). Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL).
Blood, 100(3), 768–773. https://doi.
org/10.1182/blood-2002-01-0159 MacDonald, D., Crosbie, T., Christofides,
A., Assaily, W., & Wiernikowski, J.
(2017). A Canadian perspective on the subcutaneous administration of rituximab in non-Hodgkin lymphoma.
Current Oncology, 24(1), 33–39. https://
doi.org/10.3747/co.24.3470
Martin, J. (2013). The subcutaneous administration of Bortezomib Practice Guideline Capstone Project (Regis University). Retrieved from https://
epublications.regis.edu/theses/202
Martin, J. R., Beegle, N. L., Zhu, Y., &
Hanisch, E. M. (2015). Subcutaneous administration of Bortezomib: A pilot survey of oncology nurses. Journal of the Advanced Practitioner in Oncology, 6(4), 308–318.
Möbus, V., Mahlberg, R., Janni, W., Tomé, O., Marmé, F., Forstbauer, H.,
… Loibl, S. (2018). Abstract P5-20- 09: Pharmacokinetic results of a subcutaneous injection of trastuzumab into the thigh versus into the abdominal wall in patients with HER2-positive primary breast cancer (BC) treated within the neo-/adjuvant GAIN-2 study. Cancer Research, 78(4 Suppl.), P5-20-09–P5-20–
09. https://doi.org/10.1158/1538-7445.
SABCS17-P5-20-09
Pivot, X., Verma, S., Fallowfield, L., Müller, V., Lichinitser, M., Jenkins, V., … Gligorov, J. (2017). Efficacy and safety of subcutaneous trastuzumab and intravenous trastuzumab as part of adjuvant therapy for HER2-positive early breast cancer: Final analysis of the randomised, two-cohort PrefHer study.
European Journal of Cancer, 86, 82–90.
https://doi.org/10.1016/j.ejca.2017.08.019 Platzbecker, U., Aul, C., Ehninger, G., &
Giagounidis, A. (2010). Reduction of 5-azacitidine induced skin reactions in MDS patients with evening primrose oil. Annals of Hematology, 89(4), 427–428.
https://doi.org/10.1007/s00277-009-0824-5 Sanofi Genzyme. (2018). MABCAMPATH
(alemtuzumab) Product Monograph.
Retrieved from https://health- products.canada.ca/dpd-bdpp/info.
do?lang=en&code=77636
Stilgenbauer, S., Zenz, T., Winkler, D., Bühler, A., Schlenk, R. F., Groner, S.,
… Döhner, H. (2009). Subcutaneous Alemtuzumab in Fludarabine-Refractory chronic lymphocytic leukemia: Clinical results and prognostic marker analyses from the CLL2H Ssudy of the German Chronic Lymphocytic Leukemia Study Group. Journal of Clinical Oncology, 27(24), 3994–4001. https://doi.
org/10.1200/JCO.2008.21.1128
