Original Article
Tolerability of Velcade (Bortezomib) subcutaneous administration using a maximum volume of 3 mL per injection site
J Oncol Pharm Practice 2015, Vol. 21(4) 285–292 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155214533367 opp.sagepub.com
Pamela Ng1, Diana Incekol2, Roy Lee1, Emma Paisley2, Celina Dara1, Ian Brandle2, Marina Kaufman2, Christine Chen3, Suzanne Trudel3, Rodger Tiedemann3, Donna Reece3 and Vishal Kukreti3
Abstract Subcutaneous injection is now commonly used as a standard for bortezomib administration. The bortezomib (VelcadeÕ ) product monograph recommends that intravenous injections be prepared at a concentration of 1 mg/mL, while subcutaneous injections may be prepared at a concentration of 2.5 mg/mL. Many institutions and subcutaneous administration guidelines use 2 mL as the maximum volume for subcutaneous injection. Using 2 mL as the maximum volume for injection would mean that many patients receiving bortezomib will receive two injections during each visit with common dosing parameters. In this prospective study evaluating a change to subcutaneous administration, bortezomib 1 mg/mL was administered subcutaneously at a higher maximum of 3 mL per injection site. For 57 individual patients, 339 doses were administered. Skin reactions were noted in 42% with all reactions being Grade 1 or 2. Patients tolerated subcutaneous injections well and only four patients were switched back to intravenous route. This is the first time that subcutaneous bortezomib of a volume up to a maximum of 3 mL (bortezomib 3 mg) per injection site has been reported. This higher single dose is well tolerated with limited skin reactions, no significant hypotension and facilitates ease of administration with only 5 patients needing two injections per visit. If the maximum volume for injection was kept at 2 mL, a total of 46 patients would have received two injections per visit.
Keywords Subcutaneous, injection, maximum volume, 3 mL, bortezomib
Background The proteasome inhibitor bortezomib is approved for the treatment of multiple myeloma, and mantle cell lymphoma in patients who have received at least 1 prior therapy.1 Initial approval of bortezomib was for intravenous (IV) administration. In 2012, the US Food and Drug Administration (FDA) and Health Canada approved the use of the subcutaneous (SC) route as an alternate route for administration of bortezomib.1,2 Studies have shown that bortezomib SC administration has comparable efficacy to IV administration, and that the incidence of peripheral neuropathy is significantly lower when bortezomib is given subcutanously than
when given intravenously.3 Bortezomib SC injection improves patient convenience and resolves the issue of venous access in many patients who have poor veins.
1
Dept. of Pharmacy, Princess Margaret Cancer Centre, UHN Toronto, ON 2 Dept. of Nursing, Princess Margaret Cancer Centre, UHN, Toronto, ON 3 Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, UHN, Toronto, ON Corresponding author: Pamela Ng, Princess Margaret Cancer Centre 610 University Avenue, Toronto, ON Ontario M5G 2M9. Canada. Email: [email protected]
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Bortezomib is supplied as a 3.5 mg vial. The product monograph for Bortezomib (VelcadeÕ ) recommends that IV injections be prepared at a concentration of 1 mg/mL, while SC injections may be prepared at a concentration of 2.5 mg/mL.1 At the Princess Margaret Cancer Centre, bortezomib is given subcutaneously to all patients, except for amyloid patients or patients concurrently requiring IV hydration with bortezomib dosing. Amyloidosis patients who often have edema, fragile skin and increased risk for bleeding remain on IV bortezomib until more data are available on SC dosing’s safety and efficacy. We made an institutional safety decision to keep a single concentration of bortezomib 1 mg/mL when used for either IV or SC administration to avoid potential medication errors with having two different concentrations of bortezomib. Bortezomib 2.5 mg/mL was not considered for IV administration due to the limited data on using this as an IV push. The product monograph also recommends that patients who develop skin irritation and cannot tolerate bortezomib 2.5 mg/mL as SC injection be given a lower bortezomib 1 mg/mL concentration SC. If this were to occur, the hospital would have to carry two different concentrations of bortezomib which would increase the risk of medication errors. The challenge in administering a lower concentration subcutaneously is the resulting higher volume of medication for injection. Many institutions and SC administration guidelines use 2 mL as the maximum volume for SC injection, although there is no evidence to support this practice. New drugs such as degarelix and azacitidine have been approved for SC administration in volumes of 3 to 4 mL per injection site based on their product monographs, however injection site reaction (ISR) details remain limited.4,5 Moreover, the 2mL maximum volume per injection site would mean that over half of our patients will receive two injections of bortezomib during each visit. Anecdotally, many centres use a maximum volume of 2.5 to 3 mL per bortezomib injection site and report good tolerability, but this has not been published. The initial Phase 1 study comparing SC and IV administration of bortezomib used a concentration of 1 mg/mL but did not state what the maximum volume was for each injection site.6 After contacting the author, we were informed that the maximum volume injected into each injection site was 3 mL; this paper however was a very small study (12 patients who received IV and 12 who received SC bortezomib) and did not include the actual SC volumes injected or details on the ISRs, but concluded that the SC injections were tolerable. The larger Phase 3 study by Moreau et al.,3 which led to the approval of the SC injections as an alternate injection route for bortezomib, used a concentration of 2.5 mg/mL; using this new concentration would
mean that most patients would receive a single injection volume that is less than 2 mL per injection at each visit.3 Most common subcutaneously-administered medications (eg. insulin, heparin) are administered in small volumes (less than 2 mL); therefore, limited data are available on higher SC injection volumes. Hypotension is another known adverse effect of IV bortezomib.1 Many institutions currently monitor blood pressure before and after IV bortezomib, and patients are given hydration after IV bortezomib administration if blood pressure drops by a certain amount; however, there is limited data on whether SC bortezomib administration affects blood pressure. Our study also looks at the effects of SC bortezomib on blood pressure, which we felt was necessary as this patient population will have no IV access at the time of SC administration. The main objectives of this study are (1) to determine the tolerability of a 3-mL maximum volume per SC injection and (2) to determine the changes in blood pressure associated with SC injection. This paper describes our experience using a 3-mL maximum volume for SC injection.
Methods At the Princess Margaret Cancer Centre from September to December 2012, all consecutive patients previously on IV bortezomib or receiving first time bortezomib received SC bortezomib at a concentration of 1 mg/mL (3.5 mg bortezomib reconstituted with 3.5 mL Normal Saline), with a maximum of 3 mL injected into each SC injection site. Bortezomib doses range from 1 to 1.5 mg/m2, and all patients received weekly bortezomib. SC injection sites were documented and were alternated between the right and left abdomen, upper and lower quadrant, or right and left thigh with successive injections. Arms could be used as a last resort. Injections at the same site within a cycle were avoided. Patients whose bortezomib doses were higher than 3 mg (3 mL) received the dose as split SC injections (half the dose injected into two sites). Nurses followed proper injection guidelines recommended by the institution’s nursing policy to help ensure good delivery of medication, which includes: the use of a 27-gauge needle and using the ‘‘air sandwich’’ technique. The air sandwich technique is described as follows: a new, unprimed SC needle is attached to the bortezomib syringe, then 0.4 to 1 mL of air is drawn into the syringe. When the syringe is inverted for injection, the air will travel up the syringe barrel next to the plunger. The bortezomib is then ‘‘sandwiched’’ between the air in the syringe barrel and the air in the SC needle. During injection, the air in the needle goes in first, then the bortezomib, which is then followed by the air in the syringe barrel.
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Air (0.4 to 1 mL) Bortezomib dose
air in new unprimed needle
Figure 1. Air sandwich.
This method of SC administration is used to prevent seeding of the drug into the injection track (Figure 1). At the patient’s subsequent visit to clinic a week after the injection, nurses assessed the previous injection site(s) for any redness, swelling, or pain in the previous injection site and reviewed any concerns related to the treatment (e.g. nausea, diarrhea, neuropathy). Patient’s baseline blood pressure before injection and blood pressure 30 minutes after injection were noted to determine whether there are any changes in blood pressure with SC bortezomib injections. ISRs were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4: Grade 1, tenderness with or without associated symptoms (eg. warmth, erythema, itching); Grade 2, pain, lipodystrophy, edema, or phlebitis; Grade 3, ulceration, necrosis, severe tissue damage, or any indication for operative intervention; Grade 4, ISRs with life-threatening consequences, requiring urgent intervention. The institutional research ethics board approved this research study.
Results Over a period of approximately three months, 57 individual patients received a total of 339 doses of SC bortezomib (Figure 2); 32 of the patients were male and 25 were female. Each patient had a median of seven visits for bortezomib injection. Age ranged from 44 to 85
years, median age is 66. With the maximum volume per injection site of 3 mL, a total of 52 patients received one injection per visit, and five patients received two injections per visit. Assessment of previous injection sites were documented as per patient history and clinical exam at next treatment day in 274 of 339 (81%) visits; baseline and post-administration blood pressure were documented in 300 of 339 (88%) visits. Skin reactions were noted in 114 of 274 (42%) doses, with all reactions being Grade 1 or 2. Injection site reactions (ISRs) described as Grade 1 reactions were counted as Grade 1 only. ISRs in patients who experience both Grades 1 and 2 (pain) ISRs were categorized as Grade 2. Figure 3 shows the distribution of the ISRs based on the injection sites noted. ISRs were similar between injection sites (abdomen and thigh), and injection volumes. For injections into the abdomen, ISRs occurred in 19 of 51 (37%), 14 of 38 (37%), and 20 of 45 (44%) injection sites with injection volumes of 0–2 mL, 2.1–2.5 mL, and 2.51– 3 mL respectively (Figure 3a). For injections into the thigh, ISRs occurred in 9 of 19 (47%), 10 of 20 (50%), and 16 of 35 (46%) injection sites with injection volumes of 0–2 mL, 2.1–2.5 mL, and 2.51–3 mL, respectively (Figure 3b). For injections with injection site not documented, ISRs occurred in 9 of 23 (39%), 6 of 27 (22%), and 11 of 28 (39%) injection sites with injection volumes of 0–2 mL, 2.1–2.5 mL, and 2.51–3 mL, respectively (Figure 3c). Most ISRs for injections into either the thigh or abdomen were Grade 1 in nature. Two patients who received injections into the abdomen, one with a volume in the range of 2.01–2.50 mL and another patient who received a volume in the range of 2.51–3 mL developed Grade 2 reactions. One patient who received an injection to the thigh and another one with an unspecified site of injection, with a 2.1–2.5 mL injection volume developed Grade 2 reactions. Categorized by gender, 26 of 72 (36%) of males experienced an ISR compared to 29 of 63 (47%) of females for injections into the abdomen (Figure 4a). For injections into the thigh, the ISR rates were similar at 21 of 42 (50%) injection sites for males compared to 15 of 33 (46%) injection sites for females (Figure 4b). Most ISRs in both males and females were Grade 1 in nature. Grade 2 reactions were noted in similar rates between males and females (1 male with ISR in abdomen and 2 females with ISR in thigh). Overall, patients tolerated SC injections well; however, four patients were switched back to IV. The first patient received an injection volume of 1.96 mL SC and complained of nausea for 4 days after her second SC injection. The second patient received an injection volume of 1.63 mL, and had redness, bruising
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339 visits (assessed 57 patients)
274 visits included assessment of previous week’s injection site(s)
65 visits did not include assessment of previous week’s injection site(s)
114 assessments reported ISRs
160 assessments reported normal injection site
110 assessments reported Grade 1 ISR
4 assessments reported Grade 2 ISR (i.e. pain)
109 ISRs with redness/bruising
5 ISRs with rash
3 ISRs with swelling
1 ISR with tenderness
45 ISRs with redness/bruising 5 cm
5 ISRs with unspecified redness/bruising
Figure 2. Description of assessments.
and itchiness at the injection site. The third patient received an injection volume of 2.55 mL and experienced ISRs with the first two injections. After the third injection, he continued to have redness, itching, and developed an extensive rash. It is important to note that this patient also has a long-standing history of pruritus, myalgias, and was being followed by dermatology with no clear diagnosis. The last patient received an injection volume of 2.53 mL and developed a rash that was red and itchy. All patients requested to change back to IV bortezomib either due to nausea or discomfort at the SC injection site. Of note is that two of these patients who were switched back to IV bortezomib had an injection volume less than 2 mL bortezomib, while the other two had volumes higher than 2 mL injected (2.55 and 2.53). Changes in systolic blood pressure compared to baseline were less than 20 mmHg in 264 of 300 (88%) patients and between 20 and 30 mmHg in 36 of 300 (12%) patients. Changes in diastolic blood pressure compared to baseline were less than 20 mmHg in 289 of 300 (96%) patients and between 20 and 30 mmHg in 11 of 300 (4%) patients. None of these patients were symptomatic from the blood pressure changes, so no patient was given IV hydration. Most patients who received SC bortezomib had a minimal change in blood pressure 30 minutes post injection. There were no cases of clinically symptomatic hypotension that required infusion of IV fluids (Figure 5).
Discussion Our study of myeloma patients at Princess Margaret showed that SC administration of bortezomib up to an injection volume of 3 mL per injection site is very well tolerated. The primary objective of this study was to assess tolerability to SC bortezomib injections at a higher maximum volume for injection (3 mL). In our study, ISRs were generally mild, (40% Grade 1 reactions), and only 4% were Grade 2 in nature. None of our patients experienced a Grade 3 or higher reaction during our study, although four patients were switched back to IV bortezomib for various reasons. Three of the four patients were switched back to IV bortezomib due to discomfort at the SC injection site; one patient complained of nausea for 4 days after her second SC bortezomib injection. Nausea has been associated with bortezomib at rates of 16– 56%,7 and ondansetron 16 mg PO daily is routinely given prior to bortezomib at our institution as an antiemetic. It is difficult to be certain about the actual cause of nausea in this case. In the Moreau Phase 3 study, nine of 147 (6%) patients had one or more SC ISRs reported as an adverse event; these ISRs resulted in a bortezomib dose modification in two (1%) patients (discontinuation or dose withholding).3 The most common reaction was redness (classified as Grade 1 based on definition in NCI-CTCAE but not considered as an ISR in the Moreau study), which was reported in
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Injection sites in abdominal region
(a) Number of injection sites
60
0 1
50 1
19
40
20
ISR (Grade 2)
13
30
ISR (Grade 1)
20
32
10
Normal
24
25
2.01-2.50
2.51-3.00
0 0.00-2.00
Injection volume (mL) Injection sites in thigh region
Number of injection sites
(b) 40
0
35 30 25 20 15
16
0
1
9
10
ISR (Grade 2) ISR (Grade 1)
10 5
19 10
10
0.00-2.00
2.01-2.50
Normal
0 2.51-3.00
Injection volume (mL) Injection sites in unspecified regions
(c) Number of injection sites
30 25 20
0
1 0 6
11
9 ISR (Grade 2)
15
5
ISR (Grade 1)
20
10
17
14
Normal
0 0.00-2.00
2.01-2.50
2.51-3.00
Injection volume (mL)
Figure 3. Injection site reactions (ISRs) based on injection site and volume. (a) Injection sites in abdominal region. (b) Injection sites in thigh region. (c) Injection sites in unspecified region.
57% of patients. In the Kamimura study, Grade 1 ISRs were reported in 40 of 158 injections (25%), and Grade 2 ISRs were reported in seven of 158 injections (4%).8 Our data are comparable to the Moreau and Kamimura study which have grades 1 and 2 ISR rates of 57% and 29.7%, respectively.3,8 The Moreau study also had four of 147 (2.7%) patients in the SC group who had severe ISRs (Grade 3). Bortezomib in the Moreau study was given in a higher concentration and lower volume.3 There is limited information about these patients who experienced Grade 3 ISRs, but higher concentrations of bortezomib may have
contributed to more severe ISRs. The VelcadeÕ Product Monograph recommends that patients who develop ISRs with SC bortezomib 2.5 mg/mL receive a lower concentration of SC bortezomib 1 mg/mL, which is the concentration we use for all our patients. Since the approval of the use of the SC bortezomib, several papers have reported on associated injection site reactions. A Letter to the Editor to the European Journal of Hematology reported that the median duration of ISRs was 5 days (range 3–23 days) and that topical hydrocortisone butyrate was helpful in a patient who developed a Grade 2 ISR with erythema and
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Injection sites in abdominal region
(a) 80
1
Number of injection sites
70 60
1 25
50
28
40
ISR (Grade 1)
30 20
ISR (Grade 2)
Normal
46 34
10 0 Male
(b)
Injection sites in thigh area
45 Number of injection sites
Female
0
40 1
35 30
21
25
14
ISR (Grade 1)
20 15 10
ISR (Grade 2)
Normal 21
18
5 0 Male
Female
Figure 4. Injection sites categorized by gender. (a) Injection sites in abdominal region categorized by gender. (b) Injection sites in thigh region categorized by gender.
phlebitis; itching and phlebitis around the injection site quickly disappeared on the day after administration of topical hydrocortisone.9 The other patients’ ISRs spontaneously disappeared within a couple of days. The only detailed case report of a Grade 3 or higher ISR was in a patient who presented with a necrotizing skin eruption, along with fever. Biopsy was negative for microbial organisms.10 The patient responded to IV methylprednisolone with defervesence, subjective wellbeing, and regression of the lesion. An alternative chemotherapeutic regimen was substituted for bortezomib at the discretion of the treating hematologist. There did not seem to be a notable difference in the ISR between different injection sites (range is 34–48%) (Figure 3). There also did not seem to be a notable trend towards higher ISR with injection volumes higher than 2 mL compared to injection volumes less than 2 mL regardless of injection site. However, the four cases of Grade 2 reactions were only noted with injection volumes of over 2 mL. Median number of injections received by patients in our study is 7, and the ISR with this higher bortezomib SC volume injected (greater than 2 mL) seem reasonable. However, further studies are needed to determine long-term tolerability
with injections of these higher volumes. At our institution, bortezomib has been administered SC with a 3mL maximum per injection site for a year, with no reported concerns. This change in practice for our institution to the 3mL maximum (with a 1 mg/1mL concentration) also translates to fewer patients receiving two injections per visit. In this study, a total of five patients received two injections per visit (bortezomib dose over 3 mg). If the maximum volume for injection was kept at 2 mL, a total of 32 patients would receive two injections per visit. Decreasing the number of injections received by patients means that injection sites can be rotated better, and each injection site used less frequently. Rotation of SC injection sites is recommended by the product monograph, and other published literature, especially in diabetes where this has been more extensively studied to prevent buildup of fibrous tissue and allow complete absorption of medications.11 One of the limitations of the study is its short duration and a lack of consecutive follow-up post SC injection on a daily basis. Other studies used various methods for assessing injection sites; one particular study addressing injection site reactions included a
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100
94 Systolic blood pressure
90
Diastolic blood pressure 78
80
Number of patients
70
66 60
59
60 50 38
40
33 28
30
29
23
20 20 10
5 0
13
10
7 1
3
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2 2 3
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0 han
rt ate
Gre
5 5 0 15 –5 20 10 30 25 15 +20 –29 to –2 +30 to 0 1 to + to +1 to – 9 to – 4 to – –9 to to + 6 to + than to + 16 to + –4 +6 –1 + –29 –24 –1 +2 ater +21 +11 Gre
Change in blood pressure (mmHg)
Figure 5. Blood pressure changes 30 minutes after injection compared to baseline.
systematic evaluation of the injection site 2 hours after the injection and every day during the first treatment cycle during hospitalization.8 After the second cycle, injection site reactions were evaluated at every visit, and between visits, patients documented their own ISRs in a detailed diary. At our centre, assessments of the injection sites were done by the nurse at the next chemotherapy visit. This assessment would not have captured the reaction that occurred immediately after injection. However, we believe that closer assessment of injection sites are not necessary because any severe injection site reactions (especially those warranting a change in therapy) would have been reported by the patient either by calling their clinic nurse or physician, or at the next chemotherapy visit. Unlike the study by Kamimura, we did not find a notable difference in injection site reactions based on the injection site. Prior to this study, patients receiving bortezomib IV at our institution were monitored for vital sign changes before and after bortezomib administration. Patients who experience a drop in blood pressure before and after IV bortezomib of 20 mmHg or more were given hydration with 250 mL normal saline, regardless of symptoms. At the start of the study, we hypothesized that since SC bortezomib is absorbed differently (maximum concentration is higher for IV bortezomib, and time to maximum concentration also occurs sooner for IV bortezomib), blood pressure changes and symptomatic changes as a result will not be noted while the
patient is in hospital. In this study, we found that blood pressure changes with SC bortezomib were minimal (Figure 4), and patients were not symptomatic from the blood pressure changes, therefore no patient was given additional hydration for blood pressure changes. After the analysis of our study data, we changed practice at our institution to eliminate the need to monitor vital signs post SC bortezomib, as well as removed the need to give IV hydration with SC bortezomib. Combined data from patients treated in Phases 2 and 3 relapsed multiple myeloma studies with IV bortezomib have shown the incidence of orthostatic/postural hypotension in 11–15% of patients (1–4% Grade 3, 1% Grade 4).1 Hypotension was not reported in the studies with SC bortezomib. This is a reminder that patients, especially those with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated, should be regularly monitored for hypotension and treated as necessary due to the later onset of hypotension with SC injections. A recent study of patient preferences comparing SC versus IV bortezomib in 92 patients have concluded that SC administration of bortezomib is preferred by patients primarily as a result of convenience (shorter time in chair).12 The institution also highly benefitted from the savings in chair time. This savings in chair time is particularly beneficial in these times when more lines of therapy are available to
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patients, as well as increasing patient volumes at the various cancer sites. Of interest is also that 50% of the survey participants agreed that they would feel comfortable self-administering SC bortezomib at home. Given the number of oral chemotherapy, and supportive medications given subcutaneously (e.g. filgrastim) that are available for patients to take/ self-administer at home, this might be an area for consideration for future drug development and research.
Conflict of interest Diana Incekol received honoraria from Janssen for nursing education regarding Velcade administration. Christine Chen received honoraria from Janssen. The rest of the authors declare no conflicts of interest.
Acknowledgements We sincerely thank the team of Chemotherapy Daycare nursing staff, pharmacists, and Aaron Lo for their dedication and collaboration in this project.
Conclusion This is the first time that the tolerability of SC bortezomib of a volume up to a maximum of 3 mL (or 3 mg of bortezomib) per injection site has been described. Our study has found that this higher injection volume is well tolerated with limited skin reactions and no clinically significant hypotension. Using a higher maximum volume for injection means that fewer patients required more than one injection per visit, compared to our previous standard of 2 mL. Since this study, there has been significant interest in studying higher maximum injection volumes for drugs. For instance, although the azacitidine (VidazaÕ ) product monograph recommends that injection volumes of higher than 4 mL be split into two injection sites (i.e. to give a maximum of 4 mL per injection site), most centres do not follow this practice due to hesitation by nurses to administer such high volumes subcutaneously, as well as lack of more specific data on injection site reactions with larger injection volumes. In this instance, many centres such as ours, have used a 3-mL maximum for injection as a result of our positive experience with this volume of injection with bortezomib, and potentially explore the use of higher volume for injection in the future. We also anticipate that this data would stimulate future research on SC injection of other drugs that are given in large volumes such as filgrastim, which is commonly administered at our institution for stem cell mobilization. Authorship contributions PN and VK had the primary responsibility for analyses, and interpretation of data and for manuscript preparation. All authors participated in conception, manuscript preparation, and review and approval of the final manuscript.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
References 1. VelcadeÕ (Product Monograph). Canada: Janssen Inc.; 2013. 2. Arnulf B, Pylypenko H, Grosicki S, et al. Updated survival analysis of a randomized phase III study of subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma. Haematologica 2012; 97: 1925–1928. 3. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomized, phase 3, non-inferiority study. Lancet Oncol 2011; 12: 431–440. 4. FirmagonÕ (Product Monograph). Canada: Ferring Pharmaceuticals; 2013. 5. VidazaÕ (Product Monograph). Canada: Celegene Inc; 2012. 6. Moreau P, Coiteux V, Hulin C, et al. Prospective comparison of subcutaneous versus intravenous administration of bortezomib in patients with multiple myeloma. Haematologica 2008; 93: 1908–1911. 7. LexicompTM, Hudson, Ohio: Lexi-Comp, Inc; accessed January 28, 2014. 8. Kamimura T, Miyamoto T, Takashima S, et al. Injection site reaction after subcutaneous administration of bortezomib in Japanese patients with multiple myeloma. Int J Hematol 2012; 96: 525–527. 9. Kamimura T, Miyamoto T, Yokota N, et al. Higher incidence of injection site reactions after subcutaneous bortezomib administration on the thigh compared with the abdomen. Eur J Haematol 2012; 90: 157–161. 10. Obeid KM, Ferrara R and Sharma M. Cutaneous lesion induced by a subcutaneous administration of bortezomib. Clin Lymphoma Myeloma Leuk 2012; 12: 284–286. 11. Chowdhury TA and Escudier V. Poor glycaemic control caused by insulin induced lipohypertrophy. BMJ 2003; 327: 383–384. 12. Barbee MS, Harvey RD, Lonial S, et al. Subcutaneous versus intravenous bortezomib: efficiency practice variables and patient preferences. Ann Pharmacother 2013; 47: 1136–1142.
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Tolerability of Velcade (Bortezomib) subcutaneous administration using a maximum volume of 3 mL per injection site
J Oncol Pharm Practice 2015, Vol. 21(4) 285–292 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155214533367 opp.sagepub.com
Pamela Ng1, Diana Incekol2, Roy Lee1, Emma Paisley2, Celina Dara1, Ian Brandle2, Marina Kaufman2, Christine Chen3, Suzanne Trudel3, Rodger Tiedemann3, Donna Reece3 and Vishal Kukreti3
Abstract Subcutaneous injection is now commonly used as a standard for bortezomib administration. The bortezomib (VelcadeÕ ) product monograph recommends that intravenous injections be prepared at a concentration of 1 mg/mL, while subcutaneous injections may be prepared at a concentration of 2.5 mg/mL. Many institutions and subcutaneous administration guidelines use 2 mL as the maximum volume for subcutaneous injection. Using 2 mL as the maximum volume for injection would mean that many patients receiving bortezomib will receive two injections during each visit with common dosing parameters. In this prospective study evaluating a change to subcutaneous administration, bortezomib 1 mg/mL was administered subcutaneously at a higher maximum of 3 mL per injection site. For 57 individual patients, 339 doses were administered. Skin reactions were noted in 42% with all reactions being Grade 1 or 2. Patients tolerated subcutaneous injections well and only four patients were switched back to intravenous route. This is the first time that subcutaneous bortezomib of a volume up to a maximum of 3 mL (bortezomib 3 mg) per injection site has been reported. This higher single dose is well tolerated with limited skin reactions, no significant hypotension and facilitates ease of administration with only 5 patients needing two injections per visit. If the maximum volume for injection was kept at 2 mL, a total of 46 patients would have received two injections per visit.
Keywords Subcutaneous, injection, maximum volume, 3 mL, bortezomib
Background The proteasome inhibitor bortezomib is approved for the treatment of multiple myeloma, and mantle cell lymphoma in patients who have received at least 1 prior therapy.1 Initial approval of bortezomib was for intravenous (IV) administration. In 2012, the US Food and Drug Administration (FDA) and Health Canada approved the use of the subcutaneous (SC) route as an alternate route for administration of bortezomib.1,2 Studies have shown that bortezomib SC administration has comparable efficacy to IV administration, and that the incidence of peripheral neuropathy is significantly lower when bortezomib is given subcutanously than
when given intravenously.3 Bortezomib SC injection improves patient convenience and resolves the issue of venous access in many patients who have poor veins.
1
Dept. of Pharmacy, Princess Margaret Cancer Centre, UHN Toronto, ON 2 Dept. of Nursing, Princess Margaret Cancer Centre, UHN, Toronto, ON 3 Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, UHN, Toronto, ON Corresponding author: Pamela Ng, Princess Margaret Cancer Centre 610 University Avenue, Toronto, ON Ontario M5G 2M9. Canada. Email: [email protected]
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Bortezomib is supplied as a 3.5 mg vial. The product monograph for Bortezomib (VelcadeÕ ) recommends that IV injections be prepared at a concentration of 1 mg/mL, while SC injections may be prepared at a concentration of 2.5 mg/mL.1 At the Princess Margaret Cancer Centre, bortezomib is given subcutaneously to all patients, except for amyloid patients or patients concurrently requiring IV hydration with bortezomib dosing. Amyloidosis patients who often have edema, fragile skin and increased risk for bleeding remain on IV bortezomib until more data are available on SC dosing’s safety and efficacy. We made an institutional safety decision to keep a single concentration of bortezomib 1 mg/mL when used for either IV or SC administration to avoid potential medication errors with having two different concentrations of bortezomib. Bortezomib 2.5 mg/mL was not considered for IV administration due to the limited data on using this as an IV push. The product monograph also recommends that patients who develop skin irritation and cannot tolerate bortezomib 2.5 mg/mL as SC injection be given a lower bortezomib 1 mg/mL concentration SC. If this were to occur, the hospital would have to carry two different concentrations of bortezomib which would increase the risk of medication errors. The challenge in administering a lower concentration subcutaneously is the resulting higher volume of medication for injection. Many institutions and SC administration guidelines use 2 mL as the maximum volume for SC injection, although there is no evidence to support this practice. New drugs such as degarelix and azacitidine have been approved for SC administration in volumes of 3 to 4 mL per injection site based on their product monographs, however injection site reaction (ISR) details remain limited.4,5 Moreover, the 2mL maximum volume per injection site would mean that over half of our patients will receive two injections of bortezomib during each visit. Anecdotally, many centres use a maximum volume of 2.5 to 3 mL per bortezomib injection site and report good tolerability, but this has not been published. The initial Phase 1 study comparing SC and IV administration of bortezomib used a concentration of 1 mg/mL but did not state what the maximum volume was for each injection site.6 After contacting the author, we were informed that the maximum volume injected into each injection site was 3 mL; this paper however was a very small study (12 patients who received IV and 12 who received SC bortezomib) and did not include the actual SC volumes injected or details on the ISRs, but concluded that the SC injections were tolerable. The larger Phase 3 study by Moreau et al.,3 which led to the approval of the SC injections as an alternate injection route for bortezomib, used a concentration of 2.5 mg/mL; using this new concentration would
mean that most patients would receive a single injection volume that is less than 2 mL per injection at each visit.3 Most common subcutaneously-administered medications (eg. insulin, heparin) are administered in small volumes (less than 2 mL); therefore, limited data are available on higher SC injection volumes. Hypotension is another known adverse effect of IV bortezomib.1 Many institutions currently monitor blood pressure before and after IV bortezomib, and patients are given hydration after IV bortezomib administration if blood pressure drops by a certain amount; however, there is limited data on whether SC bortezomib administration affects blood pressure. Our study also looks at the effects of SC bortezomib on blood pressure, which we felt was necessary as this patient population will have no IV access at the time of SC administration. The main objectives of this study are (1) to determine the tolerability of a 3-mL maximum volume per SC injection and (2) to determine the changes in blood pressure associated with SC injection. This paper describes our experience using a 3-mL maximum volume for SC injection.
Methods At the Princess Margaret Cancer Centre from September to December 2012, all consecutive patients previously on IV bortezomib or receiving first time bortezomib received SC bortezomib at a concentration of 1 mg/mL (3.5 mg bortezomib reconstituted with 3.5 mL Normal Saline), with a maximum of 3 mL injected into each SC injection site. Bortezomib doses range from 1 to 1.5 mg/m2, and all patients received weekly bortezomib. SC injection sites were documented and were alternated between the right and left abdomen, upper and lower quadrant, or right and left thigh with successive injections. Arms could be used as a last resort. Injections at the same site within a cycle were avoided. Patients whose bortezomib doses were higher than 3 mg (3 mL) received the dose as split SC injections (half the dose injected into two sites). Nurses followed proper injection guidelines recommended by the institution’s nursing policy to help ensure good delivery of medication, which includes: the use of a 27-gauge needle and using the ‘‘air sandwich’’ technique. The air sandwich technique is described as follows: a new, unprimed SC needle is attached to the bortezomib syringe, then 0.4 to 1 mL of air is drawn into the syringe. When the syringe is inverted for injection, the air will travel up the syringe barrel next to the plunger. The bortezomib is then ‘‘sandwiched’’ between the air in the syringe barrel and the air in the SC needle. During injection, the air in the needle goes in first, then the bortezomib, which is then followed by the air in the syringe barrel.
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Air (0.4 to 1 mL) Bortezomib dose
air in new unprimed needle
Figure 1. Air sandwich.
This method of SC administration is used to prevent seeding of the drug into the injection track (Figure 1). At the patient’s subsequent visit to clinic a week after the injection, nurses assessed the previous injection site(s) for any redness, swelling, or pain in the previous injection site and reviewed any concerns related to the treatment (e.g. nausea, diarrhea, neuropathy). Patient’s baseline blood pressure before injection and blood pressure 30 minutes after injection were noted to determine whether there are any changes in blood pressure with SC bortezomib injections. ISRs were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4: Grade 1, tenderness with or without associated symptoms (eg. warmth, erythema, itching); Grade 2, pain, lipodystrophy, edema, or phlebitis; Grade 3, ulceration, necrosis, severe tissue damage, or any indication for operative intervention; Grade 4, ISRs with life-threatening consequences, requiring urgent intervention. The institutional research ethics board approved this research study.
Results Over a period of approximately three months, 57 individual patients received a total of 339 doses of SC bortezomib (Figure 2); 32 of the patients were male and 25 were female. Each patient had a median of seven visits for bortezomib injection. Age ranged from 44 to 85
years, median age is 66. With the maximum volume per injection site of 3 mL, a total of 52 patients received one injection per visit, and five patients received two injections per visit. Assessment of previous injection sites were documented as per patient history and clinical exam at next treatment day in 274 of 339 (81%) visits; baseline and post-administration blood pressure were documented in 300 of 339 (88%) visits. Skin reactions were noted in 114 of 274 (42%) doses, with all reactions being Grade 1 or 2. Injection site reactions (ISRs) described as Grade 1 reactions were counted as Grade 1 only. ISRs in patients who experience both Grades 1 and 2 (pain) ISRs were categorized as Grade 2. Figure 3 shows the distribution of the ISRs based on the injection sites noted. ISRs were similar between injection sites (abdomen and thigh), and injection volumes. For injections into the abdomen, ISRs occurred in 19 of 51 (37%), 14 of 38 (37%), and 20 of 45 (44%) injection sites with injection volumes of 0–2 mL, 2.1–2.5 mL, and 2.51– 3 mL respectively (Figure 3a). For injections into the thigh, ISRs occurred in 9 of 19 (47%), 10 of 20 (50%), and 16 of 35 (46%) injection sites with injection volumes of 0–2 mL, 2.1–2.5 mL, and 2.51–3 mL, respectively (Figure 3b). For injections with injection site not documented, ISRs occurred in 9 of 23 (39%), 6 of 27 (22%), and 11 of 28 (39%) injection sites with injection volumes of 0–2 mL, 2.1–2.5 mL, and 2.51–3 mL, respectively (Figure 3c). Most ISRs for injections into either the thigh or abdomen were Grade 1 in nature. Two patients who received injections into the abdomen, one with a volume in the range of 2.01–2.50 mL and another patient who received a volume in the range of 2.51–3 mL developed Grade 2 reactions. One patient who received an injection to the thigh and another one with an unspecified site of injection, with a 2.1–2.5 mL injection volume developed Grade 2 reactions. Categorized by gender, 26 of 72 (36%) of males experienced an ISR compared to 29 of 63 (47%) of females for injections into the abdomen (Figure 4a). For injections into the thigh, the ISR rates were similar at 21 of 42 (50%) injection sites for males compared to 15 of 33 (46%) injection sites for females (Figure 4b). Most ISRs in both males and females were Grade 1 in nature. Grade 2 reactions were noted in similar rates between males and females (1 male with ISR in abdomen and 2 females with ISR in thigh). Overall, patients tolerated SC injections well; however, four patients were switched back to IV. The first patient received an injection volume of 1.96 mL SC and complained of nausea for 4 days after her second SC injection. The second patient received an injection volume of 1.63 mL, and had redness, bruising
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339 visits (assessed 57 patients)
274 visits included assessment of previous week’s injection site(s)
65 visits did not include assessment of previous week’s injection site(s)
114 assessments reported ISRs
160 assessments reported normal injection site
110 assessments reported Grade 1 ISR
4 assessments reported Grade 2 ISR (i.e. pain)
109 ISRs with redness/bruising
5 ISRs with rash
3 ISRs with swelling
1 ISR with tenderness
45 ISRs with redness/bruising 5 cm
5 ISRs with unspecified redness/bruising
Figure 2. Description of assessments.
and itchiness at the injection site. The third patient received an injection volume of 2.55 mL and experienced ISRs with the first two injections. After the third injection, he continued to have redness, itching, and developed an extensive rash. It is important to note that this patient also has a long-standing history of pruritus, myalgias, and was being followed by dermatology with no clear diagnosis. The last patient received an injection volume of 2.53 mL and developed a rash that was red and itchy. All patients requested to change back to IV bortezomib either due to nausea or discomfort at the SC injection site. Of note is that two of these patients who were switched back to IV bortezomib had an injection volume less than 2 mL bortezomib, while the other two had volumes higher than 2 mL injected (2.55 and 2.53). Changes in systolic blood pressure compared to baseline were less than 20 mmHg in 264 of 300 (88%) patients and between 20 and 30 mmHg in 36 of 300 (12%) patients. Changes in diastolic blood pressure compared to baseline were less than 20 mmHg in 289 of 300 (96%) patients and between 20 and 30 mmHg in 11 of 300 (4%) patients. None of these patients were symptomatic from the blood pressure changes, so no patient was given IV hydration. Most patients who received SC bortezomib had a minimal change in blood pressure 30 minutes post injection. There were no cases of clinically symptomatic hypotension that required infusion of IV fluids (Figure 5).
Discussion Our study of myeloma patients at Princess Margaret showed that SC administration of bortezomib up to an injection volume of 3 mL per injection site is very well tolerated. The primary objective of this study was to assess tolerability to SC bortezomib injections at a higher maximum volume for injection (3 mL). In our study, ISRs were generally mild, (40% Grade 1 reactions), and only 4% were Grade 2 in nature. None of our patients experienced a Grade 3 or higher reaction during our study, although four patients were switched back to IV bortezomib for various reasons. Three of the four patients were switched back to IV bortezomib due to discomfort at the SC injection site; one patient complained of nausea for 4 days after her second SC bortezomib injection. Nausea has been associated with bortezomib at rates of 16– 56%,7 and ondansetron 16 mg PO daily is routinely given prior to bortezomib at our institution as an antiemetic. It is difficult to be certain about the actual cause of nausea in this case. In the Moreau Phase 3 study, nine of 147 (6%) patients had one or more SC ISRs reported as an adverse event; these ISRs resulted in a bortezomib dose modification in two (1%) patients (discontinuation or dose withholding).3 The most common reaction was redness (classified as Grade 1 based on definition in NCI-CTCAE but not considered as an ISR in the Moreau study), which was reported in
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Injection sites in abdominal region
(a) Number of injection sites
60
0 1
50 1
19
40
20
ISR (Grade 2)
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30
ISR (Grade 1)
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10
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Number of injection sites
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0
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16
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(c) Number of injection sites
30 25 20
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11
9 ISR (Grade 2)
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Injection volume (mL)
Figure 3. Injection site reactions (ISRs) based on injection site and volume. (a) Injection sites in abdominal region. (b) Injection sites in thigh region. (c) Injection sites in unspecified region.
57% of patients. In the Kamimura study, Grade 1 ISRs were reported in 40 of 158 injections (25%), and Grade 2 ISRs were reported in seven of 158 injections (4%).8 Our data are comparable to the Moreau and Kamimura study which have grades 1 and 2 ISR rates of 57% and 29.7%, respectively.3,8 The Moreau study also had four of 147 (2.7%) patients in the SC group who had severe ISRs (Grade 3). Bortezomib in the Moreau study was given in a higher concentration and lower volume.3 There is limited information about these patients who experienced Grade 3 ISRs, but higher concentrations of bortezomib may have
contributed to more severe ISRs. The VelcadeÕ Product Monograph recommends that patients who develop ISRs with SC bortezomib 2.5 mg/mL receive a lower concentration of SC bortezomib 1 mg/mL, which is the concentration we use for all our patients. Since the approval of the use of the SC bortezomib, several papers have reported on associated injection site reactions. A Letter to the Editor to the European Journal of Hematology reported that the median duration of ISRs was 5 days (range 3–23 days) and that topical hydrocortisone butyrate was helpful in a patient who developed a Grade 2 ISR with erythema and
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Injection sites in abdominal region
(a) 80
1
Number of injection sites
70 60
1 25
50
28
40
ISR (Grade 1)
30 20
ISR (Grade 2)
Normal
46 34
10 0 Male
(b)
Injection sites in thigh area
45 Number of injection sites
Female
0
40 1
35 30
21
25
14
ISR (Grade 1)
20 15 10
ISR (Grade 2)
Normal 21
18
5 0 Male
Female
Figure 4. Injection sites categorized by gender. (a) Injection sites in abdominal region categorized by gender. (b) Injection sites in thigh region categorized by gender.
phlebitis; itching and phlebitis around the injection site quickly disappeared on the day after administration of topical hydrocortisone.9 The other patients’ ISRs spontaneously disappeared within a couple of days. The only detailed case report of a Grade 3 or higher ISR was in a patient who presented with a necrotizing skin eruption, along with fever. Biopsy was negative for microbial organisms.10 The patient responded to IV methylprednisolone with defervesence, subjective wellbeing, and regression of the lesion. An alternative chemotherapeutic regimen was substituted for bortezomib at the discretion of the treating hematologist. There did not seem to be a notable difference in the ISR between different injection sites (range is 34–48%) (Figure 3). There also did not seem to be a notable trend towards higher ISR with injection volumes higher than 2 mL compared to injection volumes less than 2 mL regardless of injection site. However, the four cases of Grade 2 reactions were only noted with injection volumes of over 2 mL. Median number of injections received by patients in our study is 7, and the ISR with this higher bortezomib SC volume injected (greater than 2 mL) seem reasonable. However, further studies are needed to determine long-term tolerability
with injections of these higher volumes. At our institution, bortezomib has been administered SC with a 3mL maximum per injection site for a year, with no reported concerns. This change in practice for our institution to the 3mL maximum (with a 1 mg/1mL concentration) also translates to fewer patients receiving two injections per visit. In this study, a total of five patients received two injections per visit (bortezomib dose over 3 mg). If the maximum volume for injection was kept at 2 mL, a total of 32 patients would receive two injections per visit. Decreasing the number of injections received by patients means that injection sites can be rotated better, and each injection site used less frequently. Rotation of SC injection sites is recommended by the product monograph, and other published literature, especially in diabetes where this has been more extensively studied to prevent buildup of fibrous tissue and allow complete absorption of medications.11 One of the limitations of the study is its short duration and a lack of consecutive follow-up post SC injection on a daily basis. Other studies used various methods for assessing injection sites; one particular study addressing injection site reactions included a
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100
94 Systolic blood pressure
90
Diastolic blood pressure 78
80
Number of patients
70
66 60
59
60 50 38
40
33 28
30
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rt ate
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5 5 0 15 –5 20 10 30 25 15 +20 –29 to –2 +30 to 0 1 to + to +1 to – 9 to – 4 to – –9 to to + 6 to + than to + 16 to + –4 +6 –1 + –29 –24 –1 +2 ater +21 +11 Gre
Change in blood pressure (mmHg)
Figure 5. Blood pressure changes 30 minutes after injection compared to baseline.
systematic evaluation of the injection site 2 hours after the injection and every day during the first treatment cycle during hospitalization.8 After the second cycle, injection site reactions were evaluated at every visit, and between visits, patients documented their own ISRs in a detailed diary. At our centre, assessments of the injection sites were done by the nurse at the next chemotherapy visit. This assessment would not have captured the reaction that occurred immediately after injection. However, we believe that closer assessment of injection sites are not necessary because any severe injection site reactions (especially those warranting a change in therapy) would have been reported by the patient either by calling their clinic nurse or physician, or at the next chemotherapy visit. Unlike the study by Kamimura, we did not find a notable difference in injection site reactions based on the injection site. Prior to this study, patients receiving bortezomib IV at our institution were monitored for vital sign changes before and after bortezomib administration. Patients who experience a drop in blood pressure before and after IV bortezomib of 20 mmHg or more were given hydration with 250 mL normal saline, regardless of symptoms. At the start of the study, we hypothesized that since SC bortezomib is absorbed differently (maximum concentration is higher for IV bortezomib, and time to maximum concentration also occurs sooner for IV bortezomib), blood pressure changes and symptomatic changes as a result will not be noted while the
patient is in hospital. In this study, we found that blood pressure changes with SC bortezomib were minimal (Figure 4), and patients were not symptomatic from the blood pressure changes, therefore no patient was given additional hydration for blood pressure changes. After the analysis of our study data, we changed practice at our institution to eliminate the need to monitor vital signs post SC bortezomib, as well as removed the need to give IV hydration with SC bortezomib. Combined data from patients treated in Phases 2 and 3 relapsed multiple myeloma studies with IV bortezomib have shown the incidence of orthostatic/postural hypotension in 11–15% of patients (1–4% Grade 3, 1% Grade 4).1 Hypotension was not reported in the studies with SC bortezomib. This is a reminder that patients, especially those with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated, should be regularly monitored for hypotension and treated as necessary due to the later onset of hypotension with SC injections. A recent study of patient preferences comparing SC versus IV bortezomib in 92 patients have concluded that SC administration of bortezomib is preferred by patients primarily as a result of convenience (shorter time in chair).12 The institution also highly benefitted from the savings in chair time. This savings in chair time is particularly beneficial in these times when more lines of therapy are available to
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patients, as well as increasing patient volumes at the various cancer sites. Of interest is also that 50% of the survey participants agreed that they would feel comfortable self-administering SC bortezomib at home. Given the number of oral chemotherapy, and supportive medications given subcutaneously (e.g. filgrastim) that are available for patients to take/ self-administer at home, this might be an area for consideration for future drug development and research.
Conflict of interest Diana Incekol received honoraria from Janssen for nursing education regarding Velcade administration. Christine Chen received honoraria from Janssen. The rest of the authors declare no conflicts of interest.
Acknowledgements We sincerely thank the team of Chemotherapy Daycare nursing staff, pharmacists, and Aaron Lo for their dedication and collaboration in this project.
Conclusion This is the first time that the tolerability of SC bortezomib of a volume up to a maximum of 3 mL (or 3 mg of bortezomib) per injection site has been described. Our study has found that this higher injection volume is well tolerated with limited skin reactions and no clinically significant hypotension. Using a higher maximum volume for injection means that fewer patients required more than one injection per visit, compared to our previous standard of 2 mL. Since this study, there has been significant interest in studying higher maximum injection volumes for drugs. For instance, although the azacitidine (VidazaÕ ) product monograph recommends that injection volumes of higher than 4 mL be split into two injection sites (i.e. to give a maximum of 4 mL per injection site), most centres do not follow this practice due to hesitation by nurses to administer such high volumes subcutaneously, as well as lack of more specific data on injection site reactions with larger injection volumes. In this instance, many centres such as ours, have used a 3-mL maximum for injection as a result of our positive experience with this volume of injection with bortezomib, and potentially explore the use of higher volume for injection in the future. We also anticipate that this data would stimulate future research on SC injection of other drugs that are given in large volumes such as filgrastim, which is commonly administered at our institution for stem cell mobilization. Authorship contributions PN and VK had the primary responsibility for analyses, and interpretation of data and for manuscript preparation. All authors participated in conception, manuscript preparation, and review and approval of the final manuscript.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
References 1. VelcadeÕ (Product Monograph). Canada: Janssen Inc.; 2013. 2. Arnulf B, Pylypenko H, Grosicki S, et al. Updated survival analysis of a randomized phase III study of subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma. Haematologica 2012; 97: 1925–1928. 3. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomized, phase 3, non-inferiority study. Lancet Oncol 2011; 12: 431–440. 4. FirmagonÕ (Product Monograph). Canada: Ferring Pharmaceuticals; 2013. 5. VidazaÕ (Product Monograph). Canada: Celegene Inc; 2012. 6. Moreau P, Coiteux V, Hulin C, et al. Prospective comparison of subcutaneous versus intravenous administration of bortezomib in patients with multiple myeloma. Haematologica 2008; 93: 1908–1911. 7. LexicompTM, Hudson, Ohio: Lexi-Comp, Inc; accessed January 28, 2014. 8. Kamimura T, Miyamoto T, Takashima S, et al. Injection site reaction after subcutaneous administration of bortezomib in Japanese patients with multiple myeloma. Int J Hematol 2012; 96: 525–527. 9. Kamimura T, Miyamoto T, Yokota N, et al. Higher incidence of injection site reactions after subcutaneous bortezomib administration on the thigh compared with the abdomen. Eur J Haematol 2012; 90: 157–161. 10. Obeid KM, Ferrara R and Sharma M. Cutaneous lesion induced by a subcutaneous administration of bortezomib. Clin Lymphoma Myeloma Leuk 2012; 12: 284–286. 11. Chowdhury TA and Escudier V. Poor glycaemic control caused by insulin induced lipohypertrophy. BMJ 2003; 327: 383–384. 12. Barbee MS, Harvey RD, Lonial S, et al. Subcutaneous versus intravenous bortezomib: efficiency practice variables and patient preferences. Ann Pharmacother 2013; 47: 1136–1142.
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