Original Article
Intra-vitreal Bevacizumab (IVB):
Safety of Multiple Doses Preparation from a Single Vial
in Tertiary Care Centre
Asfandyar Asghar, Amna
Rizwan, Naila Obaid, Ume Sughara, Badar-ud-Din Ather Naeem, Tehmina Nazir
DOI 10.36351/pjo.v35i4.888 Pak J Ophthalmol 2019, Vol. 35, No. 4
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See end of article for authors affiliations …..……………………….. Correspondence to: Dr. Asfandyar Asghar Professor, Ophthalmology
Department Fauji Foundation
Hospital, Rawalpindi Email: docasfandyar@gmail.com |
Purpose: To determine the safety of multiple
doses preparation of bevacizumab from a single vial in minor operation
theatre. Study Design: Retrospective exposure
assessment. Place and Duration of Study: Department
of Ophthalmology, Fauji Foundation Hospital (FFH), Rawalpindi, from June 2016
to March 2018. Material and Methods: 1690
eyes belonging to 1001 patients were included using computer logs of patients
receiving intravitreal bevacizumab (IVB). We allocated three consecutive days
every month in order to administer IVB at FFH. Approximately 50 patients were
given IVB over three-days period. 1-2 ml (depending upon the number of
patients) of bevacizumab was withdrawn in a 3cc syringe. Later 1 cc insulin
syringe with 29 G needle was taken and, 0.05 ml (1.25 mg) bevacizumab was
injected from behind using the 3cc syringe, resulting in preparation of 10-20
injections of IVB. The bevacizumab vial was then stored at 4 degrees Celsius. Results: Total 1690 eyes belonging to
1001 patients were analyzed. The occurrence of endophthalmitis was 2/1690
(0.12%) corresponding to a 95% CI of 0.03%-0.43%, which does not represent an
increase in cases as compared to endophthalmitis resulting from using a
compounding pharmacy. Conclusion: Preparation of IVB from single
vial technique using proper sterilization protocols is safe and economical in
a minor eye operation theater. Key Words: Bevacizumab, Intravitreal
injection, Endophthalmitis. |
Intravitreal anti-vascular
endothelial growth factor (anti- VEGF) agents have revolutionized therapeutic
advances in ophthalmology1. Anti -VEGF agents are increasingly being
used to treat retinal diseases including age related macular degeneration (ARMD),
diabetic macular edema (DME), macular edema secondary to retinal vein occlusion(RVO)
etc2. Of these anti-VEGF agents, the three most commonly used are
aflibercept (Eylea®), ranibizumab (Lucentis®) and bevacizumab (Avastin®)3.
These anti-VEGF agents are administered intravitreally and often needs repeat
dosages for continued therapeutic effects4.There is, thus, a cost
associated with these expensive drug treatments5.
In addition,
intravitreal administration may lead to endophthalmitis as a serious
complication6. Studies have shown that the frequency of endophthalmitis
ascribed to intravitreal administration in trials of anti-VEGF usage is between
0.019% and 0.09%7.
In our clinical
practice, we usually use bevacizumab, an off-label drug initially prescribed
for colon cancer treatment, whose ophthalmological efficacy has been well-demonstrated8,9.
The low cost of bevacizumab compared with other anti-VEGF agents is a deciding
factor in its favor, particularly in the developing world.
It is to be
noted that the risk of contamination may be exacerbated by the method of
preparation as the drug is prepared in batches. This is because bevacizumab is
commercially available in concentrations of 100 mg/4mL vials. These high
concentrations are meant to be used for colon cancer patients as a single dose.
However, the ophthalmic use of bevacizumab requires much less concentrations10.In
a bid to reduce the health care costs, the same vial is used for approximately
more than 30 injections11. Currently, there is no consensus on
whether compounding the vial into a large number of aliquots is better than
repeated usage from the same vial. For instance, several studies deny the
existence of cluster endophthalmitis following withdrawal of anti VEGF agents
from a single vial for a batch of patients6,10,12,13, and,
therefore, see no statistically significant difference in using the drug from
compounded aliquots. Khan et al, however, do claim the opposite and report
cluster endophthalmitis even in the scenario of multiple withdrawals in one
sitting from the same vial14. The rationale of this retrospective
study is to confirm the assertion, in our clinical setting, that preparing bevacizumab
in minor operation theatre (i.e. in the absence of a compounding frequency)
leads to no statistically significant increase in cases of endophthalmitis.
Certainly, it is desirable to reduce both the cost and risk of
infection by figuring out an optimum protocol for drug preparation in the clinic.
We work with the hypothesis that the method of multiple dosage preparation and
administration is clinically safer in terms of leading to reduced frequency of
endophthalmitis.
Purpose of this study was to determine the safety of multiple
doses preparation of bevacizumab from single vial in a minor operation theatre.
MATERIAL AND METHODS
A retrospective
exposure assessment series was conducted at Ophthalmology Department, Fauji Foundation
Hospital (FFH), from June 2016 to March 2018. Ethical committee of hospital
approved this study. Total 1690 eyes belonging to 1001patients were analyzed.
Age of the patients ranged from 25-85 years and both genders were included.
Patients diagnosed with proliferative diabetic retinopathy, diabetic
maculopathy, non-ischemic central retinal vein occlusion (CRVO) and wet type of
age related macular degeneration were included. Exclusion criteria were
intravitreal injections of non–anti-VEGF medications (eg steroids and
antibiotics), or concomitant surgical procedures (e.g. phacoemulsification and
vitrectomy).
Patients were informed about the off-label conditions of
intravitreal bevacizumab. At each post-injection visit, patients were monitored
for ocular and systemic side-effects. Best corrected visual acuity,
intra-ocular pressure (IOP), slit-lamp biomicroscopy and indirect
ophthalmoscopy was also performed.
Three
consecutive days every month were reserved in FFH in order to administer
intravitreal bevacizumab (IVB) to our patients. Around 50 patients were
typically seen over a three-day period. Extreme care was taken for proper
sterilization, including scrubbing by using manorapid and properly wearing head
cap, mask, gown and gloves. 1-2 ml (depending upon the number of patients) of
bevacizumab was withdrawn with the help of 3 cc disposable syringe, taking care
to keep the aluminium and rubber seals intact. 1 cc insulin syringe with 29 G
needle was taken and, after removal of piston of insulin syringe, 0.05 ml (1.25
mg) bevacizumab was injected from behind. This resulted in preparation of 10-20
injections of bevacizumab. The bevacizumab vial was then stored at 4 degrees
Celsius after replacing the plastic seal atop it. On second and third day of
IVB injection administration, the rubber seal of the bevacizumab vial was
doused with 10% povidone iodine for 3-4 minutes.
In all patients
before intravitreal injection the blood glucose level was monitored and 10%
povidone- iodine was used to cleanse the eyelids and orbital adenexa.
Proparacaine (Alcain) was then instilled 2- 3 times with an interval of 4-5
minutes, followed by 5% povidone – iodine instillation in conjunctival sac
region for 2-3 minutes before IVB. Sterilized towel and speculum were used in all
cases. Depending on the status of the lens, IVB was given 3.5 mm or 4.00 mm
away from the limbus. After IVB injection, 5% povidone - iodine was again
instilled in conjunctival sac. Ofloxacin eye drops 4 times a day were recommended
for a 5-day period.
Complications
like endophthalmitis and others were identified from the computerized system logs
of our hospital. All the cases of post intravitreal endophthalmitis,
irrespective of the cause, received intravitreal antibiotics followed by pars
plana vitrectomy if there was no response of antibiotics. We evaluated
endophthalmitis cases that occurred after IVB. Data was collected on age, sex,
pre-injection best corrected visual acuity (BCVA), indication for IVB, date of
injection, date of onset of symptoms of endophthalmitis, nature of symptoms, and
date of presentation. Data was also collected regarding the findings of
examination at presentation, treatment, response to treatment, and any
additional procedures and findings at final follow-up and BCVA at last follow-
up were noted. Data was further acquired on the results of microbial laboratory
investigations such as Gram stain, culture and sensitivity to antimicrobials.
The occurrence of endophthalmitis was computed and was reported as
a percentage. The corresponding 95% confidence intervals (CIs) were calculated
by using the freely available utility at http://vassarstats.net/prop1.html.6
RESULTS
We studied the
effects of intravitreal bevacizumab on 1690 eyes belonging to 1001 patients.
Out of these, 95% were female while the remaining 5% were males. This gender
disparity is due to the fact that FFH typically caters to the families of
ex-service men. The mean age of our study subjects was 60.73 years with a standard
deviation of 9.1 years.
The patients
presented with varying diagnoses. As shown in Table 1, maximum number of
patients had diabetic maculopathy.
Intravitreal injections were distributed in four quadrants such
that the bulk of injections (1484/1690) were given at the inferotemporal site.
The remaining 143, 47 and 16 injections were given at the superotemporal,
superonasal and inferonasal quadrants, respectively, as shown in Figure 1
below.
The occurrence
of endophthalmitis was 2/1690 (0.12%) corresponding to a 95% CI of 0.03%-0.43%.
Both cases presented within 48 hours of intravitreal bevacizumab, with pain,
redness associated with loss of vision. A summary of the clinical findings in
the two cases thus presented is given in Table 2.
In Table 3 we present the complications resulting from IVB. As can
be seen, 1564/1690 eyes did not exhibit any side effects. The most common
problem was subconjunctival hemorrhage which was present in 4.7% of the eyes.
Table 1: Diagnosis of patients included in the study (n = 1001).
|
Diagnosis |
No. of Patients (n) |
N (%) |
||
|
Diabetic maculopathy |
649 |
64.83% |
||
|
CRVO |
102 |
10.18% |
||
|
PDR |
83 |
8.29% |
||
|
BRVO |
67 |
6.69% |
||
|
Vitreous hemorrhage |
50 |
4.99% |
||
|
ARMD |
47 |
4.69% |
||
|
NVG |
3 |
0.29% |
||
|
Total Patients |
1001 |
100 |
||
Age related macular degeneration (ARMD), Branch retinal
vein occlusion (BRVO), Central retinal vein occlusion (CRVO), Neovascular glaucoma
(NVG), Proliferative diabetic retinopathy (PDR).
Fig. 1: Site of intravitreal injection.
Table 2: Description of Endophthalmitis Cases.
|
Case # |
Age/ Gender |
Pre-injection BCVA |
BCVA at Diagnosis of Endophthalmitis |
Interval b/w Injection and Endophthalmitis |
Symptoms |
Bacteria Isolated C/S |
Treatment Given |
Final BCVA |
|
1 |
55/F |
6/24 |
PL |
2 days |
Pain, redness, ↓ VA |
Staph aureus |
IVAB PPV |
6/24 |
|
2 |
49/F |
6/9 |
CF |
1 day |
Pain, redness, ↓ VA |
No growth |
IVAB |
6/12 |
BCVA (best corrected visual acuity), C/S
(culture/sensitivity), CF (counting fingers), PL (perception of light), VA (visual
acuity), IVAB (intravitreal antibiotics)
Table 3: Post intravitreal injection complications in patients.
|
Complication |
# of Eyes (n) |
Percentage (%) |
|
|
Nil |
1564 |
92.5% |
|
|
Subconjunctival hemorrhage |
79 |
4.7% |
|
|
Raised IOP |
37 |
2.2% |
|
|
Corneal abrasion |
8 |
0.5% |
|
|
Endophthalmitis |
2 |
0.1% |
|
|
Total Eyes |
1690 |
100 |
|
Table 4: Comparison of studies with respect to preparation
techniques and complications.
|
Study (Country) |
Method of Preparing Aliquots |
Number of Injection |
Number and Rate of Endophthalmitis |
Number and Rate of Culture – Positive
Endophthalmitis |
Percentage of Culture-Positive Cases |
|
Jan15 et al (Pakistan) |
Multiple injection from same vial |
6107 |
03 (0.069%) |
------ |
------ |
|
Falavarjani16 et al (Iran) |
Multiple injection from same vial |
5901 |
06 (0.10%) |
1 (0.01) |
16.6 |
|
Artunay17 et al (Turkey) |
Multiple injection from same vial |
3022 |
03 (0.09) |
2 (0.06) |
66 |
|
Inoue18 et al (Japan) |
Multiple injection from same vial |
1209 |
05 (0.41) |
2 (0.16) |
40 |
|
This study |
Multiple injection from same vial |
1690 |
02(0.12) |
1 |
50 |
DISCUSSION
In recent times, the advent and
increasing use of anti-VEGF agents for intraocular use has resulted in a paradigm
shift in the management of various medical retinal pathologies including
neovascular AMD, diabetic retinopathy, DME, and RVO. Numerous trials conducted
worldwide (CATT trial, IVAN trial, GEFAL, MANTA)3,13,19,20 on
thousands of patients have shown equivalent results of bevacizumab and
ranibizumab regarding efficacy and safety. In bevacizumab, added advantage is
reduced cost of treatment. In developing countries because of limited resources
it plays key role in reducing the financial burden of multiple injections19.
Compounding of
bevacizumab has been a major safety concern ever since the first intravitreal
use. Several outbreaks of compounding-related endophthalmitis have been
reported in the United States and Canada in patients receiving bevacizumab. In
almost all cases, the endophthalmitis outbreak occurred because of breakdown in
sterile technique owing to inability to follow United States Pharmacopeia
Chapter 797 guidelines20.
The risk of
endophthalmitis due to compounded bevacizumab was a concern of the past, with
recent reports suggesting that the overall incidence of endophthalmitis may be
lower with bevacizumab compared with either ranibizumab or aflibercept21.
The method of
preparation of bevacizumab is different in every Centre where compounding
pharmacies are not present. Some ophthalmologists withdraw the required dose
from the vial of bevacizumab directly to insulin syringe and then change the
needle and inject it intravitreally. Other ophthalmologists withdraw a maximum
of ten doses from the vial during a session for 10 patients and discard the
remaining drug. Yet others use the maximum number of doses that are required on
that day and discard the remaining drug. Another technique in vogue is for ophthalmologists
to withdraw bevacizumab from the same vial using separate needle and syringe
for several patients for a period of 03 weeks of the first use of vial. All
these methods of preparation have not reported any cluster of endophthalmitis and
incidence of endophthalmitis in these studies was 0 – 0.41%6.
However, Khan et al reported cluster of endophthalmitis after IVB injection
prepared from same vial multiple times14.
The method of
preparing multiple intravitreal bevacizumab, 1.25 mg/0.05 ml in minor operating
theatre (OT) in our study, differs from other studies. We prepared bevacizumab for
intravitreal use daily for three consecutive days and kept the vial in the refrigerator
at 4 degrees Celsius. The incidence of endophthalmitis after intravitreal bevacizumab
(IVB) in our study was 0.12% which is comparable to national and international studies
(0.027% - 0.19%)22,23,24 when multiple intravitreal injections were
prepared from same vial. Both cases presented within 48 hours of intravitreal
bevacizumab, with pain, redness associated with loss of vision. Visual acuity
dropped to PL–CF in both patients. B-scan was performed to confirm our diagnoses
followed by vitreous tap and intravitreal vancomycin 2 mg/0.1 ml and
ceftazidime 2 mg/0.1 ml. One patient started improving after intravitreal antibiotics
and in the other patient, pars plana vitrectomy was done with intra-vitreal
vancomycin and ceftazidime. Vitreous tap report showed staphylococous aureus in
one patient and no growth in the other. Visual acuity improved in both cases; 6/24
in pars plana vitrectomy (PPV) patient and 6/12 in patient where intravitreal
antibiotics were given. Probably patient who had undergone PPV had severe
diabetic maculopathy and in other there was focal diabetic maculopathy.
Most common
complications experienced in this study was subconjunctival hemorrhage in 4.7% of
eyes. It was reported in the range of 17.1% to 72% in other studies19,25.
Subconjunctival hemorrhage develops due to rupture in small capillaries and
vessels during the procedure and gets resolved within 9–15 days26. National
and international studies showed that 0.06% to 0.5% eyes developed corneal
abrasions10,25 which is consistent with our rate of 0.5%. In our
study 2.1% eyes developed raised intraocular pressure after intravitreal bevacizumab
injection, which correlates with a reported incidence of 1-5% as mentioned by
Yannuzzi NA8. It is hypothesized that bevacizumab, being a higher molecular
weight protein (148k-Da) may obstruct the trabecular meshwork. It has been
reported that sustained increase in IOP was associated with the number of
injections. In particular, it has been reported that those who had received
more than 29 injections had 16.1% more chance of increased IOP than those with
less than 12 injections15. No eyes developed retinal detachment, retinal
ischemia or cataract in our study.
To conclude, we present in Table 4 a comparison of several similar
studies. The findings of these studies are fairly consistent.
CONCLUSION
Multiple injections preparation from a single vial is one of the options
available to prepare the intravitreal bevacizumab where compounded pharmacy is
not available with nearly equal outcomes in comparison of sight threatening
endophthalmitis.
FINANCIAL DISCLOSURE
None.
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Author’s
Affiliation
Dr Asfandyar Asghar
Professor, Ophthalmology Department
Fauji Foundation Hospital, Rawalpindi
Dr Amna Rizwan
Trainee, Ophthalmology Department
Fauji Foundation Hospital, Rawalpindi
Dr Naila Obaid
Assistant Professor, Ophthalmology Department
Fauji Foundation Hospital, Rawalpindi
Dr Ume Sughara
Al-Shifa School of Public Health
Pakistan Institute of Ophthalmology, Rawalpindi
Dr. Badar-ud-Din Ather Naeem
Professor, Head of Ophthalmology Department
Fauji Foundation Hospital, Rawalpindi
Dr. Tehmina Nazir
Assistant Professor, Ophthalmology Department
Fauji Foundation Hospital, Rawalpindi
Author’s Contribution
Dr. Asfandyar Asghar
Study design, data collection, data
analysis, manuscript writing and final review.
Dr. Amna Rizwan
Study design, data collection, data
analysis, manuscript writing and final review.
Dr. Naila Obaid
Study design, data collection, data
analysis and final review.
Dr Ume Sughara
Study design, data collection, data
analysis and final review.
Dr. Badar-ud-Din Ather Naeem
Study design, data collection, data
analysis and final review.
Dr. Tehmina Nazir
Study design, data collection, data
analysis and final review.