Original Article

Intraocular Injection of Stivant® (A Biosimilar to
Bevacizumab): A Case Series

Ahmad Mirshahi, MD; Alireza Lashay, MD; Hamid Riazi-Esfahani, MD; Nazanin Ebrahimiadib, MD
Hassan Khojasteh, MD; Fariba Ghassemi, MD; Fatemeh Bazvand, MD; Alireza Khodabande, MD

Ramak Roohipour, MD; Elias Khalili Pour, MD; Hooshang Faghihi, MD

Translational Ophthalmology Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran

ORCID:
Ahmad Mirshahi: https://orcid.org/0000-0002-4890-5023
Elias Khalili Pour: https://orcid.org/0000-0001-8123-4375
Hooshang Faghihi: https://orcid.org/0000-0001-9371-4915

Abstract
Purpose: To report the results of intravitreal injection of a bevacizumab biosimilar called Stivant®.
Methods: This prospective interventional case series was conducted on eyes with neovascular
age-related macular degeneration (nAMD), retinal vein occlusion (RVO), and diabetic macular
edema (DME). Stivant® was injected in three consecutive months and changes in best-corrected
visual acuity (BCVA) and central macular thickness (CMT) were measured at baseline and monthly
up to one month after the third injection.
Results: Three hundred and eighty-five eyes with DME (234 eyes, 61%), nAMD (87 eyes, 22%), and
macular edema secondary to RVO (64 eyes, 17%) were enrolled. The mean ± standard deviation
age of the patients was 61.7 ± 7.20 years. The mean BCVA and CMT changed from 0.63 ± 0.3
to 0.51 ± 0.3 LogMAR (P = 0.12 ) and from 420.4 ± 47.3μm at baseline to 316.7 ± 50.6 μm (P <
0.001) in the DME group; from 0.79 ± 0.3 to 0.68 ± 0.3 LogMAR (P = 0.19) and from 376.1 ± 31.7
μm to 303 ± 31.3 μm (P = 0.019) in the nAMD group; and from 0.81 ± 0.4 to 0.63 ± 0.4 LogMAR (P
= 0.05) and from 424.21 ± 18 μm to 303.4 ± 18.8 μm (P < 0.001) in the RVO group, respectively.
Conclusion: Our limited experience showed that the intravitreal injection of Stivant® was well
tolerated. Although the results of this case series showed relative improvement in CMT one month
after the last injection of Stivant®, BCVA improvement was statistically significant only in the RVO
group. This would be essential to design a randomized clinical trial to evaluate the non-inferiority
of Stivant® in comparison to bevacizumab.

Keywords: Stivant®; Bevacizumab; Anti-VEGFs; Anti-vascular Endothelial Growth Factors; Diabetic Macular
Edema; Retinal Vein Occlusion; Neovascular Age-related Macular Degeneration

J Ophthalmic Vis Res 2021; 16 (1): 28–33

Correspondence to:

Elias Khalili Pour, MD; Translational Ophthalmology
Research Center, Farabi Eye Hospital, Tehran University
of Medical Sciences, Tehran 13366, Iran.
E-mail: ekhalilipour@gmail.com
Hooshang Faghihi, MD. Translational Ophthalmology
Research Center, Farabi Eye Hospital, Tehran University
of Medical Sciences, Tehran 13366, Iran.
Email: faghihih@hotmail.com
Received: 01-09-2019 Accepted: 06-11-2020

Access this article online

Website: https://knepublishing.com/index.php/JOVR

DOI: 10.18502/jovr.v16i1.8248

INTRODUCTION

Introduction of anti-VEGFs has revolutionized
the management of numerous retinal diseases
over the past decade. They turned out to be

This is an open access journal, and articles are distributed under the terms of
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allows others to remix, tweak, and build upon the work non-commercially, as
long as appropriate credit is given and the new creations are licensed under the
identical terms.

How to cite this article: Mirshahi A, Lashay A, Riazi-Esfahani H, Ebrahimiadib
N, Khojasteh H, Ghassemi F, Bazvand F, Khodabande A, Roohipour R,
Khalili Pour E, Faghihi H. Intraocular Injection of Stivant® (A Biosimilar to
Bevacizumab): A Case Series. J Ophthalmic Vis Res 2021;16:28–33.

28© 2021 MIRSHAHI ET AL. THIS IS AN OPEN ACCESS ARTICLE DISTRIBUTED UNDER THE CREATIVE COMMONS ATTRIBUTION LICENSE | PUBLISHED BY
KNOWLEDGE E

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A Case Series of Stivant® Intraocular Injection; Mirshahi et al

the first-line treatment for diabetic macular
edema (DME), neovascular age-related macular
degeneration (nAMD), and retinal vein occlusion
(RVO)-associated macular edema. Among various
anti-VEGF drugs, the off-label intravitreal injection
of bevacizumab [Avastin; Genentech/Roche
/Basel, Switzerland] as a less expensive and
effective alternative is the preferred choice in
many countries[1].

Results of clinical trials such as CATT
(Comparison of AMD Treatments Trials), MANTA
(Multicentre Anti-VEGF Trial in Austria), IVAN
(The Inhibition of VEGF in Age-related choroidal
Neovascularization), LUCAS (Lucentis Compared
to Avastin Study), and GEFAL (Groupe d’Etude
Français Avastin versus Lucentis ) showed the
noninferiority of bevacizumab in comparison to
ranibizumab with the same safety profile[2–6].
Besides, the 20 times lower cost of bevacizumab
compared to ranibizumab and aflibercept makes
this agent the most common anti-VEGFs used for
intravitreal injection[7].

The World Health Organization (WHO) defines
biosimilar drugs as a biotherapeutic product that
is similar in terms of quality, safety, and efficacy
to an already licensed reference biotherapeutic
product. Biosimilars have the potential to reduce
the healthcare costs relative to reference biologics,
thereby increasing the treatment access [8–10].
Stivant® (CinnaGen Co., Iran) has been developed
as a biosimilar to Avastin®. Both Stivant® and
the reference product are humanized monoclonal
antibodies of the IgG1 subclass. Safety of this
product has already been shown during an animal
study conducted by our team on New Zealand
albino rabbits. Intravitreal injection of 2.5 mg
Stivant® did not show any adverse effect on
retinal function evaluated by electroretinography
(ERG). Additionally, histologic examination of the
enucleated globes did not reveal any visible
histopathologic changes at the cellular level[8].

Herein, we aimed to share our experience with
visual and anatomical outcomes of intravitreal
injection of Stivant® in a case series.

METHODS

This prospective interventional case series was
approved by the Institutional Review Board of
Tehran University of Medical Sciences. Written
informed consent was obtained from participants

before enrollment. Patients with neovascular AMD
(nAMD), DME, and macular edema due to RVO
were recruited from September 2018 to February
2019 at Farabi Eye Hospital, Tehran, Iran. They
were either treatment-naïve or had not receive the
last intravitreal injection during the past six months.

The exclusion criteria of the study included
previous vitrectomy, signs of any ocular infection,
history of cerebrovascular accident or myocardial
infarction, pregnancy, or breastfeeding. All patients
were scheduled for three monthly injections of
Stivant®.

Complete ocular examinations were performed
by ophthalmologists and included measurement
of best-corrected visual acuity (BCVA) with the
Snellen chart being converted into LogMAR,
applanation tonometry, slit-lamp biomicroscopy of
the anterior and posterior segments, and indirect
ophthalmoscopy at baseline and on days 1, 7,
and 30 after each injection. Spectral-domain
optical coherence tomography (SD-OCT) (RTVue-
XR; Optovue, Inc., Fremont, CA, USA) imaging
was obtained at baseline and 30 days after each
injection for all patients.

Parameters for safety included severe
inflammation or endophthalmitis and IOP > 21
mm Hg, retinal hemorrhages, retinal vasculitis,
and retinal necrosis or detachment within three
months post-injection. Systemic evaluations at
baseline and on days 1, 7, and 30 included a
detailed medical history during which patients
were asked about current medications and any
systemic adverse events (AEs), thromboembolic or
neurological issues and measurement of arterial
blood pressure. Primary outcome measures were
changes in CMT and BCVA. Secondary outcome
measures comprised any ocular or systemic AEs.

Intravitreal Injection

Stivant® is manufactured in a vial with a
concentration of 25 mg/ml identical to the
reference product (Avastin). Intravitreal injections
were performed in the operating room under
the sterile situation. Topical anesthetic drops
were given first and then a lid speculum was
inserted. After the application of povidone iodine
5% into the conjunctival sac for about 3 min,
intravitreal injection of 1.25 mg/ 0.05 ml Stivant®
was performed with a 29-gauge needle (1 ml
tuberculin syringes; DispoVan) through the pars

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A Case Series of Stivant® Intraocular Injection; Mirshahi et al

plana 4 mm and 3.5 mm posterior to the limbus
in phakic and pseudophakic eyes, respectively.
The needle was carefully removed using a sterile
cotton applicator to prevent reflux. Pre-injection
topical antibiotics were not ordered, but all patients
received topical chloramphenicol 0.5% four times
a day for five days after the injection.

Statistical Analysis

Data were entered into a Microsoft Excel sheet
and analyzed using the SPSS version 22 software
(IBM). Categorical data were represented in the
form of frequencies and proportions. Chi-square
was used as the test of significance. Continuous
variables were summarized by count, mean,
standard deviation, median, and minimum and
maximum. BCVA and CMT data were analyzed
using two-tailed paired t-tests. P ≤ 0.05 was
considered statistically significant.

RESULTS

Three hundred and eighty-five eyes of 351 patients
with DME (234 eyes, 61%), nAMD (87 eyes, 22%),
and macular edema secondary to RVO (64 eyes,
17%) were enrolled. Intravitreal injection of Stivant®
from separate glass vials was performed in both
eyes of 34 patients with bilateral DME. The mean
age of the patients was 61.7 ± 7.20 years. Out of
the 385 injections, 212 (55.1%) were performed in
male patients. Of the 385 eyes, 197 and 188 were
phakic and pseudophakic, respectively.

BCVA Findings

The mean BCVA improved from 0.67 ± 0.41
LogMAR at baseline to 0.57 ± 0.37 LogMAR one
month after the last injection (P = 0. 10). The mean
BCVA improved from 0.63 ± 0.3 to 0.51 ± 0.3
LogMAR (P = 0.12) in the DME group; from 0.79 ±
0.3 to 0.68 ± 0.3 LogMAR (P = 0.19) in the nAMD
group; and from 0.81 ± 0.4 to 0.63 ± 0.4 LogMAR
(P = 0.05) in the RVO group [Figure 1].

Central Macular Thickness Findings

The mean CMT in all groups improved consistently
from baseline through consequent injections.
Although there was a trend in decreasing CMT after
the first injection, the amount of change was not

statistically significant until the third injection. The
mean CMT of 425 ± 54.9 μm at baseline decreased
to 312.20 ± 40.81 μm one month after the last
intravitreal injection (P < 0.001) in all groups. In the
DME group, the mean thickness decreased from
420.4 ± 47.3 μm at baseline to 316.7 ± 50.6 μm (P <
0.001) one month after the last intravitreal injection
and from 376.1 ± 31.7 μm to 303 ± 31.3 μm (P =
0.019) in the nAMD group and from 424.21 ± 18 μm
to 303.4 ± 18.8 μm (P < 0.001) in the RVO group
[Figures 2 and 3].

Adverse Events (AEs)

There was no reported drug-related blurred
vision and/or ocular pain at any of the follow-up
visits. None of the eyes developed intraocular
inflammation, endophthalmitis, corneal edema,
cataract, vitritis, retinal detachment, or optic
atrophy. Vitreous hemorrhage was reported in
a diabetic patient one day after injection, which
resolved three weeks later. None of the patients
experienced moderate or severe vision loss (>0.3
LogMAR). The mean IOP at day 30 was 16.1 ± 3.0
mmHg. No systemic or serious AEs were reported.

DISCUSSION

In the current case series, we showed the
relative safety of intravitreal injection of a
bevacizumab biosimilar (Stivant®) in eyes with
different indications for anti-VEGF therapy.

Although the short-term results in the present
study showed statistically significant improvement
in terms of CMT reduction following intravitreal
Stivant® injection in all three groups, the mean
BCVA improvement reached statistical significance
only in the RVO group. To demonstrate the
substitutability of Stivant® as a biosimilar of Avastin,
there is a need to design a randomized clinical trial
(RCT) with an appropriate sample size.

We previously disclosed the safety of Stivant®
during an animal study. This biosimilar did not
show histopathologic changes at the cellular level
after being injected into the eyes of albino
rabbits evaluated by clinical examinations, ERG,
and histopathological assessment.[8]

Biosimilars which are produced by modified
cellular processes are identical to their reference
biologic agents in terms of structure and active
substance, although some minor variations are

30 JOURNAL OF OPHTHALMIC AND VISION RESEARCH VOLUME 16, ISSUE 1, JANUARY-MARCH 2021



A Case Series of Stivant® Intraocular Injection; Mirshahi et al

Figure 1. Mean BCVA (LogMAR) at baseline and one month after the third Stivant® injection. (P-value = 0.12, 0.19, 0.05, and 0.10
in the DME, wet-type AMD, RVO, and in all patients, respectively).

Figure 2. Central macular thickness (CMT) changes. Mean CMT ± SE (μm) at baseline and one month after the first and third
Stivant® injection in the DME, AMD, RVO, and in all patients.

Figure 3. Response to Stivant® injections; samples from each subgroup (DME, nAMD, RVO) under study (A–C).

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A Case Series of Stivant® Intraocular Injection; Mirshahi et al

inevitable. Therefore, biosimilars are the end
products similar to the original molecule with minor
non-significant differences.[9–12]

In February 2015, Razumab® (Intas
Pharmaceuticals, Ahmedabad, India), the first
biosimilar to ranibizumab, was approved by the
drug controller general of India for the treatment
of nAMD, DME, RVO-associated macular edema,
and myopic choroidal neovascularization. In a
prospective study, the safety and efficacy of
Razumab® was demonstrated in Indian patients
with retinal vascular diseases including RVO.[13, 14]
Afterward, Warudkar et al showed the safety and
efficacy of intravitreal injection of Zybev (Cadila
Healthcare, India) as a bevacizumab biosimilar
for macular edema secondary to retinal vascular
diseases.[15] As the patent of Avastin has recently
expired, it is speculated that its biosimilars will
soon grow in number.[10, 11]

Biosimilar production is >25% cheaper than
that of the reference drug.[10, 11] As a result, more
patients, especially in developing countries, can
adhere to their treatment protocols and sustain
their vision.

With the increasing production of biosimilar
drugs in different countries and lower costs of
these drugs compared to reference biologics, the
widespread usage of these drugs requires special
attention of healthcare systems to evaluate them
from several aspects, including pharmacokinetics,
pharmacodynamics, immunogenicity, safety,
and efficacy in comparison to the reference
drugs.[11]

While the main focus of the reference drug
producer is to display safety and efficacy in
large clinical trials, biosimilar expansion mainly
relies on thorough studies to approve that the
product is indistinguishable from reference
drug in terms of construction, synthesis, and
in vitro activity. As a minimum, one clinical
investigation is required to compare the
pharmacokinetics between a reference and
biosimilar drug and at least one adequately large
randomized controlled trial to exhibit the clinical
equality.[9–11]

Safety and efficacy equivalency of the
biosimilar drugs to the reference drug concerning
pharmacokinetic, pharmacodynamic, and
immunogenic properties must be confirmed
through well-designed clinical trials. If the results
of these trials are satisfactory and a biosimilar drug

is approved for one indication, all other indications,
for which the reference product is approved, are
accepted, provided there is appropriate scientific
justification. In general, patients are expected to
be able to shift from a biosimilar to a reference
product and vice versa without a drug efficacy
lapse or increased risk.[9, 10]

Recently, the US Food and Drug Administration
(FDA) gave directions to address the extra
administrative requirements that biosimilars
need to be endorsed as compatible drugs, and
has recommended patrons to conduct at least
one switching investigation to exhibit that the
biosimilar and the reference drug can be securely
substituted without loss of efficacy. Interestingly,
in the European Union (EU), the European
Medicines Agency (EMA) has not assigned
biosimilars as interchangeable substitution of a
reference medicine, leaving the choice to national
authorities.[10]

As mentioned previously, this study is just a
case series of patients and our findings cannot
replace a well-designed, controlled RCT to show
the equivalency of Stivant® with the reference
drug. The other limitations of our study are
the short-term follow-up of four months and
the lack of data on metabolic profiles such as
HbA1C and blood pressure of enrolled diabetic
patients.

In conclusion, our limited experience showed
that the intravitreal injection of Stivant® was well
tolerated over four months. Although the results
of this case series showed relative improvement
in CMT one month after the last injection of
Stivant®, the mean BCVA improvement was
statistically significant only in the RVO group. To
evaluate the non-inferiority, safety, and efficacy
of Stivant® in comparison to the reference drug,
it is essential to design a randomized clinical
trial.

Acknowledgement

The authors would like to thank Leila Buzh Abadi
and Pouran Fadakar for their kind contribution to
this study.

Financial Support and Sponsorship

The study received support from the Eye Research
Center, Farabi Eye Hospital, Tehran University of
Medical Sciences, TUMS#40777.

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A Case Series of Stivant® Intraocular Injection; Mirshahi et al

Conflicts of Interest

None of the authors have any proprietary interests
or conflicts of interest related to this study.

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