APPROVED FOR wAMD| DME | DR with DME | RVO*

PRECISION & PERFORMANCE

W H E R E I T M AT T E R S
*Macular edema following RVO.
LUCENTIS is FDA approved for less-frequent-than-monthly dosing in wAMD1
While monthly dosing is more effective, the HARBOR trial demonstrated that dosing frequency may be individualized
based on retreatment criteria and regular assessment1,2

INDICATION

LUCENTIS (ranibizumab injection) is indicated for the

treatment of patients with:
Neovascular (wet) age-related macular degeneration (wAMD)
Macular edema following retinal vein occlusion (RVO)
Diabetic macular edema (DME)
Diabetic retinopathy (Non Proliferative DR (NPDR) and
Proliferative DR (PDR)) with diabetic macular edema (DME)

IMPORTANT SAFETY INFORMATION

LUCENTIS is contraindicated in patients with ocular or

periocular infections or hypersensitivity to ranibizumab
or any of the excipients in LUCENTIS.

WARNINGS AND PRECAUTIONS

Fatal events occurred more frequently in patients with

DME and DR at baseline treated monthly with LUCENTIS
compared with control. Although the rate of fatal events
was low and included causes of death typical of patients
with advanced diabetic complications, a potential
relationship between these events and intravitreal use of
VEGF inhibitors cannot be excluded.

ADVERSE EVENTS

Serious adverse events related to the injection procedure

that occurred in <0.1% of intravitreal injections included
endophthalmitis, rhegmatogenous retinal detachment,
and iatrogenic traumatic cataract.
In the LUCENTIS Phase III clinical trials, the most
common ocular side effects included conjunctival
hemorrhage, eye pain, vitreous floaters, and increased
intraocular pressure. The most common non-ocular side
effects included nasopharyngitis, headache, influenza,
sinusitis, cough, and nausea.

Intravitreal injections, including those with LUCENTIS,

have been associated with endophthalmitis, retinal
detachment, and iatrogenic traumatic cataract. Proper
aseptic injection technique should always be utilized
when administering LUCENTIS. Patients should be
monitored during the week following the injection to
For additional safety information, please see LUCENTIS Brief
permit early treatment, should an infection occur.
Summary on adjacent page.
Increases in intraocular pressure (IOP) have been noted REFERENCES: 1. LUCENTIS [package insert]. South San Francisco, CA:
both pre-injection and post-injection (at 60 minutes) with Genentech, Inc; 2015. 2. Ho AC, Busbee BG, Regillo CD, et al; HARBOR Study
LUCENTIS. IOP and perfusion of the optic nerve head
Group. Twenty-four-month efficacy and safety of 0.5 mg or 2.0 mg
ranibizumab in patients with subfoveal neovascular age-related macular
should be monitored and managed appropriately.
Although there was a low rate of arterial thromboembolic degeneration. Ophthalmology. 2014;121:2182-2192.
events (ATEs) observed in the LUCENTIS clinical trials,
For more information, visit www.LUCENTIS.com.
there is a potential risk of ATEs following intravitreal use
of VEGF inhibitors. ATEs are defined as nonfatal stroke,
nonfatal myocardial infarction, or vascular death
(including deaths of unknown cause).
2015 Genentech USA, Inc. So. San Francisco, CA
All rights reserved. LUC/020915/0044(1) 08/15 www.LUCENTIS.com

Table 1 Ocular reactions in the DME and DR, AMD, and RVO studies

Adverse Reaction
Conjunctival
hemorrhage
Eye pain
Vitreous floaters
Intraocular
pressure increased
Vitreous
detachment
Intraocular
inflammation
Cataract
Foreign body
sensation in eyes
Eye irritation
Lacrimation
increased
Blepharitis
Dry eye
Visual disturbance
or vision blurred
Eye pruritus
Ocular hyperemia
Retinal disorder
Maculopathy
Retinal degeneration
Ocular discomfort
Conjunctival
hyperemia
Posterior capsule
opacification
Injection site
hemorrhage

Control

Control

LUCENTIS
0.5 mg

Control

LUCENTIS
0.5 mg

Control

DME and DR
AMD 2-year AMD 1-year RVO 6-month
2-year
LUCENTIS
0.5 mg

n=250 n=250 n=379 n=379 n=440 n=441 n=259 n=260

47% 32% 74% 60% 64% 50% 48% 37%
17% 13% 35% 30% 26% 20% 17% 12%
10% 4% 27% 8% 19% 5% 7% 2%
5%

7%

2%

11% 15% 21% 19% 15% 15%

18%

4%

2%

4%

7%

3%

24%

18%

7%

8%

17%

13%

7%

1%

3%

28% 32% 17% 14% 11%

9%

2%

2%

10%

5%

16% 14% 13% 10%

7%

5%

8%

5%

15% 15% 13% 12%

7%

6%

5%

4%

14% 12%

8%

8%

2%

3%

3%
5%

2%
3%

12%
12%

8%
7%

5%
7%

0%
3%

1%
3%

8%
7%

8%

4%

18% 15% 13% 10%

5%

3%

4%
9%
2%
5%
1%
2%

4%
9%
2%
7%
0%
1%

12% 11%
11% 8%
10% 7%
9% 9%
8% 6%
7% 4%

1%
5%
2%
11%
1%
2%

2%
3%
1%
7%
0%
2%

9%
7%
8%
6%
5%
5%

7%
4%
4%
6%
3%
2%

1%

2%

7%

6%

5%

4%

0%

0%

4%

3%

7%

4%

2%

2%

0%

1%

1%

0%

5%

2%

3%

1%

0%

0%

Non-ocular reactions
Non-ocular adverse reactions with an incidence of 5% in patients receiving LUCENTIS
for DR, DME, AMD, and/or RVO and which occurred at a 1% higher frequency in
patients treated with LUCENTIS compared to control are shown in Table 2. Though
less common, wound healing complications were also observed in some studies.

Table 2 Non-ocular reactions in the DME and DR, AMD and RVO studies

n=250 n=250
12% 6%
11% 10%
10% 9%
9% 4%
8% 4%
8% 4%

n=441
9%
3%
5%
4%
4%
2%

Control

n=440
8%
4%
5%
5%
3%
2%

LUCENTIS
0.5 mg

Control

LUCENTIS
0.5 mg

n=379 n=379
16% 13%
8% 7%
9% 6%
9% 8%
5% 7%
4% 4%

AMD 1-year RVO 6-month

Control

Adverse Reaction
Nasopharyngitis
Anemia
Nausea
Cough
Constipation
Seasonal allergy
Hypercholesterolemia
Influenza
Renal failure
Upper respiratory
tract infection
Gastroesophageal
reflux disease
Headache
Edema peripheral
Renal failure
chronic
Neuropathy
peripheral
Sinusitis
Bronchitis
Atrial fibrillation
Arthralgia
Chronic obstructive
pulmonary disease
Wound healing
complications

Control

LUCENTIS
0.3 mg

DME and DR
AMD 2-year
2-year

LUCENTIS
0.5 mg

1 INDICATIONS AND USAGE

LUCENTIS is indicated for the treatment of patients with:
1.1 Neovascular (wet) age-related macular degeneration (AMD)
1.2 Macular edema following retinal vein occlusion (RVO)
1.3 Diabetic macular edema (DME)
1.4 Diabetic retinopathy (non proliferative diabetic retinopathy (NPDR),
proliferative diabetic retinopathy (PDR)) in patients with diabetic
macular edema (DME)
2 DOSAGE AND ADMINISTRATION
2.1 General dosing information
FOR OPHTHALMIC INTRAVITREAL INJECTION ONLY.
2.2 Neovascular (wet) age-related macular degeneration (AMD)
LUCENTIS 0.5 mg (0.05 mL of 10 mg/mL LUCENTIS solution) is recommended
to be administered by intravitreal injection once a month (approximately 28 days).
Although not as effective, patients may be treated with 3 monthly doses followed
by less frequent dosing with regular assessment. In the nine months after 3 initial
monthly doses, less frequent dosing with 4-5 doses on average is expected to maintain
visual acuity while monthly dosing may be expected to result in an additional average
1-2 letter gain. Patients should be assessed regularly [see Clinical Studies (14.1)].
Although not as effective, patients may also be treated with one dose every 3 months
after 4 monthly doses. Compared with continued monthly dosing, dosing every 3
months over the next 9 months will lead to an approximate 5-letter (1-line) loss of
visual acuity benefit, on average. Patients should be assessed regularly [see Clinical
Studies (14.1)].
2.3 Macular edema following retinal vein occlusion (RVO)
LUCENTIS 0.5 mg (0.05 mL of 10 mg/mL LUCENTIS solution) is recommended
to be administered by intravitreal injection once a month (approximately 28 days).
In Studies RVO-1 and RVO-2, patients received monthly injections of LUCENTIS for
6 months. In spite of being guided by optical coherence tomography and visual acuity
re-treatment criteria, patients who were then not treated at Month 6 experienced on
average, a loss of visual acuity at Month 7, whereas patients who were treated at
Month 6 did not. Patients should be treated monthly [see Clinical Studies (14.2)].
2.4 Diabetic macular edema (DME)
LUCENTIS 0.3 mg (0.05 mL of 6 mg/mL LUCENTIS solution) is recommended to be
administered by intravitreal injection once a month (approximately 28 days).
2.5 Diabetic retinopathy in patients with diabetic macular edema
LUCENTIS 0.3 mg (0.05 mL of 6 mg/mL LUCENTIS solution) is recommended to be
administered by intravitreal injection once a month (approximately 28 days).
2.6 Preparation for administration
Using aseptic technique, all of the LUCENTIS vial contents are withdrawn through
a 5-micron, 19-gauge filter needle attached to a 1-cc tuberculin syringe. The filter
needle should be discarded after withdrawal of the vial contents and should not
be used for intravitreal injection. The filter needle should be replaced with a sterile
30-gauge x 1/2-inch needle for the intravitreal injection. The contents should be
expelled until the plunger tip is aligned with the line that marks 0.05 mL on the syringe.
2.7 Administration
The intravitreal injection procedure should be carried out under controlled aseptic
conditions, which include the use of sterile gloves, a sterile drape, and a sterile eyelid
speculum (or equivalent). Adequate anesthesia and a broad-spectrum microbicide
should be given prior to the injection.
Prior to and 30 minutes following the intravitreal injection, patients should be monitored
for elevation in intraocular pressure using tonometry. Monitoring may also consist of
a check for perfusion of the optic nerve head immediately after the injection [see
Warnings and Precautions (5.2)]. Patients should also be monitored for and instructed
to report any symptoms suggestive of endophthalmitis without delay following the
injection [see Warnings and Precautions (5.1)].
Each vial should only be used for the treatment of a single eye. If the contralateral
eye requires treatment, a new vial should be used and the sterile field, syringe,
gloves, drapes, eyelid speculum, filter, and injection needles should be changed
before LUCENTIS is administered to the other eye.
No special dosage modification is required for any of the populations that have been
studied (e.g., gender, elderly).
4 CONTRAINDICATIONS
4.1 Ocular or periocular infections
LUCENTIS is contraindicated in patients with ocular or periocular infections.
4.2 Hypersensitivity
LUCENTIS is contraindicated in patients with known hypersensitivity to ranibizumab
or any of the excipients in LUCENTIS. Hypersensitivity reactions may manifest as
severe intraocular inflammation.
5 WARNINGS AND PRECAUTIONS
5.1 Endophthalmitis and retinal detachments
Intravitreal injections, including those with LUCENTIS, have been associated with
endophthalmitis and retinal detachments. Proper aseptic injection technique should
always be used when administering LUCENTIS. In addition, patients should be
monitored following the injection to permit early treatment should an infection occur
[see Dosage and Administration (2.6, 2.7) and Patient Counseling Information (17)].
5.2 Increases in intraocular pressure
Increases in intraocular pressure have been noted both pre-injection and post-injection
(at 60 minutes) while being treated with LUCENTIS. Monitor intraocular pressure prior
to and following intravitreal injection with LUCENTIS and manage appropriately [see
Dosage and Administration (2.7)].
5.3 Thromboembolic events
Although there was a low rate of arterial thromboembolic events (ATEs) observed in
the LUCENTIS clinical trials, there is a potential risk of ATEs following intravitreal use
of VEGF inhibitors. ATEs are defined as nonfatal stroke, nonfatal myocardial infarction,
or vascular death (including deaths of unknown cause).
Neovascular (wet) age-related macular degeneration
The ATE rate in the three controlled neovascular AMD studies (AMD-1, AMD-2, AMD-3)
during the first year was 1.9% (17 of 874) in the combined group of patients treated
with 0.3 mg or 0.5 mg LUCENTIS compared with 1.1% (5 of 441) in patients from the
control arms [see Clinical Studies (14.1)]. In the second year of Studies AMD-1 and
AMD-2, the ATE rate was 2.6% (19 of 721) in the combined group of LUCENTIS-treated
patients compared with 2.9% (10 of 344) in patients from the control arms. In Study
AMD-4, the ATE rates observed in the 0.5 mg arms during the first and second year
were similar to rates observed in Studies AMD-1, AMD-2, and AMD-3.

LUCENTIS
0.3 mg

Brief summaryplease see the LUCENTIS package

insert for full prescribing information.

In a pooled analysis of 2-year controlled studies (AMD-1, AMD-2, and a study of

LUCENTIS used adjunctively with verteporfin photodynamic therapy), the stroke rate
(including both ischemic and hemorrhagic stroke) was 2.7% (13 of 484) in patients
treated with 0.5 mg LUCENTIS compared to 1.1% (5 of 435) in patients in the control
arms (odds ratio 2.2 (95% confidence interval (0.8-7.1))).
Macular edema following retinal vein occlusion
The ATE rate in the two controlled RVO studies during the first 6 months was 0.8% in
both the LUCENTIS and control arms of the studies (4 of 525 in the combined group of
patients treated with 0.3 mg or 0.5 mg LUCENTIS and 2 of 260 in the control arms)
[see Clinical Studies (14.2)]. The stroke rate was 0.2% (1 of 525) in the combined
group of LUCENTIS-treated patients compared to 0.4% (1 of 260) in the control arms.
Diabetic macular edema and diabetic retinopathy
Safety data are derived from studies D-1 and D-2. All enrolled patients had DME and
DR at baseline [see Clinical Studies (14.3, 14.4)].
In a pooled analysis of Studies D-1 and D-2 [see Clinical Studies (14.3)], the ATE rate at
2 years was 7.2% (18 of 250) with 0.5 mg LUCENTIS, 5.6% (14 of 250) with 0.3 mg
LUCENTIS, and 5.2% (13 of 250) with control. The stroke rate at 2 years was 3.2%
(8 of 250) with 0.5 mg LUCENTIS, 1.2% (3 of 250) with 0.3 mg LUCENTIS, and 1.6%
(4 of 250) with control. At 3 years, the ATE rate was 10.4% (26 of 249) with 0.5 mg
LUCENTIS and 10.8% (27 of 250) with 0.3 mg LUCENTIS; the stroke rate was 4.8%
(12 of 249) with 0.5 mg LUCENTIS and 2.0% (5 of 250) with 0.3 mg LUCENTIS.
5.4 Fatal events in patients with DME and DR at baseline
Diabetic macular edema and diabetic retinopathy
Safety data are derived from studies D-1 and D-2. All enrolled patients had DME and
DR at baseline [see Clinical Studies (14.3, 14.4)].
A pooled analysis of Studies D-1 and D-2 [see Clinical Studies (14.3)], showed that
fatalities in the first 2 years occurred in 4.4% (11 of 250) of patients treated with
0.5 mg LUCENTIS, in 2.8% (7 of 250) of patients treated with 0.3 mg LUCENTIS,
and in 1.2% (3 of 250) of control patients. Over 3 years, fatalities occurred in 6.4%
(16 of 249) of patients treated with 0.5 mg LUCENTIS and in 4.4% (11 of 250) of
patients treated with 0.3 mg LUCENTIS. Although the rate of fatal events was low and
included causes of death typical of patients with advanced diabetic complications,
a potential relationship between these events and intravitreal use of VEGF inhibitors
cannot be excluded.
6 ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in the Warnings and
Precautions (5) section of the label:
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6.1 Injection procedure
Serious adverse reactions related to the injection procedure have occurred in < 0.1% of
intravitreal injections, including endophthalmitis [see Warnings and Precautions (5.1)],
rhegmatogenous retinal detachment, and iatrogenic traumatic cataract.
6.2 Clinical studies experience
Because clinical trials are conducted under widely varying conditions, adverse
reaction rates observed in one clinical trial of a drug cannot be directly compared
with rates in the clinical trials of the same or another drug and may not reflect the
rates observed in practice.
The data below reflect exposure to 0.5 mg LUCENTIS in 440 patients with neovascular
AMD in Studies AMD-1, AMD-2, and AMD-3, and 259 patients with macular edema
following RVO. The data also reflect exposure to 0.3 mg LUCENTIS in 250 patients
with DME and DR at baseline [see Clinical Studies (14)].
Safety data observed in Study AMD-4 were consistent with these results. On average,
the rates and types of adverse reactions in patients were not significantly affected
by dosing regimen.
Ocular reactions
Table 1 shows frequently reported ocular adverse reactions in LUCENTIS-treated
patients compared with the control group.

n=259 n=260
5% 4%
1% 1%
1% 2%
1% 2%
0% 1%
0% 2%

7%

5%

5%

5%

3%

2%

1%

1%

7%
7%

3%
6%

7%
1%

5%
1%

3%
0%

2%
0%

3%
0%

2%
0%

7%

7%

9%

8%

5%

5%

2%

2%

6%

4%

4%

6%

3%

4%

1%

0%

6%
6%

8%
4%

12%
3%

9%
5%

6%
2%

5%
3%

3%
0%

3%
1%

6%

2%

0%

1%

0%

0%

0%

0%

5%

3%

1%

1%

1%

0%

0%

0%

5%
4%
3%
3%

8%
4%
3%
3%

8%
11%
5%
11%

7%
9%
4%
9%

5%
6%
2%
5%

5%
5%
2%
5%

3%
0%
1%
2%

2%
2%
0%
1%

1%

1%

6%

3%

3%

1%

0%

0%

1%

0%

1%

1%

1%

0%

0%

0%

6.3 Immunogenicity
As with all therapeutic proteins, there is the potential for an immune response in
patients treated with LUCENTIS. The immunogenicity data reflect the percentage of
patients whose test results were considered positive for antibodies to LUCENTIS in
immunoassays and are highly dependent on the sensitivity and specificity of the assays.
The pre-treatment incidence of immunoreactivity to LUCENTIS was 0%-5% across
treatment groups. After monthly dosing with LUCENTIS for 6 to 24 months, antibodies
to LUCENTIS were detected in approximately 1%-9% of patients.
The clinical significance of immunoreactivity to LUCENTIS is unclear at this time. Among
neovascular AMD patients with the highest levels of immunoreactivity, some were
noted to have iritis or vitritis. Intraocular inflammation was not observed in patients with
DME and DR at baseline, or RVO patients with the highest levels of immunoreactivity.
7 DRUG INTERACTIONS
Drug interaction studies have not been conducted with LUCENTIS.
LUCENTIS intravitreal injection has been used adjunctively with verteporfin
photodynamic therapy (PDT). Twelve (12) of 105 (11%) patients with neovascular
AMD developed serious intraocular inflammation; in 10 of the 12 patients, this occurred
when LUCENTIS was administered 7 days ( 2 days) after verteporfin PDT.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
There are no studies of LUCENTIS in pregnant women. An embryo-fetal developmental
toxicity study was performed on pregnant cynomolgus monkeys. Pregnant animals
received intravitreal injections of ranibizumab every 14 days starting on Day 20 of
gestation, until Day 62 at doses of 0, 0.125, and 1 mg/eye. Skeletal abnormalities
including incomplete and/or irregular ossification of bones in the skull, vertebral
column, and hindlimbs and shortened supernumerary ribs were seen at a low
incidence in fetuses from animals treated with 1 mg/eye of ranibizumab. The
1 mg/eye dose resulted in trough serum ranibizumab levels up to 13 times higher than
predicted Cmax levels with single eye treatment in humans. No skeletal abnormalities
were seen at the lower dose of 0.125 mg/eye, a dose which resulted in trough
exposures equivalent to single eye treatment in humans. No effect on the weight or
structure of the placenta, maternal toxicity, or embryotoxicity was observed.
Animal reproduction studies are not always predictive of human response. It is also not
known whether ranibizumab can cause fetal harm when administered to a pregnant
woman or can affect reproduction capacity. Based on the anti-VEGF mechanism of
action for ranibizumab [see Clinical Pharmacology (12.1)], treatment with LUCENTIS
may pose a risk to embryo-fetal development (including teratogenicity) and reproductive
capacity. LUCENTIS should be given to a pregnant woman only if clearly needed.
8.3 Nursing mothers
It is not known whether ranibizumab is excreted in human milk. Because many drugs
are excreted in human milk, and because the potential for absorption and harm to
infant growth and development exists, caution should be exercised when LUCENTIS
is administered to a nursing woman.
8.4 Pediatric use
The safety and effectiveness of LUCENTIS in pediatric patients have not been
established.
8.5 Geriatric use
In the clinical studies, approximately 79% (2387 of 3005) of patients randomized to
treatment with LUCENTIS were 65 years of age and approximately 54% (1636 of
3005) were 75 years of age [see Clinical Studies (14)]. No notable differences in
efficacy or safety were seen with increasing age in these studies. Age did not have a
significant effect on systemic exposure.
10 OVERDOSAGE
More concentrated doses as high as 2 mg ranibizumab in 0.05 mL have been
administered to patients. No additional unexpected adverse reactions were seen.
17 PATIENT COUNSELING INFORMATION
Advise patients that in the days following LUCENTIS administration, patients are at
risk of developing endophthalmitis. If the eye becomes red, sensitive to light, painful,
or develops a change in vision, advise the patient to seek immediate care from an
ophthalmologist [see Warnings and Precautions (5.1)].

LUCENTIS [ranibizumab injection]

Manufactured by:
Genentech, Inc.
A Member of the Roche Group
1 DNA Way
South San Francisco, CA
94080-4990

Initial US Approval: June 2006

Revision Date: LUC/021815/0050 2015
LUCENTIS is a registered trademark
of Genentech, Inc.
2015 Genentech, Inc.