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INDICATION AND IMPORTANT SAFETY INFORMATION

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)

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

Intravitreal injections, including those with LUCENTIS, have been associated with endophthalmitis and retinal detachment. Proper aseptic injection technique should always be utilized when administering LUCENTIS. Patients should be monitored during the week following the injection to permit early treatment, should an infection occur.

Increases in intraocular pressure (IOP) have been noted both pre-injection and post-injection (at 60 minutes) with LUCENTIS. IOP and perfusion of the optic nerve head should be monitored and managed appropriately.

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 3 controlled neovascular AMD studies during the first year was 1.9% in the combined group of patients treated with 0.3 mg or 0.5 mg LUCENTIS compared with 1.1% in patients from the control arms. In the second year of Studies AMD-1 and AMD-2, the ATE rate was 2.6% in the combined group of LUCENTIS-treated patients compared with 2.9% in patients from the control arms. In Study AMD-4, the ATE rates observed in the study during the first year were similar to rates observed in Studies AMD-1, AMD-2, and AMD-3.

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% in patients treated with 0.5 mg LUCENTIS compared to 1.1% 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 2 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). The stroke rate was 0.2% in the combined group of LUCENTIS-treated patients compared to 0.4% in the control arms.

Diabetic macular edema

In a pooled analysis of Studies DME-1 and DME-2, the ATE rate at 2 years was 7.2% with 0.5 mg LUCENTIS, 5.6% with 0.3 mg LUCENTIS, and 5.2% with control. The stroke rate at 2 years was 3.2% with 0.5 mg LUCENTIS, 1.2% with 0.3 mg LUCENTIS, and 1.6% with control. At 3 years, the ATE rate was 10.4% with 0.5 mg LUCENTIS and 10.8% with 0.3 mg LUCENTIS; the stroke rate was 4.8% with 0.5 mg LUCENTIS and 2.0% with 0.3 mg LUCENTIS.

A pooled analysis of Studies DME-1 and DME-2 showed that fatalities in the first 2 years occurred in 4.4% of patients treated with 0.5 mg LUCENTIS, in 2.8% of patients treated with 0.3 mg LUCENTIS, and in 1.2% of control patients. Over 3 years, fatalities occurred in 6.4% of patients treated with 0.5 mg LUCENTIS and in 4.4% 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.

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 clinical trials in neovascular (wet) age-related macular degeneration, the most common ocular side effects included conjunctival hemorrhage, eye pain, vitreous floaters, increased IOP, vitreous detachment, and intraocular inflammation. The most common non-ocular side effects included nasopharyngitis, headache, arthralgia, and bronchitis.

In clinical trials in macular edema following retinal vein occlusion, the most common ocular side effects included conjunctival hemorrhage, eye pain, and maculopathy. The most common non-ocular side effects included nasopharyngitis, headache, influenza, and sinusitis.

In clinical trials in diabetic macular edema, the most common ocular side effects included conjunctival hemorrhage, cataract, increased IOP, and vitreous detachment. The most common non-ocular side effects included nasopharyngitis, anemia, and nausea.

As with all therapeutic proteins, there is the potential for an immune response in patients treated with LUCENTIS. The clinical significance of immunoreactivity to LUCENTIS is unclear at this time.

For additional safety information, please see LUCENTIS full prescribing information.



EFFICACY OUTCOMES

LUCENTIS 0.3 mg Is the First and Only FDA Approved Drug for DME
Shown to Improve Vision

RIDE and RISE

  • 3-LINE GAINS
  • 20/40
  • BCVA
  • CFT
  • ADVERSE EVENTS

Primary end point: patients gaining ≥3 lines from baseline at month 241

3-LINE GAINS
  • Approximately 40% of LUCENTIS-treated patients gained ≥3 lines from baseline at month 24 vs 15% with sham1
  • These improvements were seen regardless of previous treatment—more than 64% of patients had prior laser therapy, and more than 16% had previous anti-VEGF therapy1
  • Fewer LUCENTIS-treated patients lost >15 letters compared to sham (2% vs 9.3%, respectively)1

Secondary end point: patients with 20/40 or better Snellen equivalent BCVA at
month 241-3

Patients with 20/40 or better Snellen equivalent BCVA at month 242

16.4% of LUCENTIS 0.3 mg patients and 19.5% of sham patients had 20/40 or better vision at baseline.

  • LUCENTIS improved the majority of patients to at least 20/40 Snellen equivalent BCVA at month 24, vs 36.2% with sham1
  • These improvements were seen regardless of previous treatment—more than 64% of patients had prior laser therapy, and 16% had previous anti–VEGF therapy1

Secondary end point: mean change in BCVA from baseline by visit1,2

Mean change in BCVA from baseline by visit2

72% of sham-treated patients received protocol-specified laser vs 37.6% of LUCENTIS-treated patients.

  • LUCENTIS demonstrated rapid and significant visual gains as early as day 71
  • Visual gains continued through year 3 in LUCENTIS-treated patients (+12.4 letters at month 36)1
  • Continued improvements through year 3 reinforce the benefits of consistent dosing
  • Patients receiving 0.3 mg LUCENTIS at the beginning of the studies had greater VA gains after 12 monthly injections than those who started receiving LUCENTIS beginning at month 25, reinforcing the need to treat early1

*Crossover to LUCENTIS 0.5 mg was optional.
LUCENTIS is approved for a 0.3 mg dose in DME.

Secondary end point: mean change in OCT CFT over time1,2

Mean change in OCT CFT over time2

Last observation carried forward imputation method was used. Central foveal thickness (CFT) is defined as center point thickness.

  • LUCENTIS demonstrated rapid and significant differences in CFT as early as day 71
  • Improvements in CFT continued through year 3 (-261.5 microns at month 36)1
  • Continued improvement through year 3 reinforces the benefits of consistent dosing

*Crossover to LUCENTIS 0.5 mg was optional.
LUCENTIS is approved for a 0.3 mg dose in DME.

LUCENTIS systemic and ocular safety has been well studied in DME1

Diabetes patients are at a greater risk for vascular complications, highlighting the importance of systemic safety when considering treatment

Systemic safety2

Systemic SAEs potentially related to VEGF inhibition through primary end point of month 24
SAE group term, %(n)
LUCENTIS 0.3 mg (n=250)
Sham (n=250)
Any event
10.8% (27)
11.6% (29)
ATE bleeding/hemorrhage AE
2.8% (7)
2.8% (7)
Bleeding/hemorrhage (CNS and cerebrovascular hemorrhage)
1.2% (3)
1.2% (3)
Bleeding/hemorrhage (non-CNS hemorrhage)
1.6% (4)
1.6% (4)
Congestive heart failure
2.8% (7)
4.4% (11)
Fistulae (other)
0.4% (1)
0
Gastrointestinal perforation
0
0
Hypertension
1.2% (3)
0.4% (1)
Proteinuria
0
0
Thromboembolic event, arterial
5.6% (14)
6.8% (17)
Thromboembolic event, venous
1.6% (4)
0.4% (1)
Wound healing complications
0
0
APTC events through primary end point of month 243
Event type, (%) n
LUCENTIS 0.3 mg (n=250)
Sham (n=250)
Any event
6.4% (16)
5.2% (13)
Deaths, Overall
2.8% (7)
1.2% (3)
Vascular
2% (5)
1.2% (3)
Nonvascular
0.8% (2)
0
Unknown cause
0
0
Myocardial infarction, Overall
3.6% (9)
3.6% (9)
Fatal
0.8% (2)
0.8% (2)
Nonfatal
2.8% (7)
2.8% (7)
CVA, Overall
1.2% (3)
1.6% (4)
Fatal
0.4% (1)
0.4% (1)
Nonfatal
0.8% (2)
1.2% (3)
APTC events*
5.6% (14)
5.2% (13)

Some patients may have experienced multiple events.

  • The ATE rate at 2 years with 0.3 mg LUCENTIS was 5.6% (14 of 250) vs 5.2% (13 of 250) with sham; at 3 years the rate was 10.8% (27 of 250) with LUCENTIS 0.3 mg*2
  • Over 3 years, fatalities occurred in 4.4% of patients treated with 0.3 mg LUCENTIS. Although causes of death were those typical of patients with advanced diabetic complications, a potential relationship between these events and intravitreal use of VEGF inhibitors cannot be excluded2

*There is no pure sham control group at month 36, so it is not valid to compare the sham groups with the LUCENTIS treatment groups.

APTC, Antiplatelet Trialists' Collaborations; ATE, arterial thromboembolic event; CVA, cerebrovascular accident; DME, diabetic macular edema; MI, myocardial infarction; VEGF, vascular endothelial growth factor.

Ocular safety3

Key ocular serious adverse events in the study eye through month 24
SAEs, n (%)
MedDRA high-level term or preferred term
LUCENTIS 0.3 mg (n=250)
Sham (n=250)
Any serious adverse event
3.2% (8)
6.4% (16)
Cataract
0.4% (1)
0
Cataract, traumatic
0.4% (1)
0
Endophthalmitis
0.8% (2)
0
Retinal detachment
0
0.4% (1)
Uveitis
0.4% (1)
0
Visual acuity reduced
0
1.6% (4)
Vitreous hemorrhage
0
2.8% (7)

MedDRA, Medical Dictionary for Regulatory Activities, Version 13.1; SAE, serious adverse event.

  • Overall incidence of ocular SAEs at 36 months was 4.8% vs 8.8% for LUCENTIS and sham-treated patients, respectively2
Key ocular adverse events in the study eye through month 24*
AEs, n (%)
MedDRA high-level term or preferred term
LUCENTIS 0.3 mg (n=250)
Sham (n=250)
Any adverse event
86.4% (216)
86.4% (216)
Cataract conditions
28.0% (70)
31.6% (79)
Glaucoma (excluding congenital)
2.8% (7)
2.4% (6)
Intraocular inflammation
3.6% (9)
3.2% (8)
Intraocular pressure increased
17.6% (44)
6.8% (17)
Iris neovascularization
0.4% (1)
0.8% (2)
Retinal detachment
0.4% (1)
1.2% (3)
Retinal neovascularization
0.8% (2)
9.6% (24)

*This table includes serious and nonserious adverse events. Refers to investigator-reported adverse events of elevated IOP, including IOP elevated >60 minutes following injection, and IOP elevated prior to injection.

DME, diabetic macular edema; IOP, intraocular pressure; MedDRA, Medical Dictionary for Regulatory Activities, Version 13.1; SAE, serious adverse event.

References: 1. Food and Drug Administration. Dermatologic and Ophthalmic Drugs Advisory Committee meeting briefing package for sBLA 125156 LUCENTIS (ranibizumab injection). http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/dermatologicandophthalmicdrugsadvisory committee/ucm313088.pdf. Accessed August 1, 2012.

References: 1. Food and Drug Administration. Dermatologic and Ophthalmic Drugs Advisory Committee meeting briefing package for sBLA 125156 LUCENTIS (ranibizumab injection). http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/dermatologicandophthalmicdrugsadvisory committee/ucm313088.pdf. Accessed August 1, 2012. 2. Data on file. Genentech, Inc. South San Francisco, CA. 3. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119:789-801.

References: 1. Food and Drug Administration. Dermatologic and Ophthalmic Drugs Advisory Committee meeting briefing package for sBLA 125156 LUCENTIS (ranibizumab injection). http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/dermatologicandophthalmicdrugsadvisory committee/ucm313088.pdf. Accessed August 1, 2012. 2. Data on file. Genentech, Inc. South San Francisco, CA.

References: 1. Food and Drug Administration. Dermatologic and Ophthalmic Drugs Advisory Committee meeting briefing package for sBLA 125156 LUCENTIS (ranibizumab injection). http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/dermatologicandophthalmicdrugsadvisory committee/ucm313088.pdf. Accessed August 1, 2012. 2. Data on file. Genentech, Inc. South San Francisco, CA.

References: 1. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119:789-801. 2. Food and Drug Administration. Dermatologic and Ophthalmic Drugs Advisory Committee meeting briefing package for sBLA 125156 LUCENTIS (ranibizumab injection). http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/dermatologicandophthalmic drugsadvisorycommittee/ucm313088.pdf. Accessed August 1, 2012. 3. Boyer DS. Ranibizumab (anti-VEGF) improves vision in diabetic macular edema: results from 2 phase III randomized trials. Paper presented at: 115th Annual Meeting of the American Academy of Ophthalmology; October 22-25, 2011; Orlando, FL.