LUCENTIS Dailymed

Recent Major Changes Section

Dosage and Administration, General Dosing Information (2.1)	8/2023
Dosage and Administration, Preparation for Administration (2.6)	8/2023
Dosage and Administration, Administration (2.7)	8/2023
Warnings and Precautions, Retinal Vasculitis with or without Occlusion (5.5)	2/2024

1 Indications And Usage

LUCENTIS is indicated for the treatment of patients with:


LUCENTIS, a vascular endothelial growth factor (VEGF) inhibitor, is indicated for the treatment of patients with:

• Neovascular (Wet) Age-Related Macular Degeneration (AMD) (1.1)
• Macular Edema Following Retinal Vein Occlusion (RVO) (1.2)
• Diabetic Macular Edema (DME) (1.3)
• Diabetic Retinopathy (DR) (1.4)
• Myopic Choroidal Neovascularization (mCNV) (1.5)

1.1Neovascular (Wet) Age-Related Macular Degeneration (AMD)

 

1.2Macular Edema Following Retinal Vein Occlusion (RVO)

1.3Diabetic Macular Edema (DME)

1.4 Diabetic Retinopathy (DR)

1.5Myopic Choroidal Neovascularization (mCNV)

2 Dosage And Administration

For ophthalmic intravitreal injection only (2.1)

• Neovascular (Wet) Age-Related Macular Degeneration (AMD) (2.2): LUCENTIS 0.5 mg (0.05 mL of 10 mg/mL 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.
  • -Although not as effective, patients may also be treated with one dose every 3 months after 4 monthly doses. Patients should be assessed regularly.
• Macular Edema Following Retinal Vein Occlusion (RVO) (2.3): LUCENTIS 0.5 mg (0.05 mL of 10 mg/mL solution) is recommended to be administered by intravitreal injection once a month (approximately 28 days).
• Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR) (2.4): LUCENTIS 0.3 mg (0.05 mL of 6 mg/mL solution) is recommended to be administered by intravitreal injection once a month (approximately 28 days).
• Myopic Choroidal Neovascularization (mCNV) (2.5): LUCENTIS 0.5 mg (0.05 mL of 10 mg/mL solution) is recommended to be initially administered by intravitreal injection once a month (approximately 28 days) for up to three months. Patients may be retreated if needed.

2.1General Dosing Information

FOR OPHTHALMIC INTRAVITREAL INJECTION.

2.2Neovascular (Wet) Age-Related Macular Degeneration (AMD)

LUCENTIS 0.5 mg (0.05 mL of 10 mg/mL 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 9 months after three 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)].

2.3Macular Edema Following Retinal Vein Occlusion (RVO)

LUCENTIS 0.5 mg (0.05 mL of 10 mg/mL 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)].

2.4Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR)

LUCENTIS 0.3 mg (0.05 mL of 6 mg/mL solution) is recommended to be administered by intravitreal injection once a month (approximately 28 days).

2.5 Myopic Choroidal Neovascularization (mCNV)

LUCENTIS 0.5 mg (0.05 mL of 10 mg/mL LUCENTIS solution) is recommended to be initially administered by intravitreal injection once a month (approximately 28 days) for up to 3 months. Patients may be retreated if needed [see Clinical Studies (14.5)].

2.6Preparation for Administration

Prefilled Syringe:

The prefilled syringe is sterile and is for single-dose only. Do not use the product if the packaging is damaged or has been tampered with.

To prepare LUCENTIS for intravitreal administration, please adhere to these instructions for use. Read all the instructions carefully before using the prefilled syringe.

The opening of the sealed tray and all subsequent steps should be done under aseptic conditions.

For the intravitreal injection, a 30-gauge × ½ inch sterile injection needle should be used (not provided).

Note: the dose must be set to 0.05 mL.
the syringe cap is detached from the Luer lock.

the syringe is damaged.

particulates, cloudiness, or discoloration are visible.

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-

-

Device description
LUCENTIS prefilled syringes are available in 2 dose strengths: LUCENTIS 0.5 mg prefilled syringe with a CLEAR finger grip.
LUCENTIS 0.3 mg prefilled syringe with an ORANGE finger grip.
Check the labels on the LUCENTIS carton, syringe tray and prefilled syringe to make sure you have the correct dose strength.
Step 1: Prepare
Make sure that your pack contains a sterile prefilled syringe in a sealed tray. Peel the lid off the syringe tray and, using aseptic technique, remove the syringe.
Step 2: Inspect syringe
LUCENTIS should be colorless to pale yellow. Do not use the prefilled syringe if:
Step 3: Remove syringe cap
Snap off (do not turn or twist) the syringe cap (see Figure 2).
Step 4: Attach needle
Attach a 30G × ½ inch sterile injection needle firmly onto the syringe by screwing it tightly onto the Luer lock (see Figure 3). Carefully remove the needle cap by pulling it straight off. Note: Do not wipe the needle at any time.
Step 5: Dislodge air bubbles
Hold the syringe with the needle pointing up. If there are any air bubbles, gently tap the syringe with your finger until the bubbles rise to the top (see Figure 4).
Step 6: Expel air and adjust drug dose
Hold the syringe at eye level, and carefully push the plunger rod until the edge below the dome of the rubber stopper is aligned with the 0.05 mL dose mark (see Figure 5). Note: The plunger rod is not attached to the rubber stopper – this is to prevent air being drawn into the syringe.
Step 7: Inject
The injection procedure should be carried out under aseptic conditions. Insert the needle into the injection site. Inject slowly until rubber stopper reaches the bottom of the syringe to deliver the volume of 0.05 mL. After injection, do not recap the needle or detach it from the syringe. Dispose of the used syringe together with the needle in a sharps disposal container or in accordance with local requirements.

2.7Administration

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 prefilled syringe should only be used for the treatment of a single eye. If the contralateral eye requires treatment, a new prefilled syringe should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, and injection needle 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).

• Endophthalmitis and retinal detachments may occur following intravitreal injections. Patients should be monitored following the injection (5.1).
• Increases in intraocular pressure (IOP) have been noted both pre- and post-intravitreal injection (5.2).
• There is a potential risk of arterial thromboembolic events following intravitreal use of VEGF inhibitors (5.3).
• Fatal events occurred more frequently in patients with DME and DR at baseline, who were treated monthly with LUCENTIS compared with control (5.4).

5.1Endophthalmitis 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)].

5.2Increases 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)].

5.3Thromboembolic 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. Arterial thromboembolic events 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.

In a pooled analysis of 2-year controlled studies [AMD-1, AMD-2, and a study of LUCENTIS used adjunctively with verteporfin photodynamic therapy (PDT)], 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.

5.4Fatal Events in Patients with Diabetic Macular Edema and Diabetic Retinopathy 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.

5.5Retinal Vasculitis with or without Occlusion

Retinal vasculitis with or without occlusion, typically in the presence of preexisting intraocular inflammation or post-treatment with other intravitreal agents, have been reported with the use of LUCENTIS. Discontinue treatment with LUCENTIS in patients who develop these events. Patients should be instructed to report any change in vision without delay [see Patient Counseling Information (17)].

6 Adverse Reactions

The following adverse reactions are discussed in greater detail in other sections of the label:

• Endophthalmitis and Retinal Detachments [see Warnings and Precautions (5.1)]
• Increases in Intraocular Pressure [see Warnings and Precautions (5.2)]
• Thromboembolic Events [see Warnings and Precautions (5.3)]
• Fatal Events in patients with DME and DR at baseline [see Warnings and Precautions (5.4)]

• The most common adverse reactions (reported more frequently in LUCENTIS-treated subjects than control subjects) are conjunctival hemorrhage, eye pain, vitreous floaters, and increased IOP (6.2).

To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Injection 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.

6.2Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of 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; in 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 224 patients with mCNV, as well as Studies AMD-4 and D-3, 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.

Table 1 Ocular Reactions in the DME and DR, AMD, and RVO Studies

	DME and DR2-year		AMD2-year		AMD1-year		RVO6-month
Adverse Reaction	LUCENTIS0.3 mg	Control	LUCENTIS0.5 mg	Control	LUCENTIS0.5 mg	Control	LUCENTIS0.5 mg	Control
	n=250	n=250	n=379	n=379	n=440	n=441	n=259	n=260
Conjunctival hemorrhage	47%	32%	74%	60%	64%	50%	48%	37%
Eye pain	17%	13%	35%	30%	26%	20%	17%	12%
Vitreous floaters	10%	4%	27%	8%	19%	5%	7%	2%
Intraocular pressure increased	18%	7%	24%	7%	17%	5%	7%	2%
Vitreous detachment	11%	15%	21%	19%	15%	15%	4%	2%
Intraocular inflammation	4%	3%	18%	8%	13%	7%	1%	3%
Cataract	28%	32%	17%	14%	11%	9%	2%	2%
Foreign body sensation in eyes	10%	5%	16%	14%	13%	10%	7%	5%
Eye irritation	8%	5%	15%	15%	13%	12%	7%	6%
Lacrimation increased	5%	4%	14%	12%	8%	8%	2%	3%
Blepharitis	3%	2%	12%	8%	8%	5%	0%	1%
Dry eye	5%	3%	12%	7%	7%	7%	3%	3%
Visual disturbance or vision blurred	8%	4%	18%	15%	13%	10%	5%	3%
Eye pruritis	4%	4%	12%	11%	9%	7%	1%	2%
Ocular hyperemia	9%	9%	11%	8%	7%	4%	5%	3%
Retinal disorder	2%	2%	10%	7%	8%	4%	2%	1%
Maculopathy	5%	7%	9%	9%	6%	6%	11%	7%
Retinal degeneration	1%	0%	8%	6%	5%	3%	1%	0%
Ocular discomfort	2%	1%	7%	4%	5%	2%	2%	2%
Conjunctival hyperemia	1%	2%	7%	6%	5%	4%	0%	0%
Posterior capsule opacification	4%	3%	7%	4%	2%	2%	0%	1%
Injection site hemorrhage	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

	DME and DR2-year		AMD2-year		AMD1-year		RVO6-month
Adverse Reaction	LUCENTIS0.3 mg	Control	LUCENTIS0.5 mg	Control	LUCENTIS0.5 mg	Control	LUCENTIS0.5 mg	Control
	n=250	n=250	n=379	n=379	n=440	n=441	n=259	n=260
Nasopharyngitis	12%	6%	16%	13%	8%	9%	5%	4%
Anemia	11%	10%	8%	7%	4%	3%	1%	1%
Nausea	10%	9%	9%	6%	5%	5%	1%	2%
Cough	9%	4%	9%	8%	5%	4%	1%	2%
Constipation	8%	4%	5%	7%	3%	4%	0%	1%
Seasonal allergy	8%	4%	4%	4%	2%	2%	0%	2%
Hypercholesterolemia	7%	5%	5%	5%	3%	2%	1%	1%
Influenza	7%	3%	7%	5%	3%	2%	3%	2%
Renal failure	7%	6%	1%	1%	0%	0%	0%	0%
Upper respiratory tract infection	7%	7%	9%	8%	5%	5%	2%	2%
Gastroesophageal reflux disease	6%	4%	4%	6%	3%	4%	1%	0%
Headache	6%	8%	12%	9%	6%	5%	3%	3%
Edema peripheral	6%	4%	3%	5%	2%	3%	0%	1%
Renal failure chronic	6%	2%	0%	1%	0%	0%	0%	0%
Neuropathy peripheral	5%	3%	1%	1%	1%	0%	0%	0%
Sinusitis	5%	8%	8%	7%	5%	5%	3%	2%
Bronchitis	4%	4%	11%	9%	6%	5%	0%	2%
Atrial fibrillation	3%	3%	5%	4%	2%	2%	1%	0%
Arthralgia	3%	3%	11%	9%	5%	5%	2%	1%
Chronic obstructive pulmonary disease	1%	1%	6%	3%	3%	1%	0%	0%
Wound healing complications	1%	0%	1%	1%	1%	0%	0%	0%

6.3Immunogenicity

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.

6.4Postmarketing Experience

The following adverse reaction has been identified during post-approval use of LUCENTIS. Because this reaction was reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

• Ocular: Tear of retinal pigment epithelium among patients with neovascular AMD

7 Drug Interactions

Drug interaction studies have not been conducted with LUCENTIS.

LUCENTIS intravitreal injection has been used adjunctively with PDT. Twelve 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 PDT.

8 Use In Specific Populations

8.1 Pregnancy

Risk Summary

There are no adequate and well-controlled studies of LUCENTIS administration in pregnant women.

Administration of ranibizumab to pregnant monkeys throughout the period of organogenesis resulted in a low incidence of skeletal abnormalities at intravitreal doses 13-times the predicted human exposure (based on maximal serum trough levels [C_max]) after a single eye treatment at the recommended clinical dose. No skeletal abnormalities were observed at serum trough levels equivalent to the predicted human exposure after a single eye treatment at the recommended clinical dose [see Animal Data].

Animal reproduction studies are not always predictive of human response, and it is not known whether ranibizumab can cause fetal harm when administered to a pregnant woman. Based on the anti-VEGF mechanism of action for ranibizumab [see Clinical Pharmacology (12.1)], treatment with LUCENTIS may pose a risk to human embryofetal development.

LUCENTIS should be given to a pregnant woman only if clearly needed.

Data

Animal Data

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 C_max 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.

8.2 Lactation

Risk Summary

There are no data available on the presence of ranibizumab in human milk, the effects of ranibizumab on the breastfed infant or the effects of ranibizumab on milk production/excretion.

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.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for LUCENTIS and any potential adverse effects on the breastfed child from ranibizumab.

8.3 Females and Males of Reproductive Potential

Infertility

No studies on the effects of ranibizumab on fertility have been conducted and it is not known whether ranibizumab can affect reproduction capacity. Based on the anti-VEGF mechanism of action for ranibizumab, treatment with LUCENTIS may pose a risk to reproductive capacity.

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 76% (2449 of 3227) of patients randomized to treatment with LUCENTIS were ≥ 65 years of age and approximately 51% (1644 of 3227) 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.