PRINCIPAL DISPLAY PANEL - 0.5 mg Vial Carton

NDC 64406-019-01

Rx only

Byooviz™ 0.5mg wAMD RVO mCNO

(ranibizumab-nuna)

Injection

0.5 mg single-dose vial.

Discard unused portion.

IMPORTANT:

A 5-micron sterilefilter needle (19-gauge x 1-1/2 inch) is required for preparation, but not included.

See enclosed package insert.

For intravitreal injection.

INDICATED FOR:

Neovascular (wet) age-related macular degeneration (AMD)

Macular edema following retinal vein occlusion (RVO)

Myopic choroidal neovascularization (mCNV)

KEEP REFRIGERATED.

DO NOT FREEZE.

PROTECT VIAL FROM LIGHT.

SAMSUNG BIOEPIS, Biogen®

4 CONTRAINDICATIONS

4.1 Ocular or Periocular Infections

BYOOVIZ is contraindicated in patients with ocular or periocular infections.

4.2 Hypersensitivity

BYOOVIZ is contraindicated in patients with known hypersensitivity to ranibizumab products or any of the excipients in BYOOVIZ. Hypersensitivity reactions may manifest as severe intraocular inflammation.

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)]

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 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 the same or another drug and may not reflect the rates observed in practice.

The data below reflect exposure to 0.5 mg ranibizumab in 440 patients with neovascular AMD in Studies AMD-1, AMD-2, and AMD-3; in 259 patients with macular edema following RVO.

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 ranibizumab- treated patients compared with the control group.

Table 1 Ocular Reactions in the AMD, and RVO Studies

Adverse Reaction	AMD 2-year	AMD 1-year	RVO 6-month
Ranibizumab 0.5 mg	Control	Ranibizumab 0.5 mg	Control	Ranibizumab 0.5 mg	Control
n=379	n=379	n=440	n=441	n=259	n=260
Conjunctival hemorrhage	74%	60%	64%	50%	48%	37%
Eye pain	35%	30%	26%	20%	17%	12%
Vitreous floaters	27%	8%	19%	5%	7%	2%
Intraocular pressure increased	24%	7%	17%	5%	7%	2%
Vitreous detachment	21%	19%	15%	15%	4%	2%
Intraocular inflammation	18%	8%	13%	7%	1%	3%
Cataract	17%	14%	11%	9%	2%	2%
Foreign body sensation in eyes	16%	14%	13%	10%	7%	5%
Eye irritation	15%	15%	13%	12%	7%	6%
Lacrimation increased	14%	12%	8%	8%	2%	3%
Blepharitis	12%	8%	8%	5%	0%	1%
Dry eye	12%	7%	7%	7%	3%	3%
Visual disturbance or vision blurred	18%	15%	13%	10%	5%	3%
Eye pruritis	12%	11%	9%	7%	1%	2%
Ocular hyperemia	11%	8%	7%	4%	5%	3%
Retinal disorder	10%	7%	8%	4%	2%	1%
Maculopathy	9%	9%	6%	6%	11%	7%
Retinal degeneration	8%	6%	5%	3%	1%	0%
Ocular discomfort	7%	4%	5%	2%	2%	2%
Conjunctival hyperemia	7%	6%	5%	4%	0%	0%
Posterior capsule opacification	7%	4%	2%	2%	0%	1%
Injection site hemorrhage	5%	2%	3%	1%	0%	0%

Non-Ocular Reactions

Non-ocular adverse reactions with an incidence of ≥ 5% in patients receiving ranibizumab for AMD, and/or RVO and which occurred at a ≥ 1% higher frequency in patients treated with ranibizumab 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 AMD, and RVO Studies

Adverse Reaction	AMD 2-year	AMD 1-year	RVO 6-month
Ranibizumab 0.5 mg	Control	Ranibizumab 0.5 mg	Control	Ranibizumab 0.5 mg	Control
n=379	n=379	n=440	n=441	n=259	n=260
Nasopharyngitis	16%	13%	8%	9%	5%	4%
Anemia	8%	7%	4%	3%	1%	1%
Nausea	9%	6%	5%	5%	1%	2%
Cough	9%	8%	5%	4%	1%	2%
Constipation	5%	7%	3%	4%	0%	1%
Seasonal allergy	4%	4%	2%	2%	0%	2%
Hypercholesterolemia	5%	5%	3%	2%	1%	1%
Influenza	7%	5%	3%	2%	3%	2%
Renal failure	1%	1%	0%	0%	0%	0%
Upper respiratory tract infection	9%	8%	5%	5%	2%	2%
Gastroesophageal reflux disease	4%	6%	3%	4%	1%	0%
Headache	12%	9%	6%	5%	3%	3%
Edema peripheral	3%	5%	2%	3%	0%	1%
Renal failure chronic	0%	1%	0%	0%	0%	0%
Neuropathy peripheral	1%	1%	1%	0%	0%	0%
Sinusitis	8%	7%	5%	5%	3%	2%
Bronchitis	11%	9%	6%	5%	0%	2%
Atrial fibrillation	5%	4%	2%	2%	1%	0%
Arthralgia	11%	9%	5%	5%	2%	1%
Chronic obstructive pulmonary disease	6%	3%	3%	1%	0%	0%
Wound healing complications	1%	1%	1%	0%	0%	0%

6.3 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other ranibizumab products may be misleading.

The pre-treatment incidence of immunoreactivity to ranibizumab was 0%-5% across treatment groups. After monthly dosing with ranibizumab for 6 to 24 months, antibodies to ranibizumab were detected in approximately 1%-9% of patients.

The clinical significance of immunoreactivity to ranibizumab products are 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 RVO patients with the highest levels of immunoreactivity.

6.4 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ranibizumab products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal studies have not been conducted to determine the carcinogenic potential of ranibizumab products. Based on the anti-VEGF mechanism of action of ranibizumab products, treatment with ranibizumab products may pose a risk to reproductive capacity [see Females and Males of Reproductive Potential (8.3)].

16 HOW SUPPLIED/STORAGE AND HANDLING

Each BYOOVIZ 0.5 mg carton (NDC 64406-019-01) contains a single-dose, 2-mL glass vial designed to deliver 0.05 mL of 10 mg/mL ranibizumab-nuna solution that is clear to slightly opalescent and colorless to pale yellow.

EACH CARTON IS FOR SINGLE-EYE USE ONLY.

BYOOVIZ should be refrigerated at 2°C to 8°C (36°F to 46°F). DO NOT FREEZE. Do not use beyond the date stamped on the label. Protect BYOOVIZ vials from light and store in the original carton until time of use.

Prior to use, the unopened vial can be stored at temperatures up to 86°F (30°C) for up to 72 hours.