Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

BEOVU (BLA-761125)

(brolucizumab-dbll)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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07/29/2024 (SUPPL-21)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

In clinical trials, scleritis and episcleritis were reported (incidence < 1%).

…

09/28/2023 (SUPPL-20)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

There are no adequate and well-controlled studies of BEOVU administration in pregnant women. In an animal reproduction study, intravitreal administration of brolucizumab to pregnant monkeys once every 4 weeks in one eye from organogenesis to birth did not indicate any harmful effects with respect to pre- or postnatal development at 10-fold the maximum recommended human dose (MRHD) on a mg/kg basis (see Data).

…

Data

Animal Data

In an enhanced pre- and postnatal development (ePPND) study in pregnant cynomolgus monkeys, brolucizumab was administered to all animals by intravitreal (IVT) injection to one eye at doses of 3 or 6 mg once every 4 weeks until delivery. There was no impact of IVT administration of brolucizumab on embryo-fetal development, pregnancy or parturition; or on the survival, growth, or postnatal development of offspring at 6 mg/eye (10-fold the MRHD on a mg/kg basis).

12/19/2022 (SUPPL-17)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

…

Table 1: Common Adverse Reactions (greater than or equal to 1%) in the AMD and DME Clinical Trials

Revisions made to Table 1, please refer to label to view Table 1.

…

05/27/2022 (SUPPL-8)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined

…

A total of 1,646 patients treated with brolucizumab constituted the safety population in four Phase 3 studies. Among these, 1,098 patients were treated with the recommended dose of 6 mg.

A total of 1088 patients treated with brolucizumab, constituted the safety population in the two controlled neovascular AMD Phase 3 studies (HAWK and HARRIER) with a cumulative 96-week exposure to BEOVU, and 730 patients treated with the recommended dose of 6 mg [see Clinical Studies (14.1)]. A total of 558 patients treated with brolucizumab constituted the safety population in the two controlled DME Phase 3 studies (KESTREL and KITE) from baseline to week 52, including 368 patients treated with the recommended dose of 6 mg [see Clinical Studies (14.2)].

Table 1: Common Adverse Reactions (? 1%) in the AMD and DME Clinical Trials

Please refer to label to view Table1.

…

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined

Risk Summary

There are no adequate and well-controlled studies of BEOVU administration in pregnant women. In an animal reproduction study, intravitreal administration of brolucizumab to pregnant monkeys once every 4 weeks in one eye from organogenesis to birth caused fetal loss and a structural abnormality (bilateral absent metatarsal) in offspring at 10-fold the maximum recommended human dose (MRHD) on a mg/kg basis [see Data].

…

Data

Animal Data

In an enhanced pre- and postnatal development (ePPND) study in pregnant cynomolgus monkeys, brolucizumab was administered to all animals by intravitreal (IVT) injection to one eye at doses of 3 or 6 mg once every 4 weeks until delivery. Given the intermittent exposure profile and low group delivered animal numbers, this study is not sufficient to provide a complete developmental and reproductive toxicity profile or estimate a safe clinical dose.

Increased incidence of mid- and late-pregnancy fetal loss was observed for the 6 mg/eye group (10-fold the MRHD, on a mg/kg basis). Fetal loss was not observed for the 3 mg/eye group. Fetal malformation (bilateral absent metatarsal) was observed at 6 mg/eye.

VEGF inhibition has been shown to cause malformations, embryo-fetal resorption, and decreased fetal weight. VEGF also been shown to affect follicular development, corpus luteum function, and fertility.

8.5 Geriatric Use

Additions and/or revisions underlined

In the two Phase 3 clinical studies in AMD, approximately 90% (978/1089) of patients randomized to treatment with BEOVU were greater than or equal to 65 years of age and approximately 60% (648/1089) were greater than or equal to 75 years of age. In the two Phase 3 clinical studies in DME, approximately 45% (164/368) of patients randomized to treatment with BEOVU were greater than or equal to 65 years of age and approximately 10% (37/368) were greater than or equal to 75 years of age. No significant differences in efficacy or safety were seen with increasing age in these studies. No dosage regimen adjustment is required in patients 65 years and above.

02/18/2022 (SUPPL-10)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Retinal Vasculitis and/or Retinal Vascular Occlusion

Additions and/or revisions underlined:

Retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, have been reported with the use of BEOVU. These immune mediated adverse events may occur following the first intravitreal injection. Discontinue treatment with BEOVU in patients who develop these events. Patients treated with BEOVU who experience intraocular inflammation may be at risk of developing retinal vasculitis and/or retinal vascular occlusion and should be closely monitored [see Contraindications (4.2) and Adverse Reactions (6.1, 6.2)]. Patients should be instructed to report any change in vision without delay.

6 Adverse Reactions

6.1 Clinical Trials Experience

Table 1: Common Adverse Reactions (greater than or equal to 1%) in the HAWK and HARRIER wet AMD Clinical Trials

Newly added information:

In a clinical study (MERLIN), patients with nAMD who received BEOVU every 4-week maintenance dosing experienced a higher incidence of intraocular inflammation (including retinal vasculitis) and retinal vascular occlusion than patients who received BEOVU every 8 or 12-week maintenance dosing in the clinical studies (HAWK and HARRIER). The interval between two BEOVU doses during maintenance treatment should not be less than 8 weeks.

6.2 Immunogenicity

Additions and/or revisions underlined:

… Anti-brolucizumab antibodies were detected in the pre-treatment sample of 36% to 52% of treatment naive patients. After initiation of dosing, anti-brolucizumab antibodies were detected in at least one serum sample in 53% to 67% of patients treated with BEOVU. Intraocular inflammation was observed in 6% of patients with anti-brolucizumab antibodies detected during dosing with BEOVU. Retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, are immune mediated adverse events related to exposure to BEOVU. This treatment emergent antibody response may develop following the first intravitreal injection.

Anti-brolucizumab antibodies were not associated with an impact on clinical efficacy.

02/18/2022 (SUPPL-12)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Retinal Vasculitis and/or Retinal Vascular Occlusion

Additions and/or revisions underlined:

6 Adverse Reactions

6.1 Clinical Trials Experience

Table 1: Common Adverse Reactions (greater than or equal to 1%) in the HAWK and HARRIER wet AMD Clinical Trials

Newly added information:

6.2 Immunogenicity

Additions and/or revisions underlined:

Anti-brolucizumab antibodies were not associated with an impact on clinical efficacy.

02/18/2022 (SUPPL-13)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Retinal Vasculitis and/or Retinal Vascular Occlusion

Additions and/or revisions underlined:

6 Adverse Reactions

6.1 Clinical Trials Experience

Table 1: Common Adverse Reactions (greater than or equal to 1%) in the HAWK and HARRIER wet AMD Clinical Trials

Newly added information:

6.2 Immunogenicity

Additions and/or revisions underlined:

Anti-brolucizumab antibodies were not associated with an impact on clinical efficacy.

06/09/2020 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Retinal Vasculitis and/or Retinal Vascular Occlusion

(Newly added subsection)

Retinal vasculitis and/or retinal vascular occlusion, typically in the presence of intraocular inflammation, have been reported with the use of BEOVU. Patients should be instructed to report any change in vision without delay.

6 Adverse Reactions

(Additions and/or revisions underlined)

The following potentially serious adverse reactions are described elsewhere in the labeling:

Hypersensitivity
Endophthalmitis and Retinal Detachment
Retinal Vasculitis and/or Retinal Vascular Occlusion

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise patients that in the days following BEOVU administration, patients are at risk of developing endophthalmitis., retinal detachment, retinal vasculitis and/or retinal vascular occlusion. If the eye becomes red, sensitive to light, painful, or if a patient develops any change in vision, instruct the patient to seek immediate care from an ophthalmologist.

Patients may experience temporary visual disturbances after an intravitreal injection with BEOVU and the associated eye examination. Advise patients not to drive or use machinery until visual function has recovered sufficiently.