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.

COMBIGAN (NDA-021398)

(BRIMONIDINE TARTRATE; TIMOLOL MALEATE)

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

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03/17/2026 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Contamination of Topical Ophthalmic Products After Use

Additions and/or revisions underlined:

… Do not touch the tip of the dispensing container to the eye or surrounding structures. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions [see Patient Counseling Information (17)].

6 Adverse Reactions

Addition of the following bulleted line listing:

Hypersensitivity Reactions [see Contraindications (4.4)]
Potential for Severe Respiratory or Cardiac Reactions [see Warnings and Precautions (5.1)]
Cardiac Failure [see Warnings and Precautions (5.2)]
Potentiation of Vascular Insufficiency [see Warnings and Precautions (5.4)]
Increased Reactivity to Allergens [see Warnings and Precautions (5.5)]
Potentiation of Muscle Weakness [see Warnings and Precautions (5.6)]
Masking of Hypoglycemic Symptoms in Patients with Diabetes Mellitus [see Warnings and Precautions (5.7)]
Masking of Thyrotoxicosis [see Warnings and Precautions (5.8)]
Ocular Hypersensitivity [see Warnings and Precautions (5.9)]
Contamination of Topical Ophthalmic Products after Use [see Warnings and Precautions (5.10)]
Impairment of Beta-adrenergically Mediated Reflexes During Surgery [see Warnings and Precautions (5.11)]
6.2 Postmarketing Experience
Additions and/revisions underlined:
Bradycardia, eyelid erythema extending to the cheek or forehead, hypersensitivity, iritis, keratoconjunctivitis sicca, miosis, nausea, skin reactions (including erythema, rash, and vasodilation), syncope, and tachycardia.
…

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion:

Risk Summary

There are no adequate and well-controlled studies with COMBIGAN in pregnant women.

Limited available data from postmarketing safety reports and published literature reviews with COMBIGAN use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes (see Data).

In animal studies, brimonidine crossed the placenta and entered into the fetal circulation to a limited extent. Oral administration of brimonidine tartrate or timolol maleate to pregnant rats and rabbits during organogenesis at dose exposures 580 and 37 times the recommended human ophthalmic dose (RHOD) resulted in no adverse developmental effects (see Data).

Oral administration of timolol maleate to mice, rats, and rabbits during organogenesis at dose exposures up to 4,200 times the RHOD resulted in no evidence of fetal malformations (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Human Data

Limited available data from postmarketing safety reports and published literature with topical use of brimonidine ophthalmic solution in pregnant women are insufficient to inform a drug-associated risk of pregnancy-related adverse outcomes including miscarriage, stillbirth, congenital anomaly, and events experienced by the breastfed infant.

Animal Data

Embryofetal development studies were conducted with oral administration of brimonidine tartrate during organogenesis in rats (gestation days 6 to 15) and rabbits (gestation days 6 to 18). No adverse developmental effects were observed in rats up to 2.5 mg/kg/day and rabbits up to 5 mg/kg/day. These doses represent exposures 580 and 37 times higher, respectively, than the recommended human ophthalmic dose (RHOD) of COMBIGAN at 1 drop in both eyes twice daily.

Orally administered brimonidine crossed the placenta in pregnant rats and entered the fetal circulation to a limited extent.

Embryofetal development studies conducted with timolol during organogenesis in mice, rats, and rabbits at oral doses up to 50 mg/kg/day [4,200 times the maximum recommended human ophthalmic dose of 0.012 mg/kg/day on a mg/kg basis (MRHOD)] demonstrated no evidence of fetal malformations. Although delayed fetal ossification was observed at this dose in rats, there were no adverse effects on postnatal development of offspring. Doses of 1,000 mg/kg/day (83,000 times the MRHOD) were maternotoxic in mice and resulted in an increased number of fetal resorptions. Increased fetal resorptions were also seen in rabbits at doses 8,300 times the MRHOD without apparent maternotoxicity.

8.2 Lactation

PLLR conversion:

Risk Summary

Timolol has been detected in human milk following oral and ophthalmic drug administration.

It is not known whether brimonidine tartrate is excreted in human milk. In animal studies, brimonidine tartrate has been shown to be excreted in breast milk.

Because of the potential for serious adverse reactions in the breastfed infant, including central nervous system depression and apnea, COMBIGAN is not recommended for use during lactation.

Data

Animal Data

After a single oral dose of 14C-labeled brimonidine tartrate to lactating rats, brimonidine tartrate and trace metabolites were detected in milk after 30 minutes. There was 30% higher milk concentration compared to maternal plasma concentration 30 minutes after dosing and a 10-fold higher milk concentration compared to maternal plasma concentration 8 hours after dosing. No radiolabeled brimonidine tartrate or metabolites were detectable in milk 24 hours after dosing.

8.4 Pediatric Use

Additions and/or revisions underlined:

…

The safety and effectiveness of COMBIGAN for the reduction of elevated intraocular pressure (IOP) in patients with glaucoma or ocular hypertension who require adjunctive or replacement therapy due to inadequately controlled IOP have been established in pediatric patients aged 2 years and older. Use of COMBIGAN for this indication is supported by evidence from adequate and well-controlled studies of COMBIGAN in adults with additional data from a study of the concomitant use of brimonidine tartrate ophthalmic solution 0.2% and timolol maleate ophthalmic solution in pediatric glaucoma patients (ages 2 to 7 years).

…