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.

BETOPTIC S (NDA-019845)

(BETAXOLOL HYDROCHLORIDE)

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

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06/09/2021 (SUPPL-30)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Systemic Absorption

(Subsection title revised)

5.2 Cardiac Failure

(Additions and/or revisions underlined)

BETOPTIC S has been shown to have a minor effect on heart rate and blood pressure in clinical studies. Caution should be used in treating patients with a history of cardiac failure or heart block. Treatment with BETOPTIC S should be discontinued at the first signs of cardiac failure.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Subsection title revised)

7 Drug Interactions

7.1 Oral Beta-Adrenergic Receptor Inhibitors

(Additions and/or revisions underlined)

Patients who are receiving a beta-adrenergic receptor inhibitor orally and BETOPTIC S should be observed for a potential additive effect either on the IOP or on the known systemic effects of beta blockade.

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary

There are no adequate and well-controlled studies of BETOPTIC S administration in pregnant women to inform a drug- associated risk. There are limited data with the use of betaxolol eye drops in pregnant women. Epidemiological studies have not revealed malformative effects but show a risk for intrauterine growth retardation when beta-blockers are administered by the oral route.

In animal reproductive studies, no drug-induced maternal toxicity or teratogenicity was observed at clinically relevant doses (see Data).

Because animal reproductive studies are not always predictive of human response, BETOPTIC S should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Data

Animal Data

In a rat embryo-fetal development (EFD) study, oral administration of 4, 40, or 400 mg/kg/day betaxolol on gestational days 6 through 18, the period of organogenesis, resulted in marked embryo-fetal lethality, increased incidence of skeletal and visceral abnormalities, and decreased fetal weights at the maternally toxic dose of 400 mg/kg/day (7785 times higher than the maximum recommended human ophthalmic dose [MRHOD] of 0.0083 mg/kg/day, on a mg/m2 basis). The no- observed-adverse-effect-level (NOAEL) for maternal or embryo-fetal toxicity was 40 mg/kg/day (778 times higher than the MRHOD, on a mg/m2 basis). In a rabbit EFD study, oral administration of 1, 4, 12, and 36 mg/kg/day betaxolol on gestational days 6 through 18, the period of organogenesis, resulted in a marked increase in embryo-fetal lethality at 36 mg/kg/day (1400 times higher than the MRHOD, on a mg/m2 basis). No maternal toxicity was reported in this study.

In a perinatal and postnatal development study in rats, oral administration of 4, 32, and 256 mg/kg/day betaxolol during late gestation through lactation resulted in a marked decrease in offspring survival within 4 days postpartum at the highest dose (4982 times higher than the MRHOD, on a mg/m2 basis). In surviving F1 offspring, growth/development and reproductive function were also affected. The NOAEL was 32 mg/kg/day (623 times higher than the MRHOD, on a mg/m2 basis).

In a prenatal and postnatal development study in rats, an oral betaxolol dose of 150 mg/kg/day (2920 times higher than the MRHOD, on mg/m2 basis) administered throughout the entire gestation period and lactation, resulted in maternal and developmental toxicity in F1 offspring, including decreased offspring survival, body weight and growth/development and functional deficits in surviving offspring. No NOAEL for developmental or maternal toxicity was established in this study.

Oral administration of 4, 32, and 256 mg/kg/day betoxolol to rats prior to mating and through late gestation, or until weaning, produced embryo-fetal lethality, neonatal mortality, decreased mean fetal weight, growth/development and functional deficits in surviving offspring at 256 mg/kg/day (4982 times higher than the MRHOD, on a mg/m2 basis). At 32 mg/kg/day (623 higher than the MRHOD, on a mg/m2 basis), decreased mean fetal weight on Gestation Day 20, and pup weight at birth and on Day 4 postpartum were observed. At 4 mg/kg/day (78 times higher than the MRHOD, on a mg/m2 basis), a slight decrease in mean fetal weight was observed on Gestation Day 20.

8.2 Lactation

(PLLR conversion)

Risk Summary

Beta-blockers are excreted in breast milk following oral administration, having the potential to cause serious undesirable effects in the infant of the nursing mother. It is not known whether measurable levels of betaxolol would be present in maternal milk following topical ocular administration.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BETOPTIC S, and any potential adverse effects on the breast-fed child from BETOPTIC S.

02/01/2017 (SUPPL-25)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Vascular Insufficiency

Additions and/or revisions underlined:

Because of potential effects of beta-adrenergic receptor inhibitors on blood pressure and pulse, these inhibitors should be used with caution in patients with vascular insufficiency. If signs or symptoms suggesting reduced cerebral blood flow or Raynaud’s phenomenon develop following initiation of therapy with BETOPTIC S, alternative therapy should be considered.

5.13 Contact Lens Wear

Newly Added Subsection:

The preservative in BETOPTIC S Ophthalmic Suspension 0.25%, benzalkonium chloride, may be absorbed by soft contact lenses. Contact lenses should be removed during instillation of BETOPTIC S Ophthalmic Suspension 0.25% but may be reinserted 15 minutes after instillation.

5.8 Atopy/Anaphylaxis

Additions and/or revisions underlined:

While taking beta-adrenergic receptor inhibitors, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenge with such allergens. Such patients may be unresponsive to the usual doses of epinephrine used to treat anaphylactic reactions.

7 Drug Interactions

7.4 Calcium Antagonists, Antiarrhythmics, and Digitalis

Newly added subsection:

The concomitant use of a beta-adrenergic receptor inhibitor with calcium antagonists, antiarrhythmics (including amiodarone) or digitalis may have additive effects resulting in hypotension and/or marked bradycardia.

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

PATIENT COUNSELING INFORMATION

The following headings and information were added:

Avoiding Contamination of the Product …

Intercurrent Ocular Conditions …

Concomitant Topical Ocular Therapy …

Temporary Blurred Vision …

Vision may be temporarily blurred following dosing with BETOPTIC S Ophthalmic Suspension 0.25%. Care should be exercised in operating machinery or driving a motor vehicle.

Contact Lens Wear

The preservative in BETOPTIC S Ophthalmic Suspension 0.25%, benzalkonium chloride, may be absorbed by soft contact lenses. Remove contact lenses during instillation of BETOPIC S Ophthalmic Suspension 0.25%. Contact lenses may be reinserted 15 minutes after instillation.