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.

LOPRESSOR HCT (NDA-018303)

(HYDROCHLOROTHIAZIDE; METOPROLOL TARTRATE)

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

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12/22/2023 (SUPPL-42)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Masked Symptoms of Hypoglycemia

Newly added information:

Beta-blockers may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at anytime during treatment, especially in patients with diabetes mellitus or children and patients who are fasting (i.e., surgery, not eating regularly, or are vomiting). If severe hypoglycemia occurs, patients should be instructed to seek emergency treatment.

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

PATIENT COUNSELING INFORMATION

Newly added information:

Inform patients or caregivers that there is a risk of hypoglycemia when Lopressor HCT is given to patients who are fasting or who are vomiting. Instruct patients or caregivers how to monitor for signs of hypoglycemia [see Warnings and Precautions (5.6)].

05/03/2022 (SUPPL-40)

Approved Drug Label (PDF)

4 Contraindications

Subsection revised to be consistent with the current thinking regarding metoprolol labeling; additions and/or revisions underlined

LOPRESSOR HCT is contraindicated in patients with:

Cardiogenic shock or decompensated heart failure.
Sinus bradycardia, sick sinus syndrome, and greater than first-degree block unless a permanent pacemaker is in place.
Anuria
Hypersensitivity to metoprolol tartrate or hydrochlorothiazide or to other sulfonamide- derived drugs.

5 Warnings and Precautions

The following subsections created to be consistent with the current thinking regarding metoprolol labeling; please refer to label for complete information.

5.1 Abrupt Cessation of Therapy

5.2 Heart Failure

5.3 Bronchospastic Disease

5.4 Bradycardia

5.5 Major Surgery

5.6 Masked Symptoms of Hypoglycemia

5.7 Electrolyte and Metabolic Effects

5.8 Renal Impairment

5.9 Peripheral Vascular Disease

5.10 Pheochromocytoma

5.11 Thyrotoxicosis

5.12 Anaphylactic Reaction

5.13 Acute Myopia and Second Angle-Closure Glaucoma

5.14 Exacerbation of Systemic Lupus Erythematosus

6 Adverse Reactions

Additions underlined

The following adverse reactions are described in more detail elsewhere in the label;

Worsening angina or myocardial infarction [see Warnings and Precautions (5)]
Worsening heart failure [see Warnings and Precautions (5)]
Worsening AV block [see Contraindications (4)]
6.2 Postmarketing Experience
Subsection revised; please refer to label for complete information.

7 Drug Interactions

The following subsections created; please refer to label for complete information.

7.1Drug Interactions with Metoprolol

7.2 Drug Interactions with Hydrochlorothiazide

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; please refer to label for complete information.

8.2 Lactation

PLLR conversion

Risk Summary

There are no data on the presence of LOPRESSOR HCT in human milk, the effects on the breastfed infant, or the effects on milk production. However, data are available on the individual components of LOPRESSOR HCT. Available data from published literature on metoprolol and hydrochlorothiazide report that each drug is present in human milk (see Data). There are no reports of adverse effects on breastfed infants exposed to metoprolol or hydrochlorothiazide during lactation. Doses of hydrochlorothiazide associated with clinically significant diuresis have been associated with impaired milk production. There is no information regarding the effects of metoprolol on milk production. Monitor infants exposed to LOPRESSOR HCT though breastmilk for drowsiness or poor feeding (see Clinical Considerations).

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LOPRESSOR HCT and any potential adverse effects on the breastfed child from LOPRESSOR HCT or from the underlying maternal condition.

Clinical Considerations

Monitor the breastfed infant for bradycardia or somnolence. Data

Metoprolol

Based on published case reports, the estimated daily infant dose of metoprolol received from breastmilk ranged from 0.05 mg to less than 1 mg. The estimated relative infant dosage was 0.5% to 2% of the mother’s weight-adjusted dosage.

In two women who were taking unspecified amount of metoprolol, milk samples were taken after one dose of metoprolol. The estimated amount of metoprolol and alpha-hydroxymetoprolol in breast milk is reported to be less than 2% of the mother's weight-adjusted dosage.

In a small study, breast milk was collected every 2 to 3 hours over one dosage interval, in three mothers (at least 3 months postpartum) who took metoprolol of unspecified amount. The average amount of metoprolol present in breast milk was 71.5 mcg/day (range 17.0 to 158.7). The average relative infant dosage was 0.5% of the mother's weight-adjusted dosage.

Hydrochlorothiazide

A single study involving one woman and her infant showed a peak concentration of 275 mcg/L at 3 hours following 50 mg dose. No drug was detected (< 20 mcg/L) in the infant’s plasma at 2 and 11 hours following mother’s dose.

8.3 Females and Males of Reproductive Potential

PLLR conversion

Infertility

Males

Based on the published literature, beta blockers (including metoprolol) may cause erectile dysfunction and inhibit sperm motility. No evidence of impaired fertility due to metoprolol or hydrochlorothiazide was observed in rats [see Nonclinical Toxicology (13.1)].

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

PATIENT COUNSELING INFORMATION

New section added

Advise patients to take Lopressor HCT as directed, with or immediately following meals. If a dose is missed, advise the patient to take only the next scheduled dose (without doubling it). Advise patients to not discontinue Lopressor HCT without consulting their healthcare provider.

Other

PLR conversion

08/20/2020 (SUPPL-41)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

Newly added information:

Patient Information

Non-melanoma Skin Cancer: Instruct patients taking hydrochlorothiazide to protect skin from the sun and undergo regular skin cancer screening.

6 Adverse Reactions

Postmarketing Experience

Newly added information:

Non-melanoma Skin Cancer: Hydrochlorothiazide is associated with an increased risk of non- melanoma skin cancer. In a study conducted in the Sentinel System, increased risk was predominantly for squamous cell carcinoma (SCC) and in white patients taking large cumulative doses. The increased risk for SCC in the overall population was approximately 1 additional case per 16,000 patients per year, and for white patients taking a cumulative dose of greater than or equal to 50,000mg the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.

To report SUSPECTED ADVERSE REACTIONS, contact Validus Pharmaceuticals LLC at 1-866-982-5438 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.