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.

HEPARIN SODIUM (NDA-017651)

(HEPARIN SODIUM)

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

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10/24/2024 (SUPPL-78)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.9 Hyperkalemia

Newly added subsection:

Heparin can suppress adrenal secretion of aldosterone leading to hyperkalemia, particularly in patients with diabetes mellitus, chronic renal failure, pre- existing metabolic acidosis, a raised plasma potassium, or taking potassium sparing drugs. The risk of hyperkalemia appears to increase with duration of therapy but is usually reversible upon discontinuation of heparin.

Measure blood potassium in patients at risk of hyperkalemia before starting heparin therapy and periodically in all patients treated for more than 5 days or earlier as deemed fit by the clinician.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Hyperkalemia [see Warnings and Precautions (5.9)]

6.1 Postmarketing Experience

Additions and/or revisions underlined:

…

Metabolism and Nutrition Disorders – Hyperkalemia.

07/02/2020 (SUPPL-66)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Fatal Medication Errors

Additions and/or revisions underlined:

Do not use Heparin Sodium Injection as a “catheter lock flush” product. Heparin Sodium Injection is supplied in vials containing various strengths of heparin, including vials that contain a highly concentrated solution of 10,000 units in 1 mL …

Newly added subsection:

5.4 Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative

Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including Heparin Sodium Injection multiple-dose vials. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations.

When prescribing Heparin Sodium Injection multiple-dose vials in infants consider the combined daily metabolic load of benzyl alcohol from all sources including Heparin Sodium Injection multiple-dose vials and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which toxicity may occur is not known [see Use in Specific Populations (8.4)].

5.6 Coagulation Testing and Monitoring

Additions and/or revisions underlined:

When using a full dose heparin regimen, adjust the heparin dose based on frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, discontinue heparin promptly [see Overdosage (10)]. Periodically monitor platelet counts, hematocrit, and occult blood in stool during the entire course of heparin therapy, regardless of the route of administration [see Dosage and Administration (2.2)].

6 Adverse Reactions

Newly added to bulleted line listing:

Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative [see Warnings and Precautions (5.4)]

8 Use in Specific Populations

8.1 Pregnancy

Revised to adhere to PLLR; additions and/or revisions underlined:

… If available, preservative-free Heparin Sodium Injection is recommended when heparin therapy is needed during pregnancy. There are no known adverse outcomes associated with fetal exposure to the preservative benzyl alcohol through maternal drug administration; however, the preservative benzyl alcohol can cause serious adverse events and death when administered intravenously to neonates and infants [see Use in Specific Populations (8.4)].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown …

8.2 Lactation

Revised to adhere to PLLR; additions and/or revisions underlined:

Risk Summary

If available, preservative-free Heparin Sodium Injection is recommended when heparin therapy is needed during lactation. Benzyl alcohol present in maternal serum is likely to cross into human milk and may be orally absorbed by a breastfed infant. There is no information regarding the presence of Heparin Sodium Injection in human milk, the effects on the breastfed infant, or the effects on milk production. Due to its large molecular weight, heparin is not likely to be excreted in human milk, and any heparin in milk would not be orally absorbed by a breastfed infant …

8.4 Pediatric Use

Additions and/or revisions underlined:

There are no adequate and well controlled studies on heparin use in pediatric patients. Pediatric dosing recommendations are based on clinical experience [see Dosage and Administration (2.4)].

Carefully examine all Heparin Sodium Injection vials to confirm choice of the correct strength prior to administration of the drug. Pediatric patients, including neonates, have died as a result of medication errors in which Heparin Sodium Injection vials have been confused with “catheter lock flush” vials [see Warnings and Precautions (5.1)].

Benzyl Alcohol Toxicity

Use preservative-free Heparin Sodium Injection in neonates and infants.

Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.

Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol.