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 PRESERVATIVE FREE (NDA-201370)

(HEPARIN SODIUM)

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

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09/24/2025 (SUPPL-22)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Unresponsiveness to Heparin with Concomitant Use with Andexanet Alfa

Newly added subsection:

Unresponsiveness to unfractionated heparin leading to non-prolongation of activated clotting times and serious thrombotic events has occurred when unfractionated heparin was administered after use of andexanet alfa for the reversal of direct Factor Xa inhibitors (apixaban and rivaroxaban). Avoid use of heparin after use of andexanet alfa. Use an alternative anticoagulant to heparin [see Drug Interactions (7.3)].

7 Drug Interactions

7.3 Unresponsiveness to Heparin with Concomitant Use with Andexanet Alfa

Newly added subsection:

Andexanet binds to heparin-bound antithrombin III (ATIII) and may reduce the anticoagulant effect of heparin. Unresponsiveness to unfractionated heparin may lead to serious and life-threatening thrombotic events. Use of andexanet alfa as an antidote for heparin has not been established. Avoid use of heparin after use of andexanet alfa for the reversal of direct Factor Xa inhibitors (apixaban and rivaroxaban). If anticoagulation is needed, use an alternative anticoagulant to heparin [see Warnings and Precautions (5.5)].

10/24/2024 (SUPPL-21)

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.

…

09/19/2019 (SUPPL-13)

Approved Drug Label (PDF)

4 Contraindications

(additions underlined)

…

History of thrombocytopenia with pentosan polysulfate

…

An uncontrollable bleeding state

5 Warnings and Precautions

5.3 Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis

(additions underlined)

Heparin-induced thrombocytopenia (HIT) is a serious antibody-mediated reaction resulting from irreversible aggregation of platelets. HIT occurs in patients treated with heparin and is due to the development of antibodies to a platelet Factor 4-heparin complex that induce in vivo platelet aggregation.

…

5.6 Coagulation Testing and Monitoring

(additions 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. Periodically monitor platelet counts, hematocrit, and occult blood in stool during the entire course of heparin therapy, regardless of the route of administration.

09/19/2019 (SUPPL-14)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary

There are no available data on heparin sodium use in pregnant women to infor a drug associated risk of major birth defects and miscarriage. In published reports, heparin exposure during pregnancy did not show evidence of an increased risk of adverse maternal or fetal outcomes in humans. No teratogenicity, but early embryo-fetal death was observed in animal reproductive studies with administration of heparin sodium to pregnant rats and rabbits during organogenesis at doses approximately 10 times the maximum recommended human dose (MRHD) of 40,000 USP units/24 hours infusion (see Data). Consider the benefits and risks of HEPARIN SODIUM INJECTION to a pregnant woman and possible risks to the fetus when prescribing HEPARIN SODIUM INJECTION to a pregnant woman.

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 .

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a 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

The maternal and fetal outcomes associated with uses of heparin via various dosing methods and administration routes during pregnancy have been investigated in numerous studies. These studies generally reported normal deliveries with no maternal or fetal bleeding and no other complications.

Animal Data

In a published study conducted in rats and rabbits, pregnant animals received heparin intravenously during organogenesis at a dose of 10,000 units/kg/day, approximately 10 times the maximum human daily dose based on body weight. The number of early resorptions increased in both species. There was no evidence of teratogenic effects.

8.2 Lactation

(PLLR conversion)

Risk Summary

There is no information regarding the presence of heparin in human milk, the effects on the breastfed child, 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 child. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HEPARIN SODIUM INJECTION and any potential adverse effects on the breastfed child from HEPARIN SODIUM INJECTION or from the underlying maternal condition. Benzyl alcohol present in maternal serum is likely to cross into human milk and may be orally absorbed by a nursing infant.

08/09/2016 (SUPPL-10)

Approved Drug Label (PDF)

5 Warnings and Precautions

Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative (renamed)

Use preservative-free HEPARIN SODIUM INJECTION in neonates and infants.

Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low-birth weight infants treated with benzyl alcohol-preserved formulation in infusion solutions, including HEPARIN SODIUM INJECTION. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations.

When prescribing HEPARIN SODIUM INJECTION in infants consider the combined daily metabolic load of benzyl alcohol from all sources including HEPARIN SODIUM INJECTION (HEPARIN SODIUM INJECTION contains 9.45 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which toxicity may occur is not known.

6 Adverse Reactions

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

Hemorrhage
Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis
Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative
Thrombocytopenia
Heparin Resistance
Hypersensitivity

7 Drug Interactions

Oral Anticoagulants

Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at least 5 hours after the last intravenous dose or 24 hours after the last subcutaneous dose should elapse before blood is drawn if a valid prothrombin time is to be obtained.

Other Interactions

Digitalis, tetracyclines, nicotine, or antihistamines, or intravenous (IV) nitroglycerin may partially counteract the anticoagulant action of heparin sodium.

Antithrombin III (human) – The anticoagulant effect of heparin is enhanced by concurrent treatment with antithrombin III (human) in patients with hereditary antithrombin III deficiency. To reduce the risk of bleeding, a reduced dosage of heparin is recommended during treatment with ntithrombin III (human).

Platelet Inhibitors

Drugs such as NSAIDs(including salicylic acid, ibuprofen, indomethacin, and celecoxib), dextran, phenylbutazone, thienopyridines, dipyridamole, hydroxychloroquine, glycoprotein IIb/IIIa antagonists (including abciximab, eptifibatide, and tirofiban), and others that interfere with platelet-aggregation reactions (the main hemostatic defense of heparinized patients) may induce bleeding and should be used with caution in patients receiving heparin sodium.

8 Use in Specific Populations

Pediatric Use (updated)

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 low-birth weight infants in the neonatal intensive care unit who received benzyl alcohol as a preservative in infusion solutions. 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.

When prescribing HEPARIN SODIUM INJECTION in infants consider the combined daily metabolic load of benzyl alcohol from all sources including HEPARIN SODIUM INJECTION (HEPARIN SODIUM INJECTION contains 9.45 mg of benzyl alcohol) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known