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.

LOVENOX (NDA-020164)

(ENOXAPARIN SODIUM)

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

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12/11/2018 (SUPPL-116)

Approved Drug Label (PDF)

4 Contraindications

Addition of the phrase ‘Lovenox is contraindicated in patients with’

5 Warnings and Precautions

Additions and/or revisions underlined:

5.2 Increased Risk of Bleeding following Percutaneous Coronary Revascularization Procedures

5.3 Increased Risk of Bleeding in Patients with Concomitant Medical Conditions

5.4 Risk of Heparin-Induced Thrombocytopenia with or Without Thrombosis

Lovenox may cause Heparin-Induced Thrombocytopenia (HIT) or Heparin-Induced Thrombocytopenia with Thrombosis (HITTS). HITTS may lead to organ infarction, limb ischemia, or death. Monitor thrombocytopenia of any degree closely …

5.7 Increased Risk of Thrombosis in Pregnant Women with Mechanical Prosthetic Heart Valves

Use of Lovenox for thromboprophylaxis in pregnant women with mechanical prosthetic heart valves may result in valve thrombosis …

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; additions and/or revisions underlined:

Placental transfer of enoxaparin was observed in the animal studies. Human data from … to increase the risk of major developmental abnormalities. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

8.2 Lactation

PLLR conversion; additions and/or revisions underlined:

Risk Summary

It is unknown whether Lovenox is excreted in human milk. In lactating rats, the passage of enoxaparin or its metabolites in the milk is very limited. There is no information available on the effect of enoxaparin or its metabolites on the breastfed child, or on the milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Lovenox and any potential adverse effects on the breastfed child from Lovenox or from the underlying maternal condition.

Other

Lovenox replaces enoxaparin sodium throughout.

10/26/2017 (SUPPL-110)

Approved Drug Label (PDF)

4 Contraindications

(additions underlined)

Active major bleeding
History of immune-mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or in the presence of circulating antibodies
Known hypersensitivity to enoxaparin sodium (e.g., pruritus, urticaria, anaphylactic/anaphylactoid reactions)
Known hypersensitivity to heparin or pork products
Known hypersensitivity to benzyl alcohol (which is in only the multidose formulation of Lovenox)

5 Warnings and Precautions

5.4 History of Heparin-Induced Thrombocytopenia

(additions underlined)

Use of Lovenox in patients with a history of immune-mediated HIT within the past 100 days or in the presence of circulating antibodies is contraindicated.

Circulating antibodies may persist for several years.

In patients with a history of HIT, Lovenox should only be used if more than 100 days have elapsed since the prior HIT episode and no circulating antibodies are present. Because HIT may still occur in these circumstances, the decision to use Lovenox in such a case must be made only after a careful benefit-risk assessment and after non-heparin alternative treatments are considered.

5.8Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative

(additions underlined)

Lovenox multiple-dose vials are not approved for use in neonates or infants.

Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs, including Lovenox multiple- dose vials. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (Lovenox multiple-dose vials contain 15mg of benzyl alcohol per mL).

Because benzyl alcohol may cross the placenta, if anticoagulation with Lovenox is needed during pregnancy, use the preservative-free formulations where possible.

6 Adverse Reactions

6.1 Clinical Trials Experirnce

(addition underlined)

…

Adverse Reactions in Lovenox-Treated Patients with Acute ST-Segment Elevation Myocardial Infarction

In a clinical trial in patients with acute ST-segment elevation myocardial infarction, thrombocytopenia occurred at a rate of 1.5%.

8 Use in Specific Populations

8.4 Pediatric Use

(additions underlined)

Safety and effectiveness of Lovenox in pediatric patients have not been established.

Lovenox is not approved for use in neonates or 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 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. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known.

Lovenox multiple-dose vials contain 15 mg/mL of benzyl alcohol (at the dose of 1.5 mg/kg twice a day, benzyl alcohol exposure in patients is 0.45 mg/kg daily).

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

PATIENT COUNSELING INFORMATION

(additions underlined)

If patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking concomitant NSAIDs, platelet inhibitors, or other anticoagulants, advise them to watch for signs and symptoms of spinal or epidural hematoma, such as tingling, numbness (especially in the lower limbs) and muscular weakness. Instruct the patient to seek immediate medical attention if any of these symptoms occur.

Additionally, the use of aspirin and other NSAIDs may enhance the risk of hemorrhage. When possible, discontinue their use prior to Lovenox therapy. Monitor the patient’s clinical and laboratory status if coadministration is essential.

Inform patients:

of the instructions for injecting Lovenox if they continue Lovenox therapy after discharge from the hospital.
that it may take them longer than usual to stop bleeding.
that they may bruise and/or bleed more easily when they use Lovenox.
that they should report any unusual bleeding, bruising, or signs of thrombocytopenia (such as a rash of dark red spots under the skin) to their physician
that risks are associated with the use of benzyl alcohol, a preservative in Lovenox multi- dose vials, in neonates, infants, and pregnant women.
to tell their physicians and dentists they are taking Lovenox and/or any other product known to affect bleeding before any surgery is scheduled and before any new drug is taken.
to tell their physicians and dentists of all medications they are taking, including those obtained without a prescription, such as aspirin or other NSAIDs