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.

FRAGMIN (NDA-020287)

(DALTEPARIN SODIUM)

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

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10/24/2024 (SUPPL-81)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Metabolism and nutrition disorders: Hyperkalemia

10/15/2024 (SUPPL-80)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Newly added subsection:

. . .

Neonatal Patients

No controlled clinical trials have been conducted with FRAGMIN in neonatal patients with VTE; however, data are available from a non-interventional retrospective medical chart review study of 16 neonates with VTE in the UK who were admitted to hospital between January 2010 and December 2021 and were treated with FRAGMIN. The mean (plus or minus SD) duration of dalteparin treatment was 62 plus or minus 30 days. For these 16 neonatal patients, the mean (plus or minus SD) daily dose of dalteparin at initiation was 365 plus or minus 196 units/kg (median:309 units/kg). The mean (plus or minus SD) daily dose of dalteparin including dose at initiation and dose changes was 575 plus or minus 320 units/kg (median: 450 units/kg). After the initial dose, all patients required one or more dose changes; 15 of 16 patients required dose increases due to anti- Xa level being initially below the target range of 0.5 units/mL to 1 units/mL.

The safety profile in neonates was similar to other pediatric patients.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of FRAGMIN for the treatment of symptomatic venous thromboembolism (VTE) in patients have been established in pediatric patients from birth (gestational age at least 35 weeks) to less than 17 years of age.

Use of FRAGMIN for this indication is supported by evidence from well-controlled studies in adults with additional pharmacokinetic, pharmacodynamic, efficacy, and safety data from two separate prospective studies in pediatric patients aged 1 month and older with symptomatic VTE, and a retrospective study in neonatal patients aged birth (gestational age at least 35 weeks) to 1 month with VTE [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.5]. The frequency, type and severity of adverse reactions observed were generally consistent with those observed in adults.

. . .

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise the patient to read the FDA-approved patient labeling (Patient Information). Risk of Hemorrhage including Spinal/Epidural Hematomas

. . .

06/26/2020 (SUPPL-74)

Approved Drug Label (PDF)

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

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Risk of Hemorrhage including Spinal/Epidural Hematomas

If patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking concomitant NSAIDs, platelet inhibitors, or other anticoagulants, inform the patients to watch for signs and symptoms of spinal or epidural hematoma, such as tingling, numbness (especially in the lower limbs) and muscular weakness. If any of these symptoms occur the patient should contact his or her physician immediately.

Additionally, the use of aspirin and other NSAIDs may enhance the risk of hemorrhage. Discontinue their use prior to FRAGMIN therapy whenever possible; if co-administration is essential, the patient’s clinical and laboratory status should be closely monitored [see Drug Interactions (7)].

Inform Patients:

of the instructions for injecting FRAGMIN if their therapy is to continue after discharge from the hospitals.
it may take them longer than usual to stop bleeding.
they may bruise and/or bleed more easily when they are treated with FRAGMIN.
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 [see Warnings and Precautions (5.1, 5.2)].
to tell their physicians and dentists they are taking FRAGMIN and/or any other product known to affect bleeding before any surgery is scheduled and before any new drug is taken [see Warnings and Precautions (5.1)].
to tell their physicians and dentists of all medications they are taking, including those obtained without a prescription, such as aspirin or other NSAIDs [see Drug Interactions (7)].
Risks are associated with benzyl alcohol in neonates, infants, and pregnant women [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)].
to tell their physicians and care givers if they are allergic to natural rubber latex [see Dosage and Administration (2.7)].

05/16/2019 (SUPPL-72)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Thrombocytopenia

Newly added information to the end of the subsection:

In the clinical trial of pediatric patients with or without cancer with acute symptomatic VTE treated for up to 3 months with FRAGMIN, platelet counts of <100,000/mm3 occurred in 37% of patients, including 21% who also had platelet counts less than 50,000/mm3. In the same clinical trial, thrombocytopenia was reported as an adverse reaction in 21% of patients. FRAGMIN dose was interrupted in patients whose platelet counts fell below 50,000/mm3.

5.4 Laboratory Tests

Additions and/or revisions underlined:

… unsuitable for monitoring the anticoagulant effect of FRAGMIN. Monitor anti-Xa level periodically in pediatric patients. Anti-Xa may be used to monitor …

6 Adverse Reactions

Clinically Significant replaces serious in the first sentence.

6.1 Clinical Trials Experience

Additions and/or revisions underlined (specific changes bolded):

Adult Patients with Cancer and Acute Symptomatic VTE

Table 11 summarizes the number of patients with bleeding reactions that occurred in the clinical trial of adult patients with cancer and acute symptomatic VTE.

Newly added information:

Pediatric Patients with Symptomatic VTE

The data below reflect exposure to FRAGMIN from two studies in pediatric patients from newborn to less than 18 years of age with or without cancer and symptomatic VTE (n = 50). Patients were started on FRAGMIN using age and weight-based dosing via subcutaneous injection twice daily. Anti-Xa levels were measured prior to the 4th dose and then periodically to determine whether dose adjustments were required, using 25 IU/kg increments, to achieve a target anti-Xa level of 0.5 – 1.0 IU/ml. The median time on treatment with FRAGMIN was 86 days (range 2 to 170 days).

In pediatric patients with symptomatic VTE, the most common (greater than 10%) adverse reactions were injection site bruising (30%), contusion (12%), and epistaxis (10%).

Major bleeding was defined as any fatal bleeding, clinically overt bleeding with a decrease in hemoglobin of ?2gm/dl in 24 hours, overt bleeding deemed by the attending physician to be unrelated to the subject’s underlying condition and accompanied by blood product administration, overt bleeding that was retroperitoneal, intracranial, intraspinal, intraocular, or intraarticular, or overt bleeding deemed by the attending physician to necessitate permanent discontinuation of trial medication. Major bleeding (intestinal hematoma) occurred in one patient (2%). Discontinuation due to adverse reactions occurred in 12% of patients, most often due to thrombocytopenia (4%).

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Musculoskeletal System: Osteoporosis

Skin or subcutaneous tissues disorders: Skin necrosis, cases of alopecia reported …

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of FRAGMIN for the treatment of symptomatic venous thromboembolism (VTE) in patients have been established in pediatric patients aged 1 month and older.

Newly added to the end of the subsection:

The long-term effects of treatment with FRAGMIN in pediatric patients, including effects on growth and bone metabolism, are unknown.

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

PATIENT COUNSELING INFORMATION

Newly added to the end of the subsection:

This product’s label may have been updated. For full prescribing information, please visit www.pfizer.com.

05/12/2017 (SUPPL-69)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Risk of Serious Adverse Reactions in Neonates and Infants due to Benzyl Alcohol Preservative

(Subsection title has been revised)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

Hemorrhage

The most commonly reported adverse reactions are hematoma at the injection site and hemorrhagic complications.

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

Risk Summary

Available data from published literature and postmarketing reports have not reported a clear association with dalteparin and adverse developmental outcomes. There are risks to the mother associated with untreated venous thromboembolism (VTE) in pregnancy, and a potential for adverse effects on the preterm infant when dalteparin is used in pregnancy. In animal reproduction studies, there was no evidence of embryo-fetal toxicity or teratogenicity when dalteparin sodium was administered to pregnant rats and rabbits during organogenesis at doses 2 to 4 times (rats) and 4 times (rabbits) the human dose of 100 IU/kg dalteparin based on the body surface area…

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

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Published data describe that women with a previous history of VTE in pregnancy are at higher risk for recurrence during subsequent pregnancies compared to those with no risk factor for VTE (4.5% versus 2.7% respectively, relative risk 1.7, 95% CI: 1.0-2.8).

…

Data

Animal Data

In reproductive and developmental toxicity studies, pregnant rats and rabbits received dalteparin sodium during organogenesis at intravenous doses up to 2,400 IU/kg (14,160 IU/m2) (rats) and 4,800 IU/kg (40,800 IU/m2) (rabbits). These exposures were 2 to 4 times (rats) and 4 times (rabbits) the human dose of 100 IU/kg dalteparin based on the body surface area. These studies revealed no evidence of teratogenicity or embryo-fetal toxicity.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

Risk Summary

Limited published data indicate that dalteparin is present in human milk in small amounts . No adverse effects on the breastfed infant have been reported. There are no data on the effects of the drug on milk production. Oral absorption of dalteparin is expected to be low, but the clinical implications, if any, of this small amount of anticoagulant activity on a breastfed infant are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for FRAGMIN and any potential adverse effects on the breastfed child from FRAGMIN or from the underlying maternal condition.

Data

A study evaluated samples of maternal blood and breast milk in 15 lactating women receiving prophylactic doses of dalteparin in the immediate postpartum period (days 4-8 after Cesarean-section). The samples were collected before and 3-4 hours after daily injections of 2500 IU dalteparin. Small amounts of anti-Xa activity (range<0.005 to 0.037 IU/mL) in breast milk were detected in 11 of the 15 women. Because this study evaluated colostrum or transitional milk at a single timepoint during the 24-hour dosing interval, the clinical relevance of this data is unclear in regards to passage of drug into mature milk and the quantification of drug exposure to the infant over the full dosing interval.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Inform Patients:

Risks are associated with benzyl alcohol in neonates, infants, and pregnant women

08/04/2016 (SUPPL-67)

Approved Drug Label (PDF)

5 Warnings and Precautions

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

Use preservative-free FRAGMIN in neonates and infants.

Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low-birth weight infants treated with medications that contain the preservative benzyl alcohol. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. When prescribing FRAGMIN in infants, consider the combined daily metabolic load of benzyl alcohol from all sources including FRAGMIN multiple-dose vial contains 14 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known. Because benzyl alcohol may cross the placenta, use caution when administering FRAGMIN preserved with benzyl alcohol to pregnant women. If anticoagulation with FRAGMIN is needed during pregnancy, use preservative-free formulations; where possible.

8 Use in Specific Populations

Pediatric Use

Use preservative-free FRAGMIN 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 preserved medications. 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 FRAGMIN multiple-dose vials in infants consider the combined daily metabolic load of benzyl alcohol from all sources including FRAGMIN multiple-dose vials (FRAGMIN contains 14 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known.

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

PCI - Risk of Hemorrhage including Spinal/Epidural Hematoma (new subheading above first paragraph)