Drug Safety-related Labeling Changes (SrLC)

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PRADAXA (NDA-022512)

(DABIGATRAN ETEXILATE MESYLATE)

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

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04/20/2021 (SUPPL-42)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

(Newly Added Subsection)

Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.

The risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants including Pradaxa should be assessed in females of reproductive potential and those with abnormal uterine bleeding.

07/01/2020 (SUPPL-39)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reactions have been identified during post approval use of PRADAXA: angioedema, thrombocytopenia, esophageal ulcer, alopecia, neutropenia, agranulocytosis.

11/22/2019 (SUPPL-38)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome

(Newly added section)

Direct-acting oral anticoagulants (DOACs), including PRADAXA, are not recommended for use in patients with triple-positive antiphospholipid syndrome (APS). For patients with APS (especially those who are triple-positive [positive for lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

6 Adverse Reactions

(Additions and/or revisions underlined)

The following clinically significant adverse reactions are described elsewhere in the labeling:

  • Increased Risk of Thrombotic Events after Premature Discontinuation

  • Risk of Bleeding

  • Spinal/Epidural Anesthesia or Puncture

  • Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves

  • Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome

6.2  Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during post approval use of PRADAXA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during post approval use of PRADAXA: angioedema, thrombocytopenia, esophageal ulcer, alopecia.

03/13/2018 (SUPPL-35)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; newly added information:

Risk Summary

The limited available data on PRADAXA use in pregnant women are insufficient to determine drug-associated risks for adverse developmental outcomes. There are risks to the mother associated with untreated venous thromboembolism in pregnancy and a risk of hemorrhage in the mother and fetus associated with the use of anticoagulants. In pregnant rats treated from implantation until weaning, dabigatran increased the number of dead offspring and caused excess vaginal/uterine bleeding close to parturition at an exposure 2.6 times the human exposure. At a similar exposure, dabigatran decreased the number of implantations when rats were treated prior to mating and up to implantation (gestation Day 6). Dabigatran administered to pregnant rats and rabbits during organogenesis up to exposures 8 and 13 times the human exposure, respectively, did not induce major malformations. However, the incidence of delayed or irregular ossification of fetal skull bones and vertebrae was increased in the rat.

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

Pregnancy confers an increased risk for thromboembolism that is higher for women with underlying thromboembolic disease and certain high-risk pregnancy conditions. Published data describe that women with a previous history of venous thrombosis are at high risk for recurrence during pregnancy.

Fetal/Neonatal adverse reaction

Use of anticoagulants, including PRADAXA, may increase the risk of bleeding in the fetus and neonate. Monitor neonates for bleeding.

Labor or delivery

All patients receiving anticoagulants, including pregnant women, are at risk for bleeding. PRADAXA use during labor or delivery in women who are receiving neuraxial anesthesia may result in epidural or spinal hematomas. Consider discontinuation or use of shorter acting anticoagulant as delivery approaches.

Data

Animal Data

Dabigatran has been shown to decrease the number of implantations when male and female rats were treated at a dosage of 70 mg/kg (about 2.6 to 3.0 times the human exposure at MRHD of 300 mg/day based on area under the curve [AUC] comparisons) prior to mating and up to implantation (gestation Day 6). Treatment of pregnant rats after implantation with dabigatran at the same dose increased the number of dead offspring and caused excess vaginal/uterine bleeding close to parturition.

Dabigatran administered to pregnant rats and rabbits during organogenesis up to maternally toxic doses of 200 mg/kg (8 and 13 times the human exposure, respectively,

at a MRHD of 300 mg/day based on AUC comparisons) did not induce major malformations, but increased the incidence of delayed or irregular ossification of fetal skull bones and vertebrae in the rat.

Death of offspring and mother rats … (about 2.6 times the human exposure at MRHD of 300 mg/day based on AUC comparisons).

8.2 Lactation

PLLR conversion; newly added information

Risk Summary

There are no data on the presence of dabigatran in human milk, the effects on the breastfed child, or on milk production. Dabigatran and/or its metabolites were present in rat milk. Breastfeeding is not recommended during treatment with PRADAXA.

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

MEDICATION GUIDE

What should I tell my doctor before taking PRADAXA?

Before you take PRADAXA, tell your doctor if you:

Additions and/or revisions underlined:

  • are pregnant or plan to become pregnant. It is not known if PRADAXA will harm your unborn baby. Tell your doctor right away if you become pregnant during treatment with PRADAXA.

  • are breastfeeding or plan to breastfeed. It is not known if PRADAXA passes into your breast milk. You and your doctor should decide if you will take PRADAXA or breastfeed.

PATIENT COUNSELING INFORMATION

Newly added subsections:

17.7 Pregnancy

Advise patients to inform their healthcare provider immediately if they become pregnant or intend to become pregnant during treatment with PRADAXA.

17.8 Lactation

Advise patients not to breastfeed if they are taking PRADAXA.

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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