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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06/21/2021 (SUPPL-41)

Approved Drug Label (PDF)

4 Contraindications

Additions underlined

    • History of a serious hypersensitivity reaction to dabigatran, dabigatran etexilate, or to one of the excipients of the product (e.g., anaphylactic reaction or anaphylactic shock) [see Adverse Reactions (6.1)]

5 Warnings and Precautions

5.2 Risk of Bleeding

Additions underlined

Reversal of Anticoagulant Effect:

In adults, a specific reversal agent (idarucizumab) for PRADAXA is available when reversal of the anticoagulant effect of dabigatran is needed:

      • For emergency surgery/urgent procedures

      • In life-threatening or uncontrolled bleeding

         

        In pediatric patients, the efficacy and safety of idarucizumab have not been established.

5.4 Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves

Additions underlined

These bleeding and thromboembolic events were seen both in patients who were initiated on PRADAXA Capsules postoperatively within three days of mechanical bileaflet valve implantation, as well as in patients whose valves had been implanted more than three months prior to enrollment. Therefore, the use of PRADAXA is contraindicated in all patients with mechanical prosthetic valves [see Contraindications (4)].

5.5 Effect of P-gp Inducers and Inhibitors on Dabigatran Exposure

Additions underlined

Treatment and reduction in risk of recurrence of VTE in pediatric patients

The concomitant use of PRADAXA Capsules with P-gp-inhibitors has not been studied in pediatric patients but may increase exposure to dabigatran.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions underlined

Pediatric Trials

Treatment of VTE in Pediatric Patients

The safety of PRADAXA in the treatment of VTE in pediatric patients was studied in one phase III trial (DIVERSITY). The DIVERSITY study was a randomized, open-label, active-controlled, parallel-group trial comparing PRADAXA with standard of care – SOC (vitamin K antagonists, low molecular weight heparin, or fondaparinux). There were 266 pediatric patients who received study treatment, 176 patients treated with PRADAXA and 90 patients treated with SOC. Patients on PRADAXA received age- and weight-adjusted doses of an age-appropriate formulation of PRADAXA (capsules, pellets, or oral solution) twice daily.

Patients had a median age of 14 years (range: 0-17 years), 92% were white, and half the patients were male (50%). Following at least 5 days of parenteral anticoagulant therapy, the median duration of treatment with PRADAXA was 85 days (range: 1-105). Patients with estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73m2 were excluded from the trial.

Bleeding

Data on adjudicated major bleeding, clinically relevant non-major (CRNM) bleeding and minor bleeding events, for the PRADAXA group and the SOC group in the DIVERSITY study, are reported in Table 9. There was no statistically significant difference in the time to first major bleeding event.

 

Table 9           Summary of All Adjudicated Bleeding Events During On-Treatment Period in DIVERSITY

Please refer to label to view Table 9

 

Site-specific bleeding rates were comparable between the two arms, with the exception of the rate of any gastrointestinal bleeds (5.7% in PRADAXA arm vs. 1.8% in SOC arm).

 

Gastrointestinal Adverse Reactions

The incidence of gastrointestinal adverse reactions for patients on PRADAXA and SOC was 32% and 12%, respectively, with the following occurring in ?5% of patients taking PRADAXA: dyspepsia (including term gastro-esophageal reflux disease, gastric pH decreased and esophagitis) in 9% (vs. 2%), upper abdominal pain in 5% (vs. 1%), vomiting in 8% (vs. 2%), nausea 5% (vs. 4%), and diarrhea 5% (vs. 1%).

 

Reduction in Risk of Recurrence of VTE in Pediatric Patients

The safety of PRADAXA in the reduction in the risk of recurrence of VTE in pediatric patients was studied in one open-label single-arm trial (Study 2). Study 2 enrolled patients who required further anticoagulation due to the presence of a clinical risk factor after completing the initial treatment for confirmed VTE (for at least

3 months) or after completing the DIVERSITY study and received PRADAXA until the clinical risk factor resolved, or up to a maximum of 12 months. There were 213 pediatric patients treated with PRADAXA, in a similar fashion as in the DIVERSITY trial.

Patients had a median age of 14 years (range: 0–18 years), 91% were white, and 55% of patients were male. Patients previously enrolled on DIVERSITY accounted for 43% of patients enrolled on Study 2 (29% from PRADAXA arm and 14% from SOC arm). The median duration of treatment with PRADAXA in Study 2 was 42 weeks (range: 0 – 56 weeks), with 45% of patients completing the 12-months planned duration, 17% stopping due to resolution of VTE risk factors, 12% stopping due to failure to attain target dabigatran concentration and 6% had an adverse event leading to discontinuation.

During the on-treatment period of Study 2, 3 patients (1.4%) had a major bleeding event, 3 patients (1.4%) had a clinically relevant non-major bleeding event, and 44 patients (20%) had a minor bleeding event. The most common drug-related adverse reactions were dyspepsia (5%), epistaxis (3.3%), nausea (3.3%) and menorrhagia (2.8%).

The adverse reaction profile in pediatric patients was generally consistent with that of adult patients.

7 Drug Interactions

7.4 Treatment and Reduction in Risk of Recurrence of VTE in Pediatric Patients

 

New subsection added

The concomitant use of PRADAXA with P-gp inhibitors has not been studied in pediatric patients but may increase exposure to dabigatran. [see Warnings and Precautions (5.5)].

8 Use in Specific Populations

8.4 Pediatric Use

Subsection revised, additions underline

The safety and effectiveness of PRADAXA Capsules for the treatment and the reduction in risk of recurrence of venous thromboembolism have been established in pediatric patients 8 to less than 18 years of age. Use of PRADAXA for this indication is supported by evidence from adequate and well-controlled studies in pediatric patients. These studies included an open-label, randomized, parallel-group study and an open-label, single-arm safety study [see Adverse Reactions (6.1) and Clinical Studies (14.4, 14.5)]. Other age-appropriate pediatric dosage forms of dabigatran etexilate are available for pediatric patients less than 8 years of age for these indications.

Safety and effectiveness of PRADAXA Capsules have not been established in pediatric patients with non-valvular atrial fibrillation or those who have undergone hip replacement surgery.

8.6 Renal Impairment

Additions underlined

Treatment and Reduction in the Risk of Recurrence of VTE in Pediatric Patients

PRADAXA has not been studied in pediatric patients with eGFR < 50 mL/min/1.73m2. Reduced renal function could increase exposure. Dosing recommendations cannot be provided for treatment of these patients. Avoid use of PRADAXA Capsules in these patients [see Dosage and Administration (2.4)].

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

MEDICATION GUIDE

Extensive additions and revisions, please refer to label for complete information

PATIENT COUNSELING INFORMATION

Additions underlined

Allergic Reactions

Advise adult patients and caregivers that some adults taking PRADAXA have developed symptoms of an allergic reaction. Advise adult patients or caregivers to inform their healthcare provider if they or their child develop symptoms of an allergic reaction, such as hives, rash, or itching. Advise adult patients or caregivers to seek emergency medical attention if they or their child develop chest pain or tightness, swelling of the face or tongue, trouble breathing or wheezing, or feeling dizzy or faint.

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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