Drug Safety-related Labeling Changes (SrLC)
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Guide
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.
PRADAXA (NDA-022512)
(DABIGATRAN ETEXILATE MESYLATE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
11/17/2023 (SUPPL-47)
06/21/2021 (SUPPL-41)
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 BleedingAdditions 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.
…
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)].
…
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 ExperienceAdditions 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 UseSubsection 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.
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 GUIDEExtensive additions and revisions, please refer to label for complete 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.
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