1.1 Treatment of Venous Thromboembolic Events in Pediatric Patients

PRADAXA Oral Pellets are indicated for the treatment of venous thromboembolic events (VTE) in pediatric patients aged 3 months to less than 12 years of age who have been treated with a parenteral anticoagulant for at least 5 days.

1.2 Reduction in the Risk of Recurrence of Venous Thromboembolic Events in Pediatric Patients

PRADAXA Oral Pellets are indicated to reduce the risk of recurrence of VTE in pediatric patients aged 3 months to less than 12 years of age who have been previously treated.

2.1 Important Dosage Information

Dabigatran etexilate is available in different dosage forms and not all dosage forms are approved for the same indications and age groups. In addition, there are differences between the dosage forms with respect to dosing due to differences in bioavailability. Do not substitute different dosage forms (for example, capsules) for oral pellets on a milligram-to-milligram basis and do not combine more than one dosage form to achieve the total dose [see Clinical Pharmacology (12.3)].

2.2 Recommended PRADAXA Oral Pellets Dosage for Pediatric Patients

PRADAXA Oral Pellets can be used in pediatric patients aged 3 months to less than 12 years as soon as they are able to swallow soft food. For the treatment of VTE in pediatric patients, treatment should be initiated following treatment with a parenteral anticoagulant for at least 5 days. For reduction in risk of recurrence of VTE, treatment should be initiated following previous treatment.

The recommended dosage of PRADAXA Oral Pellets is based on the patient's age and actual weight as shown in the tables below. PRADAXA Oral Pellets is administered twice daily. Adjust the dosage according to age and actual weight as treatment progresses.

Evaluation of the extent of anticoagulation in pediatric patients on PRADAXA Oral Pellets may be accomplished using dTT or ECT, and not INR [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)].

2.3 Dosage Adjustments

2.4 Administration

PRADAXA Oral Pellets are administered twice daily, one dose in the morning and one dose in the evening, at approximately the same time every day. The dosing interval should be as close to 12 hours as possible.

If a dose of PRADAXA Oral Pellets is not taken at the scheduled time, the dose should be taken as soon as possible on the same day; the missed dose should be skipped if it cannot be taken at least 6 hours before the next scheduled dose. The dose of PRADAXA Oral Pellets should not be doubled to make up for a missed dose.

If a partial dose has been taken, a second dose should not be administered at that time. The next dose should be taken as scheduled approximately 12 hours later.

The prepared medication should be given before meals to ensure that the patient takes the full dose.

PRADAXA Oral Pellets should be administered immediately after mixing or within 30 minutes after mixing. If the PRADAXA dose is not administered within 30 minutes of mixing, the dose should be discarded, and a new dose prepared.

PRADAXA Oral Pellets should be administered with only specific soft foods or apple juice.

2.5 Converting from or to Warfarin

When converting patients from warfarin therapy to PRADAXA Oral Pellets, discontinue warfarin and start PRADAXA Oral Pellets when the INR is below 2.0.

When converting from PRADAXA Oral Pellets to warfarin, adjust the starting time of warfarin as follows:

• For eGFR ≥ 50 mL/min/1.73 m2, start warfarin 3 days before discontinuing PRADAXA Oral Pellets.
• Patients with an eGFR < 50 mL/min/1.73 m2 have not been studied. Avoid use of PRADAXA Oral Pellets in these patients.

Because PRADAXA Oral Pellets can increase INR, the INR will better reflect warfarin's effect only after PRADAXA Oral Pellets have been stopped for at least 2 days [see Clinical Pharmacology (12.2)].

2.6 Converting from or to Parenteral Anticoagulants

For pediatric patients currently receiving a parenteral anticoagulant, start PRADAXA Oral Pellets 0 to 2 hours before the time that the next dose of the parenteral drug was to have been administered or at the time of discontinuation of a continuously administered parenteral drug (e.g., intravenous unfractionated heparin).

For pediatric patients currently taking PRADAXA Oral Pellets, wait 12 hours after the last dose before switching to a parenteral anticoagulant [see Clinical Pharmacology (12.3)].

2.7 Discontinuation for Surgery and Other Interventions

If possible, discontinue PRADAXA Oral Pellets before invasive or surgical procedures because of the increased risk of bleeding. For pediatric patients, PRADAXA Oral Pellets should be stopped 24 hours before an elective surgery (eGFR > 80 mL/min/1.73 m2) or 2 days before an elective surgery (eGFR 50-80 mL/min/1.73 m2). Pediatric patients with an eGFR < 50 mL/min/1.73 m2 have not been studied, avoid use of PRADAXA Oral Pellets in these patients.

Consider longer times for patients undergoing major surgery, spinal puncture, or placement of a spinal or epidural catheter or port, in whom complete hemostasis may be required [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

If surgery cannot be delayed, there is an increased risk of bleeding [see Warnings and Precautions (5.2)]. This risk of bleeding should be weighed against the urgency of intervention [see Warnings and Precautions (5.1, 5.3)]. In adults, a specific reversal agent (idarucizumab) is available in case of emergency surgery or urgent procedures when reversal of the anticoagulant effect of dabigatran is needed. Efficacy and safety of idarucizumab have not been established in pediatric patients [see Warnings and Precautions (5.2)]. Refer to the idarucizumab prescribing information for additional information. Restart PRADAXA Oral Pellets as soon as medically appropriate.

5.1 Increased Risk of Thrombotic Events after Premature Discontinuation

Premature discontinuation of any oral anticoagulant, including PRADAXA, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. If PRADAXA Oral Pellets are discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant and restart PRADAXA Oral Pellets as soon as medically appropriate [see Dosage and Administration (2.5, 2.6, 2.7)].

5.2 Risk of Bleeding

PRADAXA increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding. Promptly evaluate any signs or symptoms of blood loss (e.g., a drop in hemoglobin and/or hematocrit or hypotension). Discontinue PRADAXA Oral Pellets in patients with active pathological bleeding [see Dosage and Administration (2.2)].

Risk factors for bleeding include the concomitant use of other drugs that increase the risk of bleeding (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs). PRADAXA's anticoagulant activity and half-life are increased in patients with renal impairment [see Clinical Pharmacology (12.2)].

5.3 Spinal/Epidural Anesthesia or Puncture

When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning].

To reduce the potential risk of bleeding associated with the concurrent use of PRADAXA and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of dabigatran [see Clinical Pharmacology (12.3)]. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of dabigatran is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.

Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), and bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.

5.4 Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves

The safety and efficacy of PRADAXA Capsules in adult patients with bileaflet mechanical prosthetic heart valves was evaluated in the RE-ALIGN trial, in which patients with bileaflet mechanical prosthetic heart valves (recently implanted or implanted more than three months prior to enrollment) were randomized to dose-adjusted warfarin or 150 mg, 220 mg, or 300 mg of PRADAXA Capsules twice a day. RE-ALIGN was terminated early due to the occurrence of significantly more thromboembolic events (valve thrombosis, stroke, transient ischemic attack, and myocardial infarction) and an excess of major bleeding (predominantly postoperative pericardial effusions requiring intervention for hemodynamic compromise) in the PRADAXA treatment arm as compared to the warfarin treatment arm. 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)].

The use of PRADAXA for the prophylaxis of thromboembolic events in patients with atrial fibrillation in the setting of other forms of valvular heart disease, including the presence of a bioprosthetic heart valve, has not been studied and is not recommended.

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

The concomitant use of PRADAXA with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided [see Clinical Pharmacology (12.3)].

P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran [see Clinical Pharmacology (12.3)]. Concomitant use of P-gp inhibitors in patients with renal impairment is expected to produce increased exposure of dabigatran compared to that seen with either factor alone.

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

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

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.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.2 Postmarketing Experience

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.

Blood and Lymphatic System Disorders: Agranulocytosis, neutropenia, thrombocytopenia
Gastrointestinal Disorders: Esophageal ulcer
Immune System Disorders: Angioedema
Renal and Urinary Disorders: Anticoagulant-related nephropathy
Skin and Subcutaneous Tissue Disorders: Alopecia

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

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.

8.4 Pediatric Use

The safety and effectiveness of PRADAXA Oral Pellets for the treatment and the reduction in risk of recurrence of venous thromboembolism have been established in pediatric patients less than 12 years of age. Use of PRADAXA Oral Pellets 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 (14.1, 14.2)]. Other age-appropriate pediatric formulations of dabigatran etexilate are available for pediatric patients aged 12 years and older for these indications.

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

8.5 Geriatric Use

Clinical studies of PRADAXA Oral Pellets did not include patients 65 years of age and older. Information on the use of PRADAXA Capsules in geriatric patients is available in that prescribing information.

8.6 Renal Impairment

PRADAXA has not been studied in pediatric patients with an eGFR < 50 mL/min/1.73 m2. Reduced renal function could increase exposure. Dosing recommendations cannot be provided for treatment of these patients. Avoid use of PRADAXA in these patients [see Dosage and Administration (2.3)].

12.1 Mechanism of Action

Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors. Because thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties.

12.2 Pharmacodynamics

At recommended therapeutic doses, dabigatran etexilate prolongs the coagulation markers such as aPTT, ECT, TT, and dTT. INR is relatively insensitive to the exposure to dabigatran and cannot be interpreted the same way as used for warfarin monitoring.

As in adults, there is a correlation between plasma dabigatran concentrations and the degree of its anticoagulant effect in pediatric patients with venous thromboembolism. The parameters dTT and ECT increased in direct linear proportion to the plasma concentration of dabigatran, whereas aPTT prolongation increases in a nonlinear fashion with dabigatran plasma concentrations.

Similar PK/PD relationships for aPTT, ECT and dTT were observed across age groups of pediatric patients (ages 26 days to < 18 years) and between pediatric and adult patients with venous thromboembolism. This similarity in PK/PD relationship suggests that similar exposure-response relationship is expected for dabigatran etexilate treatment across the pediatric age groups and adult patients.

12.3 Pharmacokinetics

Dabigatran etexilate mesylate is absorbed as the dabigatran etexilate ester. The ester is then hydrolyzed, forming dabigatran, the active moiety. Dabigatran is metabolized to four different acyl glucuronides and both the glucuronides and dabigatran have similar pharmacological activity. Pharmacokinetics described here refer to the sum of dabigatran and its glucuronides. Dabigatran displays dose-proportional pharmacokinetics in healthy adult subjects and adult patients in the range of doses from 10 mg to 400 mg. Given twice daily, dabigatran's accumulation factor in pediatric patients receiving pellets is 1.5-1.7.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Dabigatran was not carcinogenic when administered by oral gavage to mice and rats for up to 2 years. The highest doses tested (200 mg/kg/day) in mice and rats were approximately 3.6 and 6 times, respectively, the human exposure at MRHD of 300 mg/day based on AUC comparisons.

Dabigatran was not mutagenic in in vitro tests, including bacterial reversion tests, mouse lymphoma assay and chromosomal aberration assay in human lymphocytes, and the in vivo micronucleus assay in rats.

In the rat fertility study with oral gavage doses of 15, 70, and 200 mg/kg, males were treated for 29 days prior to mating, during mating up to scheduled termination, and females were treated 15 days prior to mating through gestation Day 6. No adverse effects on male or female fertility were observed at 200 mg/kg or 9 to 12 times the human exposure at MRHD of 300 mg/day based on AUC comparisons. However, the number of implantations decreased in females receiving 70 mg/kg, or 3 times the human exposure at MRHD based on AUC comparisons.

14.1 Treatment of VTE in Pediatric Patients

The DIVERSITY study was conducted to demonstrate the efficacy and safety of PRADAXA compared to standard of care (SOC) for the treatment of venous thromboembolism (VTE) in pediatric patients from birth to less than 18 years of age. The study was designed as an open-label, randomized, parallel-group, non-inferiority study. Patients enrolled were randomized according to a 2:1 scheme to either an age-appropriate formulation (capsules, oral pellets, or oral solution) of PRADAXA (dosages adjusted for age and weight) after at least 5 days and no longer than 21 days of treatment with a parenteral anticoagulant, or to SOC comprised of low molecular weight heparins (LMWH) or vitamin K antagonists (VKA) or fondaparinux. For patients on PRADAXA, drug concentration was determined prior to the 7th dose and a single titration was permitted to achieve drug target levels of 50-250 ng/ml. Inability to achieve target, after one up-titration, resulted in premature termination of study drug in 12 patients (6.8%).

The median treatment duration during the treatment period was 85 days. In total, 267 patients entered the study (leading index VTE was 64% deep vein thrombosis, 10% cerebral venous thrombosis or sinus thrombosis, and 9.0% pulmonary embolism), with 18% of patients having a central line-associated thrombosis. The patient population was 49.8% male, 91.8% white, 4.9% Asian, and 1.5% black; 168 patients were 12 to < 18 years old, 64 patients 2 to < 12 years, and 35 patients were younger than 2 years. The concomitant VTE-related risk factors of patients in this trial among study arms were as follows: inherited thrombophilia disorder (PRADAXA: 20%; SOC: 22%), congenital heart disease (PRADAXA: 12%; SOC: 30%), heart failure (PRADAXA: 3%; SOC: 18%), history of cancer (PRADAXA: 10%; SOC: 1%), CVL insertion (PRADAXA: 23%; SOC: 27%), immobility (PRADAXA: 13%; SOC: 10%) and significant infection (PRADAXA: 15%; SOC: 13%). The number of patients taking concomitant medications with hemostatic effects was similar in both treatment groups (PRADAXA: 15%; SOC: 16%).

The efficacy of PRADAXA was established based on a composite endpoint of patients with complete thrombus resolution, freedom from recurrent venous thromboembolic event, and freedom from mortality related to venous thromboembolic event (composite primary endpoint). Of the 267 randomized patients, 81 patients (45.8%) in the dabigatran etexilate group and 38 patients (42.2%) in the SOC group met the criteria for the composite primary endpoint. The corresponding rate difference and 95% CI was -0.038 (-0.161, 0.086) and thus demonstrated non-inferiority of PRADAXA to SOC, since the upper bound of the 95% CI was lower than the predefined non-inferiority margin of 20% (see Table 5).

Subgroup analyses showed that there were no outliers in the treatment effect for the subgroups by age, sex, region, and presence of certain risk factors (central venous line, congenital heart disease, malignant disease). For the 3 different age strata, the proportions of patients that met the efficacy endpoint in the PRADAXA and SOC groups, respectively, were 13/22 (59.1%) and 7/13 (53.8%) for patients from birth to < 2 years [Rate Difference -0.052; (95%CI: -0.393, 0.288)], 21/43 (48.8%) and 12/21 (57.1%) for patients aged 2 to < 12 years [Rate Difference 0.083; (95%CI: -0.176, 0.342)], and 47/112 (42.0%) and 19/56 (33.9%) for patients aged 12 to < 18 years [Rate Difference -0.080; (95%CI: -0.234, 0.074)].

14.2 Reduction in the Risk of Recurrence of VTE in Pediatric Patients

Study 2 was an open-label, single-arm safety study to assess the safety of PRADAXA for the prevention of recurrent VTE in pediatric patients from birth to < 18 years. 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 were included in the study. Eligible patients received age- and weight-adjusted dosages of an age-appropriate formulation (capsules or oral pellets) of PRADAXA until the clinical risk factor resolved, or up to a maximum of 12 months. The primary endpoints of the study included the recurrence of VTE, major and minor bleeding events, and mortality (overall and related to thrombotic or thromboembolic events) at 6 and 12 months.

Of the 214 patients in the study, 162 patients were 12 to < 18 years old, 43 patients were 2 to < 12 years old, and 9 patients were aged 6 months to < 2 years old.

The overall probability of being free from recurrence of VTE during the on-treatment period was 0.990 (95% CI: 0.960, 0.997) at 3 months, 0.984 (95% CI: 0.950, 0.995) at 6 months, and 0.984 (95% CI: 0.950, 0.995) at 12 months. The probability of being free from bleeding events during the on-treatment period was 0.849 (95% CI: 0.792, 0.891) at 3 months, 0.785 (95% CI: 0.718, 0.838) at 6 months, and 0.723 (95% CI: 0.645, 0.787) at 12 months. No on-treatment deaths occurred.

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in the original package to protect from moisture.

Do not open the packets until ready for use. Use the PRADAXA Oral Pellets within 6 months of opening the aluminum bag containing the packets.

Instructions for Patients

• Tell patients or their caregivers to take or administer PRADAXA Oral Pellets exactly as prescribed.
• Tell patients or their caregivers to remove desiccant from the aluminum bag and throw away.
• Remind patients or their caregivers not to discontinue PRADAXA Oral Pellets without talking to the healthcare provider who prescribed it.
• Provide the following instructions on administration to the patients or caregivers:
  • Take the prescribed dosage of PRADAXA Oral Pellets twice a day, approximately 12 hours apart;
  • PRADAXA Oral Pellets may be sprinkled on mashed carrots, apple sauce, or mashed banana, or may be taken with approximately 1-2 ounces of apple juice;
  • PRADAXA Oral Pellets should not be mixed with milk or with foods that contain milk;
  • Once the PRADAXA Oral Pellets are mixed with the soft food or apple juice, the patient should take the dose within 30 minutes;
  • If a dose of PRADAXA Oral Pellets is not taken at the scheduled time, the dose should be skipped if it cannot be taken at least 6 hours before the next scheduled dose. The dose of PRADAXA Oral Pellets should not be doubled to make up for a missed dose.

[see Boxed Warning, and Dosage and Administration (2.2, 2.4)]

Bleeding

Inform patients or their caregivers that they may bleed more easily, may bleed longer, and should call their healthcare provider for any signs or symptoms of bleeding [see Warnings and Precautions (5.2)].

Instruct patients or their caregivers to seek emergency care right away if they have any of the following, which may be a sign or symptom of serious bleeding:

• Unusual bruising (bruises that appear without known cause or that get bigger)
• Pink or brown urine
• Red or black, tarry stools
• Coughing up blood
• Vomiting blood, or vomit that looks like coffee grounds

Instruct patients or their caregivers to call their healthcare provider or to get prompt medical attention if they experience any signs or symptoms of bleeding:

• Pain, swelling or discomfort in a joint
• Headaches, dizziness, or weakness
• Reoccurring nose bleeds
• Unusual bleeding from gums
• Bleeding from a cut that takes a long time to stop
• Menstrual bleeding or vaginal bleeding that is heavier than normal

If patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking concomitant NSAIDs or platelet inhibitors, advise patients or their caregivers to watch for signs and symptoms of spinal or epidural hematoma, such as back pain, tingling, numbness (especially in the lower limbs), muscle weakness, and stool or urine incontinence. If any of these symptoms occur, advise the patient or their caregivers to contact his or her physician immediately [see Boxed Warning].

Gastrointestinal Adverse Reactions

Instruct patients or their caregivers to call their healthcare provider if they experience any signs or symptoms of dyspepsia or gastritis:

• Dyspepsia (upset stomach), burning, or nausea
• Abdominal pain or discomfort
• Epigastric discomfort, GERD (gastric indigestion)

[see Adverse Reactions (6.1)]

Invasive or Surgical Procedures

Instruct patients or their caregivers to inform their healthcare provider that they are taking PRADAXA before any invasive procedure (including dental procedures) is scheduled [see Dosage and Administration (2.7)].

Concomitant Medications

Ask patients or their caregivers to list all prescription medications, over-the-counter medications, or dietary supplements they are taking or plan to take so the patient's healthcare provider knows about other treatments that may affect bleeding risk (e.g., aspirin or NSAIDs) or dabigatran exposure (e.g., dronedarone or systemic ketoconazole) [see Warnings and Precautions (5.2, 5.5)].

Prosthetic Heart Valves

Instruct patients or their caregivers to inform their healthcare provider if they will have or have had surgery to place a prosthetic heart valve [see Warnings and Precautions (5.4)].

Allergic Reactions

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

Pregnancy

Advise patients to inform their healthcare provider immediately if they become pregnant or intend to become pregnant during treatment with PRADAXA [see Use in Specific Populations (8.1)].

Lactation

Advise patients not to breastfeed if they are taking PRADAXA [see Use in Specific Populations (8.2)].