Pradaxa
Generic Name: dabigatran etexilate mesylate
Dosage Form: capsule
WARNING:
(A) PREMATURE DISCONTINUATION OF Pradaxa INCREASES THE RISK OF THROMBOTIC
EVENTS, and (B) SPINAL/EPIDURAL HEMATOMA
(A) PREMATURE DISCONTINUATION OF Pradaxa INCREASES THE RISK OF
THROMBOTIC EVENTS
Premature
discontinuation of any oral anticoagulant, including Pradaxa, increases the
risk of thrombotic events. If anticoagulation with Pradaxa is discontinued for
a reason other than pathological bleeding or completion of a course of therapy,
consider coverage with another anticoagulant [see
Dosage and Administration (2.4, 2.5, 2.6) and Warnings and Precautions (5.1)].
(B)
SPINAL/EPIDURAL HEMATOMA
Epidural
or spinal hematomas may occur in patients treated with Pradaxa who are
receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas
may result in long-term or permanent paralysis. Consider these risks when
scheduling patients for spinal procedures. Factors that can increase the risk
of developing epidural or spinal hematomas in these patients include:
•
use of indwelling epidural catheters
•
concomitant use of other drugs that affect hemostasis, such as non-steroidal
anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
•
a history of traumatic or repeated epidural or spinal punctures
•
a history of spinal deformity or spinal surgery
•
optimal timing between the administration of Pradaxa and neuraxial procedures
is not known [see Warnings and Precautions (5.3)].
Monitor
patients frequently for signs and symptoms of neurological impairment. If
neurological compromise is noted, urgent treatment is necessary [see Warnings and
Precautions (5.3)].
Consider
the benefits and risks before neuraxial intervention in patients anticoagulated
or to be anticoagulated [see Warnings
and Precautions (5.3)].
1 INDICATIONS AND USAGE
Reduction of Risk of Stroke and Systemic Embolism in
Non-valvular Atrial Fibrillation
Pradaxa
is indicated to reduce the risk of stroke and systemic embolism in patients
with non-valvular atrial fibrillation.
Treatment of Deep Venous Thrombosis and Pulmonary
Embolism
Pradaxa
is indicated for the treatment of deep venous thrombosis and pulmonary embolism
in patients who have been treated with a parenteral anticoagulant for 5-10
days.
Reduction in the Risk of Recurrence of Deep Venous
Thrombosis and Pulmonary Embolism
Pradaxa
is indicated to reduce the risk of recurrence of deep venous thrombosis and
pulmonary embolism in patients who have been previously treated.
Prophylaxis of Deep Vein Thrombosis and Pulmonary
Embolism Following Hip Replacement Surgery
Pradaxa
is indicated for the prophylaxis of deep vein thrombosis and pulmonary embolism,
in patients who have undergone hip replacement surgery.
2 DOSAGE AND ADMINISTRATION
Recommended Dose
|
Indication
|
Dosage
|
|
Reduction in Risk of Stroke and Systemic Embolism
in Non-valvular AF
|
CrCl >30 mL/min:
|
150 mg twice daily
|
|
CrCl 15 to 30 mL/min:
|
75 mg twice daily
|
|
CrCl <15
mL/min or on dialysis:
|
Dosing
recommendations cannot be provided
|
|
CrCl 30 to 50 mL/min with concomitant use of P-gp
inhibitors:
|
Reduce dose to 75 mg twice daily if given with P-gp
inhibitors dronedarone or systemic ketoconazole.
|
|
CrCl <30
mL/min with concomitant use of P-gp inhibitors:
|
Avoid
co-administration
|
|
Treatment of DVT and PE
Reduction in the Risk of
Recurrence of DVT and PE
|
CrCl >30 mL/min:
|
150 mg twice daily
|
|
CrCl ≤30 mL/min
or on dialysis:
|
Dosing
recommendations cannot be provided
|
|
CrCl <50
mL/min with concomitant use of P-gp inhibitors:
|
Avoid
co-administration
|
|
Prophylaxis of DVT and PE Following Hip
Replacement Surgery
|
CrCl >30 mL/min:
|
110 mg for first day, then 220 mg once daily
|
|
CrCl ≤30 mL/min
or on dialysis:
|
Dosing
recommendations cannot be provided
|
|
CrCl <50
mL/min with concomitant use of P-gp inhibitors:
|
Avoid
co-administration
|
Reduction of Risk of Stroke and Systemic Embolism in
Non-valvular Atrial Fibrillation
For
patients with creatinine clearance (CrCl) >30 mL/min, the recommended dose
of Pradaxa is 150 mg taken orally, twice daily. For patients with severe renal
impairment (CrCl 15-30 mL/min), the recommended dose of Pradaxa is 75 mg twice
daily [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. Dosing recommendations for patients with a CrCl <15 mL/min
or on dialysis cannot be provided.
Treatment of Deep Venous Thrombosis and Pulmonary Embolism
For
patients with CrCl >30 mL/min, the recommended dose of Pradaxa is 150 mg
taken orally, twice daily, after 5-10 days of parenteral anticoagulation.
Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis
cannot be provided [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
Reduction in the Risk of Recurrence of Deep Venous Thrombosis
and Pulmonary Embolism
For
patients with CrCl >30 mL/min, the recommended dose of Pradaxa is 150 mg
taken orally, twice daily after previous treatment. Dosing recommendations for
patients with a CrCl ≤30 mL/min or on dialysis cannot be provided [see
Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism
Following Hip Replacement Surgery
For
patients with CrCl >30 mL/min, the recommended dose of Pradaxa is 110 mg
taken orally 1-4 hours after surgery and after hemostasis has been achieved,
then 220 mg taken once daily for 28-35 days. If Pradaxa is not started on the
day of surgery, after hemostasis has been achieved initiate treatment with 220
mg once daily. Dosing recommendations for patients with a CrCl ≤30 mL/min or on
dialysis cannot be provided [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.2, 12.3)].
Dosing Adjustments
Assess
renal function prior to initiation of treatment with Pradaxa. Periodically
assess renal function as clinically indicated (i.e., more frequently in
clinical situations that may be associated with a decline in renal function)
and adjust therapy accordingly. Discontinue Pradaxa in patients who develop
acute renal failure while on Pradaxa and consider alternative anticoagulant
therapy.
Generally,
the extent of anticoagulation does not need to be assessed. When necessary, use
aPTT or ECT, and not INR, to assess for anticoagulant activity in patients on
Pradaxa [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)].
Reduction of Risk of Stroke and Systemic Embolism in Non-valvular
Atrial Fibrillation
In
patients with moderate renal impairment (CrCl 30-50 mL/min), concomitant use of
the P-gp inhibitor dronedarone or systemic ketoconazole can be expected to
produce dabigatran exposure similar to that observed in severe renal
impairment. Reduce the dose of Pradaxa to 75 mg twice daily [see
Warnings and Precautions (5.5), Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
Treatment and Reduction in the Risk of Recurrence of Deep Venous
Thrombosis and Pulmonary Embolism
Dosing
recommendations for patients with CrCl ≤30 mL/min cannot be provided. Avoid use
of concomitant P-gp inhibitors in patients with CrCl <50 mL/min [see
Warnings and Precautions (5.5), Drug Interactions (7.2) and Clinical Pharmacology (12.3)].
Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism
Following Hip Replacement Surgery
Dosing
recommendations for patients with CrCl ≤30 mL/min or on dialysis cannot be
provided. Avoid use of concomitant P-gp inhibitors in patients with CrCl <50
mL/min [see Warnings and Precautions (5.5), Drug Interactions (7.3) and Clinical Pharmacology (12.2, 12.3)].
Instructions to Patients
Instruct
patients to swallow the capsules whole. Pradaxa should be taken with a full
glass of water. Breaking, chewing, or emptying the contents of the capsule can
result in increased exposure [see Clinical
Pharmacology (12.3)].
If a dose
of Pradaxa 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
should not be doubled to make up for a missed dose.
Converting from or to Warfarin
When
converting patients from warfarin therapy to Pradaxa, discontinue warfarin and
start Pradaxa when the INR is below 2.0.
When
converting from Pradaxa to warfarin, adjust the starting time of warfarin based
on creatinine clearance as follows:
· For CrCl ≥50 mL/min, start warfarin 3 days before
discontinuing Pradaxa.
· For CrCl 30-50 mL/min, start warfarin 2 days before
discontinuing Pradaxa.
· For CrCl 15-30 mL/min, start warfarin 1 day before
discontinuing Pradaxa.
· For CrCl <15 mL/min, no recommendations can be
made.
Because
Pradaxa can increase INR, the INR will better reflect warfarin’s effect only
after Pradaxa has been stopped for at least 2 days [see Clinical
Pharmacology (12.2)].
Converting from or to Parenteral Anticoagulants
For
patients currently receiving a parenteral anticoagulant, start Pradaxa 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
patients currently taking Pradaxa, wait 12 hours (CrCl ≥30 mL/min) or 24 hours
(CrCl <30 mL/min) after the last dose of Pradaxa before initiating treatment
with a parenteral anticoagulant [see Clinical
Pharmacology (12.3)].
Discontinuation for Surgery and Other Interventions
If
possible, discontinue Pradaxa 1 to 2 days (CrCl ≥50 mL/min) or 3 to 5 days
(CrCl <50 mL/min) before invasive or surgical procedures because of the
increased risk of bleeding. 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)].
Use a specific reversal agent (idarucizumab) in case of emergency surgery or
urgent procedures when reversal of the anticoagulant effect of dabigatran is
needed. Refer to the idarucizumab prescribing information for additional
information. Restart Pradaxa as soon as medically appropriate.
3 DOSAGE FORMS AND STRENGTHS
150 mg
capsules with a light blue opaque cap imprinted in black with the Boehringer
Ingelheim company symbol and a white opaque body imprinted in black with
“R150”.
110 mg
capsules with a light blue opaque cap imprinted in black with the Boehringer
Ingelheim company symbol and a light blue opaque body imprinted in black with
“R110”.
75 mg
capsules with a white opaque cap imprinted in black with the Boehringer
Ingelheim company symbol and a white opaque body imprinted in black with “R75”.
4 CONTRAINDICATIONS
Pradaxa
is contraindicated in patients with:
· Active pathological bleeding [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].
· History of a serious hypersensitivity reaction to
Pradaxa (e.g., anaphylactic reaction or anaphylactic shock) [see Adverse Reactions (6.1)].
· Mechanical prosthetic heart valve [see
Warnings and Precautions (5.4)].
5 WARNINGS AND PRECAUTIONS
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 is discontinued for a reason other than pathological bleeding or
completion of a course of therapy, consider coverage with another anticoagulant
and restart Pradaxa as soon as medically appropriate [see Dosage and
Administration (2.4, 2.5, 2.6)].
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 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)].
Reversal of Anticoagulant Effect:
A
specific reversal agent (idarucizumab) for dabigatran is available when
reversal of the anticoagulant effect of dabigatran is needed:
· For emergency surgery/urgent procedures
· In life-threatening or uncontrolled bleeding
Hemodialysis
can remove dabigatran; however the clinical experience supporting the use of
hemodialysis as a treatment for bleeding is limited [see Overdosage
(10)].
Prothrombin complex concentrates, or recombinant Factor VIIa may be considered
but their use has not been evaluated in clinical trials. Protamine sulfate and
vitamin K are not expected to affect the anticoagulant activity of dabigatran.
Consider administration of platelet concentrates in cases where
thrombocytopenia is present or long-acting antiplatelet drugs have been used.
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 dabigatran
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),
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.
Thromboembolic and Bleeding Events in Patients with
Prosthetic Heart Valves
The
safety and efficacy of Pradaxa in 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, 220, or 300 mg of Pradaxa 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 post-operative 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
post-operatively 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
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.
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.
Reduction of Risk of Stroke and Systemic Embolism in
Non-valvular Atrial Fibrillation
Reduce
the dose of Pradaxa to 75 mg twice daily when dronedarone or systemic
ketoconazole is coadministered with Pradaxa in patients with moderate renal
impairment (CrCl 30-50 mL/min). Avoid use of Pradaxa and P-gp inhibitors in
patients with severe renal impairment (CrCl 15-30 mL/min) [see
Drug Interactions (7.1) and Use in Specific Populations (8.6)].
Treatment and Reduction in the Risk of Recurrence of Deep Venous
Thrombosis and Pulmonary Embolism
Avoid use
of Pradaxa and concomitant P-gp inhibitors in patients with CrCl <50
mL/min [see Drug Interactions (7.2) and Use in Specific Populations (8.6)].
Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism
Following Hip Replacement Surgery
Avoid use
of Pradaxa and concomitant P-gp inhibitors in patients with CrCl <50
mL/min [see Drug Interactions (7.3) and Use in Specific Populations (8.6)].
6 ADVERSE REACTIONS
The
following serious adverse reactions are described elsewhere in the labeling:
· Increased Risk of Thrombotic Events after Premature
Discontinuation [see Warnings and Precautions (5.1)]
· Risk of Bleeding [see Warnings
and Precautions (5.2)]
· Spinal/Epidural Anesthesia or Puncture [see
Warnings and Precautions (5.3)]
· Thromboembolic and Bleeding Events in Patients with
Prosthetic Heart Valves [see Warnings and Precautions (5.4)]
The most
serious adverse reactions reported with Pradaxa were related to bleeding [see
Warnings and Precautions (5.2)].
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.
Reduction of Risk of Stroke and Systemic Embolism in
Non-valvular Atrial Fibrillation
The RE-LY
(Randomized Evaluation of Long-term Anticoagulant Therapy) study provided
safety information on the use of two doses of Pradaxa and warfarin [see
Clinical Studies (14.1)].
The numbers of patients and their exposures are described in Table 1. Limited
information is presented on the 110 mg dosing arm because this dose is not
approved.
Table 1 Summary of Treatment Exposure in
RE-LY
|
|
|
Pradaxa
110 mg twice daily
|
Pradaxa
150 mg twice daily
|
Warfarin
|
|
Total number
treated
|
5983
|
6059
|
5998
|
|
Exposure
|
|
|
|
|
|
> 12 months
|
4936
|
4939
|
5193
|
|
|
> 24 months
|
2387
|
2405
|
2470
|
|
Mean exposure
(months)
|
20.5
|
20.3
|
21.3
|
|
Total
patient-years
|
10,242
|
10,261
|
10,659
|
Drug Discontinuation in RE-LY
The rates
of adverse reactions leading to treatment discontinuation were 21% for Pradaxa
150 mg and 16% for warfarin. The most frequent adverse reactions leading to
discontinuation of Pradaxa were bleeding and gastrointestinal events (i.e.,
dyspepsia, nausea, upper abdominal pain, gastrointestinal hemorrhage, and
diarrhea).
Bleeding [see Warnings and Precautions (5.2)]
Table 2
shows the number of adjudicated major bleeding events during the treatment
period in the RE-LY study, with the bleeding rate per 100 subject-years (%).
Major bleeding is defined as bleeding accompanied by one or more of the
following: a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of
packed red blood cells, bleeding at a critical site or with a fatal outcome.
Intracranial hemorrhage included intracerebral (hemorrhagic stroke),
subarachnoid, and subdural bleeds.
Table 2 Adjudicated Major Bleeding
Events in Treated Patientsa
|
|
aPatients during treatment
or within 2 days of stopping study treatment. Major bleeding events within
each subcategory were counted once per patient, but patients may have
contributed events to multiple subcategories.
bAnnual event rate per 100 pt-years = 100 * number
of subjects with event/subject-years. Subject-years is defined as cumulative
number of days from first drug intake to event date, date of last drug intake
+ 2, death date (whatever occurred first) across all treated subjects divided
by 365.25. In case of recurrent events of the same category, the first event
was considered.
cDefined as bleeding accompanied by one or more of
the following: a decrease in hemoglobin of ≥2 g/dL, a transfusion of 2
or more units of packed red blood cells, bleeding at a critical site or with
fatal outcome.
dIntracranial bleed included intracerebral
(hemorrhagic stroke), subarachnoid, and subdural bleeds.
eOn-treatment analysis based on the safety
population, compared to ITT analysis presented in Section 14 Clinical
Studies.
fFatal bleed: Adjudicated major bleed as defined
above with investigator reported fatal outcome and adjudicated death with
primary cause from bleeding.
gNon-intracranial fatal bleed: Adjudicated major
bleed as defined above and adjudicated death with primary cause from bleeding
but without symptomatic intracranial bleed based on investigator’s clinical
assessment.
|
|
Event
|
Pradaxa 150 mg
N = 6059
n (%/yearb)
|
Warfarin
N = 5998
n (%/yearb)
|
Pradaxa 150 mg
vs. Warfarin
HR (95% CI)
|
|
Major Bleedingc
|
350 (3.47)
|
374 (3.58)
|
0.97 (0.84, 1.12)
|
|
Intracranial Hemorrhage (ICH)d
|
23 (0.22)
|
82 (0.77)
|
0.29 (0.18, 0.46)
|
|
Hemorrhagic
Strokee
|
6 (0.06)
|
40 (0.37)
|
0.16 (0.07, 0.37)
|
|
Other ICH
|
17 (0.17)
|
46 (0.43)
|
0.38 (0.22, 0.67)
|
|
Gastrointestinal
|
162 (1.59)
|
111 (1.05)
|
1.51 (1.19, 1.92)
|
|
Fatal Bleedingf
|
7 (0.07)
|
16 (0.15)
|
0.45 (0.19, 1.10)
|
|
ICH
|
3 (0.03)
|
9 (0.08)
|
0.35 (0.09, 1.28)
|
|
Non-intracranialg
|
4 (0.04)
|
7 (0.07)
|
0.59 (0.17, 2.02)
|
There was
a higher rate of any gastrointestinal bleeds in patients receiving Pradaxa 150
mg than in patients receiving warfarin (6.6% vs. 4.2%, respectively).
The risk
of major bleeds was similar with Pradaxa 150 mg and warfarin across major
subgroups defined by baseline characteristics (see Figure 1), with the
exception of age, where there was a trend towards a higher incidence of major
bleeding on Pradaxa (hazard ratio 1.2, 95% CI: 1.0 to 1.5) for patients ≥75
years of age.
Figure 1 Adjudicated Major Bleeding
by Baseline Characteristics Including Hemorrhagic Stroke Treated Patients
Note: The figure above presents effects in various
subgroups all of which are baseline characteristics and all of which were
pre-specified. The 95% confidence limits that are shown do not take into
account how many comparisons were made, nor do they reflect the effect of a
particular factor after adjustment for all other factors. Apparent homogeneity
or heterogeneity among groups should not be over-interpreted.
Gastrointestinal Adverse Reactions
Patients on Pradaxa 150 mg had an increased
incidence of gastrointestinal adverse reactions (35% vs. 24% on warfarin).
These were commonly dyspepsia (including abdominal pain upper, abdominal pain,
abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms
(including GERD, esophagitis, erosive gastritis, gastric hemorrhage,
hemorrhagic gastritis, hemorrhagic erosive gastritis, and gastrointestinal
ulcer).
Hypersensitivity Reactions
In the RE-LY study, drug hypersensitivity
(including urticaria, rash, and pruritus), allergic edema, anaphylactic reaction,
and anaphylactic shock were reported in <0.1% of patients receiving Pradaxa.
Treatment and Reduction in the Risk
of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism
Pradaxa was studied in 4387 patients in 4 pivotal,
parallel, randomized, double-blind trials. Three of these trials were
active-controlled (warfarin) (RE-COVER, RE-COVER II, and RE-MEDY), and one
study (RE-SONATE) was placebo-controlled. The demographic characteristics were
similar among the 4 pivotal studies and between the treatment groups within
these studies. Approximately 60% of the treated patients were male, with a mean
age of 55.1 years. The majority of the patients were white (87.7%), 10.3% were
Asian, and 1.9% were black with a mean CrCl of 105.6 mL/min.
Bleeding events for the 4 pivotal studies were
classified as major bleeding events if at least one of the following criteria
applied: fatal bleeding, symptomatic bleeding in a critical area or organ
(intraocular, intracranial, intraspinal or intramuscular with compartment syndrome,
retroperitoneal bleeding, intra-articular bleeding, or pericardial bleeding),
bleeding causing a fall in hemoglobin level of 2.0 g/dL (1.24 mmol/L or more,
or leading to transfusion of 2 or more units of whole blood or red cells).
RE-COVER and RE-COVER II studies compared Pradaxa
150 mg twice daily and warfarin for the treatment of deep vein thrombosis and
pulmonary embolism. Patients received 5-10 days of an approved parenteral
anticoagulant therapy followed by 6 months, with mean exposure of 164 days, of
oral only treatment; warfarin was overlapped with parenteral therapy. Table 3
shows the number of patients experiencing bleeding events in the pooled
analysis of RE-COVER and RE-COVER II studies during the full treatment
including parenteral and oral only treatment periods after randomization.
Table 3 Bleeding Events in RE-COVER
and RE-COVER II Treated Patients
|
|
Note: MBE can belong to more than one criterion.
aPatients with at least one MBE.
bBleeding site based on investigator assessment.
Patients can have more than one site of bleeding.
cConfidence interval
|
|
|
Bleeding Events-Full Treatment Period
Including Parenteral Treatment
|
|
|
Pradaxa
150 mg twice daily
N (%)
|
Warfarin
N (%)
|
Hazard Ratio
(95% CI)c
|
|
Patients
|
N=2553
|
N=2554
|
|
|
Major bleeding eventa
|
37 (1.4)
|
51 (2.0)
|
0.73 (0.48, 1.11)
|
|
|
Fatal bleeding
|
1 (0.04)
|
2 (0.1)
|
|
|
|
Bleeding in a critical area or organ
|
7 (0.3)
|
15 (0.6)
|
|
|
|
Fall in hemoglobin ≥2 g/dL or transfusion ≥2
units of whole blood or packed red blood cells
|
32 (1.3)
|
38 (1.5)
|
|
|
Bleeding sites for MBEb
|
|
|
|
|
|
Intracranial
|
2 (0.1)
|
5 (0.2)
|
|
|
|
Retroperitoneal
|
2 (0.1)
|
1 (0.04)
|
|
|
|
Intraarticular
|
2 (0.1)
|
4 (0.2)
|
|
|
|
Intramuscular
|
2 (0.1)
|
6 (0.2)
|
|
|
|
Gastrointestinal
|
15 (0.6)
|
14 (0.5)
|
|
|
|
Urogenital
|
7 (0.3)
|
14 (0.5)
|
|
|
|
Other
|
8 (0.3)
|
8 (0.3)
|
|
|
Clinically relevant non-major bleeding
|
101 (4.0)
|
170 (6.7)
|
0.58 (0.46, 0.75)
|
|
Any bleeding
|
411 (16.1)
|
567 (22.7)
|
0.70 (0.61, 0.79)
|
The rate of any gastrointestinal bleeds in patients
receiving Pradaxa 150 mg in the full treatment period was 3.1% (2.4% on
warfarin).
The RE-MEDY and RE-SONATE studies provided safety
information on the use of Pradaxa for the reduction in the risk of recurrence
of deep vein thrombosis and pulmonary embolism.
RE-MEDY was an active-controlled study (warfarin)
in which 1430 patients received Pradaxa 150 mg twice daily following 3 to 12
months of oral anticoagulant regimen. Patients in the treatment studies who
rolled over into the RE-MEDY study had a combined treatment duration of up to
more than 3 years, with mean exposure of 473 days. Table 4 shows the number of
patients experiencing bleeding events in the study.
Table 4 Bleeding Events in RE-MEDY
Treated Patients
|
|
Note:
MBE can belong to more than one criterion.
aPatients with at least one MBE.
bBleeding site based on investigator assessment.
Patients can have more than one site of bleeding.
cConfidence interval
|
|
|
Pradaxa
150
mg twice daily
N
(%)
|
Warfarin
N
(%)
|
Hazard Ratio
(95%
CI)c
|
|
Patients
|
N=1430
|
N=1426
|
|
|
Major
bleeding eventa
|
13 (0.9)
|
25 (1.8)
|
0.54 (0.25, 1.16)
|
|
|
Fatal
bleeding
|
0
|
1 (0.1)
|
|
|
|
Bleeding
in a critical area or organ
|
7 (0.5)
|
11 (0.8)
|
|
|
|
Fall
in hemoglobin ≥2 g/dL or transfusion ≥2 units of whole blood or packed red blood cells
|
7 (0.5)
|
16 (1.1)
|
|
|
Bleeding
sites for MBEb
|
|
|
|
|
|
Intracranial
|
2 (0.1)
|
4 (0.3)
|
|
|
|
Intraocular
|
4 (0.3)
|
2 (0.1)
|
|
|
|
Retroperitoneal
|
0
|
1 (0.1)
|
|
|
|
Intraarticular
|
0
|
2 (0.1)
|
|
|
|
Intramuscular
|
0
|
4 (0.3)
|
|
|
|
Gastrointestinal
|
4 (0.3)
|
8 (0.6)
|
|
|
|
Urogenital
|
1 (0.1)
|
1 (0.1)
|
|
|
|
Other
|
2 (0.1)
|
4 (0.3)
|
|
|
Clinically
relevant non-major bleeding
|
71 (5.0)
|
125 (8.8)
|
0.56 (0.42, 0.75)
|
|
Any
bleeding
|
278 (19.4)
|
373 (26.2)
|
0.71 (0.61, 0.83)
|
In the RE-MEDY study, the rate of any
gastrointestinal bleeds in patients receiving Pradaxa 150 mg was 3.1% (2.2% on
warfarin).
RE-SONATE was a placebo-controlled study in which
684 patients received Pradaxa 150 mg twice daily following 6 to 18 months of
oral anticoagulant regimen. Patients in the treatment studies who rolled over
into the RE-SONATE study had combined treatment duration up to 9 months, with
mean exposure of 165 days. Table 5 shows the number of patients experiencing
bleeding events in the study.
Table 5 Bleeding Events in RE-SONATE
Treated Patients
|
|
Note:
MBE can belong to more than one criterion.
aPatients with at least one MBE.
bBleeding site based on investigator assessment.
Patients can have more than one site of bleeding.
cConfidence interval
|
|
|
Pradaxa
150
mg twice daily
N
(%)
|
Placebo
N
(%)
|
Hazard Ratio
(95%
CI)c
|
|
Patients
|
N=684
|
N=659
|
|
|
Major
bleeding eventa
|
2 (0.3)
|
0
|
|
|
|
Bleeding
in a critical area or organ
|
0
|
0
|
|
|
|
Gastrointestinalb
|
2 (0.3)
|
0
|
|
|
Clinically
relevant non-major bleeding
|
34 (5.0)
|
13 (2.0)
|
2.54 (1.34, 4.82)
|
|
Any
bleeding
|
72 (10.5)
|
40 (6.1)
|
1.77 (1.20, 2.61)
|
In the RE-SONATE study, the rate of any
gastrointestinal bleeds in patients receiving Pradaxa 150 mg was 0.7% (0.3% on
placebo).
Clinical Myocardial Infarction Events
In the active-controlled VTE studies, a higher rate of clinical myocardial
infarction was reported in patients who received Pradaxa [20 (0.66 per 100
patient-years)] than in those who received warfarin [5 (0.17 per 100
patient-years)]. In the placebo-controlled study, a similar rate of non-fatal
and fatal clinical myocardial infarction was reported in patients who received
Pradaxa [1 (0.32 per 100 patient-years)] and in those who received placebo [1
(0.34 per 100 patient-years)].
Gastrointestinal Adverse Reactions
In the four pivotal studies, patients on Pradaxa 150 mg had a similar incidence
of gastrointestinal adverse reactions (24.7% vs. 22.7% on warfarin). Dyspepsia
(including abdominal pain upper, abdominal pain, abdominal discomfort, and
epigastric discomfort) occurred in patients on Pradaxa in 7.5% vs. 5.5% on
warfarin, and gastritis-like symptoms (including gastritis, GERD, esophagitis,
erosive gastritis and gastric hemorrhage) occurred at 3.0% vs. 1.7%,
respectively.
Hypersensitivity Reactions
In the 4 pivotal studies, drug hypersensitivity (including urticaria, rash, and
pruritus), allergic edema, anaphylactic reaction, and anaphylactic shock were
reported in 0.1% of patients receiving Pradaxa.
Prophylaxis of Deep Vein Thrombosis
and Pulmonary Embolism Following Hip Replacement Surgery
Pradaxa was studied in 5476 patients, randomized and treated in two
double-blind, active-controlled non-inferiority trials (RE-NOVATE and RE-NOVATE
II). The demographic characteristics were similar across the two studies and
between the treatment groups within these studies. Approximately 45.3 % of the
treated patients were male, with a mean age of 63.2 years. The majority of the
patients were white (96.1%), 3.6% were Asian, and 0.3% were black with a mean
CrCl of 92 mL/min.
Bleeding events for the RE-NOVATE and RE-NOVATE II
studies were classified as major bleeding events if at least one of the
following criteria applied: fatal bleeding, symptomatic bleeding in a critical
area or organ (intraocular, intracranial, intraspinal or retroperitoneal
bleeding), bleeding causing a fall in hemoglobin level of 2.0 g/dL (1.24
mmol/L) or more, or leading to transfusion of 2 or more units of whole blood or
red cells, requiring treatment cessation or leading to re-operation.
The RE-NOVATE study compared Pradaxa 75 mg taken
orally 1-4 hours after surgery followed by 150 mg once daily, Pradaxa 110 mg
taken orally 1-4 hours after surgery followed by 220 mg once daily and
subcutaneous enoxaparin 40 mg once daily initiated the evening before surgery
for the prophylaxis of deep vein thrombosis and pulmonary embolism in patients
who had undergone hip replacement surgery. The RE-NOVATE II study compared
Pradaxa 110 mg taken orally 1-4 hours after surgery followed by 220 mg once
daily and subcutaneous enoxaparin 40 mg once daily initiated the evening before
surgery for the prophylaxis of deep vein thrombosis and pulmonary embolism in
patients who had undergone hip replacement surgery. In the RE-NOVATE and
RE-NOVATE II studies, patients received 28-35 days of Pradaxa or enoxaparin
with median exposure of 33 days. Tables 6 and 7 show the number of patients
experiencing bleeding events in the analysis of RE-NOVATE and RE-NOVATE II.
Table 6 Bleeding Events in RE-NOVATE
Treated Patients
|
|
|
Pradaxa 220 mg
N
(%)
|
Enoxaparin
N
(%)
|
|
Patients
|
N=1146
|
N=1154
|
|
Major
bleeding event
|
23 (2.0)
|
18 (1.6)
|
|
Clinically
relevant non-major bleeding
|
48 (4.2)
|
40 (3.5)
|
|
Any
bleeding
|
141 (12.3)
|
132 (11.4)
|
Table 7 Bleeding Events in RE-NOVATE
II Treated Patients
|
|
|
Pradaxa 220 mg
N
(%)
|
Enoxaparin
N
(%)
|
|
Patients
|
N=1010
|
N=1003
|
|
Major
bleeding event
|
14 (1.4)
|
9 (0.9)
|
|
Clinically
relevant non-major bleeding
|
26 (2.6)
|
20 (2.0)
|
|
Any
bleeding
|
98 (9.7)
|
83 (8.3)
|
In the two studies, the rate of major
gastrointestinal bleeds in patients receiving Pradaxa and enoxaparin was the
same (0.1%) and for any gastrointestinal bleeds was 1.4% for Pradaxa 220 mg and
0.9% for enoxaparin.
Gastrointestinal Adverse Reactions
In the two studies, the incidence of gastrointestinal adverse reactions for
patients on Pradaxa 220 mg and enoxaparin was 39.5% and 39.5%, respectively.
Dyspepsia (including abdominal pain upper, abdominal pain, abdominal
discomfort, and epigastric discomfort) occurred in patients on Pradaxa 220 mg
in 4.1% vs. 3.8% on enoxaparin, and gastritis-like symptoms (including
gastritis, GERD, esophagitis, erosive gastritis and gastric hemorrhage)
occurred at 0.6% vs. 1.0%, respectively.
Hypersensitivity Reactions
In the two studies, drug hypersensitivity (such as urticaria, rash, and
pruritus) was reported in 0.3% of patients receiving Pradaxa 220 mg.
Clinical Myocardial Infarction Events
In the two studies, clinical myocardial infarction was reported in 2 (0.1%) of
patients who received Pradaxa 220 mg and 6 (0.3%) of patients who received
enoxaparin.
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. The following adverse reactions
have been identified during post approval use of Pradaxa: angioedema,
thrombocytopenia, esophageal ulcer.
7 DRUG INTERACTIONS
Reduction of Risk of Stroke and Systemic Embolism in
Non-valvular Atrial Fibrillation
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.
In
patients with moderate renal impairment (CrCl 30-50 mL/min), reduce the dose of
Pradaxa to 75 mg twice daily when administered concomitantly with the P-gp
inhibitors dronedarone or systemic ketoconazole. The use of the P-gp inhibitors
verapamil, amiodarone, quinidine, clarithromycin, and ticagrelor does not
require a dose adjustment of Pradaxa. These results should not be extrapolated
to other P-gp inhibitors [see Warnings and Precautions (5.5), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
The
concomitant use of Pradaxa and P-gp inhibitors in patients with severe renal
impairment (CrCl 15-30 mL/min) should be avoided [see Warnings
and Precautions (5.5), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
Treatment and Reduction in the Risk of Recurrence of
Deep Venous Thrombosis and Pulmonary Embolism
Avoid use
of Pradaxa and P-gp inhibitors in patients with CrCl <50 mL/min [see
Warnings and Precautions (5.5), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
Prophylaxis of Deep Vein Thrombosis and Pulmonary
Embolism Following Hip Replacement Surgery
In
patients with CrCl ≥50 mL/min who have concomitant administration of P-gp
inhibitors such as dronedarone or systemic ketoconazole, it may be helpful to
separate the timing of administration of dabigatran and the P-gp inhibitor by
several hours. The concomitant use of Pradaxa and P-gp inhibitors in patients
with CrCl <50 mL/min should be avoided [see Warnings
and Precautions (5.5), Use in Specific Populations (8.6) and Clinical Pharmacology (12.2, 12.3)].
8 USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C
There are
no adequate and well-controlled studies in pregnant women.
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 maximum recommended human dose [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. Although dabigatran
increased the incidence of delayed or irregular ossification of fetal skull
bones and vertebrae in the rat, it did not induce major malformations in rats
or rabbits.
Labor and Delivery
Safety
and effectiveness of Pradaxa during labor and delivery have not been studied in
clinical trials. Consider the risks of bleeding and of stroke in using Pradaxa
in this setting [see Warnings and Precautions (5.2)].
Death of
offspring and mother rats during labor in association with uterine bleeding
occurred during treatment of pregnant rats from implantation (gestation Day 7)
to weaning (lactation Day 21) with dabigatran at a dose of 70 mg/kg (about 2.6
times the human exposure at MRHD of 300 mg/day based on AUC comparisons).
Nursing Mothers
It is not
known whether dabigatran is excreted in human milk. Because many drugs are
excreted in human milk and because of the potential for serious adverse
reactions in nursing infants from Pradaxa, a decision should be made whether to
discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.
Pediatric Use
Safety
and effectiveness of Pradaxa in pediatric patients have not been established.
Geriatric Use
Of the
total number of patients in the RE-LY study, 82% were 65 and over, while 40%
were 75 and over. The risk of stroke and bleeding increases with age, but the
risk-benefit profile is favorable in all age groups [see Warnings
and Precautions (5), Adverse Reactions (6.1), and Clinical Studies (14.1)].
Renal Impairment
Reduction of Risk of Stroke and Systemic Embolism in
Non-valvular Atrial Fibrillation
No dose
adjustment of Pradaxa is recommended in patients with mild or moderate renal
impairment [see Clinical Pharmacology (12.3)].
Reduce the dose of Pradaxa in patients with severe renal impairment (CrCl 15-30
mL/min) [see Dosage and Administration (2.1, 2.2) and Clinical Pharmacology (12.3)].
Dosing recommendations for patients with CrCl <15 mL/min or on dialysis
cannot be provided.
Adjust
dose appropriately in patients with renal impairment receiving concomitant P-gp
inhibitors [see Warnings and Precautions (5.5), Drug Interactions (7.1), and Clinical Pharmacology (12.3)].
Treatment and Reduction in the Risk of Recurrence of
Deep Venous Thrombosis and Pulmonary Embolism
Patients
with severe renal impairment (CrCl ≤30 mL/min) were excluded from RE-COVER.
Dosing
recommendations for patients with CrCl ≤30 mL/min or on dialysis cannot be
provided. Avoid use of Pradaxa with concomitant P-gp inhibitors in patients
with CrCl <50 mL/min [see Warnings and Precautions (5.5), Drug Interactions (7.2), and Clinical Pharmacology (12.3)].
Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism
Following Hip Replacement Surgery
Patients with severe renal impairment (CrCl <30 mL/min) were excluded from
RE-NOVATE and RE-NOVATE II.
Dosing
recommendations for patients with CrCl <30 mL/min or on dialysis cannot be
provided.
Avoid use
of Pradaxa with concomitant P-gp inhibitors in patients with CrCl <50
mL/min [see Warnings and Precautions (5.5), Drug Interactions (7.3) and Clinical Pharmacology (12.2, 12.3)].
10 OVERDOSAGE
Accidental
overdose may lead to hemorrhagic complications. In the event of hemorrhagic
complications, initiate appropriate clinical support, discontinue treatment
with Pradaxa, and investigate the source of bleeding. A specific reversal agent
(idarucizumab) is available.
Dabigatran
is primarily eliminated by the kidneys with a low plasma protein binding of
approximately 35%. Hemodialysis can remove dabigatran; however, data supporting
this approach are limited. Using a high-flux dialyzer, blood flow rate of 200
mL/min, and dialysate flow rate of 700 mL/min, approximately 49% of total
dabigatran can be cleared from plasma over 4 hours. At the same dialysate flow
rate, approximately 57% can be cleared using a dialyzer blood flow rate of 300
mL/min, with no appreciable increase in clearance observed at higher blood flow
rates. Upon cessation of hemodialysis, a redistribution effect of approximately
7% to 15% is seen. The effect of dialysis on dabigatran’s plasma concentration
would be expected to vary based on patient specific characteristics.
Measurement of aPTT or ECT may help guide therapy [see Warnings
and Precautions (5.2) and Clinical Pharmacology (12.2)].
11 DESCRIPTION
The
chemical name for dabigatran etexilate mesylate, a direct thrombin inhibitor,
is β-Alanine,
N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate.
The empirical formula is C34H41N7O5 ⋅ CH4O3S and the molecular weight is 723.86 (mesylate salt),
627.75 (free base). The structural formula is:
Dabigatran
etexilate mesylate is a yellow-white to yellow powder. A saturated solution in
pure water has a solubility of 1.8 mg/mL. It is freely soluble in methanol,
slightly soluble in ethanol, and sparingly soluble in isopropanol.
Pradaxa
capsules are supplied in 75, 110, and 150 mg strengths for oral administration.
Each capsule contains dabigatran etexilate mesylate as the active ingredient:
172.95 mg dabigatran etexilate mesylate (equivalent to 150 mg dabigatran
etexilate), 126.83 mg dabigatran etexilate mesylate (equivalent to 110 mg
dabigatran etexilate), or 86.48 mg dabigatran etexilate mesylate (equivalent to
75 mg dabigatran etexilate) along with the following inactive ingredients:
acacia, dimethicone, hypromellose, hydroxypropyl cellulose, talc, and tartaric
acid. The capsule shell is composed of carrageenan, hypromellose, potassium
chloride, titanium dioxide, black edible ink, and FD&C Blue No. 2 (150 mg
and 110 mg capsules only).
12 CLINICAL PHARMACOLOGY
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.
Pharmacodynamics
At
recommended therapeutic doses, dabigatran etexilate prolongs the coagulation
markers such as aPTT, ECT, and TT. INR is relatively insensitive to the
exposure to dabigatran and cannot be interpreted the same way as used for
warfarin monitoring.
The aPTT
test provides an approximation of Pradaxa’s anticoagulant effect. The average
time course for effects on aPTT, following approved dosing regimens in patients
with various degrees of renal impairment is shown in Figure 2. The curves
represent mean levels without confidence intervals; variations should be
expected when measuring aPTT. While advice cannot be provided on the level of
recovery of aPTT needed in any particular clinical setting, the curves can be
used to estimate the time to get to a particular level of recovery, even when
the time since the last dose of Pradaxa is not precisely known. In the RE-LY
trial, the median (10th to 90th percentile)
trough aPTT in patients receiving the 150 mg dose was 52 (40 to 76) seconds.
Figure 2 Average Time Course for Effects of Dabigatran on aPTT,
Following Approved Pradaxa Dosing Regimens in Patients with Various Degrees of
Renal Impairment*
*Simulations
based on PK data from a study in subjects with renal impairment and PK/aPTT
relationships derived from the RE-LY study; aPTT prolongation in RE-LY was
measured centrally in citrate plasma using PTT Reagent Roche Diagnostics GmbH,Mannheim,Germany.
There may be quantitative differences between various established methods for
aPTT assessment.
The
degree of anticoagulant activity can also be assessed by the ecarin clotting
time (ECT). This test is a more specific measure of the effect of dabigatran
than activated partial thromboplastin time (aPTT). In the RE-LY trial, the
median (10th to 90th percentile)
trough ECT in patients receiving the 150 mg dose was 63 (44 to 103) seconds.
In
orthopedic hip surgery patients, maximum aPTT response (Emax) to dabigatran and
baseline aPTT were higher shortly after surgery than at later time points (e.g.
≥3 days after surgery).
Cardiac Electrophysiology
No
prolongation of the QTc interval was observed with dabigatran etexilate at
doses up to 600 mg.
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 subjects and patients in the
range of doses from 10 to 400 mg.
Absorption
The
absolute bioavailability of dabigatran following oral administration of
dabigatran etexilate is approximately 3 to 7%. Dabigatran etexilate is a
substrate of the efflux transporter P-gp. After oral administration of
dabigatran etexilate in healthy volunteers, Cmax occurs
at 1 hour post-administration in the fasted state. Coadministration of Pradaxa
with a high-fat meal delays the time to Cmax by
approximately 2 hours but has no effect on the bioavailability of dabigatran;
Pradaxa may be administered with or without food.
The oral
bioavailability of dabigatran etexilate increases by 75% when the pellets are
taken without the capsule shell compared to the intact capsule formulation.
Pradaxa capsules should therefore not be broken, chewed, or opened before
administration.
Distribution
Dabigatran
is approximately 35% bound to human plasma proteins. The red blood cell to
plasma partitioning of dabigatran measured as total radioactivity is less than
0.3. The volume of distribution of dabigatran is 50 to 70 L. Dabigatran
pharmacokinetics are dose proportional after single doses of 10 to 400 mg.
Given twice daily, dabigatran’s accumulation factor is approximately two.
Elimination
Dabigatran
is eliminated primarily in the urine. Renal clearance of dabigatran is 80% of
total clearance after intravenous administration. After oral administration of
radiolabeled dabigatran, 7% of radioactivity is recovered in urine and 86% in
feces. The half-life of dabigatran in healthy subjects is 12 to 17 hours.
After
oral administration, dabigatran etexilate is converted to dabigatran. The
cleavage of the dabigatran etexilate by esterase-catalyzed hydrolysis to the
active principal dabigatran is the predominant metabolic reaction. Dabigatran
is not a substrate, inhibitor, or inducer of CYP450 enzymes. Dabigatran is
subject to conjugation forming pharmacologically active acyl glucuronides. Four
positional isomers, 1-O, 2-O, 3-O, and 4-O-acylglucuronide exist, and each
accounts for less than 10% of total dabigatran in plasma.
Renal Impairment
An open, parallel-group
single-center study compared dabigatran pharmacokinetics in healthy subjects
and patients with mild to moderate renal impairment receiving a single dose of
Pradaxa 150 mg. Exposure to dabigatran increases with severity of renal
function impairment (Table 8). Similar findings were observed in the RE-LY,
RE-COVER and RE-NOVATE II trials.
Table 8 Impact of Renal Impairment on
Dabigatran Pharmacokinetics
|
|
+Patients
with severe renal impairment were not studied in RE-LY, RE-COVER and RE-NOVATE
II. Dosing recommendations in subjects with severe renal impairment are based
on pharmacokinetic modeling [see Dosage and Administration (2.1, 2.2) and Use in
Specific Populations (8.6)].
|
|
Renal
Function
|
CrCl
(mL/min)
|
Increase
in AUC
|
Increase
in Cmax
|
t1/2
(h)
|
|
Normal
|
≥ 80
|
1x
|
1x
|
13
|
|
Mild
|
50-80
|
1.5x
|
1.1x
|
15
|
|
Moderate
|
30-50
|
3.2x
|
1.7x
|
18
|
|
Severe+
|
15-30
|
6.3x
|
2.1x
|
27
|
Hepatic Impairment
Administration
of Pradaxa in patients with moderate hepatic impairment (Child-Pugh B) showed a
large inter-subject variability, but no evidence of a consistent change in
exposure or pharmacodynamics.
Drug Interactions
A summary
of the effect of coadministered drugs on dabigatran exposure is shown in
Figures 3.1 and 3.2.
In the
orthopedic hip surgery patients, limited clinical data with P-gp inhibitors is
available.
Figure 3.1 Effect of P-gp Inhibitor or Inducer (rifampicin)
Drugs on Peak and Total Exposure to Dabigatran (Cmax and AUC). Shown are the
Geometric Mean Ratios (Ratio) and 90% Confidence Interval (90% CI). The
Perpetrator and Dabigatran Etexilate Dose and Dosing Frequency are given as
well as the Time of Perpetrator Dosing in Relation to Dabigatran Etexilate Dose
(Time Difference)
Figure 3.2 Effect of Non-P-gp Inhibitor or Inducer, Other Drugs,
on Peak and Total Exposure to Dabigatran (Cmax and AUC). Shown are the
Geometric Mean Ratios (Ratio) and 90% Confidence Interval (90% CI). The
Perpetrator and Dabigatran Etexilate Dose and Dosing Frequency are given as
well as the Time of Perpetrator Dosing in Relation to Dabigatran Etexilate Dose
(Time Difference)
In RE-LY,
dabigatran plasma samples were also collected. The concomitant use of proton
pump inhibitors, H2 antagonists, and digoxin did not appreciably change the
trough concentration of dabigatran.
Impact of Dabigatran on Other Drugs
In clinical studies exploring CYP3A4, CYP2C9, P-gp and other pathways,
dabigatran did not meaningfully alter the pharmacokinetics of amiodarone,
atorvastatin, clarithromycin, diclofenac, clopidogrel, digoxin, pantoprazole,
or ranitidine.
13 NONCLINICAL TOXICOLOGY
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 CLINICAL STUDIES
Reduction of Risk of Stroke and Systemic Embolism in
Non-valvular Atrial Fibrillation
The
clinical evidence for the efficacy of Pradaxa was derived from RE-LY
(Randomized Evaluation of Long-term Anticoagulant Therapy), a multi-center,
multi-national, randomized parallel group trial comparing two blinded doses of
Pradaxa (110 mg twice daily and 150 mg twice daily) with open-label warfarin
(dosed to target INR of 2 to 3) in patients with non-valvular, persistent,
paroxysmal, or permanent atrial fibrillation and one or more of the following
additional risk factors:
· Previous stroke, transient ischemic attack (TIA), or
systemic embolism
· Left ventricular ejection fraction <40%
· Symptomatic heart failure, ≥ New York Heart
Association Class 2
· Age ≥75 years
· Age ≥65 years and one of the following: diabetes
mellitus, coronary artery disease (CAD), or hypertension
The
primary objective of this study was to determine if Pradaxa was non-inferior to
warfarin in reducing the occurrence of the composite endpoint, stroke (ischemic
and hemorrhagic) and systemic embolism. The study was designed to ensure that
Pradaxa preserved more than 50% of warfarin’s effect as established by previous
randomized, placebo-controlled trials of warfarin in atrial fibrillation.
Statistical superiority was also analyzed.
A total
of 18,113 patients were randomized and followed for a median of 2 years. The
patients’ mean age was 71.5 years and the mean CHADS2 score
was 2.1. The patient population was 64% male, 70% Caucasian, 16% Asian, and 1%
black. Twenty percent of patients had a history of a stroke or TIA and 50% were
Vitamin K antagonist (VKA) naïve, defined as less than 2 months total lifetime
exposure to a VKA. Thirty-two percent of the population had never been exposed
to a VKA. Concomitant diseases of patients in this trial included hypertension
79%, diabetes 23%, and CAD 28%. At baseline, 40% of patients were on aspirin
and 6% were on clopidogrel. For patients randomized to warfarin, the mean
percentage of time in therapeutic range (INR 2 to 3) was 64%.
Relative
to warfarin and to Pradaxa 110 mg twice daily, Pradaxa 150 mg twice daily
significantly reduced the primary composite endpoint of stroke and systemic
embolism (see Table 9 and Figure 4).
Table 9 First Occurrence of Stroke or
Systemic Embolism in the RE-LY Study*
|
|
* Randomized ITT
|
|
|
Pradaxa
150
mg twice daily
|
Pradaxa
110
mg twice daily
|
Warfarin
|
|
Patients
randomized
|
6076
|
6015
|
6022
|
|
Patients (%)
with events
|
135 (2.2%)
|
183 (3%)
|
203 (3.4%)
|
|
Hazard ratio vs.
warfarin (95% CI)
|
0.65 (0.52, 0.81)
|
0.89 (0.73, 1.09)
|
|
|
P-value
for superiority
|
0.0001
|
0.27
|
|
|
Hazard ratio vs.
Pradaxa 110 mg (95% CI)
|
0.72 (0.58, 0.91)
|
|
|
|
P-value
for superiority
|
0.005
|
|
|
Figure 4 Kaplan-Meier Curve Estimate of Time to First Stroke or
Systemic Embolism
The
contributions of the components of the composite endpoint, including stroke by
subtype, are shown in Table 10. The treatment effect was primarily a reduction
in stroke. Pradaxa 150 mg twice daily was superior in reducing ischemic and
hemorrhagic strokes relative to warfarin.
Table 10 Strokes and Systemic Embolism in
the RE-LY Study
|
|
|
Pradaxa
150
mg twice daily
|
Warfarin
|
Hazard ratio
vs. warfarin
(95%
CI)
|
|
Patients
randomized
|
6076
|
6022
|
|
|
Stroke
|
123
|
187
|
0.64 (0.51, 0.81)
|
|
Ischemic
stroke
|
104
|
134
|
0.76 (0.59, 0.98)
|
|
Hemorrhagic
stroke
|
12
|
45
|
0.26 (0.14, 0.49)
|
|
Systemic
embolism
|
13
|
21
|
0.61 (0.30, 1.21)
|
In the
RE-LY trial, the rate of all-cause mortality was lower on dabigatran 150 mg
than on warfarin (3.6% per year versus 4.1% per year). The rate of vascular
death was lower on dabigatran 150 mg compared to warfarin (2.3% per year versus
2.7% per year). Non-vascular death rates were similar in the treatment arms.
The
efficacy of Pradaxa 150 mg twice daily was generally consistent across major
subgroups (see Figure 5).
Figure 5 Stroke and Systemic Embolism Hazard Ratios by Baseline
Characteristics*
*
Randomized ITT
Note: The figure above presents effects in various subgroups all of which are
baseline characteristics and all of which were pre-specified. The 95%
confidence limits that are shown do not take into account how many comparisons
were made, nor do they reflect the effect of a particular factor after
adjustment for all other factors. Apparent homogeneity or heterogeneity among
groups should not be over-interpreted.
In RE-LY,
a higher rate of clinical myocardial infarction was reported in patients who
received Pradaxa (0.7 per 100 patient-years for 150 mg dose) than in those who
received warfarin (0.6).
Treatment and Reduction in the Risk of Recurrence of
Deep Venous Thrombosis and Pulmonary Embolism
In the
randomized, parallel group, double-blind trials, RE-COVER and RE-COVER II,
patients with deep vein thrombosis and pulmonary embolism received Pradaxa 150
mg twice daily or warfarin (dosed to target INR of 2 to 3) following initial
treatment with an approved parenteral anticoagulant for 5-10 days.
In
RE-COVER, the median treatment duration during the oral only treatment period
was 174 days. A total of 2539 patients (30.9% patients with symptomatic PE with
or without DVT and 68.9% with symptomatic DVT only) were treated with a mean
age of 54.7 years. The patient population was 58.4% male, 94.8% white, 2.6%
Asian, and 2.6% black. The concomitant diseases of patients in this trial
included hypertension (35.9%), diabetes mellitus (8.3%), coronary artery
disease (6.5%), active cancer (4.8%), and gastric or duodenal ulcer (4.4%).
Concomitant medications included agents acting on renin-angiotensin system
(25.2%), vasodilators (28.4%), serum lipid-reducing agents (18.2%), NSAIDs
(21%), beta-blockers (14.8%), calcium channel blockers (8.5%), ASA (8.6%), and
platelet inhibitors excluding ASA (0.6%). Patients randomized to warfarin had a
mean percentage of time in the INR target range of 2.0 to 3.0 of 60% in
RE-COVER study.
In
RE-COVER II, the median treatment duration during the oral only treatment
period was 174 days. A total of 2568 patients (31.8% patients with symptomatic
PE with or without DVT and 68.1% with symptomatic DVT only) were treated with a
mean age of 54.9 years. The patient population was 60.6% male, 77.6% white,
20.9% Asian, and 1.5% black. The concomitant diseases of patients in this trial
included hypertension (35.1%), diabetes mellitus (9.8%), coronary artery
disease (7.1%), active cancer (3.9%), and gastric or duodenal ulcer (3.8%).
Concomitant medications included agents acting on renin-angiotensin system
(24.2%), vasodilators (28.6%), serum lipid-reducing agents (20.0%), NSAIDs
(22.3%), beta-blockers (14.8%), calcium channel blockers (10.8%), ASA (9.8%),
and platelet inhibitors excluding ASA (0.8%). Patients randomized to warfarin
had a mean percentage of time in the INR target range of 2.0 to 3.0 of 57% in
RE-COVER II study.
In
studies RE-COVER and RE-COVER II, the protocol specified non-inferiority margin
(2.75) for the hazard ratio was derived based on the upper limit of the 95%
confidence interval of the historical warfarin effect. Pradaxa was demonstrated
to be non-inferior to warfarin (dosed to target INR of 2 to 3) (Table 11) based
on the primary composite endpoint (fatal PE or symptomatic non-fatal PE and/or
DVT) and retains at least 66.9% (RE-COVER) and 63.9% (RE-COVER II) of the
historical warfarin effect, respectively.
Table 11 Primary Efficacy Endpoint for
RE-COVER and RE-COVER II – Modified ITTa Population
|
|
aModified
ITT analyses population consists of all randomized patients who received at
least one dose of study medication.
bNumber of
patients with one or more event.
cNumber of
events. For patients with multiple events each event is counted
independently.
|
|
|
Pradaxa
150 mg twice daily
N (%)
|
Warfarin
N (%)
|
Hazard ratio vs.
warfarin (95% CI)
|
|
RE-COVER
|
N=1274
|
N=1265
|
|
|
Primary
Composite Endpointb
|
34 (2.7)
|
32 (2.5)
|
1.05 (0.65, 1.70)
|
|
|
Fatal PEc
|
1 (0.1)
|
3 (0.2)
|
|
|
|
Symptomatic
non-fatal PEc
|
16 (1.3)
|
8 (0.6)
|
|
|
|
Symptomatic
recurrent DVTc
|
17 (1.3)
|
23 (1.8)
|
|
|
RE-COVER II
|
N=1279
|
N=1289
|
|
|
Primary
Composite Endpointb
|
34 (2.7)
|
30 (2.3)
|
1.13 (0.69, 1.85)
|
|
|
Fatal PEc
|
3 (0.2)
|
0
|
|
|
|
Symptomatic
non-fatal PEc
|
9 (0.7)
|
15 (1.2)
|
|
|
|
Symptomatic
recurrent DVTc
|
30 (2.3)
|
17 (1.3)
|
|
In the
randomized, parallel group, double-blind, pivotal trial, RE-MEDY, patients
received Pradaxa 150 mg twice daily or warfarin (dosed to target INR of 2 to 3)
following 3 to 12 months of treatment with anticoagulation therapy for an acute
VTE. The median treatment duration during the treatment period was 534 days. A
total of 2856 patients were treated with a mean age of 54.6 years. The patient
population was 61% male, and 90.1% white, 7.9% Asian and 2.0% black. The
concomitant diseases of patients in this trial included hypertension (38.6%),
diabetes mellitus (9.0%), coronary artery disease (7.2%), active cancer (4.2%),
and gastric or duodenal ulcer (3.8%). Concomitant medications included agents
acting on renin-angiotensin system (27.9%), vasodilators (26.7%), serum lipid
reducing agents (20.6%), NSAIDs (18.3%), beta-blockers (16.3%), calcium channel
blockers (11.1%), aspirin (7.7%), and platelet inhibitors excluding ASA (0.9%).
Patients randomized to warfarin had a mean percentage of time in the INR target
range of 2.0 to 3.0 of 62% in the study.
n study
RE-MEDY, the protocol specified non-inferiority margin (2.85) for the hazard
ratio was derived based on the point estimate of the historical warfarin
effect. Pradaxa was demonstrated to be non-inferior to warfarin (dosed to
target INR of 2 to 3) (Table 12) based on the primary composite endpoint (fatal
PE or symptomatic non-fatal PE and/or DVT) and retains at least 63.0% of
the historical warfarin effect. If the non-inferiority margin was derived based
on the 50% retention of the upper limit of the 95% confidence interval, Pradaxa
was demonstrated to retain at least 33.4% of the historical warfarin effect
based on the composite primary endpoint.
Table 12 Primary Efficacy Endpoint for
RE-MEDY – Modified ITTa Population
|
|
aModified
ITT analyses population consists of all randomized patients who received at
least one dose of study medication.
bNumber of
patients with one or more event.
cNumber of
events. For patients with multiple events each event is counted
independently.
|
|
|
Pradaxa
150 mg twice daily
N=1430
N (%)
|
Warfarin
N=1426
N (%)
|
Hazard ratio vs.
warfarin (95% CI)
|
|
Primary
Composite Endpointb
|
26 (1.8)
|
18 (1.3)
|
1.44 (0.78, 2.64)
|
|
|
Fatal PEc
|
1 (0.07)
|
1 (0.07)
|
|
|
|
Symptomatic
non-fatal PEc
|
10 (0.7)
|
5 (0.4)
|
|
|
|
Symptomatic
recurrent DVTc
|
17 (1.2)
|
13 (0.9)
|
|
In a
randomized, parallel group, double-blind, pivotal trial, RE-SONATE, patients
received Pradaxa 150 mg twice daily or placebo following 6 to 18 months of
treatment with anticoagulation therapy for an acute VTE. The median treatment
duration was 182 days. A total of 1343 patients were treated with a mean age of
55.8 years. The patient population was 55.5% male, 89.0% white, 9.3% Asian, and
1.7% black. The concomitant diseases of patients in this trial included
hypertension (38.8%), diabetes mellitus (8.0%), coronary artery disease (6.0%),
history of cancer (6.0%), gastric or duodenal ulcer (4.5%), and heart failure
(4.6%). Concomitant medications included agents acting on renin-angiotensin
system (28.7%), vasodilators (19.4%), beta-blockers (18.5%), serum lipid
reducing agents (17.9%), NSAIDs (12.1%), calcium channel blockers (8.9%),
aspirin (8.3%), and platelet inhibitors excluding ASA (0.7%). Based on the
outcome of the primary composite endpoint (fatal PE, unexplained death, or
symptomatic non-fatal PE and/or DVT), Pradaxa was superior to placebo (Table
13).
Table 13 Primary Efficacy Endpoint for
RE-SONATE – Modified ITTa Population
|
|
aModified
ITT analyses population consists of all randomized patients who received at
least one dose of study medication.
bNumber of
patients with one or more events.
cNumber of
events. For patients with multiple events each event is counted
independently.
|
|
|
Pradaxa
150 mg twice daily
N=681
N (%)
|
Placebo
N=662
N (%)
|
Hazard ratio vs.
placebo (95% CI)
|
|
Primary
Composite Endpointb
|
3 (0.4)
|
37 (5.6)
|
0.08 (0.02, 0.25)
p-value <0.0001
|
|
|
Fatal PE and
unexplained deathc
|
0
|
2 (0.3)
|
|
|
|
Symptomatic
non-fatal PEc
|
1 (0.1)
|
14 (2.1)
|
|
|
|
Symptomatic
recurrent DVTc
|
2 (0.3)
|
23 (3.5)
|
|
Prophylaxis of Deep Vein Thrombosis and Pulmonary
Embolism Following Hip Replacement Surgery
In the
randomized, parallel group, double-blind, non-inferiority trials, RE-NOVATE and
RE-NOVATE II patients received Pradaxa 75 mg orally 1-4 hours after surgery
followed by 150 mg daily (RE-NOVATE), Pradaxa 110 mg orally 1-4 hours after
surgery followed by 220 mg daily (RE-NOVATE and RE-NOVATE II) or subcutaneous
enoxaparin 40 mg once daily initiated the evening before surgery (RE-NOVATE and
RE-NOVATE II) for the prophylaxis of deep vein thrombosis and pulmonary
embolism in patients who have undergone hip replacement surgery.
Overall,
in RE-NOVATE and RE-NOVATE II, the median treatment duration was 33 days for
Pradaxa and 33 days for enoxaparin. A total of 5428 patients were treated with
a mean age of 63.2 years. The patient population was 45.3% male, 96.1% white,
3.6% Asian, and 0.4 % black. The concomitant diseases of patients in these
trials included hypertension (46.1%), venous insufficiency (15.4%), coronary
artery disease (8.2%), diabetes mellitus (7.9%), reduced renal function (5.3%),
heart failure (3.4%), gastric or duodenal ulcer (3.0%), VTE (2.7%), and
malignancy (0.1%). Concomitant medications included cardiac therapy (69.7%),
NSAIDs (68%), vasoprotectives (29.7%), agents acting on renin-angiotensin
system (29.1%), beta-blockers (21.5%), diuretics (20.8%), lipid modifying
agents (18.2%), any antithrombin/anticoagulant (16.0%), calcium channel
blockers (13.6%), low molecular weight heparin (7.8%), aspirin (7.0%), platelet
inhibitors excluding ASA (6.9%), other antihypertensives (6.7%), and peripheral
vasodilators (2.6%).
For
efficacy evaluation all patients were to have bilateral venography of the lower
extremities at 3 days after last dose of study drug unless an endpoint event
had occurred earlier in the study. In the primary efficacy analysis, Pradaxa
110 mg orally 1-4 hours after surgery followed by 220 mg daily was non-inferior
to enoxaparin 40 mg once daily in a composite endpoint of confirmed VTE
(proximal or distal DVT on venogram, confirmed symptomatic DVT, or confirmed
PE) and all cause death during the treatment period (Tables 14 and 15). In the
studies 2628 (76.5%) patients in RE-NOVATE and 1572 (78.9%) patients in
RE-NOVATE II had evaluable venograms at study completion.
Table 14 Primary
Efficacy Endpoint for RE-NOVATE
|
|
aFull
Analysis Set (FAS): The FAS included all randomized patients who received at
least one subcutaneous injection or one oral dose of study medication,
underwent surgery and subjects for whom the presence or absence of an
efficacy outcome at the end of the study was known, i.e., an evaluable
negative venogram for both distal and proximal DVT in both legs or any of the
following: positive venography in one or both legs, or confirmed symptomatic
DVT, PE, or death during the treatment period.
bVTE is defined as proximal DVT and PE
|
|
|
Pradaxa
220
mg
N
(%)
|
Enoxaparin
N
(%)
|
|
Number of Patientsa
|
N=880
|
N= 897
|
|
Primary
Composite Endpoint
|
53 (6.0)
|
60 (6.7)
|
|
Risk
difference (%) vs. enoxaparin (95% CI)
|
-0.7 (-2.9, 1.6)
|
|
|
Number of Patients
|
N=909
|
N=917
|
|
Composite
endpoint of major VTEb and VTE related mortality
|
28 (3.1)
|
36 (3.9)
|
|
Number of Patients
|
N=905
|
N=914
|
|
Proximal DVT
|
23 (2.5)
|
33 (3.6)
|
|
Number of Patients
|
N=874
|
N=894
|
|
Total DVT
|
46 (5.3)
|
57 (6.4)
|
|
Number of Patients
|
N=1137
|
N=1142
|
|
Symptomatic DVT
|
6 (0.5)
|
1 (0.1)
|
|
PE
|
5 (0.4)
|
3 (0.3)
|
|
Death
|
3 (0.3)
|
0
|
Table 15 Primary
Efficacy Endpoint for RE-NOVATE II
|
|
aFull
Analysis Set (FAS): The FAS included all randomized patients who received at
least one subcutaneous injection or one oral dose of study medication,
underwent surgery and subjects for whom the presence or absence of an
efficacy outcome at the end of the study was known, i.e., an evaluable
negative venogram for both distal and proximal DVT in both legs or any of the
following: positive venography in one or both legs, or confirmed symptomatic
DVT, PE, or death during the treatment period.
bVTE is defined as proximal DVT and PE
|
|
|
Pradaxa
220
mg
N
(%)
|
Enoxaparin
N
(%)
|
|
Number of Patientsa
|
N=792
|
N= 786
|
|
Primary
Composite Endpoint
|
61 (7.7)
|
69 (8.8)
|
|
Risk
difference (%) vs. enoxaparin (95% CI)
|
-1.1 (-3.8, 1.6)
|
|
|
Number of Patients
|
N=805
|
N=795
|
|
Composite
endpoint of major VTEb and VTE related mortality
|
18 (2.2)
|
33 (4.2)
|
|
Number of Patients
|
N=804
|
N=793
|
|
Proximal DVT
|
17 (2.1)
|
31 (3.9)
|
|
Number of Patients
|
N=791
|
N=784
|
|
Total DVT
|
60 (7.6)
|
67 (8.5)
|
|
Number of Patients
|
N=1001
|
N=992
|
|
Symptomatic DVT
|
0
|
4 (0.4)
|
|
PE
|
1 (0.1)
|
2 (0.2)
|
|
Death
|
0
|
1 (0.1)
|
16 HOW SUPPLIED/STORAGE AND HANDLING
Pradaxa
75 mg capsules have a white opaque cap imprinted with the Boehringer Ingelheim
company symbol and a white opaque body imprinted with “R75”. The color of the
imprinting is black. The capsules are supplied in the packages listed:
· NDC 0597-0355-09 Unit of use bottle
of 60 capsules
· NDC 0597-0355-56 Blister package
containing 60 capsules (10 x 6 capsule blister cards)
Pradaxa
110 mg capsules have a light blue opaque cap imprinted with the Boehringer
Ingelheim company symbol and a light blue opaque body imprinted with “R110”.
The color of the imprinting is black. The capsules are supplied in the packages
listed:
· NDC 0597-0108-54 Unit of use bottle
of 60 capsules
· NDC 0597-0108-60 Blister package
containing 60 capsules (10 x 6 capsule blister cards)
Pradaxa
150 mg capsules have a light blue opaque cap imprinted with the Boehringer
Ingelheim company symbol and a white opaque body imprinted with “R150”. The
color of the imprinting is black. The capsules are supplied in the packages
listed:
· NDC 0597-0360-55 Unit of use bottle
of 60 capsules
· NDC 0597-0360-82 Blister package
containing 60 capsules (10 x 6 capsule blister cards)
Bottles
Store at
25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP
Controlled Room Temperature]. Once opened, the product must be used within 4
months. Keep the bottle tightly closed. Store in the original package to
protect from moisture.
Blisters
Store at
25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP
Controlled Room Temperature]. Store in the original package to protect from
moisture.
Keep out
of the reach of children.
17 PATIENT COUNSELING INFORMATION
Advise
the patient to read the FDA-approved patient labeling (Medication Guide).
Instructions for Patients
· Tell patients to take Pradaxa exactly as prescribed.
· Remind patients not to discontinue Pradaxa without
talking to the health care provider who prescribed it.
· Keep Pradaxa in the original bottle to protect from
moisture. Do not put Pradaxa in pill boxes or pill organizers.
· When more than one bottle is dispensed to the
patient, instruct them to open only one bottle at a time.
· Instruct patient to remove only one capsule from the
opened bottle at the time of use. The bottle should be immediately and tightly
closed.
· Advise patients not to chew or break the capsules
before swallowing them and not to open the capsules and take the pellets alone.
· Advise patients that the capsule should be taken with
a full glass of water.
Bleeding
Inform
patients that they may bleed more easily, may bleed longer, and should call
their health care provider for any signs or symptoms of bleeding.
Instruct
patients 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 to call their health care 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 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 to
contact his or her physician immediately [see Boxed Warning].
Gastrointestinal Adverse Reactions
Instruct
patients to call their health care 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)
Invasive or Surgical Procedures
Instruct
patients to inform their health care provider that they are taking Pradaxa
before any invasive procedure (including dental procedures) is scheduled.
Concomitant Medications
Ask
patients to list all prescription medications, over-the-counter medications, or
dietary supplements they are taking or plan to take so their health care
provider knows about other treatments that may affect bleeding risk (e.g.,
aspirin or NSAIDs) or dabigatran exposure (e.g., dronedarone or systemic
ketoconazole).
Prosthetic Heart Valves
Instruct
patients to inform their health care provider if they will have or have had
surgery to place a prosthetic heart valve.
Distributed
by:
Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield,CT06877USA
Copyright
2017 Boehringer Ingelheim Pharmaceuticals, Inc.
ALL RIGHTS RESERVED
IT5060AIG262017
|
MEDICATION GUIDE
Pradaxa (pra dax a)
(dabigatran etexilate
mesylate)
capsules
|
|
Read this
Medication Guide before you start taking Pradaxa and each time you get a
refill. There may be new information. This Medication Guide does not take the
place of talking with your doctor about your medical condition or your
treatment.
|
|
What is the most important information I should
know about Pradaxa?
· For
people taking Pradaxa for atrial fibrillation:
People with atrial fibrillation (a type of irregular heartbeat) are at an
increased risk of forming a blood clot in the heart, which can travel to the
brain, causing a stroke, or to other parts of the body. Pradaxa lowers your
chance of having a stroke by helping to prevent clots from forming. If you
stop taking Pradaxa, you may have increased risk of forming a clot in your
blood.
Do not stop taking Pradaxa
without talking to the doctor who prescribes it for you. Stopping Pradaxa
increases your risk of having a stroke.
Pradaxa may need to be stopped, if possible, prior to surgery or a medical or
dental procedure. Ask the doctor who prescribed Pradaxa for you when you
should stop taking it. Your doctor will tell you when you may start taking
Pradaxa again after your surgery or procedure. If you have to stop taking
Pradaxa, your doctor may prescribe another medicine to help prevent a blood
clot from forming.
· Pradaxa can cause bleeding which can be
serious, and sometimes lead to death. This is because Pradaxa is a blood
thinner medicine that lowers the chance of blood clots forming in your body.
· You
may have a higher risk of bleeding if you take Pradaxa and:
o are
over 75 years old
o have
kidney problems
o have
stomach or intestine bleeding that is recent or keeps coming back, or you
have a stomach ulcer
o take
other medicines that increase your risk of bleeding, including:
o aspirin
or aspirin containing products
o long-term
(chronic) use of non-steroidal anti-inflammatory drugs (NSAIDs)
o warfarin
sodium (Coumadin®, Jantoven®)
o a
medicine that contains heparin
o clopidogrel
bisulfate (Plavix®)
o prasugrel
(Effient®)
have
certain kidney problems and also take the medicines dronedarone (Multaq®) or ketoconazole tablets (Nizoral®).
Tell your doctor if you take any of these medicines. Ask your doctor or
pharmacist if you are not sure if your medicine is one listed above.
Pradaxa
can increase your risk of bleeding because it lessens the ability of your
blood to clot. While you take Pradaxa:
you
may bruise more easily
it
may take longer for any bleeding to stop
Call
your doctor or get medical help right away if you have any of these signs or
symptoms of bleeding:
unexpected
bleeding or bleeding that lasts a long time, such as:
o unusual
bleeding from the gums
o nose
bleeds that happen often
o menstrual
bleeding or vaginal bleeding that is heavier than normal
bleeding
that is severe or you cannot control
pink
or brown urine
red
or black stools (looks like tar)
bruises
that happen without a known cause or get larger
cough
up blood or blood clots
vomit
blood or your vomit looks like “coffee grounds”
unexpected
pain, swelling, or joint pain
headaches,
feeling dizzy or weak
Take
Pradaxa exactly as prescribed. Do not stop taking Pradaxa without first
talking to the doctor who prescribes it for you. Stopping Pradaxa may
increase your risk of a stroke.
Pradaxa may need to be stopped, if possible, for one or more days before any
surgery, or medical or dental procedure. If you need to stop taking Pradaxa
for any reason,
talk to the doctor who prescribed Pradaxa for you to find out when you should
stop taking it. Your doctor will tell you when to start taking Pradaxa again
after your surgery or procedure.
Spinal or epidural blood clots
(hematoma). People
who take a blood thinner medicine (anticoagulant) like Pradaxa, and have
medicine injected into their spinal and epidural area, or have a spinal
puncture have a risk of forming a blood clot that can cause long-term or
permanent loss of the ability to move (paralysis). Your risk of developing a
spinal or epidural blood clot is higher if:
a
thin tube called an epidural catheter is placed in your back to give you
certain medicine.
you
take NSAIDs or a medicine to prevent blood from clotting
you
have a history of difficult or repeated epidural or spinal punctures
you
have a history of problems with your spine or have had surgery on your spine.
If you take Pradaxa and receive spinal
anesthesia or have a spinal puncture, your doctor should watch you closely
for symptoms of spinal or epidural blood clots. Tell your doctor right away
if you have back pain, tingling, numbness, muscle weakness (especially in
your legs and feet), loss of control of the bowels or bladder (incontinence).
See “What are the possible side effects of
Pradaxa?” for more information about side effects.
|
|
What is Pradaxa?
Pradaxa is a prescription blood thinner medicine that lowers the chance of
blood clots forming in your body. Pradaxa is used to:
· reduce the risk of stroke and blood clots
in people who have a medical condition called atrial fibrillation. With
atrial fibrillation, part of the heart does not beat the way it should. This
can lead to blood clots forming and increase your risk of a stroke.
· treat blood clots in the veins of your
legs (deep vein thrombosis) or lungs (pulmonary embolism) and reduce the risk
of them occurring again.
· to help prevent blood clots in the legs
and lungs of people who have just had hip replacement surgery.
Pradaxa is not
for use in people with artificial (prosthetic) heart valves.
It is not known if Pradaxa is safe and works in children.
|
|
Who should not take Pradaxa?
Do not take
Pradaxa if you:
· currently have certain types of abnormal
bleeding. Talk to your doctor before taking Pradaxa if you currently have
unusual bleeding.
· have had a serious allergic reaction to
Pradaxa. Ask your doctor if you are not sure.
· have ever had or plan to have a valve in
your heart replaced
|
|
What should I tell my doctor before taking
Pradaxa?
Before you
take Pradaxa, tell your doctor if you:
· have kidney problems
· have ever had bleeding problems
· have ever had stomach ulcers
· have any other medical condition
· are pregnant or plan to become pregnant.
It is not known if Pradaxa will harm your unborn baby.
· are breastfeeding or plan to breastfeed.
It is not known if Pradaxa passes into your breast milk.
Tell all of your doctors and dentists that you are taking Pradaxa.
They should talk to the doctor who prescribed Pradaxa for you, before you
have any surgery,
or a medical or dental procedure.
Tell your doctor about
all the medicines you take, including prescription and
over-the-counter medicines, vitamins, and herbal supplements.
Some of your other medicines may affect the way Pradaxa works. Certain medicines
may increase your risk of bleeding. See “What is the most important information I should
know about Pradaxa?”
Especially tell your doctor if you take:
· rifampin (Rifater®, Rifamate®, Rimactane®, Rifadin®)
Know the medicines you take. Keep a list of them and show it to your doctor
and pharmacist when you get a new medicine.
|
|
How should I take Pradaxa?
· Your doctor will decide how long you
should take Pradaxa. Do
not stop taking Pradaxa without first talking with your doctor. Stopping
Pradaxa may increase your risk of having a stroke or forming blood clots.
· Take
Pradaxa exactly as prescribed by your doctor.
· Take Pradaxa capsules twice a day
(approximately every 12 hours).
· If you miss a dose of Pradaxa, take it as
soon as you remember. If your next dose is less than 6 hours away, skip the
missed dose. Do not take two doses of Pradaxa at the same time.
· Swallow Pradaxa capsules whole. Do not
break, chew, or empty the pellets from the capsule.
· You can take Pradaxa with or without
food.
· You should take Pradaxa with a full glass
of water.
· Do not run out of Pradaxa. Refill your
prescription before you run out. If you plan to have surgery, or a medical or
a dental procedure, tell your doctor and dentist that you are taking Pradaxa.
You may have to stop taking Pradaxa for a short time. See “What is the most
important information I should know about Pradaxa?”.
· If you take too much Pradaxa, go to the
nearest hospital emergency room or call your doctor.
· Call your doctor or healthcare provider
right away if you fall or injure yourself, especially if you hit your head.
Your doctor or healthcare provider may need to check you.
· Pradaxa comes in a bottle or in a blister
package.
· Only open 1 bottle of Pradaxa at a time.
Finish your opened bottle of Pradaxa before opening a new bottle.
· After opening a bottle of Pradaxa, use
within 4 months. See “How should I store Pradaxa?”
· When it is time for you to take a dose of
Pradaxa, only remove your prescribed dose of Pradaxa from your open bottle or
blister package.
· Tightly close your bottle of Pradaxa
right away after you take your dose.
|
|
What are the possible side effects of Pradaxa?
Pradaxa can
cause serious side effects, including:
· See “What is the most important
information I should know about Pradaxa?”
· Allergic Reactions. In some people,
Pradaxa can cause symptoms of an allergic reaction, including hives, rash,
and itching. Tell your doctor or get medical help right away if you get any of
the following symptoms of a serious allergic reaction with Pradaxa:
|
|
o chest
pain or chest tightness
o swelling
of your face or tongue
|
o trouble
breathing or wheezing
o feeling
dizzy or faint
|
|
|
Common side
effects of Pradaxa include:
· indigestion,
upset stomach, or burning
· stomach
pain
Tell your doctor
if you have any side effect that bothers you or that does not go away.
These are not all of the possible side effects of Pradaxa. For more
information, ask your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side
effects to FDA at 1-800-FDA-1088.
|
|
How should I store Pradaxa?
· Store Pradaxa at room temperature 68°F to
77°F (20°C to 25°C). After opening the bottle, use Pradaxa within 4 months.
Safely throw away any unused Pradaxa after 4 months.
· Keep
Pradaxa in the original bottle or blister package to keep it dry (protect the
capsules from moisture). Do not put Pradaxa in pill boxes or pill organizers.
· Tightly
close your bottle of Pradaxa right away after you take your dose.
Keep Pradaxa and all medicines out of the reach
of children.
|
|
General information about the safe and effective
use of Pradaxa
Medicines are sometimes prescribed for purposes other than those listed in a
Medication Guide. Do not use Pradaxa for a condition for which it was not
prescribed. Do not give Pradaxa to other people, even if they have the same
symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about
Pradaxa. If you would like more information, talk with your doctor. You can
ask your pharmacist or doctor for information about Pradaxa that is written
for health professionals.
For more information, go to www.Pradaxa.com or call Boehringer Ingelheim Pharmaceuticals,
Inc. at 1-800-542-6257 or (TTY) 1-800-459-9906, or scan here to go to www.Pradaxa.com.
|
|
What are the ingredients in Pradaxa?
Active ingredient: dabigatran etexilate mesylate
Inactive ingredients: acacia, dimethicone, hypromellose, hydroxypropyl
cellulose, talc, and tartaric acid. The capsule shell is composed of
carrageenan, hypromellose, potassium chloride, titanium dioxide, black edible
ink, and FD&C Blue No. 2 (150 mg and 110 mg capsules only).
Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc.;Ridgefield,CT06877USA
The brands listed above are trademarks of their respective owners and are not
trademarks of Boehringer Ingelheim Pharmaceuticals, Inc. The owners of these
brands are not affiliated with and do not endorse Boehringer Ingelheim
Pharmaceuticals, Inc., or its products.
Copyright 2017 Boehringer Ingelheim Pharmaceuticals, Inc.
ALL RIGHTS RESERVED
IT5060AIG262017
|
This
Medication Guide has been approved by the U.S. Food and Drug Administration. Revised:
July 2017
|
Pradaxa dabigatran etexilate mesylate capsule
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:0597-0149
|
|
Route of
Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
DABIGATRAN ETEXILATE MESYLATE (DABIGATRAN)
|
DABIGATRAN
ETEXILATE
|
75 mg
|
|
|
Product
Characteristics
|
|
Color
|
WHITE (Cream
colored)
|
Score
|
no score
|
|
Shape
|
CAPSULE
|
Size
|
18mm
|
|
Flavor
|
|
Imprint Code
|
R75
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:0597-0149-54
|
1 BOTTLE in 1
CARTON
|
|
|
1
|
|
60 CAPSULE in 1
BOTTLE
|
|
|
2
|
NDC:0597-0149-60
|
10 BLISTER PACK
in 1 CARTON
|
|
|
2
|
|
6 CAPSULE in 1
BLISTER PACK
|
|
|
3
|
NDC:0597-0149-12
|
2 BLISTER PACK
in 1 CARTON
|
|
|
3
|
|
6 CAPSULE in 1
BLISTER PACK
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA022512
|
08/08/2011
|
|
|
|
Pradaxa dabigatran etexilate mesylate capsule
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:0597-0108
|
|
Route of
Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
DABIGATRAN ETEXILATE MESYLATE (DABIGATRAN)
|
DABIGATRAN
ETEXILATE
|
110 mg
|
|
|
Product
Characteristics
|
|
Color
|
BLUE (Blue)
|
Score
|
no score
|
|
Shape
|
CAPSULE
|
Size
|
20mm
|
|
Flavor
|
|
Imprint Code
|
R110
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:0597-0108-54
|
1 BOTTLE in 1
CARTON
|
|
|
1
|
|
60 CAPSULE in 1
BOTTLE
|
|
|
2
|
NDC:0597-0108-60
|
10 BLISTER PACK
in 1 CARTON
|
|
|
2
|
|
6 CAPSULE in 1
BLISTER PACK
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA022512
|
11/23/2015
|
|
|
|
Pradaxa dabigatran etexilate mesylate capsule
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:0597-0135
|
|
Route of
Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
DABIGATRAN ETEXILATE MESYLATE (DABIGATRAN)
|
DABIGATRAN ETEXILATE
|
150 mg
|
|
|
Product
Characteristics
|
|
Color
|
BLUE (Light
Blue) , WHITE (Cream colored)
|
Score
|
no score
|
|
Shape
|
CAPSULE
|
Size
|
22mm
|
|
Flavor
|
|
Imprint Code
|
R150
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:0597-0135-54
|
1 BOTTLE in 1
CARTON
|
|
|
1
|
|
60 CAPSULE in 1
BOTTLE
|
|
|
2
|
NDC:0597-0135-12
|
2 BLISTER PACK
in 1 CARTON
|
|
|
2
|
|
6 CAPSULE in 1
BLISTER PACK
|
|
|
3
|
NDC:0597-0135-60
|
10 BLISTER PACK
in 1 CARTON
|
|
|
3
|
|
6 CAPSULE in 1
BLISTER PACK
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA022512
|
10/26/2010
|
|
|
|
Pradaxa dabigatran etexilate mesylate capsule
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:0597-0355
|
|
Route of
Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
DABIGATRAN ETEXILATE MESYLATE (DABIGATRAN)
|
DABIGATRAN
ETEXILATE
|
75 mg
|
|
|
Product
Characteristics
|
|
Color
|
WHITE
|
Score
|
no score
|
|
Shape
|
CAPSULE
|
Size
|
18mm
|
|
Flavor
|
|
Imprint Code
|
R75
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:0597-0355-09
|
1 BOTTLE in 1
CARTON
|
|
|
1
|
|
60 CAPSULE in 1
BOTTLE
|
|
|
2
|
NDC:0597-0355-56
|
60 BLISTER PACK
in 1 CARTON
|
|
|
2
|
|
1 CAPSULE in 1 BLISTER
PACK
|
|
|
3
|
NDC:0597-0355-53
|
12 BLISTER PACK
in 1 CARTON
|
|
|
3
|
|
1 CAPSULE in 1
BLISTER PACK
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA022512
|
08/08/2011
|
|
|
|
Pradaxa dabigatran etexilate mesylate capsule
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:0597-0360
|
|
Route of
Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of Strength
|
Strength
|
|
DABIGATRAN ETEXILATE MESYLATE (DABIGATRAN)
|
DABIGATRAN
ETEXILATE
|
150 mg
|
|
|
Product
Characteristics
|
|
Color
|
BLUE, WHITE
|
Score
|
no score
|
|
Shape
|
CAPSULE
|
Size
|
22mm
|
|
Flavor
|
|
Imprint Code
|
R150
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:0597-0360-55
|
1 BOTTLE in 1
CARTON
|
|
|
1
|
|
60 CAPSULE in 1
BOTTLE
|
|
|
2
|
NDC:0597-0360-42
|
12 BLISTER PACK
in 1 CARTON
|
|
|
2
|
|
1 CAPSULE in 1
BLISTER PACK
|
|
|
3
|
NDC:0597-0360-82
|
60 BLISTER PACK
in 1 CARTON
|
|
|
3
|
|
1 CAPSULE in 1
BLISTER PACK
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA022512
|
07/28/2017
|
|
|
|
Labeler - Boehringer Ingelheim Pharmaceuticals Inc.
(603175944)
|
|
Registrant - Boehringer Ingelheim Pharmaceuticals Inc.
(603175944)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
West-Ward
Columbus Inc.
|
|
058839929
|
LABEL(0597-0149,
0597-0108, 0597-0360, 0597-0355, 0597-0135), PACK(0597-0360, 0597-0149,
0597-0108, 0597-0355, 0597-0135)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Boehringer
Ingelheim Pharma GmbH & Co. KG
|
|
551147440
|
ANALYSIS(0597-0149,
0597-0360, 0597-0355, 0597-0108, 0597-0135), API MANUFACTURE(0597-0108,
0597-0360, 0597-0135, 0597-0355, 0597-0149), LABEL(0597-0149, 0597-0108,
0597-0360, 0597-0355, 0597-0135), MANUFACTURE(0597-0149, 0597-0355,
0597-0360, 0597-0108, 0597-0135), PACK(0597-0360, 0597-0149, 0597-0108,
0597-0355, 0597-0135)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Bidachem S.p.a.
|
|
429232812
|
API
MANUFACTURE(0597-0108, 0597-0360, 0597-0355, 0597-0135, 0597-0149),
ANALYSIS(0597-0149, 0597-0360, 0597-0355, 0597-0135, 0597-0108)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Boehringer
Ingelheim Pharma GmbH and Co. KG
|
|
340700520
|
LABEL(0597-0149,
0597-0108, 0597-0360, 0597-0355, 0597-0135), PACK(0597-0360, 0597-0149,
0597-0108, 0597-0355, 0597-0135)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Gfm Gesellschaft
Fuer Micronisierung Mbh
|
|
328866827
|
API
MANUFACTURE(0597-0108, 0597-0360, 0597-0135, 0597-0355, 0597-0149)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Micro-Macinazione
SA
|
|
480918515
|
API MANUFACTURE(0597-0108,
0597-0360, 0597-0135, 0597-0355, 0597-0149)
|
Revised: 08/2017
Boehringer
Ingelheim Pharmaceuticals Inc.
