Drug Safety-related Labeling Changes (SrLC)

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XARELTO (NDA-022406)

(RIVAROXABAN)

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

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08/23/2021 (SUPPL-37)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Because clinical trials are conducted under widely varying conditions, adverse reaction 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 clinical practice.

During clinical development for the approved indications, 34,947 patients were exposed to XARELTO.

Table 6: Bleeding Events in MAGELLAN* Study–Safety Analysis Set - On Treatment Plus 2 Days

Reduction of Risk of Major Cardiovascular Events in Patients with CAD

In the COMPASS trial overall, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 2.7% for XARELTO 2.5 mg twice daily vs. 1.2% for placebo on background therapy for all patients with aspirin 100 mg once daily. The incidences of important bleeding events in the CAD and PAD populations in COMPASS were similar.

Table 7: Major Bleeding Events in COMPASS - On Treatment Plus 2 days*

* Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within 2 days of stopping treatment in the safety analysis set in COMPASS patients.

† Treatment schedule: XARELTO 2.5 mg twice daily or placebo. All patients received background therapy with aspirin 100 mg once daily.

Reduction of Risk of Major Thrombotic Vascular Events in Patients with Peripheral Artery Disease (PAD), Including Patients after Lower Extremity Revascularization due to Symptomatic PAD

The incidence of premature permanent discontinuation due to bleeding events for XARELTO

2.5 mg twice daily vs. placebo on background therapy with aspirin 100 mg once daily in VOYAGER was 4.1% vs. 1.6% and in COMPASS PAD was 2.7% vs. 1.3%, respectively.

Table 8 shows the number of patients experiencing various types of TIMI (Thrombolysis in Myocardial Infarction) major bleeding events in the VOYAGER trial. The most common site of bleeding was gastrointestinal.

Table 8: Major Bleeding Events* in VOYAGER- On Treatment Plus 2 days Newly added table; please refer to label for complete information

* Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories.

† Treatment schedule: XARELTO 2.5 mg twice daily or placebo. All patients received background therapy with aspirin 100 mg once daily.

CABG: Coronary artery bypass graft; CI: confidence interval; HR: hazard ratio; TIMI: Thrombolysis in Myocardial Infarction Bleeding Criteria

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

Of the total number of adult patients in clinical trials for the approved indications of XARELTO (N=64,943 patients), 64 percent were 65 years and over, with 27 percent 75 years and over. In clinical trials the efficacy of XARELTO in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients [see Clinical Pharmacology (12.3) and Clinical Studies (14)].

8.6 Renal Impairment

Additions and/or revisions underlined and bolded:

Reduction of Risk of Major Cardiovascular Events in Patients with CAD and Reduction of Risk of Major Thrombotic Vascular Events in Patients with PAD, Including Patients After Recent Lower Extremity Revascularization due to Symptomatic PAD

Patients with Chronic Kidney Disease not on Dialysis

Patients with a CrCl <15 mL/min at screening were excluded from COMPASS and VOYAGER, and limited data are available for patients with a CrCl of 15 to 30 mL/min …

Patients with End-Stage Renal Disease on Dialysis

No clinical outcome data is available for the use of XARELTO with aspirin in patients with ESRD on dialysis since these patients were not enrolled in COMPASS or VOYAGER. In patients with ESRD …

01/28/2021 (SUPPL-36)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

(Additions and/or revisions underlined)

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

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

03/10/2020 (SUPPL-35)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Patients with Prosthetic Heart Valves

Additions and/or revisions underlined:

On the basis of the GALILEO study, use of XARELTO is not recommended in patients who have had transcatheter aortic valve replacement (TAVR) because patients randomized to XARELTO experienced higher rates of death and bleeding compared to those randomized to an anti-platelet regimen. The safety and efficacy of XARELTO have not been studied in patients with other prosthetic heart valves or other valve procedures. Use of XARELTO is not recommended in patients with prosthetic heart valves.

11/15/2019 (SUPPL-27)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

5.4 Use in Patients with Renal Impairment

Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE

In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl

<15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO in these patients.

Discontinue XARELTO in patients who develop acute renal failure while on treatment.

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery

In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl

<15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO in these patients.

Discontinue XARELTO in patients who develop acute renal failure while on treatment.

Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding

In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO in these patients.

Discontinue XARELTO in patients who develop acute renal failure while on treatment.

8 Use in Specific Populations

8.6 Renal Impairment

Additions and/or revisions underlined:

Treatment of DVT and/or PE and Reduction in the Risk of Recurrence of DVT and/or PE

In the EINSTEIN trials, patients with CrCl values <30 mL/min at screening were excluded from the studies, but administration of XARELTO is expected to result in serum concentrations ofrivaroxaban similar to those in patients with moderate renal impairment (CrCl 30 to <50 mL/min). Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 15 to <30 mL/min. Avoid the use of XARELTO in patients with CrCl <15 mL/min.

Prophylaxis of DVT Following Hip or Knee Replacement Surgery

The combined analysis of the RECORD 1-3 clinical efficacy studies did not show an increase in bleeding risk for patients with CrCl 30 to 50 mL/min and reported a possible increase in total venous thromboemboli in this population. In the RECORD 1-3 trials, patients with CrCl values

<30 mL/min at screening were excluded from the studies, but administration of XARELTO 10 mg once daily is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment (CrCl 30 to <50 mL/min). Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 15 to <30 mL/min. Avoid the use of XARELTO in patients with CrCl <15 mL/min.

Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding

Patients with CrCl values <30 mL/min at screening were excluded from the MAGELLAN study. In patients with CrCl <30 mL/min a dose of XARELTO 10 mg once daily is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment (CrCl 30 to <50 mL/min). Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 15 to <30 mL/min. Avoid use of XARELTO in patients with CrCl <15 mL/min.

Reduction of Risk of Major Cardiovascular Events in Patients with Chronic CAD or PAD

Patients with Chronic Kidney Disease not on Dialysis

Patients with a CrCl <15 mL/min at screening were excluded from COMPASS, and limited data are available for patients with a CrCl of 15 to 30 mL/min. In patients with CrCl <30 mL/min, a dose of 2.5 mg XARELTO twice daily is expected to give an exposure similar to that in patients with moderate renal impairment (CrCl 30 to <50 mL/min).

10/11/2019 (SUPPL-33)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Risk of Bleeding

Newly added information:

Risk of Hemorrhage in Acutely Ill Medical Patients at High Risk of Bleeding

Acutely ill medical patients with the following conditions are at increased risk of bleeding with the use of XARELTO for primary VTE prophylaxis: history of bronchiectasis, pulmonary cavitation, or pulmonary hemorrhage, active cancer (i.e. undergoing acute, in-hospital cancer treatment), active gastroduodenal ulcer in the three months prior to treatment, history of bleeding in the three months prior to treatment, or dual antiplatelet therapy. XARELTO is not for use for primary VTE prophylaxis in these hospitalized, acutely ill medical patients at high risk of bleeding.

5.4 Use in Patients with Renal Impairment

Newly added information:

Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding

Avoid the use of XARELTO in patients with CrCl less than 30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population. Consider discontinuation of XARELTO in patients who develop acute renal failure while on XARELTO.

Additions and/or revisions underlined:

5.10 Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome

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

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

During clinical development for the approved indications, 31,691 patients were exposed to XARELTO …

4487 patients who received XARELTO 10 mg orally once daily for prophylaxis of DVT following hip or knee replacement surgery (RECORD 1-3); 3997 patients who received 10 mg orally once daily for prophylaxis of VTE and VTE-related death in acutely ill medical patients (MAGELLAN) and 9134 patients who received XARELTO 2.5 mg orally twice daily, in combination with aspirin 100 mg once daily, for the reduction in risk of major cardiovascular events in patients with chronic CAD or PAD (COMPASS).

Newly added information following Table 5: Bleeding Events in Patients Undergoing Hip or Knee Replacement Surgeries (RECORD 1-3):

Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding

In the MAGELLAN study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events. Cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed. Patients with bronchiectasis/pulmonary cavitation, active cancer (i.e., undergoing acute, in-hospital cancer treatment), dual antiplatelet therapy or active gastroduodenal ulcer or any bleeding in the previous three months all had an excess of bleeding with XARELTO compared with enoxaparin/placebo and are excluded from all MAGELLAN data presented in Table 6. The incidence of bleeding leading to drug discontinuation was 2.5% for XARELTO vs. 1.4% for enoxaparin/placebo. Table 6 shows the number of patients experiencing various types of bleeding events in the MAGELLAN study.

Table 6: Bleeding Events in MAGELLAN* Study–Safety Analysis Set - On Treatment Plus 2 Days (See label for complete table information).

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

… In the EINSTEIN DVT, PE and Extension clinical studies approximately 37% were 65 years and over and about 16% were greater than 75 years. In EINSTEIN CHOICE, approximately 39% were 65 years and over and about 12% were greater than 75 years. In the MAGELLAN study, approximately 67% were 65 years and over and about 37% were greater than 75 years. In the COMPASS study …

8.6 Renal Impairment

Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding

In the MAGELLAN study, patients with a baseline CrCl less than 30 mL/min were excluded. Avoid use of XARELTO in patients with CrCl less than 30 mL/min.

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

MEDICATION GUIDE

Additions and/or revisions underlined:

What is the most important information I should know about XARELTO? XARELTO may cause serious side effects, including:

  • Increased risk of bleeding. XARELTO can cause bleeding which can be serious and may lead to death. This is because XARELTO is a blood thinner medicine (anticoagulant) that lowers blood clotting. During treatment with XARELTO you are likely to bruise more easily, and it may take longer for bleeding to stop. You may have a higher risk of bleeding if you take XARELTO and have certain other medical problems.

08/23/2019 (SUPPL-34)

Approved Drug Label (PDF)

5 Warnings and Precautions

Newly added subsection:

5.10 Increased Risk of Thrombosis in Patients with Antiphospholipid Syndrome

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

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

MEDICATION GUIDE


Additions and/or revisions underlined:

XARELTO is not for use in people with antiphospholipid syndrome (APS), especially with positive triple antibody testing, who have a history of blood clots.

Before taking XARELTO, tell your doctor about all of your medical conditions, including if you:

  • have antiphospholipid syndrome (APS)

01/15/2019 (SUPPL-30)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Risk of Bleeding

(Additions and/or revisions are underlined)

Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fibrinolytic therapy, non-steroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

During clinical development for the approved indications, 27,694 patients were exposed to XARELTO. These included 7111 patients who received XARELTO 15 mg or 20 mg orally once daily for a mean of 19 months (5558 for 12 months and 2512 for 24 months) to reduce the risk of stroke and systemic embolism in nonvalvular atrial fibrillation (ROCKET AF); 6962 patients who received XARELTO 15 mg orally twice daily for three weeks followed by 20 mg orally once daily to treat DVT or PE (EINSTEIN DVT, EINSTEIN PE), 10 mg or 20 mg orally once daily (EINSTEIN Extension, EINSTEIN CHOICE) to reduce the risk of recurrence of DVT and/or PE; 4487 patients who received XARELTO 10 mg orally once daily for prophylaxis of DVT following hip or knee replacement surgery (RECORD 1-3); and 9134 patients who received XARELTO 2.5 mg orally twice daily, in combination with aspirin 100 mg once daily, for the reduction in risk of major cardiovascular events in patients with chronic CAD or PAD (COMPASS).

Reduction of Risk of Major Cardiovascular Events in Patients with Chronic CAD or PAD In the COMPASS trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 2.7% for XARELTO 2.5 mg twice daily in combination with aspirin 100 mg once daily vs. 1.2% for aspirin 100 mg once daily.

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS)

8 Use in Specific Populations

8.5 Geriatric Use

(Additions and/or revisions are underlined)

Of the total number of patients in the RECORD 1-3 clinical studies evaluating XARELTO, about 54% were 65 years and over, while about 15% were >75 years. In ROCKET AF, approximately 77% were 65 years and over and about 38% were >75 years. In the EINSTEIN DVT, PE and Extension clinical studies approximately 37% were 65 years and over and about 16% were >75 years. In EINSTEIN CHOICE, approximately 39% were 65 years and over and about 12% were >75 years. In the COMPASS study, approximately 76% were 65 years and over and about 17% were >75 years. In clinical trials the efficacy of XARELTO in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups.
8.6 Renal Impairment

(Additions and/or revisions are underlined)

Reduction of Risk of Major Cardiovascular Events in Patients with Chronic CAD or PAD

Patients with Chronic Kidney Disease not on Dialysis

Patients with a CrCl <15 mL/min at screening were excluded from COMPASS, and limited data are available for patients with a CrCl of 15-30 mL/min. In patients with CrCl less than or equal to 30 mL/min, a dose of 2.5 mg XARELTO twice daily is expected to give an exposure similar to that in patients with moderate renal impairment, whose efficacy and safety outcomes were similar to those with preserved renal function.

Patients with End-Stage Renal Disease on Dialysis

No clinical outcome data is available for the use of XARELTO with aspirin in patients with ESRD on dialysis since these patients were not enrolled in COMPASS. In patients with ESRD maintained on intermittent hemodialysis, administration of XARELTO 2.5 mg twice daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in moderate renal impaired patients in the COMPASS study. It is not known whether these concentrations will lead to similar CV risk reduction and bleeding risk in patients with ESRD on dialysis as was seen in COMPASS.

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

MEDICATION GUIDE

(Extensive changes; please refer to labeling)

01/15/2019 (SUPPL-32)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Risk of Bleeding

(Additions and/or revisions are underlined)

Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fibrinolytic therapy, non-steroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

During clinical development for the approved indications, 27,694 patients were exposed to XARELTO. These included 7111 patients who received XARELTO 15 mg or 20 mg orally once daily for a mean of 19 months (5558 for 12 months and 2512 for 24 months) to reduce the risk of stroke and systemic embolism in nonvalvular atrial fibrillation (ROCKET AF); 6962 patients who received XARELTO 15 mg orally twice daily for three weeks followed by 20 mg orally once daily to treat DVT or PE (EINSTEIN DVT, EINSTEIN PE), 10 mg or 20 mg orally once daily (EINSTEIN Extension, EINSTEIN CHOICE) to reduce the risk of recurrence of DVT and/or PE; 4487 patients who received XARELTO 10 mg orally once daily for prophylaxis of DVT following hip or knee replacement surgery (RECORD 1-3); and 9134 patients who received XARELTO 2.5 mg orally twice daily, in combination with aspirin 100 mg once daily, for the reduction in risk of major cardiovascular events in patients with chronic CAD or PAD (COMPASS).

Reduction of Risk of Major Cardiovascular Events in Patients with Chronic CAD or PAD In the COMPASS trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 2.7% for XARELTO 2.5 mg twice daily in combination with aspirin 100 mg once daily vs. 1.2% for aspirin 100 mg once daily.

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS)

8 Use in Specific Populations

8.5 Geriatric Use

(Additions and/or revisions are underlined)

Of the total number of patients in the RECORD 1-3 clinical studies evaluating XARELTO, about 54% were 65 years and over, while about 15% were >75 years. In ROCKET AF, approximately 77% were 65 years and over and about 38% were >75 years. In the EINSTEIN DVT, PE and Extension clinical studies approximately 37% were 65 years and over and about 16% were >75 years. In EINSTEIN CHOICE, approximately 39% were 65 years and over and about 12% were >75 years. In the COMPASS study, approximately 76% were 65 years and over and about 17% were >75 years. In clinical trials the efficacy of XARELTO in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups.

8.6 Renal Impairment

(Additions and/or revisions are underlined)

Reduction of Risk of Major Cardiovascular Events in Patients with Chronic CAD or PAD

Patients with Chronic Kidney Disease not on Dialysis

Patients with a CrCl <15 mL/min at screening were excluded from COMPASS, and limited data are available for patients with a CrCl of 15-30 mL/min. In patients with CrCl less than or equal to 30 mL/min, a dose of 2.5 mg XARELTO twice daily is expected to give an exposure similar to that in patients with moderate renal impairment, whose efficacy and safety outcomes were similar to those with preserved renal function.

Patients with End-Stage Renal Disease on Dialysis

No clinical outcome data is available for the use of XARELTO with aspirin in patients with ESRD on dialysis since these patients were not enrolled in COMPASS. In patients with ESRD maintained on intermittent hemodialysis, administration of XARELTO 2.5 mg twice daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in moderate renal impaired patients in the COMPASS study. It is not known whether these concentrations will lead to similar CV risk reduction and bleeding risk in patients with ESRD on dialysis as was seen in COMPASS.

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

MEDICATION GUIDE

(Extensive changes; please refer to labeling)

11/07/2018 (SUPPL-29)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Risk of Bleeding

Reversal of Anticoagulant Effect

Additions and/or revisions underlined:

… anticoagulant activity of rivaroxaban. Use of procoagulant reversal agents, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate or recombinant factor VIIa, may be considered but has not been evaluated in clinical efficacy and safety studies. Monitoring for the anticoagulation effect of rivaroxaban using a clotting test (PT, INR or aPTT) or anti-factor Xa (FXa) activity is not recommended.

Other

In all instances where CYP3A4 or 3A4 stands alone, the 4 has been dropped to read CYP3A or 3A.

07/30/2018 (SUPPL-28)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Risk of Bleeding

Additions and/or revisions underlined:

Reversal of Anticoagulant Effect

An agent to reverse the anti-factor Xa activity of rivaroxaban is available.

10/27/2017 (SUPPL-24)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

During clinical development for the approved indications, 18560 patients were exposed to XARELTO. These included 7111 patients who received XARELTO 15 mg or 20 mg orally once daily for a mean of 19 months (5558 for 12 months and 2512 for 24 months) to reduce the risk of stroke and systemic embolism in nonvalvular atrial fibrillation (ROCKET AF); 6962 patients who received XARELTO 15 mg orally twice daily for three weeks followed by 20 mg orally once daily to treat DVT or PE (EINSTEIN DVT, EINSTEIN PE), 10 mg or 20 mg orally once daily (EINSTEIN Extension, EINSTEIN CHOICE) to reduce the risk of recurrence of DVT and/or PE; and 4487 patients who received XARELTO 10 mg orally once daily for prophylaxis of DVT following hip or knee replacement surgery (RECORD 1-3).

Treatment of Deep Vein Thrombosis (DVT) and/or Pulmonary Embolism (PE)

EINSTEIN DVT and EINSTEIN PE Studies

 

Reduction in the Risk of Recurrence of DVT and/or PE

EINSTEIN CHOICE Study

In the EINSTEIN CHOICE clinical study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 1% for XARELTO 10 mg, 2% for XARELTO 20 mg, and 1% for acetylsalicylic acid (aspirin) 100 mg. The mean duration of treatment was 293 days for XARELTO 10 mg-treated patients and 286 days for aspirin 100 mg-treated patients.

Table 3 shows the number of patients experiencing bleeding events in the EINSTEIN CHOICE study.

Table 3: Bleeding Events* in EINSTEIN CHOICE

(Table has been revised; please refer to label)

In the EINSTEIN CHOICE study, there was an increased incidence of bleeding, including major and CRNM bleeding in the XARELTO 20 mg group compared to the XARELTO 10 mg or aspirin 100 mg groups.

 

Other Adverse Reactions

Non-hemorrhagic adverse reactions reported in greater than or equal to 1% of XARELTO-treated patients in the EINSTEIN DVT and EINSTEIN PE studies are shown in Table 5.

Table 5: Other Adverse Reactions* Reported by ?1% of XARELTO-Treated Patients in EINSTEIN DVT and EINSTEIN PE Studies

(Table has been revised; please refer to label)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

Risk Summary

The limited available data on XARELTO in pregnant women are insufficient to inform a drug- associated risk of adverse developmental outcomes. Use XARELTO with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery with an anticoagulant that is not readily reversible. The anticoagulant effect of XARELTO cannot be reliably monitored with standard laboratory testing. Consider the benefits and risks of XARELTO for the mother and possible risks to the fetus when prescribing XARELTO to a pregnant woman.

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

 

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Pregnancy is a risk factor for venous thromboembolism and that risk is increased in women with inherited or acquired thrombophilias. Pregnant women with thromboembolic disease have an increased risk of maternal complications including pre-eclampsia. Maternal thromboembolic disease increases the risk for intrauterine growth restriction, placental abruption and early and late pregnancy loss.


Fetal/Neonatal Adverse Reactions

Based on the pharmacologic activity of Factor Xa inhibitors and the potential to cross the placenta, bleeding may occur at any site in the fetus and/or neonate.


Labor or Delivery

All patients receiving anticoagulants, including pregnant women, are at risk for bleeding and this risk may be increased during labor or delivery. The risk of bleeding should be balanced with the risk of thrombotic events when considering the use of XARELTO in this setting.

 

Data

Human Data

Post-marketing experience is currently insufficient to determine a rivaroxaban-associated risk for major birth defects or miscarriage. In an in vitro placenta perfusion model, unbound rivaroxaban was rapidly transferred across the human placenta.

Animal Data

…Fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg during the period of organogenesis… In rats, peripartal maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg (about 6 times maximum human exposure of the unbound drug at the human dose of 20 mg/day).

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

Risk Summary

Rivaroxaban has been detected in human milk. There are insufficient data to determine the effects of rivaroxaban on the breastfed child or on milk production. Rivaroxaban and/or its metabolites were present in the milk of rats. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XARELTO and any potential adverse effects on the breastfed infant from XARELTO or from the underlying maternal condition.

 

Data

Animal data

Following a single oral administration of 3 mg/kg of radioactive [14C]-rivaroxaban to lactating rats between Day 8 to 10 postpartum, the concentration of total radioactivity was determined in milk samples collected up to 32 hours post-dose. The estimated amount of radioactivity excreted with milk within 32 hours after administration was 2.1% of the maternal dose.

 

8.3 Females and Males of Reproductive Potential

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; subsection title has been revised)

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

8.5 Geriatric Use

(Additions and/or revisions are underlined)

In EINSTEIN CHOICE, approximately 39% were 65 years and over and about 12% were >75 years

 

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Instructions for Patient Use

  • Advise patients for initial treatment of DVT and/or PE to take XARELTO 15 mg or 20 mg tablets with food at approximately the same time every day.

  • Advise patients who are at a continued risk of recurrent DVT and/or PE after at least 6 months of initial treatment, to take XARELTO 10 mg once daily with or without food.

Lactation

Advise patients to discuss with their physician the benefits and risks of XARELTO for the mother and for the child if they are nursing or intend to nurse during anticoagulant treatment.

Females and Males of Reproductive Potential

Advise patients who can become pregnant to discuss pregnancy planning with their physician.

MEDICATION GUIDE

(Additions and/or revisions are underlined)

What is the most important information I should know about XARELTO?

  • XARELTO can cause bleeding which can be serious, and rarely may lead to death. This is because XARELTO is a blood thinner medicine (anticoagulant) that reduces blood clotting…

What is XARELTO?

XARELTO is a prescription medicine used to:

  • treat blood clots in the veins of your legs (deep vein thrombosis or DVT) or lungs (pulmonary embolism or PE)

  • reduce the risk of blood clots happening again in people who continue to be at risk for DVT or PE after receiving treatment for blood clots for at least 6 months.

Before taking XARELTO, tell your doctor about all of your medical conditions, including if you:

  • are pregnant or plan to become pregnant. It is not known if XARELTO will harm your unborn baby.

    • Tell your doctor right away if you become pregnant during treatment with XARELTO. Taking XARELTO while you are pregnant may increase the risk of bleeding in you or in your unborn baby.

    • If you take XARELTO during pregnancy tell your doctor right away if you have any signs or symptoms of bleeding or blood loss. See “What is the most important information I should know about XARELTO?” for signs and symptoms of bleeding.

  • are breastfeeding or plan to breastfeed. XARELTO may pass into your breast milk

How should I take XARELTO?

  • If you take XARELTO for:

    • blood clots in the veins of your legs or lungs:

      • Take XARELTO 1 or 2 times a day as prescribed by your doctor.

      • For the 15 mg and 20 mg doses, XARELTO should be taken with food.

      • For the 10 mg dose, XARELTO may be taken with or without food.

      • If you miss a dose:

        • If you take the 15 mg dose of XARELTO 2 times a day (a total of 30 mg of XARELTO in 1 day):

06/28/2017 (SUPPL-23)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Risk of Bleeding

(additions underlined)

Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, non- steroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors.

Concomitant use of drugs that are known combined P-gp and strong CYP3A4 inhibitors increases rivaroxaban exposure and may increase bleeding risk.

5.6 Use with P-gp and Strong CYP3A4 Inhibitors or Inducers

(additions underlined)

Avoid concomitant use of XARELTO with known combined P-gp and strong CYP3A4 inhibitors.

Avoid concomitant use of XARELTO with drugs that are known combined P-gp and strong CYP3A4 inducers.

7 Drug Interactions

7.1 General Inhibition and Induction Properties

(additions underlined)

Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Combined P-gp and strong CYP3A4 inhibitors increase exposure to rivaroxaban and may increase the risk of bleeding. Combined P-gp and strong CYP3A4 inducers decrease exposure to rivaroxaban and may increase the risk of thromboembolic events.

7.2 Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems

(additions underlined)

InInteraction with Combined P-gp and Strong CYP3A4 Inhibitors

Avoid concomitant administration of XARELTO with known combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole and ritonavir).  

Although clarithromycin is a combined P-gp and strong CYP3A4 inhibitor, pharmacokinetic data suggests that no precautions are necessary with concomitant administration with XARELTO as the change in exposure is unlikely to affect the bleeding risk.

Interaction with Combined P-gp and Moderate CYP3A4 Inhibitors in Patients with Renal Impairment

XARELTO should not be used in patients with CrCl 15 to <80 mL/min who are receiving concomitant combined P-gp and moderate CYP3A4 inhibitors (e.g., erythromycin) unless the potential benefit justifies the potential risk.

7.4 Anticoagulants and NSAIDs/Aspirin

(additions underlined)

Coadministration of enoxaparin, warfarin, aspirin, clopidogrel and chronic NSAID use may increase the risk of bleeding.

Avoid concurrent use of XARELTO with other anticoagulants due to increased bleeding risk unless benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs.

08/25/2016 (SUPPL-19)

Approved Drug Label (PDF)

5 Warnings and Precautions

Spinal/Epidural Anesthesia or Puncture

  • An indwelling epidural or intrathecal catheter should not be removed before at least 2 half-lifes have elapsed (i.e., 18 hours in young patients aged 20 to 45 years and 26 hours in elderly patients aged 60 to 76 years), after the last administration of XARELTO. The next XARELTO dose should not be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of XARELTO for 24 hours (revised).

08/17/2016 (SUPPL-17)

Approved Drug Label (PDF)

5 Warnings and Precautions

Risk of Bleeding (additions are bolded)

  • Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include: … NSAIDs … selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors.
Use in Patients with Renal Impairment

Nonvalvular Atrial Fibrillation (updated)

  • Periodically assess renal function as clinically indicated (i.e., more frequently in situations in which renal function may decline) and adjust therapy accordingly. Consider dose adjustment or discontinuation of XARELTO in patients who develop acute renal failure while on XARELTO.

6 Adverse Reactions

Clinical Trials Experience

Nonvalvular Atrial Fibrillation

  • Table 1 shows the number of patients experiencing various types of bleeding events in the ROCKET AF trial.
  • Table 1: Bleeding Events in ROCKET AF*- On Treatment Plus 2 Days replaces Table 1: Bleeding Events in ROCKET AF*
    • Table extensively updated; please refer to label.
  • Figure 1: Risk of Major Bleeding Events by Baseline Characteristics in ROCKET AF – On Treatment Plus 2 Days (addition; please refer to label)
    • Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified (diabetic status was not pre-specified in the subgroup, but was a criterion for the CHADS2 score). 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.

7 Drug Interactions

Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems (Revised)

  • In drug interaction studies, conducted in subjects with normal renal function, evaluating the concomitant use with drugs that are combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir), increases in rivaroxaban exposure (up to 2.6-fold) and pharmacodynamic effects (i.e., factor Xa inhibition and PT prolongation) were observed. Significant increases in rivaroxaban exposure may increase bleeding risk.
General Inhibition and Induction Properties (new subheading)

  • Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and …

8 Use in Specific Populations

Renal Impairment

Patients with End-Stage Renal Disease on Dialysis (additional section)

  • Clinical efficacy and safety studies with XARELTO did not enroll patients with end-stage renal disease (ESRD) on dialysis. In patients with ESRD maintained on intermittent hemodialysis, administration of XARELTO 15 mg once daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in the ROCKET AF study.

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

MG - What is the most important information I should know about XARELTO?

XARELTO can cause bleeding …

  • You may have a higher risk of bleeding if you take XARELTO and take other medicines that increase your risk of bleeding, including:
    • selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs)

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

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