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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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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