Janssen Research & Development Submits Application to U.S. FDA for XARELTO® (rivaroxaban) to Reduce Secondary Cardiovascular Events in Patients with Acute Coronary Syndrome

RARITAN, N.J., Dec. 29, 2011 /PRNewswire/ -- Janssen Research & Development, LLC (JRD) announced today that it has submitted a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) seeking approval for the use of XARELTO^® (rivaroxaban), an oral anticoagulant, to reduce the risk of (thrombotic) cardiovascular events in patients with Acute Coronary Syndrome (ACS).

The filing is supported by data from the pivotal Phase 3 ATLAS ACS 2 TIMI 51 (Anti-Xa Therapy to Lower cardiovascular events in Addition to aspirin with/without thienopyridine therapy in Subjects with Acute Coronary Syndrome) trial, which was presented in November at the American Heart Association Scientific Sessions and published in the New England Journal of Medicine (10.1056/NEJMoa1112277).

ACS is a complication of coronary heart disease, which is the leading cause of death in the U.S. and also one of the most prevalent non-communicable diseases in the world. ACS occurs when a blood clot blocks a coronary artery, reducing blood supply to the heart. This disruption of blood flow can cause a heart attack, or unstable angina, a condition signifying that a heart attack may soon occur. Each year, an estimated 1.2 million patients in the U.S. are discharged from the hospital with a primary or secondary diagnosis of ACS.

About XARELTO^® (rivaroxaban)

XARELTO^® belongs to a group of medicines called anticoagulants, and works by blocking the blood clotting Factor Xa, thereby reducing the tendency to form clots. In the U.S., XARELTO^® is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE) in people undergoing knee or hip replacement surgery, and for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. There are limited data on the relative effectiveness of XARELTO^® and warfarin in reducing the risk of stroke and systemic embolism in nonvalvular atrial fibrillation patients when warfarin therapy is well-controlled.

Additionally, XARELTO^® is being evaluated for the prevention and treatment of a broad range of disorders in which blood clotting plays a major role. By the time of its completion, more than 75,000 patients will have participated in the rivaroxaban clinical development program. Rivaroxaban is being developed jointly by JRD and Bayer HealthCare. U.S. marketing rights for XARELTO^® are held by Janssen Pharmaceuticals, Inc.

More information for patients and caregivers can be accessed at http://www.xarelto-us.com/.

About Janssen Research & Development, LLC

At Janssen, we are dedicated to addressing and solving some of the most important unmet medical needs of our time in oncology, immunology, neuroscience, infectious diseases and vaccines, and cardiovascular and metabolic diseases. Driven by our commitment to patients, we develop innovative products, services and healthcare solutions to help people throughout the world. Janssen Research & Development, LLC and Janssen Pharmaceuticals, Inc., are Janssen Pharmaceutical Companies. Please visit http://www.janssenrnd.com for more information.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

• Active pathological bleeding
• Severe hypersensitivity reaction to XARELTO^®

WARNINGS AND PRECAUTIONS

• Increased Risk of Stroke After Discontinuation in Nonvalvular Atrial Fibrillation: Discontinuing XARELTO^®, in the absence of adequate alternative anticoagulation, increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO^® to warfarin in clinical trials in atrial fibrillation patients. If XARELTO^® must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant.
• Risk of Bleeding: XARELTO^® increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO^® to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding. Promptly evaluate any signs or symptoms of blood loss. Discontinue XARELTO^® in patients with active pathological hemorrhage.
  • A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trials.
  • Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and NSAIDs.
  • Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (eg, ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk.
• Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis.

An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO^®. The next XARELTO^® dose is not to be administered earlier than 6 hours after the removal of the catheter. Delay the administration of XARELTO^® for 24 hours if traumatic puncture occurs.

• Risk of Pregnancy-Related Hemorrhage: Use with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus. The anticoagulant effect of XARELTO^® cannot be monitored with standard laboratory testing and is not readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (eg, a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress). Pregnancy Category C
• Severe Hypersensitivity Reactions: There were postmarketing cases of anaphylaxis in patients treated with XARELTO^® to reduce the risk of deep vein thrombosis (DVT). Patients who have a history of a severe hypersensitivity reaction to XARELTO^® should not receive XARELTO^®.

DOSING AND ADMINISTRATION

• Nonvalvular Atrial Fibrillation: For patients with creatinine clearance (CrCl) >50 mL/min, the recommended dose of XARELTO^® is 20 mg taken orally once daily with the evening meal. For patients with CrCl 15 to 50 mL/min, the recommended dose is 15 mg once daily with the evening meal.
• Prophylaxis of Deep Vein Thrombosis: The recommended dose of XARELTO^® is 10 mg taken orally once daily with or without food. The initial dose should be taken at least 6 to 10 hours after surgery once hemostasis has been established.
  • For patients undergoing hip replacement surgery, treatment duration of 35 days is recommended.
  • For patients undergoing knee replacement surgery, treatment duration of 12 days is recommended.
• Missed Dose: If a dose of XARELTO^® is not taken at the scheduled time, administer the dose as soon as possible on the same day.
• Instructions for Patient Use
  • Remind patients to not discontinue XARELTO^® without first talking to their healthcare professional to minimize the risk of post-discontinuation thrombotic events.
  • Advise patients with atrial fibrillation to take XARELTO^® once daily with the evening meal.

DRUG INTERACTIONS

• Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant administration of XARELTO^® with combined P-gp and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan), which cause significant increases in rivaroxaban exposure that may increase bleeding risk.
• Drugs That Induce CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant use of XARELTO^® with drugs that are combined P-gp and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John's wort) due to decreases in rivaroxaban exposure that may decrease efficacy.
• NSAIDs/Aspirin: NSAIDs/aspirin are known to increase bleeding; therefore, bleeding risk may be increased when these drugs are used concomitantly with XARELTO^®. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs.
• Clopidogrel: Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with clopidogrel.
• Drug-Disease Interactions With Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Use in patients with CrCl 15 mL/min to 50 mL/min who are receiving concomitant combined  P-gp and weak or moderate CYP3A4 inhibitors only if the potential benefit justifies the potential risk (eg, amiodarone, diltiazem, verapamil, quinidine, ranolazine, dronedarone, felodipine, erythromycin, azithromycin, chloramphenicol, and cimetidine).
• Prophylaxis of Deep Vein Thrombosis
  • Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: When clinical data suggest a change in exposure is unlikely to affect bleeding risk (eg, clarithromycin, erythromycin), no precautions are necessary during coadministration with drugs that are P-gp and CYP3A4 inhibitors.
  • Anticoagulants: Avoid concurrent use of XARELTO^® with other anticoagulants due to the increased bleeding risk. Promptly evaluate any signs or symptoms of blood loss.

USE IN SPECIFIC POPULATIONS

• Nursing Mothers: It is not known if rivaroxaban is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO^®, taking into account the importance of the drug to the mother.
• Geriatric Use: 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.
• Renal Impairment
  • Patients with renal impairment taking P-gp and weak to moderate CYP3A4 inhibitors may have significant increases in exposure, which may increase bleeding risk.
  • Nonvalvular Atrial Fibrillation: For patients with CrCl 15 mL/min to 50 mL/min, the recommended dose of XARELTO^® is 15 mg once daily with the evening meal. Avoid use in patients with CrCl <15 mL/min. Periodically assess renal function as clinically indicated (ie, more frequently in situations in which renal function may decline) and adjust therapy accordingly. Discontinue XARELTO^® in patients who develop acute renal failure while on XARELTO^®.
  • Prophylaxis of Deep Vein Thrombosis: Avoid use in severe renal impairment
    (CrCl <30 mL/min) due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with moderate renal impairment (CrCl 30 mL/min to 50 mL/min). Patients who develop acute renal failure while on XARELTO^® should discontinue treatment.
• Hepatic Impairment: No clinical data are available for patients with severe hepatic impairment. Avoid the use of XARELTO^® in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.

OVERDOSAGE

• Overdose of XARELTO^® may lead to hemorrhage. A specific antidote for rivaroxaban is not available. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. Discontinue XARELTO^® and initiate appropriate therapy if bleeding complications associated with overdosage occur. The use of activated charcoal to reduce absorption in case of XARELTO^® overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable.

ADVERSE REACTIONS IN CLINICAL STUDIES  

• Hemorrhage: The most common adverse reactions with XARELTO^® were bleeding complications.
• Nonvalvular Atrial Fibrillation: The most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO^® versus 3.1% for warfarin. The incidence of discontinuations for nonbleeding adverse events was similar in both treatment groups. In XARELTO^®- versus warfarin-treated patients, respectively, major bleeding events were 5.6% versus 5.4%.
• Prophylaxis of Deep Vein Thrombosis: In the RECORD clinical trials, the overall incidence rate of adverse reactions leading to permanent treatment discontinuation was 3.7% with XARELTO^®. In XARELTO^®- versus enoxaparin-treated patients, respectively, major bleeding event rates reported in hip surgery studies were 0.2% versus 0.1% and any bleeding events were 6.1% versus 5.8%; major bleeding events reported in the knee surgery study were 0.6% versus 0.5% and any bleeding events were 5.0% versus 4.9%. Other adverse drug reactions included wound secretion (2.8% vs 2.0%) and syncope (1.2% vs 0.7%) in XARELTO^®- versus enoxaparin-treated patients, respectively.
• Other Clinical Trial Experience: In an investigational study of acute medically ill patients being treated with XARELTO^® 10-mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed.

Please see full Prescribing Information, including Boxed WARNINGS.

(This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995.  The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events.  If underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC and/or Johnson & Johnson.  Risks and uncertainties include, but are not limited to, general industry conditions and competition; economic factors, such as interest rate and currency exchange rate fluctuations; technological advances and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approvals; domestic and foreign health care reforms and governmental laws and regulations; trends toward health care cost containment; and increased scrutiny of the healthcare industry by government agencies. A further list and description of these risks, uncertainties and other factors can be found in Exhibit 99 of Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended January 2, 2011.  Copies of this Form 10-K, as well as subsequent filings, are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. Neither Janssen Pharmaceutical Research & Development, LLC, nor Johnson & Johnson, undertake to update any forward-looking statements as a result of new information or future events or developments.)

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SOURCE Janssen Research & Development, LLC