On November 5, 2015 Johnson & Johnson reported that at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, Janssen Research & Development, LLC will present new data for both approved and investigational oncology and cardiovascular compounds across 10 disease areas (Press release, Johnson & Johnson, NOV 5, 2015, View Source [SID:1234508028]). More than 40 abstracts from company-sponsored studies have been accepted for presentation, including 17 oral presentations, the largest presence of company data to date. Oral presentations from five Janssen brands across two therapeutic areas will be presented at the meeting, including ibrutinib, daratumumab, siltuximab, imetelstat and rivaroxaban. Data and posters from bortezomib, decitabine and JNJ56022473 (formerly CSL362) will be presented as well.
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"The depth and breadth of data presented at ASH (Free ASH Whitepaper) 2015 demonstrate our deep passion for developing transformational medical solutions to treat and prevent disease in novel ways, with the goal of radically improving health for patients in need," said William N. Hait, M.D., Ph.D., Global Head, Janssen Research & Development, LLC.
Ibrutinib will be featured in 23 presentations sponsored by either Janssen or its collaboration partner, Pharmacyclics, seven of which are orals. Presentations include data evaluating its use as a single agent and in combination with other therapies across several disease states. IMBRUVICA is jointly developed and commercialized by Janssen Biotech, Inc. and Pharmacyclics LLC, an AbbVie company.
Daratumumab will be featured in 10 presentations sponsored or supported by Janssen, three of which are orals. The company will present data evaluating the fully human anti-CD38 monoclonal antibody as a single agent and in combination with standard therapies in multiple myeloma patients who are relapsed or refractory to standard therapies.
Siltuximab will be featured in one presentation sponsored by Janssen, reporting data from a Phase 2 study assessing the economic burden of relapsed or refractory multiple myeloma.
Imetelstat will be featured in two oral presentations sponsored by either Janssen or its licensing and collaboration partner, Geron Corporation.
Rivaroxaban will be featured in four oral presentations on anticoagulant use in venous thromboembolic disease sponsored by Janssen Pharmaceuticals, Inc. and its development partner for this medicine, Bayer HealthCare.
Ibrutinib Oral Presentations:
Chronic Lymphocytic Leukemia
Results from the International, Randomized Phase 3 Study of Ibrutinib Versus Chlorambucil in Patients 65 Years and Older with Treatment-Naïve CLL/SLL (RESONATE-2TM). (Abstract 495)
Outcome of Ibrutinib Treatment by Baseline Genetic Features in Patients with Relapsed or Refractory CLL/SLL With del17p in the RESONATE-17 Study. (Abstract 833)
Ibrutinib Plus Bendamustine/Rituximab (BR) is Associated with Greater Reductions in Fatigue Than Placebo Plus BR Among Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia and Fatigue. (Abstract 267)
Mantle Cell Lymphoma
Ibrutinib vs Temsirolimus: Results From a Phase 3, International, Randomized, Open-Label, Multicenter Study in Patients With Previously Treated Mantle Cell Lymphoma (MCL). (Abstract 469)
Multiple Myeloma
Combination Treatment with the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib and Carfilzomib in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma: Initial Results from a Multicenter Phase 1/2b Study. (Abstract 377)
Diffuse Large B-cell Lymphoma
The Role of PIM1 in Ibrutinib-Resistant ABC Subtype of Diffuse Large B-Cell Lymphoma. (Abstract 699)
Follicular Lymphoma
Ibrutinib Plus Rituximab in Treatment-Naïve Patients with Follicular Lymphoma: Results from a Multicenter, Phase 2 Study. (Abstract 470)
Daratumumab Oral Presentations:
Multiple Myeloma
Clinical Efficacy of Daratumumab Monotherapy in Patients with Heavily Pretreated Relapsed or Refractory Multiple Myeloma. (Abstract 29)
Daratumumab in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma: Updated Results of a Phase 1/2 Study (GEN503). (Abstract 507)
Open-label, Multicenter, Phase 1b Study of Daratumumab in Combination with Pomalidomide and Dexamethasone in Patients with at Least 2 Lines of Prior Therapy and Relapsed or Relapsed and Refractory Multiple Myeloma. (Abstract 508)
Siltuximab Oral Presentation:
Multiple Myeloma
Economic Burden of Relapsed or Refractory Multiple Myeloma: Results from an International Trial. (Abstract 875)
Imetelstat Oral Presentations:
Telomerase Inhibitor Imetelstat Therapy in Refractory Anemia with Ring Sideroblasts with or without Thrombocytosis. (Abstract 55)
Dynamics of Mutations in Patients with ET Treated with Imetelstat. (Abstract 57)
Rivaroxaban Oral Presentations:
Deep Vein Thrombosis and Pulmonary Embolism
Safe and Effective Use of Rivaroxaban for Treatment of Cancer-Associated Venous Thromboembolic Disease: A Quality Improvement Initiative. (Abstract 431)
Current Practice Patterns and Patient Persistence on Anticoagulant Treatments for Cancer-Associated Thrombosis. (Abstract 626)
Xalia, a Non-Interventional Study Comparing Rivaroxaban with Standard Anticoagulation for Initial and Long-Term Therapy in Deep Vein Thrombosis. (Abstract 894)
Validation of the Inhospital Mortality for Pulmonary Embolism Using Claims Data (IMPACT) Prediction Rule within an All-Payer Inpatient Administrative Claims Database. (Abstract 747)
About IMBRUVICA (ibrutinib)
IMBRUVICA was one of the first therapies to receive U.S. approval after having received the FDA’s Breakthrough Therapy Designation. IMBRUVICA works by blocking a specific protein called Bruton’s tyrosine kinase (BTK).1 The BTK protein transmits important signals that tell B cells to mature and produce antibodies and is needed by specific cancer cells to multiply and spread.1, 2 IMBRUVICA targets and blocks BTK, inhibiting cancer cell survival and spread.1 For more information, visit www.IMBRUVICA.com.
Additional Information about IMBRUVICA
INDICATIONS
IMBRUVICA is indicated to treat people with:
Chronic lymphocytic leukemia (CLL) who have received at least one prior therapy
Chronic lymphocytic leukemia (CLL) with 17p deletion
Waldenström’s macroglobulinemia (WM)
Mantle cell lymphoma (MCL) who have received at least one prior therapy
Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Hemorrhage – Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA.
The mechanism for the bleeding events is not well understood. IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding.
Infections – Fatal and non-fatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 26% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA. Monitor patients for fever and infections and evaluate promptly.
Cytopenias – Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA. Monitor complete blood counts monthly.
Atrial Fibrillation – Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA treatment and dose modification.
Second Primary Malignancies – Other malignancies (range, 5 to 14%) including non-skin carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 11%).
Tumor Lysis Syndrome – Tumor lysis syndrome has been reported with IMBRUVICA therapy. Monitor patients closely and take appropriate precautions in patients at risk for tumor lysis syndrome (e.g., high tumor burden).
Embryo-Fetal Toxicity – Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
ADVERSE REACTIONS
The most common adverse reactions (≥25%) in patients with B-cell malignancies (MCL, CLL, WM) were thrombocytopenia* (57%, 52%, 43%), neutropenia* (47%, 51%, 44%), diarrhea (51%, 48%, 37%), anemia* (41%, 36%, 13%), fatigue (41%, 28%, 21%), musculoskeletal pain (37%, 28%†, NA‡), bruising (30%, 12%†, 16%†), nausea (31%, 26%, 21%), upper respiratory tract infection (34%, 16%, 19%), and rash (25%, 24%†, 22%†).
*Based on adverse reactions and/or laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased).
†Includes multiple ADR terms.
‡Not applicable; no associated ADRs.
The most common Grade 3 or 4 non-hematological adverse reactions (≥5%) in MCL patients were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5%), diarrhea (5%), fatigue (5%), and skin infections (5%).
Approximately 6% (CLL), 14% (MCL), and 11% (WM) of patients had a dose reduction due to adverse events.
Approximately 5% (CLL), 9% (MCL), and 6% (WM) of patients discontinued due to adverse events. Most frequent adverse events leading to discontinuation were infections, subdural hematomas, and diarrhea in CLL patients and subdural hematoma (1.8%) in MCL patients.
DRUG INTERACTIONS
CYP3A Inhibitors – Avoid co-administration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose.
CYP3A Inducers – Avoid co-administration with strong CYP3A inducers.
SPECIFIC POPULATIONS
Hepatic Impairment – Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA dose.
Please see full Prescribing Information: View Source
About Daratumumab
Daratumumab is an investigational human monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is believed to induce rapid tumor cell death through multiple immune-mediated mechanisms, including complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity, as well as via induction of apoptosis.3, 4, 5 Five Phase 3 clinical studies with daratumumab in relapsed and frontline settings are currently ongoing. Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma and non-Hodgkin lymphoma. In August 2012, Genmab granted Janssen Biotech, Inc. an exclusive worldwide license to develop, manufacture and commercialize daratumumab.
About SYLVANT (siltuximab)
SYLVANT is an anti-interleukin-6 (IL-6) chimeric monoclonal antibody that binds to human IL-6.6 IL-6 is a multifunctional cytokine produced by various cells such as T cells, B cells, monocytes, fibroblasts and endothelial cells. Dysregulated overproduction of IL-6 from activated B cells in affected lymph nodes has been implicated in the pathogenesis of, or mechanism causing, MCD.7 Information about ongoing studies with siltuximab can be found at www.clinicaltrials.gov.
Additional Information about SYLVANT
INDICATION
SYLVANT (siltuximab) is indicated for the treatment of patients with multicentric Castleman’s disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative.
Limitation of Use. SYLVANT was not studied in patients with MCD who are HIV positive or HHV-8 positive because SYLVANT did not bind to virally produced IL‐6 in a nonclinical study.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS – Severe hypersensitivity reaction to siltuximab or any of the excipients in SYLVANT.
Concurrent Active Severe Infections – Do not administer to patients with severe infections until the infection resolves. SYLVANT may mask signs and symptoms of acute inflammation including suppression of fever and of acute phase reactants such as C-reactive protein (CRP). Monitor patients closely for infections. Institute prompt anti-infective therapy and do not administer further SYLVANT until the infection resolves.
Vaccinations – Do not administer live vaccines to patients receiving SYLVANT because interleukin-6 (IL-6) inhibition may interfere with the normal immune response to new antigens.
Infusion Related Reactions and Hypersensitivity – Stop the infusion if the patient develops signs of anaphylaxis. Discontinue further therapy.
Stop the infusion if the patient develops mild to moderate infusion reactions. If the reaction resolves, the infusion may be restarted at a lower infusion rate. Consider medicating with antihistamines, acetaminophen, and corticosteroids. Discontinue SYLVANT if the patient does not tolerate the infusion following these interventions. [see Adverse Reactions (6)].
Administer SYLVANT in a setting that provides resuscitation equipment, medication, and personnel trained to provide resuscitation.
Gastrointestinal (GI) Perforation – Use with caution in patients who may be at increased risk for GI perforation. Promptly evaluate patients presenting with symptoms that may be associated with or suggestive of GI perforation.
Adverse Reactions – The most common adverse reactions (>10% compared to placebo) in the MCD clinical trial were pruritus, increased weight, rash, hyperuricemia, and upper respiratory tract infection.
Drug Interactions – Cytochrome P450 (CYP450) Substrates – Upon initiation or discontinuation of SYLVANT, in patients being treated with CYP450 substrates with narrow therapeutic index, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) as needed and adjust dose. Exercise caution when SYLVANT is co-administered with CYP3A4 substrate drugs where a decrease in effectiveness would be undesirable (e.g., oral contraceptives, lovastatin, atorvastatin).
For more information on SYLVANT, including the full prescribing information, visit www.SYLVANT.com.
About Imetelstat
Janssen entered into an exclusive worldwide license and collaboration agreement with Geron Corporation (Nasdaq: GERN) in November 2014 to develop and commercialize imetelstat, an investigational telomerase inhibitor. Imetelstat is a specially designed and modified short oligonucleotide, which targets and binds directly with high affinity to the active site of telomerase. Imetelstat has not been approved for marketing by any regulatory authority.
About XARELTO (rivaroxaban)
XARELTO works by blocking the blood clotting Factor Xa. XARELTO does not require routine blood monitoring. XARELTO has a broad indication profile and is approved for six indications that include:
To reduce the risk of strokes and blood clots in patients with atrial fibrillation not caused by a heart valve problem. For patients currently well managed on warfarin, there is limited information on how XARELTO and warfarin compare in reducing the risk of stroke.
To treat patients with deep vein thrombosis (DVT).
To treat patients with pulmonary embolism (PE).
To reduce the risk of recurrence of DVT or PE following an initial six-month treatment for acute venous thromboembolism.
To reduce the risk of blood clots in the legs and lungs of patients who have just had knee replacement surgery.
To reduce the risk of blood clots in the legs and lungs of patients who have just had hip replacement surgery.
IMPORTANT SAFETY INFORMATION
WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA
A. PREMATURE DISCONTINUATION OF XARELTO INCREASES THE RISK OF THROMBOTIC EVENTS
Premature discontinuation of any oral anticoagulant, including XARELTO, increases the risk of thrombotic events. If anticoagulation with XARELTO is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.
B. SPINAL/EPIDURAL HEMATOMA
Epidural or spinal hematomas have occurred in patients treated with XARELTO 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, see Drug Interactions
A history of traumatic or repeated epidural or spinal punctures
A history of spinal deformity or spinal surgery <
Optimal timing between the administration of XARELTO and neuraxial procedures is not known
Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.
Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.
CONTRAINDICATIONS
Active pathological bleeding
Severe hypersensitivity reaction to XARELTO (eg, anaphylactic reactions)
WARNINGS AND PRECAUTIONS
Increased Risk of Thrombotic Events After Premature Discontinuation: Premature discontinuation of any oral anticoagulant, including 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 is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.
Risk of Bleeding: XARELTO increases the risk of bleeding and can cause serious or fatal bleeding. Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. 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.
Concomitant use of other drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and NSAIDs.
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. To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of rivaroxaban. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. 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. If traumatic puncture occurs, the administration of XARELTO is to be delayed for 24 hours. 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), or 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.
Use in Patients With Renal Impairment:
Nonvalvular Atrial Fibrillation: Avoid the use of XARELTO in patients with creatinine clearance (CrCl) <15 mL/min, since drug exposure is increased. Discontinue XARELTO in patients who develop acute renal failure while on XARELTO.
Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE: Avoid the use of XARELTO in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population.
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery: Avoid the use of XARELTO in patients with 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 CrCl 30 to 50 mL/min. Patients who develop acute renal failure while on XARELTO should discontinue the treatment.
Use in Patients With Hepatic Impairment: No clinical data are available for patients with severe hepatic impairment. Avoid 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, since drug exposure and bleeding risk may be increased.
Use With P-gp and Strong CYP3A4 Inhibitors or Inducers: Avoid concomitant use of XARELTO with combined P-gp and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan). Avoid concomitant use of XARELTO with drugs that are P-gp and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort).
Risk of Pregnancy-Related Hemorrhage: In pregnant women, XARELTO should be used only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied. 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).
Patients With Prosthetic Heart Valves: The safety and efficacy of XARELTO have not been studied in patients with prosthetic heart valves. Therefore, use of XARELTO is not recommended in these patients.
Acute PE in Hemodynamically Unstable Patients/Patients Who Require Thrombolysis or Pulmonary Embolectomy: Initiation of XARELTO is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.
DRUG INTERACTIONS
Avoid concomitant 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.
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 unless the potential benefit justifies the potential risk.
USE IN SPECIFIC POPULATIONS
Pregnancy Category C: XARELTO should be used during pregnancy only if the potential benefit justifies the potential risk to mother and fetus. There are no adequate or well-controlled studies of XARELTO in pregnant women, and dosing for pregnant women has not been established. 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.
Labor and Delivery: Safety and effectiveness of XARELTO during labor and delivery have not been studied in clinical trials.
Nursing Mothers: It is not known if rivaroxaban is excreted in human milk.
Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
Females of Reproductive Potential: Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.
OVERDOSAGE
Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur. A specific antidote for rivaroxaban is not available. 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
The most common adverse reactions with XARELTO were bleeding complications.