Module 1: Orthopedic Surgery: Disease State

XARELTO Product Brief ORS Rivaroxaban tablets Course Summary Module 1: Orthopedic Surgery: Disease State Orthopedic Surgery: Overview Pain and altered function of the hip and knee, due to conditions such as arthritis, affect patients quality of life and are the basis for considerable healthcare use and costs. After trying conservative treatment without relief, patients may consider total hip or total knee replacement surgery elective surgeries that can relieve pain, improve function, and have proven to be cost-effective. Elderly people are the primary recipients of joint replacements; however, disorders requiring joint surgery may occur in patients of all ages. Conditions associated with a need for joint replacement include osteoarthritis, rheumatoid arthritis, trauma, and bone necrosis. Potential Complications of Orthopedic Surgery As in any surgical procedure, total joint replacement is associated with potential complications. Although complications are uncommon, they do occur and can be serious. Careful preoperative assessment and planning are important to ensure that complications are kept to a minimum. Potential complications of total hip or total knee replacement may include: Hip dislocation after surgery Deep infection Neurovascular injury Venous thromboembolism (VTE) Cardiovascular and central nervous system disease Note that cardiovascular and central nervous system complications are uncommon, but are possible given that many patients who undergo joint replacement are elderly. Venous Thromboembolism (VTE) Venous thromboembolism (VTE) is an overall, general term used to describe both deep vein thrombosis (DVT) and pulmonary embolism (PE). VTE is a major health problem. The total annual number of VTE events and related deaths in the United States is unknown, largely because the spectrum of disease occurring in the community is underrecognized. Recent estimates show that more than 900,000 people in the United States experience VTE events each year. More than 60% of these events occur in hospitalized patients and one third of all events are fatal. Deep Vein Thrombosis (DVT) A DVT is a thrombus that forms in a deep vein in the body. The most common site for a DVT is in the deep veins of the legs. Most DVTs develop in the calf, though some may form in the proximal veins, that is, the veins above the knee. These clots are more likely to embolize and cause a PE. Signs and symptoms of DVT may include: Leg pain, tenderness, and swelling (edema) Erythema A palpable cord Cyanosis Venous distention Warmth in the affected area Pulmonary Embolism (PE) Pulmonary embolism occurs when a thrombus fragment breaks away from the wall of a vein, travels through the venous circulation to the heart, enters the pulmonary circulation, and blocks a pulmonary artery or one of its branches. When this happens, blood flow to the lung served by that pulmonary artery is blocked. Most pulmonary emboli arise from DVT in the legs. Signs and symptoms of PE are typically related to breathing the primary function of the lungs and may include: Dyspnea Pleuritic chest pain 1

Cough Palpitations Anxiety/nervousness Lightheadedness Tachypnea and tachycardia Syncope Sudden death Epidemiology of VTE in Orthopedic Surgery Patients undergoing major orthopedic surgery are at particularly high risk for VTE. Without thromboprophylaxis, the incidence of hospital-acquired DVT is approximately 40% 60% following major orthopedic surgery. Asymptomatic DVT is common and, in the absence of thromboprophylaxis, affects at least half of all patients. Most symptomatic VTE occurs after hospital discharge, and the risk continues to be high for at least two months after surgery. Information on the risk of VTE in patients undergoing total hip or total knee replacement surgery is summarized in the table below. Pharmacologic agents that may be used for VTE prophylaxis include: Aspirin Unfractionated heparin Low molecular-weight heparins (LMWHs) Vitamin K antagonists Fondaparinux sodium Total Hip Replacement Surgery Hip replacement patients are at a high risk for both asymptomatic DVT (incidence, 40% 60%) and symptomatic VTE (incidence, 2% 5%) Without thromboprophylaxis, fatal PE occurs in approximately 1 patient per 300 elective hip replacements Total Knee Replacement Surgery The risk of DVT without thromboprophylaxis is higher after total knee replacement than after total hip replacement Proximal DVT occurs less commonly after knee replacement than hip replacement and the period of increased risk for symptomatic VTE after discharge is shorter Prevention of VTE After Orthopedic Surgery Patients at high risk for VTE, such as those undergoing total hip or total knee replacement surgeries, require prophylactic anticoagulant drugs to prevent thrombi from developing. Presently, two organizations have published guidelines to aid in the selection of appropriate thromboprophylaxis for such patients: the American College of Chest Physicians (ACCP) and the American Academy of Orthopedic Surgeons (AAOS). 2

Module 2: Orthopedic Surgery: The Marketplace Orthopedic Surgery: Scope of the Problem In 2009, the combined total of hip and knee replacement procedures performed in the United States exceeded 1 million. By the year 2030, the number of total hip replacement procedures is estimated to increase by almost 200%, and the number of total knee replacement procedures may grow by almost 700%. Plus, the chance of developing DVT following major orthopedic surgery is between 40% 60% if thromboprophylaxis is not given. Total Number of Discharges Mean Length of Hospital Stay Hip and Knee Surgery: 2008 US Hospital Statistics Total and Partial Hip Replacements 436,736 680,839 4.5 days 3.5 days Mean Costs* $16,798 $15,263 Mean Charges $51,360 $45,783 Knee Arthroplasty (surgical reconstruction or replacement) *Costs: Total hospital charges use cost-to-charge ratios from the Centers for Medicare & Medicaid Services. These reflect actual costs of production/hospital charges and not professional (physician) fees or costs outside of the hospital. Charges: These reflect what the hospital billed for stay; these do not reflect professional (physician) fees. Generally more than what it costs to provide care. Venous thromboembolism is a potential complication of orthopedic surgery that can impact its cost. Venous thromboembolism also increases mortality and morbidity. However, VTE risk can be reduced substantially through VTE prophylaxis. According to data from 2002, the average Medicare payment per case of postoperative VTE is $27,420. *Please note: the numbers presented in this graphic are projections. Adapted from Kurz et al. J Bone Joint Surg Am. 2007;89(4):780-785. Cost of Orthopedic Surgery The total costs of orthopedic surgery, including follow-up care, are hard to determine. They may include costs for: Hospitalization Professional services VTE prophylaxis and other medications Complications Rehabilitation Physical therapy Lost days of work In the United States in 2008, mean hospital costs were estimated at $16,798 for hip replacement surgery and $15,263 for knee surgery, while mean total hospital charges were $51,360 and $45,783 respectively. Key Stakeholders Involved in Anticoagulant Prophylaxis Various stakeholders are involved with orthopedic surgery and anticoagulant prophylaxis. Among these, the primary stakeholder is the orthopedic surgeon. Primary decision maker and attending physician for patients undergoing hip or knee surgery Determines anticoagulant prophylaxis Manages patient care In addition to orthopedic surgeons, three other types of key stakeholders involved in anticoagulant prophylaxis may be seen on a continuum: Internal/general medicine physician or hospitalist Hospital discharge planner/case manager/social worker Physiatrist 3

Major Antithrombotic Agents The major antithrombotic agents used for VTE prophylaxis in the orthopedic surgery marketplace can be categorized into one of two groups: parenteral agents and oral agents. Parenteral Agents Parenteral agents include drugs that are administered by intravenous (IV) infusion or subcutaneous (SC) injection. Examples of parenteral agents used for VTE prophylaxis in the orthopedic surgery marketplace include: Unfractionated heparin Low molecular-weight heparins (eg, Lovenox ) Synthetic pentasaccharide (ie, Arixtra ) Unfractionated Heparin Lovenox (enoxaparin sodium injection) Arixtra (fondaparinux sodium) Description Heterogeneous (nonuniform) mixture of glycosaminoglycans (carbohydrates) LMWH initially approved in the United States in 1993; generic version approved in 2010 Synthetic pentasaccharide initially approved in the United States in 2001 Mechanism of action Indirect inhibition of thrombin (factor IIa) and factors IXa, Xa, XIa, and XIIa Anticoagulant activity mediated by binding to cofactor (antithrombin) Indirect inhibition of factor Xa and, to a lesser extent, thrombin (factor IIa) Anticoagulant activity mediated by binding to cofactor (antithrombin) Indirect inhibition of factor Xa Anticoagulant activity mediated by binding to cofactor (antithrombin) Dosing and administration When used prophylactically, low dose is administered subcutaneously 2 or 3 times daily for prophylaxis without routine monitoring of coagulation parameters When used for treatment of VTE, specific dosage must be adjusted for each patient based on individual characteristics (weight) and results of coagulation tests, and routine monitoring is required Administered once or twice daily without routine anticoagulant monitoring Administered once daily in fixed doses without routine anticoagulant monitoring Safety No boxed warning Adverse reactions include bleeding, thrombocytopenia (including a very serious form called heparin-induced thrombocytopenia), local irritation, hypersensitivity, osteoporosis, and serum aminotransferase elevations Boxed warning: spinal/epidural hematoma Adverse reactions include bleeding, thrombocytopenia, serum aminotransferase elevations, local reactions, and anemia Boxed warning: spinal/epidural hematoma Adverse reactions include bleeding, local reactions, serum aminotransferase elevations, anemia, thrombocytopenia, and increased wound drainage 4

Oral Agents The oral agents used for VTE prophylaxis in the orthopedic surgery marketplace are administered as oral tablets. Examples include the vitamin K antagonist, Coumadin (warfarin sodium), and the antiplatelet, aspirin (see the table below). Description Mechanism of action Dosing and administration Safety Coumadin (warfarin sodium) Vitamin K antagonist that received initial US approval in 1954; widely available as a generic Interferes with the liver synthesis of vitamin K dependent clotting factors factors II, VII, IX, and X Dosage and administration must be individualized based on the patient s PT/INR response to the drug Frequent coagulation monitoring is essential to monitor patient response and make dosage adjustments Boxed warning: bleeding risk Narrow therapeutic range Known to interact with a number of foods, drugs, and herbal medicines Aspirin (acetylsalicylic acid) Prototype antiplatelet agent that has been used clinically for >50 years Interferes with platelet aggregation No labeled indication for use in VTE prophylaxis, but recommended by AAOS guidelines for the prevention of PE in certain patients undergoing total hip or knee replacement surgery No boxed warning 5

Module 3: XARELTO Product Information Mechanism of Action XARELTO (rivaroxaban) is the first oral, selective inhibitor of factor Xa approved by the FDA. It binds directly to factor Xa without requiring a cofactor such as antithrombin III for activity. XARELTO acts at a central point in the coagulation cascade where the intrinsic and extrinsic pathways converge and factor X is converted to factor Xa. The Intrinsic Pathway (Contact Activation) Blood trauma, contact with collagen, or contact with a negatively charged surface XII kallikrein XI XIIa IX Ca ++ XIa X IXa Ca ++ VIIIa Tenase Ca ++ Va Xa Prothrombin (II) Release of tissue factor (III) by injured cells Ca ++ Va Ca ++ Prothrombinase (prothrombinase complex) Fibrinogen (I) Indications and Usage The Extrinsic Pathway (Tissue Factor Pathway) Tissue Damage Xa VIIa Tissue factor/viia complex X Thrombin (IIa) VII The Common Pathway Fibrin (Ia) Stable fibrin clot with crosslinked fibrin strands XARELTO is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE) in patients undergoing knee or hip replacement surgery. Dosage and Administration Note that XARELTO has a boxed warning regarding the risk of epidural or spinal hematomas in patients who are anticoagulated and are receiving neuraxial anesthesia or XIII XIIIa undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. The risks must be considered when scheduling patients for spinal procedures, and patients must be monitored frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. The recommended dose for XARELTO is 10 mg taken orally once daily, with or without food, with the initial dose given at least 6 10 hours after surgery once hemostasis has been established. The duration of prophylaxis depends on the type of orthopedic surgery: Hip replacement surgery: 35 days Knee replacement surgery: 12 days Contraindications XARELTO is contraindicated in patients with hypersensitivity to rivaroxaban or active major bleeding. Warnings and Precautions The XARELTO prescribing information contains five Warnings and Precautions. Spinal/epidural hematoma has a boxed warning. Spinal/Epidural Anesthesia or Puncture When either neuraxial anesthesia or spinal puncture is employed in a patient being treated with an anticoagulant for prevention of thromboembolic complications, there is a risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis To reduce the risk of spinal or epidural hematoma: 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 an epidural catheter If traumatic puncture occurs, administration of XARELTO is to be delayed for 24 hours 6

Risk of Bleeding XARELTO increases the risk of bleeding and can cause serious and fatal bleeding Major hemorrhages have been reported, including: Intracranial, epidural hematoma, gastrointestinal, retinal, and adrenal bleeding Drugs that increase the risk of bleeding: Platelet aggregation inhibitors Other thrombotic agents Fibrinolytics Thienopyridines NSAIDs (chronic use) Any signs or symptoms of blood loss should be promptly evaluated XARELTO should be used with caution in conditions with increased risk of hemorrhage Risk of Pregnancy-Related Hemorrhage XARELTO should be used with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus Dosing in pregnancy has not been studied Signs or symptoms of blood loss should be promptly evaluated Renal Impairment Severe (CrCl <30 ml/min) Use of XARELTO should be avoided Moderate (CrCl 30 to <50 ml/min) Observe closely Promptly evaluate any signs or symptoms of blood loss Patients who develop acute renal failure while taking XARELTO should discontinue the treatment Hepatic Impairment XARELTO use should be avoided in patients with: Moderate hepatic impairment Severe hepatic impairment Any hepatic disease associated with coagulopathy XARELTO was administered at a dose of 10 mg orally once per day, and the mean duration of treatment was 11.9 days in the total knee replacement study and 33.4 days in the total hip replacement studies. In these studies, the overall incidence of adverse reactions leading to permanent treatment discontinuation of XARELTO was 3.7%. Remember that adverse reaction rates observed in the clinical trials of one drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice, because clinical trials are conducted under widely varying conditions. The most common adverse reactions with XARELTO were bleeding complications. The rates of major bleeding events and any bleeding events observed in patients in the RECORD clinical trials are shown in the following table. Adverse Reactions in Clinical Trials XARELTO was studied in 4487 patients in three Phase 3 studies in elective joint replacement known as the REgulation of Coagulation in ORthopedic Surgery to Prevent DVT and PE (RECORD) studies. 7

Adverse Reactions: Bleeding Events* in Patients Undergoing Hip or Knee Replacement Surgery (RECORD 1 3) XARELTO 10 mg n (%) Enoxaparin n (%) Total treated patients (N = 4487) (N = 4524) Major bleeding event Fatal bleeding Bleeding into a critical organ Bleeding that required reoperation Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells Any bleeding event 14 (0.3) 2 (<0.1) 7 (0.2) 4 (0.1) 261 (5.8) 9 (0.2) 0 3 (0.1) 5 (0.1) 251 (5.6) Hip surgery studies (N = 3281) (N = 3298) Major bleeding event Fatal bleeding Bleeding into a critical organ Bleeding that required reoperation Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells Any bleeding event 7 (0.2) 2 (0.1) 3 (0.1) 201 (6.1) 3 (0.1) 0 191 (5.8) Knee surgery study (N = 1206) (N = 1226) Major bleeding event Fatal bleeding Bleeding into a critical organ Bleeding that required reoperation Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells Any bleeding event 7 (0.6) 0 1 (0.1) 5 (0.4) 1 (0.1) 60 (5.0) 6 (0.5) 0 2 (0.2) 4 (0.3) 0 60 (4.9) *Bleeding events occurring any time following the first dose of double-blind study medication (which may have been prior to administration of active drug) until two days after the last dose of double-blind study medication. Patients may have more than one event. Includes the placebo-controlled period of the RECORD 2 study; enoxaparin dosing was 40 mg once daily (RECORD 1 3). Includes major bleeding events. Other Adverse Drug Reactions Other adverse reactions (ie, adverse reactions other than bleeding) that were reported by at least 1% of XARELTOtreated patients included wound secretion, pain in extremity, muscle spasm, syncope, pruritus, and blister (see the table below). Other Adverse Drug Reactions* Reported by 1% of XARELTO-Treated Patients in the RECORD Studies (1 3) System/Organ Class Adverse Reaction Injury, poisoning and procedural complications XARELTO 10 mg (N = 4487) n (%) Enoxaparin (N = 4524) n (%) Wound secretion 125 (2.8) 89 (2.0) Musculoskeletal and connective tissue disorders Pain in extremity Muscle spasm Nervous system disorders 74 (1.7) 52 (1.2) 55 (1.2) 32 (0.7) Syncope 55 (1.2) 32 (0.7) Skin and subcutaneous tissue disorders Pruritus Blister 96 (2.1) 63 (1.4) 79 (1.8) 40 (0.9) *An adverse drug reaction was defined as occurring any time following the first dose of double-blind medication, which may have been prior to administration of active drug, until two days after the last dose of double-blind study medication. Includes the placebo-controlled period of the RECORD 2 study; enoxaparin dosing was 40 mg once daily (RECORD 1 3). The incidence of major bleeding events was similar between XARELTO-treated patients and enoxaparintreated patients. The majority of major bleeding complications with XARELTO occurred during the first week after surgery. 8

Specific Populations The following table presents a synopsis of information from the XARELTO PI on the use of rivaroxaban in specific populations. Pregnancy Labor and delivery Nursing mothers Pediatric Geriatric Females of reproductive potential Moderate renal impairment Severe renal impairment Hepatic impairment Category C; use only if potential benefit justifies potential risk to mother and fetus Safety and efficacy not studied in clinical trials Discontinue nursing or discontinue the drug Safety and effectiveness not established Consider assessment of renal function prior to starting therapy Should discuss pregnancy planning with their physician Observe closely, promptly evaluate signs/symptoms of blood loss Avoid use in severe renal impairment Avoid use in moderate or severe hepatic impairment or any hepatic disease associated with coagulopathy Note that rivaroxaban is classified as Pregnancy Category C, which means that animal reproduction studies have shown an adverse effect on the fetus. There are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. In geriatric patients, consideration should be given to assessment of renal function prior to initiating therapy with XARELTO because elderly subjects exhibited an increase in exposure that may be caused by age-related changes in renal function. Drug Interactions As seen in the following table, there are some important drug/drug interactions to be considered when administering XARELTO. In some cases, a dose increase or decrease in the dose of XARELTO may be needed. In some cases, concomitant use of XARELTO and the drug in question must be avoided entirely. Drug Class Recommendation Drugs affecting rivaroxaban elimination pathways Combined P-gp and strong or moderate CYP3A4 inhibitors Significant increase in exposure to XARELTO (eg, ketoconazole, ritonavir) Smaller increase in exposure to XARELTO (eg, clarithromycin, erythromycin Combined P-gp and strong CYP3A4 inducers Significant decrease in exposure to XARELTO (eg, rifampin) Drugs that increase bleeding risk Anticoagulants (eg, warfarin, enoxaparin) NSAIDs (eg, ibuprofen)/aspirin Clopidogrel Avoid concomitant use XARELTO dose adjustment not required a Consider XARELTO dose increase Avoid concomitant use Promptly evaluate signs/symptoms of blood loss if used concomitantly Avoid concomitant use a Further increases in exposure may occur in patients with renal impairment; use only if the potential benefit justifies the risk. Clinical Pharmacology Highlights of the clinical pharmacology section of the XARELTO PI are presented below. Dose-dependent factor Xa inhibition Maximal plasma levels (C ) in 2 4 hours max Absolute bioavailability ~80% 100% for the 10-mg dose AUC or C of the 10-mg dose not affected by max intake with food Plasma protein binding ~92% 95% Hepatic metabolism by cytochrome P450 dependent and independent mechanisms Elimination by renal (~66%) and fecal routes Half-life 5 9 hours in healthy subjects aged 20 to 45 years The terminal elimination half-life is 11 to 13 hours in the elderly (65 or older) Allows for convenient once-daily dosing Routine monitoring of INR or other coagulation parameters not required Dose adjustments not required for age, body weight, gender, or race 9

How Supplied/Storage and Handling XARELTO is supplied as round, light red, biconvex, filmcoated tablets. One side has a triangle pointing down with the number 10 below it and the other side has the letters Xa. XARELTO is available in bottles of 30 tablets and is also available in a blister package containing 100 tablets. Each blister package includes 10 blister cards, each housing 10 tablets. XARELTO should be stored at 77 F or room temperature. Excursions are permitted to 59 F 86 F. 10