Xigris

Generic Name: Drotrecogin Alfa (Activated)
Class: Other Miscellaneous Therapeutic Agents
Chemical Name: Drotrecogin Alfa (Activated) for Injection
CAS Number: 42617-41-4

Special Alerts:

[Posted 10/25/2011] ISSUE: FDA notified healthcare professionals and the public that on October 25, 2011, Eli Lilly and Company announced a worldwide voluntary market withdrawal of drotrecogin alfa (activated) [Xigris]. In a recently completed clinical trial (PROWESS-SHOCK trial), drotrecogin alfa (activated) failed to show a survival benefit for patients with severe sepsis and septic shock.

BACKGROUND: Drotrecogin alfa (activated) is indicated for the reduction of mortality in adult patients with severe sepsis who have a high risk of death.

RECOMMENDATION: For more information visit the FDA website at: and .

Introduction

Biosynthetic (recombinant DNA origin) form of human activated protein C with antithrombotic, anti-inflammatory, and profibrinolytic properties.^{1 2 5 6}

Uses for Xigris

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Severe Sepsis

Used for mortality reduction in adults with severe sepsis and a high risk of death (e.g., as determined by an Acute Physiology and Chronic Health Evaluation [APACHE II] score of ≥25).^{1 2 4 7 9} International guidelines for the management of severe sepsis and septic shock suggest use in patients who generally have multiple organ failure and an APACHE score of ≥25.²¹

Efficacy not established and use not recommended in patients with a lower risk of death (e.g., APACHE II score <25) or in pediatric patients.^{1 2 11 16 18 21 22}

Accurate diagnosis of severe sepsis and assessment of risk of death are critical when considering patients for therapy.^{1 11}

Xigris Dosage and Administration

General

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

  Discontinue therapy 2 hours prior to an invasive surgical procedure or procedures with an inherent risk of bleeding.^{1 9} Once adequate hemostasis is achieved, reconsider reinitiating therapy at initial recommended doses 12 hours after major invasive procedures or surgery or immediately following uncomplicated, less invasive procedures.¹

  
  


• 
  

  Immediately discontinue therapy in patients with clinically important bleeding.¹

  
  

Administration

Administer by continuous IV infusion using a controlled infusion device (i.e., infusion pump or syringe pump).^{1 9}

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Do not admix or infuse concomitantly with other drugs.¹ (See Compatibility under Stability.)

Reconstitution

Determine appropriate number of vials to reconstitute by calculating the amount of drug required for a particular infusion period based on patient's actual body weight (in kg) and duration of infusion (in hours); round total amount to nearest 5-mg increment to avoid wastage.¹ A maximum infusion period of 12 hours is recommended for each infusion bag or syringe; multiple infusions are required to cover recommended 96-hour duration of therapy.¹

Reconstitute vial containing 5 or 20 mg of drotrecogin alfa (activated) with 2.5 or 10 mL of sterile water for injection, respectively, to provide solutions containing 2 mg/mL.¹

Swirl vial gently to ensure dissolution; do not invert or shake vial.¹ Must be diluted further before IV administration.¹

Reconstituted solutions contain no preservatives; solutions preferably should be diluted immediately after reconstitution.¹ If not used immediately, solution may be stored at 20–25°C, but must be used within 3 hours.¹

Dilution

Dilute reconstituted solution with 0.9% sodium chloride injection in an IV infusion bag or syringe compatible with a syringe pump according to the manufacturer's directions to yield a concentration of 100–200 mcg/mL.¹

Administer at room temperature within 12 hours of dilution; if not used immediately, store at 2–8°C for up to 12 hours.¹ Total in-use time, including dilution, refrigeration, and administration, should not exceed 24 hours.^{1 4 10}

Rate of Administration

Administer by IV infusion at 24 mcg/kg per hour for a total of 96 hours.^{1 9} If infusion is interrupted for >1 hour, extend infusion time to account for interruptions (i.e., allow for a total infusion duration of 96 hours) unless the interruption lasts for ≥36 hours.⁴

When administering the drug at low flow rates (< approximately 5 mL/hr), prime syringe pump for approximately 15 minutes at a flow rate of approximately 5 mL/hour.¹

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Dosage escalation or loading doses are not recommended.¹

Dosage adjustment based on clinical or laboratory parameters is not recommended.¹

Adults

Severe Sepsis

IV

24 mcg/kg per hour for a total of 96 hours.^{1 9}

Special Populations

Renal Impairment

Dosage adjustment not required in patients with renal impairment undergoing hemodialysis or peritoneal dialysis.¹

Hepatic Impairment

Dosage adjustment not required.¹

Geriatric Patients

Dosage adjustment not required.¹

Cautions for Xigris

Contraindications

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  Active internal bleeding.^{1 7 9}

  
  


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  Recent (within 3 months) hemorrhagic stroke.^{1 7 9}

  
  


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  Recent (within 2 months) intracranial or intraspinal surgery or severe head trauma.^{1 7 9}

  
  


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  Trauma with an increased risk of life-threatening bleeding.^{1 7 9}

  
  


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  Presence of an epidural catheter.^{1 7 9}

  
  


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  Intracranial neoplasm or mass lesion, or evidence of cerebral herniation.^{1 7 9}

  
  

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Hematologic Effects

Serious bleeding events, including intracranial hemorrhage, have occurred in patients receiving drotrecogin alfa (activated) therapy.^{1 2 14 16 19 20} Possible increased risk of bleeding in patients with one or more of the following conditions: concurrent heparin therapy to treat an active thrombotic or embolic event; platelet counts <30,000/mm³ (even if the platelet count is increased after transfusions); PT-INR >3; recent (within 6 weeks) GI bleeding; recent (within 3 days) thrombolytic therapy; recent (within 7 days) administration of oral anticoagulants, platelet glycoprotein (GP IIb/IIIa) inhibitors or other platelet-aggregation inhibitors (e.g., > 650 mg of aspirin daily); recent (within 3 months) ischemic stroke (see Contraindications under Cautions); intracranial arteriovenous malformation or aneurysm; known bleeding diathesis; chronic severe hepatic disease; or any other condition in which bleeding constitutes a substantial hazard or would be particularly difficult to manage because of its location.¹

In a retrospective study of patients who received drotrecogin alfa (activated) for sepsis, serious bleeding events and deaths occurred in substantially more patients with baseline bleeding risk factors than those without such risk factors.^{13 14 15} FDA is currently investigating these preliminary findings and is working with the manufacturer to further evaluate the risk of serious bleeding and mortality in patients receiving drotrecogin alfa (activated).¹³ Pending completion of the safety review, FDA states that clinicians should carefully weigh the anticipated benefits of drotrecogin alfa (activated) against the risk of bleeding in any patient being considered for therapy.^{1 13}

Some clinicians suggest avoiding use in patients with baseline bleeding risk factors.^{14 15} If clinically important bleeding occurs, immediately discontinue therapy.^{1 22} Also evaluate continued use of other agents affecting the coagulation system.¹ (See Specific Drugs under Interactions.) Manufacturer states that resumption of therapy may be considered once adequate hemostasis has been achieved;¹ however, some clinicians recommend against reinitiation of therapy in patients who develop severe bleeding during the infusion.²² (See General under Dosage and Administration.)

Patients with Single-Organ Dysfunction and Recent Surgery

Higher mortality reported in placebo-controlled clinical studies within a small subset of patients receiving drotrecogin alfa (activated) therapy who had single-organ dysfunction and recent surgery (i.e., within 30 days prior to treatment).^{1 2 11 16} Some of these patients had a lower risk of death (e.g., APACHE II score <25 or sepsis-induced single-organ failure at any APACHE II score) than that of the indicated population for this drug.^{1 11 16 22}

Patients with single-organ dysfunction and recent surgery may not be at high risk of death (regardless of APACHE II score); drotrocegin alfa (activated) therapy is not recommended in such patients.^{1 11 21 22}

Concomitant Administration of Prophylactic Heparin

Higher rates of mortality demonstrated in patients receiving drotrecogin alfa (activated) who discontinue prophylactic enoxaparin or unfractionated heparin therapy.^{1 20} Consider continuing low molecular weight heparin for prophylaxis of venous thromboembolism in patients receiving drotrecogin alfa (activated) unless discontinuance is medically necessary.^{1 20}

Laboratory Test Interferences

May interfere with one-stage coagulation assays (e.g., factor VIII, IX, XI assays) based on aPTT; minimal effect on PT.¹

Invasive Procedures

Discontinue drug prior to any invasive procedure (e.g., surgery) associated with an inherent risk of bleeding.^{1 9} (See General under Dosage and Administration.)

Minimize invasive procedures, including arterial and venous punctures, during drotrecogin alfa (activated) therapy; avoid establishing IV access at noncompressible sites (e.g., subclavian or jugular veins).¹ (See Hematologic Effects under Cautions.)

Laboratory Monitoring

Do not use aPTT to monitor degree of coagulopathy; may use PT instead.¹

Sensitivity Reactions

Antibody Formation

Antibodies to drotrecogin alfa (activated) reported in 1.5% of patients in clinical trials; a few patients tested positive for neutralizing antibodies.¹ No apparent correlation between presence of antibodies and adverse effects.¹

Limited experience with readministration (i.e., >1 course of therapy) of drotrecogin alfa (activated) in patients with severe sepsis;¹ no hypersensitivity reactions or evidence of antibody development reported.^{1 4}

Specific Populations

Pregnancy

Category C.¹

Lactation

Not known whether drotrecogin alfa (activated) is distributed into milk.¹ Discontinue nursing or the drug, taking into account the importance of the drug to the mother.¹

Pediatric Use

Safety and efficacy not demonstrated in children <18 years of age;^{1 18} not indicated for use in pediatric patients with severe sepsis.^{1 21 22}

Interim analysis of a randomized, double-blind study evaluating safety and efficacy in pediatric patients with severe sepsis showed that treatment with drotrecogin alfa (activated) was highly unlikely to result in improvement in the primary end point (composite time to complete organ failure resolution over a 14-day period) compared with placebo; as a result, the study was discontinued before completion.^{1 18} In addition, the rate of CNS bleeding was numerically greater in the drotrecogin alfa (activated) group than in the placebo group.^{1 18} Of patients with intracranial hemorrhage, the majority were <60 days of age.¹⁸ The incidence of 28-day all-cause mortality, fatal CNS bleeding, serious adverse events, overall serious bleeding events, and major amputations appeared to be similar between the groups.^{1 18}

Geriatric Use

No overall differences in safety and efficacy relative to younger adults.¹

Common Adverse Effects

Bleeding (e.g., ecchymoses, GI bleeding, intracranial hemorrhage).¹

Interactions for Xigris

Specific Drugs

Drug	Interaction	Comments
Antiplatelet agents (e.g., aspirin, GP IIb/IIIa-receptor inhibitors)	Potential increased risk of bleeding1	Use with caution1
Anticoagulants, oral	Potential increased risk of bleeding1	Use with caution1
Heparin	Concomitant use of enoxaparin 40 mg every 24 hours or sub-Q unfractionated heparin sodium 5000 units every 12 hours did not increase risk of serious bleeding, but increased incidence of nonserious bleeding;1 clearance and steady-state plasma concentrations of drotrecogin alfa (activated) not altered1	No dosage adjustment necessary1
NSAIAs	Potential increased risk of bleeding1	Use with caution1
Thrombolytic agents	Potential increased risk of bleeding1	Use with caution1

Xigris Pharmacokinetics

Absorption

Plasma Concentrations

Steady-state plasma drotrecogin alfa (activated) concentrations are rapidly attained (e.g., within 2 hours) after the start of infusion and rapidly decrease after the end of infusion.¹

Elimination

Metabolism

Drotrecogin alfa (activated) and endogenous activated protein C are inactivated by endogenous plasma protease inhibitors.¹

Special Populations

Plasma clearance of the drug in patients with severe sepsis is approximately 50% higher than that in healthy individuals.¹

In patients without sepsis undergoing peritoneal dialysis or hemodialysis, clearance of drotrecogin alfa (activated) was similar to that observed in healthy individuals.¹

Stability

Storage

Parenteral

Powder for Injection

2–8°C.¹ Do not freeze; protect from light.¹

If the reconstituted solution is not used immediately, store at 20–25°C and use within 3 hours.¹

Diluted IV Solutions

Administer within 12 hours if stored at 20–25°C.¹

Alternatively, store at 2–8°C for a maximum of 12 hours prior to administration.^{1 4 10} If refrigerated, total in-use time, including dilution, preparation, refrigeration, and administration, should not exceed 24 hours.¹

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Compatible with glass infusion bottles or infusion bags and syringes made of polyvinyl chloride, polyethylene, polypropylene, or polyolefin.¹

Solution Compatibility

Compatible
Sodium chloride 0.9%

Drug Compatibility

Y-Site Compatibility

Compatible
Dextrose 5%
Dextrose and sodium chloride injections
Lactated Ringer’s injection
Sodium chloride 0.9%

Actions

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  A serine protease structurally similar to endogenous human plasma-derived activated protein C that has antithrombotic, anti-inflammatory, and profibrinolytic properties but does not exhibit direct antimicrobial activity.^{1 2 5 6}

  
  


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  Produces the same biologic effects as endogenous activated protein C.⁴

  
  


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  Produces dose-dependent decreases in D-dimer (a breakdown product of cross-linked fibrin) and interleukin-6, which are markers of coagulopathy and inflammation, respectively; however precise mechanism of action is not known.^{1 2 3 4 5 6}

  
  

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• 
  

  Importance of informing patients of potential risks and benefits associated with therapy, including risk of severe bleeding.¹ (See Hematologic Effects under Cautions.)

  
  


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  Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.^{1 4}

  
  


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  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.¹

  
  


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  Importance of informing patients of other important precautionary information. (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Drotrecogin Alfa (Activated)

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection, for IV infusion	5 mg	Xigris	Lilly
		20 mg	Xigris	Lilly

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 26, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Eli Lilly and Company. Xigris (drotrecogin alfa [activated]) injection prescribing information. Indianapolis, IN; 2008 Oct.

2. Bernard GR, Vincet JL, Laterre PF et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001; 344:699-709. [IDIS 461713] [PubMed 11236773]

3. Matthay MA. Severe sepsis—a new treatment with both anticoagulant and antiinflammatory properties. N Engl J Med. 2001; 344:759-62. [IDIS 461714] [PubMed 11236781]

4. Eli Lilly and Company. Indianapolis, IN: Personal communication.

5. Mann HJ. Recombinant human activated protein C in severe sepsis. Am J Health-Syst Pharm. 2002; 59(Suppl 1):S19-23. [IDIS 478158] [PubMed 11885409]

6. Kinasewitz GT,, Margolis B, Freebairn C et al. Changes in markers of coagulation and inflammation in patients with severe sepsis treated with recombinant human activated protein C. Crit Care Med. 2000; 28(Suppl 12):A68.

7. Anon. FDA approves first biologic treatment for sepsis. Rockville, MD: Food and Drug Administration; 2001 Nov 21. From FDA web site.

8. Anti-infective Drugs Advisory Committee. Gaithersburg, MD: Food and Drug Administration; 2001 Oct 16. From FDA web site.

9. Anon. Activated protein C (Xigris) for severe sepsis. Med Lett Drugs Ther. 2002; 44:17-18. [PubMed 11856952]

10. Vanscoy G. Addendum. Am J Health-Syst Pharm. 2002; 59(Suppl):S28-9.

11. Eisenberg P. Dear healthcare professional letter regarding important drug warning for Xigris. Indianapolis, IN: Eli Lilly and Company; 2005 Feb 4.

12. Food and Drug Administration. Xigris (drotrecogin alfa [activated]) [Apr 21, 2005: Eli Lilly]. Medwatch 2005 safety alert. Rockville, MD; April 2005. From FDA website.

13. Food and Drug Administration. Early communication about an ongoing safety review of Xigris (drotrecogin alfa [activated]). Rockville, MD; 2009 June 18. From FDA website.

14. Gentry CA, Gross KB, Sud B et al. Adverse outcomes associated with the use of drotrecogin alfa (activated) in patients with severe sepsis and baseline bleeding precautions. Crit Care Med. 2009; 37:19-25. [PubMed 19050637]

15. Sweeney DA, Natanson C, Eichacker PQ. Recombinant human activated protein C, package labeling, and hemorrhage risks. Crit Care Med. 2009; 37:327-9. [PubMed 19112285]

16. Abraham E, Laterre PF, Garg R et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med. 2005; 353:1332-41. [PubMed 16192478]

17. Angus DC, Laterre PF, Helterbrand J et al. The effect of drotrecogin alfa (activated) on long-term survival after severe sepsis. Crit Care Med. 2004; 32:2199-206. [PubMed 15640631]

18. Nadel S, Goldstein B, Williams MD et al. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet. 2007; 369:836-43. [PubMed 17350452]

19. Vincent JL, Bernard GR, Beale R et al. Drotrecogin alfa (activated) treatment in severe sepsis from the global open-label trial ENHANCE: further evidence for survival and safety and implications for early treatment. Crit Care Med. 2005; 33:2266-77. [PubMed 16215381]

20. Levy M, Levi M, Williams MD et al. Comprehensive safety analysis of concomitant drotrecogin alfa (activated) and prophylactic heparin use in patients with severe sepsis. Intensive Care Med. 2009; 35:1196-203. [PubMed 19367397]

21. Dellinger RP, Levy MM, Carlet JM et al, for the International Surviving Sepsis Campaign Guidelines Committee. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008; 36:296-327. [PubMed 18158437]

22. Toussaint S, Gerlach H. Activated Protein C for sepsis. New Engl J Med 2009; 361:2646-52. [PubMed 20042756]

More Xigris resources

• Xigris Side Effects (in more detail)
• Xigris Use in Pregnancy & Breastfeeding
• Xigris Drug Interactions
• Xigris Support Group
• 0 Reviews for Xigris - Add your own review/rating

• Xigris Prescribing Information (FDA)


• Xigris Concise Consumer Information (Cerner Multum)


• Xigris Advanced Consumer (Micromedex) - Includes Dosage Information


• Xigris MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Xigris with other medications

• Sepsis

Xarelto

Dosage Form: tablet, film coated
FULL PRESCRIBING INFORMATION

WARNINGS: (A) DISCONTINUING Xarelto IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION INCREASES RISK OF STROKE, (B) SPINAL/EPIDURAL HEMATOMA

 A. DISCONTINUING Xarelto IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION

 Discontinuing Xarelto places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following Xarelto discontinuation in clinical trials in atrial fibrillation patients. If anticoagulation with Xarelto must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.1), Warnings and Precautions (5.1), and Clinical Studies (14.1)].

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


• a history of traumatic or repeated epidural or spinal punctures


• a history of spinal deformity or spinal surgery

[see Warnings and Precautions (5.2, 5.3) and Adverse Reactions (6.2)].

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions (5.3)].

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions (5.3)].

Indications and Usage for Xarelto

Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation

 Xarelto (rivaroxaban) is indicated to reduce 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 when warfarin therapy is well-controlled [see Clinical Studies (14.1)].

Prophylaxis of Deep Vein Thrombosis

Xarelto (rivaroxaban) 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.

Xarelto Dosage 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 [see Use in Specific Populations (8.7)].

 Switching from or to Warfarin - When switching patients from warfarin to Xarelto, discontinue warfarin and start Xarelto as soon as the International Normalized Ratio (INR) is below 3.0 to avoid periods of inadequate anticoagulation.

 No clinical trial data are available to guide converting patients from Xarelto to warfarin. Xarelto affects INR, so INR measurements made during co-administration with warfarin may not be useful for determining the appropriate dose of warfarin. One approach is to discontinue Xarelto and begin both a parenteral anticoagulant and warfarin at the time the next dose of Xarelto would have been taken.

 Switching from or to Anticoagulants other than Warfarin - For patients currently receiving an anticoagulant other than warfarin, start Xarelto 0 to 2 hours prior to the next scheduled evening administration of the drug (e.g., low molecular weight heparin or non-warfarin oral anticoagulant) and omit administration of the other anticoagulant. For unfractionated heparin being administered by continuous infusion, stop the infusion and start Xarelto at the same time.

 For patients currently taking Xarelto and transitioning to an anticoagulant with rapid onset, discontinue Xarelto and give the first dose of the other anticoagulant (oral or parenteral) at the time that the next Xarelto dose would have been taken [see Drug Interactions (7.3)].

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.

General Dosing Instructions

 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 [see Use in Specific Populations (8.8)].

 Renal Impairment

 Nonvalvular Atrial Fibrillation

 Avoid the use of Xarelto in patients with CrCl <15 mL/min. Periodically assess renal function as clinically indicated (i.e., 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 [see Use in Specific Populations (8.7)].

 Prophylaxis of Deep Vein Thrombosis

 Avoid the use of Xarelto in patients with 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 to 50 mL/min). Patients who develop acute renal failure while on Xarelto should discontinue the treatment [see Use in Specific Populations (8.7)].

 Surgery and Intervention

 If anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other procedures, Xarelto should be stopped at least 24 hours before the procedure. In deciding whether a procedure should be delayed until 24 hours after the last dose of Xarelto, the increased risk of bleeding should be weighed against the urgency of intervention. Xarelto should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established. If oral medication cannot be taken after surgical intervention, consider administering a parenteral anticoagulant.

 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.

 Use with P-gp and Strong CYP3A4 Inhibitors or Inducers

 Avoid concomitant use of Xarelto with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan) [see Drug Interactions (7.1)].

 Avoid concomitant use of Xarelto with drugs that are combined P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort) [see Drug Interactions (7.2)].

Dosage Forms and Strengths

• 10 mg tablets: Round, light red, biconvex and film-coated with a triangle pointing down above a "10" marked on one side and "Xa" on the other side


• 15 mg tablets: Round, red, biconvex, and film-coated with a triangle pointing down above a "15" marked on one side and "Xa" on the other side


• 20 mg tablets: Triangle-shaped, dark red, and film-coated with a triangle pointing down above a "20" marked on one side and "Xa" on the other side

Contraindications

Xarelto is contraindicated in patients with:

•  active pathological bleeding [see Warnings and Precautions (5.2)]


•  severe hypersensitivity reaction to Xarelto [see Warnings and Precautions (5.5)]

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 [see Dosage and Administration (2.1) and Clinical Studies (14.1)].

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 [see Clinical Pharmacology (12.3)]. 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 non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions (7.3), (7.4), (7.5)].

 Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (e.g. ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions (7.1)].

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 [see Boxed Warning].

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.

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. Xarelto dosing in pregnancy has not been studied. The anticoagulant effect of Xarelto cannot be monitored with standard laboratory testing nor readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).

Severe Hypersensitivity Reactions

 There were postmarketing cases of anaphylaxis in patients treated with Xarelto to reduce the risk of DVT. Patients who have a history of a severe hypersensitivity reaction to Xarelto should not receive Xarelto [see Adverse Reactions (6.2)].

Adverse Reactions

Clinical Trials Experience

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, 11598 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) and 4487 patients who received Xarelto 10 mg orally once daily for prophylaxis of DVT following hip or knee replacement surgery (RECORD 1–3).

Hemorrhage

The most common adverse reactions with Xarelto were bleeding complications [see Warnings and Precautions (5.2)].

Nonvalvular Atrial Fibrillation

In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for Xarelto vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups.

Table 1 shows the number of patients experiencing various types of bleeding events in the ROCKET AF study.

Table 1: Bleeding Events in ROCKET AF*

Parameter	Xarelto N = 7111 n (%)	Event Rate (per 100 Pt-yrs)	Warfarin N = 7125 n (%)	Event Rate (per 100 Pt-yrs)
* For all sub-types of major bleeding, single events may be represented in more than one row, and individual patients may have more than one event. † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥ 2 g/dL, transfusion of ≥ 2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes are counted as both bleeding and efficacy events. Major bleeding rates excluding strokes are 3.3 per 100 Pt-yrs for Xarelto vs. 2.9 per 100 Pt-yrs for warfarin. ‡ The majority of the events were intracranial, and also included intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal.
Major bleeding†	395 (5.6)	3.6	386 (5.4)	3.5
Bleeding into a critical organ‡	91 (1.3)	0.8	133 (1.9)	1.2
Fatal bleeding	27 (0.4)	0.2	55 (0.8)	0.5
Bleeding resulting in transfusion of ≥ 2 units of whole blood or packed red blood cells	183 (2.6)	1.7	149 (2.1)	1.3
Gastrointestinal bleeding	221 (3.1)	2.0	140 (2.0)	1.2

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.

The mean duration of Xarelto treatment was 11.9 days in the total knee replacement study and 33.4 days in the total hip replacement studies. Overall, in the RECORD program, the mean age of the patients studied in the Xarelto group was 64 years, 59% were female and 82% were Caucasian. Twenty-seven percent (1206) of patients underwent knee replacement surgery and 73% (3281) underwent hip replacement surgery.

The rates of major bleeding events and any bleeding events observed in patients in the RECORD clinical trials are shown in Table 2.

Table 2: Bleeding Events* in Patients Undergoing Hip or Knee Replacement Surgeries (RECORD 1–3)

	Xarelto 10 mg	Enoxaparin†
* 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 for RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1–3) ‡ Includes major bleeding events
Total treated patients	N = 4487 n (%)	N = 4524 n (%)
Major bleeding event	14 (0.3)	9 (0.2)
Fatal bleeding	1 (<0.1)	0
Bleeding into a critical organ	2 (<0.1)	3 (0.1)
Bleeding that required re-operation	7 (0.2)	5 (0.1)
Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells	4 (0.1)	1 (<0.1)
Any bleeding event‡	261 (5.8)	251 (5.6)
Hip Surgery Studies	N = 3281 n (%)	N = 3298 n (%)
Major bleeding event	7 (0.2)	3 (0.1)
Fatal bleeding	1 (<0.1)	0
Bleeding into a critical organ	1 (<0.1)	1 (<0.1)
Bleeding that required re-operation	2 (0.1)	1 (<0.1)
Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells	3 (0.1)	1 (<0.1)
Any bleeding event‡	201 (6.1)	191 (5.8)
Knee Surgery Study	N = 1206 n (%)	N = 1226 n (%)
Major bleeding event	7 (0.6)	6 (0.5)
Fatal bleeding	0	0
Bleeding into a critical organ	1 (0.1)	2 (0.2)
Bleeding that required re-operation	5 (0.4)	4 (0.3)
Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells	1 (0.1)	0
Any bleeding event‡	60 (5.0)	60 (4.9)

Following Xarelto treatment, the majority of major bleeding complications (≥60%) occurred during the first week after surgery.

Other Adverse Reactions

Non-hemorrhagic adverse drug reactions (ADRs) reported in ≥1% of Xarelto-treated patients are shown in Table 3.

Table 3: Other Adverse Drug Reactions* Reported by ≥1% of Xarelto-Treated Patients in RECORD 1–3 Studies

System/Organ Class   Adverse Reaction	Xarelto 10 mg (N = 4487) n (%)	Enoxaparin†   (N = 4524) n (%)
* ADR 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 RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1–3)
Injury, poisoning and procedural complications
Wound secretion	125 (2.8)	89 (2.0)
Musculoskeletal and connective tissue disorders
Pain in extremity	74 (1.7)	55 (1.2)
Muscle spasm	52 (1.2)	32 (0.7)
Nervous system disorders
Syncope	55 (1.2)	32 (0.7)
Skin and subcutaneous tissue disorders
Pruritus	96 (2.1)	79 (1.8)
Blister	63 (1.4)	40 (0.9)

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.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of rivaroxaban. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: agranulocytosis

Gastrointestinal disorders: retroperitoneal hemorrhage

Hepatobiliary disorders: jaundice, cholestasis, cytolytic hepatitis

Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock

Nervous system disorders: cerebral hemorrhage, subdural hematoma, epidural hematoma, hemiparesis

Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome

Drug Interactions

Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Inhibitors and inducers of these CYP450 enzymes or transporters (e.g., P-gp) may result in changes in rivaroxaban exposure.

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

In drug interaction studies evaluating the concomitant use with drugs that are combined P-gp and CYP3A4 inhibitors, increases in rivaroxaban exposure and pharmacodynamic effects (i.e., factor Xa inhibition and PT prolongation) were observed. Significant increases in rivaroxaban exposure may increase bleeding risk.

• Ketoconazole (combined P-gp and strong CYP3A4 inhibitor): Steady-state rivaroxaban AUC and Cmax increased by 160% and 70%, respectively. Similar increases in pharmacodynamic effects were also observed.


• Ritonavir (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 150% and 60%, respectively. Similar increases in pharmacodynamic effects were also observed.


• Clarithromycin (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 50% and 40%, respectively. The smaller increases in exposure observed for clarithromycin compared to ketoconazole or ritonavir may be due to the relative difference in P-gp inhibition.


• Erythromycin (combined P-gp and moderate CYP3A4 inhibitor): Both the single-dose rivaroxaban AUC and Cmax increased by 30%.


• Fluconazole (moderate CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 40% and 30%, respectively.

Avoid concomitant administration of Xarelto with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan), which cause significant increases in rivaroxaban exposure that may increase bleeding risk.

Prophylaxis of Deep Vein Thrombosis

When clinical data suggest a change in exposure is unlikely to affect bleeding risk (e.g., clarithromycin, erythromycin), no precautions are necessary during coadministration with drugs that are combined P-gp and CYP3A4 inhibitors.

Drugs that Induce Cytochrome P450 3A4 Enzymes and Drug Transport Systems

In a drug interaction study, co-administration of Xarelto (20 mg single dose with food) with a drug that is a combined P-gp and strong CYP3A4 inducer (rifampicin titrated up to 600 mg once daily) led to an approximate decrease of 50% and 22% in AUC and Cmax, respectively. Similar decreases in pharmacodynamic effects were also observed. These decreases in exposure to rivaroxaban may decrease efficacy.

Avoid concomitant use of Xarelto with drugs that are combined P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort).

Anticoagulants

In a drug interaction study, single doses of enoxaparin (40 mg subcutaneous) and Xarelto (10 mg) given concomitantly resulted in an additive effect on anti-factor Xa activity. Enoxaparin did not affect the pharmacokinetics of rivaroxaban. In another study, single doses of warfarin (15 mg) and Xarelto (5 mg) resulted in an additive effect on factor Xa inhibition and PT. Warfarin did not affect the pharmacokinetics of rivaroxaban.

Prophylaxis of Deep Vein Thrombosis

Avoid concurrent use of Xarelto with other anticoagulants due to the increased bleeding risk. Promptly evaluate any signs or symptoms of blood loss [see Warnings and Precautions (5.2)].

NSAIDs/Aspirin

In ROCKET AF, concomitant aspirin use (almost exclusively at a dose of 100 mg or less) during the double-blind phase was identified as an independent risk factor for major bleeding. NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with Xarelto. In a single-dose drug interaction study there were no pharmacokinetic or pharmacodynamic interactions observed after concomitant administration of naproxen or aspirin (acetylsalicylic acid) with Xarelto.

Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs [see Warnings and Precautions (5.2)].

Clopidogrel

In two drug interaction studies where clopidogrel (300 mg loading dose followed by 75 mg daily maintenance dose) and Xarelto (15 mg single dose) were co-administered in healthy subjects, an increase in bleeding time to 45 minutes was observed in approximately 45% and 30% of subjects in these studies, respectively. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. There was no change in the pharmacokinetics of either drug.

Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with clopidogrel [see Warnings and Precautions (5.2)].

Drug-Disease Interactions with Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems

Based on simulated pharmacokinetic data, patients with renal impairment receiving full dose Xarelto in combination with drugs classified as combined P-gp and weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil, quinidine, ranolazine, dronedarone, felodipine, erythromycin, and azithromycin) may have significant increases in exposure compared with patients with normal renal function and no inhibitor use, since both pathways of rivaroxaban elimination are affected.

While increases in rivaroxaban exposure can be expected under such conditions, results from an analysis in the ROCKET AF trial, which allowed concomitant use with combined P-gp and weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil, chloramphenicol, cimetidine, and erythromycin), did not show an increase in bleeding in patients with CrCl 30 to <50 mL/min [Hazard Ratio (95% CI): 1.05 (0.77, 1.42)]. Xarelto should be used in patients with CrCL 15 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 [see Use in Specific Populations (8.7)].

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C

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. Animal reproduction studies showed no increased risk of structural malformations, but increased post-implantation pregnancy loss occurred in rabbits. Xarelto should be used during pregnancy only if the potential benefit justifies the potential risk to mother and fetus [see Warnings and Precautions (5.4)].

Rivaroxaban crosses the placenta in animals. Animal reproduction studies have shown pronounced maternal hemorrhagic complications in rats and an increased incidence of post-implantation pregnancy loss in rabbits. Rivaroxaban increased fetal toxicity (increased resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits were given oral doses of ≥10 mg/kg rivaroxaban during the period of organogenesis. This dose corresponds to about 4 times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 20 mg/day. Fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg. This dose corresponds to about 14 times the human exposure of unbound drug.

Labor and Delivery

Safety and effectiveness of Xarelto during labor and delivery have not been studied in clinical trials. However, in animal studies 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).

Nursing Mothers

It is not known if rivaroxaban is excreted in human milk. Rivaroxaban and/or its metabolites were excreted into the milk of rats. Because many drugs are excreted in human milk and 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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

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 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 [see Clinical Pharmacology (12.3) and Clinical Studies (14)].

Females of Reproductive Potential

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

Renal Impairment

The safety and pharmacokinetics of single-dose Xarelto (10 mg) were evaluated in a study in healthy subjects [CrCl ≥80 mL/min (n=8)] and in subjects with varying degrees of renal impairment (see Table 4). Compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased in subjects with renal impairment. Increases in pharmacodynamic effects were also observed.

Table 4: Percent Increase of Rivaroxaban PK and PD Parameters from Normal in Subjects with Renal Insufficiency from a Dedicated Renal Impairment Study

		Renal Impairment Class [CrCl (mL/min)]
Parameter		Mild	Moderate	Severe
		[50 to 79] N=8	[30 to 49] N=8	[15 to 29] N=8
PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the concentration or effect curve; Cmax = maximum concentration; Emax = maximum effect; and CrCl = creatinine clearance
Exposure	AUC	44	52	64
(% increase relative to normal)	Cmax	28	12	26
FXa Inhibition	AUC	50	86	100
(% increase relative to normal)	Emax	9	10	12
PT Prolongation	AUC	33	116	144
(% increase relative to normal)	Emax	4	17	20

Patients with renal impairment taking P-gp and weak to moderate CYP3A4 inhibitors may have significant increases in exposure which may increase bleeding risk [see Drug Interactions (7.6)].

Nonvalvular Atrial Fibrillation

In the ROCKET AF trial, patients with CrCl 30 to 50 mL/min were administered Xarelto 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered Xarelto 20 mg once daily. Patients with CrCl 15 to 30 mL/min were not studied, but administration of Xarelto 15 mg once daily is also expected to result in serum concentrations of rivaroxaban similar to those in patients with normal renal function [see Dosage and Administration (2.1)].

Prophylaxis of Deep Vein Thrombosis

The combined analysis of the RECORD 1–3 clinical efficacy studies did not show an increase in bleeding risk for patients with moderate renal impairment and reported a possible increase in total VTE in this population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with moderate renal impairment (CrCl 30 to <50 mL/min). Avoid the use of Xarelto in patients with severe renal impairment (CrCl <30 mL/min) [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)].

Hepatic Impairment

The safety and pharmacokinetics of single-dose Xarelto (10 mg) were evaluated in a study in healthy subjects (n=16) and subjects with varying degrees of hepatic impairment (see Table 5). No patients with severe hepatic impairment (Child-Pugh C) were studied. Compared to healthy subjects with normal liver function, significant increases in rivaroxaban exposure were observed in subjects with moderate hepatic impairment (Child-Pugh B). Increases in pharmacodynamic effects were also observed.

Table 5: Percent Increase of Rivaroxaban PK and PD Parameters from Normal in Subjects with Hepatic Insufficiency from a Dedicated Hepatic Impairment Study

		Hepatic Impairment Class (Child-Pugh Class)
Parameter		Mild	Moderate
		(Child-Pugh A) N=8	(Child-Pugh B) N=8
PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the concentration or effect curve; Cmax = maximum concentration; Emax = maximum effect
Exposure	AUC	15	127
(% increase relative to normal)	Cmax	0	27
FXa Inhibition	AUC	8	159
(% increase relative to normal)	Emax	0	24
PT Prolongation	AUC	6	114
(% increase relative to normal)	Emax	2	41

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 [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)].

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 [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

Xarelto Description

Rivaroxaban, a factor Xa inhibitor, is the active ingredient in Xarelto Tablets with the chemical name 5 - Chloro - N - ({(5S) - 2 - oxo - 3 - [4 - (3 - oxo - 4 - morpholinyl)phenyl] - 1,3 - oxazolidin - 5 - yl}methyl) - 2 - thiophenecarboxamide. The molecular formula of rivaroxaban is C19H18ClN3O5S and the molecular weight is 435.89. The structural formula is:

Rivaroxaban is a pure (S)-enantiomer. It is an odorless, non-hygroscopic, white to yellowish powder. Rivaroxaban is only slightly soluble in organic solvents (e.g., acetone, polyethylene glycol 400) and is practically insoluble in water and aqueous media.

Each Xarelto tablet contains 10 mg, 15 mg, or 20 mg of rivaroxaban. The inactive ingredients of Xarelto are: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. Additionally, the proprietary film coating mixture used for Xarelto 10 mg tablets is Opadry® Pink and Xarelto 15 mg tablets is Opadry® Red, containing ferric oxide red, hypromellose, polyethylene glycol 3350, and titanium dioxide, and for Xarelto 20 mg tablets is Opadry® II Dark Red, containing ferric oxide red, polyethylene glycol 3350, polyvinyl alcohol (partially hydrolyzed), talc, and titanium dioxide.

Xarelto - Clinical Pharmacology

Mechanism of Action

Xarelto is an orally bioavailable factor Xa inhibitor that selectively blocks the active site of factor Xa and does not require a cofactor (such as Anti-thrombin III) for

Xolair

Generic Name: Omalizumab
Class: Respiratory Tract Agents, Miscellaneous
VA Class: IM600
Chemical Name: Immunoglobulin G, anti-(human immunoglobulin E Fc region) (human-mouse monoclonal E25 clone pSVIE26 γ-chain), disulfide with human-mouse monoclonal E25 clone pSVIE26 κ-chain, dimer
CAS Number: 242138-07-4

• 
  

  Anaphylaxis (e.g., bronchospasm, hypotension, syncope, urticaria, angioedema of throat or tongue) reported.¹

  
  


• 
  

  Anaphylaxis can occur after the first or second dose of omalizumab, but may occur after >1 year of therapy.¹ Monitor patient for an appropriate period of time following administration.¹ (See Cautions: Medical Personnel and Facilities and see Sensitivity Reactions.)

  
  


• 
  

  Administer omalizumab in a setting prepared to manage potentially life-threatening anaphylaxis; clinicians administering the drug should be familiar with management of anaphylaxis.¹

  
  


• 
  

  Inform patient of the signs and symptoms of anaphylaxis and instruct patient to obtain immediate medical care should symptoms develop.¹

  
  

REMS:

FDA approved a REMS for omalizumab to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of omalizumab and consists of the following: medication guide. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Antiasthmatic agent; a chimeric human-murine (humanized) IgG1κ anti-IgE monoclonal antibody.^{1 2 3 4}

Uses for Xolair

Allergic Asthma

Management of moderate to severe persistent allergic (a positive skin test or in vitro reactivity to a perennial aeroallergen) asthma inadequately controlled with inhaled corticosteroids.^{1 5} However, some experts reserve use mainly for management of severe allergic asthma.^{5 10} Manufacturer states that the safety and efficacy of omalizumab in the management of other allergic conditions not established.¹ Some experts state that omalizumab is effective for the management of concurrent rhinitis†.⁵

In adults and adolescents with severe persistent allergic asthma inadequately controlled with high-dose inhaled corticosteroids and a long-acting β₂-adrenergic agonist bronchodilator, some experts recommend addition of omalizumab.¹⁰

Xolair Dosage and Administration

General

• 
  

  If used for extended periods, periodically reassess the need for continued therapy based on the patient’s severity of asthma and degree of asthma control.^{1 8}

  
  


• 
  

  After treatment interruptions of <1 year, base dosage on serum IgE concentrations obtained prior to treatment initiation.¹

  
  


• 
  

  If omalizumab therapy has been interrupted for ≥1 year, may reevaluate total serum IgE concentrations for dosage determination.¹

  
  


• 
  

  Adjust dosage if the patient’s body weight changes substantially; apparent clearance of the drug is proportional to body weight.^{1 4}

  
  

Reduction of Concurrent Inhaled Corticosteroid Therapy

• 
  

  Should not discontinue abruptly concomitant inhaled or systemic corticosteroid therapy upon initiation of omalizumab therapy.¹ Reduce concomitant corticosteroid dosage gradually (after 16 weeks in clinical trials), and supervise such reduction carefully.^{1 4}

  
  

Administration

Sub-Q Administration

Administer once every 2 or 4 weeks by a clinician.^{1 8} (See Medical Personnel and Facilities under Cautions.)

In general, administer ≤150 mg per injection site; divide doses >150 mg and inject at various sites.^{1 10}

Reconstitution

Reconstitute vial containing 202.5 mg of omalizumab lyophilized powder with 1.4 mL of sterile water for injection to provide a solution containing 150 mg per 1.2 mL.¹

Swirl vial gently for approximately 1 minute to wet the lyophilized powder and then for 5–10 seconds approximately every 5 minutes in order to dissolve (could take >20 minutes) any remaining solids.¹ Do not shake vial.¹ Small bubbles or foam may remain in the vial.¹ Resulting solution will be slightly viscous.¹ Discard the solution if the drug does not dissolve completely within 40 minutes after attempting reconstitution.¹

Rate of Administration

May take 5–10 seconds to inject sub-Q.¹

Dosage

Pediatric Patients

Moderate to Severe Allergic Asthma

Sub-Q

Adolescents ≥12 years of age: 150–375 mg every 2 or 4 weeks.¹ Base dosage and dosing frequency on total serum IgE concentrations, measured prior to therapy, and body weight (see Table 1 and see Table 2).^{1 10}

Adults

Moderate to Severe Allergic Asthma

Sub-Q

150–375 mg every 2 or 4 weeks.¹ Base dosage and dosing frequency on total serum IgE concentrations, measured prior to therapy, and body weight (see Table 1 and see Table 2).¹

See Table 2.

Table 1. Omalizumab Doses (mg) Administered Every 4 Weeks

	Body Weight (kg)
Pretreat- ment Serum IgE (IU/mL)	30–60	>60–70	>70–90	>90–150
≥30–100	150	150	150	300
>100–200	300	300	300	–
>200–300	300	–	–	–
>300–400	–	–	–	–
>400–500	–	–	–	–
>500–600	–	–	–	–

See Table 1.

Do not administer.

Table 2. Omalizumab Doses (mg) Administered every 2 Weeks

	Body Weight (kg)
Pretreat- ment Serum IgE (IU/mL)	30–60	>60–70	>70–90	>90–150
≥30–100	–	–	–	–
>100–200	–	–	–	225
>200–300	–	225	225	300
>300–400	225	225	300	–
>400–500	300	300	375	–
>500–600	300	375	–	–
>600–700	375	–	–	–

Prescribing Limits

Pediatric Patients

Moderate to Severe Allergic Asthma

Sub-Q

Maximum 750 mg every 4 weeks.¹

Adults

Moderate to Severe Allergic Asthma

Sub-Q

Maximum 750 mg every 4 weeks.¹

Special Populations

No special population (i.e., age, race, ethnicity, gender) dosage recommendations at this time.¹

Cautions for Xolair

Contraindications

• 
  

  Known history of severe hypersensitivity to omalizumab or any ingredient in the formulation.^{1 8 9}

  
  

Warnings/Precautions

Warnings

Cardiovascular and Cerebrovascular Effects

Disproportionate increase in ischemic heart disease, arrhythmias, cardiomyopathy and cardiac failure, pulmonary hypertension, cerebrovascular disorders, and embolic, thrombotic, and thrombophlebitic events observed in patients receiving omalizumab from an ongoing study, Evaluating the Clinical Effectiveness and Long-term Safety in Patients with Moderate to Severe Asthma (EXCELS).¹² FDA is continuing to review the strengths and limitations of these interim study results.¹²

Patients with asthma should not stop taking omalizumab before consulting their clinician.¹²

Be aware of the potential increased risk of cardiovascular and cerebrovascular events.¹² Report all such adverse events to FDA MedWatch Program.¹²

Malignancy

Breast, melanoma, non-melanoma skin, prostate, parotid gland neoplasms, and other types of neoplasms have been observed with <1 year of therapy.¹ Risk of malignancy with longer exposure to omalizumab or use in patients at higher risk for malignancy (e.g., geriatric individuals, current smokers) is not known.^{1 4}

Medical Personnel and Facilities

Should be administered by a clinician familiar with management of potentially life-threatening anaphylaxis in a setting where parenteral drugs, oxygen, and equipment are immediately available.^{1 8 10} Anaphylaxis can occur after any dose of omalizumab, even if prior doses were well tolerated;^{1 8 9} onset of anaphylaxis may be delayed (e.g., up to 4 days) after administration.^{1 8 9} Monitor patients following administration (e.g., 2 hours following administration of at least the first 3 doses); optimal observation period not established.^{1 4 8 10} If a severe hypersensitivity reaction occurs, discontinue drug.^{1 4 8 9} (See Sensitivity Reactions under Cautions.)

Sensitivity Reactions

Anaphylaxis (e.g., bronchospasm, hypotension, syncope, urticaria, angioedema of throat or tongue) has occurred in patients after administration of omalizumab.^{1 8} Other signs and symptoms of anaphylaxis included wheezing or dyspnea, dizziness, throat tightness, cough, cutaneous angioedema, generalized pruritus, rapid or weak heartbeat, anxiety (e.g., feeling of impending doom), hoarseness, dysphagia, and flushing or warm feeling.^{1 8 9} Most cases of anaphylaxis occurred within the first 60 minutes after the first or second dose of omalizumab, but may occur after >1 year of maintenance therapy.^{1 8 10}

Report all serious adverse effects to FDA MedWatch Program by phone (800-FDA-1088), fax (800-FDA-0178), through the Internet (), or by mail (MedWatch, HF-2, FDA, 5600 Fishers Lane, Rockville, MD 20852-9787).⁸

General Precautions

Acute or Worsening Asthma

Not effective in alleviating acute asthma exacerbations; do not use for treatment of acute bronchospasm or status asthmaticus.¹

Eosinophilia and Churg-Strauss Syndrome

Systemic eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, reported rarely; in almost all cases, these events were associated with reduction of oral corticosteroid therapy.¹ Be alert to the development of such manifestations; causal relationship not established.¹

Parasitic (Geohelminthic) Infections

Increased incidence and risk of helminthic infection.¹ Monitor patients who are at high risk for geohelminthic infections during therapy.^{1 6} Insufficient data are available to determine the duration of monitoring for such infections after treatment discontinuance.¹

Specific Populations

Pregnancy

Category B. Pregnancy registry at 866-496-5247.¹

Lactation

Distributed into milk in cynomolgus monkeys.¹ Since IgG distributes into milk in humans, it is expected that omalizumab (IgG1κ monoclonal antibody) will be present in human milk.¹ Use with caution.¹

Pediatric Use

Safety and efficacy in children <12 years of age not established.¹

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently from younger adults.¹

Common Adverse Effects

Injection site reactions (bruising, redness, warmth, burning, stinging, pruritus, urticaria, pain, induration, injection site mass, inflammation), viral infections, upper respiratory tract infection, sinusitis, headache, pharyngitis.¹

Interactions for Xolair

No formal drug interaction studies to date.¹

Xolair Pharmacokinetics

Absorption

Bioavailability

Absorbed slowly; peak serum concentrations attained after an average of 7–8 days.¹ Absolute bioavailability averages 62%.¹

Onset

Serum free IgE concentrations reduced ≤1 hour following administration.¹

Duration

Total IgE does not return to pretreatment concentrations for ≤1 year after drug discontinuance.¹

Distribution

Extent

In animals, no specific uptake of radiolabeled drug by any organ or tissue.¹

Elimination

Metabolism

Degradation of omalizumab (IgG1κ monoclonal antibody) by the reticuloendothelial system and endothelial cells in the liver, and clearance of omalizumab-IgE complexes by the reticuloendothelial system.¹

Elimination Route

Eliminated in part into the bile as unchanged drug.¹

Half-life

26 days in asthmatic patients.¹

Stability

Storage

Parenteral

Powder for Sub-Q Injection

Ship at ≤30°C.¹ Store at 2–8°C.^{1 10} When reconstituted with sterile water for injection, solutions prepared in single-use vials are stable for ≤8 hours at 2–8°C or ≤4 hours at room temperature.¹

Actions

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  Binds specifically to circulating IgE and blocks its binding with the high-affinity IgE receptor (FcεRI) on the surface of mast cells and basophils.^{1 2} Inhibition of such binding interferes with the synthesis and release of mediators of the allergic response (e.g., leukotrienes, cytokines, chemokines).^{1 2 5 10}

  
  


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  Reduces the number of FcεRI receptors on basophils and submucosal cells in atopic patients.^{1 10}

  
  


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  Reduces mean serum concentrations of free (unbound) IgE in patients with allergic asthma at recommended dosages.^{1 2}

  
  


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  Attenuates the early- and late-phase inflammatory response and the influx of eosinophils into the airways following allergen challenge.^{2 7 10}

  
  

Advice to Patients

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  Importance of providing a copy of the manufacturer’s medication guide for omalizumab to the patient each time the drug is dispensed.^{1 8 9}

  
  


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  Risk of potentially life-threatening anaphylaxis after any dose of omalizumab.^{1 8 9} Importance of informing patients of signs and symptoms of anaphylaxis.^{8 9} (See Sensitivity Reactions under Cautions.)

  
  


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  Importance of receiving omalizumab in a health-care setting (e.g., doctor’s office) where monitoring for possible anaphylaxis can be performed.^{1 8 9 10} (See Medical Personnel and Facilities under Cautions.)

  
  


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  Importance of informing patients of potential for delayed anaphylaxis (e.g., up to 4 days after administration).^{1 8}

  
  


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  Importance of seeking emergency medical attention if signs or symptoms of anaphylaxis occur after leaving the doctor’s office.^{1 8 9}

  
  


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  Importance of patient understanding how to obtain emergency medical treatment and further medical care for anaphylaxis.⁸

  
  


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  Importance of adherence to dosing schedules of concomitant antiasthmatic therapy, including not altering the dose or frequency of such drugs unless otherwise instructed by a clinician.^{1 8 9}

  
  


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  Importance of informing patients of possible delay in the effectiveness of omalizumab upon treatment initiation.^{1 8}

  
  


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  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.¹

  
  


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  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

  
  


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  Importance of informing patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Omalizumab

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For subcutaneous use	202.5 mg (delivers 150 mg/1.2 mL)	Xolair	Genentech

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Genentech. Xolair (omalizumab) for subcutaneous use prescribing information. South San Francisco, CA; 2008 Jul.

2. Johansson SG, Haahtela T, and O’Byrne PM. Omalizumab and the immune system: an overview of preclinical and clinical data. Ann Allergy Asthma Immunol. 2002; 89:132-8. [IDIS 485387] [PubMed 12197568]

3. Genentech Inc. Manufacturing of Xolair (omalizumab) for subcutaneous use. Available from website. Accessed 2003 June 30.

4. Genentech, San Francisco, CA: Personal communication.

5. National Institutes of Health, National Heart, Lung, and Blood Institute. Global initiative for asthma: global strategy for asthma management and prevention NHLBI/WHO Workshop Report. Bethesda, MD: National Institutes of Health. 2008. NIH/NHLBI Publication No. 02-3659. Available from website. Accessed 2009 Feb 27.

6. Chitkara RK, Sarinas PS, Fick RB. Immunoglobulin-E and anti-IgE treatment in lung disease. Monaldi Arch Chest Dis. 2001; 56:514-20. [PubMed 11980283]

7. National Asthma Education and Prevention Program. Expert panel report: guidelines for the diagnosis and management of asthma-update on selected topics 2002. Bethesda, Md: National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program Coordinating Committee; 2003 Jun. Available from National Heart, Lung, and Blood Institute Information Center, NIH Publication No. 02-5074. Also available from website. Accessed 2004 Sep. 15.

8. Center for Drug Evaluation and Research, Food and Drug Administration. FDA Information for healthcare professionals: Omalizumab (marketed as Xolair) for subcutaneous use. 2007 Jul. Available at FDA website from website. Accessed 2007 Sep 28.

9. Genentech. Xolair (omalizumab) medication guide. South San Francisco, CA; 2008 Jul.

10. National Asthma Education and Prevention Program. Expert panel report III: guidelines for the diagnosis and management of asthma. 2007 Jul. Bethesda, MD: U.S. Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute. Available from website. Accessed Jul 27, 2008.

11. British Thoracic Society/Scottish Intercollegiate Guidelines Network. Guidelines on the management of asthma: a national clinical guideline. London, Eng; British Thoracic Society. 2008 May. Available from website. Accessed Dec 5, 2008.

12. Food and Drug Administration. Early communication about an ongoing safety review of omalizumab (marketed as Xolair). 2009 Jul 16. Available from FDA website.

More Xolair resources

• Xolair Side Effects (in more detail)
• Xolair Use in Pregnancy & Breastfeeding
• Xolair Drug Interactions
• Xolair Support Group
• 9 Reviews for Xolair - Add your own review/rating

• Xolair Prescribing Information (FDA)


• Xolair Consumer Overview


• Xolair Advanced Consumer (Micromedex) - Includes Dosage Information


• Xolair MedFacts Consumer Leaflet (Wolters Kluwer)


• Omalizumab Professional Patient Advice (Wolters Kluwer)

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