XARELTO®

(rivaroxaban)

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This information is intended for US healthcare professionals to access current scientific information about J&J Innovative Medicine products. It is prepared by Medical Information and is not intended for promotional purposes, nor to provide medical advice.

XARELTO® (rivaroxaban)

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Adverse Event of XARELTO - Hypersensitivity Reactions and Skin Disorders

Last Updated: 10/16/2024

Summary

Hypersensitivity reactions and skin disorders were reported in the RECORD 1-3 studies, as well as in Postmarketing Experience.¹
Case reports have been published describing hypersensitivity reactions and skin disorders in patients who were treated with XARELTO.²^-⁹
Additional case reports and studies have been identified during a literature search and are provided in the REFERENCES section for review.¹⁰^-²²

PRODUCT LABELING

Please refer to the following sections of the enclosed Full Prescribing Information that are relevant to your inquiry: CONTRAINDICATIONS and ADVERSE REACTIONS.¹

CONTRAINDICATIONS

XARELTO is contraindicated in patients with severe hypersensitivity reaction to XARELTO (e.g., anaphylactic reactions).¹

ADVERSE REACTIONS

Other Adverse Reactions See Table: Other Adverse Drug Reactions^a Reported by ≥1% of XARELTO-Treated Patients in RECORD 1-3 Studies

Other Adverse Drug Reactions^a Reported by >1% of XARELTO-Treated Patients in RECORD 1-3 Studies¹

Body System Adverse Reaction		XARELTO 10mg N=4487 n (%)	Enoxaparin^b N=4524 n (%)
Skin and subcutaneous tissue disorders
	Pruritus	96 (2.1)	79 (1.8)
	Blister	63 (1.4)	40 (0.9)
^aAdverse reaction 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. ^bIncludes the placebo-controlled period of RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1-3).

Other Adverse Reactions See Table: See Table: Other Adverse Reactions^c Reported by ≥1% of XARELTO-Treated Patients in EINSTEIN PE Studies

Other Adverse Reactions^c Reported by >1% of XARELTO-Treated Patients in EINSTEIN PE Studies ¹

Body System Adverse Reaction		XARELTO 20mg N=2412 n (%)	Enoxaparin/VKA N=2405 n (%)
Skin and subcutaneous tissue disorders
	Pruritus	53 (2.2)	27 (1.1)
Abbreviations: VKA; vitamin k antagonist^cAdverse reaction with Relative Risk >1.5 for XARELTO versus comparator

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of XARELTO. 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.¹

Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock, angioedema
Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS)

CASE REPORTS

Author (Year)	Patient Characteristics	Clinical Signs and Symptoms	Outcomes
Mohammadi et al (2024)⁸	28-year-old male Indication: Recent VTE episode Initial Medication: Patient switched from apixaban to XARELTO	Developed mild, brief itching without rash on apixaban. Symptoms improved but apixaban switched to XARELTO. XARELTO day 5: patient experienced maculopapular rash and generalized itching. Lesions disappeared under pressure. Diagnosis of XARELTO-induced hypersensitivity. Naranjo Adverse Drug Reaction Probability Scale score was 5 (probable). XARELTO discontinued, apixaban resumed.	Oral fexofenadine and topical calamine, zinc oxide and moisturizer were started. Symptoms resolved within a few days
Nash et al (2023)⁷	57-year-old male Indication: Pulmonary embolism in the setting of active UC Initial Medication: Patient transitioned from warfarin to XARELTO	XARELTO day 14: routine blood test revealed eosinophilia and liver enzyme elevation. XARELTO day 21: patient hospitalized with jaundice; CRP 25.4 mg/L and ESR 56 mm/hr. XARELTO discontinued due to suspected DILI. Other lab work at day 14, 21 and 28 respectively: ALT: 740 U/L, 627 U/L and 251 U/L AST: 768 U/L, 473 U/L and 228 U/L Eosinophils (x 10⁹/L): 11.5, 15.6 and 10.5 Liver ultrasound and MRI: nonspecific focal intrahepatic duct dilation and periportal and hepatic parenchymal edema with reactive enlarged porta hepatis and upper abdominal lymph nodes. XARELTO day 33: developed diffuse erythematous skin rash with multiple hematologic abnormalities. Liver biopsy consistent with an immune-allergic drug response. Diagnosis of DRESS (RegiSCAR score 7/9).	Liver and lab biochemistry recovered following IV hydrocortisone (started on day 33). Warfarin restarted following liver biopsy. XARELTO day 40: discharged on an oral prednisone taper. Recovery persisted after cessation of prednisone.
Gumbis et al (2023)⁹	61-year-old female Indication: Post-orthopedic surgery left leg Initial Medication: XARELTO 10 mg	10-15 minutes after ingestion of XARELTO patient developed shortness of breath, itchy palms, swollen face and lips, flushed face and loss of consciousness. Paramedics administered IM adrenaline, IM clemastine, IV dexamethasone, IV fluids and supplemental oxygen for suspected anaphylactic shock. Lab work: Serum tryptase level 30.6 µg/l. Patient had a history of previous allergic reactions to XARELTO including mild urticaria, mild swelling and itchiness of the lips. Diagnosis of hypersensitivity to XARELTO.	1 month after anaphylaxis serum tryptase level was normal at 5.46 µg/l.
Chiasson et al (2017)⁶	Female patient in her early 30s Indication: Left upper limb DVT (Paget-Schroetter syndrome) Initial Medication: XARELTO 15 mg twice daily for 3 weeks, followed by 20 mg once daily for 3 months	XARELTO day 3: readmitted to hospital due to progressive edema of the left upper limb. After 5 days of hospitalization and completion of catheter directed thrombolytic therapy (IV alteplase) plus UFH, patient discharged and instructed to continue XARELTO. 1 day after resuming XARELTO, patient developed a mild, pruritic, papular rash involving the trunk area. Skin biopsy: acute spongiotic dermatitis with perivascular lymphocytes and eosinophilic infiltrates compatible with a drug reaction. Lab work: ALT 209 U/L, AST 115 U/L, hemoglobin 119 g/L, CRP 10.3 mg/L, and eosinophil count 0.4 X 10⁹/L. Diagnosis of drug-induced hypersensitivity syndrome due to XARELTO. XARELTO discontinued and patient discharged on enoxaparin. Warfarin initiated 6 days post-discharge.	Rash disappeared within 48 hours of XARELTO discontinuation. AST, ALT, and CRP levels declined, and anemia resolved. 1 month follow-up: all lab values within normal limits
Vernon et al (2016)²	64-year-old male Indication: Pulmonary embolism Initial Medication: Following inpatient treatment with enoxaparin, patient was discharged on XARELTO 15 mg twice daily	XARELTO Day 1: developed a red, bumpy, itchy rash all over his body. XARELTO Day 3: XARELTO discontinued but rash persisted. Approximately 7 days after discontinuation, patient presented to ED with skin peeling on lower legs. Skin examination: peeling noted over scalp, neck, ears, trunk, arms, and lower extremities. Eczematous plaques, along with crusting, were observed over thighs with woody induration, erythema, warmth, tense bullae with clear fluid, and resolving blisters on lower legs. Lab testing: baseline creatinine level of 1.5, ESR 22, and a low sensitivity CRP 1.4 (units not provided for lab results). Punch biopsy: fibrin deposition in the dermis but no significant immunoprotein deposition. Patient discharged from ED on enoxaparin and topical triamcinolone 0.1%.	During dermatology follow-up, rash reported as resolved, with some evidence of post-inflammatory hyperpigmentation. No further care required.
Snyder et al (2015)³	61-year-old male Indication: VTE prophylaxis following right total knee arthroplasty Initial Medication: XARELTO 10 mg once daily for 10 days	XARELTO Day 10: developed painful swelling and a diffuse, erythematous rash with welts. XARELTO discontinued. 2 days after XARELTO discontinued: rash/welts resolving but pain and generalized swelling continued. Patient transferred to ED with fever, chills, bilateral forearm pain, neck pain, swelling in extremities, fatigue and profound weakness (grip strength 2 of 5). Lab tests: ALT 82 IU/L, AST 42 IU/L, direct bilirubin 0.9 mg/dL, eosinophils 0.5%. Rheumatology/immunology services determined patient experienced serum sickness secondary to XARELTO: ANA positive (titer 1:160), CRP >270 mg/L, ESR 76 mm/hr C3 complement 58 mg/dL, C4 complement <8 mg/dL and total complement <10 CAE units	Patient improved over several days of hospitalization and did not require any acute interventions. Patient discharged back to rehabilitation facility
Barrett et al (2015)⁴	77-year-old male Indication: Antiphospholipid antibody syndrome and retinal thrombosis Initial Medication: Patient switched from warfarin to XARELTO	XARELTO Day 42: presented with fever, malaise, fatigue, arthralgia and cholestatic pattern of liver test elevation. XARELTO Day 45: no clinical improvement, LFT’s increased further. XARELTO discontinued and patient hospitalized with painful tenosynovitis, pitting edema, and a faint maculopapular rash from inner arms to axilla and trunk. Skin biopsy: perivascular lymphocytes, eosinophils, and neutrophil vascular margination consistent with a dermal hypersensitivity reaction. Liver biopsy: non-zonal areas of necrosis with no viral inclusions. Diagnosis of drug-induced skin injury (XARELTO assessed as probable cause using DRESS)^a Diagnosis of DILI (XARELTO assessed as probable cause using RUCAM criteria for hepatic injury.	Patient treated with methylprednisolone taper Liver enzymes and serum creatinine improved within a week. Fatigue and arthralgia improved. Rash resolved completely. Patient restarted warfarin.
Yates et al (2013)⁵	57-year-old male Indication: VTE prophylaxis following right knee replacement Initial Medication: XARELTO 10mg once daily times 14 days	XARELTO day 2: on the evening of discharge, patient observed an erythematous and itchy rash in his groin. XARELTO day 7: presented to ED complaining rash had spread to his trunk and upper limbs. At this time, his only medication was XARELTO. The maculopapular rash was located on the groin, anterior chest, upper back, bilateral upper limbs, and face with some pustules on the upper arms and back. XARELTO discontinued and tinzaparin was started. Diagnosis of drug-induced rash secondary to XARELTO with the possibility of acute, generalized, exanthematous pustulosis.	Treated with oral antihistamines, topical mometasone and liquid paraffin 50%/white soft paraffin, which led to an improvement in his condition. Patient discharged on this regimen.
Abbreviations: ALT, alanine transaminase; ANA, antinuclear antibody; AST, aspartate aminotransferase; CAE, complement activity enzyme; CRP, C-reactive protein; DILI, drug-induced liver injury; DRESS, drug reaction with eosinophilia and systemic symptoms; ED, emergency department; ESR, erythrocyte sedimentation rate; IM, intramuscular; INR, international normalized ratio; IV, intravenous; MRI, magnetic resonance imaging; RegiSCAR, Registry of Severe Cutaneous Adverse Reactions; RUCAM, Roussel Uclaf Causality Assessment Method; UC, ulcerative colitis; UFH, unfractioned heparin; VTE, venous thromboembolism. ^aDRESS generally presents at a later onset (3-8 weeks) after the use of the causative agent and is characterized by fever, skin eruption, eosinophilia, lymphocyte activation, and multi-visceral involvement.¹⁶

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 18 September 2024.

References

Show

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2	Vernon HM, Nielsen AK, O’Bryan EC. Hypersensitivity reaction after administration of rivaroxaban (Xarelto). Am J Emerg Medicine. 2016;34(7):1325.e1-1325.e2.
3	Snyder DJ, Matusik FB. Rivaroxaban-induced serum sickness after total knee arthroplasty. Am J Health-syst Ph. 2015;72(18):1567-1571.
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22	Cesnaviciute I, Vosyliute R, Gegeckiene D, et al. An unexpected anaphylactic reaction following rivaroxaban and nimesulide ingestion: A clinical case report. Abstract presented at: European Academy of Allergy and Clinical Immunology Annual Congress; July 1-3, 2022; Prague, Czech Republic & Virtual.