RIVAROXABAN (rivaroxaban 2.5 mg) Dailymed

6 Adverse Reactions

The following clinically significant adverse reactions are also discussed in other sections of the labeling:

• Increased Risk of Stroke After Discontinuation in Nonvalvular Atrial Fibrillation[see Boxed Warning and Warnings and Precautions (5.1)]
• Bleeding Risk [see Warnings and Precautions (5.2, 5.4, 5.5, 5.6, 5.7)]
• Spinal/Epidural Hematoma [see Boxed Warning and Warnings and Precautions (5.3)]

• The most common adverse reaction (>5 %) in adult patients was bleeding. (6.1)
• The most common adverse reactions (>10 %) in pediatric patients were bleeding, cough, vomiting, and gastroenteritis. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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, 34, 947 adult patients were exposed to rivaroxaban tablets.

Hemorrhage

The most common adverse reactions with rivaroxaban tablets were bleeding complications [see Warnings and Precautions (5.2)].
Reduction of Risk of Major Cardiovascular Events in Patients with CAD:

In the COMPASS trial overall, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 2.7 % for rivaroxaban tablets 2.5 mg twice daily vs. 1.2 % for placebo on background therapy for all patients with aspirin 100 mg once daily. The incidences of important bleeding events in the CAD and PAD populations in COMPASS were similar.

Table 10 shows the number of patients experiencing various types of major bleeding events in the COMPASS trial.

Table 10: Major Bleeding Events in COMPASS -On Treatment Plus 2 Days^*

*Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within 2 days of stopping treatment in the safety analysis set in COMPASS patients.
†Treatment schedule: rivaroxaban tablets 2.5 mg twice daily or placebo. All patients received background therapy with aspirin 100 mg once daily
‡Defined as i) fatal bleeding, or ii) symptomatic bleeding in a critical area or organ, such as intraarticular, intramuscular with compartment syndrome, intraspinal, intracranial, intraocular, respiratory, pericardial, liver, pancreas, retroperitoneal, adrenal gland or kidney; or iii) bleeding into the surgical site requiring reoperation, or iv) bleeding leading to hospitalization.
CI:confidence interval; HR: hazard ratio; ISTH: International Society on Thrombosis and Hemostasis
Parameter	Rivaroxaban Tablets † N=9134 n (%/year)	Placebo † N=9107 n (%/year)	Rivaroxaban Tablets plus Placebo HR (95 % CI)
Modified ISTH Major Bleeding‡	263 (1.6)	144 (0.9)	1.8 (1.5, 2.3)
-      Fatal bleeding event Intracranial hemorrhage (ICH) Non-intracranial	12 (<0.1) 6 (<0.1) 6 (<0.1)	8 (<0.1) 3 (<0.1) 5 (<0.1)	1.5 (0.6, 3.7) 2.(0.5, 8) 1.2 (0.4, 4)
-     Symptomatic bleeding in critical organ (non-fatal) -      ICH (fatal and non-fatal) Hemorrhagic Stroke Other ICH	58 (0.3) 23 (0.1) 18 (0.1) 6 (<0.1)	43 (0.3) 21 (0.1) 13 (<0.1) 9 (<0.1)	1.4 (0.9, 2) 1.1 (0.6, 2) 1.4 (0.7, 2.8) 0.7 (0.2, 1.9)
-      Bleeding into the surgical site requiring reoperation (non-fatal, not in critical organ)	7 (<0.1)	6 (<0.1)	1.2 (0.4, 3.5)
-      Bleeding leading to hospitalization (non-fatal, not in critical organ, not requiring reoperation)	188 (1.1)	91 (0.5)	2.1 (1.6, 2.7)
Major GI bleeding	117 (0.7)	49 (0.3)	2.4 (1.7, 3.4)

Reduction of Risk of Major Thrombotic Vascular Events in Patients with Peripheral Artery Disease (PAD), Including Patients after Lower Extremity Revascularization due to Symptomatic PAD:

The incidence of premature permanent discontinuation due to bleeding events for rivaroxaban tablets 2.5 mg twice daily vs. placebo on background therapy with aspirin 100 mg once daily in VOYAGER was 4.1 % vs. 1.6 % and in COMPASS PAD was 2.7 % vs. 1.3 %, respectively.

Table 11 shows the number of patients experiencing various types of TIMI (Thrombolysis in Myocardial Infarction) major bleeding events in the VOYAGER trial. The most common site of bleeding was gastrointestinal.

Table 11: Major Bleeding Events^* in VOYAGER-On Treatment Plus 2 Days

* Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories.
† Treatment schedule: rivaroxaban tablets 2.5 mg twice daily or placebo. All patients received background therapy with aspirin 100 mg once daily.
CABG: Coronary artery bypass graft; CI: confidence interval; HR: hazard ratio; TIMI: Thrombolysis in Myocardial Infarction Bleeding Criteria
	Rivaroxaban Tablets † N=3256		Placebo † N=3248		Rivaroxaban Tablets vs. Placebo HR (95 % CI)
Parameter	n (%)	Event rate %/year	n (%)	Event rate %/year
TIMI Major Bleeding (CABG/non-CABG)	62 (1.9)	0.96	44 (1.4)	0.67	1.4 (1, 2.1)
Fatal bleeding	6 (0.2)	0.09	6 (0.2)	0.09	1 (0.3, 3.2)
Intracranial bleeding	13 (0.4)	0.20	17 (0.5)	0.26	0.8 (0.4, 1.6)
Clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥5 g/dL or drop in hematocrit of ≥15 %	46 (1.4)	0.71	24 (0.7)	0.36	1.9 (1.2, 3.2)

Other Adverse Reactions

Non-hemorrhagic adverse reactions reported in ≥1 % of rivaroxaban-treated patients in the EINSTEIN DVT and EINSTEIN PE studies are shown in Table 12.

Table 12: Other Adverse Reactions Adverse reaction with Relative Risk >1.5 for rivaroxaban tablets versus comparator Reported by ≥1 % of Rivaroxaban-Treated Patients in EINSTEIN DVT and EINSTEIN PE Studies

Body System Adverse Reaction		Â
EINSTEIN DVT Study	Rivaroxaban Tablets 20 mg   N=1718 n (%)	Enoxaparin/VKA   N=1711 n (%)
Gastrointestinal disorders	Â	Â
Abdominal pain	46 (2.7)	25 (1.5)
General disorders and administration site conditions	Â	Â
Fatigue	24 (1.4)	15 (0.9)
Musculoskeletal and connective tissue disorders	Â	Â
Back pain	50 (2.9)	31 (1.8)
Muscle spasm	23 (1.3)	13 (0.8)
Nervous system disorders	Â	Â
Dizziness	38 (2.2)	22 (1.3)
Psychiatric disorders	Â	Â
Anxiety	24 (1.4)	11 (0.6)
Depression	20 (1.2)	10 (0.6)
Insomnia	28 (1.6)	18 (1.1)
EINSTEIN PE Study	Rivaroxaban Tablets 20 mg   N=2412 n (%)	Enoxaparin/VKA   N=2405 n (%)
Skin and subcutaneous tissue disorders	Â	Â
Pruritus	53 (2.2)	27 (1.1)

Non-hemorrhagic adverse reactions reported in ≥1 % of rivaroxaban-treated patients in RECORD 1 to 3 studies are shown in Table 13.

Table 13: Other Adverse Drug Reactions^*Reported by ≥1 % of Rivaroxaban -Treated Patients in RECORD 1 to 3 Studies

*    Adverse 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
†             Includes the placebo-controlled period of RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1 to 3)
Body System Adverse Reaction	Rivaroxaban Tablets 10 mg N=4487 n (%)	Enoxaparin† N=4524 n (%)
Injury, poisoning and procedural complications
Wound secretion	125 (2.8)	89 (2)
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)
Buler	63 (1.4)	40 (0.9)

Non-bleeding adverse reactions reported in ≥5 % of rivaroxaban-treated patients are shown in Table 17.

Table 17: Other Adverse Reactions^{* Reported by ≥5 % of Rivaroxaban -Treated Patients in UNIVERSE Study (Part B)}

* Adverse reaction with Relative Risk >1.5 for rivaroxaban tablets versus aspirin.
† The following terms were combined:
Gastroenteritis: gastroenteritis, gastroenteritis viral
Rash: rash, rash maculo-papular, viral rash
Adverse Reaction	Rivaroxaban Tablets N=64 n (%)	Aspirin N=34 n (%)
Cough	10 (15.6)	3 (8.8)
Vomiting	9 (14.1)	3 (8.8)
Gastroenteritisâ€	8 (12.5)	1 (2.9)
Rashâ€	6 (9.4)	2 (5.9)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of rivaroxaban tablets. 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, thrombocytopenia

Hepatobiliary Disorders: jaundice, cholestasis, hepatitis (including hepatocellular injury)

Immune System Disorders : hypersensitivity, anaphylactic reaction, anaphylactic shock, angioedema

Nervous System Disorders: hemiparesis

Renal Disorders : Anticoagulant-related nephropathy

Respiratory, Thoracic and Mediastinal Disorders : Eosinophilic pneumonia

Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS)