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 13).
Hemorrhage
The most common adverse reactions with XARELTO were bleeding complications [see Warnings and Precautions].
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 AFFor 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.
Parameter |
XARELTO N = 7111 n (%) |
Event Rate (per 100 Pt-yrs) |
Warfarin N = 7125 n (%) |
Event Rate (per 100 Pt-yrs) |
Major bleedingDefined 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.
|
395 (5.6) |
3.6 |
386 (5.4) |
3.5 |
Bleeding into a critical organThe majority of the events were intracranial, and also included intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal.
|
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 EventsBleeding 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. in Patients Undergoing Hip or Knee Replacement Surgeries (RECORD 13)
|
XARELTO 10 mg |
EnoxaparinIncludes the placebo-controlled period for RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 13)
|
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 ReactionsADR 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. Reported by ≥1% of XARELTO-Treated Patients in RECORD 13 Studies
System/Organ Class Adverse Reaction |
XARELTO 10 mg (N = 4487) n (%) |
EnoxaparinIncludes the placebo-controlled period of RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 13)
(N = 4524) n (%) |
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
|