Adverse reactions : תופעות לוואי

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described in more detail in other sections of the prescribing information.
•   Risk of Hemorrhage including Spinal/Epidural Hematomas [see Warnings and Precautions (5.1)] •   Thrombocytopenia [see Warnings and Precautions (5.2)]

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 accurately reflect the rates observed in practice.
Hemorrhage
The most commonly reported adverse reactions are hematoma at the injection site and hemorrhagic complications. The risk for bleeding varies with the indication and may increase with higher doses.
Unstable Angina and Non-Q-Wave Myocardial Infarction
Table 3 summarizes major bleeding reactions that occurred with FRAGMIN, heparin, and placebo in clinical trials of unstable angina and non-Q-wave myocardial infarction.
Table 3
Major Bleeding Reactions in Unstable Angina and
Non-Q-Wave Myocardial Infarction
Indication                                              Dosing Regimen Heparin2                 Placebo
FRAGMIN
Unstable Angina and                                                       intravenous and            every 12 hr Non-Q-Wave MI                      120 IU/kg/12 hr subcutaneous1 subcutaneous2            subcutaneous n (%) n (%)                   n (%)
3,4
Major Bleeding Reactions                     15/1497 (1.0)                   7/731 (1.0)             4/760 (0.5) 1
Treatment was administered for 5 to 8 days.
2
Heparin intravenous infusion for at least 48 hours, APTT 1.5 to 2 times control, then 12,500 U subcutaneously every 12 hours for 5 to 8 days.
3
Aspirin (75 to 165 mg per day) and beta blocker therapies were administered concurrently.
4
Bleeding reactions were considered major if: 1) accompanied by a decrease in hemoglobin of ≥2 g/dL in connection with clinical symptoms; 2) a transfusion was required; 3) bleeding led to interruption of treatment or death; or 4) intracranial bleeding.
Hip Replacement Surgery
Table 4 summarizes: 1) all major bleeding reactions and, 2) other bleeding reactions possibly or probably related to treatment with FRAGMIN (preoperative dosing regimen), warfarin sodium, or heparin in two hip replacement surgery clinical trials.


Table 4
Bleeding Reactions Following Hip Replacement Surgery
FRAGMIN vs                                FRAGMIN vs
Indication                       Warfarin Sodium                              Heparin Dosing Regimen                           Dosing Regimen
FRAGMIN2                  Warfarin               FRAGMIN4                 Heparin Hip
5,000 IU once daily         Sodium1 oral         5,000 IU once daily    5,000 U three times Replacement subcutaneous                                     subcutaneous        a day subcutaneous Surgery n (%)                    n (%)                   n (%)                  n (%) Major Bleeding
7/274 (2.6)              1/279 (0.4)                  0                  3/69 (4.3) Reactions3
Other Bleeding
Reactions5                       8/274 (2.9)              5/279 (1.8)                  0                       0 Hematuria
Wound Hematoma                   6/274 (2.2)                    0                      0                       0 Injection Site
3/274 (1.1)                    NA                 2/69 (2.9)             7/69 (10.1) Hematoma
1
Warfarin sodium dosage was adjusted to maintain a prothrombin time index of 1.4 to 1.5, corresponding to an International Normalized Ratio (INR) of approximately 2.5.
2
Includes three treated patients who did not undergo a surgical procedure.
3
A bleeding event was considered major if: 1) hemorrhage caused a significant clinical event, 2) it was associated with a hemoglobin decrease of ≥2 g/dL or transfusion of 2 or more units of blood products, 3) it resulted in reoperation due to bleeding, or 4) it involved retroperitoneal or intracranial hemorrhage.
4
Includes two treated patients who did not undergo a surgical procedure.
5
Occurred at a rate of at least 2% in the group treated with FRAGMIN 5,000 IU once daily.
Six of the patients treated with FRAGMIN experienced seven major bleeding reactions. Two of the reactions were wound hematoma (one requiring reoperation), three were bleeding from the operative site, one was intraoperative bleeding due to vessel damage, and one was gastrointestinal bleeding.

In the third hip replacement surgery clinical trial, the incidence of major bleeding reactions was similar in all three treatment groups: 3.6% (18/496) for patients who started FRAGMIN before surgery; 2.5% (12/487) for patients who started FRAGMIN after surgery; and 3.1% (15/489) for patients treated with warfarin sodium.
Abdominal Surgery
Table 5 summarizes bleeding reactions that occurred in clinical trials which studied FRAGMIN 2,500 and 5,000 IU administered once daily to abdominal surgery patients.

Table 5
Bleeding Reactions Following Abdominal Surgery
FRAGMIN vs Placebo                           FRAGMIN vs FRAGMIN
Indication
Dosing Regimen                                  Dosing Regimen
FRAGMIN                                     FRAGMIN                 FRAGMIN Placebo
2,500 IU                                    2,500 IU                5,000 IU once daily
Abdominal                        once                                        once                    once subcutaneous
Surgery                   daily subcutaneous                          daily subcutaneous      daily subcutaneous n (%) n (%)                                       n (%)                   n (%) Postoperative                 14/182              13/182               89/1,025             125/1,033 Transfusions                   (7.7)               (7.1)                 (8.7)                (12.1) Wound                          2/79                2/77                 1/1,030              4/1,039 Hematoma                       (2.5)               (2.6)                 (0.1)                 (0.4) Reoperation                      1/79              1/78                2/1,030               13/1,038 Due to Bleeding                  (1.3)             (1.3)                (0.2)                  (1.3) Injection Site                   8/172             2/174               36/1,026              57/1,035 Hematoma                         (4.7)             (1.1)                 (3.5)                 (5.5) 
Table 5 Cont.
Bleeding Reactions Following Abdominal Surgery
FRAGMIN vs Heparin
Indication
Dosing Regimen
FRAGMIN             Heparin           FRAGMIN                   Heparin 2,500 IU           5,000 U            5,000 IU                 5,000 U Abdominal                       once           twice daily             once                 twice daily Surgery                  daily subcutaneous   subcutaneous     daily subcutaneous          subcutaneous n (%)             n (%)               n (%)                    n (%)
Postoperative                  26/459            36/454              81/508                   63/498 Transfusions                    (5.7)              (7.9)              (15.9)                  (12.7) Wound                          16/467            18/467              12/508                    6/498 Hematoma                        (3.4)              (3.9)               (2.4)                   (1.2) Reoperation                      2/392             3/392                4/508                  2/498 Due to Bleeding                  (0.5)             (0.8)                (0.8)                  (0.4) Injection Site                   1/466             5/464               36/506                 47/493 Hematoma                         (0.2)             (1.1)                (7.1)                  (9.5) 
In a trial comparing FRAGMIN 5,000 IU once daily to FRAGMIN 2,500 IU once daily in patients undergoing surgery for malignancy, the incidence of bleeding reactions was 4.6% and 3.6%, respectively (n.s.). In a trial comparing FRAGMIN 5,000 IU once daily to heparin 5,000 U twice daily, in the malignancy subgroup the incidence of bleeding reactions was 3.2% and 2.7%, respectively for FRAGMIN and Heparin (n.s.).


Medical Patients with Severely Restricted Mobility During Acute Illness Table 6summarizes major bleeding reactions that occurred in a clinical trial of medical patients with severely restricted mobility during acute illness.
Table 6
Bleeding Reactions in Medical Patients with Severely Restricted Mobility During Acute Illness Indication                                              Dosing Regimen Medical Patients with Severely                      FRAGMIN
Placebo
Restricted Mobility                             5,000 IU once daily once daily subcutaneous subcutaneous n (%) n (%)
Major Bleeding Reactions1 at Day 14                8/1,848 (0.4)                           0/1,833 (0) Major Bleeding Reactions1 at Day 21                9/1,848 (0.5)                         3/1,833 (0.2) 1
A bleeding event was considered major if: 1) it was accompanied by a decrease in hemoglobin of ≥2 g/dL in connection with clinical symptoms; 2) intraocular, spinal/epidural, intracranial, or retroperitoneal bleeding; 3) required transfusion of ≥ 2 units of blood products; 4) required significant medical or surgical intervention; or 5) led to death.
Three of the major bleeding reactions that occurred by Day 21 were fatal, all due to gastrointestinal hemorrhage (two patients in the group treated with FRAGMIN and one in the group receiving placebo).
Adult Patients with Cancer and Acute Symptomatic VTE
Table 7 summarizes the number of patients with bleeding reactions that occurred in the clinical trial of adult patients with cancer and acute symptomatic VTE. A bleeding event was considered major if it: 1) was accompanied by a decrease in hemoglobin of ≥ 2 g/dL in connection with clinical symptoms; 2) occurred at a critical site (intraocular, spinal/epidural, intracranial, retroperitoneal, or pericardial bleeding); 3) required transfusion of ≥ 2 units of blood products; or 4) led to death. Minor bleeding was classified as clinically overt bleeding that did not meet criteria for major bleeding.
At the end of the six-month study, a total of 46 (13.6%) patients in the FRAGMIN arm and 62 (18.5%) patients in the OAC arm experienced any bleeding event. One bleeding event (hemoptysis in a patient in the FRAGMIN arm at Day 71) was fatal.
Table 7
Bleeding Reactions (Major and Any) (As treated population)1
FRAGMIN
200 IU/kg (max. 18,000 IU) subcutaneous                                 OAC once daily x 1 month, then 150 IU/kg (max.   FRAGMIN 200 IU/kg (max 18,000 IU) subcutaneous once 18,000 IU) subcutaneous once daily x 5       daily x 5-7 days and OAC for 6 months (target INR 2-3) Study months period
Patients
Patients with Any                   Patients with      Patients with Any Number with Major                             Number at
Bleeding                       Major Bleeding           Bleeding at risk    Bleeding                              risk n (%)                             n (%)                 n (%) n (%)
Total during         338        19 (5.6)           46 (13.6)             335            12 (3.6)                62 (18.5) study
Week 1         338         4 (1.2)            15 (4.4)             335             4 (1.2)                 12 (3.6) Weeks 2-
332         9 (2.7)            17 (5.1)             321             1 (0.3)                 12 (3.7) 4
Weeks 5-
297         9 (3.0)            26 (8.8)             267             8 (3.0)                40 (15.0)
28

1
Patients with multiple bleeding episodes within any time interval were counted only once in that interval. However, patients with multiple bleeding episodes that occurred at different time intervals were counted once in each interval in which the event occurred.
Elevations of Serum Transaminases
In FRAGMIN clinical trials supporting non-cancer indications, where hepatic transaminases were measured, asymptomatic increases in transaminase levels (SGOT/AST and SGPT/ALT) greater than three times the upper limit of normal of the laboratory reference range were seen in 4.7% and 4.2%, respectively, of patients during treatment with FRAGMIN.
In the FRAGMIN clinical trial of patients with cancer and acute symptomatic venous thromboembolism treated with FRAGMIN for up to 6 months, asymptomatic increases in transaminase levels, AST and ALT, greater than three times the upper limit of normal of the laboratory reference range were reported in 8.9% and 9.5% of patients, respectively. The frequencies of Grades 3 and 4 increases in AST and ALT, as classified by the National Cancer Institute, Common Toxicity Criteria (NCI-CTC) Scoring System, were 3% and 3.8%, respectively. Grades 2, 3 & 4 combined have been reported in 12% and 14% of patients, respectively.
Other
Allergic Reactions: Allergic reactions (i.e., pruritus, rash, fever, injection site reaction, bullous eruption) have occurred.
Cases of anaphylactoid reactions have been reported.
Local Reactions: Pain at the injection site was reported in 4.5% of patients treated with FRAGMIN 5,000 IU once daily vs 11.8% of patients treated with heparin 5,000 U twice daily in the abdominal surgery trials. In the hip replacement trials, pain at injection site was reported in 12% of patients treated with FRAGMIN 5,000 IU once daily vs 13% of patients treated with heparin 5,000 U three times a day.

6.2 Post Marketing Experience
The following adverse reactions have been identified during postapproval use of FRAGMIN. 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.
Since first international market introduction in 1985, there have been more than 15 reports of epidural or spinal hematoma formation with concurrent use of FRAGMIN and spinal/epidural anesthesia or spinal puncture. The majority of patients had postoperative indwelling epidural catheters placed for analgesia or received additional drugs affecting hemostasis. In some cases the hematoma resulted in long-term or permanent paralysis (partial or complete) [see Boxed Warning].
Musculoskeletal System: Osteoporosis
Skin or subcutaneous tissues disorders: Skin necrosis, cases of alopecia reported that improved on drug discontinuation 
6.3 Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/